Implant for sculpturing, filling or correcting facial features such as chin

Abstract

The present application provides an injectable device for long-lasting facial sculpture and correction of facial features, such as for filling and shaping contours, including, for example, the chin, mandibular contour or nose in a human, comprising a hyaluronic acid-based composition. Methods of treatment are also provided.

Description

[0001] This application is a divisional application of the Chinese Invention Patent Application No. 201680010274.6, with the title of "Implants for Sculpting, Augmenting or Correcting Facial Features such as the Chin", filed on February 12, 2016.

[0002] The present invention relates generally to injectable compositions, and more particularly to injectable implants for adding structure and contour to the lower part of the face.

[0003] Dermal fillers are injectable, biocompatible compositions that are well known to correct wrinkles and folds and to add volume to the face. Hyaluronic acid (HA) is still considered by many to be one of the most desirable dermal fillers because it does not pose a risk of allergic reactions, and it is temporary and reversible. The vast majority of hyaluronic acid-based dermal fillers have been specifically developed for the treatment of wrinkles and folds of the skin. In order to be useful for facial contouring or substantial volumizing, it would be advantageous to increase the bulking effect (also called "lifting") of the composition. It would also be advantageous to maximize the resistance of the composition to shear and normal deformation that occurs in the soft tissues of the face. One of the drawbacks of maximizing these resistances (e.g. elasticity and cohesion) is that one can expect that the viscosity of the composition will increase to the point that they will be difficult to inject with a fine needle.

[0004] Therefore, there is a need for an injectable HA-based implant that is specifically designed to effectively add substantial volume to the face, for example for contouring the lower part of the face, for example for augmenting or correcting the chin, for example for the correction of a receding chin, or for example for filling or correcting the nose. It would be highly advantageous if such an implant, despite having a high viscosity, would still be easy to inject with a fine needle.

[0005] The shape of the chin has long been considered an important feature of the face that elicits strong aesthetic perceptions that tend to be associated with personality traits of the individual. A deficient chin that lacks projection is often stigmatized as a "weak chin", while a prominent chin is stigmatized as a "strong chin", both of which imply strength or weakness of personality.

[0006] Several studies have shown that faces with average proportions are considered the most attractive, and small chin features are considered attractive in women, while expanded chins and lower jaws due to maturation are considered attractive in men. The appearance of the chin is a determinant of perceived attractiveness and can even affect the social psychological well-being of the individual.

[0007] Chin augmentation is typically performed by surgically placing a permanent implant over the lower jaw. This procedure is one of the top cosmetic surgical procedures performed by the American Society for Aesthetic Plastic Surgery (ASAPS) and has increased by 71% since 2010.

[0008] A receding chin can be due to changes in the growth of the lower third of the face during maturation, trauma, or facial aging, with the latter exacerbating deformities or asymmetries due to the former two. The nature of the mandible affects the mouth, chin, and neck. As individuals age, the reduction in skeletal support in this area makes the soft tissue atrophy apparent, makes the jowl larger, reduces chin projection, and makes the jawline weaker. Chin deformity is one of the most common bony deformities of the face, with the most common being a horizontal microgenia characterized by the presence of a normally vertically high and receding bony chin.

[0009] Because the mandible and chin form the skeleton of the lower face, augmentation methods have been explored for decades to treat age-related chin recession and contour changes in the chin area or to treat microgenia. When the approach to correct chin recession is to add volume, treatment methods include chin implants, genioplasty, and injections of silicone and semi-permanent fillers such as polymethylmethacrylate microspheres and calcium hydroxyapatite. However, all of these treatment methods have drawbacks. For example, chin implants and genioplasty involve painful surgical procedures that can not correct chin recession and aesthetic mix in the area. This approach can exacerbate bone resorption and infection, leading to the need to remove the implant. Injection of semi-permanent fillers is a compromise between the augmentation capacity and adverse events associated with semi-permanent fillers. SUMMARY

[0010] Accordingly, the present invention provides an injectable implant for facial sculpting, e.g., for filling, correcting, repairing, or creating volume in a person's chin and other facial features.

[0011] The present invention provides temporary, reversible, HA-based structural gels that are specifically engineered to provide a safe, minimally invasive method of creating facial volume or facial contour. The implants of the present invention provide improved augmentation and lifting performance relative to other HA-based injectables due to a combination of mechanical properties, including high elasticity and high cohesiveness, while still being easily injectable with a fine gauge needle. The implants of the present invention can be used for injection into subcutaneous and / or supraperiosteal space. In many embodiments, the implants are moldable after injection, thus allowing sculpting, contouring, and shaping of the entire injection area (e.g., chin and jaw area).

[0012] The implants generally comprise a composition comprising hyaluronic acid (HA) crosslinked with a crosslinking agent selected from the group consisting of 1,4-butanediol diglycidyl ether (BDDE), 1,4-bis(2,3-epoxypropoxy)butane, 1,4-bisglycidyloxybutane, 1,2-bis(2,3-epoxypropoxy)ethylene, and l-(2,3-epoxypropyl)-2,3-epoxycyclohexane. In some embodiments, the implants generally comprise a composition comprising hyaluronic acid (HA) crosslinked with BDDE. The compositions are suitable for injection, e.g., through a fine gauge needle, and are capable of filling, correcting, or creating volume or lift in the face, e.g., in the lower portion of the face, such as the chin or jaw, or in the middle portion of the face, such as the nose.

[0013] In some embodiments, the HA concentration is greater than 20 mg / g. In some embodiments, the HA concentration is about 21 mg / g, or about 22 mg / g, or about 23 mg / g, or about 24 mg / g, or about 25 mg / g, or about 26 mg / g, or about 27 mg / g, or about 28 mg / g, or about 29 mg / g, or about 30 mg / g or greater. In other embodiments, the composition has a HA concentration of 22.5 mg / g to 27.5 mg / g, e.g., 25.0 mg / g.

[0014] In some embodiments, the method increases the volume and lift of the chin or jaw contour or nose of the patient over a period of about 9 months to about 24 months after administration or injection into the chin or jaw contour of the patient. The composition can be moldable, e.g., by physical manipulation of the tissue near the implant over a period of time after injection. The set time of the composition can be within about 24 to about 48 hours after implantation or injection, at which time the composition is no longer moldable and substantially retains its shape over the implantation period.

[0015] In some embodiments, the composition further comprises an anesthetic, such as lidocaine HC1. For example, the composition can comprise about 0.3% w / w lidocaine HC1.

[0016] In preferred embodiments, the composition comprises hyaluronic acid gel in phosphate buffered saline (pH 7.2), preferably in an amount of about 25 mg; and lidocaine HC1, preferably in an amount of about 3 mg, preferably volume filled to 1 mL.

