Reducing or preventing tissue damage using hyaluronidase administration

Abstract

The present disclosure discloses compositions comprising ultra-high concentration hyaluronidase, devices comprising such compositions, methods and uses of such compositions and devices for reducing or eliminating hyaluronic acid induced occlusion of one or more blood vessels supplying blood to an area of ​​tissue in an individual, methods and uses of such compositions and devices for reducing or inhibiting vascular occlusion in an area of ​​tissue in an individual, and methods and uses of such compositions and devices for reducing or inhibiting hyaluronic acid induced tissue loss in an individual.

Description

[Technical field]

[0001] This application claims the benefit of priority pursuant to 35 U.S.C. §119(e) of, and is entitled to the filing date of, U.S. Provisional Patent Application No. 63 / 248,447, filed September 25, 2021, the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to the reduction or treatment of tissue damage caused by vascular occlusion in tissue by the administration of hyaluronic acid based soft tissue dermal fillers. [Background technology]

[0003] The use of fillers for facial soft tissue augmentation in individuals has become one of the most commonly performed cosmetic procedures. For example, soft tissue filler injections are the second most commonly performed cosmetic procedure after botulinum toxin treatment. The most commercially popular soft tissue dermal fillers are those that use hyaluronic acid.

[0004] Unfortunately, as the field of soft tissue augmentation becomes more and more popular, reports of adverse events have increased. One of the more serious side effects is the blockage of blood flow at the administration site. Prevention of blood to the tissue, called vaso-occlusion, can result in irreversible damage due to lack of sufficient oxygen and nutrients supply to the surrounding tissue, including, for example, cell necrosis, scarring, local nerve desensitization or paralysis, and potential systemic complications. Vascular blockage of the dermal and epidermal layers of the skin after soft tissue augmentation procedures, for example in the face and neck area, can result in permanent disfigurement and loss of function of the affected tissue area.

[0005] Unfortunately, there is no proven, consistent and effective treatment for vascular occlusion after soft tissue filler injection. Thus, if an occlusion event occurs in the blood vessels of tissue, the damage done is potentially serious and permanent. Furthermore, if there is early recognition of a vascular occlusion event but blood flow cannot be restored, the tissue damage associated with soft tissue filler injection may become irreversible. Given the vulnerability of skin tissue to filler-induced vascular occlusion events, a method is needed to reduce or eliminate this occlusion. Summary of the Invention

[0006] The present disclosure provides such a solution for soft tissue dermal fillers containing hyaluronic acid. The compositions, devices, methods and uses disclosed herein administer hyaluronidase to an area of ​​tissue. Such administration can deliver hyaluronidase to blood vessels supplying the area of ​​tissue in about 5 to 30 minutes. This rapid delivery of hyaluronidase allows the enzyme to reduce or eliminate hyaluronic acid causing vascular blockage, thereby reducing or eliminating the risk of permanent damage to the tissue affected by the blockage.

[0007] Some embodiments herein disclose a method of reducing or eliminating hyaluronic acid-induced blockage in one or more blood vessels supplying blood to an area of ​​tissue in an individual in need thereof. The disclosed method comprises administering to an individual a composition comprising ultra-high concentration hyaluronidase in a manner to reduce or eliminate hyaluronic acid-induced blockage in one or more blood vessels supplying blood to an area of ​​tissue affected by said blockage. In some embodiments, the disclosed method administers a composition comprising ultra-high concentration hyaluronidase to the dermis portion of a skin area. In other embodiments, the disclosed method administers a composition comprising ultra-high concentration hyaluronidase using a delivery system, such as, for example, a manual or automatic injection device. The disclosed method can administer a composition comprising ultra-high concentration hyaluronidase in a single or multiple doses of hyaluronidase ranging from about 250 IU / mL to about 500,000 IU / mL.

[0008] Some embodiments herein disclose methods of reducing or inhibiting vascular occlusion in an area of ​​tissue in an individual in need thereof. The disclosed methods include administering a composition comprising ultra-high concentration hyaluronidase to an individual in a manner that reduces or eliminates hyaluronic acid-induced occlusion in one or more blood vessels that supply blood to an area of ​​tissue affected by said occlusion, thereby reducing or inhibiting vascular occlusion. In some embodiments, the disclosed methods administer a composition comprising ultra-high concentration hyaluronidase to the dermis portion of a skin area. In other embodiments, the disclosed methods administer a composition comprising ultra-high concentration hyaluronidase using a delivery system, such as, for example, a manual or automatic injection device. The disclosed methods can administer a composition comprising ultra-high concentration hyaluronidase in a single or multiple doses of hyaluronidase ranging from about 250 IU / mL to about 500,000 IU / mL.

[0009] Some embodiments of the present disclosure disclose a method of reducing or inhibiting hyaluronic acid-induced tissue loss in an individual in need thereof. The disclosed method includes administering to an individual a composition comprising ultra-high concentration hyaluronidase in a manner that reduces or eliminates hyaluronic acid-induced blockage in one or more blood vessels supplying blood to an area of ​​tissue affected by said blockage, thereby reducing or inhibiting hyaluronic acid-induced tissue loss in the individual. In some embodiments, the disclosed method administers a composition comprising ultra-high concentration hyaluronidase to the dermis portion of a skin area. In other embodiments, the disclosed method administers a composition comprising ultra-high concentration hyaluronidase using a delivery system, such as, for example, a manual or automatic injection device. The disclosed method can administer a composition comprising ultra-high concentration hyaluronidase in a single or multiple doses of hyaluronidase ranging from about 250 IU / mL to about 500,000 IU / mL.

[0010] Other aspects of the present disclosure disclose delivery systems, such as manual or automatic injection devices, that contain compositions comprising ultra-high concentration hyaluronidase. In some aspects, the delivery systems of the present disclosure deliver compositions comprising ultra-high concentration hyaluronidase to an area of ​​tissue. The delivery systems of the present disclosure can administer compositions comprising ultra-high concentration hyaluronidase in single or multiple doses ranging from about 250 IU / mL to about 500,000 IU / mL of hyaluronidase.

[0011] Other aspects of the present disclosure disclose the use of compositions comprising ultra-high concentration hyaluronidase. In some aspects, the uses of the present disclosure include compositions comprising ultra-high concentration hyaluronidase contained in a delivery system, such as a manual or automatic injection device. In other aspects, the uses of the present disclosure include compositions comprising ultra-high concentration hyaluronidase contained in an automatic injection device. In other aspects, the uses of the present disclosure include compositions comprising ultra-high concentration hyaluronidase contained in a manual injection device. The uses of the present disclosure can administer compositions comprising ultra-high concentration hyaluronidase in single or multiple doses of hyaluronidase ranging from about 250 IU / mL to about 500,000 IU / mL.

[0012] Other aspects of the present disclosure disclose the use of a delivery system, such as a manual or automatic injection device, that includes a composition comprising ultra-high concentration hyaluronidase. In some aspects, the use of the present disclosure includes an automatic injection device that includes a composition comprising ultra-high concentration hyaluronidase. In some aspects, the use of the present disclosure includes a manual injection device that includes a composition comprising ultra-high concentration hyaluronidase. The use of the present disclosure can administer a composition comprising ultra-high concentration hyaluronidase in single or multiple doses of hyaluronidase ranging from about 250 IU / mL to about 500,000 IU / mL.

[0013] Other aspects of the present disclosure disclose the use of compositions comprising ultra-high concentration hyaluronidase in the manufacture of a medicament. In some aspects, the medicament of the present disclosure comprises a composition comprising ultra-high concentration hyaluronidase contained in a delivery system, such as a manual or automatic injection device. In other aspects, the medicament of the present disclosure comprises a composition comprising ultra-high concentration hyaluronidase contained in an automatic injection device. In other aspects, the medicament of the present disclosure comprises a composition comprising ultra-high concentration hyaluronidase contained in a manual injection device. The use of the present disclosure can administer a composition comprising ultra-high concentration hyaluronidase in a single or multiple doses of hyaluronidase ranging from about 250 IU / mL to about 500,000 IU / mL.

[0014] Other aspects of the present disclosure disclose compositions comprising ultra-high concentration hyaluronidase for use in inhibiting hyaluronic acid-induced occlusion of one or more blood vessels supplying blood to a region of tissue. In some embodiments, the compositions comprising ultra-high concentration hyaluronidase are contained in a delivery system, such as a manual or automatic injection device. In other embodiments, the compositions comprising ultra-high concentration hyaluronidase are contained in an automatic injection device. In other embodiments, the compositions comprising ultra-high concentration hyaluronidase are contained in a manual injection device. The compositions comprising ultra-high concentration hyaluronidase of the present disclosure can include single or multiple doses of hyaluronidase ranging from about 250 IU / mL to about 500,000 IU / mL.

[0015] Other aspects of the present disclosure disclose a delivery system, such as a manual or automatic injection device, that includes a composition comprising ultra-high concentration hyaluronidase for use in inhibiting hyaluronic acid-induced occlusion of one or more blood vessels supplying blood to a region of tissue. The delivery system of the present disclosure that includes a composition comprising ultra-high concentration hyaluronidase can include single or multiple doses of hyaluronidase ranging from about 250 IU / mL to about 500,000 IU / mL. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Skin is the outer layer of the mammalian body, protecting the underlying muscles, bones, ligaments and internal organs. Typically the largest organ of the integumentary system, skin consists of three main layers: the epidermis, dermis and subcutaneous tissue. The epidermis is the outermost epithelial layer of skin, forming a waterproof, protective wrap over the surface of the body, which also acts as a barrier against infection. The dermis is the epithelial layer of skin just below the epidermis, protecting the body from stress and strain. The subcutaneous tissue lies below the dermis and contains loose connective tissue, adipose tissue and elastin. Although not composed of epithelial tissue and therefore not part of the skin, the subcutaneous tissue attaches the skin to the underlying bones and muscles and supplies the skin with blood vessels and nerves.

[0017] Unfortunately, administration of soft tissue dermal fillers, such as hyaluronic acid fillers, to the face can result in the filler entering the dermal circulation, which can cause occlusion of one or more blood vessels that supply blood to areas of tissue, such as the subcutaneous tissue, dermis, or epidermis. Such occlusion can impede or prevent blood flow, resulting in a lack of oxygen and nutrients to the areas supplied by the occluded vessels. If blood flow through the occluded vessels is not quickly restored, tissue damage with cellular ischemia and / or corresponding necrosis, local nerve damage, and systemic complications can occur. These adverse events occur rapidly, and permanent damage can occur if such vascular occlusions are left untreated or are not treated in a timely manner.

[0018] Furthermore, administration of soft tissue dermal fillers such as hyaluronic acid fillers can cause delayed hypersensitivity reactions that are difficult to treat. Such hypersensitivity can appear within weeks or even years after administration. When hypersensitivity reactions occur, symptoms such as pain, tenderness, disfigurement and scarring can last for months or years and can even become permanent. The cause of these reactions is unclear, and current treatment options include oral antibiotics, oral steroids, steroid injections, low-dose hyaluronidase injections and 5-fluorouracil (5-FU) injections, all of which may require numerous treatment cycles in combination with each other. However, such combinations of treatments may cause adverse events that do not occur when such treatments are given individually.

[0019] Of the above treatments, hyaluronidase injections are widely considered to be one of the most important treatment options, as hyaluronidase actually removes the HA dermal fillers that cause the reaction in question. However, currently only low-concentration hyaluronidase can be administered in humans in the United States. Unfortunately, low-concentration hyaluronidase may have limited effectiveness in dissolving HA dermal fillers in these scenarios due to the inflammation induced by these HA dermal fillers, which will likely require many treatment cycles of low-concentration hyaluronidase as described above. High-concentration hyaluronidase, in contrast, treats these types of hypersensitivity reactions quickly and efficiently. Patients and practitioners alike would welcome the introduction of high-concentration hyaluronidase for the treatment of these hypersensitivity reactions to more effectively mitigate such hypersensitivity reactions and the corresponding adverse events, including permanent adverse events. This is especially true in light of current efforts by manufacturers to create relatively long-lasting HA dermal fillers that are more resistant to hyaluronidase and therefore last longer in vivo. As a result, these longer lasting products are more resistant to exogenous hyaluronidase treatment, and therefore it is important to make high concentrations of hyaluronidase available to counteract undesirable effects from these longer lasting products when necessary.

[0020] Hyaluronidase is a family of enzymes that catalyze the degradation of hyaluronic acid. Thus, one possible solution to hyaluronic acid-induced blockage of one or more blood vessels that supply blood to a tissue region is to administer hyaluronidase to the site of such blockage. However, currently, there is no recognized method for delivering an effective amount of hyaluronidase to the circulation in a manner that reduces or eliminates hyaluronic acid-induced blockage in one or more blood vessels that supply blood to the tissue region affected by the blockage.

[0021] One problem facing hyaluronidase treatment of hyaluronic acid-induced obstruction of one or more blood vessels is the fact that hyaluronidase is very fragile and has a very short half-life. For example, studies have shown that the half-life of intravenous administration of hyaluronidase is about 2 minutes, and the half-life of the enzyme administered intradermally or subcutaneously is less than about 30 minutes. Thus, hyaluronidase is rapidly lost when administered directly into blood or tissue. Furthermore, the standard concentrations of commercially available hyaluronidase range from 150 IU / mL to 200 IU / mL. This low concentration requires the administration of large amounts of hyaluronidase, such as 40 mL or more, to reach a therapeutically effective amount to break down hyaluronic acid-induced obstruction of one or more blood vessels. Administration of such amounts into the blood is virtually impossible. For example, stocking multiple vials of hyaluronidase would be very costly for a practitioner, especially due to the relatively short shelf life of the types of hyaluronidase currently commercially approved for human use. Even if sufficient quantities were available, the standard 150 IU / mL to 200 IU / mL concentrations would be too low to achieve a therapeutic effect, as this low enzyme concentration would degrade rapidly once in the blood. Also, direct injection into blood vessels at the site of hyaluronic acid-induced occlusion is incredibly difficult, even when imaging equipment such as ultrasound machines would facilitate visualization of these vessels, as the affected vessels are very small in diameter, and unfortunately the majority of practitioners do not have any imaging equipment in their clinics. As a countermeasure to this lack of imaging equipment on hand, ultra-high concentration hyaluronidase would allow practitioners to reverse the types of occlusions described above even when injecting fewer vials of hyaluronidase, and ultra-high concentration hyaluronidase would help allow practitioners to be less precise with their placement of their hyaluronidase when treating HA-induced vascular occlusion.

[0022] Another problem facing hyaluronidase treatment of hyaluronic acid-induced blockage of one or more blood vessels relates to establishing a concentration gradient large enough to introduce hyaluronidase into the blood vessels such that an effective amount of the enzyme reaches the blocked area and degrades the hyaluronic acid causing the blockage. Standard concentrations of commercially available hyaluronidase range from 150 IU / mL to 200 IU / mL, and these low concentrations of hyaluronidase, even when administered in large amounts, are insufficient to consistently establish a concentration gradient large enough to deliver a therapeutically effective amount of the enzyme to degrade the hyaluronic acid-induced blockage of one or more blood vessels. During such administration, only a portion of the administered hyaluronidase can enter the blood system, and this small amount of hyaluronidase is quickly degraded. Furthermore, the limited amount of hyaluronidase that enters blood vessels containing the types of blockages described above has a very limited ability to completely clear such blockages due to such limited amount.

[0023] What is needed, therefore, is a composition containing an ultra-high concentration of hyaluronidase that can establish a concentration gradient large enough to facilitate a sufficient amount of hyaluronidase entering the bloodstream, reaching the occluded area, and providing a therapeutic effect by breaking down hyaluronic acid-induced obstruction of one or more blood vessels. The compositions, devices, methods, and uses of the present disclosure achieve this desired effect.

[0024] The compositions, devices, methods and uses disclosed herein deliver an effective amount of hyaluronidase to one or more blood vessels in a manner that reduces or eliminates hyaluronic acid-induced blockage in one or more blood vessels that supply blood to an area of ​​tissue affected by said blockage. Such reduction or elimination of hyaluronic acid-induced vascular blockage includes administration of ultra-high concentration hyaluronidase to an area of ​​tissue affected by hyaluronic acid-induced blockage of one or more blood vessels. Ultra-high concentration hyaluronidase overcomes the fast clearance rate of the enzyme in the blood, ensuring that an effective amount can reach the desired target area. Furthermore, the high concentration of the enzyme ensures that a gradient is established that is steep enough to facilitate the transport of sufficient amounts of hyaluronidase into the blood. Furthermore, practitioners do not need to inject hyaluronidase as many times due to its higher concentration relative to types of hyaluronidase currently commercially available in the United States. This fewer injections with high concentrations of hyaluronidase also allows patients suffering from HA obstruction to recover more quickly. This delivery of ultra-high concentration hyaluronidase allows the enzyme to reduce or eliminate hyaluronic acid that causes vascular obstruction, thereby reducing or eliminating the risk of permanent damage to the tissue. In summary, patients suffering from HA obstruction will have a greater chance of avoiding irreversible tissue damage resulting from HA obstruction in addition to recovering faster if such patients are injected with ultra-high concentration hyaluronidase rather than low concentration hyaluronidase.

[0025] Some aspects of the present specification disclose pharmaceutical compositions. The pharmaceutical compositions disclosed herein refer to a therapeutically effective concentration of an active ingredient, such as the ultra-high concentration hyaluronidase disclosed herein. Preferably, the pharmaceutical compositions disclosed herein do not cause adverse reactions, allergic reactions or other untoward or undesirable reactions when administered to an individual. The pharmaceutical compositions disclosed herein are useful for medical and veterinary applications. The pharmaceutical compositions disclosed herein may be formulated as liquid pharmaceutical compositions or as dry pharmaceutical compositions, such as lyophilized or freeze-dried formulations.

[0026] The pharmaceutical compositions disclosed herein may be administered to an individual alone or in combination with supplemental active compounds, agents, drugs and / or hormones. In some embodiments, the pharmaceutical compositions disclosed herein further comprise a local anesthetic. Non-limiting examples of local anesthetics include, for example, 3-(p-fluorobenzoyloxy)tropane, amylocaine, amoproxan (3,4,5-trimethoxybenzoyl), articaine, benzocaine, bupivacaine, butacaine, butamben, butanilicaine, carticaine, chloroprocaine, cinchocaine, (dibucaine), cocaine, cyclomethycaine, dimethocaine, etidocaine, α-eucaine, etc. , beta-eucaine, hexylcaine, isobucaine, levobupivacaine, lidocaine, rukaine, mepivacaine, meprylcaine, metabutetamine, metabutoxycaine, nitracaine, orthocaine, piperocaine, prilocaine, propoxycaine, procaine (novocaine), proxymetacaine, lysocaine, ropivacaine, tetracaine, trimecaine, or any combination thereof.

[0027] Some embodiments of the present specification disclose hyaluronidase. Hyaluronidase hydrolyzes hyaluronic acid. According to their enzymatic mechanism, hyaluronidase is hyaluronoglucosidase (EC 3.2.1.35), i.e., they cleave the (1->4) bond between N-acetylglucosamine and glucuronic acid. The term "hyaluronidase" may also refer to hyaluronoglucuronidase (EC 3.2.1.36), which cleaves the (1->3) bond. The pharmacokinetics of hyaluronidase has been evaluated in animal studies after intravitreal injection. Hyaluronidase can be obtained commercially from animals, typically extracted from sheep or bovine testes (Vitrase, Bausch Health Companies, Laval, Quebec, Canada), leeches or bacteria. Hyaluronidase can also be obtained recombinantly, for example by genetically engineering human recombinant DNA in Chinese hamster ovary cells (Hylenex, Halozyme Therapeutics, San Diego, CA). Recombinant hyaluronidase is easier to produce commercially in large quantities and easier to concentrate compared to animal-derived hyaluronidase preparations. Human-derived recombinant hyaluronidase also theoretically has a lower incidence of allergy problems. Commercially available ultra-high concentration hyaluronidase is manufactured by Creative BioMart, which produces the enzyme in concentrations ranging from 1,000 IU / mL to 50,000 IU / mL, where one unit is defined as causing a rate of change of OD of 0.33 / min in this amount of hyaluronic acid at pH 5.7 at 37°C, as measured by a spectrophotometer at 600 nm.

[0028] In one aspect, the present specification discloses a therapeutically effective amount. The therapeutically effective amount of hyaluronidase is an amount sufficient to reduce or eliminate hyaluronic acid-induced obstruction in one or more blood vessels of a tissue. In some aspects of this embodiment, the therapeutically effective amount of hyaluronidase is an amount sufficient to reduce one or more physiological conditions or symptoms associated with hyaluronic acid-induced obstruction in one or more blood vessels of a tissue, or an amount sufficient to protect an individual from one or more physiological conditions or symptoms associated with hyaluronic acid-induced obstruction in one or more blood vessels of a tissue. As used herein, the term "therapeutically effective amount" includes the terms "sufficient amount," "therapeutically sufficient amount," "effective amount," "effective dose," and "therapeutically effective dose," and refers to the minimum amount of hyaluronidase required to achieve the desired therapeutic effect, and includes an amount sufficient to reduce or inhibit one or more physiological conditions or symptoms associated with hyaluronic acid-induced obstruction in one or more blood vessels of a tissue.

[0029] In some aspects of this embodiment, a therapeutically effective amount of ultra-high concentration hyaluronidase disclosed herein reduces or inhibits one or more physiological conditions or symptoms associated with hyaluronic acid-induced obstruction in one or more blood vessels of a tissue, for example, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100%. In other aspects of this embodiment, an effective amount of ultra-high concentration hyaluronidase disclosed herein reduces or inhibits one or more physiological conditions or symptoms associated with hyaluronic acid-induced obstruction in one or more blood vessels of a tissue, for example, by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90% or at most 100%. In yet another aspect of this embodiment, an effective amount of ultra-high concentration hyaluronidase disclosed herein can be used to alleviate one or more physiological conditions or symptoms associated with hyaluronic acid-induced occlusion in one or more blood vessels in a tissue, for example, by about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 20% to about 30%, about 30% to about 100%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 30% to about 10 ... % to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, about 30% to about 50%, about 30% to about 40%, about 40% to about 100%, about 40% to about 90%, about 40% to about 80%, about 40% to about 70%, about 40% to about 60%, about 40% to about 50%, about 50% to about 100%, about 50% to about 90%, about 50 % to about 80%, about 50% to about 70%, about 50% to about 60%, about 60% to about 100%, about 60% to about 90%, about 60% to about 80%, about 60% to about 70%, about 70% to about 100%, about 70% to about 90%, about 70% to about 80%, about 80% to about 100%, about 80% to about 90% or about 90% to about 100%.In yet other aspects of this embodiment, an effective amount of ultra-high concentration hyaluronidase disclosed herein reduces or inhibits one or more physiological conditions or symptoms associated with hyaluronic acid induced occlusion in one or more blood vessels of a tissue, e.g., for at least 1 week, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months.

[0030] In some aspects of this embodiment, a therapeutically effective amount of the ultra-high concentration hyaluronidase disclosed herein restores or maintains one or more qualitative or quantitative aspects of normal blood circulation, for example, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%. In other aspects of this embodiment, an effective amount of the ultra-high concentration hyaluronidase disclosed herein restores or maintains one or more qualitative or quantitative aspects of normal blood circulation, for example, at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100%. In yet another aspect of this embodiment, an effective amount of ultra-high concentration hyaluronidase disclosed herein improves one or more qualitative or quantitative aspects of normal blood circulation, for example, about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 20% to about 30%, about 30% to about 100%, about 30% to about 90%, about 30% ~80%, ~30%~70%, ~30%~60%, ~30%~50%, ~30%~40%, ~40%~100%, ~40%~90%, ~40%~80%, ~40%~70%, ~40%~60%, ~40%~50%, ~50%~100%, ~50%~90%, ~50%~80% %, about 50% to about 70%, about 50% to about 60%, about 60% to about 100%, about 60% to about 90%, about 60% to about 80%, about 60% to about 70%, about 70% to about 100%, about 70% to about 90%, about 70% to about 80%, about 80% to about 100%, about 80% to about 90% or about 90% to about 100% recovery or maintenance.In still other aspects of this embodiment, an effective amount of ultra-high concentration hyaluronidase disclosed herein restores or maintains one or more qualitative or quantitative aspects of normal blood circulation, for example, for at least 1 week, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months.

[0031] The actual therapeutically effective amount of the ultra-high concentration hyaluronidase disclosed herein to be used or administered to an individual can be determined by those skilled in the art by taking into consideration factors including, but not limited to, the type of hyaluronic acid-induced occlusion, the specific physiological condition or condition associated with the hyaluronic acid-induced occlusion, the severity of the hyaluronic acid-induced occlusion, the degree of relief desired for the hyaluronic acid-induced occlusion, the duration of relief desired for the hyaluronic acid-induced occlusion, the specific soft tissue dermal filler used, the excretion rate of the specific hyaluronidase used, the potency of the specific hyaluronidase used, the nature of other compounds included in the treatment, the specific route of administration used, the specific characteristics of the individual, such as age, weight and general health, medical history and risk factors, or any combination thereof. It is known by those skilled in the art that the effective amount of the ultra-high concentration hyaluronidase disclosed herein can be estimated from in vitro assays and in vivo administration studies using animal models prior to administration to humans. Variations in dosage levels can be adjusted using standard empirical routines of optimization well known to those of skill in the art. Precise therapeutically effective dosage levels and patterns are preferably determined by the attending health care professional, taking into consideration the factors identified above.

[0032] Depending on the concentration of ultra-high concentration hyaluronidase in the compositions disclosed herein, the dosage may be a single dose or multiple doses. Typically, when formulated as a single dose, the concentration of ultra-high concentration hyaluronidase in the compositions disclosed herein is such that it effectively reduces or eliminates hyaluronic acid-induced blockage in one or more blood vessels in the region of the tissue affected by the blockage. When the compositions disclosed herein are formulated for multiple dose administration, the total amount of ultra-high concentration hyaluronidase administered cumulatively in multiple doses is such that it effectively reduces or eliminates hyaluronic acid-induced blockage in one or more blood vessels in the region of the tissue affected by the blockage.

[0033] The compositions disclosed herein can include ultra-high concentration hyaluronidase at a concentration of about 250 IU / mL to about 500,000 IU / mL. In some aspects of this embodiment, the compositions disclosed herein comprise hyaluronidase at a concentration of, e.g., at least 25,000 IU / mL, at least 50,000 IU / mL, at least 75,000 IU / mL, at least 100,000 IU / mL, at least 125,000 IU / mL, at least 150,000 IU / mL, at least 175,000 IU / mL, at least 200,000 IU / mL, at least 225,000 IU / mL, at least 250,000 IU / mL, at least 300,000 IU / mL, at least 350,000 IU / mL, at least 400,000 IU / mL, at least 450,000 IU / mL, or at least 500,000 IU / mL. In other aspects of this embodiment, the compositions disclosed herein comprise ultra-high concentration hyaluronidase, e.g., at a concentration of at most 25,000 IU / mL, at most 50,000 IU / mL, at most 75,000 IU / mL, at most 100,000 IU / mL, at most 125,000 IU / mL, at most 150,000 IU / mL, at most 175,000 IU / mL, at most 200,000 IU / mL, at most 225,000 IU / mL, at most 250,000 IU / mL, at most 300,000 IU / mL, at most 350,000 IU / mL, at most 400,000 IU / mL, at most 450,000 IU / mL, or at most 500,000 IU / mL.

[0034] In yet another aspect of this embodiment, the compositions disclosed herein can be administered in a concentration of, for example, about 25,000 IU / mL to about 50,000 IU / mL, about 25,000 IU / mL to about 75,000 IU / mL, about 25,000 IU / mL to about 100,000 IU / mL, about 25,000 IU / mL to about 125,000 IU / mL, about 25,000 IU / mL to about 150,000 IU / mL, about 25,000 IU / mL to about 175,000 IU / mL, about 25,000 IU / mL to about 200,000 IU / mL, about 25,000 IU / mL to about 225,000 IU / mL. , about 25,000IU / mL to about 250,000IU / mL, about 25,000IU / mL to about 300,000IU / mL, about 25,000IU / mL to about 350,000IU / mL, about 25,000IU / mL to about 400,000IU / mL, about 25,000IU / mL to about 4 50,000IU / mL, approximately 25,000IU / mL to approximately 500,000IU / mL, approximately 50,000IU / mL to approximately 75,000IU / mL, approx. 50,000IU / mL ~ approx. 100,000IU / mL, approx. 50,000IU / mL ~ approx. 125,000IU / mL, approx. 50,00 0IU / mL ~ approx. 150,000IU / mL, approx. 50,000IU / mL ~ approx. 175,000IU / mL, approx. 50,000IU / mL ~ approx. 200,000IU / mL, approx. 50,000IU / mL ~ approx. 225,000IU / mL, approx. 50,000IU / mL ~ approx. 250,000I U / mL, approximately 50,000IU / mL to approximately 300,000IU / mL, approximately 50,000IU / mL to approximately 350,000IU / mL, approximately 50,000IU / mL to approximately 400,000IU / mL, approximately 50,000IU / mL to approximately 450,000IU / mL, approximately 50,000IU / mL ~500,000IU / mL, approximately 75,000IU / mL~approximately 100,000IU / mL, approximately 75,000IU / mL~approximately 125,000IU / mL, approximately 75,000IU / mL~approximately 150,000IU / mL, approx. 75,000IU / mL ~ approx. 200,000IU / mL, approx. 75,000IU / mL ~ approx. 225,000IU / mL, approx. 75,000IU / mL ~ approx. 250,000IU / mL, approx. 75,000IU / mL ~ approx. 300,000IU / mL, approx. 75,000IU / mL ~ approx. 350,000 IU / mL, from about 75,000 IU / mL to about 400,000 IU / mL, from about 75,000 IU / mL to about 450,000 IU / mL, from about 75,000 IU / mL to about 500,000 IU / mL, from about 100,000 IU / mL to about 125,000 IU / mL, from about 100,000 IU / mL to about 150,000 IU / mL, from about 100,000 IU / mL to about 175,000 IU / mL, from about 100,000 IU / mL to about 200,000 IU / mL, from about 100,000 IU / mL to about 225,000 IU / mL, from about 100,000 IU / mL to about 250,000 IU / mL, from about 100,000 IU / mL to about 300,000 IU / mL, from about 100,000 IU / mL to about 350,000 IU / mL, from about 100,000 IU / mL to about 400,000 IU / mL, from about 100,000 IU / mL to about 450,000 IU / mL, from about 100,000 IU / mL to about 500,000 IU / mL, from about 150,000 IU / mL to about 200,000 IU / mL, from about 150,000 IU / mL to about 225,000 IU / mL, from about 150,000 IU / mL to about 250,000 IU / mL, from about 150,000 IU / mL to about 300,000 IU / mL, from about 150,000 IU / mL to about 350,000 IU / mL, from about 150,000 IU / mL to about 400,000 IU / mL, from about 150,000 IU / mL to about 450,000 IU / mL, from about 150,000 IU / mL to about 500,000 IU / mL, from about 200,000 IU / mL to about 225,000 IU / mL, from about 200,000 IU / mL to about 250,000 IU / mL, from about 200,000 IU / mL to about 300,000 IU / mL, from about 200,000 IU / mL to about 350,000 IU / mL, from about 200,000 IU / mL to about 400,000 IU / mL, from about 200,000 IU / mL to about 450,000 IU / mL, from about 200,000 IU / mL to about 500,000 IU / mL, from about 250,000 IU / mL to about 300,000 IU / mL, from about 250,000 IU / mL to about 350,000 IU / mL, from about 250,000 IU / mL to about 400,000 IU / mL, from about 250,000 IU / mL to about 450,000 IU / mL, from about 250,000 IU / mL to about 500,000 IU / mL, from about 300,000 IU / mL to about 350,000 IU / mL, from about 300,The ultra-high concentration hyaluronidase includes a concentration of about 400,000 IU / mL, about 300,000 IU / mL to about 450,000 IU / mL, about 300,000 IU / mL to about 500,000 IU / mL, about 350,000 IU / mL to about 400,000 IU / mL, about 350,000 IU / mL to about 450,000 IU / mL, about 350,000 IU / mL to about 500,000 IU / mL, about 400,000 IU / mL to about 450,000 IU / mL, about 400,000 IU / mL to about 500,000 IU / mL, or about 450,000 IU / mL to about 500,000 IU / mL.

[0035] In some aspects of this embodiment, the compositions disclosed herein comprise hyaluronidase at a concentration of, for example, at least 10,000 IU / mL, at least 20,000 IU / mL, at least 30,000 IU / mL, at least 40,000 IU / mL, at least 50,000 IU / mL, at least 60,000 IU / mL, at least 70,000 IU / mL, at least 80,000 IU / mL, at least 90,000 IU / mL or at least 100,000 IU / mL. In other aspects of this embodiment, the compositions disclosed herein include hyaluronidase at a concentration of, for example, at most 10,000 IU / mL, at most 20,000 IU / mL, at most 30,000 IU / mL, at most 40,000 IU / mL, at most 50,000 IU / mL, at most 60,000 IU / mL, at most 70,000 IU / mL, at most 80,000 IU / mL, at most 90,000 IU / mL, or at most 100,000 IU / mL.

[0036] In yet another aspect of this embodiment, the compositions disclosed herein can be administered in a concentration of, for example, about 10,000 IU / mL to about 20,000 IU / mL, about 10,000 IU / mL to about 30,000 IU / mL, about 10,000 IU / mL to about 40,000 IU / mL, about 10,000 IU / mL to about 50,000 IU / mL, about 10,000 IU / mL to about 60,000 IU / mL, about 10,000 IU / mL to about 70,000 IU / mL, about 10,000 IU / mL to about 80,000 IU / mL, about 10,000 IU / mL to about 90,000 IU / mL, about 10,000 IU / mL to about 110,000 IU / mL, about 120,000 IU / mL to about 130,000 IU / mL, about 130,000 IU / mL to about 140,000 IU / mL, about 140,000 IU / mL to about 150,000 IU / mL, about 150,000 IU / mL to about 160,000 IU / mL, about 160,000 IU / mL to about 170,000 IU / mL, about 170,000 IU / mL to about 180,000 IU / mL, about 180,000 IU / mL to about 200,000 IU / mL, about 180,000 IU / mL to about 220,000 IU / mL, about 180,000 IU / mL to about 230,000 IU / mL, about 000IU / mL ~ approx. 100,000IU / mL, approx. 20,000IU / mL ~ approx. 30,000IU / mL, approx. 20,000IU / mL ~ approx. 40,000IU / mL, approx. 20,000IU / mL ~ approx. 50,000IU / mL, approx. 20,000IU / mL ~ approx. 60,000IU / mL, about 20,000IU / mL to about 70,000IU / mL, about 20,000IU / mL to about 80,000IU / mL, about 20,000IU / mL to about 90,000IU / mL, about 20,000IU / mL to about 100,000IU / mL, about 30,000IU / mL to about 40, 000IU / mL, approximately 30,000IU / mL to approximately 50,000IU / mL, approximately 30,000IU / mL to approximately 60,000IU / mL, approximately 30,000IU / mL to approximately 70,000IU / mL, approximately 30,000IU / mL to approximately 80,000IU / mL, approximately 30,000IU / m L ~ about 90,000IU / mL, about 30,000IU / mL - about 100,000IU / mL, about 40,000IU / mL - about 50,000IU / mL, about 40,000IU / mL - about 60,000IU / mL, about 40,000IU / mL - about 70,000IU / mL, about 40, 000IU / mL ~ approx. 80,000IU / mL, approx. 40,000IU / mL ~ approx. 90,000IU / mL, approx. 40,000IU / mL ~ approx. 100,000IU / mL, approx. 50,000IU / mL ~ approx. 60,000IU / mL, approx. 50,000IU / mL ~ approx. 70,000IU / mL, about 50,000IU / mL to about 80,000IU / mL, about 50,000IU / mL to about 90,000IU / mL, about 50,000IU / mL to about 100,000IU / mL, about 60,000IU / mL to about 70,000IU / mL, about 60,000IU / mL to about 80,The ultra-high concentration hyaluronidase is contained at a concentration of about 1,000 IU / mL, about 60,000 IU / mL to about 90,000 IU / mL, about 60,000 IU / mL to about 100,000 IU / mL, about 70,000 IU / mL to about 80,000 IU / mL, about 70,000 IU / mL to about 90,000 IU / mL, about 70,000 IU / mL to about 100,000 IU / mL, about 80,000 IU / mL to about 90,000 IU / mL, about 80,000 IU / mL to about 100,000 IU / mL, or about 90,000 IU / mL to about 100,000 IU / mL.

[0037] In some aspects of this embodiment, the compositions disclosed herein comprise hyaluronidase at a concentration of, e.g., at least 5,000 IU / mL, at least 6,000 IU / mL, at least 7,000 IU / mL, at least 8,000 IU / mL, at least 9,000 IU / mL, at least 10,000 IU / mL, at least 11,000 IU / mL, at least 12,000 IU / mL, at least 13,000 IU / mL, at least 14,000 IU / mL, at least 15,000 IU / mL, at least 16,000 IU / mL, at least 17,000 IU / mL, at least 18,000 IU / mL, at least 19,000 IU / mL, or at least 20,000 IU / mL. In other aspects of this embodiment, the compositions disclosed herein comprise ultra high concentration hyaluronidase, e.g., at most 5,000 IU / mL, at most 6,000 IU / mL, at most 7,000 IU / mL, at most 8,000 IU / mL, at most 9,000 IU / mL, at most 10,000 IU / mL, at most 11,000 IU / mL, at most 12,000 IU / mL, at most 13,000 IU / mL, at most 14,000 IU / mL, at most 15,000 IU / mL, at most 16,000 IU / mL, at most 17,000 IU / mL, at most 18,000 IU / mL, at most 19,000 IU / mL, or at most 20,000 IU / mL.

[0038] In yet another aspect of this embodiment, the compositions disclosed herein can be administered in a concentration of, for example, about 5,000 IU / mL to about 6,000 IU / mL, about 5,000 IU / mL to about 7,000 IU / mL, about 5,000 IU / mL to about 8,000 IU / mL, about 5,000 IU / mL to about 9,000 IU / mL, about 5,000 IU / mL to about 10,000 IU / mL, about 5,000 IU / mL to about 11,000 IU / mL, about 5,000 IU / mL to about 12,000 IU / mL, about 5,000 IU / mL to about 13,000 IU / mL, about 5,000 IU / mL to about 14, 000IU / mL, approximately 5,000IU / mL to approximately 15,000IU / mL, approximately 5,000IU / mL to approximately 16,000IU / mL, approximately 5,000IU / mL to approximately 17,000IU / mL, approximately 5,000IU / mL to approximately 18,000IU / mL, approximately 5,000IU / mL to approximately 19 ,000IU / mL, about 5,000IU / mL to about 20,000IU / mL, about 6,000IU / mL to about 7,000IU / mL, about 6,000IU / mL to about 8,000IU / mL, about 6,000IU / mL to about 9,000IU / mL, about 6,000IU / mL to about 10,0 00IU / mL, approximately 6,000IU / mL to approximately 11,000IU / mL, approximately 6,000IU / mL to approximately 12,000IU / mL, approximately 6,000IU / mL to approximately 13,000IU / mL, approximately 6,000IU / mL to approximately 14,000IU / mL, approximately 6,000IU / mL to approximately 15, 000IU / mL, approximately 6,000IU / mL to approximately 16,000IU / mL, approximately 6,000IU / mL to approximately 17,000IU / mL, approximately 6,000IU / mL to approximately 18,000IU / mL, approximately 6,000IU / mL to approximately 19,000IU / mL, approximately 6,000IU / mL to approximately 20 ,000IU / mL, about 7,000IU / mL to about 8,000IU / mL, about 7,000IU / mL to about 9,000IU / mL, about 7,000IU / mL to about 10,000IU / mL, about 7,000IU / mL to about 11,000IU / mL, about 7,000IU / mL to about 12, 000IU / mL, approximately 7,000IU / mL to approximately 13,000IU / mL, approximately 7,000IU / mL to approximately 14,000IU / mL, approximately 7,000IU / mL to approximately 15,000IU / mL, approximately 7,000IU / mL to approximately 16,000IU / mL, approximately 7,000IU / mL to approximately 17,000 IU / mL, approximately 7,000 IU / mL to approximately 18,000 IU / mL, approximately 7,000 IU / mL to approximately 19,000 IU / mL, approximately 7,000 IU / mL to approximately 20,000 IU / mL, approximately 8,000 IU / mL to approximately 9,000 IU / mL, approximately 8,000 IU / mL to approximately 10,000 IU / mL, approximately 8,000 IU / mL to approximately 11,000 IU / mL, approximately 8,000 IU / mL to approximately 12,000 IU / mL, approximately 8,000 IU / mL to approximately 13,000 IU / mL, approximately 8,000 IU / mL to approximately 14,000 IU / mL, approximately 8,000 IU / mL to approximately 15,000 IU / mL, approximately 8,000 IU / mL to approximately 16,000 IU / mL, approximately 8,000 IU / mL to approximately 17,000 IU / mL, approximately 8,000 IU / mL to approximately 18,000 IU / mL, approximately 8,000 IU / mL to approximately 19,000 IU / mL, approximately 8,000 IU / mL to approximately 20,000 IU / mL, approximately 9,000 IU / mL to approximately 10,000 IU / mL, approximately 9,000 IU / mL to approximately 11,000 IU / mL, approximately 9,000 IU / mL to approximately 12,000 IU / mL, approximately 9,000 IU / mL to approximately 13,000 IU / mL, approximately 9,000 IU / mL to approximately 14,000 IU / mL, approximately 9,000 IU / mL to approximately 15,000 IU / mL, approximately 9,000 IU / mL to approximately 16,000 IU / mL, approximately 9,000 IU / mL to approximately 17,000 IU / mL, approximately 9,000 IU / mL to approximately 18,000 IU / mL, approximately 9,000 IU / mL to approximately 19,000 IU / mL, approximately 9,000 IU / mL to approximately 20,000 IU / mL, approximately 10,000 IU / mL to approximately 11,000 IU / mL, approximately 10,000 IU / mL to approximately 12,000 IU / mL, approximately 10,000 IU / mL to approximately 13,000 IU / mL, approximately 10,000 IU / mL to approximately 14,000 IU / mL, approximately 10,000 IU / mL to approximately 15,000 IU / mL, approximately 10,000 IU / mL to approximately 16,000 IU / mL, approximately 10,000 IU / mL to approximately 17,000 IU / mL, approximately 10,000 IU / mL to approximately 18,000 IU / mL, approximately 10,000 IU / mL to approximately 19,000 IU / mL, approximately 10,000 IU / mL to approximately 20,000 IU / mL, approximately 11,000 IU / mL to approximately 12,000 IU / mL, approximately 11,000 IU / mL to approximately 13,000 IU / mL, approximately 11,000 IU / mL to approximately 14,000 IU / mL, approximately 11,000 IU / mL to approximately 15,000 IU / mL, approximately 11,000 IU / mL to approximately 16,000 IU / mL, approximately 11,000 IU / mL to approximately 17,000 IU / mL, approximately 11,000 IU / mL to approximately 18,000 IU / mL, approximately 11,000 IU / mL to approximately 19,000 IU / mL, approximately 11,000 IU / mL to approximately 20,000 IU / mL, approximately 12,000 IU / mL to approximately 13,000 IU / mL, approximately 12,000 IU / mL to approximately 14,000 IU / mL, approximately 12,000 IU / mL to approximately 15,000 IU / mL, approximately 12,000 IU / mL to approximately 16,000 IU / mL, approximately 12,000 IU / mL to approximately 17,000 IU / mL, approximately 12,000 IU / mL to approximately 18,000 IU / mL, approximately 12,000 IU / mL to approximately 19,000 IU / mL, approximately 12,000 IU / mL to approximately 20,000 IU / mL, approximately 13,000 IU / mL to approximately 14,000 IU / mL, approximately 13,000 IU / mL to approximately 15,000 IU / mL, approximately 13,000 IU / mL to approximately 16,000 IU / mL, approximately 13,000 IU / mL to approximately 17,000 IU / mL, approximately 13,000 IU / mL to approximately 18,000 IU / mL, approximately 13,000 IU / mL to approximately 19,000 IU / mL, approximately 13,000 IU / mL to approximately 20,000 IU / mL, approximately 14,000 IU / mL to approximately 15,000 IU / mL, approximately 14,000 IU / mL to approximately 16,000 IU / mL, approximately 14,000 IU / mL to approximately 17,000 IU / mL, approximately 14,000 IU / mL to approximately 18,000 IU / mL, approximately 14,000 IU / mL to approximately 19,000 IU / mL, approximately 14,000 IU / mL to approximately 20,000 IU / mL, approximately 15,000 IU / mL to approximately 16,000 IU / mL, approximately 15,000 IU / mL to approximately 17,000 IU / mL, approximately 15,000 IU / mL to approximately 18,000 IU / mL, approximately 15,000 IU / mL to approximately 19,000 IU / mL, approximately 15,000 IU / mL to approximately 20,000 IU / mL, approximately 16,000 IU / mL to approximately 17,000 IU / mL, approximately 16,000 IU / mL to approximately 18,000 IU / mL, approximately 16,000 IU / mL to approximately 19,000 IU / mL, approximately 16,000 IU / mL to approximately 20,000 IU / mL, approximately 17,000 IU / mL to approximately 18,000 IU / mL, approximately 17,000 IU / mL to approximately 19,000 IU / mL, approximately 17,000 IU / mL to approximately 20,The ultra-high concentration hyaluronidase is about 1,000 IU / mL, about 18,000 IU / mL to about 19,000 IU / mL, about 18,000 IU / mL to about 20,000 IU / mL, or about 19,000 IU / mL to about 20,000 IU / mL.

[0039] In some aspects of this embodiment, the compositions disclosed herein comprise hyaluronidase at a concentration of, e.g., at least 250 IU / mL, at least 500 IU / mL, at least 750 IU / mL, at least 1,000 IU / mL, at least 1,500 IU / mL, at least 2,000 IU / mL, at least 2,500 IU / mL, at least 3,000 IU / mL, at least 3,500 IU / mL, at least 4,000 IU / mL, at least 4,500 IU / mL, or at least 5,000 IU / mL. In other aspects of this embodiment, the compositions disclosed herein comprise ultra-high concentration hyaluronidase, e.g., at a concentration of at most 250 IU / mL, at most 500 IU / mL, at most 750 IU / mL, at most 1,000 IU / mL, at most 1,500 IU / mL, at most 2,000 IU / mL, at most 2,500 IU / mL, at most 3,000 IU / mL, at most 3,500 IU / mL, at most 4,000 IU / mL, at most 4,500 IU / mL, or at most 5,000 IU / mL.

[0040] In yet another aspect of this embodiment, the compositions disclosed herein can be administered in a concentration of, for example, about 250 IU / mL to about 500 IU / mL, about 250 IU / mL to about 750 IU / mL, about 250 IU / mL to about 1,000 IU / mL, about 250 IU / mL to about 1,500 IU / mL, about 250 IU / mL to about 2,000 IU / mL, about 250 IU / mL to about 2,500 IU / mL, about 250 IU / mL to about 3,000 IU / mL, about 250 IU / mL to about 3,500 IU / mL, about 250 IU / mL to about 4,000 IU / mL, about 250 IU / mL to about 4,500 IU / mL, or about 250 IU / mL to about 5,000 IU / mL. / mL, about 250IU / mL to about 5,000IU / mL, about 500IU / mL to about 750IU / mL, about 500IU / mL to about 1,000IU / mL, about 500IU / mL to about 1,500IU / mL, about 500IU / mL to about 2,000IU / mL, about 500IU / mL to about 2 ,500IU / mL, about 500IU / mL to about 3,000IU / mL, about 500IU / mL to about 3,500IU / mL, about 500IU / mL to about 4,000IU / mL, about 500IU / mL to about 4,500IU / mL, about 500IU / mL to about 5,000IU / mL, about 750 IU / mL~about 1,000IU / mL, about 750IU / mL~about 1,500IU / mL, about 750IU / mL~about 2,000IU / mL, about 750IU / mL~about 2,500IU / mL, about 750IU / mL~about 3,000IU / mL, about 750IU / mL~about 3,500IU / mL, about 750IU / mL to about 4,000IU / mL, about 750IU / mL to about 4,500IU / mL, about 750IU / mL to about 5,000IU / mL, about 1,000IU / mL to about 1,500IU / mL, about 1,000IU / mL to about 2,000IU / mL, about 1,000 IU / mL~about 2,500IU / mL, about 1,000IU / mL~about 3,000IU / mL, about 1,000IU / mL~about 3,500IU / mL, about 1,000IU / mL~about 4,000IU / mL, about 1,000IU / mL~about 4,500IU / mL, about 1,000IU / m L ~ about 5,000IU / mL, about 1,500IU / mL - about 2,000IU / mL, about 1,500IU / mL - about 2,500IU / mL, about 1,500IU / mL - about 3,000IU / mL, about 1,500IU / mL - about 3,500IU / mL, about 1,500IU / mL - about 4,000IU / mL, approximately 1,500IU / mL to approximately 4,500IU / mL, approximately 1,500IU / mL to approximately 5,000IU / mL, approximately 2,000IU / mL to approximately 2, 500IU / mL, approximately 2,000IU / mL to approximately 3,000IU / mL, approximately 2,000IU / mL to approximately 3,500IU / mL, approximately 2,000IU / mL to approximately 4,0 00IU / mL, approximately 2,000IU / mL to approximately 4,500IU / mL, approximately 2,000IU / mL to approximately 5,000IU / mL, approximately 2,500IU / mL to approximately 3,00 0IU / mL, approximately 2,500IU / mL to approximately 3,500IU / mL, approximately 2,500IU / mL to approximately 4,000IU / mL, approximately 2,500IU / mL to approximately 4,500 IU / mL, approximately 2,500IU / mL to approximately 5,000IU / mL, approximately 3,000IU / mL to approximately 3,500IU / mL, approximately 3,000IU / mL to approximately 4,000 IU / mL, approximately 3,000IU / mL to approximately 4,500IU / mL, approximately 3,000IU / mL to approximately 5,000IU / mL, approximately 3,500IU / mL to approximately 4,000I U / mL, about 3,500 IU / mL to about 4,500 IU / mL, about 3,500 IU / mL to about 5,000 IU / mL, about 4,000 IU / mL to about 4,500 IU / mL, about 4,000 IU / mL to about 5,000 IU / mL, or about 4,500 IU / mL to about 5,000 IU / mL.

[0041] A single dose of a composition comprising ultra-high concentration hyaluronidase used to effectively reduce or eliminate hyaluronic acid-induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction can contain from about 250 IU / mL to about 500,000 IU / mL of hyaluronidase. In some aspects of this embodiment, a single dose of a composition comprising hyaluronidase used to effectively reduce or eliminate hyaluronic acid-induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction can contain, for example, at least 25,000 IU / mL, at least 50,000 IU / mL, at least 75,000 IU / mL, at least 100,000 IU / mL, at least 125,000 IU / mL, at least 10 ... The hyaluronidase can include an amount of 50,000 IU / mL, at least 175,000 IU / mL, at least 200,000 IU / mL, at least 225,000 IU / mL, at least 250,000 IU / mL, at least 300,000 IU / mL, at least 350,000 IU / mL, at least 400,000 IU / mL, at least 450,000 IU / mL or at least 500,000 IU / mL. In another aspect of this embodiment, a single dose of a composition comprising hyaluronidase used to effectively reduce or eliminate hyaluronic acid-induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction can be, for example, at most 25,000 IU / mL, at most 50,000 IU / mL, at most 75,000 IU / mL, at most 100,000 IU / mL, at most 125,000 IU / mL, at most 1 The hyaluronidase can be in an amount of 50,000 IU / mL, at most 175,000 IU / mL, at most 200,000 IU / mL, at most 225,000 IU / mL, at most 250,000 IU / mL, at most 300,000 IU / mL, at most 350,000 IU / mL, at most 400,000 IU / mL, at most 450,000 IU / mL or at most 500,000 IU / mL.

[0042] In yet another aspect of this embodiment, a single dose of a composition comprising hyaluronidase used to effectively reduce or eliminate hyaluronic acid-induced obstruction in one or more blood vessels in the region of the tissue affected by the obstruction may be, for example, about 25,000 IU / mL to about 50,000 IU / mL, about 25,000 IU / mL to about 75,000 IU / mL, about 25,000 IU / mL to about 100,000 IU / mL, about 25,000 IU / mL to about 125,000 IU / mL, about 25,000 IU / mL to about 150 ... Approx. 175,000IU / mL, Approx. 25,000IU / mL ~ Approx. 200,000IU / mL, Approx. 25,000IU / mL ~ Approx. 225,000IU / mL, Approx. 25,000IU / mL ~ Approx. 250,000IU / mL, Approx. 25,000IU / mL ~ Approx. 300,000IU / mL, Approx. 2 5,000IU / mL ~ approx. 350,000IU / mL, approx. 25,000IU / mL ~ approx. 400,000IU / mL, approx. 25,000IU / mL ~ approx. 450,000IU / mL, approx. 25,000IU / mL ~ approx. 500,000IU / mL, approx. 50,000IU / mL ~ approx. 75,00 0IU / mL, approximately 50,000IU / mL to approximately 100,000IU / mL, approximately 50,000IU / mL to approximately 125,000IU / mL, approximately 50,000IU / mL to approximately 150,000IU / mL, approximately 50,000IU / mL to approximately 175,000IU / mL, approximately 50,000IU / mL ~ approx. 200,000IU / mL, approx. 50,000IU / mL ~ approx. 225,000IU / mL, approx. 50,000IU / mL ~ approx. 250,000IU / mL, approx. 50,000IU / mL ~ approx. 300,000IU / mL, approx. 50,000IU / mL ~ approx. 350,000IU / m L, approx. 50,000IU / mL ~ approx. 400,000IU / mL, approx. 50,000IU / mL ~ approx. 450,000IU / mL, approx. 50,000IU / mL ~ approx. 125,000IU / mL, approx. 75,000IU / mL ~ approx. 150,000IU / mL, approx. 75,000IU / mL ~ approx. 175,000I U / mL, about 75,000IU / mL to about 200,000IU / mL, about 75,000IU / mL to about 225,000IU / mL, about 75,000 IU / mL to approximately 250,000 IU / mL, approximately 75,000 IU / mL to approximately 300,000 IU / mL, approximately 75,000 IU / mL to approximately 350,000 IU / mL, approximately 75,000 IU / mL to approximately 400,000 IU / mL, approximately 75,000 IU / mL to approximately 450,000 IU / mL, approximately 75,000 IU / mL to approximately 500,000 IU / mL, approximately 100,000 IU / mL to approximately 125,000 IU / mL, approximately 100,000 IU / mL to approximately 150,000 IU / mL, approximately 100,000 IU / mL to approximately 175,000 IU / mL, approximately 100,000 IU / mL to approximately 200,000 IU / mL, approximately 100,000 IU / mL to approximately 225,000 IU / mL, approximately 100,000 IU / mL to approximately 250,000 IU / mL, approximately 100,000 IU / mL to approximately 300,000 IU / mL, approximately 100,000 IU / mL to approximately 350,000 IU / mL, approximately 100,000 IU / mL to approximately 400,000 IU / mL, approximately 100,000 IU / mL to approximately 450,000 IU / mL, approximately 100,000 IU / mL to approximately 500,000 IU / mL, approximately 150,000 IU / mL to approximately 200,000 IU / mL, approximately 150,000 IU / mL to approximately 225,000 IU / mL, approximately 150,000 IU / mL to approximately 250,000 IU / mL, approximately 150,000 IU / mL to approximately 300,000 IU / mL, approximately 150,000 IU / mL to approximately 350,000 IU / mL, approximately 150,000 IU / mL to approximately 400,000 IU / mL, approximately 150,000 IU / mL to approximately 450,000 IU / mL, approximately 150,000 IU / mL to approximately 500,000 IU / mL, approximately 200,000 IU / mL to approximately 225,000 IU / mL, approximately 200,000 IU / mL to approximately 250,000 IU / mL, approximately 200,000 IU / mL to approximately 300,000 IU / mL, approximately 200,000 IU / mL to approximately 350,000 IU / mL, approximately 200,000 IU / mL to approximately 400,000 IU / mL, approximately 200,000 IU / mL to approximately 450,000 IU / mL, approximately 200,000 IU / mL to approximately 500,000 IU / mL, approximately 250,000 IU / mL to approximately 300,000 IU / mL, approximately 250,000 IU / mL to approximately 350,000 IU / mL, approximately 250,000 IU / mL to approximately 400,000 IU / mL, approximately 250,000 IU / mL to approximately 450,000IU / mL, about 250,000IU / mL to about 500,000IU / mL, about 300,000IU / mL to about 350,000IU / mL, about 300,000IU / mL to about 400, 000IU / mL, about 300,000IU / mL to about 450,000IU / mL, about 300,000IU / mL to about 500,000IU / mL, about 350,000IU / mL to about 400,0 The composition may contain hyaluronidase in an amount of about 100,000 IU / mL, about 350,000 IU / mL to about 450,000 IU / mL, about 350,000 IU / mL to about 500,000 IU / mL, about 400,000 IU / mL to about 450,000 IU / mL, about 400,000 IU / mL to about 500,000 IU / mL, or about 450,000 IU / mL to about 500,000 IU / mL.

[0043] In some aspects of this embodiment, a single dose of a composition comprising hyaluronidase used to effectively reduce or eliminate hyaluronic acid induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction can include, for example, an amount of hyaluronidase at least 10,000 IU / mL, at least 20,000 IU / mL, at least 30,000 IU / mL, at least 40,000 IU / mL, at least 50,000 IU / mL, at least 60,000 IU / mL, at least 70,000 IU / mL, at least 80,000 IU / mL, at least 90,000 IU / mL or at least 100,000 IU / mL. In other aspects of this embodiment, a single dose of a composition comprising hyaluronidase used to effectively reduce or eliminate hyaluronic acid induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction can include, for example, an amount of hyaluronidase at most 10,000 IU / mL, at most 20,000 IU / mL, at most 30,000 IU / mL, at most 40,000 IU / mL, at most 50,000 IU / mL, at most 60,000 IU / mL, at most 70,000 IU / mL, at most 80,000 IU / mL, at most 90,000 IU / mL or at most 100,000 IU / mL.

[0044] In yet another aspect of this embodiment, a single dose of a composition comprising hyaluronidase used to effectively reduce or eliminate hyaluronic acid-induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction may be, for example, about 10,000 IU / mL to about 20,000 IU / mL, about 10,000 IU / mL to about 30,000 IU / mL, about 10,000 IU / mL to about 40,000 IU / mL, about 10,000 IU / mL to about 50,000 IU / mL, about 10,000 IU / mL to about 60,000 IU / mL, about 10,000 IU / mL to about 70,000 IU / mL, or about 10,000 IU / mL to about 80,000 IU / mL. ,000IU / mL, about 10,000IU / mL to about 80,000IU / mL, about 10,000IU / mL to about 90,000IU / mL, about 10,000IU / mL to about 100,000IU / mL, about 20,000IU / mL to about 30,000IU / mL, about 20,000IU / mL ~ approx. 40,000IU / mL, approx. 20,000IU / mL ~ approx. 50,000IU / mL, approx. 20,000IU / mL ~ approx. 60,000IU / mL, approx. 20,000IU / mL ~ approx. 70,000IU / mL, approx. 20,000IU / mL ~ approx. 80,000IU / mL, approx. 000IU / mL ~ approx. 90,000IU / mL, approx. 20,000IU / mL ~ approx. 100,000IU / mL, approx. 30,000IU / mL ~ approx. 40,000IU / mL, approx. 30,000IU / mL ~ approx. 50,000IU / mL, approx. 30,000IU / mL ~ approx. 60,000IU / mL, about 30,000IU / mL to about 70,000IU / mL, about 30,000IU / mL to about 80,000IU / mL, about 30,000IU / mL to about 90,000IU / mL, about 30,000IU / mL to about 100,000IU / mL, about 40,000IU / mL to about 50 ,000IU / mL, about 40,000IU / mL to about 60,000IU / mL, about 40,000IU / mL to about 70,000IU / mL, about 40,000IU / mL to about 80,000IU / mL, about 40,000IU / mL to about 90,000IU / mL, about 40,000IU / mL mL~about 100,000IU / mL, about 50,000IU / mL~about 60,000IU / mL, about 50,000IU / mL~about 70,000IU / mL, about 50,000IU / mL~about 80,000IU / mL, about 50,000IU / mL~about 90,000IU / mL, about 50,000IU / mL ~ approx. 100,000IU / mL, approx. 60,000IU / mL ~ approx. 70,000IU / mL, approx. 60,000IU / mL ~ approx. 80,000IU / mL, approx. 6 0,000IU / mL ~ approx. 90,000IU / mL, approx. 60,000IU / mL ~ approx. 100,000IU / mL, approx. 70,000IU / mL ~ approx. 80,000IU / mL, The amount of hyaluronidase may be about 70,000 IU / mL to about 90,000 IU / mL, about 70,000 IU / mL to about 100,000 IU / mL, about 80,000 IU / mL to about 90,000 IU / mL, about 80,000 IU / mL to about 100,000 IU / mL, or about 90,000 IU / mL to about 100,000 IU / mL.

[0045] In some aspects of this embodiment, a single dose of a composition comprising hyaluronidase used to effectively reduce or eliminate hyaluronic acid induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction can include, for example, an amount of hyaluronidase at least 5,000 IU / mL, at least 6,000 IU / mL, at least 7,000 IU / mL, at least 8,000 IU / mL, at least 9,000 IU / mL, at least 10,000 IU / mL, at least 11,000 IU / mL, at least 12,000 IU / mL, at least 13,000 IU / mL, at least 14,000 IU / mL, at least 15,000 IU / mL, at least 16,000 IU / mL, at least 17,000 IU / mL, at least 18,000 IU / mL, at least 19,000 IU / mL, or at least 20,000 IU / mL. In another aspect of this embodiment, a single dose of a composition comprising hyaluronidase used to effectively reduce or eliminate hyaluronic acid-induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction may be, for example, at most 5,000 IU / mL, at most 6,000 IU / mL, at most 7,000 IU / mL, at most 8,000 IU / mL, at most 9,000 IU / mL, at most 10,000 IU / mL, at most 12,000 IU / mL, at most 16,000 IU / mL, at most 18,000 IU / mL, at most 19,000 IU / mL, at most 21,000 IU / mL, at most 22,000 IU / mL, at most 23,000 IU / mL, at most 24,000 IU / mL, at most 25,000 IU / mL, at most 26,000 IU / mL, at most 27,000 IU / mL, at most 28,000 IU / mL, at most 30,000 IU / mL, at most 31,000 IU / mL, at most 32,000 IU / mL, at most 33,000 IU / mL, at most 34,000 IU / mL, at most 35,000 IU / mL, at most 36,000 IU / mL, at most 37,000 IU / mL, at most 38,000 IU / mL, at most 39,000 IU / mL, at most 40,000 IU / mL, at most 41,000 IU / mL, at most 42,000 IU / mL, at most 43,000 IU / mL, at most 44,000 The hyaluronidase can include an amount of hyaluronidase in an amount of at most 11,000 IU / mL, at most 12,000 IU / mL, at most 13,000 IU / mL, at most 14,000 IU / mL, at most 15,000 IU / mL, at most 16,000 IU / mL, at most 17,000 IU / mL, at most 18,000 IU / mL, at most 19,000 IU / mL or at most 20,000 IU / mL.

[0046] In yet another aspect of this embodiment, a single dose of a composition comprising hyaluronidase used to effectively reduce or eliminate hyaluronic acid-induced obstruction in one or more blood vessels in the region of the tissue affected by the obstruction may be, for example, about 5,000 IU / mL to about 6,000 IU / mL, about 5,000 IU / mL to about 7,000 IU / mL, about 5,000 IU / mL to about 8,000 IU / mL, about 5,000 IU / mL to about 9,000 IU / mL, about 5,000 IU / mL to about 10,000 IU / mL, about 5,000 IU / mL to about 11,000 IU / mL, or about 5,000IU / mL to approximately 12,000IU / mL, approximately 5,000IU / mL to approximately 13,000IU / mL, approximately 5,000IU / mL to approximately 14,000IU / mL, approximately 5,000IU / mL to approximately 15,000IU / mL, approximately 5,000IU / mL to approximately 16,000IU / mL, Approximately 5,000IU / mL to approximately 17,000IU / mL, approximately 5,000IU / mL to approximately 18,000IU / mL, approximately 5,000IU / mL to approximately 19,000IU / mL, approximately 5,000IU / mL to approximately 20,000IU / mL, approximately 6,000IU / mL to approximately 7,000IU / mL, approximately 6,000IU / mL to approx. 8,000IU / mL, approx. 6,000IU / mL to approx. 9,000IU / mL, approx. 6,000IU / mL to approx. 10,000IU / mL, approx. 6,000IU / mL to approx. 11,000IU / mL, approx. 6,000IU / mL to approx. 12,000IU / mL, approx. 6 ,000IU / mL~about 13,000IU / mL, about 6,000IU / mL~about 14,000IU / mL, about 6,000IU / mL~about 15,000IU / mL, about 6,000IU / mL~about 16,000IU / mL, about 6,000IU / mL~about 17,000IU / mL, about 6 ,000IU / mL~about 18,000IU / mL, about 6,000IU / mL~about 19,000IU / mL, about 6,000IU / mL~about 20,000IU / mL, about 7,000IU / mL~about 8,000IU / mL, about 7,000IU / mL~about 9,000IU / mL, about 7, 000IU / mL ~ approx. 10,000IU / mL, approx. 7,000IU / mL ~ approx. 11,000IU / mL, approx. 7,000IU / mL ~ approx. 12,000IU / mL, approx. 7,000IU / mL ~ approx. 13,000IU / mL, approx. 7,000IU / mL ~ approx. 14,000IU / mL, approx.000 IU / mL to approximately 15,000 IU / mL, approximately 7,000 IU / mL to approximately 16,000 IU / mL, approximately 7,000 IU / mL to approximately 17,000 IU / mL, approximately 7,000 IU / mL to approximately 18,000 IU / mL, approximately 7,000 IU / mL to approximately 19,000 IU / mL, approximately 7,000 IU / mL to approximately 20,000 IU / mL, approximately 8,000 IU / mL to approximately 9,000 IU / mL, approximately 8,000 IU / mL to approximately 10,000 IU / mL, approximately 8,000 IU / mL to approximately 11,000 IU / mL, approximately 8,000 IU / mL to approximately 12,000 IU / mL, approximately 8,000 IU / mL to approximately 13,000 IU / mL, approximately 8,000 IU / mL to approximately 14,000 IU / mL, approximately 8,000 IU / mL to approximately 15,000 IU / mL, approximately 8,000 IU / mL to approximately 16,000 IU / mL, approximately 8,000 IU / mL to approximately 17,000 IU / mL, approximately 8,000 IU / mL to approximately 18,000 IU / mL, approximately 8,000 IU / mL to approximately 19,000 IU / mL, approximately 8,000 IU / mL to approximately 20,000 IU / mL, approximately 9,000 IU / mL to approximately 10,000 IU / mL, approximately 9,000 IU / mL to approximately 11,000 IU / mL, approximately 9,000 IU / mL to approximately 12,000 IU / mL, approximately 9,000 IU / mL to approximately 13,000 IU / mL, approximately 9,000 IU / mL to approximately 14,000 IU / mL, approximately 9,000 IU / mL to approximately 15,000 IU / mL, approximately 9,000 IU / mL to approximately 16,000 IU / mL, approximately 9,000 IU / mL to approximately 17,000 IU / mL, approximately 9,000 IU / mL to approximately 18,000 IU / mL, approximately 9,000 IU / mL to approximately 19,000 IU / mL, approximately 9,000 IU / mL to approximately 20,000 IU / mL, approximately 10,000 IU / mL to approximately 11,000 IU / mL, approximately 10,000 IU / mL to approximately 12,000 IU / mL, approximately 10,000 IU / mL to approximately 13,000 IU / mL, approximately 10,000 IU / mL to approximately 14,000 IU / mL, approximately 10,000 IU / mL to approximately 15,000 IU / mL, approximately 10,000 IU / mL to approximately 16,000 IU / mL, approximately 10,000 IU / mL to approximately 17,000 IU / mL, approximately 10,000 IU / mL to approximately 18,000 IU / mL, approximately 10,000 IU / mL to approximately 19,000 IU / mL, approximately 10,000 IU / mL to approximately 20,000 IU / mL, approximately 11,000 IU / mL to approximately 12,000 IU / mL, from about 11,000 IU / mL to about 13,000 IU / mL, from about 11,000 IU / mL to about 14,000 IU / mL, from about 11,000 IU / mL to about 15,000 IU / mL, from about 11,000 IU / mL to about 16,000 IU / mL, from about 11,000 IU / mL to about 17,000 IU / mL, from about 11,000 IU / mL to about 18,000 IU / mL, from about 11,000 IU / mL to about 19,000 IU / mL, from about 11,000 IU / mL to about 20,000 IU / mL, from about 12,000 IU / mL to about 13,000 IU / mL, from about 12,000 IU / mL to about 14,000 IU / mL, from about 12,000 IU / mL to about 15,000 IU / mL, from about 12,000 IU / mL to about 16,000 IU / mL, from about 12,000 IU / mL to about 17,000 IU / mL, from about 12,000 IU / mL to about 18,000 IU / mL, from about 12,000 IU / mL to about 19,000 IU / mL, from about 12,000 IU / mL to about 20,000 IU / mL, from about 13,000 IU / mL to about 14,000 IU / mL, from about 13,000 IU / mL to about 15,000 IU / mL, from about 13,000 IU / mL to about 16,000 IU / mL, from about 13,000 IU / mL to about 17,000 IU / mL, from about 13,000 IU / mL to about 18,000 IU / mL, from about 13,000 IU / mL to about 19,000 IU / mL, from about 13,000 IU / mL to about 20,000 IU / mL, from about 14,000 IU / mL to about 15,000 IU / mL, from about 14,000 IU / mL to about 16,000 IU / mL, from about 14,000 IU / mL to about 17,000 IU / mL, from about 14,000 IU / mL to about 18,000 IU / mL, from about 14,000 IU / mL to about 19,000 IU / mL, from about 14,000 IU / mL to about 20,000 IU / mL, from about 15,000 IU / mL to about 16,000 IU / mL, from about 15,000 IU / mL to about 17,000 IU / mL, from about 15,000 IU / mL to about 18,000 IU / mL, from about 15,000 IU / mL to about 19,000 IU / mL, from about 15,000 IU / mL to about 20,000 IU / mL, from about 16,000 IU / mL to about 17,000 IU / mL, from about 16,000 IU / mL to about 18,000 IU / mL, from about 16,000 IU / mL to about 19,000 IU / mL, from about 16,000 IU / mL to about 20,000 IU / mL, from about 17,The composition may contain hyaluronidase in an amount of about 1,000 IU / mL to about 18,000 IU / mL, about 17,000 IU / mL to about 19,000 IU / mL, about 17,000 IU / mL to about 20,000 IU / mL, about 18,000 IU / mL to about 19,000 IU / mL, about 18,000 IU / mL to about 20,000 IU / mL, or about 19,000 IU / mL to about 20,000 IU / mL.

[0047] In some aspects of this embodiment, a single dose of a composition comprising hyaluronidase used to effectively reduce or eliminate hyaluronic acid induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction can include, for example, an amount of hyaluronidase at least 250 IU / mL, at least 500 IU / mL, at least 750 IU / mL, at least 1,000 IU / mL, at least 1,500 IU / mL, at least 2,000 IU / mL, at least 2,500 IU / mL, at least 3,000 IU / mL, at least 3,500 IU / mL, at least 4,000 IU / mL, at least 4,500 IU / mL or at least 5,000 IU / mL. In other aspects of this embodiment, a single dose of a composition comprising hyaluronidase used to effectively reduce or eliminate hyaluronic acid induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction can include, for example, an amount of hyaluronidase at most 250 IU / mL, at most 500 IU / mL, at most 750 IU / mL, at most 1,000 IU / mL, at most 1,500 IU / mL, at most 2,000 IU / mL, at most 2,500 IU / mL, at most 3,000 IU / mL, at most 3,500 IU / mL, at most 4,000 IU / mL, at most 4,500 IU / mL or at most 5,000 IU / mL.

[0048] In yet another aspect of this embodiment, a single dose of a composition comprising hyaluronidase used to effectively reduce or eliminate hyaluronic acid-induced obstruction in one or more blood vessels in the region of the tissue affected by the obstruction may be, for example, about 250 IU / mL to about 500 IU / mL, about 250 IU / mL to about 750 IU / mL, about 250 IU / mL to about 1,000 IU / mL, about 250 IU / mL to about 1,500 IU / mL, about 250 IU / mL to about 2,000 IU / mL, about 250 IU / mL to about 2,500 IU / mL, about 250 IU / mL to about 3,000 IU / mL, or about 250 IU / mL to about 4,000 IU / mL. mL, about 250IU / mL to about 3,500IU / mL, about 250IU / mL to about 4,000IU / mL, about 250IU / mL to about 4,500IU / mL, about 250IU / mL to about 5,000IU / mL, about 500IU / mL to about 750IU / mL, about 500IU / mL to about 1,0 00IU / mL, about 500IU / mL to about 1,500IU / mL, about 500IU / mL to about 2,000IU / mL, about 500IU / mL to about 2,500IU / mL, about 500IU / mL to about 3,000IU / mL, about 500IU / mL to about 3,500IU / mL, about 500IU / mL mL~about 4,000IU / mL, about 500IU / mL~about 4,500IU / mL, about 500IU / mL~about 5,000IU / mL, about 750IU / mL~about 1,000IU / mL, about 750IU / mL~about 1,500IU / mL, about 750IU / mL~about 2,000IU / mL, Approximately 750IU / mL to approximately 2,500IU / mL, approximately 750IU / mL to approximately 3,000IU / mL, approximately 750IU / mL to approximately 3,500IU / mL, approximately 750IU / mL to approximately 4,000IU / mL, approximately 750IU / mL to approximately 4,500IU / mL, approximately 750IU / mL to approximately 5,00 0IU / mL, approximately 1,000IU / mL to approximately 1,500IU / mL, approximately 1,000IU / mL to approximately 2,000IU / mL, approximately 1,000IU / mL to approximately 2,500IU / mL, approximately 1,000IU / mL to approximately 3,000IU / mL, approximately 1,000IU / mL to approximately 3,500IU / m L, about 1,000IU / mL to about 4,000IU / mL, about 1,000IU / mL to about 4,500IU / mL, about 1,000IU / mL to about 5,000IU / mL, about 1,500IU / mL to about 2,000IU / mL, about 1,500IU / mL to about 2,500IU / mL, about 1,500IU / mL ~ approx. 3,000IU / mL, approx. 1,500IU / mL ~ approx. 3,500IU / mL, approx. 1,500IU / mL ~ approx. 4,000IU / mL, approx. 1,500IU / mL ~4,500IU / mL, approx. 1,500IU / mL ~ approx. 5,000IU / mL, approx. 2,000IU / mL ~ approx. 2,500IU / mL, approx. 2,000IU / mL ~ approx. 3,000I U / mL, approximately 2,000IU / mL to approximately 3,500IU / mL, approximately 2,000IU / mL to approximately 4,000IU / mL, approximately 2,000IU / mL to approximately 4,500IU / mL, approximately 2, 000IU / mL ~ approx. 5,000IU / mL, approx. 2,500IU / mL ~ approx. 3,000IU / mL, approx. 2,500IU / mL ~ approx. 3,500IU / mL, approx. 2,500IU / mL ~ Approximately 4,000IU / mL, approximately 2,500IU / mL to approximately 4,500IU / mL, approximately 2,500IU / mL to approximately 5,000IU / mL, approximately 3,000IU / mL to approximately 3,500IU / mL, about 3,000IU / mL to about 4,000IU / mL, about 3,000IU / mL to about 4,500IU / mL, about 3,000IU / mL to about 5,000IU / mL, about 3,50 The amount of hyaluronidase may be 0 IU / mL to about 4,000 IU / mL, about 3,500 IU / mL to about 4,500 IU / mL, about 3,500 IU / mL to about 5,000 IU / mL, about 4,000 IU / mL to about 4,500 IU / mL, about 4,000 IU / mL to about 5,000 IU / mL, or about 4,500 IU / mL to about 5,000 IU / mL.

[0049] With respect to the administration of multiple doses of compositions comprising ultra-high concentration hyaluronidase as disclosed herein, all doses should be administered as quickly as possible to be as effective as possible in reducing or eliminating hyaluronic acid-induced blockage in one or more blood vessels in the region of the tissue affected by the blockage. In some aspects of this embodiment, all doses of the multiple dose administration are administered within, for example, at least 1 minute, at least 2 minutes, at least 3 minutes, at least 4 minutes, at least 5 minutes, at least 6 minutes, at least 7 minutes, at least 8 minutes, at least 9 minutes, at least 10 minutes, at least 11 minutes, at least 12 minutes, at least 13 minutes, at least 14 minutes, at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 75 minutes, or at least 90 minutes. In other aspects of this embodiment, all doses of a multiple dose administration occur within, for example, at most 1 minute, at most 2 minutes, at most 3 minutes, at most 4 minutes, at most 5 minutes, at most 6 minutes, at most 7 minutes, at most 8 minutes, at most 9 minutes, at most 10 minutes, at most 11 minutes, at most 12 minutes, at most 13 minutes, at most 14 minutes, at most 15 minutes, at most 30 minutes, at most 45 minutes, at most 60 minutes, at most 75 minutes, or at most 90 minutes. In yet another aspect of this embodiment, all doses of the multiple dose administration are administered within a time period of, for example, about 1 to about 2 minutes, about 1 to about 3 minutes, about 1 to about 4 minutes, about 1 to about 5 minutes, about 1 to about 6 minutes, about 1 to about 10 minutes, about 1 to about 15 minutes, about 1 to about 30 minutes, about 1 to about 45 minutes, about 1 to about 60 minutes, about 1 to about 75 minutes, about 1 to about 90 minutes, about 2 to about 3 minutes, about 2 to about 4 minutes, about 2 to about 5 minutes, about 2 to about 6 minutes, about 2 to about 10 minutes, about 2 to about 15 minutes, about 2 to about 30 minutes, about 2 to about 45 minutes, about 2 to about 60 minutes, about 2 to about 75 minutes, about 2 to about 90 minutes, about 3 to about 4 minutes, about 3 to about 5 minutes, about 3 to about 6 minutes, about 3 to about 10 minutes, about 3 to about 15 minutes, about 3 to about 30 minutes, about 3 to about 45 minutes, about 3 to about 60 minutes, about 3 to about 75 minutes, about 3 to about 90 minutes, about 4 to about 5 minutes, about 4 to about 6 minutes, about 4 to about 10 minutes, about 4 to about 15 minutes, about 4 to about 30 minutes, about 4 to about 45 minutes, about 4 to about 60 minutes, about 4 to about 75 minutes, about 4 to about 90 minutes, about 5 to about 6 minutes, about 5 to about 7 minutes, about 5 to about 8 minutes, about 5 to about 9 minutes, about 5 to about 10 minutes, about 5 to about 11 minutes, about 5 to about 15 minutes, about 5 to about 30 minutes, about 5 to about 45 minutes, about 5 to about 60 minutes, about 5 to about 75 minutes, about 5 to about 90 minutes, about 6 to about 7 minutes, about 6 to about 8 minutes,About 6 to about 9 minutes, about 6 to about 10 minutes, about 6 to about 11 minutes, about 6 to about 15 minutes, about 6 to about 30 minutes, about 6 to about 45 minutes, about 6 to about 60 minutes, about 6 to about 75 minutes, about 6 to about 90 minutes, about 7 to about 8 minutes, about 7 to about 9 minutes, about 7 to about 10 minutes, about 7 to about 11 minutes, about 7 to about 15 minutes, about 7 to about 30 minutes, about 7 to about 45 minutes, about 7 to about 60 minutes, about 7 to about 75 minutes, about 7 to about 90 minutes, about 8 to about 9 minutes, about 8 to about 10 minutes, about 8 to about 11 minutes, about 8 to about 15 minutes, about 8 to about 3 0 minutes, about 8 to about 45 minutes, about 8 to about 60 minutes, about 8 to about 75 minutes, about 8 to about 90 minutes, about 9 to about 10 minutes, about 9 to about 11 minutes, about 9 to about 15 minutes, about 9 to about 30 minutes, about 9 to about 45 minutes, about 9 to about 60 minutes, about 9 to about 75 minutes, about 9 to about 90 minutes, about 10 to about 11 minutes, about 10 to about 12 minutes, about 10 to about 13 minutes, about 10 to about 14 minutes, about 10 to about 15 minutes, about 10 to about 30 minutes, about 10 to about 45 minutes, about 10 to about 60 minutes, about 10 to about 75 minutes, about 10 to about 90 minutes, about 11 to about 12 minutes, about 11 to about 13 minutes, about 11 to about 14 minutes, about 11 to about 15 minutes, about 11 to about 30 minutes, about 11 to about 45 minutes, about 11 to about 60 minutes, about 11 to about 75 minutes, about 11 to about 90 minutes, about 12 to about 13 minutes, about 12 to about 14 minutes, about 12 to about 15 minutes, about 12 to about 30 minutes, about 12 to about 45 minutes, about 12 to about 60 minutes, about 12 to about 75 minutes, about 12 to about 90 minutes, about 13 to about 14 minutes, about 13 to about 15 minutes, about 14 to about 15 minutes, about The treatment is performed within 14 to about 30 minutes, about 14 to about 45 minutes, about 14 to about 60 minutes, about 14 to about 75 minutes, about 14 to about 90 minutes, about 15 to about 30 minutes, about 15 to about 45 minutes, about 15 to about 60 minutes, about 15 to about 75 minutes, about 15 to about 90 minutes, about 30 to about 45 minutes, about 30 to about 60 minutes, about 30 to about 75 minutes, about 30 to about 90 minutes, about 45 to about 60 minutes, about 45 to about 75 minutes, about 45 to about 90 minutes, about 60 to about 75 minutes, about 60 to about 90 minutes, or about 75 to about 90 minutes. In yet another aspect of this embodiment, the number of doses administered in the multiple dose administration is, for example, about 2 to about 5 minutes, about 2 to about 10 minutes, about 2 to about 15 minutes, about 5 to about 10 minutes, about 5 to about 15 minutes, about 5 to about 30 minutes, about 10 to about 15 minutes, about 10 to about 30 minutes, about 15 to about 30 minutes, about 15 to about 45 minutes, about 15 to about 60 minutes, about 15 to about 75 minutes, or about 15 to about 90 minutes.

[0050] With respect to multiple dose administration of compositions comprising ultra-high concentration hyaluronidase as disclosed herein, the number of doses administered is the number required to achieve an effective amount of hyaluronidase to reduce or eliminate hyaluronic acid-induced obstruction in one or more blood vessels in the region of the tissue affected by the obstruction. In some aspects of this embodiment, the number of doses administered in the multiple dose administration is, for example, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 15. In other aspects of this embodiment, the number of doses administered in the multiple dose administration is, for example, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, at most 12, at most 13, at most 14, or at most 15. In yet another aspect of this embodiment, the number of doses administered in the multiple dose administration is, for example, about 2 to about 3 times, about 2 to about 4 times, about 2 to about 5 times, about 2 to about 6 times, about 3 to about 4 times, about 3 to about 5 times, about 3 to about 6 times, about 4 to about 5 times, about 4 to about 6 times, about 5 to about 6 times, about 5 to about 7 times, about 5 to about 8 times, about 5 to about 9 times, about 5 to about 10 times, about 5 to about 11 times, about 6 to about 7 times, about 6 to about 8 times, about 6 to about 9 times, about 6 to about 10 times, about 6 to about 11 times, about 7 to about 8 times, about 7 to about 9 times, about 7 to about 10 times, about 7 to about 11 times, about 8 to about 9 times, about 8 to about 10 times, about 8 to about 11 times, about 9 to about 10 times, about 9 to about 11 times, about 10 to about 11 times, about 10 to about 12 times, about 10 to about 13 times, about 10 to about 14 times, about 10 to about 15 times, about 11 to about 12 times, about 11 to about 13 times, about 11 to about 14 times, about 11 to about 15 times, about 12 to about 13 times, about 12 to about 14 times, about 12 to about 15 times, about 13 to about 14 times, about 13 to about 15 times, or about 14 to about 15 times. In still other aspects of this embodiment, the number of doses administered in the multiple dose administration is, for example, about 2 to about 5 times, about 2 to about 10 times, about 2 to about 15 times, about 5 to about 10 times, about 5 to about 15 times, or about 10 to about 15 times.

[0051] Multiple doses of ultra-high concentration hyaluronidase-containing compositions used to effectively reduce or eliminate hyaluronic acid-induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction can include a total amount of hyaluronidase from about 250 IU / mL to about 500,000 IU / mL. In some aspects of this embodiment, multiple doses of ultra-high concentration hyaluronidase-containing compositions used to effectively reduce or eliminate hyaluronic acid-induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction can include, for example, at least 25,000 IU / mL, at least 50,000 IU / mL, at least 75,000 IU / mL, at least 100,000 IU / mL, at least 125,000 IU / mL, at least The composition can include a total amount of hyaluronidase that is 150,000 IU / mL, at least 175,000 IU / mL, at least 200,000 IU / mL, at least 225,000 IU / mL, at least 250,000 IU / mL, at least 300,000 IU / mL, at least 350,000 IU / mL, at least 400,000 IU / mL, at least 450,000 IU / mL or at least 500,000 IU / mL. In another aspect of this embodiment, multiple doses of a composition comprising ultra-high concentration hyaluronidase used to effectively reduce or eliminate hyaluronic acid-induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction can be, for example, at most 25,000 IU / mL, at most 50,000 IU / mL, at most 75,000 IU / mL, at most 100,000 IU / mL, at most 12 ... The composition can include a total amount of hyaluronidase that is 150,000 IU / mL, at most 175,000 IU / mL, at most 200,000 IU / mL, at most 225,000 IU / mL, at most 250,000 IU / mL, at most 300,000 IU / mL, at most 350,000 IU / mL, at most 400,000 IU / mL, at most 450,000 IU / mL or at most 500,000 IU / mL.

[0052] In yet another aspect of this embodiment, multiple doses of a composition comprising ultra-high concentration hyaluronidase used to effectively reduce or eliminate hyaluronic acid-induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction can be, for example, from about 25,000 IU / mL to about 50,000 IU / mL, from about 25,000 IU / mL to about 75,000 IU / mL, from about 25,000 IU / mL to about 100,000 IU / mL, from about 25,000 IU / mL to about 125,000 IU / mL, from about 25,000 IU / mL to about 150,000 IU / mL, from about 25,000 IU / mL to about 150,000 IU / mL, or from about 25,000 IU / mL to about 150,000 IU / mL. / mL ~ approx. 175,000IU / mL, approx. 25,000IU / mL ~ approx. 200,000IU / mL, approx. 25,000IU / mL ~ approx. 225,000IU / mL, approx. 25,000IU / mL ~ approx. 250,000IU / mL, approx. 25,000IU / mL ~ approx. 300,000IU / mL , about 25,000IU / mL to about 350,000IU / mL, about 25,000IU / mL to about 400,000IU / mL, about 25,000 IU / mL ~ approx. 450,000 IU / mL, approx. 25,000 IU / mL ~ approx. 500,000 IU / mL, approx. 50,000 IU / mL ~ approx. 75 ,000IU / mL, about 50,000IU / mL to about 100,000IU / mL, about 50,000IU / mL to about 125,000IU / m L, approx. 50,000IU / mL ~ approx. 150,000IU / mL, approx. 50,000IU / mL ~ approx. 175,000IU / mL, approx. 50,000 IU / mL~about 200,000IU / mL, about 50,000IU / mL~about 225,000IU / mL, about 50,000IU / mL~about 250,000IU / mL, about 50,000IU / mL~about 300,000IU / mL, about 50,000IU / mL~about 350,000IU / mL, approx. 50,000IU / mL ~ approx. 400,000IU / mL, approx. 50,000IU / mL ~ approx. 450,000IU / mL, approx. 50,000IU / mL ~ approx. 125,000IU / mL, approx. 75,000IU / mL ~ approx. 150,000IU / mL, approx. 75,000IU / mL ~ approx. 175,000I U / mL, about 75,000IU / mL to about 200,000IU / mL, about 75,000IU / mL to about 225,000IU / mL, about 75,000 IU / mL to approximately 250,000 IU / mL, approximately 75,000 IU / mL to approximately 300,000 IU / mL, approximately 75,000 IU / mL to approximately 350,000 IU / mL, approximately 75,000 IU / mL to approximately 400,000 IU / mL, approximately 75,000 IU / mL to approximately 450,000 IU / mL, approximately 75,000 IU / mL to approximately 500,000 IU / mL, approximately 100,000 IU / mL to approximately 125,000 IU / mL, approximately 100,000 IU / mL to approximately 150,000 IU / mL, approximately 100,000 IU / mL to approximately 175,000 IU / mL, approximately 100,000 IU / mL to approximately 200,000 IU / mL, approximately 100,000 IU / mL to approximately 225,000 IU / mL, approximately 100,000 IU / mL to approximately 250,000 IU / mL, approximately 100,000 IU / mL to approximately 300,000 IU / mL, approximately 100,000 IU / mL to approximately 350,000 IU / mL, approximately 100,000 IU / mL to approximately 400,000 IU / mL, approximately 100,000 IU / mL to approximately 450,000 IU / mL, approximately 100,000 IU / mL to approximately 500,000 IU / mL, approximately 150,000 IU / mL to approximately 200,000 IU / mL, approximately 150,000 IU / mL to approximately 225,000 IU / mL, approximately 150,000 IU / mL to approximately 250,000 IU / mL, approximately 150,000 IU / mL to approximately 300,000 IU / mL, approximately 150,000 IU / mL to approximately 350,000 IU / mL, approximately 150,000 IU / mL to approximately 400,000 IU / mL, approximately 150,000 IU / mL to approximately 450,000 IU / mL, approximately 150,000 IU / mL to approximately 500,000 IU / mL, approximately 200,000 IU / mL to approximately 225,000 IU / mL, approximately 200,000 IU / mL to approximately 250,000 IU / mL, approximately 200,000 IU / mL to approximately 300,000 IU / mL, approximately 200,000 IU / mL to approximately 350,000 IU / mL, approximately 200,000 IU / mL to approximately 400,000 IU / mL, approximately 200,000 IU / mL to approximately 450,000 IU / mL, approximately 200,000 IU / mL to approximately 500,000 IU / mL, approximately 250,000 IU / mL to approximately 300,000 IU / mL, approximately 250,000 IU / mL to approximately 350,000 IU / mL, approximately 250,000 IU / mL to approximately 400,000 IU / mL, approximately 250,000 IU / mL to approximately 450,000IU / mL, approx. 250,000IU / mL ~ approx. 500,000IU / mL, approx. 300,000IU / mL ~ approx. 350,000IU / mL, approx. 300,000IU / mL ~ approx. 400,0 00IU / mL, about 300,000IU / mL to about 450,000IU / mL, about 300,000IU / mL to about 500,000IU / mL, about 350,000IU / mL to about 400,000 The total amount of hyaluronidase may be about 350,000 IU / mL, about 350,000 IU / mL to about 450,000 IU / mL, about 350,000 IU / mL to about 500,000 IU / mL, about 400,000 IU / mL to about 450,000 IU / mL, about 400,000 IU / mL to about 500,000 IU / mL, or about 450,000 IU / mL to about 500,000 IU / mL.

[0053] In some aspects of this embodiment, multiple doses of a composition comprising ultra-high concentration hyaluronidase used to effectively reduce or eliminate hyaluronic acid induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction can include a total amount of hyaluronidase that is, for example, at least 10,000 IU / mL, at least 20,000 IU / mL, at least 30,000 IU / mL, at least 40,000 IU / mL, at least 50,000 IU / mL, at least 60,000 IU / mL, at least 70,000 IU / mL, at least 80,000 IU / mL, at least 90,000 IU / mL or at least 100,000 IU / mL. In other aspects of this embodiment, multiple doses of a composition comprising ultra-high concentration hyaluronidase used to effectively reduce or eliminate hyaluronic acid induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction can include a total amount of hyaluronidase that is, for example, at most 10,000 IU / mL, at most 20,000 IU / mL, at most 30,000 IU / mL, at most 40,000 IU / mL, at most 50,000 IU / mL, at most 60,000 IU / mL, at most 70,000 IU / mL, at most 80,000 IU / mL, at most 90,000 IU / mL or at most 100,000 IU / mL.