[0017] In some embodiments, the composition is made from a mixture of low molecular weight hyaluronic acid and high molecular weight hyaluronic acid. For example, the crosslinked hyaluronic acid can be made from about 50% to about 100% low molecular weight hyaluronic acid, prior to crosslinking with a crosslinking agent. In some embodiments, the crosslinked hyaluronic acid is made from about 70% to about 90% low molecular weight hyaluronic acid, prior to crosslinking with a crosslinking agent. In some embodiments, the crosslinked hyaluronic acid is made from about 90% low molecular weight hyaluronic acid, prior to crosslinking with a crosslinking agent.

[0018] The use of low molecular weight HA (e.g., about 50% or greater, such as about 70% or about 90% low molecular weight HA) prior to crosslinking, rather than primarily using high molecular weight HA, results in a more robust, longer lasting, moldable hydrogel with higher cohesiveness and elasticity, particularly suitable for facial sculpting and filling by subcutaneous or supraperiosteal injection.

[0019] In some embodiments, the HA has a degree of crosslinking of about 4% to about 12%. For example, the HA has a degree of crosslinking of about 4%, or about 6%, or about 8%, or about 10%. In some embodiments, the HA has a degree of crosslinking of about 6.5%. In other embodiments, the HA has a degree of crosslinking of about 7.5%, or about 8.5%, or about 9.5%, or about 10.5%.

[0020] In another aspect of the application, a method for correcting a receding chin in a patient is provided. The method generally comprises administering an effective amount of a composition comprising BDDE-crosslinked hyaluronic acid (HA) having a degree of crosslinking of about 10% and a concentration of HA greater than 20 mg / g, by supraperiosteal administration in the chin of the patient. For example, in preferred embodiments, the concentration of HA is about 25 mg / g.

[0021] In a specific embodiment, the composition comprises low molecular weight hyaluronic acid (NaHA) crosslinked with about 10% BDDE (w / w), and is formulated in phosphate buffered saline at pH 7.2 to a concentration of about 25 mg / g (with 0.3% lidocaine HC1 (w / w)), and is supplied in a 1 mL COC (cyclic olefin copolymer) syringe.

[0022] The composition can be extruded through a fine gauge needle, e.g., a needle having a gauge of 25G, 26G, 27G, 28G, 29G, or 30G. In particular embodiments, the needle is a 27G x 13 mm / 27 G1 / 2x 26 mm.

[0023] Extrusion force is the force (in Newton, N) required to extrude the composition from its syringe at a certain rate. For example, using a provided 1 mL COC syringe and a TSK 27G x 13 mm needle, some compositions of the application can have an extrusion force of about 4 N to about 15 N when extruded at about 13 mm / min, which is considered very low. For example, the extrusion force can be about 7 N to about 12 N, preferably about 8 N to about 10 N.

[0024] In another aspect of the application, the application provides a method for contouring or correcting a facial feature (e.g., a receding chin) of an individual. The method includes, for example, the step of subcutaneously administering to a treatment area of a patient an effective amount of a composition of the application, e.g., about 1.0 ml or more, e.g., about 2.0 ml or more, e.g., about 3.0 ml or more, e.g., 4.0 mL. The facial feature to be improved or contoured can be a chin, e.g., a receding chin of the patient. The treatment area can include an area selected from the group consisting of pronasale, mentum, left prejowl sag, right prejowl sag, and sublabial crease. The treatment can include administering the composition to two or more treatment areas.

[0025] Every feature described herein, and each combination of two or more such features, is included within the scope of the present application provided that the features included in such a combination are not mutually inconsistent as would be understood by one of ordinary skill in the art. The application is not limited to the details described herein. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 Facial profile and landmarks used to calculate the G-Sn-Pog angle of a patient are shown.

[0027] Figure 2 Burstone angle of an average chin is shown. DETAILED DESCRIPTION

[0028] Certain terms used in the present specification are intended to refer to the following definitions as detailed below. To the extent a definition of a term deviates from the common meaning of the term, Applicant intends to use the definition provided below, unless specifically indicated otherwise.

[0029] The term "about" in the context of a numerical range is readily understood by those skilled in the art and preferably means that the particular value can vary by + / - 10%. With respect to the end points of a range, the modifier "about" preferably means that the lower endpoint can be reduced by 10% and the upper endpoint increased by 10%. It is also contemplated that each numerical value or range disclosed in the present application can be absolute, i.e., the modifier "about" can be deleted.

[0030] In the present text, all numbers expressing the "molecular weight" of HA are to be understood as referring to the weight average molecular weight (Mw) in Daltons.

[0031] The molecular weight of the HA is measured from the intrinsic viscosity, calculated using the following Mark Houwink relationship: Intrinsic viscosity (L / g) = 9.78 x 10-5 x Mw0.690 The intrinsic viscosity is measured according to the method specified in the European Pharmacopoeia (HA monograph No. 1472, 01 / 2009).

[0032] Unless otherwise indicated, molecular weight refers to the weight average molecular weight (Mw). The HA used to prepare the compositions of the present application can comprise a mixture of high molecular weight HA, low molecular weight HA, and / or medium molecular weight HA, wherein the high molecular weight HA has a molecular weight greater than about 2,000,000 Da (or an intrinsic viscosity greater than 2.2 L / g), and wherein the low molecular weight HA has a molecular weight less than about 1,000,000 Da (or an intrinsic viscosity less than 1.4 L / g). For example, the average molecular weight of the high molecular weight HA in the compositions of the present application can be from about 2 MDa to about 4.0 MDa, for example about 3.0 MDa (2.9 L / g). In another example, the average molecular weight of the high molecular weight HA can be from about 2.4 MDa to about 3.6 MDa, for example about 3.0 MDa. The intrinsic viscosity of the high molecular weight HA can be greater than about 2.2 L / g, for example from about 2.5 L / g to about 3.3 L / g.

[0033] The low molecular weight HA can have a molecular weight of from about 200,000 Da (0.2 MDa) to less than 1.0 MDa, for example from about 300,000 Da (0.3 Ma) to about 750,000 Da (1.1 L / g), up to but not more than 0.99 MDa (1.4 L / g). The intrinsic viscosity of the low molecular weight HA can be less than about 1.40 L / g, for example from about 0.6 L / g to about 1.2 L / g.

[0034] Preferably, there is no overlap between the molecular weight distribution of the low molecular weight HA material and the high molecular weight HA material.

[0035] Preferably, the mixture of low molecular weight HA and high molecular weight HA has a bimodal molecular weight distribution. The mixture can also have a multimodal distribution.

[0036] In one aspect of the application, the composition comprises HA having a high molecular weight component and a low molecular weight component, and the weight average molecular weight of the high molecular weight component is at least twice the weight average molecular weight of the low molecular weight component.