[0054] In yet another aspect of this embodiment, multiple doses of a composition comprising ultra-high concentration hyaluronidase used to effectively reduce or eliminate hyaluronic acid-induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction may be administered in doses of, for example, about 10,000 IU / mL to about 20,000 IU / mL, about 10,000 IU / mL to about 30,000 IU / mL, about 10,000 IU / mL to about 40,000 IU / mL, about 10,000 IU / mL to about 50,000 IU / mL, about 10,000 IU / mL to about 60,000 IU / mL, about 10,000 IU / mL to about 70,000 IU / mL, about 10,000 IU / mL to about 80,000 IU / mL, about 10,000 IU / mL to about 90,000 IU / mL, about 10,000 IU / mL to about 110,000 IU / mL, about 10,000 IU / mL to about 22,000 IU / mL, about 10,000 IU / mL to about 35,000 IU / mL, about 10,000 IU / mL to about 40,000 IU / mL, about 10,000 IU / mL to about 50,000 IU / mL, about 10,000 IU / mL to about 60,000 IU / mL, about 10,000 IU / mL to about 120,000 IU / mL, about 10,000 IU / mL to about 130,000 IU / mL, about 10,000 IU / mL to about 140,000 I ~70,000IU / mL, approximately 10,000IU / mL~approximately 80,000IU / mL, approximately 10,000IU / mL~approximately 90,000IU / mL, approximately 10,000IU / mL~approximately 100,000IU / mL, approximately 20,000IU / mL~approximately 30,000IU / mL, approximately 20,00 0IU / mL~Approx. 40,000IU / mL, Approx. 20,000IU / mL~Approx. 50,000IU / mL, Approx. 20,000IU / mL~Approx. 60,000IU / mL, Approx. 20,000IU / mL~Approx. 70,000IU / mL, Approx. 20,000IU / mL ~ approx. 90,000IU / mL, approx. 20,000IU / mL ~ approx. 100,000IU / mL, approx. 30,000IU / mL ~ approx. 40,000IU / mL, approx. 30,000IU / mL ~ approx. 50,000IU / mL, approx. 30,000IU / mL ~ approx. 60,000I U / mL, about 30,000IU / mL to about 70,000IU / mL, about 30,000IU / mL to about 80,000IU / mL, about 30,000IU / mL to about 90,000IU / mL, about 30,000IU / mL to about 100,000IU / mL, about 40,000IU / mL to about 5 0,000IU / mL, approximately 40,000IU / mL to approximately 60,000IU / mL, approximately 40,000IU / mL to approximately 70,000IU / mL , about 40,000IU / mL to about 80,000IU / mL, about 40,000IU / mL to about 90,000IU / mL, about 40,000IU / mL~about 100,000IU / mL, about 50,000IU / mL~about 60,000IU / mL, about 50,000IU / mL~about 70,000IU / mL, about 50,000IU / mL~about 80,000IU / mL, about 50,000IU / mL~about 90,000IU / mL, about 50,000IU / mL ~ approx. 100,000IU / mL, approx. 60,000IU / mL ~ approx. 70,000IU / mL, approx. 60,000IU / mL ~ approx. 80,000IU / mL, approx. 60 ,000IU / mL ~ approx. 90,000IU / mL, approx. 60,000IU / mL ~ approx. 100,000IU / mL, approx. 70,000IU / mL ~ approx. 80,000IU / mL, approx. 7 The total amount of hyaluronidase may be 0,000 IU / mL to about 90,000 IU / mL, about 70,000 IU / mL to about 100,000 IU / mL, about 80,000 IU / mL to about 90,000 IU / mL, about 80,000 IU / mL to about 100,000 IU / mL, or about 90,000 IU / mL to about 100,000 IU / mL.

[0055] In some aspects of this embodiment, multiple doses of a composition comprising ultra-high concentration hyaluronidase used to effectively reduce or eliminate hyaluronic acid-induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction can be, for example, at least 5,000 IU / mL, at least 6,000 IU / mL, at least 7,000 IU / mL, at least 8,000 IU / mL, at least 9,000 IU / mL, at least 10,000 IU / mL, at least 12,000 IU / mL, at least 14,000 IU / mL, at least 16,000 IU / mL, at least 18,000 IU / mL, at least 19,000 IU / mL, at least 20,000 IU / mL, at least 21,000 IU / mL, at least 22,000 IU / mL, at least 23,000 IU / mL, at least 24,000 IU / mL, at least 25,000 IU / mL, at least 26,000 IU / mL, at least 27,000 IU / mL, at least 28,000 IU / mL, at least 30,000 IU / mL, at least 31,000 IU / mL, at least 32,000 IU / mL, at least 33,000 IU / mL, at least 34,000 IU / mL, at least 35,000 IU / mL, at least 36,000 IU / mL, at least 37,000 IU / mL, at least 38,000 IU / mL, at least 39,000 IU / mL, at least 40,000 IU / mL, at least 40,000 IU / mL, at least 40 The enzyme may comprise a total amount of hyaluronidase that is at least 11,000 IU / mL, at least 12,000 IU / mL, at least 13,000 IU / mL, at least 14,000 IU / mL, at least 15,000 IU / mL, at least 16,000 IU / mL, at least 17,000 IU / mL, at least 18,000 IU / mL, at least 19,000 IU / mL or at least 20,000 IU / mL. In another aspect of this embodiment, multiple doses of a composition comprising ultra-high concentration hyaluronidase used to effectively reduce or eliminate hyaluronic acid-induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction can be, for example, at most 5,000 IU / mL, at most 6,000 IU / mL, at most 7,000 IU / mL, at most 8,000 IU / mL, at most 9,000 IU / mL, at most 10,000 IU / mL, at most 12,000 IU / mL, at most 16,000 IU / mL, at most 18,000 IU / mL, at most 19,000 IU / mL, at most 21,000 IU / mL, at most 22,000 IU / mL, at most 23,000 IU / mL, at most 24,000 IU / mL, at most 25,000 IU / mL, at most 26,000 IU / mL, at most 27,000 IU / mL, at most 28,000 IU / mL, at most 30,000 IU / mL, at most 31,000 IU / mL, at most 32,000 IU / mL, at most 33,000 IU / mL, at most 34,000 IU / mL, at most 35,000 IU / mL, at most 36,000 IU / mL, at most 37,000 IU / mL, at most 38,000 IU / mL, at most 39,000 IU / mL, at most 40,000 IU / mL, at most 41,000 IU / mL, at most 42,000 IU / mL, at most 43,000 IU / mL, at most 44 The invention can include a total amount of hyaluronidase that is at most 11,000 IU / mL, at most 12,000 IU / mL, at most 13,000 IU / mL, at most 14,000 IU / mL, at most 15,000 IU / mL, at most 16,000 IU / mL, at most 17,000 IU / mL, at most 18,000 IU / mL, at most 19,000 IU / mL or at most 20,000 IU / mL.

[0056] In yet another aspect of this embodiment, multiple doses of a composition comprising ultra-high concentration hyaluronidase used to effectively reduce or eliminate hyaluronic acid-induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction may be administered in doses of, for example, about 5,000 IU / mL to about 6,000 IU / mL, about 5,000 IU / mL to about 7,000 IU / mL, about 5,000 IU / mL to about 8,000 IU / mL, about 5,000 IU / mL to about 9,000 IU / mL, about 5,000 IU / mL to about 10,000 IU / mL, about 5,000 IU / mL to about 11,000 IU / mL, or about 5,000 IU / mL to about 12,000 IU / mL. mL, approximately 5,000IU / mL to approximately 12,000IU / mL, approximately 5,000IU / mL to approximately 13,000IU / mL, approximately 5,000IU / mL to approximately 14,000IU / mL, approximately 5,000IU / mL to approximately 15,000IU / mL, approximately 5,000IU / mL to approximately 16,000IU / mL, approximately 5,000IU / mL to approximately 17,000IU / mL, approximately 5,000IU / mL to approximately 18,000IU / mL, approximately 5,000IU / mL to approximately 19,000IU / mL, approximately 5,000IU / mL to approximately 20,000IU / mL, approximately 6,000IU / mL to approximately 7,000IU / m L, about 6,000IU / mL to about 8,000IU / mL, about 6,000IU / mL to about 9,000IU / mL, about 6,000IU / mL to about 10,000IU / mL, about 6,000IU / mL to about 11,000IU / mL, about 6,000IU / mL to about 12,000IU / mL, Approximately 6,000IU / mL to approximately 13,000IU / mL, approximately 6,000IU / mL to approximately 14,000IU / mL, approximately 6,000IU / mL to approximately 15,000IU / mL, approximately 6,000IU / mL to approximately 16,000IU / mL, approximately 6,000IU / mL to approximately 17,000IU / mL, Approximately 6,000IU / mL to approximately 18,000IU / mL, approximately 6,000IU / mL to approximately 19,000IU / mL, approximately 6,000IU / mL to approximately 20,000IU / mL, approximately 7,000IU / mL to approximately 8,000IU / mL, approximately 7,000IU / mL to approximately 9,000IU / mL, approximately 7 ,000IU / mL ~ approx. 10,000IU / mL, approx. 7,000IU / mL ~ approx. 11,000IU / mL, approx. 7,000IU / mL ~ approx. 12 ,000IU / mL, about 7,000IU / mL to about 13,000IU / mL, about 7,000IU / mL to about 14,000IU / mL, about 7,000 IU / mL to approximately 15,000 IU / mL, approximately 7,000 IU / mL to approximately 16,000 IU / mL, approximately 7,000 IU / mL to approximately 17,000 IU / mL, approximately 7,000 IU / mL to approximately 18,000 IU / mL, approximately 7,000 IU / mL to approximately 19,000 IU / mL, approximately 7,000 IU / mL to approximately 20,000 IU / mL, approximately 8,000 IU / mL to approximately 9,000 IU / mL, approximately 8,000 IU / mL to approximately 10,000 IU / mL, approximately 8,000 IU / mL to approximately 11,000 IU / mL, approximately 8,000 IU / mL to approximately 12,000 IU / mL, approximately 8,000 IU / mL to approximately 13,000 IU / mL, approximately 8,000 IU / mL to approximately 14,000 IU / mL, approximately 8,000 IU / mL to approximately 15,000 IU / mL, approximately 8,000 IU / mL to approximately 16,000 IU / mL, approximately 8,000 IU / mL to approximately 17,000 IU / mL, approximately 8,000 IU / mL to approximately 18,000 IU / mL, approximately 8,000 IU / mL to approximately 19,000 IU / mL, approximately 8,000 IU / mL to approximately 20,000 IU / mL, approximately 9,000 IU / mL to approximately 10,000 IU / mL, approximately 9,000 IU / mL to approximately 11,000 IU / mL, approximately 9,000 IU / mL to approximately 12,000 IU / mL, approximately 9,000 IU / mL to approximately 13,000 IU / mL, approximately 9,000 IU / mL to approximately 14,000 IU / mL, approximately 9,000 IU / mL to approximately 15,000 IU / mL, approximately 9,000 IU / mL to approximately 16,000 IU / mL, approximately 9,000 IU / mL to approximately 17,000 IU / mL, approximately 9,000 IU / mL to approximately 18,000 IU / mL, approximately 9,000 IU / mL to approximately 19,000 IU / mL, approximately 9,000 IU / mL to approximately 20,000 IU / mL, approximately 10,000 IU / mL to approximately 11,000 IU / mL, approximately 10,000 IU / mL to approximately 12,000 IU / mL, approximately 10,000 IU / mL to approximately 13,000 IU / mL, approximately 10,000 IU / mL to approximately 14,000 IU / mL, approximately 10,000 IU / mL to approximately 15,000 IU / mL, approximately 10,000 IU / mL to approximately 16,000 IU / mL, approximately 10,000 IU / mL to approximately 17,000 IU / mL, approximately 10,000 IU / mL to approximately 18,000 IU / mL, approximately 10,000 IU / mL to approximately 19,000 IU / mL, approximately 10,000 IU / mL to approximately 20,000 IU / mL, approximately 11,000 IU / mL to approximately 12,000 IU / mL, from about 11,000 IU / mL to about 13,000 IU / mL, from about 11,000 IU / mL to about 14,000 IU / mL, from about 11,000 IU / mL to about 15,000 IU / mL, from about 11,000 IU / mL to about 16,000 IU / mL, from about 11,000 IU / mL to about 17,000 IU / mL, from about 11,000 IU / mL to about 18,000 IU / mL, from about 11,000 IU / mL to about 19,000 IU / mL, from about 11,000 IU / mL to about 20,000 IU / mL, from about 12,000 IU / mL to about 13,000 IU / mL, from about 12,000 IU / mL to about 14,000 IU / mL, from about 12,000 IU / mL to about 15,000 IU / mL, from about 12,000 IU / mL to about 16,000 IU / mL, from about 12,000 IU / mL to about 17,000 IU / mL, from about 12,000 IU / mL to about 18,000 IU / mL, from about 12,000 IU / mL to about 19,000 IU / mL, from about 12,000 IU / mL to about 20,000 IU / mL, from about 13,000 IU / mL to about 14,000 IU / mL, from about 13,000 IU / mL to about 15,000 IU / mL, from about 13,000 IU / mL to about 16,000 IU / mL, from about 13,000 IU / mL to about 17,000 IU / mL, from about 13,000 IU / mL to about 18,000 IU / mL, from about 13,000 IU / mL to about 19,000 IU / mL, from about 13,000 IU / mL to about 20,000 IU / mL, from about 14,000 IU / mL to about 15,000 IU / mL, from about 14,000 IU / mL to about 16,000 IU / mL, from about 14,000 IU / mL to about 17,000 IU / mL, from about 14,000 IU / mL to about 18,000 IU / mL, from about 14,000 IU / mL to about 19,000 IU / mL, from about 14,000 IU / mL to about 20,000 IU / mL, from about 15,000 IU / mL to about 16,000 IU / mL, from about 15,000 IU / mL to about 17,000 IU / mL, from about 15,000 IU / mL to about 18,000 IU / mL, from about 15,000 IU / mL to about 19,000 IU / mL, from about 15,000 IU / mL to about 20,000 IU / mL, from about 16,000 IU / mL to about 17,000 IU / mL, from about 16,000 IU / mL to about 18,000 IU / mL, from about 16,000 IU / mL to about 19,000 IU / mL, from about 16,000 IU / mL to about 20,000 IU / mL, from about 17,The composition may contain a total amount of hyaluronidase that is about 1,000 IU / mL to about 18,000 IU / mL, about 17,000 IU / mL to about 19,000 IU / mL, about 17,000 IU / mL to about 20,000 IU / mL, about 18,000 IU / mL to about 19,000 IU / mL, about 18,000 IU / mL to about 20,000 IU / mL, or about 19,000 IU / mL to about 20,000 IU / mL.

[0057] In some aspects of this embodiment, multiple doses of a composition comprising ultra-high concentration hyaluronidase used to effectively reduce or eliminate hyaluronic acid induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction can include a total amount of hyaluronidase that is, for example, at least 250 IU / mL, at least 500 IU / mL, at least 750 IU / mL, at least 1,000 IU / mL, at least 1,500 IU / mL, at least 2,000 IU / mL, at least 2,500 IU / mL, at least 3,000 IU / mL, at least 3,500 IU / mL, at least 4,000 IU / mL, at least 4,500 IU / mL or at least 5,000 IU / mL. In other aspects of this embodiment, multiple doses of a composition comprising ultra-high concentration hyaluronidase used to effectively reduce or eliminate hyaluronic acid induced obstruction in one or more blood vessels in the region of tissue affected by the obstruction can include a total amount of hyaluronidase that is, for example, at most 250 IU / mL, at most 500 IU / mL, at most 750 IU / mL, at most 1,000 IU / mL, at most 1,500 IU / mL, at most 2,000 IU / mL, at most 2,500 IU / mL, at most 3,000 IU / mL, at most 3,500 IU / mL, at most 4,000 IU / mL, at most 4,500 IU / mL or at most 5,000 IU / mL.

[0058] In yet another aspect of this embodiment, multiple doses of a composition comprising ultra-high concentration hyaluronidase used to effectively reduce or eliminate hyaluronic acid-induced obstruction in one or more blood vessels in the region of the tissue affected by the obstruction can be, for example, from about 250 IU / mL to about 500 IU / mL, from about 250 IU / mL to about 750 IU / mL, from about 250 IU / mL to about 1,000 IU / mL, from about 250 IU / mL to about 1,500 IU / mL, from about 250 IU / mL to about 2,000 IU / mL, from about 250 IU / mL to about 2,500 IU / mL, from about 250 IU / mL to about 3, 000IU / mL, about 250IU / mL to about 3,500IU / mL, about 250IU / mL to about 4,000IU / mL, about 250IU / mL to about 4,500IU / mL, about 250IU / mL to about 5,000IU / mL, about 500IU / mL to about 750IU / mL, about 500IU / mL mL~about 1,000IU / mL, about 500IU / mL~about 1,500IU / mL, about 500IU / mL~about 2,000IU / mL, about 500IU / mL~about 2,500IU / mL, about 500IU / mL~about 3,000IU / mL, about 500IU / mL~about 3,500IU / mL , about 500IU / mL to about 4,000IU / mL, about 500IU / mL to about 4,500IU / mL, about 500IU / mL to about 5,000IU / mL, about 750IU / mL to about 1,000IU / mL, about 750IU / mL to about 1,500IU / mL, about 750IU / mL to about 2, 000IU / mL, about 750IU / mL to about 2,500IU / mL, about 750IU / mL to about 3,000IU / mL, about 750IU / mL to about 3,500IU / mL, about 750IU / mL to about 4,000IU / mL, about 750IU / mL to about 4,500IU / mL, about 750I U / mL~about 5,000IU / mL, about 1,000IU / mL~about 1,500IU / mL, about 1,000IU / mL~about 2,000IU / mL, about 1,000IU / mL~about 2,500IU / mL, about 1,000IU / mL~about 3,000IU / mL, about 1,000IU / mL ~3,500IU / mL, 1,000IU / mL~4,000IU / mL, 1,000IU / mL~4,500IU / mL, 1,000IU / mL~5,000IU / mL, 1,500IU / mL~2,000IU / mL, 1,500IU / mL~2,500IU / mL, approximately 1,500IU / mL to approximately 3,000IU / mL, approximately 1,500IU / mL to approximately 3,500IU / mL, approximately 1,500IU / mL to approximately 4,000IU / mL, approximately 1,500IU / mL ~ approx. 4,500IU / mL, approx. 1,500IU / mL ~ approx. 5,000IU / mL, approx. 2,000IU / mL ~ approx. 2,500IU / mL, approx. 2,000IU / mL ~3,000IU / mL, approximately 2,000IU / mL~approximately 3,500IU / mL, approximately 2,000IU / mL~approximately 4,000IU / mL, approximately 2,000IU / mL~approximately 4,500IU / mL, approximately 2,000IU / mL to approximately 5,000IU / mL, approximately 2,500IU / mL to approximately 3,000IU / mL, approximately 2,500IU / mL to approximately 3,500IU / mL, approximately 2,500IU / mL ~ approx. 4,000IU / mL, approx. 2,500IU / mL ~ approx. 4,500IU / mL, approx. 2,500IU / mL ~ approx. 5,000IU / mL, approx. 3,000IU / mL ~ approx. 3,500 IU / mL, about 3,000IU / mL to about 4,000IU / mL, about 3,000IU / mL to about 4,500IU / mL, about 3,000IU / mL to about 5,000IU / mL, about 3,5 The composition may contain a total amount of hyaluronidase ranging from about 00 IU / mL to about 4,000 IU / mL, about 3,500 IU / mL to about 4,500 IU / mL, about 3,500 IU / mL to about 5,000 IU / mL, about 4,000 IU / mL to about 4,500 IU / mL, about 4,000 IU / mL to about 5,000 IU / mL, or about 4,500 IU / mL to about 5,000 IU / mL.

[0059] The tissue affected by a particular hyaluronic acid-induced occlusion of one or more blood vessels will affect how quickly administration of ultra-high concentration hyaluronidase must occur to avoid irreversible damage to that tissue. For example, certain tissues can be designated as hypersensitive tissues. Hypersensitive tissues are typically well-differentiated tissues that are highly sensitive to oxygen deprivation and will suffer irreversible damage if blood flow is not restored within about 5-15 minutes. For example, brain tissue is highly susceptible to damage if blood is not reperfused within about 5 minutes. Similarly, retinal tissues are highly sensitive to interruption of blood flow even when not suffering from irreversible damage, and studies suggest that irreversible damage can occur within about 5-15 minutes.

[0060] In contrast, hyposensitive tissues are generally classified as less well differentiated and are able to avoid irreversible damage during interruption of blood flow for a much longer period of time than hypersensitive tissues can: tissues such as skin, muscle, fat, and bone can avoid irreversible damage during interruption of blood flow for long periods of time (hours to days, but no one knows for sure) before suffering irreversible damage.

[0061] Ideally, it is advantageous to restore blood flow to all tissue types as quickly as possible when an interruption in blood flow occurs. Although less sensitive tissues may be able to avoid irreparable damage for a longer period of time than more sensitive tissues during an interruption in blood flow, it is best to reperfuse all tissue types as quickly as possible to minimize the risk of irreparable damage.

[0062] The compositions comprising ultra-high concentrations of hyaluronidase disclosed herein are formulated to spread rapidly to the area of ​​tissue affected by the obstruction. Such rapid spread ensures that a sufficient amount of hyaluronidase is delivered to one or more blood vessels supplying blood to the affected tissue within about 90 minutes. In some aspects of this embodiment, the compositions comprising ultra-high concentrations of hyaluronidase disclosed herein are formulated to spread rapidly to the area of ​​tissue affected by the obstruction, for example, in no more than 15 minutes, no more than 30 minutes, no more than 45 minutes, no more than 60 minutes, no more than 75 minutes, or no more than 90 minutes. In another aspect of this embodiment, the composition comprising the ultra-high concentration hyaluronidase disclosed herein can be, for example, from about 5 minutes to about 10 minutes, from about 5 minutes to about 15 minutes, from about 5 minutes to about 30 minutes, from about 5 to about 45 minutes, from about 5 to about 60 minutes, from about 5 to about 75 minutes, from about 5 to about 90 minutes, from about 10 minutes to about 15 minutes, from about 10 minutes to about 30 minutes, from about 10 to about 45 minutes, from about 10 to about 60 minutes, from about 10 to about 75 minutes, from about 10 to about 90 minutes, from about 15 minutes to about 30 minutes, from about 15 to about 45 minutes, from about 15 to about 60 minutes, The composition is formulated to rapidly spread to the area of ​​tissue affected by the occlusion in about 15 to about 75 minutes, about 15 to about 90 minutes, about 15 to about 45 minutes, about 15 to about 60 minutes, about 15 to about 75 minutes, or about 15 to about 90 minutes, about 30 to about 45 minutes, about 30 to about 60 minutes, about 30 to about 75 minutes, about 30 to about 90 minutes, about 45 to about 60 minutes, about 45 to about 75 minutes, about 45 to about 90 minutes, about 60 to about 75 minutes, about 60 to about 90 minutes, or about 75 to about 90 minutes.

[0063] In some embodiments, rapid spreading ensures that a sufficient amount of hyaluronidase is delivered to one or more blood vessels supplying blood to the affected area of ​​tissue within about 5 to about 15 minutes. In some aspects of this embodiment, compositions comprising ultra-high concentration hyaluronidase disclosed herein are formulated to rapidly spread to the area of ​​tissue affected by the obstruction, for example, in at most 1 minute, at most 2 minutes, at most 3 minutes, at most 4 minutes, at most 5 minutes, at most 10 minutes, or at most 15 minutes. In other aspects of this embodiment, compositions comprising ultra-high concentration hyaluronidase disclosed herein are formulated to rapidly spread to the area of ​​tissue affected by the occlusion, for example, in about 1 minute to about 3 minutes, about 1 minute to about 5 minutes, about 1 minute to about 7 minutes, about 1 minute to about 10 minutes, about 1 minute to about 15 minutes, about 3 minutes to about 5 minutes, about 3 minutes to about 7 minutes, about 3 minutes to about 10 minutes, about 3 minutes to about 15 minutes, about 5 minutes to about 7 minutes, about 5 minutes to about 10 minutes, about 5 minutes to about 15 minutes, or about 10 minutes to about 15 minutes.

[0064] The volume of the composition comprising ultra-high concentration hyaluronidase delivered to the area of ​​tissue affected by the obstruction may range from about 0.5 mL to about 5.0 mL. In some aspects of this embodiment, the volume of the composition comprising ultra-high concentration hyaluronidase delivered to the area of ​​tissue affected by the obstruction may be, for example, at least 0.5 mL, at least 1.0 mL, at least 2.0 mL, at least 3.0 mL, at least 4.0 mL, or at least 5.0 mL. In other aspects of this embodiment, the volume of the composition comprising ultra-high concentration hyaluronidase delivered to the area of ​​tissue affected by the obstruction may be, for example, at most 0.5 mL, at most 1.0 mL, at most 2.0 mL, at most 3.0 mL, at most 4.0 mL, or at most 5.0 mL. In yet other aspects of this embodiment, the volume of the composition comprising ultra-high concentration hyaluronidase delivered to the area of ​​tissue affected by the occlusion can be, for example, about 0.5 mL to 1.0 mL, about 0.5 mL to 2.0 mL, about 0.5 mL to 3.0 mL, about 0.5 mL to 4.0 mL, about 0.5 mL to 5.0 mL, about 1.0 mL to 2.0 mL, about 1.0 mL to 3.0 mL, about 1.0 mL to 4.0 mL, about 1.0 to 5.0 mL, about 2.0 mL to 3.0 mL, about 2.0 mL to 4.0 mL, about 2.0 to 5.0 mL, about 3.0 mL to 4.0 mL, about 3.0 to 5.0 mL, or about 4.0 to 5.0 mL.

[0065] Some embodiments of the present specification disclose a delivery system.Non-limiting examples of delivery systems include manual injection devices, such as needle and syringe or ADG needle, and automatic injection devices, such as autoinjectors.Non-limiting examples of needle gauges useful for delivery systems, such as manual or automatic injection devices, include 21 gauge, 22 gauge, 23 gauge, 24 gauge, 25 gauge, 26 gauge, 27 gauge, 28 gauge, 29 gauge, 30 gauge, 31 gauge, 32 gauge and 33 gauge.

[0066] Some embodiments of the present disclosure disclose methods of reducing or eliminating hyaluronic acid-induced blockage in one or more blood vessels supplying blood to an area of ​​tissue. The disclosed methods include administering to an individual a composition comprising ultra-high concentration hyaluronidase in a manner to reduce or eliminate hyaluronic acid-induced blockage in one or more blood vessels supplying blood to an area of ​​tissue affected by said blockage. In some embodiments, the disclosed methods administer a composition comprising ultra-high concentration hyaluronidase to the dermis portion of a skin area. In other embodiments, the disclosed methods administer a composition comprising ultra-high concentration hyaluronidase using a delivery system disclosed herein. The disclosed methods can administer a composition comprising ultra-high concentration hyaluronidase in a single or multiple doses of hyaluronidase ranging from about 10,000 IU to about 20,000 IU.

[0067] In some aspects of this embodiment, reducing or eliminating hyaluronic acid-induced obstruction in one or more blood vessels supplying a region of tissue reduces or inhibits one or more physiological conditions or symptoms associated with hyaluronic acid-induced obstruction, e.g., by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% or more. In other aspects of this embodiment, reducing or eliminating hyaluronic acid-induced obstruction in one or more blood vessels supplying a region of tissue reduces or inhibits one or more physiological conditions or symptoms associated with hyaluronic acid-induced obstruction, e.g., by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100%. In yet another aspect of this embodiment, reducing or eliminating hyaluronic acid induced occlusion in one or more blood vessels supplying blood to a region of tissue can reduce or eliminate one or more physiological conditions or symptoms associated with hyaluronic acid induced occlusion, for example, by about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 20% to about 30%, about 30% to about 100%, about 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 5 Reduce or inhibit by 0% to about 80%, about 50% to about 70%, about 50% to about 60%, about 60% to about 100%, about 60% to about 90%, about 60% to about 80%, about 60% to about 70%, about 70% to about 100%, about 70% to about 90%, about 70% to about 80%, about 80% to about 100%, about 80% to about 90%, or about 90% to about 100%.In yet other aspects of this embodiment, reducing or eliminating hyaluronic acid induced obstruction in one or more blood vessels supplying blood to a region of tissue reduces or inhibits one or more physiological conditions or symptoms associated with hyaluronic acid induced obstruction, e.g., for at least 1 week, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months.

[0068] Some embodiments herein disclose methods of reducing or inhibiting vascular occlusion in an area of ​​tissue in an individual in need thereof. Vascular occlusion is reduced or inhibited by reducing or eliminating hyaluronic acid-induced occlusion in one or more blood vessels supplying blood to an area of ​​tissue affected by said occlusion. The disclosed methods include administering a composition comprising ultra-high concentration hyaluronidase to an individual in a manner to reduce or eliminate hyaluronic acid-induced occlusion in one or more blood vessels supplying blood to an area of ​​tissue affected by said occlusion, thereby reducing or inhibiting vascular occlusion in the area of ​​tissue. In some embodiments, the disclosed methods administer a composition comprising ultra-high concentration hyaluronidase to a dermal portion of a skin area. In other embodiments, the disclosed methods administer a composition comprising ultra-high concentration hyaluronidase using a delivery system disclosed herein. The disclosed methods can administer a composition comprising ultra-high concentration hyaluronidase in a single or multiple doses of hyaluronidase ranging from about 10,000 IU to about 20,000 IU.

[0069] In some aspects of this embodiment, reducing or inhibiting vascular occlusion in the region of the tissue reduces or inhibits one or more physiological conditions or symptoms associated with hyaluronic acid-induced occlusion in one or more blood vessels, e.g., by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%. In other aspects of this embodiment, reducing or inhibiting vascular occlusion in the region of the tissue reduces or inhibits one or more physiological conditions or symptoms associated with hyaluronic acid-induced occlusion in one or more blood vessels, e.g., by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100%. In yet another aspect of this embodiment, reducing or inhibiting vascular occlusion in a region of tissue means reducing or inhibiting one or more physiological conditions or symptoms associated with hyaluronic acid-induced occlusion in one or more blood vessels, for example, by about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 20% to about 30%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, about 30% to about 50%, about 30% to about 40%, about 40% to about 100%, about 40% to about 90%, about 40% to about 80%, about 40% to about 70%, about 40% to about 60%, about 40% to about 50%, about 50% to about 100%, about 50% to about 90%, about 50% Reduce or inhibit by about 80%, about 50% to about 70%, about 50% to about 60%, about 60% to about 100%, about 60% to about 90%, about 60% to about 80%, about 60% to about 70%, about 70% to about 100%, about 70% to about 90%, about 70% to about 80%, about 80% to about 100%, about 80% to about 90%, or about 90% to about 100%.In yet other aspects of this embodiment, reducing or inhibiting vascular occlusion in a region of tissue reduces or inhibits one or more physiological conditions or symptoms associated with hyaluronic acid-induced occlusion in one or more blood vessels, for example, for at least 1 week, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months.

[0070] Some aspects of the present disclosure disclose a method for reducing or inhibiting hyaluronic acid-induced tissue loss in an individual in need thereof. Hyaluronic acid-induced tissue loss is reduced or inhibited by reducing or eliminating hyaluronic acid-induced blockage in one or more blood vessels that supply blood to the region of tissue affected by the blockage. The method of the present disclosure includes administering a composition comprising ultra-high concentration hyaluronidase to an individual in a manner that reduces or eliminates hyaluronic acid-induced blockage in one or more blood vessels that supply blood to the region of tissue affected by the blockage, thereby reducing or inhibiting hyaluronic acid-induced tissue loss in the individual. In some aspects, the method of the present disclosure administers a composition comprising hyaluronidase to the dermis portion of the skin region. In other aspects, the method of the present disclosure administers a composition comprising ultra-high concentration hyaluronidase using a delivery system disclosed herein. The methods of the disclosure can administer compositions containing ultra-high concentration hyaluronidase in single or multiple doses ranging from about 10,000 IU to about 20,000 IU of hyaluronidase.

[0071] In some embodiments, where the methods disclosed herein include multiple doses of ultra-high concentration hyaluronidase, such administration can be done in rapid succession. In some aspects of these embodiments, 2-10 doses of the composition comprising ultra-high concentration hyaluronidase can be administered to the area of ​​tissue affected by the obstruction within 5-15 minutes. In other aspects of these embodiments, 2-7 doses of the composition comprising ultra-high concentration hyaluronidase can be administered to the area of ​​tissue affected by the obstruction within 5-15 minutes. In still other aspects of these embodiments, 2-5 doses of the composition comprising ultra-high concentration hyaluronidase can be administered to the area of ​​tissue affected by the obstruction within 5-15 minutes. In yet other aspects of these embodiments, 2-3 doses of the composition comprising ultra-high concentration hyaluronidase can be administered to the area of ​​tissue affected by the obstruction within 5-15 minutes. In still other aspects of these embodiments, two doses of a composition comprising ultra-high concentration hyaluronidase can be administered within 5 to 15 minutes to the area of ​​tissue affected by the obstruction.

[0072] In some aspects of this embodiment, reducing or eliminating hyaluronic acid-induced obstruction in one or more blood vessels supplying a region of tissue restores or maintains one or more qualitative or quantitative aspects of tissue health, e.g., by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%. In other aspects of this embodiment, reducing or eliminating hyaluronic acid-induced obstruction in one or more blood vessels supplying a region of tissue restores or maintains one or more qualitative or quantitative aspects of tissue health, e.g., by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100%. In yet another aspect of this embodiment, reducing or eliminating hyaluronic acid induced obstruction in one or more blood vessels supplying blood to a region of tissue can improve one or more qualitative or quantitative aspects of tissue health, e.g., by about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 20% to about 30%, about 30% to about 100%, about 30% to about 100%, or about 30% to about 100%. About 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, about 30% to about 50%, about 30% to about 40%, about 40% to about 100%, about 40% to about 90%, about 40% to about 80%, about 40% to about 70%, about 40% to about 60%, about 40% to about 50%, about 50% to about 100%, about 50% to about 90%, about 50% about 80%, about 50% to about 70%, about 50% to about 60%, about 60% to about 100%, about 60% to about 90%, about 60% to about 80%, about 60% to about 70%, about 70% to about 100%, about 70% to about 90%, about 70% to about 80%, about 80% to about 100%, about 80% to about 90% or about 90% to about 100% recovery or maintenance.In yet other aspects of this embodiment, reducing or eliminating hyaluronic acid-induced obstruction in one or more blood vessels supplying blood to an area of ​​tissue restores or maintains one or more qualitative or quantitative aspects of tissue health, e.g., for at least 1 week, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months.

[0073] The methods disclosed herein reduce or eliminate hyaluronic acid-induced obstruction in one or more blood vessels supplying blood to an area of ​​tissue. In some embodiments, the methods disclosed herein reduce or eliminate hyaluronic acid-induced obstruction in one or more blood vessels supplying blood to an area of ​​tissue affected by the obstruction in a time frame that prevents, reduces or stops necrosis, nerve damage or other organ or tissue damage.

[0074] In some embodiments, the methods disclosed herein reduce or eliminate hyaluronic acid-induced occlusion in one or more blood vessels supplying blood to a region of tissue within about 90 minutes. In some aspects of the present embodiments, hyaluronic acid-induced occlusion in one or more blood vessels supplying blood to a region of tissue is reduced or eliminated in, for example, at most 15 minutes, at most 30 minutes, at most 45 minutes, at most 60 minutes, at most 75 minutes, or at most 90 minutes. In other aspects of the present embodiments, hyaluronic acid-induced occlusion in one or more blood vessels supplying blood to a region of tissue is reduced or eliminated in, for example, about 5 minutes to about 10 minutes, about 5 minutes to about 15 minutes, about 5 minutes to about 30 minutes, about 5 minutes to about 45 minutes, about 5 minutes to about 60 minutes, about 5 minutes to about 75 minutes, about 5 minutes to about 90 minutes, about 10 minutes to about 15 minutes, about 10 minutes to about 30 minutes, about 10 minutes to about 45 minutes, about 10 minutes to about 60 minutes, about 10 minutes to about 75 minutes, about Reduced or eliminated in 10 to about 90 minutes, about 15 to about 30 minutes, about 15 to about 45 minutes, about 15 to about 60 minutes, about 15 to about 75 minutes, about 15 to about 90 minutes, about 30 to about 45 minutes, about 30 to about 60 minutes, about 30 to about 75 minutes, about 30 to about 90 minutes, about 45 to about 60 minutes, about 45 to about 75 minutes, about 45 to about 90 minutes, about 60 to about 75 minutes, about 60 to about 90 minutes or about 75 to about 90 minutes.

[0075] In some embodiments, the methods disclosed herein reduce or eliminate hyaluronic acid-induced occlusion in one or more blood vessels supplying a region of tissue within about 5 to about 15 minutes. In some aspects of the present embodiments, hyaluronic acid-induced occlusion in one or more blood vessels supplying a region of tissue is reduced or eliminated in, for example, at most 1 minute, at most 2 minutes, at most 3 minutes, at most 4 minutes, at most 5 minutes, at most 10 minutes, or at most 15 minutes. In other aspects of this embodiment, hyaluronic acid induced occlusion in one or more blood vessels supplying blood to a region of tissue is reduced or eliminated in, for example, about 1 minute to about 3 minutes, about 1 minute to about 5 minutes, about 1 minute to about 7 minutes, about 1 minute to about 10 minutes, about 1 minute to about 15 minutes, about 3 minutes to about 5 minutes, about 3 minutes to about 7 minutes, about 3 minutes to about 10 minutes, about 3 minutes to about 15 minutes, about 5 minutes to about 7 minutes, about 5 minutes to about 10 minutes, about 5 minutes to about 15 minutes, about 7 minutes to about 10 minutes, about 7 minutes to about 15 minutes, or about 10 minutes to about 15 minutes.

[0076] Some aspects of the present disclosure disclose kits. In one embodiment, the kit may include a container containing a composition comprising the ultra-high concentration hyaluronidase disclosed herein. In another embodiment, the kit may include multiple containers, each such container containing a composition comprising the ultra-high concentration hyaluronidase disclosed herein. For example, the kit may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more containers, each such container containing a composition comprising the ultra-high concentration hyaluronidase disclosed herein. Each of the containers of the present disclosure may contain a single dose of a composition comprising the ultra-high concentration hyaluronidase disclosed herein, multiple doses of a composition comprising the ultra-high concentration hyaluronidase disclosed herein, or a combination thereof. Each of the containers of the present disclosure may also contain a composition comprising the ultra-high concentration hyaluronidase disclosed herein in liquid or dry form.

[0077] In some embodiments, the containers disclosed herein may be vials or similar containers containing compositions comprising ultra-high concentration hyaluronidase as disclosed herein, where such compositions comprising ultra-high concentration hyaluronidase as disclosed herein require transfer to a delivery system, such as, for example, a manual or automatic injection device. In some embodiments, the kits may include one or more vials, e.g., 1-20 vials, 7-15 vials, 8-12 vials, or 10 vials, each such vial containing a composition comprising ultra-high concentration hyaluronidase as disclosed herein, and, optionally, one or more delivery systems, e.g., 1-20 delivery systems, 7-15 delivery systems, 8-12 delivery systems, or 10 delivery systems, where each such delivery system is optionally used to deliver a composition of the disclosure.

[0078] In some embodiments, the containers disclosed herein may be delivery systems that contain a composition comprising an ultra-high concentration hyaluronidase disclosed herein. In some embodiments, the kits may include one or more delivery systems, e.g., 1-20 delivery systems, 7-15 delivery systems, 8-12 delivery systems, or 10 delivery systems, each such delivery system containing a composition comprising an ultra-high concentration hyaluronidase disclosed herein. In some aspects of this embodiment, the kits may include one or more autoinjector devices, e.g., 1-20 autoinjector devices, 7-15 autoinjector devices, 8-12 autoinjector devices, or 10 autoinjector devices, each such autoinjector containing a composition comprising an ultra-high concentration hyaluronidase disclosed herein. In some aspects of this embodiment, the kit may include one or more manual injection devices, e.g., 1-20 manual injection devices, 7-15 manual injection devices, 8-12 manual injection devices, or 10 manual injection devices, each such manual injection device comprising a composition comprising an ultra-high concentration hyaluronidase disclosed herein.

[0079] The kits disclosed herein may include other components. For example, the kits disclosed herein may further include a container containing a solvent, such as water or a buffer, such as saline. The solvents disclosed herein are useful for reconstituting the dried pharmaceutical compositions disclosed herein.

[0080] The kits disclosed herein may include a delivery system. The delivery system of the kit is useful for applying the compositions disclosed herein to a desired site. The delivery or application systems disclosed herein include, but are not limited to, one or more manual and / or automatic injection devices disclosed herein. In one embodiment, the kit includes a single delivery system. In another embodiment, the kit includes multiple delivery systems. For example, each kit may include 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more delivery systems. Within the kit, the delivery systems may be packaged individually or in sets of two or more. The delivery systems may be packaged to remain sterile until their use. In certain embodiments, the delivery systems disclosed herein may be packaged in a plastic sheath. To further prevent contamination, the delivery systems disclosed herein are preferably single-use, disposable delivery systems.

[0081] The kit may also include a set of instructions. The instructions may include information useful to the end user, such as, for example, how to use a delivery system to apply the compositions disclosed herein and / or how often to apply the compositions disclosed herein. Such instructions may also include information on how to mix the solvents disclosed herein to reconstitute the dry compositions disclosed herein. Such instructions may instruct mixing to occur at a specific time prior to application, such as immediately prior to use. The instructions disclosed herein may also include information on how to apply the compositions disclosed herein directly to a site of interest, and in what order or timing the compositions disclosed herein should be applied to such site of interest.

[0082] The contents of the kit, including the container, composition, delivery system and instructions disclosed herein, are enclosed in an outer casing. The outer casing may be a box, a sealed bag, a foil pouch, etc. In certain embodiments, the delivery system, container and instructions are enclosed in a box. In other embodiments of the kit, the container and instructions are contained in a first box, the delivery system is contained in a second box, and the first and second boxes are contained together in a third box.