[0037] As used herein, "degree of crosslinking" refers to the linking of individual HA polymer molecules or monomeric chains into a permanent structure, or intermolecular linking of the soft tissue filler composition as disclosed herein. Further, for the purposes of the present disclosure, the degree of crosslinking is further defined as the weight percent of crosslinking agent to HA-monomer units within the crosslinked portion of the HA composition. It is measured by the weight ratio of crosslinking agent to HA monomer.

[0038] As used herein, "uncrosslinked HA" refers to individual HA polymer molecules that are not crosslinked. Uncrosslinked HA is generally water soluble. An uncrosslinked HA component can also be optionally included in the composition, for example, to act as a lubricant and to facilitate injection into facial tissue. Such a composition can comprise an uncrosslinked HA fraction, wherein the uncrosslinked HA added is present at a concentration of about 0.1 mg / g to about 3 mg / g. Preferably, the uncrosslinked HA can be present at a concentration of about 0.2 mg / g to about 1.5 mg / g.

[0039] In other embodiments, uncrosslinked HA is not present in the gel, or at least is not added to the gel to act as a lubricant.

[0040] The compositions described herein exhibit a high level of elasticity, which is expressed as the value of the elastic modulus (G'), measured by oscillatory rheology using a cone-plate system at a strain of 0.8%, and over a range of frequencies. In some embodiments, the elastic modulus of the composition measured at a frequency of 5 Hz is about 500 Pa to about 900 Pa. This is considered to be a high level of elasticity in the case of HA-based dermal fillers, and contributes to the lifting effect by making the implant more resistant to shear deformation.

[0041] Adhesiveness refers to the ability of the gel to remain attached to itself, for example, to resistance to cutting, and to the ability to stretch or compress the gel without separating it into pieces. According to the present application, the adhesiveness of the gel can be quantified as follows (see Derek Jones "Injectable Filers: Principles and Practice", Wiley, 201 1, Chapter 3). A small sample of the gel (e.g. 1 mL) is placed on the plane of the rheometer. The sample is placed so that it forms a small heap. The movable upper plate is placed on the sample so that it is completely covered, for example, no sample can be seen when the plate is viewed in a direction perpendicular to the surface of the rheometer. To ensure this, the plate size must be chosen to be larger than the sample size. Ideally, the center of the plate is placed on the sample. Typically, for a 1 mL gel material, a 25 mm diameter upper plate is used.

[0042] In the next step of the measurement, the gap between the movable plate and the surface is adjusted to 2.5 mm. The plate is slowly and steadily moved from this initial position to a gap width of 0.9 mm within 2 minutes, and the force exerted by the sample in the normal direction (Fn) is recorded.

[0043] Once the gap width reaches 0.9 mm, the system can relax for 12 minutes. During this time, the measurement continues. Five measurements are made. To normalize the measured forces, all 5 initial Fnvalues measured at the beginning of the test are averaged (arithmetic mean), and the resulting average is subtracted from all other data points. The maximum force at the end of the compression part of the test (when the minimum 0.9 mm gap width between the upper plate and the plane is reached) is called the compression force, and this compression force is the characteristic value used to determine the gel viscosity.

[0044] In particular, a force of 20 gmf (0.1962 N) or more represents an adhesive material in the sense of the present application. In the context of the present application, gels with lower compression force values are generally considered not to be adhesive. The accuracy of the measurement is of the order of about 5 gmf. In the context of the present application, the injectable formulation has a high adhesiveness of at least about 60 gmf, for example, from about 60 to about 200 gmf. For example, in a preferred embodiment, the adhesiveness is from about 60 to about 100 gmf, which will impart a high resistance of the implant to pressure and normal forces in the soft tissue of the face.

[0045] In the context of dermal fillers, the cohesiveness as defined above will help the lifting ability (clinically referred to as volumizing / swelling effect) provided by the gel and its elastic modulus G' in the clinic. While cohesive gels can show good volumizing effect, non-cohesive or weakly cohesive materials with similar elastic modulus show lower lifting ability because the non-cohesive gel material spreads more than the material with greater cohesiveness when subjected to vertical compression. In the context of the present invention, the composition exhibits a high level of elastic modulus and a high level of cohesiveness to maximize the lifting effect upon implantation.

[0046] In certain advantageous, exemplary embodiments, the implant or filler of the present invention generally comprises a cohesive, sterile composition that can be implanted subcutaneously or supraperiosteally into the chin area, nose, or jawline contour of a patient in need thereof, such as a patient in need of improved facial profile or stronger chin. The composition generally comprises cross-linked hyaluronic acid (HA) cross-linked with 1,4-butanediol diglycidyl ether (BDDE); and the HA concentration of the composition is greater than 20 mg / g. For example, in some embodiments, the HA concentration is about 22.5 mg / g, or about 25 mg / g, or about 27.5 mg / g. The HA used for cross-linking can be made from a mixture of low molecular weight hyaluronic acid and high molecular weight hyaluronic acid. In some embodiments, the composition has an elastic modulus at 5 Hz of about 500 Pa to about 900 Pa, and a cohesiveness of greater than about 60 gmf. Advantageously, in some embodiments, the composition has an extrusion force of about 4 N to about 15 N at 13 mm / min using a 1 mL COC syringe and a 27G x 13 mm needle.

[0047] In one aspect of the present invention, injectable HA-based implants with improved lifting ability are provided relative to commercially available HA-based dermal fillers. In certain instances of the present disclosure, the implants of the present invention can also be referred to as dermal fillers and subcutaneous fillers. The implants and fillers of the present invention are based on hyaluronic acid (HA) and pharmaceutically acceptable salts of HA, such as sodium hyaluronate (NaHA). Methods of making these compositions and methods of using these compositions are also provided.

[0048] As used herein, hyaluronic acid (HA) can refer to any of its hyaluronate salts and includes, but is not limited to, sodium hyaluronate (NaHA), potassium hyaluronate, magnesium hyaluronate, calcium hyaluronate, and combinations thereof. Both HA and its pharmaceutically acceptable salts can be used in the present invention.

[0049] In addition, in embodiments having anesthetic agents, the concentration of the anesthetic agent(s) is in an amount effective to alleviate the pain experienced upon injection of the composition. The at least one local anesthetic can be selected from the group consisting of ambucaine, amolanone, amylocaine, benoxinate, benzocaine, betoxycaine, biphenamine, bupivacaine, butacaine, butamben, butanilicaine, butethamine, butoxycaine, carticaine, chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethisoquin, dimethocaine, diperodon, dicyclomine, ecgonidine, ecgonine, chloroethane, etidocaine, beta-eucaine, euprocin, fenalcomine, formocaine, hexylcaine, hydroxytetracaine, isobutyl p-aminobenzoate, leucinocaine methanesulfonate, levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, chloromethane, myrtecaine, naepaine, octocaine, orthocaine, oxethazaine, parethoxycaine, phenacaine, phenol, piperocaine, piridocaine, polidocanol, pramoxine, prilocaine, procaine, propanocaine,Proparacaine, propipocaine, propoxycaine, pseudococaine, pyrrocaine, ropivacaine, salicyl alcohol, tetracaine, tolycaine, trimecaine, zolamine, and salts thereof. In one embodiment, the at least one anesthetic is lidocaine, e.g., in the form of lidocaine HC1. The compositions described herein can have a concentration of lidocaine of about 0.1% to about 5% by weight of the composition, e.g., about 0.2% to about 1.0% by weight of the composition. In one embodiment, the composition has a concentration of lidocaine of about 0.3% by weight (w / w %) of the composition. The concentration of lidocaine in the compositions described herein can be therapeutically effective, which means a concentration sufficient to provide a therapeutic benefit without causing harm to the patient.

[0050] The compositions of the present application can be prepared by providing a purified HA material, e.g., in the form of NaHA fibers; hydrating the HA material, which has a desired molecular weight, e.g., a mixture of low and high molecular weight HA in a desired ratio; and crosslinking the desired ratio of the hydrated HA material with a suitable crosslinking agent to form a crosslinked HA-based gel. The gel can then be neutralized and swollen. If desired, a solution containing lidocaine, preferably an acidic salt of lidocaine HC1, can be added to form an HA / lidocaine gel. The gel can be homogenized, e.g., by mastication or mixing with shear forces. The homogenized composition can then be loaded into a syringe. The syringe can then be sterilized by autoclaving at an effective temperature and pressure. For example, the composition can be sterilized by autoclaving, e.g., at a temperature of at least about 120°C to about 130°C and / or a pressure of at least about 12 pounds per square inch (PSI) to about 20 PSI for a period of time of at least about 1 minute to about 15 minutes. The sterilized syringe can be packaged with a fine needle for use by a physician.

[0051] More specifically, the initial HA starting material can comprise fibers or powder of NaHA, e.g., NaHA fibers of bacterial origin. Alternatively, the HA material can be of animal origin, e.g., from a rooster comb. It is contemplated that the HA material can be a combination of a starting material comprising HA and at least one other polysaccharide, e.g., another glycosaminoglycan (GAG).

[0052] In one method of making the composition, pure dry NaHA fibers are hydrated in a basic solution to produce an uncrosslinked NaHA gel. Any suitable basic solution can be used to hydrate the NaHA in this step, such as, but not limited to, aqueous solutions containing sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium bicarbonate (NaHC03), lithium hydroxide (LiOH), and the like. The resulting basic gel will have a pH greater than 7.5. The resulting basic gel can have a pH greater than 9, or a pH greater than 10, a pH greater than 12, or a pH greater than 13.

[0053] The next step in the manufacturing process can include the step of crosslinking the hydrated basic NaHA gel with a suitable crosslinking agent. The crosslinking agent can be any agent known to be suitable for crosslinking polysaccharides and their derivatives through their hydroxyl groups. One particularly suitable crosslinking agent is 1,4-butanediol diglycidyl ether (BDDE).

[0054] In another embodiment, crosslinking of the HA is accomplished during hydration of the HA fibers by hydrating the combined high and low molecular weight fibers in a basic solution containing a crosslinking agent, such as BDDE.

[0055] In the HA component of the composition of the present application, the degree of crosslinking is at least about 4% and up to about 12% BDDE / HA, w / w, such as about 10%, such as about 8%, such as about 6%, such as about 4%. In one particular embodiment, the degree of crosslinking is about 6.5%. In some embodiments, the HA has a degree of crosslinking of about 6.5%. In other embodiments, the HA has a degree of crosslinking of about 7.5%, or about 8.5%, or about 9.5%, or about 10.5%.

[0056] The hydrated crosslinked HA gel can be swollen to achieve the desired concentration of HA. This step can be accomplished by neutralizing the crosslinked hydrated HA gel, such as by adding an aqueous solution containing an acid, such as HC1. The gel is then swollen in a phosphate buffered saline (PBS) solution at a low temperature for a sufficient time.

[0057] The purified crosslinked HA gel can be currently purified by conventional methods, such as dialysis against phosphate buffered saline or alcohol precipitation to recover the crosslinked material, to stabilize the pH of the material and remove any unreacted crosslinking agent. Additional water or a slightly basic aqueous solution can be added to bring the HA concentration in the composition to the desired concentration. In some embodiments, the HA concentration of the composition is adjusted to greater than 20 mg / g, such as to about 25 mg / g. In other embodiments, the HA is concentration adjusted to about 21 mg / g, about 22 mg / g, about 23 mg / g, about 24 mg / g, about 26 mg / g, about 27 mg / g, about 28 mg / g, about 29 mg / g, or about 30 mg / g.

[0058] In embodiments where an anesthetic agent (e.g., lidocaine) is included in the final composition, the pH of the purified crosslinked HA gel can be adjusted to make the gel slightly basic, such that the pH of the gel is greater than about 7.2, such as from about 7.5 to about 8.0. This step can be accomplished by any suitable method, such as by adding an appropriate amount of dilute NaOH, KOH, NaHC03, or LiOH, or any other basic molecule, solution, and / or buffer composition to the gel.

[0059] An effective amount of an anesthetic agent (e.g., lidocaine, such as lidocaine HC1) is then added to the purified crosslinked NaHA gel. For example, in some embodiments, the lidocaine HC1 is provided as a powder that can be dissolved using water for injection (WFI). To have a final HA / lidocaine composition with a desired, substantially neutral pH, the gel is maintained neutral with a buffer or by adjustment with dilute NaOH. The final composition comprising lidocaine can have a lidocaine concentration of at least about 0.1 wt% to about 5 wt%, such as about 2 wt%, or in another example about 0.3 wt%, of the composition.

[0060] After the addition of the lidocaine HC1, or during the addition of the lidocaine HC1, the HA / lidocaine gel or composition is homogenized to produce a highly uniform HA / lidocaine gel having a desired consistency and stability. Preferably, the homogenization step includes mixing, stirring, or mudding the gel with controlled shear forces to obtain a substantially uniform mixture.

[0061] After the HA composition is homogenized, an amount of an uncrosslinked HA solution or gel can be added to the composition to increase lubricity.

[0062] In some embodiments, after homogenization, no solution of uncrosslinked HA is added to the composition.