[0083] Some aspects of the present specification can also be described by the following embodiments. 1. A method of reducing or eliminating hyaluronic acid induced obstruction in one or more blood vessels supplying blood to an area of ​​tissue in an individual in need thereof, comprising administering to the individual a composition comprising ultra-high concentration hyaluronidase. 2. A method of reducing or inhibiting vascular occlusion in a region of tissue in an individual in need thereof, said method comprising reducing or eliminating hyaluronic acid induced occlusion in one or more blood vessels supplying blood to a region of tissue affected by said occlusion, said method comprising administering to said individual a composition comprising ultra-high concentration hyaluronidase, thereby reducing or inhibiting said vascular occlusion in said region of tissue. 3. A method for reducing or inhibiting hyaluronic acid induced tissue loss in an individual in need thereof, said method comprising administering to an individual a composition comprising ultra-high concentration hyaluronidase, thereby reducing or eliminating hyaluronic acid induced tissue loss in one or more blood vessels supplying blood to an area of ​​tissue affected by said obstruction. 4. The method of any one of embodiments 1 to 3, wherein the composition is administered to the dermis portion of the skin area. 5. The method of any one of embodiments 1-4, wherein the composition is administered using a delivery system. 6. The composition comprises at least 25,000 IU / mL, at least 50,000 IU / mL, at least 75,000 IU / mL, at least 100,000 IU / mL, at least 125,000 IU / mL, at least 150,000 IU / mL, at least 175,000 IU / mL, at least 200,000 IU / mL, at least 225,000 IU / mL, at least 250,000 IU / mL, at least 300,000 IU / mL, at least 350,000 IU / mL, at least 400,000 IU / mL, at least 450 ,000 IU / mL or a concentration of at least 500,000 IU / mL, and / or at most 25,000 IU / mL, at most 50,000 IU / mL, at most 75,000 IU / mL, at most 100,000 IU / mL, at most 125,000 IU / mL, at most 150,000 IU / mL, at most 175,000 IU / mL, at most 200,000 IU / mL, at most 225,000 IU / mL, at most 250,000 IU / mL, at most 300,000 IU / mL, at most 350,000 IU / mL, at most 400, 000IU / mL, at most 450,000IU / mL or at most 500,000IU / mL, or about 25,000IU / mL to about 50,000IU / mL, about 25,000IU / mL to about 75,000IU / mL, about 25,000IU / mL to about 100,000IU / mL, about 25,000IU / mL to about 125,000IU / mL, about 25,000IU / mL to about 150,000IU / mL, about 25,000IU / mL to about 175,000IU / mL, about 25,000IU / mL to about 200,000IU / mL, about 25,000IU / mL L ~ about 225,000IU / mL, about 25,000IU / mL - about 250,000IU / mL, about 25,000IU / mL - about 300,000IU / mL, about 25,000IU / mL - about 350,000IU / mL, about 25,000IU / mL - about 400,000IU / mL, Approx. 25,000IU / mL~Approx. 450,000IU / mL, Approx. 25,000IU / mL~Approx. 500,000IU / mL, Approx. 50,000I U / mL ~ approx. 75,000IU / mL, approx. 50,000IU / mL ~ approx. 100,000IU / mL, approx. 50,000IU / mL ~ approx. 125,000 IU / mL, from about 50,000 IU / mL to about 150,000 IU / mL, from about 50,000 IU / mL to about 175,000 IU / mL, from about 50,000 IU / mL to about 200,000 IU / mL, from about 50,000 IU / mL to about 225,000 IU / mL, from about 50,000 IU / mL to about 250,000 IU / mL, from about 50,000 IU / mL to about 300,000 IU / mL, from about 50,000 IU / mL to about 350,000 IU / mL, from about 50,000 IU / mL to about 400,000 IU / mL, from about 50,000 IU / mL to about 450,000 IU / mL, from about 50,000 IU / mL to about 500,000 IU / mL, from about 75,000 IU / mL to about 100,000 IU / mL, from about 75,000 IU / mL to about 125,000 IU / mL, from about 75,000 IU / mL to about 150,000 IU / mL, from about 75,000 IU / mL to about 175,000 IU / mL, from about 75,000 IU / mL to about 200,000 IU / mL, from about 75,000 IU / mL to about 225,000 IU / mL, from about 75,000 IU / mL to about 250,000 IU / mL, from about 75,000 IU / mL to about 300,000 IU / mL, from about 75,000 IU / mL to about 350,000 IU / mL, from about 75,000 IU / mL to about 400,000 IU / mL, from about 75,000 IU / mL to about 450,000 IU / mL, from about 75,000 IU / mL to about 500,000 IU / mL, from about 100,000 IU / mL to about 125,000 IU / mL, from about 100,000 IU / mL to about 150,000 IU / mL, from about 100,000 IU / mL to about 175,000 IU / mL, from about 100,000 IU / mL to about 200,000 IU / mL, from about 100,000 IU / mL to about 225,000 IU / mL, from about 100,000 IU / mL to about 250,000 IU / mL, from about 100,000 IU / mL to about 300,000 IU / mL, from about 100,000 IU / mL to about 350,000 IU / mL, from about 100,000 IU / mL to about 400,000 IU / mL, from about 100,000 IU / mL to about 450,000 IU / mL, from about 100,000 IU / mL to about 500,000 IU / mL, from about 150,000 IU / mL to about 200,000 IU / mL, from about 150,000 IU / mL to about 225,000 IU / mL, from about 150,000 IU / mL to about 250,000 IU / mL, from about 150,000IU / mL ~ approx. 300,000IU / mL, approx. 150,000IU / mL ~ approx. 350,000IU / mL, approx. 150,000IU / mL ~ approx. 400,000IU / mL, approx. 150,000IU / mL ~ approx. 450,0 00IU / mL, about 150,000IU / mL to about 500,000IU / mL, about 200,000IU / mL to about 225,000IU / mL, about 200,000IU / mL to about 250,000IU / mL, about 200,00 0IU / mL ~ approx. 300,000IU / mL, approx. 200,000IU / mL ~ approx. 350,000IU / mL, approx. 200,000IU / mL ~ approx. 400,000IU / mL, approx. 200,000IU / mL ~ approx. 450,000 IU / mL, approximately 200,000IU / mL to approximately 500,000IU / mL, approximately 250,000IU / mL to approximately 300,000IU / mL, approximately 250,000IU / mL to approximately 350,000IU / mL, approximately 250,000IU / mL ~ approx. 400,000IU / mL, approx. 250,000IU / mL ~ approx. 450,000IU / mL, approx. 250,000IU / mL ~ approx. 500,000IU / mL, approx. 300,000IU / mL ~ approx. 350,000IU / mL, about 300,000IU / mL to about 400,000IU / mL, about 300,000IU / mL to about 450,000IU / mL, about 300,000IU / mL to about 500,000IU / mL, about 350,000IU / mL The method according to any one of embodiments 1 to 5, comprising the ultra-high concentration hyaluronidase at a concentration of about 400,000 IU / mL, about 350,000 IU / mL to about 450,000 IU / mL, about 350,000 IU / mL to about 500,000 IU / mL, about 400,000 IU / mL to about 450,000 IU / mL, about 400,000 IU / mL to about 500,000 IU / mL, or about 450,000 IU / mL to about 500,000 IU / mL. 7. The composition has a concentration of at least 10,000 IU / mL, at least 20,000 IU / mL, at least 30,000 IU / mL, at least 40,000 IU / mL, at least 50,000 IU / mL, at least 60,000 IU / mL, at least 70,000 IU / mL, at least 80,000 IU / mL, at least 90,000 IU / mL or at least 100,000 IU / mL, and / or at most 10,000 IU / mL, at most 20,000 IU / mL, at most 30,000 IU / mL, at most 40,0 00IU / mL, at most 50,000IU / mL, at most 60,000IU / mL, at most 70,000IU / mL, at most 80,000IU / mL, at most 90,000IU / mL or at most 100,000IU / mL, or from about 10,000IU / mL to about 20,000IU / mL, from about 10,000IU / mL to about 30,000IU / mL, from about 10,000IU / mL to about 40,000IU / mL, from about 10,000IU / mL to about 50,000IU / mL, from about 10,000IU / mL to about 60,000IU / mL, 00IU / mL ~ approx. 70,000IU / mL, approx. 10,000IU / mL ~ approx. 80,000IU / mL, approx. 10,000IU / mL ~ approx. 90,000IU / mL, approx. 10,000IU / mL ~ approx. 100,000IU / mL, approx. 20,000IU / mL ~ approx. 30,000IU / m L, about 20,000IU / mL to about 40,000IU / mL, about 20,000IU / mL to about 50,000IU / mL, about 20,000IU / mL to about 60,000IU / mL, about 20,000IU / mL to about 70,000IU / mL, about 20,000IU / mL to about 80,0 00IU / mL, about 20,000IU / mL to about 90,000IU / mL, about 20,000IU / mL to about 100,000IU / mL, about 30,000IU / mL to about 40,000IU / mL, about 30,000IU / mL to about 50,000IU / mL, about 30,000IU / m L ~ about 60,000IU / mL, about 30,000IU / mL - about 70,000IU / mL, about 30,000IU / mL - about 80,000IU / mL, about 30,000IU / mL - about 90,000IU / mL, about 30,000IU / mL - about 100,000IU / mL, about 40,000IU / mL ~ approx. 50,000IU / mL, approx. 40,000IU / mL ~ approx. 60,000IU / mL, approx. 40,000IU / mL ~ approx. 70,000IU / mL, Approx. 40,000IU / mL~Approx. 80,000IU / mL, Approx. 40,000IU / mL~Approx. 90,000IU / mL, Approx. 40,000IU / mL~Approx. 100,000I U / mL, approximately 50,000IU / mL to approximately 60,000IU / mL, approximately 50,000IU / mL to approximately 70,000IU / mL, approximately 50,000IU / mL to approximately 80, 000IU / mL, approximately 50,000IU / mL to approximately 90,000IU / mL, approximately 50,000IU / mL to approximately 100,000IU / mL, approximately 60,000IU / mL ~70,000IU / mL, approx. 60,000IU / mL ~ approx. 80,000IU / mL, approx. 60,000IU / mL ~ approx. 90,000IU / mL, approx. 60,000I U / mL ~ approx. 100,000IU / mL, approx. 70,000IU / mL ~ approx. 80,000IU / mL, approx. 70,000IU / mL ~ approx. 90,000IU / mL, approx. 70 The method according to any one of embodiments 1 to 5, comprising the ultra-high concentration hyaluronidase at a concentration of about 1,000 IU / mL to about 100,000 IU / mL, about 80,000 IU / mL to about 90,000 IU / mL, about 80,000 IU / mL to about 100,000 IU / mL, or about 90,000 IU / mL to about 100,000 IU / mL. 8. The composition comprises at least 5,000 IU / mL, at least 6,000 IU / mL, at least 7,000 IU / mL, at least 8,000 IU / mL, at least 9,000 IU / mL, at least 10,000 IU / mL, at least 11,000 IU / mL, at least 12,000 IU / mL, at least 13,000 IU / mL, at least 14,000 IU / mL, at least 15,000 IU / mL, at least 16,000 IU / mL, at least 17,000 IU / mL, at least 18,000 IU / mL, at least 19,000 IU / mL, at least 20,000 IU / mL, at least 21,000 IU / mL, at least 22,000 IU / mL, at least 23,000 IU / mL, at least 24,000 IU / mL, at least 25,000 IU / mL, at least 26,000 IU / mL, at least 27,000 IU / mL, at least 28,000 IU / mL, at least 29,000 IU / mL, at least 30,000 IU / mL, at least 31,000 IU / mL, at least 32,000 IU / mL, at least 33,000 IU / mL, at least 34,000 IU / mL, at least 35,000 IU / mL, at least 36,000 IU / mL, at least 37,000 IU / mL, at least 38,000 IU / mL, at least 39,000 IU / mL, at least 40,000 IU / mL, at least 41, a concentration of 9,000 IU / mL or at least 20,000 IU / mL, and / or at most 5,000 IU / mL, at most 6,000 IU / mL, at most 7,000 IU / mL, at most 8,000 IU / mL, at most 9,000 IU / mL, at most 10,000 IU / mL, at most 11,000 IU / mL, at most 12,000 IU / mL, at most 13,000 IU / mL, at most 14,000 IU / mL, at most 15,000 IU / mL, at most 16,000 IU / mL, at most 17,000 IU / mL, at most 1 8,000 IU / mL, at most 19,000 IU / mL or at most 20,000 IU / mL, or about 5,000 IU / mL to about 6,000 IU / mL, about 5,000 IU / mL to about 7,000 IU / mL, about 5,000 IU / mL to about 8,000 IU / mL, about 5,000 IU / mL to about 9,000 IU / mL, about 5,000 IU / mL to about 10,000 IU / mL, about 5,000 IU / mL to about 11,000 IU / mL, about 5,000 IU / mL to about 12,000 IU / mL, about 5,000 IU / mL to about 13,000 IU / mL, about 5,000IU / mL ~ approx. 14,000IU / mL, approx. 5,000IU / mL ~ approx. 15,000IU / mL, approx. 5,000IU / mL ~ approx. 16,000IU / mL, approx. 5,000IU / mL ~ approx. 17,000IU / mL, approx. 5,000IU / mL ~ approx. 18,000IU / mL, Approximately 5,000IU / mL to approximately 19,000IU / mL, approximately 5,000IU / mL to approximately 20,000IU / mL, approximately 6,000IU / mL to approximately 7,000IU / mL, approximately 6,000IU / mL to approximately 8,000IU / mL, approximately 6,000IU / mL to approximately 9,000IU / mL, approximately 6,000 IU / mL to approximately 10,000 IU / mL, approximately 6,000 IU / mL to approximately 11,000 IU / mL, approximately 6,000 IU / mL to approximately 12,000 IU / mL, approximately 6,000 IU / mL to approximately 13,000 IU / mL, approximately 6,000 IU / mL to approximately 14,000 IU / mL, approximately 6,000 IU / mL to approximately 15,000 IU / mL, approximately 6,000 IU / mL to approximately 16,000 IU / mL, approximately 6,000 IU / mL to approximately 17,000 IU / mL, approximately 6,000 IU / mL to approximately 18,000 IU / mL, approximately 6,000 IU / mL to approximately 19,000 IU / mL, approximately 6,000 IU / mL to approximately 20,000 IU / mL, approximately 7,000 IU / mL to approximately 8,000 IU / mL, approximately 7,000 IU / mL to approximately 9,000 IU / mL, approximately 7,000 IU / mL to approximately 10,000 IU / mL, approximately 7,000 IU / mL to approximately 11,000 IU / mL, approximately 7,000 IU / mL to approximately 12,000 IU / mL, approximately 7,000 IU / mL to approximately 13,000 IU / mL, approximately 7,000 IU / mL to approximately 14,000 IU / mL, approximately 7,000 IU / mL to approximately 15,000 IU / mL, approximately 7,000 IU / mL to approximately 16,000 IU / mL, approximately 7,000 IU / mL to approximately 17,000 IU / mL, approximately 7,000 IU / mL to approximately 18,000 IU / mL, approximately 7,000 IU / mL to approximately 19,000 IU / mL, approximately 7,000 IU / mL to approximately 20,000 IU / mL, approximately 8,000 IU / mL to approximately 9,000 IU / mL, approximately 8,000 IU / mL to approximately 10,000 IU / mL, approximately 8,000 IU / mL to approximately 11,000 IU / mL, approximately 8,000 IU / mL to approximately 12,000 IU / mL, approximately 8,000 IU / mL to approximately 13,000 IU / mL, approximately 8,000 IU / mL to approximately 14,000 IU / mL, approximately 8,000 IU / mL to approximately 15,000 IU / mL, approximately 8,000 IU / mL to approximately 16,000 IU / mL, approximately 8,000 IU / mL to approximately 17,000 IU / mL, approximately 8,000 IU / mL to approximately 18,000 IU / mL, approximately 8,000 IU / mL to approximately 19,000 IU / mL, approximately 8,000 IU / mL to approximately 20,000 IU / mL, approximately 9,000 IU / mL to approximately 10,000 IU / mL, approximately 9,000 IU / mL to approximately 11,000 IU / mL, approximately 9,000 IU / mL to approximately 12,000 IU / mL, approximately 9,000 IU / mL to approximately 13,000 IU / mL, approximately 9,000 IU / mL to approximately 14,000 IU / mL, approximately 9,000 IU / mL to approximately 15,000 IU / mL, approximately 9,000 IU / mL to approximately 16,000 IU / mL, approximately 9,000 IU / mL to approximately 17,000 IU / mL, approximately 9,000 IU / mL to approximately 18,000 IU / mL, approximately 9,000 IU / mL to approximately 19,000 IU / mL, approximately 9,000 IU / mL to approximately 20,000 IU / mL, approximately 10,000 IU / mL to approximately 11,000 IU / mL, approximately 10,000 IU / mL to approximately 12,000 IU / mL, approximately 10,000 IU / mL to approximately 13,000 IU / mL, approximately 10,000 IU / mL to approximately 14,000 IU / mL, approximately 10,000 IU / mL to approximately 15,000 IU / mL, approximately 10,000 IU / mL to approximately 16,000 IU / mL, approximately 10,000 IU / mL to approximately 17,000 IU / mL, approximately 10,000 IU / mL to approximately 18,000 IU / mL, approximately 10,000 IU / mL to approximately 19,000 IU / mL, approximately 10,000 IU / mL to approximately 20,000 IU / mL, approximately 11,000 IU / mL to approximately 12,000 IU / mL, approximately 11,000 IU / mL to approximately 13,000 IU / mL, approximately 11,000 IU / mL to approximately 14,000 IU / mL, approximately 11,000 IU / mL to approximately 15,000 IU / mL, approximately 11,000 IU / mL to approximately 16,000 IU / mL, approximately 11,000 IU / mL to approximately 17,000 IU / mL, approximately 11,000 IU / mL to approximately 18,000 IU / mL, approximately 11,000 IU / mL to approximately 19,000 IU / mL, approximately 11,000 IU / mL to approximately 20,000 IU / mL, approximately 12,000 IU / mL to approximately 13,000 IU / mL, approximately 12,000 IU / mL to approximately 14,000 IU / mL, approximately 12,000 IU / mL to approximately 15,000 IU / mL, approximately 12,000 IU / mL to approximately 16,000 IU / mL, approximately 12,000 IU / mL to approximately 17,000 IU / mL, approximately 12,000 IU / mL to approximately 18,000 IU / mL, approximately 12,000 IU / mL to approximately 19,000 IU / mL, approximately 12,000 IU / mL to approximately 20,000 IU / mL, approximately 13,000 IU / mL to approximately 14,000 IU / mL, approximately 13,000 IU / mL to approximately 15,000 IU / mL, approximately 13,000 IU / mL to approximately 16,000 IU / mL, approximately 13,000 IU / mL to approximately 17,000 IU / mL, approximately 13,000 IU / mL to approximately 18,000IU / mL, approximately 13,000IU / mL to approximately 19,000IU / mL, approximately 13,000IU / mL to approximately 20,000IU / mL, approximately 14,000IU / mL to approximately 15,000 IU / mL, approximately 14,000IU / mL to approximately 16,000IU / mL, approximately 14,000IU / mL to approximately 17,000IU / mL, approximately 14,000IU / mL to approximately 18,000IU / mL, approximately 14,000IU / mL to approximately 19,000IU / mL, approximately 14,000IU / mL to approximately 20,000IU / mL, approximately 15,000IU / mL to approximately 16,000IU / mL, Approx. 15,000IU / mL~Approx. 17,000IU / mL, Approx. 15,000IU / mL~Approx. 18,000IU / mL, Approx. 15,000IU / mL~Approx. 19,000IU / mL, Approx. 15, 000IU / mL ~ approx. 20,000IU / mL, approx. 16,000IU / mL ~ approx. 17,000IU / mL, approx. 16,000IU / mL ~ approx. 18,000IU / mL, approx. 16,000 IU / mL ~ approx. 19,000IU / mL, approx. 16,000IU / mL ~ approx. 20,000IU / mL, approx. 17,000IU / mL ~ approx. 18,000IU / mL, approx. 17,000IU / m The method according to any one of embodiments 1 to 5, comprising the ultra-high concentration hyaluronidase at a concentration of about 10,000 IU / mL to about 19,000 IU / mL, about 17,000 IU / mL to about 20,000 IU / mL, about 18,000 IU / mL to about 19,000 IU / mL, about 18,000 IU / mL to about 20,000 IU / mL, or about 19,000 IU / mL to about 20,000 IU / mL. 9. The composition has a concentration of at least 250 IU / mL, at least 500 IU / mL, at least 750 IU / mL, at least 1,000 IU / mL, at least 1,500 IU / mL, at least 2,000 IU / mL, at least 2,500 IU / mL, at least 3,000 IU / mL, at least 3,500 IU / mL, at least 4,000 IU / mL, at least 4,500 IU / mL or at least 5,000 IU / mL, and / or at most 250 IU / mL, at most 500 IU / mL, at most 750 IU / mL, at most 5,000 IU / mL. at most 1,000 IU / mL, at most 1,500 IU / mL, at most 2,000 IU / mL, at most 2,500 IU / mL, at most 3,000 IU / mL, at most 3,500 IU / mL, at most 4,000 IU / mL, at most 4,500 IU / mL or at most 5,000 IU / mL, or at most about 250 IU / mL to about 500 IU / mL, about 250 IU / mL to about 750 IU / mL, about 250 IU / mL to about 1,000 IU / mL, about 250 IU / mL to about 1,500 IU / mL, about 250 IU / mL to about 2,000 IU / mL, Approximately 250IU / mL to approximately 2,500IU / mL, approximately 250IU / mL to approximately 3,000IU / mL, approximately 250IU / mL to approximately 3,500IU / mL, approximately 250IU / mL to approximately 4,000IU / mL, approximately 250IU / mL to approximately 4,500IU / mL, approximately 250IU / mL to approximately 5, 000IU / mL, about 500IU / mL to about 750IU / mL, about 500IU / mL to about 1,000IU / mL, about 500IU / mL to about 1,500IU / mL, about 500IU / mL to about 2,000IU / mL, about 500IU / mL to about 2,500IU / mL, about 500IU / mL mL ~ approx. 3,000IU / mL, approx. 500IU / mL ~ approx. 3,500IU / mL, approx. 500IU / mL ~ approx. 4,000IU / mL, approx. 500IU / mL ~ approx. 4,500IU / mL, approx. 500IU / mL ~ approx. 5,000IU / mL, approx. 750IU / mL ~ approx. 1,000IU / mL , about 750IU / mL to about 1,500IU / mL, about 750IU / mL to about 2,000IU / mL, about 750IU / mL to about 2,500IU / mL, about 750IU / mL to about 3,000IU / mL, about 750IU / mL to about 3,500IU / mL, about 750IU / mL to about 4,000IU / mL, approximately 750IU / mL to approximately 4,500IU / mL, approximately 750IU / mL to approximately 5,000IU / mL, approximately 1,000IU / mL to approximately 1,500IU / mL, approximately 1,000IU / mL to approximately 2,000IU / mL, approximately 1,000IU / mL to approximately 2,500I U / mL, approximately 1,000IU / mL to approximately 3,000IU / mL, approximately 1,000IU / mL to approximately 3,500IU / mL, approximately 1,000IU / mL to approximately 4,000IU / mL, approximately 1,000IU / mL to approximately 4,500IU / mL, approximately 1,000IU / mL to approximately 5,000I U / mL, approximately 1,500IU / mL to approximately 2,000IU / mL, approximately 1,500IU / mL to approximately 2,500IU / mL, approximately 1,500IU / mL to approximately 3,000IU / mL, approximately 1,500IU / mL to approximately 3,500IU / mL, approximately 1,500IU / mL to approximately 4,000I U / mL, approximately 1,500IU / mL to approximately 4,500IU / mL, approximately 1,500IU / mL to approximately 5,000IU / mL, approximately 2,000IU / mL to approximately 2,500IU / mL, approximately 2,000IU / mL to approximately 3,000IU / mL, approximately 2,000IU / mL to approximately 3,500I U / mL, approximately 2,000IU / mL to approximately 4,000IU / mL, approximately 2,000IU / mL to approximately 4,500IU / mL, approximately 2,000IU / mL to approximately 5,000IU / mL, approximately 2,500IU / mL to approximately 3,000IU / mL, approximately 2,500IU / mL to approximately 3,500I U / mL, approximately 2,500IU / mL to approximately 4,000IU / mL, approximately 2,500IU / mL to approximately 4,500IU / mL, approximately 2,500IU / mL to approximately 5,000IU / mL, approximately 3,000IU / mL to approximately 3,500IU / mL, approximately 3,000IU / mL to approximately 4,000I The method according to any one of embodiments 1 to 5, comprising the ultra-high concentration hyaluronidase at a concentration of about 3,000 IU / mL to about 4,500 IU / mL, about 3,000 IU / mL to about 5,000 IU / mL, about 3,500 IU / mL to about 4,000 IU / mL, about 3,500 IU / mL to about 4,500 IU / mL, about 3,500 IU / mL to about 5,000 IU / mL, about 4,000 IU / mL to about 4,500 IU / mL, about 4,000 IU / mL to about 5,000 IU / mL, or about 4,500 IU / mL to about 5,000 IU / mL. 10. The ultra-high concentration hyaluronidase is at least 25,000 IU / mL, at least 50,000 IU / mL, at least 75,000 IU / mL, at least 100,000 IU / mL, at least 125,000 IU / mL, at least 150,000 IU / mL, at least 175,000 IU / mL, at least 200,000 IU / mL, at least 225,000 IU / mL, at least 250,000 IU / mL, at least 300,000 IU / mL, at least 350,000 IU / mL, at least 400,000 IU / mL mL, an amount of at least 450,000 IU / mL or at least 500,000 IU / mL, and / or an amount of at most 25,000 IU / mL, at most 50,000 IU / mL, at most 75,000 IU / mL, at most 100,000 IU / mL, at most 125,000 IU / mL, at most 150,000 IU / mL, at most 175,000 IU / mL, at most 200,000 IU / mL, at most 225,000 IU / mL, at most 250,000 IU / mL, at most 300,000 IU / mL, at most 350,000 IU / mL, at most 400,000 IU / mL, at most 450,000 IU / mL or at most 500,000 IU / mL, or from about 25,000 IU / mL to about 50,000 IU / mL, from about 25,000 IU / mL to about 75,000 IU / mL, from about 25,000 IU / mL to about 100,000 IU / mL, from about 25,000 IU / mL to about 125,000 IU / mL, from about 25,000 IU / mL to about 150,000 IU / mL, from about 25,000 IU / mL to about 175,000 IU / mL, from about 25,000 IU / mL to about 200,000 IU / mL L, about 25,000IU / mL to about 225,000IU / mL, about 25,000IU / mL to about 250,000IU / mL, about 25,000IU / mL to about 300,000IU / mL, about 25,000IU / mL to about 350,000IU / mL, about 25,000IU / mL to about 400,000IU / mL, about 25,000IU / mL to about 450,000IU / mL, about 25,000IU / mL to about 500,000IU / mL, about 50,000IU / mL to about 75,000IU / mL, about 50,000IU / mL to about 100,000IU / mL, about 50,000 IU / mL to approximately 125,000 IU / mL, approximately 50,000 IU / mL to approximately 150,000 IU / mL, approximately 50,000 IU / mL to approximately 175,000 IU / mL, approximately 50,000 IU / mL to approximately 200,000 IU / mL, approximately 50,000 IU / mL to approximately 225,000 IU / mL, approximately 50,000 IU / mL to approximately 250,000 IU / mL, approximately 50,000 IU / mL to approximately 300,000 IU / mL, approximately 50,000 IU / mL to approximately 350,000 IU / mL, approximately 50,000 IU / mL to approximately 400,000 IU / mL, approximately 50,000 IU / mL to approximately 450,000 IU / mL, approximately 50,000 IU / mL to approximately 500,000 IU / mL, approximately 75,000 IU / mL to approximately 100,000 IU / mL, approximately 75,000 IU / mL to approximately 125,000 IU / mL, approximately 75,000 IU / mL to approximately 150,000 IU / mL, approximately 75,000 IU / mL to approximately 175,000 IU / mL, approximately 75,000 IU / mL to approximately 200,000 IU / mL, approximately 75,000 IU / mL to approximately 225,000 IU / mL, approximately 75,000 IU / mL to approximately 250,000 IU / mL, approximately 75,000 IU / mL to approximately 300,000 IU / mL, approximately 75,000 IU / mL to approximately 350,000 IU / mL, approximately 75,000 IU / mL to approximately 400,000 IU / mL, approximately 75,000 IU / mL to approximately 450,000 IU / mL, approximately 75,000 IU / mL to approximately 500,000 IU / mL, approximately 100,000 IU / mL to approximately 125,000 IU / mL, approximately 100,000 IU / mL to approximately 150,000 IU / mL, approximately 100,000 IU / mL to approximately 175,000 IU / mL, approximately 100,000 IU / mL to approximately 200,000 IU / mL, approximately 100,000 IU / mL to approximately 225,000 IU / mL, approximately 100,000 IU / mL to approximately 250,000 IU / mL, approximately 100,000 IU / mL to approximately 300,000 IU / mL, approximately 100,000 IU / mL to approximately 350,000 IU / mL, approximately 100,000 IU / mL to approximately 400,000 IU / mL, approximately 100,000 IU / mL to approximately 450,000 IU / mL, approximately 100,000 IU / mL to approximately 500,000 IU / mL, approximately 150,000 IU / mL to approximately 200,000 IU / mL, approximately 150,000 IU / mL to approximately 225,000 IU / mL, approximately 150,000 IU / mL to approximately 250,000IU / mL, about 150,000IU / mL to about 300,000IU / mL, about 150,000IU / mL to about 350,000IU / mL, about 150,000IU / mL to about 400,000IU / mL, about 150,0 00IU / mL ~ approx. 450,000IU / mL, approx. 150,000IU / mL ~ approx. 500,000IU / mL, approx. 200,000IU / mL ~ approx. 225,000IU / mL, approx. 200,000IU / mL ~ approx. 250,00 0IU / mL, about 200,000IU / mL to about 300,000IU / mL, about 200,000IU / mL to about 350,000IU / mL, about 200,000IU / mL to about 400,000IU / mL, about 200,000 IU / mL ~ approx. 450,000IU / mL, approx. 200,000IU / mL ~ approx. 500,000IU / mL, approx. 250,000IU / mL ~ approx. 300,000IU / mL, approx. 250,000IU / mL ~ approx. 350,000IU / mL, about 250,000IU / mL to about 400,000IU / mL, about 250,000IU / mL to about 450,000IU / mL, about 250,000IU / mL to about 500,000IU / mL, about 300,000IU / mL mL ~ approx. 350,000IU / mL, approx. 300,000IU / mL ~ approx. 400,000IU / mL, approx. 300,000IU / mL ~ approx. 450,000IU / mL, approx. 300,000IU / mL ~ approx. 500,000IU / mL The method according to any one of embodiments 1 to 9, wherein the amount of the sucrose phosphate ... 11. The ultra-high concentration hyaluronidase is administered in an amount of at least 10,000 IU / mL, at least 20,000 IU / mL, at least 30,000 IU / mL, at least 40,000 IU / mL, at least 50,000 IU / mL, at least 60,000 IU / mL, at least 70,000 IU / mL, at least 80,000 IU / mL, at least 90,000 IU / mL or at least 100,000 IU / mL, and / or in an amount of at most 10,000 IU / mL, at most 20,000 IU / mL, at most 30,000 IU / mL, at most 40,000 IU / mL, at least 50,000 IU / mL, at least 60,000 IU / mL, at least 70,000 IU / mL, at least 80,000 IU / mL, at least 90,000 IU / mL or at least 100,000 IU / mL. an amount of at most 40,000 IU / mL, at most 50,000 IU / mL, at most 60,000 IU / mL, at most 70,000 IU / mL, at most 80,000 IU / mL, at most 90,000 IU / mL or at most 100,000 IU / mL, or from about 10,000 IU / mL to about 20,000 IU / mL, from about 10,000 IU / mL to about 30,000 IU / mL, from about 10,000 IU / mL to about 40,000 IU / mL, from about 10,000 IU / mL to about 50,000 IU / mL, from about 10,000 IU / mL to about 60,000 IU / mL, 10,000IU / mL ~ approx. 70,000IU / mL, approx. 10,000IU / mL ~ approx. 80,000IU / mL, approx. 10,000IU / m L ~ approx. 90,000IU / mL, approx. 10,000IU / mL ~ approx. 100,000IU / mL, approx. 20,000IU / mL ~ approx. 30,000I U / mL, about 20,000IU / mL to about 40,000IU / mL, about 20,000IU / mL to about 50,000IU / mL, about 20,000IU / mL to about 60,000IU / mL, about 20,000IU / mL to about 70,000IU / mL, about 20,000IU / mL to about 80 ,000IU / mL, about 20,000IU / mL to about 90,000IU / mL, about 20,000IU / mL to about 100,000IU / mL , about 30,000IU / mL to about 40,000IU / mL, about 30,000IU / mL to about 50,000IU / mL, about 30,000IU / mL ~ approx. 60,000IU / mL, approx. 30,000IU / mL ~ approx. 70,000IU / mL, approx. 30,000IU / mL ~ approx. 80,000IU / mL, approx. 30,000IU / mL ~ approx. 90,000IU / mL, approx. 30,000IU / mL ~ approx. 100,000IU / mL, approx. 40,000IU / mL ~ approx. 50,000IU / mL, approx. 40,000IU / mL ~ approx. 60,000IU / mL, approx. 40,000IU / mL ~ approx. 70,000IU / m L, about 40,000IU / mL to about 80,000IU / mL, about 40,000IU / mL to about 90,000IU / mL, about 40,000IU / mL to about 100, 000IU / mL, approximately 50,000IU / mL to approximately 60,000IU / mL, approximately 50,000IU / mL to approximately 70,000IU / mL, approximately 50,000IU / m L ~ approx. 80,000IU / mL, approx. 50,000IU / mL ~ approx. 90,000IU / mL, approx. 50,000IU / mL ~ approx. 100,000IU / mL, approx. 60,0 00IU / mL ~ approx. 70,000IU / mL, approx. 60,000IU / mL ~ approx. 80,000IU / mL, approx. 60,000IU / mL ~ approx. 90,000IU / mL , about 60,000IU / mL to about 100,000IU / mL, about 70,000IU / mL to about 80,000IU / mL, about 70,000IU / mL to about 90,0 The method according to any one of embodiments 1 to 9, wherein the serotonin is administered in an amount of about 0.00 IU / mL, about 70,000 IU / mL to about 100,000 IU / mL, about 80,000 IU / mL to about 90,000 IU / mL, about 80,000 IU / mL to about 100,000 IU / mL, or about 90,000 IU / mL to about 100,000 IU / mL. 12. The ultra-high concentration hyaluronidase is administered in an amount of at least 10,000 IU / mL, at least 11,000 IU / mL, at least 12,000 IU / mL, at least 13,000 IU / mL, at least 14,000 IU / mL, at least 15,000 IU / mL, at least 16,000 IU / mL, at least 17,000 IU / mL, at least 18,000 IU / mL, at least 19,000 IU / mL or at least 20,000 IU / mL, and / or in an amount of at most 10,000 IU / mL, at most 11,000 IU / mL L, at most 12,000 IU / mL, at most 13,000 IU / mL, at most 14,000 IU / mL, at most 15,000 IU / mL, at most 16,000 IU / mL, at most 17,000 IU / mL, at most 18,000 IU / mL, at most 19,000 IU / mL or at most 20,000 IU / mL, or an amount of about 10,000 IU / mL to about 11,000 IU / mL, about 10,000 IU / mL to about 12,000 IU / mL, about 10,000 IU / mL to about 13,000 IU / mL, about 10,000 IU / mL to about 14 ,000IU / mL, about 10,000IU / mL to about 15,000IU / mL, about 10,000IU / mL to about 16,000IU / mL, about 10,000IU / mL to about 17,000IU / mL, about 10,000IU / mL to about 18,000IU / mL, about 10,000IU / mL ~ approx. 19,000IU / mL, approx. 10,000IU / mL ~ approx. 20,000IU / mL, approx. 11,000IU / mL ~ approx. 12,000IU / mL, approx. 11,000IU / mL ~ approx. 13,000IU / mL, approx. 11,000IU / mL ~ approx. 14,000IU / mL, approx. ,000IU / mL~Approx. 15,000IU / mL, Approx. 11,000IU / mL~Approx. 16,000IU / mL, Approx. 11,000IU / mL~Approx. 17,000IU / mL, Approx. 11,000IU / mL~Approx. 18,000IU / mL, Approx. 11,000IU / mL~Approx. 19,000IU / mL, about 11,000IU / mL to about 20,000IU / mL, about 12,000IU / mL to about 13,000IU / mL, about 12,000IU / mL to about 14,000IU / mL, about 12,000IU / mL to about 15,000IU / mL, about 12,000IU / mL to about 16,000IU / mL, approximately 12,000IU / mL to approximately 17,000IU / mL, approximately 12,000IU / mL to approximately 18,000IU / mL, approximately 12,000IU / mL to approximately 19,000IU / mL, approximately 12,000IU / mL to approximately 20,000I U / mL, approximately 13,000IU / mL to approximately 14,000IU / mL, approximately 13,000IU / mL to approximately 15,000IU / mL, approximately 13,000IU / mL to approximately 16,000IU / mL, approximately 13,000IU / mL to approximately 17,000IU / mL, Approximately 13,000IU / mL to approximately 18,000IU / mL, approximately 13,000IU / mL to approximately 19,000IU / mL, approximately 13,000IU / mL to approximately 20,000IU / mL, approximately 14,000IU / mL to approximately 15,000IU / mL, approximately 14,0 00IU / mL ~ approx. 16,000IU / mL, approx. 14,000IU / mL ~ approx. 17,000IU / mL, approx. 14,000IU / mL ~ approx. 18,000IU / mL, approx. 14,000IU / mL ~ approx. 19,000IU / mL, approx. 14,000IU / mL mL ~ approx. 20,000IU / mL, approx. 15,000IU / mL ~ approx. 16,000IU / mL, approx. 15,000IU / mL ~ approx. 17,000IU / mL, approx. 15,000IU / mL ~ approx. 18,000IU / mL, approx. 15,000IU / mL ~ approx. 1 9,000IU / mL, approximately 15,000IU / mL to approximately 20,000IU / mL, approximately 16,000IU / mL to approximately 17,000IU / mL, approximately 16,000IU / mL to approximately 18,000IU / mL, approximately 16,000IU / mL to approximately 19,000 The method according to any one of embodiments 1 to 9, wherein the amount of the serotonin-containing compound is about 16,000 IU / mL to about 20,000 IU / mL, about 17,000 IU / mL to about 18,000 IU / mL, about 17,000 IU / mL to about 19,000 IU / mL, about 17,000 IU / mL to about 20,000 IU / mL, about 18,000 IU / mL to about 19,000 IU / mL, about 18,000 IU / mL to about 20,000 IU / mL, or about 19,000 IU / mL to about 20,000 IU / mL. 13. The ultra-high concentration hyaluronidase is administered in an amount of at least 250 IU / mL, at least 500 IU / mL, at least 750 IU / mL, at least 1,000 IU / mL, at least 1,500 IU / mL, at least 2,000 IU / mL, at least 2,500 IU / mL, at least 3,000 IU / mL, at least 3,500 IU / mL, at least 4,000 IU / mL, at least 4,500 IU / mL or at least 5,000 IU / mL, and / or in an amount of at most 250 IU / mL, at most 500 IU / mL, at most 750 IU / mL, at least 1,000 IU / mL, at least 1,500 IU / mL, at least 2,000 IU / mL, at least 2,500 IU / mL, at least 3,000 IU / mL, at least 3,500 IU / mL, at least 4,000 IU / mL, at least 4,500 IU / mL or at least 5,000 IU / mL. IU / mL, at most 1,000 IU / mL, at most 1,500 IU / mL, at most 2,000 IU / mL, at most 2,500 IU / mL, at most 3,000 IU / mL, at most 3,500 IU / mL, at most 4,000 IU / mL, at most 4,500 IU / mL or at most 5,000 IU / mL, or an amount of about 250 IU / mL to about 500 IU / mL, about 250 IU / mL to about 750 IU / mL, about 250 IU / mL to about 1,000 IU / mL, about 250 IU / mL to about 1,500 IU / mL, about 250 IU / mL to about 2,000 IU / mL, approximately 250IU / mL to approximately 2,500IU / mL, approximately 250IU / mL to approximately 3,000IU / mL, approximately 250IU / mL to approximately 3,500IU / mL, approximately 250IU / mL to approximately 4,000IU / mL, approximately 250IU / mL to approximately 4,500IU / mL, approximately 250IU / mL~ Approximately 5,000IU / mL, approximately 500IU / mL to approximately 750IU / mL, approximately 500IU / mL to approximately 1,000IU / mL, approximately 500IU / mL to approximately 1,500IU / mL, approximately 500IU / mL to approximately 2,000IU / mL, approximately 500IU / mL to approximately 2,500IU / mL, approximately 500I U / mL~about 3,000IU / mL, about 500IU / mL~about 3,500IU / mL, about 500IU / mL~about 4,000IU / mL, about 500IU / mL~about 4,500IU / mL, about 500IU / mL~about 5,000IU / mL, about 750IU / mL~about 1,000IU / m L, about 750IU / mL to about 1,500IU / mL, about 750IU / mL to about 2,000IU / mL, about 750IU / mL to about 2,500IU / mL, about 750IU / mL to about 3,000IU / mL, about 750IU / mL to about 3,500IU / mL, about 750IU / mL to about 4,000IU / mL, approximately 750IU / mL to approximately 4,500IU / mL, approximately 750IU / mL to approximately 5,000IU / mL, approximately 1,000IU / mL to approximately 1,500IU / mL, approximately 1,000IU / mL to approximately 2,000IU / mL, approximately 1,000IU / mL to approximately 2,50 0IU / mL, approximately 1,000IU / mL to approximately 3,000IU / mL, approximately 1,000IU / mL to approximately 3,500IU / mL, approximately 1,000IU / mL to approximately 4,000IU / mL, approximately 1,000IU / mL to approximately 4,500IU / mL, approximately 1,000IU / mL to approximately 5, 000IU / mL, approximately 1,500IU / mL to approximately 2,000IU / mL, approximately 1,500IU / mL to approximately 2,500IU / mL, approximately 1,500IU / mL to approximately 3,000IU / mL, approximately 1,500IU / mL to approximately 3,500IU / mL, approximately 1,500IU / mL to approximately 4,000IU / mL, about 1,500IU / mL~about 4,500IU / mL, about 1,500IU / mL~about 5,000IU / mL, about 2,000IU / mL~about 2,500IU / mL, about 2,000IU / mL~about 3,000IU / mL, about 2,000IU / mL~ Approximately 3,500IU / mL, approximately 2,000IU / mL to approximately 4,000IU / mL, approximately 2,000IU / mL to approximately 4,500IU / mL, approximately 2,000IU / mL to approximately 5,000IU / mL, approximately 2,500IU / mL to approximately 3,000IU / mL, approximately 2,500IU / m L ~ approx. 3,500 IU / mL, approx. 2,500 IU / mL ~ approx. 4,000 IU / mL, approx. 2,500 IU / mL ~ approx. 4,500 IU / mL, approx. 2,500 IU / mL ~ approx. 5,000 IU / mL, approx. 3,000 IU / mL ~ approx. 3,500 IU / mL, approx. The method according to any one of embodiments 1 to 9, wherein the amount of the sucrose phosphate ... 14. The method of any one of embodiments 1-13, wherein the composition is administered in a single dose or in multiple doses. 15. The composition has a volume of at least 0.5 mL, at least 1.0 mL, at least 2.0 mL, at least 3.0 mL, at least 4.0 mL or at least 5.0 mL, and / or a volume of at most 0.5 mL, at most 1.0 mL, at most 2.0 mL, at most 3.0 mL, at most 4.0 mL or at most 5.0 mL, or a volume of about 0.5 mL to 1.0 mL, about 0.5 mL to 2.0 mL, about 0.5 mL The method according to any one of embodiments 1 to 14, wherein the administration is performed in a volume of about 0.5 mL to 3.0 mL, about 0.5 mL to 4.0 mL, about 0.5 mL to 5.0 mL, about 1.0 mL to 2.0 mL, about 1.0 mL to 3.0 mL, about 1.0 mL to 4.0 mL, about 1.0 to 5.0 mL, about 2.0 mL to 3.0 mL, about 2.0 mL to 4.0 mL, about 2.0 to 5.0 mL, about 3.0 mL to 4.0 mL, about 3.0 to 5.0 mL, or about 4.0 to 5.0 mL. 16. The composition is allowed to stand for at most 1 minute, at most 2 minutes, at most 3 minutes, at most 4 minutes, at most 5 minutes, at most 10 minutes, at most 15 minutes, at most 30 minutes, at most 45 minutes, at most 60 minutes, at most 75 minutes, or at most 90 minutes, or from about 1 minute to about 2 minutes, from about 1 minute to about 3 minutes, from about 1 minute to about 5 minutes, from about 1 minute to about 7 minutes, from about 1 minute to about 10 minutes, from about 1 minute to about 15 minutes, from about 1 minute to about 30 minutes, from about 1 minute to about 45 minutes, from about 1 minute to about 60 minutes, from about 1 minute to about 75 minutes, from about 1 minute to about 90 minutes, from about 3 minutes to about 5 minutes, from about 3 minutes to about 7 minutes, from about 3 minutes to about 10 minutes, from about 3 minutes to about 15 minutes, from about 3 minutes to about 30 minutes, from about 3 minutes 16. The method according to any one of embodiments 1 to 15, wherein the tissue area is entered in about 45 minutes, about 3 minutes to about 60 minutes, about 3 minutes to about 75 minutes, about 3 minutes to about 90 minutes, about 5 minutes to about 7 minutes, about 5 minutes to about 10 minutes, about 5 minutes to about 15 minutes, about 5 minutes to about 30 minutes, about 5 minutes to about 45 minutes, about 5 minutes to about 60 minutes, about 5 minutes to about 75 minutes, about 5 minutes to about 90 minutes, about 10 minutes to about 15 minutes, about 10 minutes to about 30 minutes, about 10 minutes to about 45 minutes, about 10 minutes to about 60 minutes, about 10 minutes to about 75 minutes, about 10 minutes to about 90 minutes, about 15 minutes to about 30 minutes, about 15 minutes to about 45 minutes, about 15 minutes to about 60 minutes, about 15 minutes to about 75 minutes, or about 15 minutes to about 90 minutes. 17. The hyaluronic acid induced occlusion in the one or more blood vessels supplying blood to the area of ​​the tissue affected by the occlusion is maintained for at most 1 minute, at most 2 minutes, at most 3 minutes, at most 4 minutes, at most 5 minutes, at most 10 minutes or at most 15 minutes, at most 30 minutes, at most 45 minutes, at most 60 minutes, at most 75 minutes or at most 90 minutes, or for about 1 minute to about 2 minutes, about 1 minute to about 3 minutes, about 1 minute to about 5 minutes, about 1 minute to about 7 minutes, about 1 minute to about 10 minutes, about 1 minute to about 15 minutes, about 1 minute to about 30 minutes, about 1 minute to about 45 minutes, about 1 minute to about 60 minutes, about 1 minute to about 75 minutes, about 1 minute to about 90 minutes, about 3 minutes to about 5 minutes, about 3 minutes to about 7 minutes, about 3 minutes to about 10 minutes, about 3 minutes to about 15 minutes, about 3 minutes to about 30 minutes, about 3 minutes to about 45 minutes, about 3 minutes to about 60 minutes, about 3 minutes to about 75 minutes, about 3 minutes to about 90 minutes, about 5 minutes to about 7 minutes, about 5 minutes to about 10 minutes, about 5 minutes to about 15 minutes, about 5 minutes to about 30 minutes, about 5 minutes to about 45 minutes, about 5 minutes to about 60 minutes, about 5 minutes to about 75 minutes, about 5 minutes to about 90 minutes, about 10 minutes to about The method according to any one of embodiments 1 to 16, wherein the concentration is reduced or eliminated within 15 minutes, about 10 minutes to about 30 minutes, about 10 minutes to about 45 minutes, about 10 minutes to about 60 minutes, about 10 minutes to about 75 minutes, about 10 minutes to about 90 minutes, about 15 minutes to about 30 minutes, about 15 minutes to about 45 minutes, about 15 minutes to about 60 minutes, about 15 minutes to about 75 minutes, or about 15 minutes to about 90 minutes. 18. A composition comprising ultra-high concentration hyaluronidase for use in reducing or eliminating hyaluronic acid-induced blockage in one or more blood vessels supplying blood to an area of ​​tissue. 19. Use of a composition comprising ultra-high concentration hyaluronidase to reduce or eliminate hyaluronic acid-induced blockage in one or more blood vessels supplying blood to an area of ​​tissue. 20. A composition comprising ultra-high concentration hyaluronidase for use in the manufacture of a medicament for reducing or eliminating hyaluronic acid-induced obstruction in one or more blood vessels supplying blood to an area of ​​tissue. 21. The use according to any one of embodiments 18 to 20, wherein the composition is administered using a delivery system. 22. A delivery system comprising a composition comprising ultra-high concentration hyaluronidase for use in reducing or eliminating hyaluronic acid-induced blockage in one or more blood vessels supplying blood to an area of ​​tissue. 23. Use of a delivery system comprising a composition comprising ultra-high concentration hyaluronidase to reduce or eliminate hyaluronic acid-induced blockage in one or more blood vessels supplying blood to an area of ​​tissue. 24. A composition comprising ultra-high concentration hyaluronidase for use in the manufacture of a medicament for reducing or eliminating hyaluronic acid-induced obstruction in one or more blood vessels supplying blood to a region of tissue, the composition being contained in a delivery system. 25. The use according to any one of embodiments 18 to 24, wherein the composition is administered to the dermis portion of the skin area. 26. The composition comprises at least 25,000 IU / mL, at least 50,000 IU / mL, at least 75,000 IU / mL, at least 100,000 IU / mL, at least 125,000 IU / mL, at least 150,000 IU / mL, at least 175,000 IU / mL, at least 200,000 IU / mL, at least 225,000 IU / mL, at least 250,000 IU / mL, at least 300,000 IU / mL, at least 350,000 IU / mL, at least 400,000 IU / mL, at least 450 ,000 IU / mL or a concentration of at least 500,000 IU / mL, and / or at most 25,000 IU / mL, at most 50,000 IU / mL, at most 75,000 IU / mL, at most 100,000 IU / mL, at most 125,000 IU / mL, at most 150,000 IU / mL, at most 175,000 IU / mL, at most 200,000 IU / mL, at most 225,000 IU / mL, at most 250,000 IU / mL, at most 300,000 IU / mL, at most 350,000 IU / mL, at most 400, 000IU / mL, at most 450,000IU / mL or at most 500,000IU / mL, or about 25,000IU / mL to about 50,000IU / mL, about 25,000IU / mL to about 75,000IU / mL, about 25,000IU / mL to about 100,000IU / mL, about 25,000IU / mL to about 125,000IU / mL, about 25,000IU / mL to about 150,000IU / mL, about 25,000IU / mL to about 175,000IU / mL, about 25,000IU / mL to about 200,000IU / mL, about 25,000IU / mL L ~ about 225,000IU / mL, about 25,000IU / mL - about 250,000IU / mL, about 25,000IU / mL - about 300,000IU / mL, about 25,000IU / mL - about 350,000IU / mL, about 25,000IU / mL - about 400,000IU / mL, Approx. 