[0063] The composition is then introduced into a syringe and sterilized. Syringes that can be used in accordance with the present description include any syringe known in the art that is capable of delivering a viscous dermal filler composition. The internal volume of the syringe is typically from about 0.4 mL to about 3 mL, more preferably from about 0.5 mL to about 1.5 mL or from about 0.8 mL to about 2.5 mL. This internal volume is associated with the internal diameter of the syringe, which plays a key role in the extrusion force required to inject a highly viscous dermal filler composition. The internal diameter is typically from about 4 mm to about 9 mm, more preferably from about 4.5 mm to about 6.5 mm, or from about 4.5 mm to about 8.8 mm. In addition, the extrusion force required to deliver the HA composition from the syringe also depends on the needle gauge. The needle gauge used typically includes a gauge from about 18G to about 40G, more preferably from about 25G to about 33G or from about 25G to about 30G. For example, in some embodiments, the composition is loaded into a 1 mL syringe and injected using a 27G needle.

[0064] One preferred method of sterilizing a pre-filled syringe is through an autoclave. Autoclaving can be achieved by applying a combination of heat, pressure, and moisture to the sample that needs to be sterilized. A number of different sterilization temperatures, pressures, and cycle times can be used in this step. For example, the pre-filled syringe can be sterilized at a temperature of at least about 120 °C to about 130 °C or higher. Moisture can or can not be utilized. In some embodiments, the pressure applied depends on the temperature used in the sterilization process. The sterilization cycle can be for at least about 1 minute to about 20 minutes or more.

[0065] Another method of sterilization includes the use of a gaseous substance known to kill or eliminate infectious agents. Preferably, ethylene oxide is used as the sterilizing gas and is known in the art to be used to sterilize medical devices and products.

[0066] Another method of sterilization includes the use of a source of radiation known in the art to kill or eliminate infectious agents. A beam of radiation is targeted at the syringe containing the HA composition and the wavelength of energy kills or eliminates the unwanted infectious agents. Preferably, the energy that can be used includes, but is not limited to, ultraviolet (UV) light, gamma irradiation, visible light, microwaves, or any other wavelength or band that kills or eliminates the unwanted infectious agents, preferably without substantially altering or degrading the HA composition.

[0067] Preferably, the compositions of the present application also remain stable when stored for long periods of time. For example, many of the compositions of the present application have a shelf life of about 6 months, about 12 months, about 18 months, or about 24 months or more when stored at a temperature of about 2 to 25 degrees Celsius. In one particular embodiment, the compositions are stable for a period of at least 18 months at a temperature of 2 to 25 degrees Celsius. In another particular embodiment, the compositions are stable for a period of at least 24 months at a temperature of 2 to 25 degrees Celsius.

[0068] The technique for injecting the compositions of the present application can vary depending on the angle and orientation of the tilt and the amount of the dose. Generally, the compositions of the present application are injected subcutaneously and / or supraperiosteally to increase chin projection while limiting treatment to the pronasale, subnasale (the lower part of the chin), prejowl supramentale (left and right), and labiale inferioris (chin) folds for optimal correction and aesthetic chin contour. The appropriate injection volume will be determined by the investigator, but generally does not exceed a maximum total volume of about 4.0 mL for the combination of initial and supplemental treatments. For repeat treatments, a total of about 4.0 mL is permitted. During any treatment session, no more than about 2.0 mL is permitted to be injected into a single treatment area, where a treatment area is defined as the pronasale, subnasale, prejowl supramentale (left and right), and labiale inferioris (chin) folds.

[0069] Prior to injecting the compositions of the present application, the treatment area must be thoroughly disinfected to ensure that the injectable filler is not contaminated with bacteria or foreign matter (e.g., makeup, talcum powder from gloves).

[0070] The provided 27G 1 / 2" / 27 G x 13 mm needle should then be attached to the syringe (according to the instructions for use). Prior to injecting the compositions of the present application, the plunger rod must be depressed until product flow is visible from the needle and any excess product is wiped on sterile gauze.

[0071] The compositions of the present application are injected as follows: The compositions of the present application are injected slowly and the subject is observed for signs of color change or discoloration of the skin. The subject is observed for pain or discomfort. The compositions of the present application are injected in a smooth and measured manner. Care should be taken to note the local vascular anatomy of the injection site when inserting the needle. Aspirate to ensure that there is no backflow of blood, which indicates the position of the tip of the needle within a blood vessel.

[0072] Multiple small bolus injections can be used to inject the prejowl supraperiosteal. Multiple small bolus injections can be used to inject the jowl supraperiosteal. Deep subcutaneous fanning techniques can be used to inject the prejowl (left and right) sulcus. Superficial subcutaneous threading, either straight, retrograde or antegrade, can be used to inject the sublabial (prejowl) rhytids.

[0073] At the completion of treatment, gently massage the treated area to ensure even distribution of the product and contouring to the surrounding tissue. If overcorrection occurs, gently massage the area between the fingers or above the bone for optimal results.

[0074] Do not inject the compositions of the present application into blood vessels (intravascularly). The introduction of hyaluronic acid into blood vessels can occlude the vessels and can result in infarction or embolism. Symptoms of vessel occlusion and embolism include pain that is out of proportion to the procedure or distant from the injection site, immediate blanching that extends beyond the injection area and can exhibit a vascular branch distribution, and color changes that reflect ischemic tissue (e.g., a dark gray appearance or reticular appearance).

[0075] Overly superficial or large volume injections of the product over a small area can result in visible and persistent lumps and / or discoloration.

[0076] When using retrograde techniques, inject the compositions of the present application with even pressure on the plunger rod while slowly pulling the needle back. It is important to stop injecting just before the needle passes through the subcutaneous / skin interface to prevent material from oozing out or ending too superficially in the skin. When using antegrade techniques, ensure that the needle is in the subcutaneous tissue before starting the injection.

[0077] If the needle becomes clogged, do not increase the pressure on the plunger rod, but rather stop the injection and replace the needle.

[0078] If the treatment area swells immediately after injection, an ice pack can be applied to the area for a short period of time. If the subject reports an inflammatory reaction lasting more than 1 week, or any other side effect, the physician should take appropriate action.

[0079] In a preferred embodiment, the composition of the application comprises a hyaluronic acid gel in a phosphate buffer (pH 7.2), preferably in an amount of about 25 mg; and lidocaine hydrochloride, preferably in an amount of about 3 mg, preferably volume made up to 1 mL, pre-loaded in e.g. a 1 mL disposable syringe, wherein the hyaluronic acid gel is cross-linked with BDDE. Such pre-loaded e.g. 1 mL disposable syringe, together with two disposable needles (e.g. 27G 1 / 2'' / 27 G x 13 mm needles) can be contained in a kit (blister pack). The content of the syringe can be sterilized by moist heat. The disposable needles can be sterilized by radiation.