25,000IU / mL~Approx. 450,000IU / mL, Approx. 25,000IU / mL~Approx. 500,000IU / mL, Approx. 50,000I U / mL ~ approx. 75,000IU / mL, approx. 50,000IU / mL ~ approx. 100,000IU / mL, approx. 50,000IU / mL ~ approx. 125,000 IU / mL, from about 50,000 IU / mL to about 150,000 IU / mL, from about 50,000 IU / mL to about 175,000 IU / mL, from about 50,000 IU / mL to about 200,000 IU / mL, from about 50,000 IU / mL to about 225,000 IU / mL, from about 50,000 IU / mL to about 250,000 IU / mL, from about 50,000 IU / mL to about 300,000 IU / mL, from about 50,000 IU / mL to about 350,000 IU / mL, from about 50,000 IU / mL to about 400,000 IU / mL, from about 50,000 IU / mL to about 450,000 IU / mL, from about 50,000 IU / mL to about 500,000 IU / mL, from about 75,000 IU / mL to about 100,000 IU / mL, from about 75,000 IU / mL to about 125,000 IU / mL, from about 75,000 IU / mL to about 150,000 IU / mL, from about 75,000 IU / mL to about 175,000 IU / mL, from about 75,000 IU / mL to about 200,000 IU / mL, from about 75,000 IU / mL to about 225,000 IU / mL, from about 75,000 IU / mL to about 250,000 IU / mL, from about 75,000 IU / mL to about 300,000 IU / mL, from about 75,000 IU / mL to about 350,000 IU / mL, from about 75,000 IU / mL to about 400,000 IU / mL, from about 75,000 IU / mL to about 450,000 IU / mL, from about 75,000 IU / mL to about 500,000 IU / mL, from about 100,000 IU / mL to about 125,000 IU / mL, from about 100,000 IU / mL to about 150,000 IU / mL, from about 100,000 IU / mL to about 175,000 IU / mL, from about 100,000 IU / mL to about 200,000 IU / mL, from about 100,000 IU / mL to about 225,000 IU / mL, from about 100,000 IU / mL to about 250,000 IU / mL, from about 100,000 IU / mL to about 300,000 IU / mL, from about 100,000 IU / mL to about 350,000 IU / mL, from about 100,000 IU / mL to about 400,000 IU / mL, from about 100,000 IU / mL to about 450,000 IU / mL, from about 100,000 IU / mL to about 500,000 IU / mL, from about 150,000 IU / mL to about 200,000 IU / mL, from about 150,000 IU / mL to about 225,000 IU / mL, from about 150,000 IU / mL to about 250,000 IU / mL, from about 150,000IU / mL ~ approx. 300,000IU / mL, approx. 150,000IU / mL ~ approx. 350,000IU / mL, approx. 150,000IU / mL ~ approx. 400,000IU / mL, approx. 150,000IU / mL ~ approx. 450,0 00IU / mL, about 150,000IU / mL to about 500,000IU / mL, about 200,000IU / mL to about 225,000IU / mL, about 200,000IU / mL to about 250,000IU / mL, about 200,00 0IU / mL ~ approx. 300,000IU / mL, approx. 200,000IU / mL ~ approx. 350,000IU / mL, approx. 200,000IU / mL ~ approx. 400,000IU / mL, approx. 200,000IU / mL ~ approx. 450,000 IU / mL, approximately 200,000IU / mL to approximately 500,000IU / mL, approximately 250,000IU / mL to approximately 300,000IU / mL, approximately 250,000IU / mL to approximately 350,000IU / mL, approximately 250,000I U / mL ~ approx. 400,000IU / mL, approx. 250,000IU / mL ~ approx. 450,000IU / mL, approx. 250,000IU / mL ~ approx. 500,000IU / mL, approx. 300,000IU / mL ~ approx. 350,000IU / mL, about 300,000IU / mL to about 400,000IU / mL, about 300,000IU / mL to about 450,000IU / mL, about 300,000IU / mL to about 500,000IU / mL, about 350,000IU / mL The use according to any one of embodiments 18 to 25, wherein the hyaluronidase is present in a concentration of about 400,000 IU / mL, about 350,000 IU / mL to about 450,000 IU / mL, about 350,000 IU / mL to about 500,000 IU / mL, about 400,000 IU / mL to about 450,000 IU / mL, about 400,000 IU / mL to about 500,000 IU / mL, or about 450,000 IU / mL to about 500,000 IU / mL. 27. The composition has a concentration of at least 10,000 IU / mL, at least 20,000 IU / mL, at least 30,000 IU / mL, at least 40,000 IU / mL, at least 50,000 IU / mL, at least 60,000 IU / mL, at least 70,000 IU / mL, at least 80,000 IU / mL, at least 90,000 IU / mL or at least 100,000 IU / mL, and / or at most 10,000 IU / mL, at most 20,000 IU / mL, at most 30,000 IU / mL, at most 40, 000IU / mL, at most 50,000IU / mL, at most 60,000IU / mL, at most 70,000IU / mL, at most 80,000IU / mL, at most 90,000IU / mL or at most 100,000IU / mL, or from about 10,000IU / mL to about 20,000IU / mL, from about 10,000IU / mL to about 30,000IU / mL, from about 10,000IU / mL to about 40,000IU / mL, from about 10,000IU / mL to about 50,000IU / mL, from about 10,000IU / mL to about 60,000IU / mL, 000IU / mL ~ approx. 70,000IU / mL, approx. 10,000IU / mL ~ approx. 80,000IU / mL, approx. 10,000IU / mL ~ approx. 90,000IU / mL, approx. 10,000IU / mL ~ approx. 100,000IU / mL, approx. 20,000IU / mL ~ approx. 30,000IU / mL, about 20,000IU / mL to about 40,000IU / mL, about 20,000IU / mL to about 50,000IU / mL, about 20,000IU / mL to about 60,000IU / mL, about 20,000IU / mL to about 70,000IU / mL, about 20,000IU / mL to about 80, 000IU / mL, about 20,000IU / mL to about 90,000IU / mL, about 20,000IU / mL to about 100,000IU / mL, about 30,000IU / mL to about 40,000IU / mL, about 30,000IU / mL to about 50,000IU / mL, about 30,000IU / mL mL~about 60,000IU / mL, about 30,000IU / mL~about 70,000IU / mL, about 30,000IU / mL~about 80,000IU / mL, about 30,000IU / mL~about 90,000IU / mL, about 30,000IU / mL~about 100,000IU / mL, about 40,000IU / mL ~ approx. 50,000IU / mL, approx. 40,000IU / mL ~ approx. 60,000IU / mL, approx. 40,000IU / mL ~ approx. 70,000IU / mL , about 40,000IU / mL to about 80,000IU / mL, about 40,000IU / mL to about 90,000IU / mL, about 40,000IU / mL to about 100,000 IU / mL, approximately 50,000IU / mL to approximately 60,000IU / mL, approximately 50,000IU / mL to approximately 70,000IU / mL, approximately 50,000IU / mL to approximately 80 ,000IU / mL, approximately 50,000IU / mL to approximately 90,000IU / mL, approximately 50,000IU / mL to approximately 100,000IU / mL, approximately 60,000IU / m L ~ approx. 70,000IU / mL, approx. 60,000IU / mL ~ approx. 80,000IU / mL, approx. 60,000IU / mL ~ approx. 90,000IU / mL, approx. 60,00 0IU / mL ~ approx. 100,000IU / mL, approx. 70,000IU / mL ~ approx. 80,000IU / mL, approx. 70,000IU / mL ~ approx. 90,000IU / mL, approx. The use according to any one of embodiments 18 to 25, comprising the hyaluronidase at a concentration of 70,000 IU / mL to about 100,000 IU / mL, about 80,000 IU / mL to about 90,000 IU / mL, about 80,000 IU / mL to about 100,000 IU / mL, or about 90,000 IU / mL to about 100,000 IU / mL. 28. The composition comprises at least 5,000 IU / mL, at least 6,000 IU / mL, at least 7,000 IU / mL, at least 8,000 IU / mL, at least 9,000 IU / mL, at least 10,000 IU / mL, at least 11,000 IU / mL, at least 12,000 IU / mL, at least 13,000 IU / mL, at least 14,000 IU / mL, at least 15,000 IU / mL, at least 16,000 IU / mL, at least 17,000 IU / mL, at least 18,000 IU / mL, at least a concentration of 19,000 IU / mL or at least 20,000 IU / mL, and / or at most 5,000 IU / mL, at most 6,000 IU / mL, at most 7,000 IU / mL, at most 8,000 IU / mL, at most 9,000 IU / mL, at most 10,000 IU / mL, at most 11,000 IU / mL, at most 12,000 IU / mL, at most 13,000 IU / mL, at most 14,000 IU / mL, at most 15,000 IU / mL, at most 16,000 IU / mL, at most 17,000 IU / mL, at most 1 8,000 IU / mL, at most 19,000 IU / mL or at most 20,000 IU / mL, or about 5,000 IU / mL to about 6,000 IU / mL, about 5,000 IU / mL to about 7,000 IU / mL, about 5,000 IU / mL to about 8,000 IU / mL, about 5,000 IU / mL to about 9,000 IU / mL, about 5,000 IU / mL to about 10,000 IU / mL, about 5,000 IU / mL to about 11,000 IU / mL, about 5,000 IU / mL to about 12,000 IU / mL, about 5,000 IU / mL to about 13,000 IU / mL, about 5,000IU / mL ~ approx. 14,000IU / mL, approx. 5,000IU / mL ~ approx. 15,000IU / mL, approx. 5,000IU / mL ~ approx. 16,000IU / mL, approx. 5,000IU / mL ~ approx. 17,000IU / mL, approx. 5,000IU / mL ~ approx. 18,000IU / mL, Approximately 5,000IU / mL to approximately 19,000IU / mL, approximately 5,000IU / mL to approximately 20,000IU / mL, approximately 6,000IU / mL to approximately 7,000IU / mL, approximately 6,000IU / mL to approximately 8,000IU / mL, approximately 6,000IU / mL to approximately 9,000IU / mL, approximately 6,000 IU / mL to approximately 10,000 IU / mL, approximately 6,000 IU / mL to approximately 11,000 IU / mL, approximately 6,000 IU / mL to approximately 12,000 IU / mL, approximately 6,000 IU / mL to approximately 13,000 IU / mL, approximately 6,000 IU / mL to approximately 14,000 IU / mL, approximately 6,000 IU / mL to approximately 15,000 IU / mL, approximately 6,000 IU / mL to approximately 16,000 IU / mL, approximately 6,000 IU / mL to approximately 17,000 IU / mL, approximately 6,000 IU / mL to approximately 18,000 IU / mL, approximately 6,000 IU / mL to approximately 19,000 IU / mL, approximately 6,000 IU / mL to approximately 20,000 IU / mL, approximately 7,000 IU / mL to approximately 8,000 IU / mL, approximately 7,000 IU / mL to approximately 9,000 IU / mL, approximately 7,000 IU / mL to approximately 10,000 IU / mL, approximately 7,000 IU / mL to approximately 11,000 IU / mL, approximately 7,000 IU / mL to approximately 12,000 IU / mL, approximately 7,000 IU / mL to approximately 13,000 IU / mL, approximately 7,000 IU / mL to approximately 14,000 IU / mL, approximately 7,000 IU / mL to approximately 15,000 IU / mL, approximately 7,000 IU / mL to approximately 16,000 IU / mL, approximately 7,000 IU / mL to approximately 17,000 IU / mL, approximately 7,000 IU / mL to approximately 18,000 IU / mL, approximately 7,000 IU / mL to approximately 19,000 IU / mL, approximately 7,000 IU / mL to approximately 20,000 IU / mL, approximately 8,000 IU / mL to approximately 9,000 IU / mL, approximately 8,000 IU / mL to approximately 10,000 IU / mL, approximately 8,000 IU / mL to approximately 11,000 IU / mL, approximately 8,000 IU / mL to approximately 12,000 IU / mL, approximately 8,000 IU / mL to approximately 13,000 IU / mL, approximately 8,000 IU / mL to approximately 14,000 IU / mL, approximately 8,000 IU / mL to approximately 15,000 IU / mL, approximately 8,000 IU / mL to approximately 16,000 IU / mL, approximately 8,000 IU / mL to approximately 17,000 IU / mL, approximately 8,000 IU / mL to approximately 18,000 IU / mL, approximately 8,000 IU / mL to approximately 19,000 IU / mL, approximately 8,000 IU / mL to approximately 20,000 IU / mL, approximately 9,000 IU / mL to approximately 10,000 IU / mL, approximately 9,000 IU / mL to approximately 11,000 IU / mL, approximately 9,000 IU / mL to approximately 12,000 IU / mL, approximately 9,000 IU / mL to approximately 13,000 IU / mL, approximately 9,000 IU / mL to approximately 14,000 IU / mL, approximately 9,000 IU / mL to approximately 15,000 IU / mL, approximately 9,000 IU / mL to approximately 16,000 IU / mL, approximately 9,000 IU / mL to approximately 17,000 IU / mL, approximately 9,000 IU / mL to approximately 18,000 IU / mL, approximately 9,000 IU / mL to approximately 19,000 IU / mL, approximately 9,000 IU / mL to approximately 20,000 IU / mL, approximately 10,000 IU / mL to approximately 11,000 IU / mL, approximately 10,000 IU / mL to approximately 12,000 IU / mL, approximately 10,000 IU / mL to approximately 13,000 IU / mL, approximately 10,000 IU / mL to approximately 14,000 IU / mL, approximately 10,000 IU / mL to approximately 15,000 IU / mL, approximately 10,000 IU / mL to approximately 16,000 IU / mL, approximately 10,000 IU / mL to approximately 17,000 IU / mL, approximately 10,000 IU / mL to approximately 18,000 IU / mL, approximately 10,000 IU / mL to approximately 19,000 IU / mL, approximately 10,000 IU / mL to approximately 20,000 IU / mL, approximately 11,000 IU / mL to approximately 12,000 IU / mL, approximately 11,000 IU / mL to approximately 13,000 IU / mL, approximately 11,000 IU / mL to approximately 14,000 IU / mL, approximately 11,000 IU / mL to approximately 15,000 IU / mL, approximately 11,000 IU / mL to approximately 16,000 IU / mL, approximately 11,000 IU / mL to approximately 17,000 IU / mL, approximately 11,000 IU / mL to approximately 18,000 IU / mL, approximately 11,000 IU / mL to approximately 19,000 IU / mL, approximately 11,000 IU / mL to approximately 20,000 IU / mL, approximately 12,000 IU / mL to approximately 13,000 IU / mL, approximately 12,000 IU / mL to approximately 14,000 IU / mL, approximately 12,000 IU / mL to approximately 15,000 IU / mL, approximately 12,000 IU / mL to approximately 16,000 IU / mL, approximately 12,000 IU / mL to approximately 17,000 IU / mL, approximately 12,000 IU / mL to approximately 18,000 IU / mL, approximately 12,000 IU / mL to approximately 19,000 IU / mL, approximately 12,000 IU / mL to approximately 20,000 IU / mL, approximately 13,000 IU / mL to approximately 14,000 IU / mL, approximately 13,000 IU / mL to approximately 15,000 IU / mL, approximately 13,000 IU / mL to approximately 16,000 IU / mL, approximately 13,000 IU / mL to approximately 17,000 IU / mL, approximately 13,000 IU / mL to approximately 18,000IU / mL, approximately 13,000IU / mL to approximately 19,000IU / mL, approximately 13,000IU / mL to approximately 20,000IU / mL, approximately 14,000IU / mL to approximately 15,000 IU / mL, approximately 14,000IU / mL to approximately 16,000IU / mL, approximately 14,000IU / mL to approximately 17,000IU / mL, approximately 14,000IU / mL to approximately 18,000IU / mL, approximately 14,000IU / mL to approximately 19,000IU / mL, approximately 14,000IU / mL to approximately 20,000IU / mL, approximately 15,000IU / mL to approximately 16,000IU / mL, Approx. 15,000IU / mL~Approx. 17,000IU / mL, Approx. 15,000IU / mL~Approx. 18,000IU / mL, Approx. 15,000IU / mL~Approx. 19,000IU / mL, Approx. 15 ,000IU / mL ~ approx. 20,000IU / mL, approx. 16,000IU / mL ~ approx. 17,000IU / mL, approx. 16,000IU / mL ~ approx. 18,000IU / mL, approx. 16,00 0IU / mL ~ approx. 19,000IU / mL, approx. 16,000IU / mL ~ approx. 20,000IU / mL, approx. 17,000IU / mL ~ approx. 18,000IU / mL, approx. 17,000IU The use according to any one of embodiments 18 to 25, comprising the hyaluronidase at a concentration of about 17,000 IU / mL to about 20,000 IU / mL, about 18,000 IU / mL to about 19,000 IU / mL, about 18,000 IU / mL to about 20,000 IU / mL, or about 19,000 IU / mL to about 20,000 IU / mL. 29. The composition has a concentration of at least 250 IU / mL, at least 500 IU / mL, at least 750 IU / mL, at least 1,000 IU / mL, at least 1,500 IU / mL, at least 2,000 IU / mL, at least 2,500 IU / mL, at least 3,000 IU / mL, at least 3,500 IU / mL, at least 4,000 IU / mL, at least 4,500 IU / mL or at least 5,000 IU / mL, and / or at most 250 IU / mL, at most 500 IU / mL, at most 750 IU / mL, A concentration of at most 1,000 IU / mL, at most 1,500 IU / mL, at most 2,000 IU / mL, at most 2,500 IU / mL, at most 3,000 IU / mL, at most 3,500 IU / mL, at most 4,000 IU / mL, at most 4,500 IU / mL or at most 5,000 IU / mL, or from about 250 IU / mL to about 500 IU / mL, from about 250 IU / mL to about 750 IU / mL, from about 250 IU / mL to about 1,000 IU / mL, from about 250 IU / mL to about 1,500 IU / mL, from about 250 IU / mL to about 2,000 IU / mL , about 250IU / mL to about 2,500IU / mL, about 250IU / mL to about 3,000IU / mL, about 250IU / mL to about 3,500IU / mL, about 250IU / mL to about 4,000IU / mL, about 250IU / mL to about 4,500IU / mL, about 250IU / mL to about 5, 000IU / mL, about 500IU / mL to about 750IU / mL, about 500IU / mL to about 1,000IU / mL, about 500IU / mL to about 1,500IU / mL, about 500IU / mL to about 2,000IU / mL, about 500IU / mL to about 2,500IU / mL, about 500IU / mL mL ~ approx. 3,000IU / mL, approx. 500IU / mL ~ approx. 3,500IU / mL, approx. 500IU / mL ~ approx. 4,000IU / mL, approx. 500IU / mL ~ approx. 4,500IU / mL, approx. 500IU / mL ~ approx. 5,000IU / mL, approx. 750IU / mL ~ approx. 1,000IU / mL , about 750IU / mL to about 1,500IU / mL, about 750IU / mL to about 2,000IU / mL, about 750IU / mL to about 2,500IU / mL, about 750IU / mL to about 3,000IU / mL, about 750IU / mL to about 3,500IU / mL, about 750IU / mL to about 4,000IU / mL, about 750IU / mL to about 4,500IU / mL, about 750IU / mL to about 5,000IU / mL, about 1,000IU / mL to about 1,500IU / mL, about 1,000IU / mL to about 2,000IU / mL, about 1,000IU / mL to about 2,500 IU / mL, approximately 1,000IU / mL to approximately 3,000IU / mL, approximately 1,000IU / mL to approximately 3,500IU / mL, approximately 1,000IU / mL to approximately 4,000IU / mL, approximately 1,000IU / mL to approximately 4,500IU / mL, approximately 1,000IU / mL to approximately 5,000 IU / mL, approximately 1,500IU / mL to approximately 2,000IU / mL, approximately 1,500IU / mL to approximately 2,500IU / mL, approximately 1,500IU / mL to approximately 3,000IU / mL, approximately 1,500IU / mL to approximately 3,500IU / mL, approximately 1,500IU / mL to approximately 4,000 IU / mL, approximately 1,500IU / mL to approximately 4,500IU / mL, approximately 1,500IU / mL to approximately 5,000IU / mL, approximately 2,000IU / mL to approximately 2,500IU / mL, approximately 2,000IU / mL to approximately 3,000IU / mL, approximately 2,000IU / mL to approximately 3,500 IU / mL, approximately 2,000IU / mL to approximately 4,000IU / mL, approximately 2,000IU / mL to approximately 4,500IU / mL, approximately 2,000IU / mL to approximately 5,000IU / mL, approximately 2,500IU / mL to approximately 3,000IU / mL, approximately 2,500IU / mL to approximately 3,500 IU / mL, approximately 2,500IU / mL to approximately 4,000IU / mL, approximately 2,500IU / mL to approximately 4,500IU / mL, approximately 2,500IU / mL to approximately 5,000IU / mL, approximately 3,000IU / mL to approximately 3,500IU / mL, approximately 3,000IU / mL to approximately 4,000 The use according to any one of embodiments 18 to 25, comprising the hyaluronidase at a concentration of about 3,000 IU / mL to about 4,500 IU / mL, about 3,000 IU / mL to about 5,000 IU / mL, about 3,500 IU / mL to about 4,000 IU / mL, about 3,500 IU / mL to about 4,500 IU / mL, about 3,500 IU / mL to about 5,000 IU / mL, about 4,000 IU / mL to about 4,500 IU / mL, about 4,000 IU / mL to about 5,000 IU / mL, or about 4,500 IU / mL to about 5,000 IU / mL. 30. The ultra-high concentration hyaluronidase is at least 25,000 IU / mL, at least 50,000 IU / mL, at least 75,000 IU / mL, at least 100,000 IU / mL, at least 125,000 IU / mL, at least 150,000 IU / mL, at least 175,000 IU / mL, at least 200,000 IU / mL, at least 225,000 IU / mL, at least 250,000 IU / mL, at least 300,000 IU / mL, at least 350,000 IU / mL, at least 400,000 IU / mL mL, an amount of at least 450,000 IU / mL or at least 500,000 IU / mL, and / or an amount of at most 25,000 IU / mL, at most 50,000 IU / mL, at most 75,000 IU / mL, at most 100,000 IU / mL, at most 125,000 IU / mL, at most 150,000 IU / mL, at most 175,000 IU / mL, at most 200,000 IU / mL, at most 225,000 IU / mL, at most 250,000 IU / mL, at most 300,000 IU / mL, at most 350,000 IU / mL, at most 400,000 IU / mL, at most 450,000 IU / mL or at most 500,000 IU / mL, or from about 25,000 IU / mL to about 50,000 IU / mL, from about 25,000 IU / mL to about 75,000 IU / mL, from about 25,000 IU / mL to about 100,000 IU / mL, from about 25,000 IU / mL to about 125,000 IU / mL, from about 25,000 IU / mL to about 150,000 IU / mL, from about 25,000 IU / mL to about 175,000 IU / mL, from about 25,000 IU / mL to about 200,000 IU / mL L, about 25,000IU / mL to about 225,000IU / mL, about 25,000IU / mL to about 250,000IU / mL, about 25,000IU / mL to about 300,000IU / mL, about 25,000IU / mL to about 350,000IU / mL, about 25,000IU / mL to about 400,000IU / mL, about 25,000IU / mL to about 450,000IU / mL, about 25,000IU / mL to about 500,000IU / mL, about 50,000IU / mL to about 75,000IU / mL, about 50,000IU / mL to about 100,000IU / mL, about 50,000 IU / mL to approximately 125,000 IU / mL, approximately 50,000 IU / mL to approximately 150,000 IU / mL, approximately 50,000 IU / mL to approximately 175,000 IU / mL, approximately 50,000 IU / mL to approximately 200,000 IU / mL, approximately 50,000 IU / mL to approximately 225,000 IU / mL, approximately 50,000 IU / mL to approximately 250,000 IU / mL, approximately 50,000 IU / mL to approximately 300,000 IU / mL, approximately 50,000 IU / mL to approximately 350,000 IU / mL, approximately 50,000 IU / mL to approximately 400,000 IU / mL, approximately 50,000 IU / mL to approximately 450,000 IU / mL, approximately 50,000 IU / mL to approximately 500,000 IU / mL, approximately 75,000 IU / mL to approximately 100,000 IU / mL, approximately 75,000 IU / mL to approximately 125,000 IU / mL, approximately 75,000 IU / mL to approximately 150,000 IU / mL, approximately 75,000 IU / mL to approximately 175,000 IU / mL, approximately 75,000 IU / mL to approximately 200,000 IU / mL, approximately 75,000 IU / mL to approximately 225,000 IU / mL, approximately 75,000 IU / mL to approximately 250,000 IU / mL, approximately 75,000 IU / mL to approximately 300,000 IU / mL, approximately 75,000 IU / mL to approximately 350,000 IU / mL, approximately 75,000 IU / mL to approximately 400,000 IU / mL, approximately 75,000 IU / mL to approximately 450,000 IU / mL, approximately 75,000 IU / mL to approximately 500,000 IU / mL, approximately 100,000 IU / mL to approximately 125,000 IU / mL, approximately 100,000 IU / mL to approximately 150,000 IU / mL, approximately 100,000 IU / mL to approximately 175,000 IU / mL, approximately 100,000 IU / mL to approximately 200,000 IU / mL, approximately 100,000 IU / mL to approximately 225,000 IU / mL, approximately 100,000 IU / mL to approximately 250,000 IU / mL, approximately 100,000 IU / mL to approximately 300,000 IU / mL, approximately 100,000 IU / mL to approximately 350,000 IU / mL, approximately 100,000 IU / mL to approximately 400,000 IU / mL, approximately 100,000 IU / mL to approximately 450,000 IU / mL, approximately 100,000 IU / mL to approximately 500,000 IU / mL, approximately 150,000 IU / mL to approximately 200,000 IU / mL, approximately 150,000 IU / mL to approximately 225,000 IU / mL, approximately 150,000 IU / mL to approximately 250,000IU / mL, about 150,000IU / mL to about 300,000IU / mL, about 150,000IU / mL to about 350,000IU / mL, about 150,000IU / mL to about 400,000IU / mL, about 150,0 00IU / mL ~ approx. 450,000IU / mL, approx. 150,000IU / mL ~ approx. 500,000IU / mL, approx. 200,000IU / mL ~ approx. 225,000IU / mL, approx. 200,000IU / mL ~ approx. 250,000 IU / mL, approximately 200,000IU / mL to approximately 300,000IU / mL, approximately 200,000IU / mL to approximately 350,000IU / mL, approximately 200,000IU / mL to approximately 400,000IU / mL, approximately 200,000I U / mL ~ approx. 450,000IU / mL, approx. 200,000IU / mL ~ approx. 500,000IU / mL, approx. 250,000IU / mL ~ approx. 300,000IU / mL, approx. 250,000IU / mL ~ approx. 350,000IU / mL, about 250,000IU / mL to about 400,000IU / mL, about 250,000IU / mL to about 450,000IU / mL, about 250,000IU / mL to about 500,000IU / mL, about 300,000IU / m L ~ about 350,000IU / mL, about 300,000IU / mL - about 400,000IU / mL, about 300,000IU / mL - about 450,000IU / mL, about 300,000IU / mL - about 500,000IU / mL, The use according to any one of embodiments 18 to 29, wherein the amount of the compound is administered is about 350,000 IU / mL to about 400,000 IU / mL, about 350,000 IU / mL to about 450,000 IU / mL, about 350,000 IU / mL to about 500,000 IU / mL, about 400,000 IU / mL to about 450,000 IU / mL, about 400,000 IU / mL to about 500,000 IU / mL, or about 450,000 IU / mL to about 500,000 IU / mL. 31. The ultra-high concentration hyaluronidase is administered in an amount of at least 10,000 IU / mL, at least 20,000 IU / mL, at least 30,000 IU / mL, at least 40,000 IU / mL, at least 50,000 IU / mL, at least 60,000 IU / mL, at least 70,000 IU / mL, at least 80,000 IU / mL, at least 90,000 IU / mL or at least 100,000 IU / mL, and / or in an amount of at most 10,000 IU / mL, at most 20,000 IU / mL, at most 30,000 IU / mL, at most 50,000 IU / mL, at least 60,000 IU / mL, at least 70,000 IU / mL, at least 80,000 IU / mL, at least 90,000 IU / mL or at least 100,000 IU / mL. an amount of at most 40,000 IU / mL, at most 50,000 IU / mL, at most 60,000 IU / mL, at most 70,000 IU / mL, at most 80,000 IU / mL, at most 90,000 IU / mL or at most 100,000 IU / mL, or from about 10,000 IU / mL to about 20,000 IU / mL, from about 10,000 IU / mL to about 30,000 IU / mL, from about 10,000 IU / mL to about 40,000 IU / mL, from about 10,000 IU / mL to about 50,000 IU / mL, from about 10,000 IU / mL to about 60,000 IU / mL, 10,000IU / mL ~ approx. 70,000IU / mL, approx. 10,000IU / mL ~ approx. 80,000IU / mL, approx. 10,000IU / m L ~ approx. 90,000IU / mL, approx. 10,000IU / mL ~ approx. 100,000IU / mL, approx. 20,000IU / mL ~ approx. 30,000I U / mL, about 20,000IU / mL to about 40,000IU / mL, about 20,000IU / mL to about 50,000IU / mL, about 20,000IU / mL to about 60,000IU / mL, about 20,000IU / mL to about 70,000IU / mL, about 20,000IU / mL to about 80 ,000IU / mL, about 20,000IU / mL to about 90,000IU / mL, about 20,000IU / mL to about 100,000IU / mL , about 30,000IU / mL to about 40,000IU / mL, about 30,000IU / mL to about 50,000IU / mL, about 30,000IU / mL~about 60,000IU / mL, about 30,000IU / mL~about 70,000IU / mL, about 30,000IU / mL~about 80,000IU / mL, about 30,000IU / mL~about 90,000IU / mL, about 30,000IU / mL~about 100,000IU / mL, about 40,000IU / mL ~ approx. 50,000IU / mL, approx. 40,000IU / mL ~ approx. 60,000IU / mL, approx. 40,000IU / mL ~ approx. 70,000IU / m L, approx. 40,000IU / mL ~ approx. 80,000IU / mL, approx. 40,000IU / mL ~ approx. 90,000IU / mL, approx. 40,000IU / mL ~ approx. 100,0 00IU / mL, about 50,000IU / mL to about 60,000IU / mL, about 50,000IU / mL to about 70,000IU / mL, about 50,000IU / mL ~80,000IU / mL, approx. 50,000IU / mL ~ approx. 90,000IU / mL, approx. 50,000IU / mL ~ approx. 100,000IU / mL, approx. 60,00 0IU / mL ~ approx. 70,000IU / mL, approx. 60,000IU / mL ~ approx. 80,000IU / mL, approx. 60,000IU / mL ~ approx. 90,000IU / mL, Approx. 60,000IU / mL~Approx. 100,000IU / mL, Approx. 70,000IU / mL~Approx. 80,000IU / mL, Approx. 70,000IU / mL~Approx. 90,000 The use according to any one of embodiments 18 to 29, wherein the amount of the sedative is administered in an amount of about 70,000 IU / mL to about 100,000 IU / mL, about 80,000 IU / mL to about 90,000 IU / mL, about 80,000 IU / mL to about 100,000 IU / mL, or about 90,000 IU / mL to about 100,000 IU / mL. 32. The ultra-high concentration hyaluronidase is at least 5,000 IU / mL, at least 6,000 IU / mL, at least 7,000 IU / mL, at least 8,000 IU / mL, at least 9,000 IU / mL, at least 10,000 IU / mL, at least 11,000 IU / mL, at least 12,000 IU / mL, at least 13,000 IU / mL, at least 14,000 IU / mL, at least 15,000 IU / mL, at least 16,000 IU / mL, at least 17,000 IU / mL, at least 18,000 IU / mL L, an amount of at least 19,000 IU / mL or at least 20,000 IU / mL, and / or an amount of at most 5,000 IU / mL, at most 6,000 IU / mL, at most 7,000 IU / mL, at most 8,000 IU / mL, at most 9,000 IU / mL, at most 10,000 IU / mL, at most 11,000 IU / mL, at most 12,000 IU / mL, at most 13,000 IU / mL, at most 14,000 IU / mL, at most 15,000 IU / mL, at most 16,000 IU / mL, at most 17,000 IU / mL, An amount of at most 18,000 IU / mL, at most 19,000 IU / mL or at most 20,000 IU / mL, or from about 5,000 IU / mL to about 6,000 IU / mL, from about 5,000 IU / mL to about 7,000 IU / mL, from about 5,000 IU / mL to about 8,000 IU / mL, from about 5,000 IU / mL to about 9,000 IU / mL, from about 5,000 IU / mL to about 10,000 IU / mL, from about 5,000 IU / mL to about 11,000 IU / mL, from about 5,000 IU / mL to about 12,000 IU / mL, from about 5,000 IU / mL to about 13,000 IU / mL , about 5,000IU / mL to about 14,000IU / mL, about 5,000IU / mL to about 15,000IU / mL, about 5,000IU / mL to about 16,000IU / mL, about 5,000IU / mL to about 17,000IU / mL, about 5,000IU / mL to about 18,000IU / mL , approx. 5,000IU / mL ~ approx. 19,000IU / mL, approx. 5,000IU / mL ~ approx. 20,000IU / mL, approx. 6,000IU / mL ~ Approximately 7,000IU / mL, approximately 6,000IU / mL to approximately 8,000IU / mL, approximately 6,000IU / mL to approximately 9,000IU / mL, approximately 6,000 IU / mL to approximately 10,000 IU / mL, approximately 6,000 IU / mL to approximately 11,000 IU / mL, approximately 6,000 IU / mL to approximately 12,000 IU / mL, approximately 6,000 IU / mL to approximately 13,000 IU / mL, approximately 6,000 IU / mL to approximately 14,000 IU / mL, approximately 6,000 IU / mL to approximately 15,000 IU / mL, approximately 6,000 IU / mL to approximately 16,000 IU / mL, approximately 6,000 IU / mL to approximately 17,000 IU / mL, approximately 6,000 IU / mL to approximately 18,000 IU / mL, approximately 6,000 IU / mL to approximately 19,000 IU / mL, approximately 6,000 IU / mL to approximately 20,000 IU / mL, approximately 7,000 IU / mL to approximately 8,000 IU / mL, approximately 7,000 IU / mL to approximately 9,000 IU / mL, approximately 7,000 IU / mL to approximately 10,000 IU / mL, approximately 7,000 IU / mL to approximately 11,000 IU / mL, approximately 7,000 IU / mL to approximately 12,000 IU / mL, approximately 7,000 IU / mL to approximately 13,000 IU / mL, approximately 7,000 IU / mL to approximately 14,000 IU / mL, approximately 7,000 IU / mL to approximately 15,000 IU / mL, approximately 7,000 IU / mL to approximately 16,000 IU / mL, approximately 7,000 IU / mL to approximately 17,000 IU / mL, approximately 7,000 IU / mL to approximately 18,000 IU / mL, approximately 7,000 IU / mL to approximately 19,000 IU / mL, approximately 7,000 IU / mL to approximately 20,000 IU / mL, approximately 8,000 IU / mL to approximately 9,000 IU / mL, approximately 8,000 IU / mL to approximately 10,000 IU / mL, approximately 8,000 IU / mL to approximately 11,000 IU / mL, approximately 8,000 IU / mL to approximately 12,000 IU / mL, approximately 8,000 IU / mL to approximately 13,000 IU / mL, approximately 8,000 IU / mL to approximately 14,000 IU / mL, approximately 8,000 IU / mL to approximately 15,000 IU / mL, approximately 8,000 IU / mL to approximately 16,000 IU / mL, approximately 8,000 IU / mL to approximately 17,000 IU / mL, approximately 8,000 IU / mL to approximately 18,000 IU / mL, approximately 8,000 IU / mL to approximately 19,000 IU / mL, approximately 8,000 IU / mL to approximately 20,000 IU / mL, approximately 9,000 IU / mL to approximately 10,000 IU / mL, approximately 9,000 IU / mL to approximately 11,000 IU / mL, approximately 9,000 IU / mL to approximately 12,000 IU / mL, approximately 9,000 IU / mL to approximately 13,000 IU / mL, approximately 9,000 IU / mL to approximately 14,000 IU / mL, approximately 9,000 IU / mL to approximately 15,000 IU / mL, approximately 9,000 IU / mL to approximately 16,000 IU / mL, approximately 9,000 IU / mL to approximately 17,000 IU / mL, approximately 9,000 IU / mL to approximately 18,000 IU / mL, approximately 9,000 IU / mL to approximately 19,000 IU / mL, approximately 9,000 IU / mL to approximately 20,000 IU / mL, approximately 10,000 IU / mL to approximately 11,000 IU / mL, approximately 10,000 IU / mL to approximately 12,000 IU / mL, approximately 10,000 IU / mL to approximately 13,000 IU / mL, approximately 10,000 IU / mL to approximately 14,000 IU / mL, approximately 10,000 IU / mL to approximately 15,000 IU / mL, approximately 10,000 IU / mL to approximately 16,000 IU / mL, approximately 10,000 IU / mL to approximately 17,000 IU / mL, approximately 10,000 IU / mL to approximately 18,000 IU / mL, approximately 10,000 IU / mL to approximately 19,000 IU / mL, approximately 10,000 IU / mL to approximately 20,000 IU / mL, approximately 11,000 IU / mL to approximately 12,000 IU / mL, approximately 11,000 IU / mL to approximately 13,000 IU / mL, approximately 11,000 IU / mL to approximately 14,000 IU / mL, approximately 11,000 IU / mL to approximately 15,000 IU / mL, approximately 11,000 IU / mL to approximately 16,000 IU / mL, approximately 11,000 IU / mL to approximately 17,000 IU / mL, approximately 11,000 IU / mL to approximately 18,000 IU / mL, approximately 11,000 IU / mL to approximately 19,000 IU / mL, approximately 11,000 IU / mL to approximately 20,000 IU / mL, approximately 12,000 IU / mL to approximately 13,000 IU / mL, approximately 12,000 IU / mL to approximately 14,000 IU / mL, approximately 12,000 IU / mL to approximately 15,000 IU / mL, approximately 12,000 IU / mL to approximately 16,000 IU / mL, approximately 12,000 IU / mL to approximately 17,000 IU / mL, approximately 12,000 IU / mL to approximately 18,000 IU / mL, approximately 12,000 IU / mL to approximately 19,000 IU / mL, approximately 12,000 IU / mL to approximately 20,000 IU / mL, approximately 13,000 IU / mL to approximately 14,000 IU / mL, approximately 13,000 IU / mL to approximately 15,000 IU / mL, approximately 13,000 IU / mL to approximately 16,000 IU / mL, approximately 13,000 IU / mL to approximately 17,000 IU / mL, approximately 13,000 IU / mL to approximately 18,000IU / mL, approx. 13,000IU / mL ~ approx. 19,000IU / mL, approx. 13,000IU / mL ~ approx. 20,000IU / mL, approx. 14,000IU / mL ~ approx. 15,0 00IU / mL, approximately 14,000IU / mL to approximately 16,000IU / mL, approximately 14,000IU / mL to approximately 17,000IU / mL, approximately 14,000IU / mL to approximately 18,000 IU / mL, approximately 14,000IU / mL to approximately 19,000IU / mL, approximately 14,000IU / mL to approximately 20,000IU / mL, approximately 15,000IU / mL to approximately 16,000IU / mL, about 15,000IU / mL to about 17,000IU / mL, about 15,000IU / mL to about 18,000IU / mL, about 15,000IU / mL to about 19,000IU / m L, about 15,000IU / mL to about 20,000IU / mL, about 16,000IU / mL to about 17,000IU / mL, about 16,000IU / mL to about 18,000IU / mL, Approximately 16,000IU / mL to approximately 19,000IU / mL, approximately 16,000IU / mL to approximately 20,000IU / mL, approximately 17,000IU / mL to approximately 18,000IU / mL, approximately 1 The use according to any one of embodiments 18 to 29, wherein the amount is administered in an amount of 7,000 IU / mL to about 19,000 IU / mL, about 17,000 IU / mL to about 20,000 IU / mL, about 18,000 IU / mL to about 19,000 IU / mL, about 18,000 IU / mL to about 20,000 IU / mL, or about 19,000 IU / mL to about 20,000 IU / mL. 33. The ultra-high concentration hyaluronidase is administered in an amount of at least 250 IU / mL, at least 500 IU / mL, at least 750 IU / mL, at least 1,000 IU / mL, at least 1,500 IU / mL, at least 2,000 IU / mL, at least 2,500 IU / mL, at least 3,000 IU / mL, at least 3,500 IU / mL, at least 4,000 IU / mL, at least 4,500 IU / mL or at least 5,000 IU / mL, and / or in an amount of at most 250 IU / mL, at most 500 IU / mL, at most 750 IU / mL, at least 1,000 IU / mL, at least 1,500 IU / mL, at least 2,000 IU / mL, at least 2,500 IU / mL, at least 3,000 IU / mL, at least 3,500 IU / mL, at least 4,000 IU / mL, at least 4,500 IU / mL or at least 5,000 IU / mL. IU / mL, at most 1,000 IU / mL, at most 1,500 IU / mL, at most 2,000 IU / mL, at most 2,500 IU / mL, at most 3,000 IU / mL, at most 3,500 IU / mL, at most 4,000 IU / mL, at most 4,500 IU / mL or at most 5,000 IU / mL, or an amount of about 250 IU / mL to about 500 IU / mL, about 250 IU / mL to about 750 IU / mL, about 250 IU / mL to about 1,000 IU / mL, about 250 IU / mL to about 1,500 IU / mL, about 250 IU / mL to about 2,000 IU / mL, approximately 250IU / mL to approximately 2,500IU / mL, approximately 250IU / mL to approximately 3,000IU / mL, approximately 250IU / mL to approximately 3,500IU / mL, approximately 250IU / mL to approximately 4,000IU / mL, approximately 250IU / mL to approximately 4,500IU / mL, approximately 250IU / mL~ Approximately 5,000IU / mL, approximately 500IU / mL to approximately 750IU / mL, approximately 500IU / mL to approximately 1,000IU / mL, approximately 500IU / mL to approximately 1,500IU / mL, approximately 500IU / mL to approximately 2,000IU / mL, approximately 500IU / mL to approximately 2,500IU / mL, approximately 500I U / mL~about 3,000IU / mL, about 500IU / mL~about 3,500IU / mL, about 500IU / mL~about 4,000IU / mL, about 500IU / mL~about 4,500IU / mL, about 500IU / mL~about 5,000IU / mL, about 750IU / mL~about 1,000IU / m L, about 750IU / mL to about 1,500IU / mL, about 750IU / mL to about 2,000IU / mL, about 750IU / mL to about 2,500IU / mL, about 750IU / mL to about 3,000IU / mL, about 750IU / mL to about 3,500IU / mL, about 750IU / mL to about 4,000IU / mL, approximately 750IU / mL to approximately 4,500IU / mL, approximately 750IU / mL to approximately 5,000IU / mL, approximately 1,000IU / mL to approximately 1,500IU / mL, approximately 1,000IU / mL to approximately 2,000IU / mL, approximately 1,000IU / mL to approximately 2,50 0IU / mL, approximately 1,000IU / mL to approximately 3,000IU / mL, approximately 1,000IU / mL to approximately 3,500IU / mL, approximately 1,000IU / mL to approximately 4,000IU / mL, approximately 1,000IU / mL to approximately 4,500IU / mL, approximately 1,000IU / mL to approximately 5,0 00IU / mL, approximately 1,500IU / mL to approximately 2,000IU / mL, approximately 1,500IU / mL to approximately 2,500IU / mL, approximately 1,500IU / mL to approximately 3,000IU / mL, approximately 1,500IU / mL to approximately 3,500IU / mL, approximately 1,500IU / mL to approximately 4 ,000IU / mL, approximately 1,500IU / mL to approximately 4,500IU / mL, approximately 1,500IU / mL to approximately 5,000IU / mL, approximately 2,000IU / mL to approximately 2,500IU / mL, approximately 2,000IU / mL to approximately 3,000IU / mL, approximately 2,000IU / mL to approximately 3,500IU / mL, approximately 2,000IU / mL to approximately 4,000IU / mL, approximately 2,000IU / mL to approximately 4,500IU / mL, approximately 2,000IU / mL to approximately 5,000IU / mL, approximately 2,500IU / mL to approximately 3,000IU / mL, approximately 2,500IU / mL ~3,500IU / mL, 2,500IU / mL~4,000IU / mL, 2,500IU / mL~4,500IU / mL, 2,500IU / mL~5,000IU / mL, 3,000IU / mL~3,500IU / mL, 3,000IU / m The use according to any one of embodiments 18 to 29, wherein the amount of the sedative is administered in an amount of about 4,000 IU / mL, about 3,000 IU / mL to about 4,500 IU / mL, about 3,000 IU / mL to about 5,000 IU / mL, about 3,500 IU / mL to about 4,000 IU / mL, about 3,500 IU / mL to about 4,500 IU / mL, about 3,500 IU / mL to about 5,000 IU / mL, about 4,000 IU / mL to about 4,500 IU / mL, about 4,000 IU / mL to about 5,000 IU / mL, or about 4,500 IU / mL to about 5,000 IU / mL. 34. The method of any one of embodiments 18-33, wherein the composition or medicament is administered in a single dose or in multiple doses. 35. The composition or drug is administered in a volume of at least 0.5 mL, at least 1.0 mL, at least 2.0 mL, at least 3.0 mL, at least 4.0 mL or at least 5.0 mL, and / or in a volume of at most 0.5 mL, at most 1.0 mL, at most 2.0 mL, at most 3.0 mL, at most 4.0 mL or at most 5.0 mL, or in a volume of about 0.5 mL to 1.0 mL, about 0.5 mL to 2.0 mL, about 0.5 The use according to any one of embodiments 18 to 34, wherein the composition is administered in a volume of about 0.5 mL to 3.0 mL, about 0.5 mL to 4.0 mL, about 0.5 mL to 5.0 mL, about 1.0 mL to 2.0 mL, about 1.0 mL to 3.0 mL, about 1.0 mL to 4.0 mL, about 1.0 to 5.0 mL, about 2.0 mL to 3.0 mL, about 2.0 mL to 4.0 mL, about 2.0 to 5.0 mL, about 3.0 mL to 4.0 mL, about 3.0 to 5.0 mL, or about 4.0 to 5.0 mL. 36. The composition or drug is administered for at most 1 minute, at most 2 minutes, at most 3 minutes, at most 4 minutes, at most 5 minutes, at most 10 minutes, at most 15 minutes, at most 30 minutes, at most 45 minutes, at most 60 minutes, at most 75 minutes or at most 90 minutes, or for about 1 minute to about 2 minutes, about 1 minute to about 3 minutes, about 1 minute to about 5 minutes, about 1 minute to about 7 minutes, about 1 minute to about 10 minutes, about 1 minute to about 15 minutes, about 1 minute to about 30 minutes, about 1 minute to about 45 minutes, about 1 minute to about 60 minutes, about 1 minute to about 75 minutes, about 1 minute to about 90 minutes, about 3 minutes to about 5 minutes, about 3 minutes to about 7 minutes, about 3 minutes to about 10 minutes, about 3 minutes to about 15 minutes, about 3 minutes to about 30 minutes, The use according to any one of embodiments 26 to 35, wherein the composition enters the tissue area in about 3 minutes to about 45 minutes, about 3 minutes to about 60 minutes, about 3 minutes to about 75 minutes, about 3 minutes to about 90 minutes, about 5 minutes to about 7 minutes, about 5 minutes to about 10 minutes, about 5 minutes to about 15 minutes, about 5 minutes to about 30 minutes, about 5 minutes to about 45 minutes, about 5 minutes to about 60 minutes, about 5 minutes to about 75 minutes, about 5 minutes to about 90 minutes, about 10 minutes to about 15 minutes, about 10 minutes to about 30 minutes, about 10 minutes to about 45 minutes, about 10 minutes to about 60 minutes, about 10 minutes to about 75 minutes, about 10 minutes to about 90 minutes, about 15 minutes to about 30 minutes, about 15 minutes to about 45 minutes, about 15 minutes to about 60 minutes, about 15 minutes to about 75 minutes, or about 15 minutes to about 90 minutes. 37. The hyaluronic acid induced occlusion in the one or more blood vessels supplying blood to the area of ​​the tissue affected by the occlusion is maintained for at most 1 minute, at most 2 minutes, at most 3 minutes, at most 4 minutes, at most 5 minutes, at most 10 minutes, at most 15 minutes, at most 30 minutes, at most 45 minutes, at most 60 minutes, at most 75 minutes, or at most 90 minutes, or for about 1 minute to about 2 minutes, about 1 minute to about 3 minutes, about 1 minute to about 5 minutes, about 1 minute to about 7 minutes, about 1 minute to about 10 minutes, about 1 minute to about 15 minutes, about 1 minute to about 30 minutes, about 1 minute to about 45 minutes, about 1 minute to about 60 minutes, about 1 minute to about 75 minutes, about 1 minute to about 90 minutes, about 3 minutes to about 5 minutes, about 3 minutes to about 7 minutes, about 3 minutes to about 1 minute 0 minutes, about 3 minutes to about 15 minutes, about 3 minutes to about 30 minutes, about 3 minutes to about 45 minutes, about 3 minutes to about 60 minutes, about 3 minutes to about 75 minutes, about 3 minutes to about 90 minutes, about 5 minutes to about 7 minutes, about 5 minutes to about 10 minutes, about 5 minutes to about 15 minutes, about 5 minutes to about 30 minutes, about 5 minutes to about 45 minutes, about 5 minutes to about 60 minutes, about 5 minutes to about 75 minutes, about 5 minutes to about 90 minutes, about 10 minutes to about 1 The use according to any one of embodiments 18 to 36, wherein the concentration is reduced or eliminated within 5 minutes, about 10 minutes to about 30 minutes, about 10 minutes to about 45 minutes, about 10 minutes to about 60 minutes, about 10 minutes to about 75 minutes, about 10 minutes to about 90 minutes, about 15 minutes to about 30 minutes, about 15 minutes to about 45 minutes, about 15 minutes to about 60 minutes, about 15 minutes to about 75 minutes, or about 15 minutes to about 90 minutes. 38. A kit comprising one or more containers, each container comprising a pharmaceutical composition comprising ultra-high concentration hyaluronidase. 39. The kit of embodiment 38, wherein the pharmaceutical composition is in a liquid formulation. 40. The kit according to embodiment 38, wherein the pharmaceutical composition is in a dry formulation. 41. The kit of any one of embodiments 38-40, wherein each of the one or more containers is a delivery system. 42. The kit according to any one of embodiments 38 to 40, further comprising a delivery system. 43. The kit of any one of embodiments 38-42, further comprising another container containing a solvent. 44. The kit of any one of embodiments 38-43, further comprising instructions. EXAMPLES