[0080] The composition of the application is an injectable implant intended for the restoration and generation of facial volume (e.g. in the chin and mandibular area). The presence of lidocaine is to reduce the pain of the subject during the treatment.

[0081] Example 1 Preparation of the injectable implant according to the embodiments of the application A pre-dried sodium hyaluronate (NaHA) fiber of molecular weight of about 0.9 MDa (0.9 g) was weighed into a first container.

[0082] A pre-dried NaHA fiber of molecular weight of about 3.0 MDa (0.1 g) was weighed into a second container.

[0083] The two different grades of NaHA were combined at 20-50 °C and diluted in a 1% sodium hydroxide solution and mixed for 1-2 hours to obtain a substantially homogeneous basic HA gel.

[0084] In a separate container, the selected cross-linking agent, 1,4-butanediol diglycidyl ether (BDDE) was diluted in a 1% sodium hydroxide solution to a final concentration of 10% BDDE (wt / wt).

[0085] To the basic HA gel, 10% (wt / wt) BDDE (1 g of pre-prepared BDDE solution) was added. The resulting mixture was subjected to mechanical homogenization.

[0086] The mixture was then kept at 50 °C for 3-4.5 hours.

[0087] The resulting cross-linked HA polymer was then immersed in a phosphate buffer (PB) containing hydrochloric acid to stabilize the pH.

[0088] The cross-linked HA polymer thus obtained was then immersed in a bath of phosphate buffer to remove unreacted cross-linking agent and HA, thus providing a pure hydrogel, wherein the degree of cross-linking is about 6.5%.

[0089] Optionally, dry HA material having a high molecular weight is hydrated in 1 liter of phosphate buffered saline to obtain an uncrosslinked HA gel. This uncrosslinked HA gel can be added to the crosslinked HA composition up to 5% (w / w) of the total HA concentration.

[0090] The resulting hydrogel is then mechanically homogenized to ensure final homogeneity and is filled into syringes that have been sterilized in an autoclave.

[0091] The resulting gel is an injectable composition that can be administered subcutaneously or periosteally through a fine gauge needle, such as a 27 gauge. The composition can be used to repair, contour, or create facial volume, such as in a person's chin, jawline area, or nose, as described elsewhere herein.

[0092] In one aspect of the application, methods for improving a patient's facial profile are provided. For example, in some embodiments, methods for changing a person's G-Sn-Pog facial angle, such as for increasing a person's G-Sn-Pog facial angle, are provided. For example, in some embodiments, methods of treatment for correcting a patient's retrognathia are provided. In some embodiments of the application, the patient treated has an initial pre-treatment G-Sn-Pog facial angle of less than about 165°. After treatment, the patient's G-Sn-Pog facial angle is increased, i.e., the facial angle is greater than the initial pre-treatment facial angle. In one embodiment, after the administration step, the patient's G-Sn-Pog facial angle is about 169° or greater. The G-Sn-Pog angle can be measured using conventional equipment and calculations, such as using a Canfield Scientific facial imaging device, based on calculations of facial angles derived from a digital image of the patient. Figure 1 Facial profiles and feature points used to calculate a patient's G-Sn-Pog angle are shown, which can be used to diagnose or determine the presence and / or extent of retrognathia using known methods.

[0093] The methods generally include administering to at least one treatment area of a patient's face an effective amount of a composition comprising BDDE-crosslinked hyaluronic acid (HA), the HA having a degree of crosslinking of about 6.5% or about 10%, and the composition having a HA concentration of greater than 20 mg / g.

[0094] In some embodiments, methods of treatment are provided that include administering a composition (e.g., described herein) supraperiosteally into at least one treatment area of a patient's face, wherein the patient has a G-Sn-Pog facial angle of 145° to 165°. The facial angle value can be based on a calculation of the facial angle from a digital image of the patient or a calculation of the facial angle using other techniques. According to some embodiments, the step of administering results in an increase in the patient's G-Sn-Pog facial angle relative to the patient's G-Sn-Pog facial angle prior to the treatment (e.g., prior to the step of administering). In some embodiments, the patient has an increased G-Sn-Pog angle at a time period after the step of administering, for at least about 3 months, or more preferably at least about 6 months, e.g., about 9 months to about 24 months. For example, the patient has an increased G-Sn-Pog angle at least about 6 months, or at least about 9 months, or at least about 12 months or at least about 18 months or at least about 24 months after the step of administering.

[0095] In some embodiments, the treatment area is an area selected from the following: the pronasale, the subnasale, the left mentolabial sulcus, the right mentolabial sulcus, and the labiomental crease. The treatment can include administering the composition to two or more treatment areas. The administering includes injecting the composition supraperiosteally or subcutaneously in an amount of about 0.5 mL to about 3.0 mL per treatment area. In some embodiments, the amount injected into a given treatment area is no more than 2.0 mL. In some embodiments, the total amount injected during a single treatment - across all treatment areas - is 2.0 mL to about 6.0 mL, e.g., about 2.5 mL, about 3.0 mL, about 3.5 mL, about 4.0 mL, about 4.5 mL, about 5.0 mL, about 5.5 mL, or about 6.0 mL. In some embodiments, the amount administered during a single treatment is about 4.0 mL or less.

[0096] Restoration or creation of volume in the chin and mandible In one aspect, the present invention provides methods of restoring or creating volume in the chin and mandible, e.g., sculpting, shaping, and contouring of specific treatment areas of the entire face. The treatment areas can include one or more of the pronasale (the most prominent point on the anterior surface of the chin), the subnasale (the lowest point of the chin), the left mentolabial sulcus and the right mentolabial sulcus (the left and right antigonion notches near the gonial angle), and the labiomental crease (the fold between the lower lip and the chin).

[0097] The shape and prominence of the chin contribute to the proportional balance of the face that serves as a basis for attractiveness. A lack of chin prominence is often marked as a "weak chin," while a prominent chin is marked as a "strong chin" and implies strength of character. Several studies have shown that faces with average proportions are considered the most attractive, and that juvenile features including small chins are considered attractive in women, while strong chins and jaws are considered attractive in men. The appearance of the chin is a determinant of perceived attractiveness and can affect an individual's socio-psychological well-being.

[0098] Average proportions are defined by the analysis of silhouettes of faces in a population and include the distances and angles between the nose, lips, and chin. Several soft tissue landmarks have been used in cephalometric analysis to measure and diagnose deviations in chin protrusion and retrusion compared to average facial parameters. Extensive analysis of the intersection of the upper facial portion and the lower anterior facial portion and the angle formed by the points on the glabella, the inferior nasal septum, and the pogonion (G-Sn-Pog) has been performed to understand the average chin prominence common in a population. The Burstone angle of the average chin has been defined as approximately 169°, and the approximate angle (168° to 169°) has been confirmed in several studies. Figure 2

[0099] Deviation from the average chin increases will result in a perception of the face as unattractive. Analysis of the relationship between facial profile and perception of attractiveness shows that chin protrusion plays an important role in this perception. To understand the relationship between the degree of chin protrusion and attractiveness, a series of profile images altered by up to 2 mm compared to an ideal profile image were presented to a group of pre-treatment orthodontic patients, clinicians, and laypersons. The subjects were asked to rate each image on a 7-point Likert scale from extremely unattractive to extremely attractive. For each 2 mm of chin retrusion, the rating of perceived attractiveness on the Likert scale decreased by an average of 0.15, and after a 4 mm change, the rating of perceived attractiveness was significantly apparent. For patients and clinicians, the degree of chin retrusion that would require surgical intervention was 11 mm, while for laypersons it was 10 mm. The most attractive image was one that could show an ideal orthognathic profile with a soft tissue pogonion that rests on a true vertical line.

[0100] Example 2 Method for increasing the S GN POG facial angle in a subject having chin retrusion or a weak chin ​The composition of the application is administered as an injectable implant by subcutaneous or supraperiosteal injection in the chin and / or mandibular region of a 32 year old male subject. The subject complains that he has a "weak chin". The physician measures the facial angle of the subject and determines that the G-Sn-Pog angle is about 150°, which is significantly lower than the classic Burstone angle for an average chin (about 169°). This measurement is based on a calculation of the facial angle from digital images obtained using a Canfield imaging device and software.

[0101] The physician considers that the chin / mandibular retrusion of the subject is amenable to correction, with the treatment goal being to increase chin projection horizontally (in profile view), rather than to lengthen or widen the chin.

[0102] The physician considers that by using the implantable composition described herein, he can provide the subject with a more attractive facial profile and a stronger mandibular contour.

[0103] The subject undergoes three treatment phases, including an initial treatment, a top-up treatment, and a repeat treatment, as described below.

[0104] For each treatment, the treatment area includes at least one or more of the following treatment areas: the pronasale (the most prominent point on the anterior surface of the chin), the subnasale (the lowest point of the chin), the left mentalis pre-sulcus (a groove on the left side near the gonial angle point), the right mentalis pre-sulcus (a groove on the right side near the gonial angle point), and / or the labiomental crease (a fold between the lower lip and the chin).

[0105] During any treatment period, the physician implants no more than 2.0 mL within a single treatment area.

[0106] The initial treatment of the subject is as follows. The physician uses a sterile skin preparation and proceeds with anesthesia according to his standard procedure. Application of ice and local anesthesia can reduce injection discomfort. Injection anesthesia is limited to the treatment area and administration of injection anesthesia is determined not to distort the planned treatment area.

[0107] Using the needle provided with the kit (27 gauge x 13 mm / 27G ½''), the physician injects the composition described herein by subcutaneous and / or supraperiosteal injection to increase chin projection (horizontally in profile view), as well as to perform aesthetic sculpting, contouring, and shaping, while limiting treatment to the pronasale, subnasale, mentalis pre-sulci, and labiomental (submental) crease. Suitable injection techniques are described above. The treatment goal is to increase chin projection (horizontally in profile view) and to achieve an aesthetically pleasing chin contour. The physician determines that the appropriate injection volume for the initial treatment and possible top-up treatment of the combination is up to about 4.0 mL.

[0108] The physician uses the manual manipulation over the tissue to gently mold the treatment area to achieve the desired facial contour.

[0109] If the subject desires, or if in the physician's opinion, the best (full) increase in chin projection and / or aesthetic contour has not been achieved by the initial treatment, a supplemental treatment is given approximately 30 days after the initial treatment. If a supplemental treatment is given, the volume of the composition administered is between about 2.0 mL and about 4.0 mL in total combination (initial treatment and supplemental treatment). During this visit, the physician assesses the treatment area for any local reactions and discusses any reported symptoms. A 3D facial digital image (frontal and profile images) is captured for objective calculation of the chin retrognathic angle. If the physician determines in the supplemental follow-up visit that the best (full) increase in chin projection or aesthetic contour has not been achieved after the initial treatment, the subject should be advised that they can receive a supplemental treatment.

[0110] If the subject desires, or if in the physician's opinion, the best (full) increase in chin projection and / or aesthetic contour has not been achieved by the initial treatment, a supplemental treatment is given approximately 30 days after the initial treatment. If a supplemental treatment is given, the volume of the composition administered is between about 2.0 mL and about 4.0 mL in total combination (initial treatment and supplemental treatment). During this visit, the physician assesses the treatment area for any local reactions and discusses any reported symptoms. A 3D facial digital image (frontal and profile images) is captured for objective calculation of the chin retrognathic angle. If the physician determines in the supplemental follow-up visit that the best (full) increase in chin projection or aesthetic contour has not been achieved after the initial treatment, the subject should be advised that they can receive a supplemental treatment.

[0111] While the application has been described and illustrated in sufficient detail that those skilled in this art can make and use it, various alternate means and

[0112] Unless otherwise indicated, it will be understood that, when used in this specification and the appended claims, the terms "comprises", "comprising", "includes", "including", "has", "having", "contains", "containing", or variations thereof, mean "including but not limited to", and should not be construed as necessarily limited to the elements or steps with which they are described.

[0113] Notwithstanding that the numerical ranges and parameters setting forth the broadest scope of the application are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0114] The recitations "comprising" or "consisting essentially of can be used in the claims to further particular embodiments disclosed herein. When used in the claims, whether as filed or added later and regardless of the form of the verse, the transitional term "comprising" does not exclude any element, step, or ingredient not specified in the claim. The transitional term "consisting essentially of limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the application claimed herein are inherently or explicitly described and enabled herein.

[0115] In general, it will be understood that the embodiments of the application disclosed herein are illustrative of the principles of the present application. Other modifications that can be employed are within the scope of the application. As such, the application is not to be limited to that precisely as shown and described.

Claims

1. A sterile composition which can be implanted subcutaneously or supraperiosteally into a treatment area selected from the group consisting of the prejowl, jowl, left prejowl sulcus, right prejowl sulcus, and sublabial crease of a patient in need thereof, wherein the composition comprises crosslinked hyaluronic acid (HA) crosslinked with 1,4-butanediol diglycidyl ether (BDDE), and the weight percent of crosslinking agent to HA-monomer units within the crosslinked portion of the composition is about 4% to about 12%; wherein the HA concentration of the composition is greater than 20 mg / g; wherein the HA used for crosslinking is made from a mixture of low molecular weight HA and high molecular weight HA, the mixture contains at least 70% by weight of low molecular weight HA, and the low molecular weight HA has a weight average molecular weight of 0.2 MDa to 1.0 MDa, and the high molecular weight HA has a weight average molecular weight of 0.2 MDa to 4.0 MDa, and wherein the elastic modulus of the composition is about 500 Pa to about 900 Pa at 5 Hz, the cohesiveness of the composition is greater than 60 gmf, and the extrusion force of the composition using a 1 mL COC syringe and a 27G x 13 mm needle is about 4 N to about 15 N at 13 mm / min.