[0084] The following non-limiting examples are provided for illustrative purposes only to facilitate a more complete understanding of representative embodiments presently contemplated, and are not to be construed as limiting the embodiments described herein, including those relating to the compounds, pharmaceutical compositions, or methods and uses disclosed herein.

[0085] Example 1: Rabbit model of extravascular HA dermal filler removal using hyaluronidase This example demonstrates how to use an extravascular dermal filler animal model to evaluate the safety and efficacy of hyaluronidase treatment as disclosed herein. New Zealand White rabbits are used in this study. These animals are selected due to the similarity of their vascular anatomy to that of humans. New Zealand White rabbits weighing 2.0-4.5 kg are divided into groups based on the dose and administration time of hyaluronidase.

[0086] In one series of experiments, animals were divided into three groups and each animal was injected subcutaneously with 0.2 mL of lidocaine-containing dermal filler at three different sites along the animal's back. Ultrasonography imaging was then used to evaluate the dermal filler at each injection site for each animal. After completing this baseline analysis, the animals were then subjected to one of three treatments. Group 1 animals (control animals) were treated by injecting 0.2 mL of phosphate-buffered saline (PBS) at the dermal filler injection site. Group 2 animals were treated by injecting 0.2 mL of low concentration hyaluronidase (150 IU / mL) at the dermal filler injection site. Group 3 animals were treated by injecting 0.2 mL of high concentration hyaluronidase (31,000 IU / mL) at the dermal filler injection site. Then, 5 minutes, 10 minutes, 30 minutes, 60 minutes and 24 hours after treatment, the presence of dermal filler at each injection site was evaluated using ultrasonography imaging in all treated animals. Ultrasound measurements of the dermal filler at each injection site were taken for central area and 3D volume, and representative images of each dermal filler site were taken. Pre-treatment ultrasound measurements were taken as baseline size, and all other measurements were evaluated as a percentage increase or decrease from the pre-treatment ultrasound measurements.

[0087] As shown in Table 1, animals in group 1 administered PBS did not show any significant loss of dermal filler throughout the experimental period. Interestingly, animals in group 2 administered low concentration hyaluronidase (150 IU / mL) also failed to show any significant loss of dermal filler. On the other hand, animals in group 3 administered high concentration hyaluronidase (40,000 IU / mL) showed significant loss of dermal filler, showing about 20% size loss 30 minutes after the treatment time point, about 35% size loss 45 minutes after the treatment time point, and complete loss of dermal filler 24 hours after the treatment time point. The increase in the size rate of dermal filler in each group may possibly be secondary to tissue swelling associated with PBS or hyaluronidase injection. [Table 1]

[0088] Example 2: Rabbit model of intravascular HA dermal filler removal using hyaluronidase This example demonstrates how to use an intravascular dermal filler animal model to evaluate the safety and efficacy of hyaluronidase treatment as disclosed herein. New Zealand White rabbits are used in this study. These animals are selected due to the similarity of their vascular anatomy to that of humans. New Zealand White rabbits weighing 2.0-4.5 kg are divided into groups based on the dose and administration time of hyaluronidase.

[0089] In one series of experiments, animals were divided into three groups and each animal was injected with 0.1 mL of lidocaine-containing dermal filler into the left and right auricular arteries at one site in each ear of each animal. Ultrasonography imaging was then used to evaluate the dermal filler at each injection site for each animal. After completing this baseline analysis, the animals were then subjected to one of three treatments. Group 1 animals (control animals) were treated with intraauricular injection of 10 μL of PBS at each of the four sites containing dermal filler occlusion. Group 2 animals were treated with intraauricular injection of 0.1 mL of low concentration hyaluronidase (150 IU / mL) at each of the four sites containing dermal filler occlusion. Group 3 animals were treated with intraauricular injection of 10 μL of high concentration hyaluronidase (40,000 IU / mL) at each of the four sites containing dermal filler occlusion. Then, 5 minutes, 10 minutes, 30 minutes, 60 minutes and 24 hours after treatment, the presence of dermal filler at each injection site was evaluated using ultrasonography imaging in all treated animals. Ultrasound measurements of the dermal filler at each injection site were taken for central area and 3D volume, and representative images of each dermal filler site were taken. Pre-treatment ultrasound measurements were taken as baseline size, and all other measurements were evaluated as a percentage increase or decrease from the pre-treatment ultrasound measurements.

[0090] As shown in Table 2, animals in group 1 administered PBS did not show any significant loss of dermal filler throughout the entire experimental period. Animals in group 2 administered low concentration hyaluronidase (150 IU / mL) showed significant loss of dermal filler consistent throughout the entire time course, with approximately 43% size loss 15 minutes after the treatment time point, approximately 50% size loss 30 minutes after the treatment time point, approximately 56% size loss 45 minutes after the treatment time point, and complete loss of dermal filler 24 hours after the treatment time point. Animals in group 3 administered high concentration hyaluronidase (31,000 IU / mL) also showed significant loss of dermal filler with a dramatically increased loss rate compared to animals in group 2. For example, animals in group 3 showed approximately 70% size loss 15 minutes after the treatment time point, approximately 90% size loss 30 minutes after the treatment time point, and complete loss of dermal filler 45 minutes after the treatment time point. [Table 2]

[0091] Example 3: Rabbit model of filler-induced vascular occlusion This example demonstrates how to evaluate the safety and efficacy of hyaluronidase treatment as disclosed herein using an animal model for filler-induced vascular occlusion events. New Zealand White rabbits are used to simulate hyaluronic acid-associated vascular occlusion of an area of ​​tissue. These animals are selected due to the similarity of their vascular anatomy to that of human blood vessels. New Zealand White rabbits weighing 2.0-3.0 kg are divided into groups based on the dose and administration time of hyaluronidase.

[0092] The hyaluronic acid filler is administered to the facial or femoral artery of the animal to cause arterial occlusion. The arterial occlusion and subsequent ischemia are confirmed by suitable techniques, such as ultrasound, angiography, nerve conduction studies (NCS), electromyography (EMG) and / or electroencephalography (EEG) analysis. In addition, for femoral artery administration, a hind paw assay is performed. Different doses of ultra-high concentration hyaluronidase are administered at several post-occlusion time points to evaluate both dosing and timing effectiveness of the treatment. Control animals are injected with hyaluronic acid filler in the same way as experimental animals, except that they are not treated with hyaluronidase. Angiographic and EEG changes are recorded 30, 60, 90 and 120 minutes after administration of hyaluronidase. EEG is performed 60 and 120 minutes later to confirm tissue reperfusion and electrophysiological function.

[0093] In one series of experiments, arterial occlusion was induced in all rabbits by injecting 0.5 mL to 0.9 mL of hyaluronic acid filler into the left facial or left femoral artery, respectively, with the right facial or right femoral artery serving as an untreated control. The animals were then divided into six experimental groups, each containing two or three animals, with group 1 animals each receiving 500 μL of a composition containing ultra-high concentration hyaluronidase (10,000 IU / mL) administered subcutaneously around the occlusion 5 minutes after hyaluronic acid filler injection, group 2 animals each receiving 500 μL of a composition containing ultra-high concentration hyaluronidase (10,000 IU / mL) administered subcutaneously around the occlusion 10 minutes after hyaluronic acid filler injection, and group 3 animals each receiving 500 μL of a composition containing ultra-high concentration hyaluronidase (10,000 IU / mL) administered subcutaneously around the occlusion 5 minutes after hyaluronic acid filler injection. (12,000 IU / mL), each animal in group 4 is administered a composition containing 500 μL of ultra-high concentration hyaluronidase (12,000 IU / mL) administered subcutaneously around the occlusion 10 minutes after hyaluronic acid filler injection, each animal in group 5 is administered a composition containing 500 μL of low concentration hyaluronidase (150 IU / mL) administered subcutaneously around the occlusion 5 minutes after hyaluronic acid filler injection, and each animal in group 6 is administered a composition containing 500 μL of low concentration hyaluronidase (150 IU / mL) administered subcutaneously around the occlusion 10 minutes after hyaluronic acid filler injection.

[0094] In another series of experiments, arterial occlusion was induced in all rabbits by injecting 0.5 mL to 0.9 mL of hyaluronic acid filler into the left facial or left femoral artery, respectively, with the right facial or right femoral artery serving as untreated controls. The animals were then divided into six experimental groups, each containing two or three animals, with group 1 animals each receiving 500 μL of a composition containing ultra-high concentration hyaluronidase (15,000 IU / mL) administered subcutaneously around the occlusion 5 minutes after hyaluronic acid filler injection, group 2 animals each receiving 500 μL of a composition containing ultra-high concentration hyaluronidase (15,000 IU / mL) administered subcutaneously around the occlusion 10 minutes after hyaluronic acid filler injection, and group 3 animals each receiving 500 μL of a composition containing ultra-high concentration hyaluronidase (15,000 IU / mL) administered subcutaneously around the occlusion 5 minutes after hyaluronic acid filler injection. (20,000 IU / mL), each animal in group 4 is administered a composition containing 500 μL of ultra-high concentration hyaluronidase (20,000 IU / mL) administered subcutaneously around the occlusion 10 minutes after hyaluronic acid filler injection, each animal in group 5 is administered a composition containing 500 μL of low concentration hyaluronidase (150 IU / mL) administered subcutaneously around the occlusion 5 minutes after hyaluronic acid filler injection, and each animal in group 6 is administered a composition containing 500 μL of low concentration hyaluronidase (150 IU / mL) administered subcutaneously around the occlusion 10 minutes after hyaluronic acid filler injection.

[0095] In another series of experiments, arterial occlusion was induced in all rabbits by injecting 0.5 mL to 0.9 mL of hyaluronic acid filler into the left facial or left femoral artery, respectively, with the right facial or right femoral artery serving as untreated controls. The animals were then divided into six experimental groups, each containing two or three animals, with group 1 animals each receiving 500 μL of a composition containing ultra-high concentration hyaluronidase (10,000 IU / mL) administered subcutaneously around the occlusion 15 minutes after hyaluronic acid filler injection, group 2 animals each receiving 500 μL of a composition containing ultra-high concentration hyaluronidase (10,000 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection, and group 3 animals each receiving 500 μL of a composition containing ultra-high concentration hyaluronidase (10,000 IU / mL) administered subcutaneously around the occlusion 15 minutes after hyaluronic acid filler injection. Group 4 animals each receive 500 μL of a composition containing ultra-high concentration hyaluronidase (12,000 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection, Group 5 animals each receive 500 μL of a composition containing low concentration hyaluronidase (150 IU / mL) administered subcutaneously around the occlusion 5 minutes after hyaluronic acid filler injection, and Group 6 animals each receive 500 μL of a composition containing low concentration hyaluronidase (150 IU / mL) administered subcutaneously around the occlusion 10 minutes after hyaluronic acid filler injection.

[0096] In another series of experiments, arterial occlusion was induced in all rabbits by injecting 0.5 mL to 0.9 mL of hyaluronic acid filler into the left facial or left femoral artery, respectively, with the right facial or right femoral artery serving as untreated controls. The animals were then divided into six experimental groups, each containing two or three animals, with group 1 animals each receiving 500 μL of a composition containing ultra-high concentration hyaluronidase (15,000 IU / mL) administered subcutaneously around the occlusion 15 minutes after hyaluronic acid filler injection, group 2 animals each receiving 500 μL of a composition containing ultra-high concentration hyaluronidase (15,000 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection, and group 3 animals each receiving 500 μL of a composition containing ultra-high concentration hyaluronidase (15,000 IU / mL) administered subcutaneously around the occlusion 15 minutes after hyaluronic acid filler injection. Group 4 animals each receive 500 μL of a composition containing ultra-high concentration hyaluronidase (20,000 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection, Group 5 animals each receive 500 μL of a composition containing low concentration hyaluronidase (150 IU / mL) administered subcutaneously around the occlusion 5 minutes after hyaluronic acid filler injection, and Group 6 animals each receive 500 μL of a composition containing low concentration hyaluronidase (150 IU / mL) administered subcutaneously around the occlusion 10 minutes after hyaluronic acid filler injection.

[0097] In another series of experiments, arterial occlusion was induced in all rabbits by injecting 0.5 mL to 0.9 mL of hyaluronic acid filler into the left facial or left femoral artery, respectively, with the right facial or right femoral artery serving as untreated controls. The animals were then divided into six experimental groups, each containing two or three animals, with group 1 animals each receiving 500 μL of a composition containing ultra-high concentration hyaluronidase (10,000 IU / mL) administered subcutaneously around the occlusion 60 minutes after hyaluronic acid filler injection, group 2 animals each receiving 500 μL of a composition containing ultra-high concentration hyaluronidase (10,000 IU / mL) administered subcutaneously around the occlusion 120 minutes after hyaluronic acid filler injection, and group 3 animals each receiving 500 μL of a composition containing ultra-high concentration hyaluronidase (10,000 IU / mL) administered subcutaneously around the occlusion 60 minutes after hyaluronic acid filler injection. Group 4 animals each receive 500 μL of a composition containing ultra-high concentration hyaluronidase (12,000 IU / mL) administered subcutaneously around the occlusion 120 minutes after hyaluronic acid filler injection, Group 5 animals each receive 500 μL of a composition containing low concentration hyaluronidase (150 IU / mL) administered subcutaneously around the occlusion 5 minutes after hyaluronic acid filler injection, and Group 6 animals each receive 500 μL of a composition containing low concentration hyaluronidase (150 IU / mL) administered subcutaneously around the occlusion 10 minutes after hyaluronic acid filler injection.

[0098] In another series of experiments, arterial occlusion was induced in all rabbits by injecting 0.5 mL to 0.9 mL of hyaluronic acid filler into the left facial or left femoral artery, respectively, with the right facial or right femoral artery serving as untreated controls. The animals were then divided into six experimental groups, each containing two or three animals, with group 1 animals each receiving 500 μL of a composition containing ultra-high concentration hyaluronidase (15,000 IU / mL) administered subcutaneously around the occlusion 60 minutes after hyaluronic acid filler injection, group 2 animals each receiving 500 μL of a composition containing ultra-high concentration hyaluronidase (15,000 IU / mL) administered subcutaneously around the occlusion 120 minutes after hyaluronic acid filler injection, and group 3 animals each receiving 500 μL of a composition containing ultra-high concentration hyaluronidase (15,000 IU / mL) administered subcutaneously around the occlusion 60 minutes after hyaluronic acid filler injection. Group 4 animals each receive 500 μL of a composition containing ultra-high concentration hyaluronidase (20,000 IU / mL) administered subcutaneously around the occlusion 120 minutes after hyaluronic acid filler injection, Group 5 animals each receive 500 μL of a composition containing low concentration hyaluronidase (150 IU / mL) administered subcutaneously around the occlusion 5 minutes after hyaluronic acid filler injection, and Group 6 animals each receive 500 μL of a composition containing low concentration hyaluronidase (150 IU / mL) administered subcutaneously around the occlusion 10 minutes after hyaluronic acid filler injection.

[0099] Analysis of the experimental animals by ultrasound, angiography, NCS assay, EMG and / or EEG analysis, and hind paw assays is expected to show no significant arterial occlusion, tissue damage or tissue loss following ultra-high concentration hyaluronidase treatment, whereas control animals are expected to show no improvement in signs of filler-induced arterial occlusion and tissue damage.

[0100] Example 4: Rabbit model of filler-induced vascular occlusion This example demonstrates how to evaluate the safety and efficacy of hyaluronidase treatment as disclosed herein using an animal model for filler-induced vascular occlusion events. New Zealand White rabbits are used to simulate hyaluronic acid-associated vascular occlusion of an area of ​​tissue. These animals are selected due to the similarity of their vascular anatomy to that of human blood vessels. New Zealand White rabbits weighing 2.0-3.0 kg are divided into groups based on the dose and administration time of hyaluronidase.

[0101] Hyaluronic acid filler is administered to the animal's artery to cause arterial occlusion. This arterial occlusion and subsequent ischemia are confirmed by angiography and electroencephalogram (EEG) analysis. Different doses of ultra-high concentration hyaluronidase are administered at several post-occlusion time points to evaluate both the dosing and timing effectiveness of the treatment. Control animals are injected with hyaluronic acid filler in the same way as experimental animals, except that they do not receive hyaluronidase treatment. Angiographic and EEG changes are recorded 30, 60, 90, and 120 minutes after administration of hyaluronidase. EEG is performed 60 and 120 minutes later to confirm tissue reperfusion and electrophysiological function.

[0102] In one series of experiments, arterial occlusion is induced by injecting 0.4 mL to 0.7 mL of hyaluronic acid filler into the left canthal artery of all rabbits, with the right canthal artery serving as an untreated control. The animals are then divided into two experimental groups, each containing two or three animals, with each animal in group 1 receiving 500 μL of a composition containing low concentration hyaluronidase (150 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection, and each animal in group 2 receiving 500 μL of a composition containing ultra-high concentration hyaluronidase (15,000 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection. The above dosing strategy for each set of rabbits is repeated every 30 minutes until the blood supply in each rabbit is no longer impaired. During the study, the number of vials / units of hyaluronidase injected into each rabbit will be recorded.

[0103] In another series of experiments, arterial occlusion is induced by injecting 0.6 mL to 0.9 mL of hyaluronic acid filler into the left internal carotid artery of all rabbits, with the right internal carotid artery serving as an untreated control. The animals are then divided into two experimental groups, each containing two or three animals, with each animal in group 1 receiving a composition containing 1 mL of low-concentration hyaluronidase (150 IU / mL) administered retrobulbarly around the occlusion 30 minutes after hyaluronic acid filler injection, and each animal in group 2 receiving a composition containing 1 mL of ultra-high-concentration hyaluronidase (15,000 IU / mL) administered retrobulbarly around the occlusion 30 minutes after hyaluronic acid filler injection. The above dosing strategy for each set of rabbits is repeated every 5 minutes until the blood supply in each rabbit is no longer impaired, returning the ERG of each animal to normal. During the study, the number of vials / units of hyaluronidase injected into each rabbit will be recorded.

[0104] In another series of experiments, 0.2-0.4 mL of hyaluronic acid filler is injected into the left facial artery of all rabbits to induce arterial occlusion, with the right facial artery serving as an untreated control. The animals are then divided into two experimental groups, each containing two or three animals, with each animal in group 1 receiving 250 μL of a composition containing low concentration hyaluronidase (150 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection, and each animal in group 2 receiving 250 μL of a composition containing ultra-high concentration hyaluronidase (15,000 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection. The above dosing strategy for each set of rabbits is repeated every 30 minutes until the blood supply in each rabbit is no longer compromised. During the study, the number of vials / units of hyaluronidase injected into each rabbit will be recorded.

[0105] In another series of experiments, 0.2-0.4 mL of hyaluronic acid filler is injected into the left infraorbital artery of all rabbits to induce arterial occlusion, with the right infraorbital artery serving as an untreated control. The animals are then divided into two experimental groups, each containing two or three animals, with each animal in group 1 receiving a composition containing 200 μL of low-concentration hyaluronidase (150 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection, and each animal in group 2 receiving a composition containing 200 μL of ultra-high-concentration hyaluronidase (15,000 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection. The above dosing strategy for each set of rabbits is repeated every 30 minutes until the blood supply in each rabbit is no longer compromised. During the study, the number of vials / units of hyaluronidase injected into each rabbit will be recorded.

[0106] In another series of experiments, arterial occlusion is induced by injecting 0.2mL-0.5mL of hyaluronic acid filler into the left supratrochlear artery of all rabbits, with the right supratrochlear artery serving as an untreated control. The animals are then divided into two experimental groups, each containing two or three animals, with each animal in group 1 receiving a composition containing 300μL of low-concentration hyaluronidase (150IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection, and each animal in group 2 receiving a composition containing 300μL of ultra-high-concentration hyaluronidase (15,000IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection. The above dosing strategy for each set of rabbits is repeated every 30 minutes until the blood supply in each rabbit is no longer impaired. During the study, the number of vials / units of hyaluronidase injected into each rabbit will be recorded.

[0107] In another series of experiments, arterial occlusion is induced by injecting 0.1 mL to 0.3 mL of hyaluronic acid filler into the left supraorbital artery of all rabbits, with the right supraorbital artery serving as an untreated control. The animals are then divided into two experimental groups, each containing two or three animals, with each animal in group 1 receiving a composition containing 150 μL of low-concentration hyaluronidase (150 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection, and each animal in group 2 receiving a composition containing 150 μL of ultra-high-concentration hyaluronidase (15,000 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection. The above dosing strategy for each set of rabbits is repeated every 30 minutes until the blood supply in each rabbit is no longer impaired. During the study, the number of vials / units of hyaluronidase injected into each rabbit will be recorded.

[0108] In another series of experiments, arterial occlusion is induced by injecting 0.05mL-0.2mL of hyaluronic acid filler into the left mental artery of all rabbits, with the right mental artery serving as an untreated control. The animals are then divided into two experimental groups, each containing two or three animals, with each animal in group 1 receiving a composition containing 100μL of low-concentration hyaluronidase (150IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection, and each animal in group 2 receiving a composition containing 100μL of ultra-high-concentration hyaluronidase (15,000IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection. The above dosing strategy for each set of rabbits is repeated every 30 minutes until the blood supply in each rabbit is no longer impaired. During the study, the number of vials / units of hyaluronidase injected into each rabbit will be recorded.

[0109] In another series of experiments, 0.1-0.3 mL of hyaluronic acid filler is injected into the left superficial temporal artery of all rabbits to induce arterial occlusion, with the right superficial temporal artery serving as an untreated control. The animals are then divided into two experimental groups, each containing two or three animals, with each animal in group 1 receiving a composition containing 175 μL of low-concentration hyaluronidase (150 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection, and each animal in group 2 receiving a composition containing 175 μL of ultra-high-concentration hyaluronidase (15,000 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection. The above dosing strategy for each set of rabbits is repeated every 30 minutes until the blood supply in each rabbit is no longer compromised. During the study, the number of vials / units of hyaluronidase injected into each rabbit will be recorded.

[0110] In another series of experiments, 0.4-0.6 mL of hyaluronic acid filler is injected into the left superficial temporal artery of all rabbits to induce arterial occlusion, with the right superficial temporal artery serving as an untreated control. The animals are then divided into two experimental groups, each containing two or three animals, with each animal in group 1 receiving 350 μL of a composition containing low concentration hyaluronidase (150 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection, and each animal in group 2 receiving 350 μL of a composition containing ultra-high concentration hyaluronidase (15,000 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection. The above dosing strategy for each set of rabbits is repeated every 30 minutes until the blood supply in each rabbit is no longer impaired. During the study, the number of vials / units of hyaluronidase injected into each rabbit will be recorded.

[0111] In another series of experiments, 0.1-0.3 mL of hyaluronic acid filler is injected into the left radial artery of all rabbits to induce arterial occlusion, with the right radial artery serving as an untreated control. The animals are then divided into two experimental groups, each containing two or three animals, with each animal in group 1 receiving a composition containing 250 μL of low-concentration hyaluronidase (150 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection, and each animal in group 2 receiving a composition containing 250 μL of ultra-high-concentration hyaluronidase (15,000 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection. The above dosing strategy for each set of rabbits is repeated every 30 minutes until the blood supply in each rabbit is no longer impaired. During the study, the number of vials / units of hyaluronidase injected into each rabbit will be recorded.

[0112] In another series of experiments, arterial occlusion is induced by injecting 0.1 mL to 0.3 mL of hyaluronic acid filler into the left ulnar artery of all rabbits, with the right ulnar artery serving as an untreated control. The animals are then divided into two experimental groups, each containing two or three animals, with each animal in group 1 receiving a composition containing 125 μL of low-concentration hyaluronidase (150 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection, and each animal in group 2 receiving a composition containing 125 μL of ultra-high-concentration hyaluronidase (15,000 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection. The above dosing strategy for each set of rabbits is repeated every 30 minutes until the blood supply in each rabbit is no longer impaired. During the study, the number of vials / units of hyaluronidase injected into each rabbit will be recorded.

[0113] In another series of experiments, 0.4-0.6 mL of hyaluronic acid filler is injected into the left femoral artery of all rabbits to induce arterial occlusion, with the right femoral artery serving as an untreated control. The animals are then divided into two experimental groups, each containing two or three animals, with each animal in group 1 receiving a composition containing 500 μL of low-concentration hyaluronidase (150 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection, and each animal in group 2 receiving a composition containing 500 μL of ultra-high-concentration hyaluronidase (15,000 IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection. The above dosing strategy for each set of rabbits is repeated every 30 minutes until the blood supply in each rabbit is no longer impaired. During the study, the number of vials / units of hyaluronidase injected into each rabbit will be recorded.

[0114] In another series of experiments, 0.2mL-0.5mL of hyaluronic acid filler is injected into the left brachial artery of all rabbits to induce arterial occlusion, with the right brachial artery serving as an untreated control. The animals are then divided into two experimental groups, each containing two or three animals, with each animal in group 1 receiving 350μL of a composition containing low concentration hyaluronidase (150IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection, and each animal in group 2 receiving 350μL of a composition containing ultra-high concentration hyaluronidase (15,000IU / mL) administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection. The above dosing strategy for each set of rabbits is repeated every 30 minutes until the blood supply in each rabbit is no longer impaired. During the study, the number of vials / units of hyaluronidase injected into each rabbit will be recorded.

[0115] Example 5: Rabbit model of hypersensitivity reactions This example demonstrates how to evaluate the safety and efficacy of hyaluronidase treatments disclosed herein using an animal model for hypersensitivity reactions. New Zealand White rabbits are used to simulate hyaluronic acid-associated hypersensitivity reactions in areas of tissue. These animals are selected due to the similarity of their vascular anatomy to that of human blood vessels. New Zealand White rabbits weighing 2.0-3.0 kg are divided into groups based on the dose and time of administration of hyaluronidase.

[0116] In one series of experiments, animals suffering from hypersensitivity reactions were divided into four experimental groups, each containing two or three animals, and each animal in group 1 received a composition containing 500 μL of low concentration hyaluronidase (150 IU / mL), 500 μL of 5-fluorouracil (5-FU), and 250 μL of 1% lidocaine administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection, and each animal in group 2 received 500 μL of ultra high concentration hyaluronidase (15,000 IU / mL) administered subcutaneously around the tissue exhibiting the hypersensitivity reaction. Group 3 animals each receive a composition containing 500 μL of low concentration hyaluronidase (150 IU / mL) and 250 μL of 1% lidocaine administered subcutaneously around the occlusion 30 minutes after hyaluronic acid filler injection, and Group 4 animals each receive a composition containing 500 μL of extra high concentration hyaluronidase (15,000 IU / mL) and 250 μL of 1% lidocaine administered subcutaneously around the tissue exhibiting the hypersensitivity reaction. The above dosing strategy for each set of rabbits is repeated weekly until the hypersensitivity reaction is no longer noticeable in each rabbit.

[0117] Example 6: Rabbit model of filler-induced vascular occlusion In this example, New Zealand White rabbits are used to simulate hyaluronic acid polymer-associated vaso-occlusive vision loss. These animals were selected due to the similarity of their ocular vascular anatomy to that of the human eye.

[0118] New Zealand White rabbits weighing 2.0-3.0 kg were acclimated to the research environment for a minimum of 1 week prior to the initiation of this study. Upon completion of the acclimation period, a physical examination was performed on each animal, including examination of the skin and external ear, eyes, abdomen, neurology, behavior, and general physical condition, to determine suitability for this study. Animals determined to be in good health were released into the study. Released animals were assigned to four groups of three animals each, with each animal uniquely identified by cage card number.

[0119] On the day of surgery (Day 0), all animals were anesthetized and administered antibiotics. Each animal then underwent surgery to expose the right carotid artery in the animal's neck. Using a 25 gauge or smaller needle attached to a syringe, 0.5 mL to 0.7 mL of hyaluronic acid dermal filler was injected cranially into the right carotid artery over a minimum of 60 seconds. Upon completion of administration of the dermal filler, the surgical incision site on the animal's neck was sutured closed. Approximately 5 minutes after administration of the dermal filler, an eyelid speculum was placed over the animal's right eye, and the animals were then subjected to one of four treatment protocols. Animals in Group 1 were injection controls with no further treatment. Animals in groups 2 and 3 were administered the compositions by suprachoroidal injection with a 30-gauge needle in the inferior nasal quadrant of the right eye, with animals in group 2 receiving 0.1 mL of phosphate-buffered saline (PBS) (control composition) and animals in group 3 receiving 0.1 mL of hyaluronidase (2,400 IU / mL). Animals were allowed to recover normally from the anesthesia procedure. The left eye in all animals was not treated and served as the control in these experiments.

[0120] Both optical coherence tomography angiography (OCT-A) and electroretinography (ERG) were performed to assess visual activity. OCT-A is a non-contact retinal imaging system that uses infrared light to image the retinal vasculature and determine changes in blood flow over time. In this study, each animal was subjected to OCT-A analysis to evaluate 1) changes in blood flow pre-induction day 0 versus post-induction day 0, 2) changes in blood flow pre-induction day 0 versus post-induction day 3, and 3) changes in blood flow post-induction day 0 versus post-induction day 3. Full-field ERG was performed on both eyes of each animal on pre-induction day 0 and post-induction day 3 to obtain baseline readings. Animals were dark-adapted for at least 1 hour before ERG analysis. ERG responses were elicited by a brief flash of 0.33 Hz delivered by a maximal intensity mini-Ganzfeld light stimulator (Roland Instruments, Wiesbaden, Germany). Twenty responses for each animal were amplified, filtered and averaged (Retiport Electrophysiologic Diagnostic Systems, Roland Instruments, Wiesbaden, Germany). Animals were subjected to standard ERG measurements as prescribed by ISCEV standards, including dark-adapted (0.01 candela), dark-adapted (3 candela) and light-adapted (3 candela) measurements. A-wave and b-wave ERG analysis was performed to determine changes in a-wave and b-wave amplitude over time, comparing day 0 pre-induction (baseline) to day 3 post-induction under dark-adapted and light-adapted conditions.

[0121] On day 0 prior to induction, the right eyes of animals in group 1 showed normal blood flow to the retina based on OCT-A analysis (Table 3) and normal neural activity in the retina based on ERG readings (Table 4). However, on day 3 post-induction, all animals showed significantly reduced blood flow to the retina and flat or essentially flat ERG readings in the right eye indicating significant loss of blood flow and neural activity in the retina (Tables 3 and 4). As expected, the left eyes of these animals showed normal blood flow and neural activity in the retina (Tables 3 and 4). Similarly, the right eyes of animals in group 2 showed normal blood flow to the retina based on OCT-A analysis (Table 3) and normal neural activity in the retina based on ERG readings (Table 4). However, on day 3 post-induction, all animals showed significantly reduced blood flow to the retina and flat or essentially flat ERG readings in the right eye indicating significant loss of blood flow and neural activity in the retina. As expected, the left eyes of these animals showed normal blood flow and neural activity in the retina (Tables 3 and 4). As both group 1 and group 2 animals were controls, these results demonstrate that hyaluronic acid polymers can occlude blood flow to the retina and cause loss of retinal function and serve as a good model for hyaluronic acid polymer-associated vaso-occlusive vision loss. [Table 3] [Table 4]

[0122] Analysis of group 3 animals demonstrated that administration of hyaluronidase reversed hyaluronic acid polymer-associated vascular occlusion in the retina. On day 0 pre-induction, the right eyes of group 3 animals showed normal blood flow to the retina based on OCT-A analysis (Table 3) as well as normal neural activity in the retina based on ERG readings (Table 4). These baseline measurements indicate that the animals in group 3 showed functional neural activity. Surprisingly, on day 3 post-induction, all animals also showed significant blood flow and neural activity in the retina (Tables 3 and 4). Although these levels were distinguishable from measurements obtained from the right eye on day 0 pre-induction and from the left eye control, the measured activity still demonstrated significant recovery from the vascular occlusion caused by the presence of hyaluronic acid polymers. These results demonstrate that hyaluronic acid polymers can occlude blood flow to the retina and cause loss of retinal function and serve as a good model for hyaluronic acid polymer-associated vascular occlusion vision loss. More notably, administration of small amounts of hyaluronidase into the suprachoroidal space clears hyaluronic acid dermal filler obstruction from within the retinal circulation, allowing for reperfusion of retinal tissue and restoration of neural activity. Finally, these results show that 2,400 IU / mL hyaluronidase treatment is superior to both 150 IU / mL and 1,500 IU / mL hyaluronidase treatments when injected into the suprachoroidal space, highlighting the ability of at least 2,400 IU / mL hyaluronidase treatment to migrate from the SCS (extravascular) to the interior of the ocular vasculature, which has important implications for treatment.

[0123] Example 7: Rabbit model of filler-induced vascular occlusion New Zealand Red rabbits are used to simulate hyaluronan-associated vaso-occlusive vision loss. These animals are selected due to the similarity of the vascular anatomy of their eyes to that of the human eye. New Zealand White rabbits weighing 2.0-3.0 kg are divided into groups based on the dose and administration time of hyaluronidase.

[0124] Hyaluronic acid filler is administered to the internal carotid artery of animals to produce central retinal artery occlusion. This artery occlusion and subsequent ischemia are confirmed by fundus photography or both OCT-A and ERG analysis. Different doses of hyaluronidase are administered suprachoroidally at several post-occlusion time points to evaluate both the dose and timing effectiveness of the treatment. Hyaluronic acid filler is injected into control animals in the same way as experimental animals, except that hyaluronidase treatment is not performed. Fundus photography and electroretinogram changes are recorded 30, 60, 90, and 120 minutes after administration of hyaluronidase. Electroretinograms are performed 60 and 120 minutes later to confirm retinal reperfusion and electrophysiological function.

[0125] In one series of experiments, central retinal artery occlusion was induced by injecting 0.5 mL–0.9 mL of hyaluronic acid filler into rabbits, and these rabbits were divided into four experimental groups, each containing two or three animals, with animals in group 1 receiving 100 μL of hyaluronidase (400 IU / mL) administered suprachoroidally 5 minutes after hyaluronic acid filler injection, and animals in group 2 receiving 100 μL of hyaluronidase (400 IU / mL) administered suprachoroidally 5 minutes after hyaluronic acid filler injection. Group 3 animals receive 100 μL of hyaluronidase (400 IU / mL) administered suprachoroidally 10 minutes after filler injection, Group 4 animals receive 100 μL of hyaluronidase (600 IU / mL) administered suprachoroidally 5 minutes after hyaluronic acid filler injection, and Group 5 animals receive 100 μL of hyaluronidase (650 IU / mL) administered suprachoroidally 10 minutes after hyaluronic acid filler injection.

[0126] In another series of experiments, central retinal artery occlusion was induced by injecting 0.5 mL–0.9 mL of hyaluronic acid filler into rabbits, which were then divided into four experimental groups, each containing two or three animals, with animals in group 1 receiving 100 μL of hyaluronidase (1,000 IU / mL) administered suprachoroidally 5 minutes after hyaluronic acid filler injection and animals in group 2 receiving 100 μL of hyaluronidase (1,000 IU / mL) administered suprachoroidally 5 minutes after hyaluronic acid filler injection. - animals in group 1 receive 100 μL of hyaluronidase (1,000 IU / mL) administered suprachoroidally 10 minutes after injection, animals in group 2 receive 100 μL of hyaluronidase (3,000 IU / mL) administered suprachoroidally 5 minutes after hyaluronic acid filler injection, and animals in group 3 receive 100 μL of hyaluronidase (3,000 IU / mL) administered suprachoroidally 10 minutes after hyaluronic acid filler injection.

[0127] In another series of experiments, central retinal artery occlusion was induced by injecting 0.5 mL–0.9 mL of hyaluronic acid filler into rabbits, which were then divided into four experimental groups, each containing two or three animals, with animals in group 1 receiving 100 μL of hyaluronidase (10,000 IU / mL) administered suprachoroidally 5 minutes after hyaluronic acid filler injection and animals in group 2 receiving 100 μL of hyaluronidase (10,000 IU / mL) administered suprachoroidally 5 minutes after hyaluronic acid filler injection. Group 1 animals will receive 100 μL of hyaluronidase (10,000 IU / mL) administered suprachoroidally 10 minutes after injection, Group 2 animals will receive 100 μL of hyaluronidase (15,000 IU / mL) administered suprachoroidally 5 minutes after hyaluronic acid filler injection, and Group 3 animals will receive 100 μL of hyaluronidase (15,000 IU / mL) administered suprachoroidally 10 minutes after hyaluronic acid filler injection.

[0128] In another series of experiments, central retinal artery occlusion was induced by injecting 0.5 mL–0.9 mL of hyaluronic acid filler into rabbits, which were then divided into four experimental groups, each containing two or three animals, with animals in group 1 receiving 100 μL of hyaluronidase (15,000 IU / mL) administered suprachoroidally 5 minutes after hyaluronic acid filler injection and animals in group 2 receiving 100 μL of hyaluronidase (15,000 IU / mL) administered suprachoroidally 5 minutes after hyaluronic acid filler injection. Group 1 animals receive 100 μL of hyaluronidase (15,000 IU / mL) administered suprachoroidally 10 minutes after injection, Group 2 animals receive 100 μL of hyaluronidase (20,000 IU / mL) administered suprachoroidally 5 minutes after hyaluronic acid filler injection, and Group 3 animals receive 100 μL of hyaluronidase (20,000 IU / mL) administered suprachoroidally 10 minutes after hyaluronic acid filler injection.

[0129] In another series of experiments, central retinal artery occlusion was induced by injecting 0.5 mL–0.9 mL of hyaluronic acid filler into rabbits, which were then divided into four experimental groups, each containing two or three animals, with animals in group 1 receiving 100 μL of hyaluronidase (400 IU / mL) administered suprachoroidally 15 minutes after hyaluronic acid filler injection and animals in group 2 receiving 100 μL of hyaluronidase (400 IU / mL) administered suprachoroidally 15 minutes after hyaluronic acid filler injection. Group 1 animals received 100 μL of hyaluronidase (400 IU / mL) administered suprachoroidally 30 minutes after hyaluronic acid filler injection, Group 2 animals received 100 μL of hyaluronidase (650 IU / mL) administered suprachoroidally 15 minutes after hyaluronic acid filler injection, and Group 3 animals received 100 μL of hyaluronidase (650 IU / mL) administered suprachoroidally 30 minutes after hyaluronic acid filler injection.

[0130] In another series of experiments, central retinal artery occlusion was induced by injecting 0.5 mL–0.9 mL of hyaluronic acid filler into rabbits, which were then divided into four experimental groups, each containing two or three animals, with animals in group 1 receiving 100 μL of hyaluronidase (1,000 IU / mL) administered suprachoroidally 15 minutes after hyaluronic acid filler injection and animals in group 2 receiving 100 μL of hyaluronidase (1,000 IU / mL) administered suprachoroidally 15 minutes after hyaluronic acid filler injection. - animals in group 1 receive 100 μL of hyaluronidase (1,000 IU / mL) administered suprachoroidally 30 minutes after injection, animals in group 2 receive 100 μL of hyaluronidase (3,000 IU / mL) administered suprachoroidally 15 minutes after hyaluronic acid filler injection, and animals in group 3 receive 100 μL of hyaluronidase (3,000 IU / mL) administered suprachoroidally 30 minutes after hyaluronic acid filler injection.

[0131] In another series of experiments, central retinal artery occlusion was induced by injecting 0.5 mL–0.9 mL of hyaluronic acid filler into rabbits, which were then divided into four experimental groups, each containing two or three animals, with animals in group 1 receiving 100 μL of hyaluronidase (10,000 IU / mL) administered suprachoroidally 15 minutes after hyaluronic acid filler injection and animals in group 2 receiving 100 μL of hyaluronidase (10,000 IU / mL) administered suprachoroidally 15 minutes after hyaluronic acid filler injection. Group 1 animals will receive 100 μL of hyaluronidase (10,000 IU / mL) administered suprachoroidally 30 minutes after injection, Group 2 animals will receive 100 μL of hyaluronidase (15,000 IU / mL) administered suprachoroidally 15 minutes after hyaluronic acid filler injection, and Group 3 animals will receive 100 μL of hyaluronidase (15,000 IU / mL) administered suprachoroidally 30 minutes after hyaluronic acid filler injection.

[0132] In another series of experiments, central retinal artery occlusion was induced by injecting 0.5 mL–0.9 mL of hyaluronic acid filler into rabbits, which were then divided into four experimental groups, each containing two or three animals, with animals in group 1 receiving 100 μL of hyaluronidase (15,000 IU / mL) administered suprachoroidally 15 minutes after hyaluronic acid filler injection and animals in group 2 receiving 100 μL of hyaluronidase (15,000 IU / mL) administered suprachoroidally 15 minutes after hyaluronic acid filler injection. Group 1 animals receive 100 μL of hyaluronidase (15,000 IU / mL) administered suprachoroidally 30 minutes after injection, Group 2 animals receive 100 μL of hyaluronidase (20,000 IU / mL) administered suprachoroidally 15 minutes after hyaluronic acid filler injection, and Group 3 animals receive 100 μL of hyaluronidase (20,000 IU / mL) administered suprachoroidally 30 minutes after hyaluronic acid filler injection.

[0133] Analysis of the experimental animals' eyes by fundus photography, OCT-A and ERG analysis is expected to show no significant central retinal artery occlusion or vision loss following hyaluronidase treatment, whereas control animals are expected to show no improvement in vision suggestive of filler-induced central retinal artery occlusion or vision loss.

[0134] In closing, the above description of the embodiments of the present invention has been provided for the purposes of illustration and description. It is to be understood that, although aspects of the present invention have been emphasized by reference to specific embodiments, those skilled in the art will readily appreciate that these described embodiments are merely illustrative of the principles encompassed by the present invention. Thus, the specific embodiments are not intended to be exhaustive or to limit the invention to the precise forms disclosed. It is to be understood, therefore, that the embodiments of the disclosed subject matter are in no way limited to the specific elements, compounds, compositions, components, articles, devices, methodologies, uses, protocols, steps and / or limitations described herein, unless expressly described as such.

[0135] Also, the grouping of other embodiments, elements, steps and / or limitations of the invention should not be construed as limiting. Such groups may be referred to and claimed individually or in any combination with other groups disclosed herein. It is anticipated that one or more of the other embodiments, elements, steps and / or limitations of a group may be included in or deleted from a group for reasons of convenience and / or patentability. When any such inclusion or deletion is made, the specification shall be deemed to include the group as modified and thus satisfy all Markush group descriptions used in the appended claims.

[0136] Moreover, those skilled in the art will recognize that certain variations, modifications, substitutions, changes, additions, deletions, and subcombinations are possible in accordance with the teachings herein without departing from the spirit of the present specification. Moreover, the following appended claims and any claims hereafter introduced are intended to be construed to include all such variations, modifications, substitutions, changes, additions, deletions, and subcombinations as fall within their true spirit and scope. Accordingly, the scope of the present invention is not limited to what has been particularly shown and described herein.

[0137] Certain embodiments of the present invention are described herein, including the best mode for carrying out the invention known to the inventors. Of course, variations of these described embodiments will become apparent to those of skill in the art upon reading the above description. The inventors expect that such variations will be employed by those of skill in the art as appropriate, and the inventors intend for the invention to be practiced in ways other than as specifically described herein. Accordingly, the present invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described embodiments in all possible variations thereof is encompassed by the present invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0138] The words, language, and terms used in this specification are merely to describe certain embodiments, elements, steps, and / or limitations, and are not intended to limit the scope of the invention, which is defined solely by the claims. Furthermore, such words, language, and terms should be understood not only in their generally defined meanings, but also to include structures, materials, or acts according to specific definitions in this specification that go beyond the scope of their generally defined meanings. Thus, when an element, step, or limitation can be understood to include more than one meaning in the context of this specification, its use in the claims should be understood to be general to all possible meanings supported by the specification and the word itself.

[0139] Thus, the definitions and meanings of elements, steps or limitations recited in the claims set forth below are defined herein to include not only the literally recited combinations of elements, steps or limitations, but all equivalent structures, materials or acts for performing substantially the same function in substantially the same manner to achieve substantially the same result. In this sense, it is therefore contemplated that equivalent substitutions of two or more elements, steps and / or limitations may be made for any one of the elements, steps or limitations in the claims set forth below, or that a single element, step or limitation may be substituted in such claims with two or more elements, steps and / or limitations. Although elements, steps or limitations may be described above as functioning in a particular combination, and even may be initially claimed as such, it is to be clearly understood that one or more elements, steps and / or limitations from the claimed combination may in some cases be deleted from the combination, and that the claimed combination may relate to a subcombination or a variation of a subcombination. Thus, regardless of the fact that elements, steps and / or limitations of a claim are described below in a particular combination, it should be clearly understood that the invention includes other combinations of fewer, more or different elements, steps and / or limitations, which are disclosed herein even if not originally claimed in such combination. Moreover, minor variations from the claimed subject matter, as recognized by those skilled in the art, whether now known or later devised, are equally clearly recognized to be within the scope of the claims. Thus, obvious substitutions now known or later known to those skilled in the art are defined to be within the scope of the defined elements. Thus, the claims should be understood to include what is specifically illustrated and described above, what is conceptually equivalent, what can obviously be substituted, and what essentially incorporates the essential ideas of the invention.

[0140] Unless otherwise indicated, all numbers expressing properties, items, amounts, parameters, properties, terms, etc. used in the specification and claims should be understood to be modified in all cases by the term "about". The term "about" as used herein means that the property, item, amount, parameter, property or term so modified encompasses a range of ±10% above and below the value of the stated property, item, amount, parameter, property or term. Thus, unless specifically indicated to the contrary, the numerical parameters described in this specification and the appended claims are approximations that may vary. For example, the term "about" in the context of the mass of an ion or the mass / charge ratio of an ion refers to + / - 0.50 atomic mass units, as mass spectrometry instruments may vary slightly in determining the mass of a given analyte. At least without intending to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should be construed in light of at least the number of reported significant digits and by applying ordinary rounding techniques.

[0141] Notwithstanding that the numerical ranges and values ​​setting forth the broad scope of the present invention are approximations, the numerical ranges and values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical range or value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. The recitation of numerical ranges of values ​​herein merely serves as a shorthand method of referring individually to each individual value falling within the range. Unless otherwise indicated herein, each individual value within a numerical range is incorporated herein as if it were individually set forth herein.

[0142] The use of the term "may" or "can" in reference to an embodiment or an aspect of an embodiment also has the other meaning of "must not" or "cannot". Thus, where the specification discloses that an embodiment or an aspect of an embodiment may (can) be included as part of the subject matter of the invention, a negative limitation or exclusionary condition meaning that the embodiment or an aspect of an embodiment may not (cannot) be included as part of the subject matter of the invention is also expressly intended. Similarly, the use of the term "optionally" in reference to an embodiment or an aspect of an embodiment means that such embodiment or an aspect of such embodiment may or may not be included as part of the subject matter of the invention. Whether such a negative limitation or exclusionary condition applies depends on whether the negative limitation or exclusionary condition is recited in the claimed subject matter.

[0143] The terms "a," "an," and "the" as used in the context of describing the present invention (particularly in the context of the claims below) should be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context. Furthermore, ordinal markers such as "first," "second," "third," and the like, for identifying elements, are used to distinguish between elements, and do not indicate or imply a required or limited number of such elements, and do not indicate a particular location or order of such elements, unless specifically stated otherwise. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by the context. The use of any and all examples or example language (e.g., "etc.") provided herein is merely for the purpose of better understanding the invention, and does not limit the scope of the invention, unless otherwise stated in the claims. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0144] When used in the claims, whether in the application or added by amendment, the open-ended transitional phrase "comprising," and variations thereof, such as "comprise" and "comprises," and equivalent open-ended transitional phrases, such as "including," "containing," and "having," include all explicitly recited elements, limitations, steps, integers, and / or features, either alone or in combination with unrecited subject matter, and wherein the recited elements, limitations, steps, integers, and / or features are essential, but other unrecited elements, limitations, steps, integers, and / or features may be added and still be within the scope of the patent. Specific embodiments disclosed herein may be further limited in the claims using the restrictive transitional phrase "consisting of" or "consisting essentially of" (or variations thereof, e.g., "consist of," "consists of," etc.) as an alternative or modification to "comprising." When used in the claims, whether in filing or added by amendment, the restrictive transitional phrase "consisting of" excludes any element, limitation, step, integer, or feature not expressly recited in the claim. The restrictive transitional phrase "consisting essentially of" limits the scope of the claim to those elements, limitations, steps, integers, and / or features expressly recited and any other elements, limitations, steps, integers, and / or features that do not materially affect the basic and novel characteristics of the claimed subject matter. Accordingly, the meaning of the open-ended transitional phrase "comprising" is defined as including all specifically recited elements, limitations, steps and / or features, as well as any and all further unspecified elements, limitations, steps and / or features.The meaning of the restrictive transitional phrase "consisting of" is defined to include only those elements, limitations, steps, integers and / or features specifically recited in the claim, and the meaning of the restrictive transitional phrase "consisting essentially of" is defined to include only those elements, limitations, steps, integers and / or features specifically recited in the claim and those elements, limitations, steps, integers and / or features that do not materially affect the basic and novel characteristics of the claimed subject matter. Thus, the open-ended transitional phrase "comprising" (and its equivalent open-ended transitional phrases) includes, within its meaning, as a limited instance, the claimed subject matter specified by the open-ended transitional phrase "consisting of" or "consisting essentially of". Thus, embodiments described or claimed herein with the phrase "comprising" expressly and unambiguously describe, enable and support the phrases "consisting essentially of" and "consisting of".

[0145] Finally, the entire contents of all patents, patent publications and other references cited and identified in this specification are individually and specifically incorporated herein by reference, for example, to describe and disclose the compositions and methodologies described in such publications that may be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of this application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the accuracy of the dates or contents of these documents.

Claims

1. A composition comprising ultra-high concentration hyaluronidase for use in reducing or eliminating hyaluronic acid-induced blockage in one or more blood vessels supplying blood to an area of ​​tissue.

2. A composition comprising ultra-high concentration hyaluronidase for use in reducing or inhibiting vascular obstruction in a region of tissue.

3. A composition comprising ultra-high concentrations of hyaluronidase for use in reducing or inhibiting hyaluronic acid-induced tissue loss.

4. The composition according to any one of claims 1 to 3, wherein the composition is administered to the dermal portion of a skin area.

5. The composition of any one of claims 1 to 3, wherein the composition is administered using a delivery system.

6. The ultra-high concentration hyaluronidase may be at least 25,000 IU / mL, at least 50,000 IU / mL, at least 75,000 IU / mL, at least 100,000 IU / mL, at least 125,000 IU / mL, at least 150,000 IU / mL, at least 175,000 IU / mL, at least 200,000 IU / mL, at least 225,000 IU / mL, at least 250,000 IU / mL, at least 300,000 IU / mL, at least 350,000 IU / mL, at least 400,000 IU / mL, a concentration of at least 450,000 IU / mL or at least 500,000 IU / mL, and / or at most 25,000 IU / mL, at most 50,000 IU / mL, at most 75,000 IU / mL, at most 100,000 IU / mL, at most 125,000 IU / mL, at most 150,000 IU / mL, at most 175,000 IU / mL, at most 200,000 IU / mL, at most 225,000 IU / mL, at most 250,000 IU / mL, at most 300,000 IU / mL, at most 350,000 IU / mL at most 400,000 IU / mL, at most 450,000 IU / mL or at most 500,000 IU / mL, or from about 25,000 IU / mL to about 50,000 IU / mL, from about 25,000 IU / mL to about 75,000 IU / mL, from about 25,000 IU / mL to about 100,000 IU / mL, from about 25,000 IU / mL to about 125,000 IU / mL, from about 25,000 IU / mL to about 150,000 IU / mL, from about 25,000 IU / mL to about 175,000 IU / mL, from about 25,000 IU / mL to about 200,000 IU / mL , about 25,000 IU / mL to about 225,000 IU / mL, about 25,000 IU / mL to about 250,000 IU / mL, about 25,00 0IU / mL to about 300,000IU / mL, about 25,000IU / mL to about 350,000IU / mL, about 25,000IU / mL to about 400,000IU / mL, about 25,000IU / mL to about 450,000IU / mL, about 25,000IU / mL to about 500,000I U / mL, about 50,000 IU / mL to about 75,000 IU / mL, about 50,000 IU / mL to about 100,000 IU / mL, about 50,000IU / mL~about 125,000IU / mL, about 50,000IU / mL~about 150,000IU / mL, about 50,000IU / mL~about 175,000IU / mL, about 50,000IU / mL~about 200,000IU / mL, about 50,000IU / mL~about 225,000 IU / mL, about 50,000IU / mL to about 250,000IU / mL, about 50,000IU / mL to about 300,000IU / mL, about 50,000IU / mL to about 350,000IU / mL, about 50,000IU / mL to about 400,000IU / mL, about 50,000IU / mL L to about 450,000IU / mL, about 50,000IU / mL to about 500,000IU / mL, about 75,000IU / mL to about 100,000IU / mL, about 75,000IU / mL to about 125,000IU / mL, about 75,000IU / mL to about 150,000IU / mL, about 75,000IU / mL to about 175,000IU / mL, about 75,000IU / mL to about 200,000IU / mL, about 75,000IU / mL to about 225,000IU / mL, about 75,000IU / mL to about 250,000IU / mL, about 75,000IU / mL to about 300, 000IU / mL, about 75,000IU / mL to about 350,000IU / mL, about 75,000IU / mL to about 400,000IU / mL, about 75,000IU / mL to about 450,000IU / mL, about 75,000IU / mL to about 500,000IU / mL, about 100,000 IU / mL to about 125,000IU / mL, about 100,000IU / mL to about 150,000IU / mL, about 100,000IU / mL to about 175,000IU / mL, about 100,000IU / mL to about 200,000IU / mL, about 100,000IU / mL to about 225,00 0IU / mL, about 100,000IU / mL to about 250,000IU / mL, about 100,000IU / mL to about 300,000IU / mL, about 100,000IU / mL to about 350,000IU / mL, about 100,000IU / mL to about 400,000IU / mL, about 100,0 00IU / mL~about 450,000IU / mL, about 100,000IU / mL~about 500,000IU / mL, about 150,000IU / mL~about 200,000IU / mL, about 150,000IU / mL~about 225,000IU / mL, about 150,000IU / mL~about 250,000 IU / mL, about 150,000 IU / mL to about 300,000 IU / mL, about 150,000 IU / mL to about 350,000 IU / mL, about 150,000 IU / mL to about 400,000 IU / mL, about 150,0 00 IU / mL to about 450,000 IU / mL, about 150,000 IU / mL to about 500,000 IU / mL, about 200,000 IU / mL to about 225,000 IU / mL, about 200,000 IU / mL to about 250,00 0IU / mL, about 200,000IU / mL to about 300,000IU / mL, about 200,000IU / mL to about 350,000IU / mL, about 200,000IU / mL to about 400,000IU / mL, about 200,000 IU / mL to about 450,000 IU / mL, about 200,000 IU / mL to about 500,000 IU / mL, about 250,000 IU / mL to about 300,000 IU / mL, about 250,000 IU / mL to about 350,000 IU / mL, about 250,000 IU / mL to about 400,000 IU / mL, about 250,000 IU / mL to about 450,000 IU / mL, about 250,000 IU / mL to about 500,000 IU / mL, about 300,000 IU / mL mL to about 350,000 IU / mL, about 300,000 IU / mL to about 400,000 IU / mL, about 300,000 IU / mL to about 450,000 IU / mL, about 300,000 IU / mL to about 500,000 IU / m The composition according to any one of claims 1 to 3, wherein the concentration of the serotonin-containing soluble ...

7. The ultra-high concentration hyaluronidase may have a concentration of at least 10,000 IU / mL, at least 20,000 IU / mL, at least 30,000 IU / mL, at least 40,000 IU / mL, at least 50,000 IU / mL, at least 60,000 IU / mL, at least 70,000 IU / mL, at least 80,000 IU / mL, at least 90,000 IU / mL, or at least 100,000 IU / mL, and / or at most 10,000 IU / mL, at most 20,000 IU / mL, at most 30,000 IU / mL, at most 40,000 IU / mL, at most 50,000 IU / mL, at least 60,000 IU / mL, at least 70,000 IU / mL, at least 80,000 IU / mL, at least 90,000 IU / mL, or at least 100,000 IU / mL. and a concentration of at most 40,000 IU / mL, at most 50,000 IU / mL, at most 60,000 IU / mL, at most 70,000 IU / mL, at most 80,000 IU / mL, at most 90,000 IU / mL or at most 100,000 IU / mL, or from about 10,000 IU / mL to about 20,000 IU / mL, from about 10,000 IU / mL to about 30,000 IU / mL, from about 10,000 IU / mL to about 40,000 IU / mL, from about 10,000 IU / mL to about 50,000 IU / mL, from about 10,000 IU / mL to about 60,000 IU / mL, or from about 10,000IU / mL to about 70,000IU / mL, about 10,000IU / mL to about 80,000IU / mL, about 10,000IU / m L to about 90,000 IU / mL, about 10,000 IU / mL to about 100,000 IU / mL, about 20,000 IU / mL to about 30,000 I U / mL, about 20,000 IU / mL to about 40,000 IU / mL, about 20,000 IU / mL to about 50,000 IU / mL, about 20,0 00IU / mL to about 60,000IU / mL, about 20,000IU / mL to about 70,000IU / mL, about 20,000IU / mL to about 80 ,000IU / mL, about 20,000IU / mL to about 90,000IU / mL, about 20,000IU / mL to about 100,000IU / mL , about 30,000 IU / mL to about 40,000 IU / mL, about 30,000 IU / mL to about 50,000 IU / mL, about 30,000 IU / mL mL to about 60,000 IU / mL, about 30,000 IU / mL to about 70,000 IU / mL, about 30,000 IU / mL to about 80,000 IU / mL, about 30,000 IU / mL to about 90,000 IU / mL, about 30,000 IU / mL to about 100,000 IU / mL, about 40,000IU / mL to about 50,000IU / mL, about 40,000IU / mL to about 60,000IU / mL, about 40,000IU / mL to about 70,000IU / m L, about 40,000 IU / mL to about 80,000 IU / mL, about 40,000 IU / mL to about 90,000 IU / mL, about 40,000 IU / mL to about 100, 000IU / mL, about 50,000IU / mL to about 60,000IU / mL, about 50,000IU / mL to about 70,000IU / mL, about 50,000IU / m L to about 80,000 IU / mL, about 50,000 IU / mL to about 90,000 IU / mL, about 50,000 IU / mL to about 100,000 IU / mL, about 60, 000IU / mL to about 70,000IU / mL, about 60,000IU / mL to about 80,000IU / mL, about 60,000IU / mL to about 90,000IU / m L, about 60,000 IU / mL to about 100,000 IU / mL, about 70,000 IU / mL to about 80,000 IU / mL, about 70,000 IU / mL to about 90, The composition according to any one of claims 1 to 3, wherein the concentration is about 70,000 IU / mL to about 100,000 IU / mL, about 80,000 IU / mL to about 90,000 IU / mL, about 80,000 IU / mL to about 100,000 IU / mL, or about 90,000 IU / mL to about 100,000 IU / mL.

8. The ultra-high concentration hyaluronidase may be at least 5,000 IU / mL, at least 6,000 IU / mL, at least 7,000 IU / mL, at least 8,000 IU / mL, at least 9,000 IU / mL, at least 10,000 IU / mL, at least 11,000 IU / mL, at least 12,000 IU / mL, at least 13,000 IU / mL, at least 14,000 IU / mL, at least 15,000 IU / mL, at least 16,000 IU / mL, at least 17,000 IU / mL, at least 18,000 IU / mL, or at least 19,000 IU / mL. a concentration of at least 19,000 IU / mL or at least 20,000 IU / mL, and / or at most 5,000 IU / mL, at most 6,000 IU / mL, at most 7,000 IU / mL, at most 8,000 IU / mL, at most 9,000 IU / mL, at most 10,000 IU / mL, at most 11,000 IU / mL, at most 12,000 IU / mL, at most 13,000 IU / mL, at most 14,000 IU / mL, at most 15,000 IU / mL, at most 16,000 IU / mL, at most 17,000 IU / mL, at most at most 18,000 IU / mL, at most 19,000 IU / mL, or at most 20,000 IU / mL, or from about 5,000 IU / mL to about 6,000 IU / mL, from about 5,000 IU / mL to about 7,000 IU / mL, from about 5,000 IU / mL to about 8,000 IU / mL, from about 5,000 IU / mL to about 9,000 IU / mL, from about 5,000 IU / mL to about 10,000 IU / mL, from about 5,000 IU / mL to about 11,000 IU / mL, from about 5,000 IU / mL to about 12,000 IU / mL, from about 5,000 IU / mL to about 13,000 IU / mL, Approximately 5,000 IU / mL to approximately 14,000 IU / mL, approximately 5,000 IU / mL to approximately 15,000 IU / mL, approximately 5,000 IU / mL to about 16,000 IU / mL, about 5,000 IU / mL to about 17,000 IU / mL, about 5,000 IU / mL to about 18,000 IU / mL, Approximately 5,000 IU / mL to approximately 19,000 IU / mL, approximately 5,000 IU / mL to approximately 20,000 IU / mL, approximately 6,000 IU / mL to about 7,000 IU / mL, about 6,000 IU / mL to about 8,000 IU / mL, about 6,000 IU / mL to about 9,000 IU / mL, about 6,000IU / mL~about 10,000IU / mL, about 6,000IU / mL~about 11,000IU / mL, about 6,000IU / mL~about 12,000IU / mL, about 6,000IU / mL~about 13,000IU / mL, about 6,000IU / mL~about 14,000IU / mL, about 6 ,000IU / mL to about 15,000IU / mL, about 6,000IU / mL to about 16,000IU / mL, about 6,000IU / mL to about 17,000IU / mL, about 6,000IU / mL to about 18,000IU / mL, about 6,000IU / mL to about 19,000IU / mL, about 6 ,000IU / mL to about 20,000IU / mL, about 7,000IU / mL to about 8,000IU / mL, about 7,000IU / mL to about 9,000IU / mL, about 7,000IU / mL to about 10,000IU / mL, about 7,000IU / mL to about 11,000IU / mL, about 7, 000IU / mL~about 12,000IU / mL, about 7,000IU / mL~about 13,000IU / mL, about 7,000IU / mL~about 14,000IU / mL, about 7,000IU / mL~about 15,000IU / mL, about 7,000IU / mL~about 16,000IU / mL, about 7, 000IU / mL~about 17,000IU / mL, about 7,000IU / mL~about 18,000IU / mL, about 7,000IU / mL~about 19,000IU / mL, about 7,000IU / mL~about 20,000IU / mL, about 8,000IU / mL~about 9,000IU / mL, about 8, 000IU / mL~about 10,000IU / mL, about 8,000IU / mL~about 11,000IU / mL, about 8,000IU / mL~about 12,000IU / mL, about 8,000IU / mL~about 13,000IU / mL, about 8,000IU / mL~about 14,000IU / mL, about 8, 000IU / mL~about 15,000IU / mL, about 8,000IU / mL~about 16,000IU / mL, about 8,000IU / mL~about 17,000IU / mL, about 8,000IU / mL~about 18,000IU / mL, about 8,000IU / mL~about 19,000IU / mL, about 8, 000IU / mL~about 20,000IU / mL, about 9,000IU / mL~about 10,000IU / mL, about 9,000IU / mL~about 11,000IU / mL, about 9,000IU / mL~about 12,000IU / mL, about 9,000IU / mL~about 13,000IU / mL, about 9,000IU / mL~about 14,000IU / mL, about 9,000IU / mL~about 15,000IU / mL, about 9,000IU / mL~about 16,000IU / mL, about 9,000IU / mL~about 17,000IU / mL, about 9,000IU / mL~about 18,000IU / mL, about 9 ,000IU / mL to about 19,000IU / mL, about 9,000IU / mL to about 20,000IU / mL, about 10,000IU / mL to about 11,000IU / mL, about 10,000IU / mL to about 12,000IU / mL, about 10,000IU / mL to about 13,000IU / mL L, about 10,000IU / mL to about 14,000IU / mL, about 10,000IU / mL to about 15,000IU / mL, about 10,000IU / mL to about 16,000IU / mL, about 10,000IU / mL to about 17,000IU / mL, about 10,000IU / mL to about 18,0 00IU / mL, about 10,000IU / mL to about 19,000IU / mL, about 10,000IU / mL to about 20,000IU / mL, about 11,000IU / mL to about 12,000IU / mL, about 11,000IU / mL to about 13,000IU / mL, about 11,000IU / mL to about About 14,000IU / mL, about 11,000IU / mL to about 15,000IU / mL, about 11,000IU / mL to about 16,000IU / mL, about 11,000IU / mL to about 17,000IU / mL, about 11,000IU / mL to about 18,000IU / mL, about 11,000 IU / mL to about 19,000IU / mL, about 11,000IU / mL to about 20,000IU / mL, about 12,000IU / mL to about 13,000IU / mL, about 12,000IU / mL to about 14,000IU / mL, about 12,000IU / mL to about 15,000IU / mL, about 1 2,000IU / mL to about 16,000IU / mL, about 12,000IU / mL to about 17,000IU / mL, about 12,000IU / mL to about 18,000IU / mL, about 12,000IU / mL to about 19,000IU / mL, about 12,000IU / mL to about 20,000IU / mL, about 13,000IU / mL to about 14,000IU / mL, about 13,000IU / mL to about 15,000IU / mL, about 13,000IU / mL to about 16,000IU / mL, about 13,000IU / mL to about 17,000IU / mL, about 13,000IU / mL to about 18,000IU / mL, about 13,000IU / mL to about 19,000IU / mL, about 13,000IU / mL to about 20,000IU / mL, about 14,000IU / mL to about 15,0 00IU / mL, about 14,000IU / mL to about 16,000IU / mL, about 14,000IU / mL to about 17,000IU / mL, about 14,000IU / mL to about 18,000 IU / mL, about 14,000 IU / mL to about 19,000 IU / mL, about 14,000 IU / mL to about 20,000 IU / mL, about 15,000 IU / mL to about 16,000 I U / mL, about 15,000 IU / mL to about 17,000 IU / mL, about 15,000 IU / mL to about 18,000 IU / mL, about 15,000 IU / mL to about 19,000 IU / mL mL, about 15,000 IU / mL to about 20,000 IU / mL, about 16,000 IU / mL to about 17,000 IU / mL, about 16,000 IU / mL to about 18,000 IU / m L, about 16,000 IU / mL to about 19,000 IU / mL, about 16,000 IU / mL to about 20,000 IU / mL, about 17,000 IU / mL to about 18,000 IU / mL, The composition according to any one of claims 1 to 3, having a concentration of about 17,000 IU / mL to about 19,000 IU / mL, about 17,000 IU / mL to about 20,000 IU / mL, about 18,000 IU / mL to about 19,000 IU / mL, about 18,000 IU / mL to about 20,000 IU / mL, or about 19,000 IU / mL to about 20,000 IU / mL.

9. The ultra-high concentration hyaluronidase may have a concentration of at least 250 IU / mL, at least 500 IU / mL, at least 750 IU / mL, at least 1,000 IU / mL, at least 1,500 IU / mL, at least 2,000 IU / mL, at least 2,500 IU / mL, at least 3,000 IU / mL, at least 3,500 IU / mL, at least 4,000 IU / mL, at least 4,500 IU / mL, or at least 5,000 IU / mL, and / or at most 250 IU / mL, at most 500 IU / mL, at most 750 IU / mL. / mL, at most 1,000 IU / mL, at most 1,500 IU / mL, at most 2,000 IU / mL, at most 2,500 IU / mL, at most 3,000 IU / mL, at most 3,500 IU / mL, at most 4,000 IU / mL, at most 4,500 IU / mL or at most 5,000 IU / mL, or from about 250 IU / mL to about 500 IU / mL, from about 250 IU / mL to about 750 IU / mL, from about 250 IU / mL to about 1,000 IU / mL, from about 250 IU / mL to about 1,500 IU / mL, from about 250 IU / mL to about 2,000 IU / mL / mL, about 250 IU / mL to about 2,500 IU / mL, about 250 IU / mL to about 3,000 IU / mL, about 250 IU / mL to about 3.5 00IU / mL, about 250IU / mL to about 4,000IU / mL, about 250IU / mL to about 4,500IU / mL, about 250IU / mL to about Approximately 5,000 IU / mL, approximately 500 IU / mL to approximately 750 IU / mL, approximately 500 IU / mL to approximately 1,000 IU / mL, approximately 500 IU / m L to about 1,500 IU / mL, about 500 IU / mL to about 2,000 IU / mL, about 500 IU / mL to about 2,500 IU / mL, about 500 I U / mL to about 3,000 IU / mL, about 500 IU / mL to about 3,500 IU / mL, about 500 IU / mL to about 4,000 IU / mL, about 500IU / mL to about 4,500IU / mL, about 500IU / mL to about 5,000IU / mL, about 750IU / mL to about 1,000IU / m L, about 750 IU / mL to about 1,500 IU / mL, about 750 IU / mL to about 2,000 IU / mL, about 750 IU / mL to about 2,500 IU / mL, about 750 IU / mL to about 3,000 IU / mL, about 750 IU / mL to about 3,500 IU / mL, about 750 IU / mL to about 4,000IU / mL, about 750IU / mL to about 4,500IU / mL, about 750IU / mL to about 5,000IU / mL, about 1,000 IU / mL to about 1,500 IU / mL, about 1,000 IU / mL to about 2,000 IU / mL, about 1,000 IU / mL to about 2,50 0IU / mL, about 1,000IU / mL to about 3,000IU / mL, about 1,000IU / mL to about 3,500IU / mL, about 1.0 00IU / mL to about 4,000IU / mL, about 1,000IU / mL to about 4,500IU / mL, about 1,000IU / mL to about 5, 000IU / mL, about 1,500IU / mL to about 2,000IU / mL, about 1,500IU / mL to about 2,500IU / mL, about 1 , 500 IU / mL to about 3,000 IU / mL, about 1,500 IU / mL to about 3,500 IU / mL, about 1,500 IU / mL to about 4,000 IU / mL, about 1,500 IU / mL to about 4,500 IU / mL, about 1,500 IU / mL to about 5,000 IU / mL, Approximately 2,000 IU / mL to approximately 2,500 IU / mL, approximately 2,000 IU / mL to approximately 3,000 IU / mL, approximately 2,000 IU / mL to Approximately 3,500 IU / mL, approximately 2,000 IU / mL to approximately 4,000 IU / mL, approximately 2,000 IU / mL to approximately 4,500 IU / mL , about 2,000 IU / mL to about 5,000 IU / mL, about 2,500 IU / mL to about 3,000 IU / mL, about 2,500 IU / m L to about 3,500 IU / mL, about 2,500 IU / mL to about 4,000 IU / mL, about 2,500 IU / mL to about 4,500 IU / mL, about 2,500 IU / mL to about 5,000 IU / mL, about 3,000 IU / mL to about 3,500 IU / mL, about 3,000 IU The composition of any one of claims 1 to 3, wherein the concentration of riboflavin is from about 4,000 IU / mL to about 4,500 IU / mL, from about 3,000 IU / mL to about 4,500 IU / mL, from about 3,000 IU / mL to about 5,000 IU / mL, from about 3,500 IU / mL to about 4,000 IU / mL, from about 3,500 IU / mL to about 4,500 IU / mL, from about 3,500 IU / mL to about 5,000 IU / mL, from about 4,000 IU / mL to about 4,500 IU / mL, from about 4,000 IU / mL to about 5,000 IU / mL, or from about 4,500 IU / mL to about 5,000 IU / mL.

10. The ultra-high concentration hyaluronidase may be at least 25,000 IU / mL, at least 50,000 IU / mL, at least 75,000 IU / mL, at least 100,000 IU / mL, at least 125,000 IU / mL, at least 150,000 IU / mL, at least 175,000 IU / mL, at least 200,000 IU / mL, at least 225,000 IU / mL, at least 250,000 IU / mL, at least 300,000 IU / mL, at least 350,000 IU / mL, at least 400,000 IU / mL, or at least an amount of at most 450,000 IU / mL or at least 500,000 IU / mL, and / or at most 25,000 IU / mL, at most 50,000 IU / mL, at most 75,000 IU / mL, at most 100,000 IU / mL, at most 125,000 IU / mL, at most 150,000 IU / mL, at most 175,000 IU / mL, at most 200,000 IU / mL, at most 225,000 IU / mL, at most 250,000 IU / mL, at most 300,000 IU / mL, at most 350,000 IU / mL, at most 4 00,000 IU / mL, at most 450,000 IU / mL or at most 500,000 IU / mL, or from about 25,000 IU / mL to about 50,000 IU / mL, from about 25,000 IU / mL to about 75,000 IU / mL, from about 25,000 IU / mL to about 100,000 IU / mL, from about 25,000 IU / mL to about 125,000 IU / mL, from about 25,000 IU / mL to about 150,000 IU / mL, from about 25,000 IU / mL to about 175,000 IU / mL, from about 25,000 IU / mL to about 2 ... mL to about 225,000 IU / mL, about 25,000 IU / mL to about 250,000 IU / mL, about 25,000 IU / mL to about 300, 000 IU / mL, about 25,000 IU / mL to about 350,000 IU / mL, about 25,000 IU / mL to about 400,000 IU / mL, About 25,000 IU / mL to about 450,000 IU / mL, about 25,000 IU / mL to about 500,000 IU / mL, about 50,000 I U / mL to about 75,000 IU / mL, about 50,000 IU / mL to about 100,000 IU / mL, about 50,000 IU / mL to about 125,000IU / mL, about 50,000IU / mL to about 150,000IU / mL, about 50,000IU / mL to about 175,000IU / mL, about 50,000IU / mL to about 200,000IU / mL, about 50,000IU / mL to about 225,000IU / mL, about 50,000IU / mL U / mL to about 250,000IU / mL, about 50,000IU / mL to about 300,000IU / mL, about 50,000IU / mL to about 350,000IU / mL, about 50,000IU / mL to about 400,000IU / mL, about 50,000IU / mL to about 450,000IU / mL L, about 50,000IU / mL to about 500,000IU / mL, about 75,000IU / mL to about 100,000IU / mL, about 75,000IU / mL to about 125,000IU / mL, about 75,000IU / mL to about 150,000IU / mL, about 75,000IU / mL to about 1 75,000IU / mL, about 75,000IU / mL to about 200,000IU / mL, about 75,000IU / mL to about 225,000IU / mL, about 75,000IU / mL to about 250,000IU / mL, about 75,000IU / mL to about 300,000IU / mL, about 75,0 00IU / mL~about 350,000IU / mL, about 75,000IU / mL~about 400,000IU / mL, about 75,000IU / mL~about 450,000IU / mL, about 75,000IU / mL~about 500,000IU / mL, about 100,000IU / mL~about 125,000 IU / mL, about 100,000IU / mL to about 150,000IU / mL, about 100,000IU / mL to about 175,000IU / mL, about 100,000IU / mL to about 200,000IU / mL, about 100,000IU / mL to about 225,000IU / mL, about 100,00 0IU / mL~about 250,000IU / mL, about 100,000IU / mL~about 300,000IU / mL, about 100,000IU / mL~about 350,000IU / mL, about 100,000IU / mL~about 400,000IU / mL, about 100,000IU / mL~about 450,0 00IU / mL, about 100,000IU / mL to about 500,000IU / mL, about 150,000IU / mL to about 200,000IU / mL, about 150,000IU / mL to about 225,000IU / mL, about 150,000IU / mL to about 250,000IU / mL, about 150,000 IU / mL to about 300,000 IU / mL, about 150,000 IU / mL to about 350,000 IU / mL, about 150,000 IU / mL to about 400,000 IU / mL, about 150,000 IU / mL to about 450 ,000 IU / mL, about 150,000 IU / mL to about 500,000 IU / mL, about 200,000 IU / mL to about 225,000 IU / mL, about 200,000 IU / mL to about 250,000 IU / mL, about 200 ,000 IU / mL to about 300,000 IU / mL, about 200,000 IU / mL to about 350,000 IU / mL, about 200,000 IU / mL to about 400,000 IU / mL, about 200,000 IU / mL to about 450 ,000IU / mL, about 200,000IU / mL to about 500,000IU / mL, about 250,000IU / mL to about 300,000IU / mL, about 250,000IU / mL to about 350,000IU / mL, about 250 ,000 IU / mL to about 400,000 IU / mL, about 250,000 IU / mL to about 450,000 IU / mL, about 250,000 IU / mL to about 500,000 IU / mL, about 300,000 IU / mL to about 35 0,000 IU / mL, about 300,000 IU / mL to about 400,000 IU / mL, about 300,000 IU / mL to about 450,000 IU / mL, about 300,000 IU / mL to about 500,000 IU / mL, about 35 The composition according to any one of claims 1 to 3, wherein the composition is administered in an amount of from about 0,000 IU / mL to about 400,000 IU / mL, from about 350,000 IU / mL to about 450,000 IU / mL, from about 350,000 IU / mL to about 500,000 IU / mL, from about 400,000 IU / mL to about 450,000 IU / mL, from about 400,000 IU / mL to about 500,000 IU / mL, or from about 450,000 IU / mL to about 500,000 IU / mL.

11. The ultra-high concentration hyaluronidase may be in an amount of at least 10,000 IU / mL, at least 20,000 IU / mL, at least 30,000 IU / mL, at least 40,000 IU / mL, at least 50,000 IU / mL, at least 60,000 IU / mL, at least 70,000 IU / mL, at least 80,000 IU / mL, at least 90,000 IU / mL, or at least 100,000 IU / mL, and / or at most 10,000 IU / mL, at most 20,000 IU / mL, at most 30,000 IU / mL, at most ... most 50,000 IU / mL, at most 60,000 IU / mL, at least 70,000 IU / mL, at least 80,000 IU / mL, at least 90,000 IU / mL, or at least 100,000 IU / mL. or an amount of about 10,000 IU / mL to about 20,000 IU / mL, about 10,000 IU / mL to about 30,000 IU / mL, about 10,000 IU / mL to about 40,000 IU / mL, about 10,000 IU / mL to about 50,000 IU / mL, about 10,000 IU / mL to about 6 ...100,000 IU / mL, or an amount of about 10,000 IU / mL to about 20,000 IU / mL, about 10,000 IU / mL to about 30,000 IU / mL, about 10,000 IU / mL to about 40,000 IU / mL, about 10,000 IU / mL to about 50,000 IU / mL, about 10,000 IU / mL to about 60,000 IU / mL, about 1 0,000IU / mL to about 70,000IU / mL, about 10,000IU / mL to about 80,000IU / mL, about 10,000IU / mL ~about 90,000IU / mL, about 10,000IU / mL~about 100,000IU / mL, about 20,000IU / mL~about 30,000I U / mL, about 20,000 IU / mL to about 40,000 IU / mL, about 20,000 IU / mL to about 50,000 IU / mL, about 20,0 00IU / mL to about 60,000IU / mL, about 20,000IU / mL to about 70,000IU / mL, about 20,000IU / mL to about 80 ,000IU / mL, about 20,000IU / mL to about 90,000IU / mL, about 20,000IU / mL to about 100,000IU / mL , about 30,000 IU / mL to about 40,000 IU / mL, about 30,000 IU / mL to about 50,000 IU / mL, about 30,000 IU / mL mL to about 60,000 IU / mL, about 30,000 IU / mL to about 70,000 IU / mL, about 30,000 IU / mL to about 80,000 IU / mL, about 30,000 IU / mL to about 90,000 IU / mL, about 30,000 IU / mL to about 100,000 IU / mL, about 40,000IU / mL to about 50,000IU / mL, about 40,000IU / mL to about 60,000IU / mL, about 40,000IU / mL to about 70,000IU / m L, about 40,000 IU / mL to about 80,000 IU / mL, about 40,000 IU / mL to about 90,000 IU / mL, about 40,000 IU / mL to about 100, 000IU / mL, about 50,000IU / mL to about 60,000IU / mL, about 50,000IU / mL to about 70,000IU / mL, about 50,000IU / m L to about 80,000 IU / mL, about 50,000 IU / mL to about 90,000 IU / mL, about 50,000 IU / mL to about 100,000 IU / mL, about 60,0 00IU / mL to about 70,000IU / mL, about 60,000IU / mL to about 80,000IU / mL, about 60,000IU / mL to about 90,000IU / mL , about 60,000 IU / mL to about 100,000 IU / mL, about 70,000 IU / mL to about 80,000 IU / mL, about 70,000 IU / mL to about 90,00 The composition according to any one of claims 1 to 3, wherein the composition is administered in an amount of about 0 IU / mL, about 70,000 IU / mL to about 100,000 IU / mL, about 80,000 IU / mL to about 90,000 IU / mL, about 80,000 IU / mL to about 100,000 IU / mL, or about 90,000 IU / mL to about 100,000 IU / mL.

12. The ultra-high concentration hyaluronidase may be in an amount of at least 10,000 IU / mL, at least 11,000 IU / mL, at least 12,000 IU / mL, at least 13,000 IU / mL, at least 14,000 IU / mL, at least 15,000 IU / mL, at least 16,000 IU / mL, at least 17,000 IU / mL, at least 18,000 IU / mL, at least 19,000 IU / mL, or at least 20,000 IU / mL, and / or at most 10,000 IU / mL, at most 11,000 IU / mL, at most 20,000 IU / mL. or an amount of at most 12,000 IU / mL, at most 13,000 IU / mL, at most 14,000 IU / mL, at most 15,000 IU / mL, at most 16,000 IU / mL, at most 17,000 IU / mL, at most 18,000 IU / mL, at most 19,000 IU / mL or at most 20,000 IU / mL, or from about 10,000 IU / mL to about 11,000 IU / mL, from about 10,000 IU / mL to about 12,000 IU / mL, from about 10,000 IU / mL to about 13,000 IU / mL, from about 10,000 IU / mL to about 14,000 IU / mL L, about 10,000 IU / mL to about 15,000 IU / mL, about 10,000 IU / mL to about 16,000 IU / mL, about 10,000 I U / mL to about 17,000 IU / mL, about 10,000 IU / mL to about 18,000 IU / mL, about 10,000 IU / mL to about 19,00 0IU / mL, about 10,000IU / mL to about 20,000IU / mL, about 11,000IU / mL to about 12,000IU / mL, about 11 ,000IU / mL to about 13,000IU / mL, about 11,000IU / mL to about 14,000IU / mL, about 11,000IU / mL to about 15,000 IU / mL, about 11,000 IU / mL to about 16,000 IU / mL, about 11,000 IU / mL to about 17,000 IU / m L, about 11,000 IU / mL to about 18,000 IU / mL, about 11,000 IU / mL to about 19,000 IU / mL, about 11,000 IU / mL to about 20,000 IU / mL, about 12,000 IU / mL to about 13,000 IU / mL, about 12,000 IU / mL to about 14,00 0IU / mL, about 12,000IU / mL to about 15,000IU / mL, about 12,000IU / mL to about 16,000IU / mL, about 12,000 IU / mL to about 17,000 IU / mL, about 12,000 IU / mL to about 18,000 IU / mL, about 12,000 IU / mL to about 19,000 IU / mL, about 12,000 IU / mL to about 20,000 IU / mL, about 13,000 IU / mL to about 14,000 IU / mL, about 13,000 IU / mL to about 15,000 IU / mL, about 13,000 IU / mL to about 16,000 IU / mL, about 13,000 IU / mL to about 17,000 IU / mL, about 13,000 IU / mL mL to about 18,000 IU / mL, about 13,000 IU / mL to about 19,000 IU / mL, about 13,000 IU / mL to about 20,000 IU / mL, about 14,000 IU / mL to about 15,000 IU / mL, about 14,000 IU / mL to about 16,000 IU / mL, about 14,000 IU / mL to about 17,000 IU / mL, about 14,000 IU / mL to about 18,000 IU / mL, about 14,000 IU / mL to about 19,000 IU / mL, about 14,000 IU / mL to about 20, 000 IU / mL, about 15,000 IU / mL to about 16,000 IU / mL, about 15,000 IU / mL to about 17,000 IU / mL, about 15,000 IU / mL to about 18,000 IU / mL, about 15,000 IU / mL to about 19,000 IU / mL, about 15,000 IU / mL to about 20,000 IU / mL, about 16,000 IU / mL to about 17,000 IU / mL, about 16,000 IU / mL to about 18,000 IU / mL, about 16,000 IU / mL to about 19,000 IU / m The composition of any one of claims 1 to 3, wherein the composition is administered in an amount of about 16,000 IU / mL to about 20,000 IU / mL, about 17,000 IU / mL to about 18,000 IU / mL, about 17,000 IU / mL to about 19,000 IU / mL, about 17,000 IU / mL to about 20,000 IU / mL, about 18,000 IU / mL to about 19,000 IU / mL, about 18,000 IU / mL to about 20,000 IU / mL, or about 19,000 IU / mL to about 20,000 IU / mL.

13. The ultra-high concentration hyaluronidase may be in an amount of at least 250 IU / mL, at least 500 IU / mL, at least 750 IU / mL, at least 1,000 IU / mL, at least 1,500 IU / mL, at least 2,000 IU / mL, at least 2,500 IU / mL, at least 3,000 IU / mL, at least 3,500 IU / mL, at least 4,000 IU / mL, at least 4,500 IU / mL, or at least 5,000 IU / mL, and / or at most 250 IU / mL, at most 500 IU / mL, at most 750 IU / mL / mL, at most 1,000 IU / mL, at most 1,500 IU / mL, at most 2,000 IU / mL, at most 2,500 IU / mL, at most 3,000 IU / mL, at most 3,500 IU / mL, at most 4,000 IU / mL, at most 4,500 IU / mL or at most 5,000 IU / mL, or an amount of from about 250 IU / mL to about 500 IU / mL, from about 250 IU / mL to about 750 IU / mL, from about 250 IU / mL to about 1,000 IU / mL, from about 250 IU / mL to about 1,500 IU / mL, from about 250 IU / mL to about 2,000 IU / mL mL, about 250 IU / mL to about 2,500 IU / mL, about 250 IU / mL to about 3,000 IU / mL, about 250 IU / mL to about 3,50 0IU / mL, about 250IU / mL to about 4,000IU / mL, about 250IU / mL to about 4,500IU / mL, about 250IU / mL to about 5,000 IU / mL, about 500 IU / mL to about 750 IU / mL, about 500 IU / mL to about 1,000 IU / mL, about 500 IU / mL ~about 1,500 IU / mL, about 500 IU / mL to about 2,000 IU / mL, about 500 IU / mL to about 2,500 IU / mL, about 500 IU / mL to about 3,000 IU / mL, about 500 IU / mL to about 3,500 IU / mL, about 500 IU / mL to about 4,000 IU / mL, about 5 00IU / mL to about 4,500IU / mL, about 500IU / mL to about 5,000IU / mL, about 750IU / mL to about 1,000IU / m L, about 750 IU / mL to about 1,500 IU / mL, about 750 IU / mL to about 2,000 IU / mL, about 750 IU / mL to about 2,500 IU / mL, about 750 IU / mL to about 3,000 IU / mL, about 750 IU / mL to about 3,500 IU / mL, about 750 IU / mL to about 4,000IU / mL, about 750IU / mL to about 4,500IU / mL, about 750IU / mL to about 5,000IU / mL, about 1,000 IU / mL to about 1,500 IU / mL, about 1,000 IU / mL to about 2,000 IU / mL, about 1,000 IU / mL to about 2,50 0IU / mL, about 1,000IU / mL to about 3,000IU / mL, about 1,000IU / mL to about 3,500IU / mL, about 1.0 00IU / mL to about 4,000IU / mL, about 1,000IU / mL to about 4,500IU / mL, about 1,000IU / mL to about 5.0 00IU / mL, about 1,500IU / mL to about 2,000IU / mL, about 1,500IU / mL to about 2,500IU / mL, about 1, 500IU / mL to about 3,000IU / mL, about 1,500IU / mL to about 3,500IU / mL, about 1,500IU / mL to about 4 ,000IU / mL, about 1,500IU / mL to about 4,500IU / mL, about 1,500IU / mL to about 5,000IU / mL, about 2,000IU / mL to about 2,500IU / mL, about 2,000IU / mL to about 3,000IU / mL, about 2,000IU / mL to about 3,500 IU / mL, about 2,000 IU / mL to about 4,000 IU / mL, about 2,000 IU / mL to about 4,500 IU / mL, Approximately 2,000 IU / mL to approximately 5,000 IU / mL, approximately 2,500 IU / mL to approximately 3,000 IU / mL, approximately 2,500 IU / mL ~about 3,500 IU / mL, about 2,500 IU / mL to about 4,000 IU / mL, about 2,500 IU / mL to about 4,500 IU / m L, about 2,500 IU / mL to about 5,000 IU / mL, about 3,000 IU / mL to about 3,500 IU / mL, about 3,000 IU / m The composition of any one of claims 1 to 3, wherein the composition is administered in an amount of about 4,000 IU / mL, about 3,000 IU / mL to about 4,500 IU / mL, about 3,000 IU / mL to about 5,000 IU / mL, about 3,500 IU / mL to about 4,000 IU / mL, about 3,500 IU / mL to about 4,500 IU / mL, about 3,500 IU / mL to about 5,000 IU / mL, about 4,000 IU / mL to about 4,500 IU / mL, about 4,000 IU / mL to about 5,000 IU / mL, or about 4,500 IU / mL to about 5,000 IU / mL.