2. The composition of claim 1, wherein the concentration of the HA is about 22.5 mg / g, about 25 mg / g, or about 27.5 mg / g.

3. The composition of any one of claims 1-2, wherein the HA used for crosslinking is a mixture containing at least 90% by weight of low molecular weight HA based on the total weight of HA.

4. The composition of any one of claims 1-3, wherein (i) the cohesiveness is about 60 gmf to about 200 gmf, or about 60 gmf to about 100 gmf; (ii) the extrusion force using a 1 mL COC syringe and a 27G x 13 mm needle is about 7 N to about 12 N at 13 mm / min, or about 8 N to about 10 N at 13 mm / min.

5. The composition of any one of claims 1-4, wherein the composition further comprises an anesthetic, preferably lidocaine hydrochloride.

6. The composition of claim 5, wherein the lidocaine hydrochloride is included in an amount of about 0.3% by weight based on the total weight of the composition.

7. The composition of any one of claims 1-6, wherein the weight percent of crosslinking agent to HA-monomer units within the crosslinked portion of the composition is about 4% to about 10%, about 4%, about 6%, about 8%, about 10%, or about 6.5%.

8. The composition of any one of claims 1-7, wherein the composition comprises about 25 mg of crosslinked HA and 3 mg of lidocaine in phosphate buffer pH 7.2, q.s. 1 mL, and wherein the weight percent of crosslinking agent to HA-monomer units within the crosslinked portion of the composition is about 6.5%.

9. A pharmaceutical composition for correcting a retruded chin of a patient, comprising: BDDE-crosslinked hyaluronic acid (HA) having a HA concentration greater than 20 mg / g, and a weight percentage of crosslinker to HA-monomer units within the crosslinked portion of the composition of about 6.5%, wherein the HA used for crosslinking is made from a mixture of low molecular weight HA and high molecular weight HA, and the mixture contains at least 70% by weight of low molecular weight HA, and the low molecular weight HA has a weight average molecular weight of 0.2 MDa to 1.0 MDa, and the high molecular weight HA has a weight average molecular weight of 0.2 MDa to 4.0 MDa, the treatment area is selected from the group consisting of the prejowl, the jowl, the left premandibular sulcus, the right premandibular sulcus, and the sublabial fold, wherein the composition has an elastic modulus of about 500 Pa to about 900 Pa at 5 Hz, the composition has a Cohesiveness of greater than 60 gmf, and the composition has an Extrusion Force of about 4 N to about 15 N at 13 mm / min using a 1 mL COC syringe and a 27G x 13 mm needle.

10. The pharmaceutical composition of claim 9, wherein the G-Sn-Pog angle of a patient as a subject to whom the composition is administered is less than about 165° based on a calculation of facial angles from a digital image derived from the patient.

11. The pharmaceutical composition of any one of claims 9-10, wherein: the composition has a HA concentration of about 25 mg / g; wherein the HA used for crosslinking the composition is made from about 90% by weight of low molecular weight hyaluronic acid and about 10% by weight of high molecular weight hyaluronic acid based on the total weight of HA; wherein the composition has an elastic modulus of about 500 Pa to about 800 Pa at 5 Hz; wherein the composition has a Cohesiveness of about 60 gmf to about 100 gmf; wherein the composition has an Extrusion Force of about 8 N to about 10 N at 13 mm / min using a 1 mL COC syringe and a 27G x 13 mm needle.

12. A pharmaceutical composition for use in generating or restoring volume of a chin or mandible of a patient by subcutaneous or supraperiosteal injection into a treatment area selected from the group consisting of the prejowl, the jowl, the left premandibular sulcus, the right premandibular sulcus, and the sublabial fold, wherein the composition comprises crosslinked hyaluronic acid (HA) crosslinked with 1,4-butanediol diglycidyl ether (BDDE), and the composition has a weight percentage of crosslinker to HA-monomer units within the crosslinked portion of the composition of about 4% to about 12%; wherein the HA used for crosslinking is made from a mixture of low molecular weight HA and high molecular weight HA, and the mixture contains at least 70% by weight of low molecular weight HA, and the low molecular weight HA has a weight average molecular weight of 0.2 MDa to 1.0 MDa, and the high molecular weight HA has a weight average molecular weight of 0.2 MDa to 4.0 MDa, and wherein the composition has an elastic modulus of about 500 Pa to about 900 Pa at 5 Hz, the composition has a Cohesiveness of about 60 gmf to about 100 gmf, and the composition has an Extrusion Force of about 4 N to about 15 N at 13 mm / min using a 1 mL COC syringe and a 27G x 13 mm needle.

13. The pharmaceutical composition according to claim 12, wherein the composition has an Extrusion Force of about 8 N to about 10 N at 13 mm / min using a 1 mL COC syringe and a 27G x 13 mm needle.

14. The pharmaceutical composition according to claims 12-13, wherein the composition has a weight percentage of crosslinking agent within the crosslinked portion of the HA- monomer units of about 6%, about 6.5%, about 8%, about 8.5%, about 10%, or about 10.5%.

15. A kit comprising the composition according to any one of claims 1-8, the composition being pre-loaded in a disposable syringe, such as a 1 mL COC syringe, and at least one disposable needle, such as a 27G x 13 mm needle.

16. A pharmaceutical composition for facial sculpting in a patient, such as for filling, correcting, repairing, or creating volume in the chin or mandibular region, comprising the composition according to any one of claims 1-8, wherein the pharmaceutical composition is used in a method comprising: administering to at least one treatment area of the patient's face, by subcutaneous and / or supraperiosteal administration, an effective amount of the composition according to any one of claims 1-8 by injection of the composition; and optionally massaging the treatment area of the patient's face after administration is complete to ensure the product conforms to the contours of the surrounding tissue; wherein the treatment area is optionally sterilized prior to administration of the composition; the treatment area is selected from the group consisting of the pronasale, the chin, the left prejowl sag, the right prejowl sag, and the sublabial (chin) crease.

17. The pharmaceutical composition according to any one of claims 1-8, wherein the composition has an elastic modulus of about 500 Pa to about 900 Pa at 5 Hz, the composition has a Cohesiveness of about 60 gmf to about 100 gmf, and the composition has an Extrusion Force of about 4 N to about 15 N at 13 mm / min using a 1 mL COC syringe and a 27G x 13 mm needle.

Images