14. The composition of any one of claims 1 to 3, wherein the composition is administered in a single dose or multiple doses.

15. The composition has a volume of at least 0.5 mL, at least 1.0 mL, at least 2.0 mL, at least 3.0 mL, at least 4.0 mL or at least 5.0 mL, and / or a volume of at most 0.5 mL, at most 1.0 mL, at most 2.0 mL, at most 3.0 mL, at most 4.0 mL or at most 5.0 mL, or a volume of about 0.5 mL to 1.0 mL, about 0.5 mL to 2.0 mL, about 0.5 mL to 4. The composition of any one of claims 1 to 3, administered in a volume of about 3.0 mL, about 0.5 mL to 4.0 mL, about 0.5 mL to 5.0 mL, about 1.0 mL to 2.0 mL, about 1.0 mL to 3.0 mL, about 1.0 mL to 4.0 mL, about 1.0 to 5.0 mL, about 2.0 mL to 3.0 mL, about 2.0 mL to 4.0 mL, about 2.0 to 5.0 mL, about 3.0 mL to 4.0 mL, about 3.0 to 5.0 mL, or about 4.0 to 5.0 mL.

16. A delivery system comprising the composition of any one of claims 1 to 3 for use in reducing or eliminating hyaluronic acid-induced obstruction in one or more blood vessels supplying blood to a region of tissue.

17. 17. The delivery system of claim 16, wherein the composition is administered to the dermal portion of a skin area.

18. The hyaluronidase may be at least 25,000 IU / mL, at least 50,000 IU / mL, at least 75,000 IU / mL, at least 100,000 IU / mL, at least 125,000 IU / mL, at least 150,000 IU / mL, at least 175,000 IU / mL, at least 200,000 IU / mL, at least 225,000 IU / mL, at least 250,000 IU / mL, at least 300,000 IU / mL, at least 350,000 IU / mL, at least 400,000 IU / mL, at least 4 a concentration of 50,000 IU / mL or at least 500,000 IU / mL, and / or at most 25,000 IU / mL, at most 50,000 IU / mL, at most 75,000 IU / mL, at most 100,000 IU / mL, at most 125,000 IU / mL, at most 150,000 IU / mL, at most 175,000 IU / mL, at most 200,000 IU / mL, at most 225,000 IU / mL, at most 250,000 IU / mL, at most 300,000 IU / mL, at most 350,000 IU / mL, at most 400 ,000 IU / mL, at most 450,000 IU / mL or at most 500,000 IU / mL, or about 25,000 IU / mL to about 50,000 IU / mL, about 25,000 IU / mL to about 75,000 IU / mL, about 25,000 IU / mL to about 100,000 IU / mL, about 25,000 IU / mL to about 125,000 IU / mL, about 25,000 IU / mL to about 150,000 IU / mL, about 25,000 IU / mL to about 175,000 IU / mL, about 25,000 IU / mL to about 200,000 IU / mL, about 25,000 IU / mL mL to about 225,000 IU / mL, about 25,000 IU / mL to about 250,000 IU / mL, about 25,000 IU / mL to about 300, 000 IU / mL, about 25,000 IU / mL to about 350,000 IU / mL, about 25,000 IU / mL to about 400,000 IU / mL, About 25,000 IU / mL to about 450,000 IU / mL, about 25,000 IU / mL to about 500,000 IU / mL, about 50,000 I U / mL to about 75,000 IU / mL, about 50,000 IU / mL to about 100,000 IU / mL, about 50,000 IU / mL to about 125,000IU / mL, about 50,000IU / mL to about 150,000IU / mL, about 50,000IU / mL to about 175,000IU / mL, about 50,000IU / mL to about 200,000IU / mL, about 50,000IU / mL to about 225,000IU / mL, about 50,000IU / mL U / mL to about 250,000IU / mL, about 50,000IU / mL to about 300,000IU / mL, about 50,000IU / mL to about 350,000IU / mL, about 50,000IU / mL to about 400,000IU / mL, about 50,000IU / mL to about 450,000IU / mL L, about 50,000IU / mL to about 500,000IU / mL, about 75,000IU / mL to about 100,000IU / mL, about 75,000IU / mL to about 125,000IU / mL, about 75,000IU / mL to about 150,000IU / mL, about 75,000IU / mL to about 1 75,000IU / mL, about 75,000IU / mL to about 200,000IU / mL, about 75,000IU / mL to about 225,000IU / mL, about 75,000IU / mL to about 250,000IU / mL, about 75,000IU / mL to about 300,000IU / mL, about 75,0 00IU / mL~about 350,000IU / mL, about 75,000IU / mL~about 400,000IU / mL, about 75,000IU / mL~about 450,000IU / mL, about 75,000IU / mL~about 500,000IU / mL, about 100,000IU / mL~about 125,000 IU / mL, about 100,000IU / mL to about 150,000IU / mL, about 100,000IU / mL to about 175,000IU / mL, about 100,000IU / mL to about 200,000IU / mL, about 100,000IU / mL to about 225,000IU / mL, about 100,00 0IU / mL~about 250,000IU / mL, about 100,000IU / mL~about 300,000IU / mL, about 100,000IU / mL~about 350,000IU / mL, about 100,000IU / mL~about 400,000IU / mL, about 100,000IU / mL~about 450,0 00IU / mL, about 100,000IU / mL to about 500,000IU / mL, about 150,000IU / mL to about 200,000IU / mL, about 150,000IU / mL to about 225,000IU / mL, about 150,000IU / mL to about 250,000IU / mL, about 150,000 IU / mL to about 300,000 IU / mL, about 150,000 IU / mL to about 350,000 IU / mL, about 150,000 IU / mL to about 400,000 IU / mL, about 150,000 IU / mL to about 450,000 IU / mL, about 150,000 IU / mL to about 500,000 IU / mL, about 200,000 IU / mL to about 225,000 IU / mL, about 200,000 IU / mL to about 250,000 IU / mL, about 200,000 IU / mL to about 2 25,000 IU / mL, about 200,000 IU / mL to about 250,000 IU / mL, about 200,000 IU / mL to about 300,000 IU / mL, about 200,000 IU / mL to about 350,000 IU / mL, about 200,000 IU / mL to about 400,000 IU / mL, about 200,000 IU / mL to about 450,000 IU / mL, about 200,000 IU / mL to about 500,000 IU / mL, about 250,000 IU / mL to about 300,000 IU / mL, about 250,000 IU / mL to about 350,000 IU / mL, about 250,000 IU / mL to about 400,000 IU / mL, about 250,000 IU / mL to about 450,000 IU / mL, about 250,000 IU / mL to about 500,0 00 IU / mL, about 300,000 IU / mL to about 350,000 IU / mL, about 300,000 IU / mL to about 400,000 IU / mL, about 300,000 IU / mL to about 450,000 IU / mL, about 300,000 IU / m 17. The delivery system of claim 16, wherein the concentration is from about 100,000 IU / mL to about 500,000 IU / mL, from about 350,000 IU / mL to about 400,000 IU / mL, from about 350,000 IU / mL to about 450,000 IU / mL, from about 350,000 IU / mL to about 500,000 IU / mL, from about 400,000 IU / mL to about 450,000 IU / mL, from about 400,000 IU / mL to about 500,000 IU / mL, or from about 450,000 IU / mL to about 500,000 IU / mL.

19. The hyaluronidase may have a concentration of at least 10,000 IU / mL, at least 20,000 IU / mL, at least 30,000 IU / mL, at least 40,000 IU / mL, at least 50,000 IU / mL, at least 60,000 IU / mL, at least 70,000 IU / mL, at least 80,000 IU / mL, at least 90,000 IU / mL or at least 100,000 IU / mL, and / or at most 10,000 IU / mL, at most 20,000 IU / mL, at most 30,000 IU / mL, at most 4 and a concentration of about 10,000 IU / mL, at most 50,000 IU / mL, at most 60,000 IU / mL, at most 70,000 IU / mL, at most 80,000 IU / mL, at most 90,000 IU / mL or at most 100,000 IU / mL, or about 10,000 IU / mL to about 20,000 IU / mL, about 10,000 IU / mL to about 30,000 IU / mL, about 10,000 IU / mL to about 40,000 IU / mL, about 10,000 IU / mL to about 50,000 IU / mL, about 10,000 IU / mL to about 60,000 IU / mL, about 10 ,000IU / mL to about 70,000IU / mL, about 10,000IU / mL to about 80,000IU / mL, about 10,000IU / mL to Approximately 90,000 IU / mL, approximately 10,000 IU / mL to approximately 100,000 IU / mL, approximately 20,000 IU / mL to approximately 30,000 IU / mL, about 20,000 IU / mL to about 40,000 IU / mL, about 20,000 IU / mL to about 50,000 IU / mL, about 20,00 0IU / mL to about 60,000IU / mL, about 20,000IU / mL to about 70,000IU / mL, about 20,000IU / mL to about 80, 000 IU / mL, about 20,000 IU / mL to about 90,000 IU / mL, about 20,000 IU / mL to about 100,000 IU / mL, About 30,000 IU / mL to about 40,000 IU / mL, about 30,000 IU / mL to about 50,000 IU / mL, about 30,000 IU / mL mL to about 60,000 IU / mL, about 30,000 IU / mL to about 70,000 IU / mL, about 30,000 IU / mL to about 80,000 IU / mL, about 30,000 IU / mL to about 90,000 IU / mL, about 30,000 IU / mL to about 100,000 IU / mL, about 40,000IU / mL to about 50,000IU / mL, about 40,000IU / mL to about 60,000IU / mL, about 40,000IU / mL to about 70,000IU / mL, about 40,000 IU / mL to about 80,000 IU / mL, about 40,000 IU / mL to about 90,000 IU / mL, about 40,000 IU / mL to about 100 ,000IU / mL, about 50,000IU / mL to about 60,000IU / mL, about 50,000IU / mL to about 70,000IU / mL, about 50,000IU / mL to about 80,000 IU / mL, about 50,000 IU / mL to about 90,000 IU / mL, about 50,000 IU / mL to about 100,000 IU / mL, about 6 0,000IU / mL to about 70,000IU / mL, about 60,000IU / mL to about 80,000IU / mL, about 60,000IU / mL to about 90,000I U / mL, about 60,000 IU / mL to about 100,000 IU / mL, about 70,000 IU / mL to about 80,000 IU / mL, about 70,000 IU / mL to about 17. The delivery system of claim 16, wherein the concentration is 90,000 IU / mL, about 70,000 IU / mL to about 100,000 IU / mL, about 80,000 IU / mL to about 90,000 IU / mL, about 80,000 IU / mL to about 100,000 IU / mL, or about 90,000 IU / mL to about 100,000 IU / mL.

20. The hyaluronidase may be at least 5,000 IU / mL, at least 6,000 IU / mL, at least 7,000 IU / mL, at least 8,000 IU / mL, at least 9,000 IU / mL, at least 10,000 IU / mL, at least 11,000 IU / mL, at least 12,000 IU / mL, at least 13,000 IU / mL, at least 14,000 IU / mL, at least 15,000 IU / mL, at least 16,000 IU / mL, at least 17,000 IU / mL, at least 18,000 IU / mL, at least at most 19,000 IU / mL or at least 20,000 IU / mL, and / or at most 5,000 IU / mL, at most 6,000 IU / mL, at most 7,000 IU / mL, at most 8,000 IU / mL, at most 9,000 IU / mL, at most 10,000 IU / mL, at most 11,000 IU / mL, at most 12,000 IU / mL, at most 13,000 IU / mL, at most 14,000 IU / mL, at most 15,000 IU / mL, at most 16,000 IU / mL, at most 17,000 IU / mL, at most 18,000 IU / mL, at most 19,000 IU / mL or at most 20,000 IU / mL, or from about 5,000 IU / mL to about 6,000 IU / mL, from about 5,000 IU / mL to about 7,000 IU / mL, from about 5,000 IU / mL to about 8,000 IU / mL, from about 5,000 IU / mL to about 9,000 IU / mL, from about 5,000 IU / mL to about 10,000 IU / mL, from about 5,000 IU / mL to about 11,000 IU / mL, from about 5,000 IU / mL to about 12,000 IU / mL, from about 5,000 IU / mL to about 13,000 IU / mL, 5,000 IU / mL to about 14,000 IU / mL, about 5,000 IU / mL to about 15,000 IU / mL, about 5,000 IU / mL to about 16,000 IU / mL, about 5,000 IU / mL to about 17,000 IU / mL, about 5,000 IU / mL to about 18,000 IU / mL, Approximately 5,000 IU / mL to approximately 19,000 IU / mL, approximately 5,000 IU / mL to approximately 20,000 IU / mL, approximately 6,000 IU / mL to about 7,000 IU / mL, about 6,000 IU / mL to about 8,000 IU / mL, about 6,000 IU / mL to about 9,000 IU / mL, about 6,000IU / mL~about 10,000IU / mL, about 6,000IU / mL~about 11,000IU / mL, about 6,000IU / mL~about 12,000IU / mL, about 6,000IU / mL~about 13,000IU / mL, about 6,000IU / mL~about 14,000IU / mL, about 6 ,000IU / mL to about 15,000IU / mL, about 6,000IU / mL to about 16,000IU / mL, about 6,000IU / mL to about 17,000IU / mL, about 6,000IU / mL to about 18,000IU / mL, about 6,000IU / mL to about 19,000IU / mL, about 6 ,000IU / mL to about 20,000IU / mL, about 7,000IU / mL to about 8,000IU / mL, about 7,000IU / mL to about 9,000IU / mL, about 7,000IU / mL to about 10,000IU / mL, about 7,000IU / mL to about 11,000IU / mL, about 7, 000IU / mL~about 12,000IU / mL, about 7,000IU / mL~about 13,000IU / mL, about 7,000IU / mL~about 14,000IU / mL, about 7,000IU / mL~about 15,000IU / mL, about 7,000IU / mL~about 16,000IU / mL, about 7, 000IU / mL~about 17,000IU / mL, about 7,000IU / mL~about 18,000IU / mL, about 7,000IU / mL~about 19,000IU / mL, about 7,000IU / mL~about 20,000IU / mL, about 8,000IU / mL~about 9,000IU / mL, about 8, 000IU / mL~about 10,000IU / mL, about 8,000IU / mL~about 11,000IU / mL, about 8,000IU / mL~about 12,000IU / mL, about 8,000IU / mL~about 13,000IU / mL, about 8,000IU / mL~about 14,000IU / mL, about 8, 000IU / mL~about 15,000IU / mL, about 8,000IU / mL~about 16,000IU / mL, about 8,000IU / mL~about 17,000IU / mL, about 8,000IU / mL~about 18,000IU / mL, about 8,000IU / mL~about 19,000IU / mL, about 8, 000IU / mL~about 20,000IU / mL, about 9,000IU / mL~about 10,000IU / mL, about 9,000IU / mL~about 11,000IU / mL, about 9,000IU / mL~about 12,000IU / mL, about 9,000IU / mL~about 13,000IU / mL, about 9,000IU / mL~about 14,000IU / mL, about 9,000IU / mL~about 15,000IU / mL, about 9,000IU / mL~about 16,000IU / mL, about 9,000IU / mL~about 17,000IU / mL, about 9,000IU / mL~about 18,000IU / mL, about 9 ,000IU / mL to about 19,000IU / mL, about 9,000IU / mL to about 20,000IU / mL, about 10,000IU / mL to about 11,000IU / mL, about 10,000IU / mL to about 12,000IU / mL, about 10,000IU / mL to about 13,000IU / mL L, about 10,000IU / mL to about 14,000IU / mL, about 10,000IU / mL to about 15,000IU / mL, about 10,000IU / mL to about 16,000IU / mL, about 10,000IU / mL to about 17,000IU / mL, about 10,000IU / mL to about 18,0 00IU / mL, about 10,000IU / mL to about 19,000IU / mL, about 10,000IU / mL to about 20,000IU / mL, about 11,000IU / mL to about 12,000IU / mL, about 11,000IU / mL to about 13,000IU / mL, about 11,000IU / mL to about About 14,000IU / mL, about 11,000IU / mL to about 15,000IU / mL, about 11,000IU / mL to about 16,000IU / mL, about 11,000IU / mL to about 17,000IU / mL, about 11,000IU / mL to about 18,000IU / mL, about 11,000 IU / mL to about 19,000IU / mL, about 11,000IU / mL to about 20,000IU / mL, about 12,000IU / mL to about 13,000IU / mL, about 12,000IU / mL to about 14,000IU / mL, about 12,000IU / mL to about 15,000IU / mL, about 1 2,000IU / mL to about 16,000IU / mL, about 12,000IU / mL to about 17,000IU / mL, about 12,000IU / mL to about 18,000IU / mL, about 12,000IU / mL to about 19,000IU / mL, about 12,000IU / mL to about 20,000IU / mL, about 13,000IU / mL to about 14,000IU / mL, about 13,000IU / mL to about 15,000IU / mL, about 13,000IU / mL to about 16,000IU / mL, about 13,000IU / mL to about 17,000IU / mL, about 13,000IU / mL to about 18,000IU / mL, about 13,000IU / mL to about 19,000IU / mL, about 13,000IU / mL to about 20,000IU / mL, about 14,000IU / mL to about 15, 000IU / mL, about 14,000IU / mL to about 16,000IU / mL, about 14,000IU / mL to about 17,000IU / mL, about 14,000IU / mL to about 18,0 00IU / mL, about 14,000IU / mL to about 19,000IU / mL, about 14,000IU / mL to about 20,000IU / mL, about 15,000IU / mL to about 16,00 0IU / mL, about 15,000IU / mL to about 17,000IU / mL, about 15,000IU / mL to about 18,000IU / mL, about 15,000IU / mL to about 19,000 IU / mL, about 15,000 IU / mL to about 20,000 IU / mL, about 16,000 IU / mL to about 17,000 IU / mL, about 16,000 IU / mL to about 18,000 I U / mL, about 16,000 IU / mL to about 19,000 IU / mL, about 16,000 IU / mL to about 20,000 IU / mL, about 17,000 IU / mL to about 18,000 IU 17. The delivery system of claim 16, wherein the concentration is about 17,000 IU / mL to about 19,000 IU / mL, about 17,000 IU / mL to about 20,000 IU / mL, about 18,000 IU / mL to about 19,000 IU / mL, about 18,000 IU / mL to about 20,000 IU / mL, or about 19,000 IU / mL to about 20,000 IU / mL.

21. The hyaluronidase may have a concentration of at least 250 IU / mL, at least 500 IU / mL, at least 750 IU / mL, at least 1,000 IU / mL, at least 1,500 IU / mL, at least 2,000 IU / mL, at least 2,500 IU / mL, at least 3,000 IU / mL, at least 3,500 IU / mL, at least 4,000 IU / mL, at least 4,500 IU / mL, or at least 5,000 IU / mL, and / or at most 250 IU / mL, at most 500 IU / mL, at most 750 IU / mL , at most 1,000 IU / mL, at most 1,500 IU / mL, at most 2,000 IU / mL, at most 2,500 IU / mL, at most 3,000 IU / mL, at most 3,500 IU / mL, at most 4,000 IU / mL, at most 4,500 IU / mL or at most 5,000 IU / mL, or from about 250 IU / mL to about 500 IU / mL, from about 250 IU / mL to about 750 IU / mL, from about 250 IU / mL to about 1,000 IU / mL, from about 250 IU / mL to about 1,500 IU / mL, from about 250 IU / mL to about 2,000 IU / mL L, about 250 IU / mL to about 2,500 IU / mL, about 250 IU / mL to about 3,000 IU / mL, about 250 IU / mL to about 3,500 IU / mL, about 250 IU / mL to about 4,000 IU / mL, about 250 IU / mL to about 4,500 IU / mL, about 250 IU / mL to about 5 ,000IU / mL, about 500IU / mL to about 750IU / mL, about 500IU / mL to about 1,000IU / mL, about 500IU / mL to about Approximately 1,500 IU / mL, approximately 500 IU / mL to approximately 2,000 IU / mL, approximately 500 IU / mL to approximately 2,500 IU / mL, approximately 500 IU / mL to about 3,000 IU / mL, about 500 IU / mL to about 3,500 IU / mL, about 500 IU / mL to about 4,000 IU / mL, about 5 00IU / mL to about 4,500IU / mL, about 500IU / mL to about 5,000IU / mL, about 750IU / mL to about 1,000IU / m L, about 750 IU / mL to about 1,500 IU / mL, about 750 IU / mL to about 2,000 IU / mL, about 750 IU / mL to about 2,500 IU / mL, about 750 IU / mL to about 3,000 IU / mL, about 750 IU / mL to about 3,500 IU / mL, about 750 IU / mL to about 4,000IU / mL, about 750IU / mL to about 4,500IU / mL, about 750IU / mL to about 5,000IU / mL, about 1,00 0IU / mL to about 1,500IU / mL, about 1,000IU / mL to about 2,000IU / mL, about 1,000IU / mL to about 2.5 00IU / mL, about 1,000IU / mL to about 3,000IU / mL, about 1,000IU / mL to about 3,500IU / mL, about 1, 000IU / mL to about 4,000IU / mL, about 1,000IU / mL to about 4,500IU / mL, about 1,000IU / mL to about 5 ,000IU / mL, about 1,500IU / mL to about 2,000IU / mL, about 1,500IU / mL to about 2,500IU / mL, Approximately 1,500 IU / mL to approximately 3,000 IU / mL, approximately 1,500 IU / mL to approximately 3,500 IU / mL, approximately 1,500 IU / mL ~about 4,000IU / mL, about 1,500IU / mL to about 4,500IU / mL, about 1,500IU / mL to about 5,000IU / m L, about 2,000 IU / mL to about 2,500 IU / mL, about 2,000 IU / mL to about 3,000 IU / mL, about 2,000 IU / mL mL to about 3,500 IU / mL, about 2,000 IU / mL to about 4,000 IU / mL, about 2,000 IU / mL to about 4,500 I U / mL, about 2,000 IU / mL to about 5,000 IU / mL, about 2,500 IU / mL to about 3,000 IU / mL, about 2,500 IU / mL to about 3,500 IU / mL, about 2,500 IU / mL to about 4,000 IU / mL, about 2,500 IU / mL to about 4,50 0IU / mL, about 2,500IU / mL to about 5,000IU / mL, about 3,000IU / mL to about 3,500IU / mL, about 3.0 17. The delivery system of claim 16, wherein the concentration of the serotonin-containing serotonin-containing serotonin is from about 00 IU / mL to about 4,000 IU / mL, from about 3,000 IU / mL to about 4,500 IU / mL, from about 3,000 IU / mL to about 5,000 IU / mL, from about 3,500 IU / mL to about 4,000 IU / mL, from about 3,500 IU / mL to about 4,500 IU / mL, from about 3,500 IU / mL to about 5,000 IU / mL, from about 4,000 IU / mL to about 4,500 IU / mL, from about 4,000 IU / mL to about 5,000 IU / mL, or from about 4,500 IU / mL to about 5,000 IU / mL.

22. The ultra-high concentration hyaluronidase may be at least 25,000 IU / mL, at least 50,000 IU / mL, at least 75,000 IU / mL, at least 100,000 IU / mL, at least 125,000 IU / mL, at least 150,000 IU / mL, at least 175,000 IU / mL, at least 200,000 IU / mL, at least 225,000 IU / mL, at least 250,000 IU / mL, at least 300,000 IU / mL, at least 350,000 IU / mL, at least 400,000 IU / mL, or at least an amount of at most 450,000 IU / mL or at least 500,000 IU / mL, and / or at most 25,000 IU / mL, at most 50,000 IU / mL, at most 75,000 IU / mL, at most 100,000 IU / mL, at most 125,000 IU / mL, at most 150,000 IU / mL, at most 175,000 IU / mL, at most 200,000 IU / mL, at most 225,000 IU / mL, at most 250,000 IU / mL, at most 300,000 IU / mL, at most 350,000 IU / mL, at most 4 00,000 IU / mL, at most 450,000 IU / mL or at most 500,000 IU / mL, or from about 25,000 IU / mL to about 50,000 IU / mL, from about 25,000 IU / mL to about 75,000 IU / mL, from about 25,000 IU / mL to about 100,000 IU / mL, from about 25,000 IU / mL to about 125,000 IU / mL, from about 25,000 IU / mL to about 150,000 IU / mL, from about 25,000 IU / mL to about 175,000 IU / mL, from about 25,000 IU / mL to about 2 ... mL to about 225,000 IU / mL, about 25,000 IU / mL to about 250,000 IU / mL, about 25,000 IU / mL to about 300, 000 IU / mL, about 25,000 IU / mL to about 350,000 IU / mL, about 25,000 IU / mL to about 400,000 IU / mL, About 25,000 IU / mL to about 450,000 IU / mL, about 25,000 IU / mL to about 500,000 IU / mL, about 50,000 I U / mL to about 75,000 IU / mL, about 50,000 IU / mL to about 100,000 IU / mL, about 50,000 IU / mL to about 125,000IU / mL, about 50,000IU / mL to about 150,000IU / mL, about 50,000IU / mL to about 175,000IU / mL, about 50,000IU / mL to about 200,000IU / mL, about 50,000IU / mL to about 225,000IU / mL, about 50,000IU / mL U / mL to about 250,000IU / mL, about 50,000IU / mL to about 300,000IU / mL, about 50,000IU / mL to about 350,000IU / mL, about 50,000IU / mL to about 400,000IU / mL, about 50,000IU / mL to about 450,000IU / mL L, about 50,000IU / mL to about 500,000IU / mL, about 75,000IU / mL to about 100,000IU / mL, about 75,000IU / mL to about 125,000IU / mL, about 75,000IU / mL to about 150,000IU / mL, about 75,000IU / mL to about 1 75,000IU / mL, about 75,000IU / mL to about 200,000IU / mL, about 75,000IU / mL to about 225,000IU / mL, about 75,000IU / mL to about 250,000IU / mL, about 75,000IU / mL to about 300,000IU / mL, about 75,0 00IU / mL~about 350,000IU / mL, about 75,000IU / mL~about 400,000IU / mL, about 75,000IU / mL~about 450,000IU / mL, about 75,000IU / mL~about 500,000IU / mL, about 100,000IU / mL~about 125,000 IU / mL, about 100,000IU / mL to about 150,000IU / mL, about 100,000IU / mL to about 175,000IU / mL, about 100,000IU / mL to about 200,000IU / mL, about 100,000IU / mL to about 225,000IU / mL, about 100,00 0IU / mL~about 250,000IU / mL, about 100,000IU / mL~about 300,000IU / mL, about 100,000IU / mL~about 350,000IU / mL, about 100,000IU / mL~about 400,000IU / mL, about 100,000IU / mL~about 450,0 00IU / mL, about 100,000IU / mL to about 500,000IU / mL, about 150,000IU / mL to about 200,000IU / mL, about 150,000IU / mL to about 225,000IU / mL, about 150,000IU / mL to about 250,000IU / mL, about 150,000 IU / mL to about 300,000 IU / mL, about 150,000 IU / mL to about 350,000 IU / mL, about 150,000 IU / mL to about 400,000 IU / mL, about 150,000 IU / mL to about 450 ,000 IU / mL, about 150,000 IU / mL to about 500,000 IU / mL, about 200,000 IU / mL to about 225,000 IU / mL, about 200,000 IU / mL to about 250,000 IU / mL, about 20 0,000 IU / mL to about 300,000 IU / mL, about 200,000 IU / mL to about 350,000 IU / mL, about 200,000 IU / mL to about 400,000 IU / mL, about 200,000 IU / mL to about 4 50,000 IU / mL, about 200,000 IU / mL to about 500,000 IU / mL, about 250,000 IU / mL to about 300,000 IU / mL, about 250,000 IU / mL to about 350,000 IU / mL, about 250,000 IU / mL to about 400,000 IU / mL, about 250,000 IU / mL to about 450,000 IU / mL, about 250,000 IU / mL to about 500,000 IU / mL, about 300,000 IU / mL to about 350,000 IU / mL, about 300,000 IU / mL to about 400,000 IU / mL, about 300,000 IU / mL to about 450,000 IU / mL, about 300,000 IU / mL to about 500,000 IU / mL 17. The delivery system of claim 16, wherein the serotonin-containing compound is administered in an amount of about 350,000 IU / mL to about 400,000 IU / mL, about 350,000 IU / mL to about 450,000 IU / mL, about 350,000 IU / mL to about 500,000 IU / mL, about 400,000 IU / mL to about 450,000 IU / mL, about 400,000 IU / mL to about 500,000 IU / mL, or about 450,000 IU / mL to about 500,000 IU / mL.

23. The ultra-high concentration hyaluronidase may be in an amount of at least 10,000 IU / mL, at least 20,000 IU / mL, at least 30,000 IU / mL, at least 40,000 IU / mL, at least 50,000 IU / mL, at least 60,000 IU / mL, at least 70,000 IU / mL, at least 80,000 IU / mL, at least 90,000 IU / mL, or at least 100,000 IU / mL, and / or at most 10,000 IU / mL, at most 20,000 IU / mL, at most 30,000 IU / mL, at most ... most 50,000 IU / mL, at most 60,000 IU / mL, at least 70,000 IU / mL, at least 80,000 IU / mL, at least 90,000 IU / mL, or at least 100,000 IU / mL. or an amount of about 10,000 IU / mL to about 20,000 IU / mL, about 10,000 IU / mL to about 30,000 IU / mL, about 10,000 IU / mL to about 40,000 IU / mL, about 10,000 IU / mL to about 50,000 IU / mL, about 10,000 IU / mL to about 6 ...100,000 IU / mL, or an amount of about 10,000 IU / mL to about 20,000 IU / mL, about 10,000 IU / mL to about 30,000 IU / mL, about 10,000 IU / mL to about 40,000 IU / mL, about 10,000 IU / mL to about 50,000 IU / mL, about 10,000 IU / mL to about 60,000 IU / mL, about 1 0,000IU / mL to about 70,000IU / mL, about 10,000IU / mL to about 80,000IU / mL, about 10,000IU / mL ~about 90,000IU / mL, about 10,000IU / mL~about 100,000IU / mL, about 20,000IU / mL~about 30,000I U / mL, about 20,000 IU / mL to about 40,000 IU / mL, about 20,000 IU / mL to about 50,000 IU / mL, about 20,0 00IU / mL to about 60,000IU / mL, about 20,000IU / mL to about 70,000IU / mL, about 20,000IU / mL to about 80 ,000IU / mL, about 20,000IU / mL to about 90,000IU / mL, about 20,000IU / mL to about 100,000IU / mL , about 30,000 IU / mL to about 40,000 IU / mL, about 30,000 IU / mL to about 50,000 IU / mL, about 30,000 IU / mL mL to about 60,000 IU / mL, about 30,000 IU / mL to about 70,000 IU / mL, about 30,000 IU / mL to about 80,000 IU / mL, about 30,000 IU / mL to about 90,000 IU / mL, about 30,000 IU / mL to about 100,000 IU / mL, about 40,000IU / mL to about 50,000IU / mL, about 40,000IU / mL to about 60,000IU / mL, about 40,000IU / mL to about 70,000IU / mL, about 40,000 IU / mL to about 80,000 IU / mL, about 40,000 IU / mL to about 90,000 IU / mL, about 40,000 IU / mL to about 100 ,000IU / mL, about 50,000IU / mL to about 60,000IU / mL, about 50,000IU / mL to about 70,000IU / mL, about 50,000IU / mL mL to about 80,000 IU / mL, about 50,000 IU / mL to about 90,000 IU / mL, about 50,000 IU / mL to about 100,000 IU / mL, about 60 ,000IU / mL to about 70,000IU / mL, about 60,000IU / mL to about 80,000IU / mL, about 60,000IU / mL to about 90,000IU / mL, about 60,000 IU / mL to about 100,000 IU / mL, about 70,000 IU / mL to about 80,000 IU / mL, about 70,000 IU / mL to about 9 17. The delivery system of claim 16, wherein the serotonin-containing compound is administered in an amount of about 0,000 IU / mL, about 70,000 IU / mL to about 100,000 IU / mL, about 80,000 IU / mL to about 90,000 IU / mL, about 80,000 IU / mL to about 100,000 IU / mL, or about 90,000 IU / mL to about 100,000 IU / mL.

24. The ultra-high concentration hyaluronidase may be at least 5,000 IU / mL, at least 6,000 IU / mL, at least 7,000 IU / mL, at least 8,000 IU / mL, at least 9,000 IU / mL, at least 10,000 IU / mL, at least 11,000 IU / mL, at least 12,000 IU / mL, at least 13,000 IU / mL, at least 14,000 IU / mL, at least 15,000 IU / mL, at least 16,000 IU / mL, at least 17,000 IU / mL, at least 18,000 IU / mL, an amount of at least 19,000 IU / mL or at least 20,000 IU / mL, and / or at most 5,000 IU / mL, at most 6,000 IU / mL, at most 7,000 IU / mL, at most 8,000 IU / mL, at most 9,000 IU / mL, at most 10,000 IU / mL, at most 11,000 IU / mL, at most 12,000 IU / mL, at most 13,000 IU / mL, at most 14,000 IU / mL, at most 15,000 IU / mL, at most 16,000 IU / mL, at most 17,000 IU / mL, at most 18,000 IU / mL, at most 20,000 IU / mL, at most 21,000 IU / mL, at most 22,000 IU / mL, at most 23,000 IU / mL, at most 24,000 IU / mL, at most 25,000 IU / mL, at most 26,000 IU / mL, at most 27,000 IU / mL, at most 28,000 IU / mL, at most 29,000 IU / mL, at most 30,000 IU / mL, at most 31,000 IU / mL, at most 32,000 IU / mL, at most 33,000 IU / mL, at most 34,000 IU / mL, at most 35,000 IU / mL, at most 36,000 IU / mL, at most 37,000 IU / mL, at most 38,000 IU / mL, at most 39,000 IU / mL, at most 40, at most 18,000 IU / mL, at most 19,000 IU / mL, or at most 20,000 IU / mL, or from about 5,000 IU / mL to about 6,000 IU / mL, from about 5,000 IU / mL to about 7,000 IU / mL, from about 5,000 IU / mL to about 8,000 IU / mL, from about 5,000 IU / mL to about 9,000 IU / mL, from about 5,000 IU / mL to about 10,000 IU / mL, from about 5,000 IU / mL to about 11,000 IU / mL, from about 5,000 IU / mL to about 12,000 IU / mL, from about 5,000 IU / mL to about 13,000 IU / mL, Approximately 5,000 IU / mL to approximately 14,000 IU / mL, approximately 5,000 IU / mL to approximately 15,000 IU / mL, approximately 5,000 IU / mL to about 16,000 IU / mL, about 5,000 IU / mL to about 17,000 IU / mL, about 5,000 IU / mL to about 18,000 IU / mL, Approximately 5,000 IU / mL to approximately 19,000 IU / mL, approximately 5,000 IU / mL to approximately 20,000 IU / mL, approximately 6,000 IU / mL to about 7,000 IU / mL, about 6,000 IU / mL to about 8,000 IU / mL, about 6,000 IU / mL to about 9,000 IU / mL, about 6,000IU / mL~about 10,000IU / mL, about 6,000IU / mL~about 11,000IU / mL, about 6,000IU / mL~about 12,000IU / mL, about 6,000IU / mL~about 13,000IU / mL, about 6,000IU / mL~about 14,000IU / mL, about 6 ,000IU / mL to about 15,000IU / mL, about 6,000IU / mL to about 16,000IU / mL, about 6,000IU / mL to about 17,000IU / mL, about 6,000IU / mL to about 18,000IU / mL, about 6,000IU / mL to about 19,000IU / mL, about 6 ,000IU / mL to about 20,000IU / mL, about 7,000IU / mL to about 8,000IU / mL, about 7,000IU / mL to about 9,000IU / mL, about 7,000IU / mL to about 10,000IU / mL, about 7,000IU / mL to about 11,000IU / mL, about 7, 000IU / mL~about 12,000IU / mL, about 7,000IU / mL~about 13,000IU / mL, about 7,000IU / mL~about 14,000IU / mL, about 7,000IU / mL~about 15,000IU / mL, about 7,000IU / mL~about 16,000IU / mL, about 7, 000IU / mL~about 17,000IU / mL, about 7,000IU / mL~about 18,000IU / mL, about 7,000IU / mL~about 19,000IU / mL, about 7,000IU / mL~about 20,000IU / mL, about 8,000IU / mL~about 9,000IU / mL, about 8, 000IU / mL~about 10,000IU / mL, about 8,000IU / mL~about 11,000IU / mL, about 8,000IU / mL~about 12,000IU / mL, about 8,000IU / mL~about 13,000IU / mL, about 8,000IU / mL~about 14,000IU / mL, about 8, 000IU / mL~about 15,000IU / mL, about 8,000IU / mL~about 16,000IU / mL, about 8,000IU / mL~about 17,000IU / mL, about 8,000IU / mL~about 18,000IU / mL, about 8,000IU / mL~about 19,000IU / mL, about 8, 000IU / mL~about 20,000IU / mL, about 9,000IU / mL~about 10,000IU / mL, about 9,000IU / mL~about 11,000IU / mL, about 9,000IU / mL~about 12,000IU / mL, about 9,000IU / mL~about 13,000IU / mL, about 9,000IU / mL~about 14,000IU / mL, about 9,000IU / mL~about 15,000IU / mL, about 9,000IU / mL~about 16,000IU / mL, about 9,000IU / mL~about 17,000IU / mL, about 9,000IU / mL~about 18,000IU / mL, about 9 ,000IU / mL to about 19,000IU / mL, about 9,000IU / mL to about 20,000IU / mL, about 10,000IU / mL to about 11,000IU / mL, about 10,000IU / mL to about 12,000IU / mL, about 10,000IU / mL to about 13,000IU / mL L, about 10,000IU / mL to about 14,000IU / mL, about 10,000IU / mL to about 15,000IU / mL, about 10,000IU / mL to about 16,000IU / mL, about 10,000IU / mL to about 17,000IU / mL, about 10,000IU / mL to about 18,0 00IU / mL, about 10,000IU / mL to about 19,000IU / mL, about 10,000IU / mL to about 20,000IU / mL, about 11,000IU / mL to about 12,000IU / mL, about 11,000IU / mL to about 13,000IU / mL, about 11,000IU / mL to about About 14,000IU / mL, about 11,000IU / mL to about 15,000IU / mL, about 11,000IU / mL to about 16,000IU / mL, about 11,000IU / mL to about 17,000IU / mL, about 11,000IU / mL to about 18,000IU / mL, about 11,000 IU / mL to about 19,000IU / mL, about 11,000IU / mL to about 20,000IU / mL, about 12,000IU / mL to about 13,000IU / mL, about 12,000IU / mL to about 14,000IU / mL, about 12,000IU / mL to about 15,000IU / mL, about 1 2,000IU / mL to about 16,000IU / mL, about 12,000IU / mL to about 17,000IU / mL, about 12,000IU / mL to about 18,000IU / mL, about 12,000IU / mL to about 19,000IU / mL, about 12,000IU / mL to about 20,000IU / mL, about 13,000IU / mL to about 14,000IU / mL, about 13,000IU / mL to about 15,000IU / mL, about 13,000IU / mL to about 16,000IU / mL, about 13,000IU / mL to about 17,000IU / mL, about 13,000IU / mL to about 18,000IU / mL, about 13,000IU / mL to about 19,000IU / mL, about 13,000IU / mL to about 20,000IU / mL, about 14,000IU / mL to about 15,0 00IU / mL, about 14,000IU / mL to about 16,000IU / mL, about 14,000IU / mL to about 17,000IU / mL, about 14,000IU / mL to about 18,00 0IU / mL, about 14,000IU / mL to about 19,000IU / mL, about 14,000IU / mL to about 20,000IU / mL, about 15,000IU / mL to about 16,000 IU / mL, about 15,000 IU / mL to about 17,000 IU / mL, about 15,000 IU / mL to about 18,000 IU / mL, about 15,000 IU / mL to about 19,000 I U / mL, about 15,000 IU / mL to about 20,000 IU / mL, about 16,000 IU / mL to about 17,000 IU / mL, about 16,000 IU / mL to about 18,000 IU / mL, about 16,000 IU / mL to about 19,000 IU / mL, about 16,000 IU / mL to about 20,000 IU / mL, about 17,000 IU / mL to about 18,000 IU / mL 17. The delivery system of claim 16, wherein the IV is administered in an amount of about 17,000 IU / mL to about 19,000 IU / mL, about 17,000 IU / mL to about 20,000 IU / mL, about 18,000 IU / mL to about 19,000 IU / mL, about 18,000 IU / mL to about 20,000 IU / mL, or about 19,000 IU / mL to about 20,000 IU / mL.

25. The ultra-high concentration hyaluronidase may be in an amount of at least 250 IU / mL, at least 500 IU / mL, at least 750 IU / mL, at least 1,000 IU / mL, at least 1,500 IU / mL, at least 2,000 IU / mL, at least 2,500 IU / mL, at least 3,000 IU / mL, at least 3,500 IU / mL, at least 4,000 IU / mL, at least 4,500 IU / mL, or at least 5,000 IU / mL, and / or at most 250 IU / mL, at most 500 IU / mL, at most 750 IU / mL / mL, at most 1,000 IU / mL, at most 1,500 IU / mL, at most 2,000 IU / mL, at most 2,500 IU / mL, at most 3,000 IU / mL, at most 3,500 IU / mL, at most 4,000 IU / mL, at most 4,500 IU / mL or at most 5,000 IU / mL, or an amount of from about 250 IU / mL to about 500 IU / mL, from about 250 IU / mL to about 750 IU / mL, from about 250 IU / mL to about 1,000 IU / mL, from about 250 IU / mL to about 1,500 IU / mL, from about 250 IU / mL to about 2,000 IU / mL mL, about 250 IU / mL to about 2,500 IU / mL, about 250 IU / mL to about 3,000 IU / mL, about 250 IU / mL to about 3,50 0IU / mL, about 250IU / mL to about 4,000IU / mL, about 250IU / mL to about 4,500IU / mL, about 250IU / mL to about 5,000 IU / mL, about 500 IU / mL to about 750 IU / mL, about 500 IU / mL to about 1,000 IU / mL, about 500 IU / mL ~about 1,500 IU / mL, about 500 IU / mL to about 2,000 IU / mL, about 500 IU / mL to about 2,500 IU / mL, about 500 IU / mL to about 3,000 IU / mL, about 500 IU / mL to about 3,500 IU / mL, about 500 IU / mL to about 4,000 IU / mL, about 5 00IU / mL to about 4,500IU / mL, about 500IU / mL to about 5,000IU / mL, about 750IU / mL to about 1,000IU / m L, about 750 IU / mL to about 1,500 IU / mL, about 750 IU / mL to about 2,000 IU / mL, about 750 IU / mL to about 2,500 IU / mL, about 750 IU / mL to about 3,000 IU / mL, about 750 IU / mL to about 3,500 IU / mL, about 750 IU / mL to about 4,000IU / mL, about 750IU / mL to about 4,500IU / mL, about 750IU / mL to about 5,000IU / mL, about 1,00 0IU / mL to about 1,500IU / mL, about 1,000IU / mL to about 2,000IU / mL, about 1,000IU / mL to about 2.5 00IU / mL, about 1,000IU / mL to about 3,000IU / mL, about 1,000IU / mL to about 3,500IU / mL, about 1, 000IU / mL to about 4,000IU / mL, about 1,000IU / mL to about 4,500IU / mL, about 1,000IU / mL to about 5 ,000IU / mL, about 1,500IU / mL to about 2,000IU / mL, about 1,500IU / mL to about 2,500IU / mL, about 1,500 IU / mL to about 3,000 IU / mL, about 1,500 IU / mL to about 3,500 IU / mL, about 1,500 IU / mL to Approximately 4,000 IU / mL, approximately 1,500 IU / mL to approximately 4,500 IU / mL, approximately 1,500 IU / mL to approximately 5,000 IU / mL , about 2,000 IU / mL to about 2,500 IU / mL, about 2,000 IU / mL to about 3,000 IU / mL, about 2,000 IU / m L to about 3,500 IU / mL, about 2,000 IU / mL to about 4,000 IU / mL, about 2,000 IU / mL to about 4,500 IU / mL, about 2,000 IU / mL to about 5,000 IU / mL, about 2,500 IU / mL to about 3,000 IU / mL, about 2,500 IU / mL to about 3,500IU / mL, about 2,500IU / mL to about 4,000IU / mL, about 2,500IU / mL to about 4,500I U / mL, about 2,500 IU / mL to about 5,000 IU / mL, about 3,000 IU / mL to about 3,500 IU / mL, about 3,000 17. The delivery system of claim 16, wherein the medicament is administered in an amount of about 4,000 IU / mL, about 3,000 IU / mL to about 4,500 IU / mL, about 3,000 IU / mL to about 5,000 IU / mL, about 3,500 IU / mL to about 4,000 IU / mL, about 3,500 IU / mL to about 4,500 IU / mL, about 3,500 IU / mL to about 5,000 IU / mL, about 4,000 IU / mL to about 4,500 IU / mL, about 4,000 IU / mL to about 5,000 IU / mL, or about 4,500 IU / mL to about 5,000 IU / mL.

26. 17. The delivery system of claim 16, wherein the composition is administered in a single dose or multiple doses.

27. The composition or medicament may have a volume of at least 0.5 mL, at least 1.0 mL, at least 2.0 mL, at least 3.0 mL, at least 4.0 mL or at least 5.0 mL, and / or a volume of at most 0.5 mL, at most 1.0 mL, at most 2.0 mL, at most 3.0 mL, at most 4.0 mL or at most 5.0 mL, or a volume of about 0.5 mL to 1.0 mL, about 0.5 mL to 2.0 mL, about 0.5 mL to 5.0 mL.

17. The delivery system of claim 16, wherein the delivery system is administered in a volume of about 0.5 mL to 3.0 mL, about 0.5 mL to 4.0 mL, about 0.5 mL to 5.0 mL, about 1.0 mL to 2.0 mL, about 1.0 mL to 3.0 mL, about 1.0 mL to 4.0 mL, about 1.0 to 5.0 mL, about 2.0 mL to 3.0 mL, about 2.0 mL to 4.0 mL, about 2.0 to 5.0 mL, about 3.0 mL to 4.0 mL, about 3.0 to 5.0 mL, or about 4.0 to 5.0 mL.

28. A kit comprising one or more containers, each container containing a pharmaceutical composition according to any one of claims 1 to 3.

29. 29. The kit of claim 28, wherein the pharmaceutical composition is in a liquid formulation or a dry formulation.

30. 30. The kit of claim 28, wherein the one or more containers are each a delivery system.

31. 30. The kit of claim 28, further comprising a delivery system.

32. 30. The kit of claim 28, further comprising a separate container containing the solvent, instructions, or both.