Storage-stable formulations of sulfated glycosaminoglycans and derivative fragments thereof for treatment of pain and other medical conditions

Abstract

One aspect of the present application relates to a pharmaceutical composition comprising a sulfated glycosaminoglycan having an average molecular weight in the range of 3,000 to 15,000 Daltons, a skin penetrant wherein the skin penetrant promotes transdermal penetration of the sulfated glycosaminoglycan when applied to an intact skin surface, and a drug carrier for topical application, wherein the drug carrier is mixed with the sulfated glycosaminoglycan and the skin penetrant. The compositions may be used in performing methods of treating pain, ankylosis, soft tissue injury, connective tissue conditions, and / or muscular soreness in a subject.

Description

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 411,363, filed on September 29, 2022, which is hereby incorporated by reference in its entirety. Technical Field

[0002] The present application relates to storage-stable formulations of sulfated glycosaminoglycans and derived fragments thereof for use in the treatment of pain and other medical conditions. Background Art

[0003] Osteoarthritis (OA) is the most common form of arthritis and causes significant suffering and medical costs; one-third of people over the age of 45 seek treatment for OA, and 81% of these people experience persistent pain or limited mobility (Arthritis Research UK, "Osteoarthritis in General Practice: Data and Perspectives," (last accessed January 17, 2017) (2013). Most joint replacements can be attributed to OA pain. By 2030, it is expected that 560,000 hip replacements will be performed annually in the United States (Neogi T., "The Epidemiology and Impact of Pain in Osteoarthritis," Osteoarthritis Cartilage. 21(9): 1145-53 (2013)). That said, OA has lagged behind rheumatoid arthritis (RA) in terms of research and drug development. With an aging population and increasing obesity, the incidence of symptomatic OA and joint replacements is increasing year by year, and the cost is becoming increasingly unaffordable (Losina et al., "Lifetime Medical Costs of Knee Osteoarthritis Management in the United States: Impact of Extending Indications for Total Knee Arthroplasty,” Arthritis Care Res. 67(2): 203-15 (2015). OA is now becoming a disease that often affects young people in their 40s and 50s, who are not yet suitable for arthroplasty. This makes the unmet need for new pharmacological treatments increasingly obvious and growing.

[0004] Osteoarthritis is caused by the loss of cartilage that normally protects the joints, which leads to pain, swelling, and stiffness. OA is a progressive disease whose symptoms worsen as the cartilage erodes over time. Since there is currently no cure for the disease, standard treatment for OA involves managing these symptoms. The main pharmacological treatments for the symptoms of OA are analgesics, including acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids (Conaghan et al., “Treating Osteoarthritis Pain: Recent Approaches Using Pharmacological Therapies,” Clin. Exp. Rheumatol. 37 Suppl 120(5):S124-29 (2019)). Acetaminophen is often recommended as the first-line analgesic of choice and, if successful, is the preferred long-term analgesic due to its superior safety profile to NSAIDs (Zang et al., "EULAR Evidence Based Recommendations for the Management of HipOsteoarthritis: Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT)," Ann. Rheum. Dis. 64(5):669-81 (2005)). However, acetaminophen is associated with an increased risk of hepatic, hypertensive, and cardiovascular adverse reactions (Chan et al., "Nonsteroidal Antiinflammatory Drugs, Acetaminophen, and the Risk of Cardiovascular Events," Circulation. 113(12):1578-87 (2006); Pincus et al., Ann. Rheum. Dis. 63(8):931-9 (2004)).NSAIDs provide analgesia, anti-inflammatory and antipyretic effects, but may cause side effects, including gastrointestinal events (e.g., bleeding, inflammation, ulcers, etc.) and cardiovascular events (e.g., myocardial infarction and stroke) (Antman et al., "Use of Nonsteroidal Anti-inflammatory Drugs: An update for Clinicians: A Scientific Statement from the American Heart Association," Circulation 115(12): 1634-42 (2007)). When acetaminophen and NSAIDs are ineffective in treating OA pain, opioid analgesics can be used, but their use is limited because of their potential for serious adverse reactions, including constipation, respiratory depression, tolerance and dependence (. et al., "Recent Advances in the Treatment of Osteoarthritis," F1000 Res. 9: F1000 Faculty Rev-325 (2020)). Intra-articular and intramuscular injections of corticosteroids are also commonly used to relieve symptoms of OA, but this treatment usually only provides short-term benefits (Conaghan et al., "Treating Osteoarthritis Pain: Recent Approaches Using Pharmacological Therapies," Clin. Exp. Rheumatol. 37 Suppl 120 (5): S124-29 (2019)). When these non-invasive treatments fail, surgical options (such as joint replacement) are often considered.

[0005] In addition to the joint damage caused by arthritis, the normal function of joints and their movements and other parts of the body may also be seriously damaged due to trauma or after orthopedics and other surgical operations. The joints of the human body, especially the knee joint, ankle joint, hip joint, elbow joint, wrist joint, finger joint and vertebral joint, are prone to degeneration due to disease, trauma and long-term repeated use, eventually leading to pain. This injury may cause tenderness, dull pain, pain and a long recovery time, as well as loss of joint mobility or reduction in the range of motion of joints / joint structures (such as muscles, tendons, joint capsules, bones or ligaments), tension reduction or elasticity reduction. Reduced joint mobility may also involve permanent changes or shortening of joints or tissue structures. Changes or abnormalities in joint mobility or joint structure may also be related to or caused by multiple injuries and diseases, such as metabolic disorders, ischemia, joint injuries, joint capsule injuries, bone injuries, cartilage injuries, tendon injuries, ligament injuries or muscle injuries, fractures, subluxations, dislocations, compression injuries, long-term immobilization (for example, immobilizing joints with plaster or splints) and paralysis. As with osteoarthritis, current evidence-based guidelines support pharmacological treatment of these other forms of joint damage with acetaminophen or oral NSAIDs to reduce pain and inflammation. Due to the potential side effects of these analgesics, other treatment options are needed to treat the pain that occurs with osteoarthritis as well as other types of joint degeneration, soft tissue injuries, muscle aches, etc. Furthermore, these analgesics only treat symptoms. Treatments that can not only relieve symptoms, but also have a disease-modifying effect (improving the underlying cause of the condition), as well as potentially reversing damage, are needed.

[0006] Topical analgesics are used to relieve pain, such as that associated with arthritis, as well as pain, joint stiffness, and muscle aches resulting from sports injuries or other physical activity. However, such topically applied treatments can cause adverse reactions, including rash, nausea, vomiting, heartburn, bloating, diarrhea, constipation, and stomach pain.

[0007] The present application is directed to alleviating the deficiencies of previous treatments. Summary of the invention

[0008] One aspect of the present application relates to a storage-stable pharmaceutical composition comprising a sulfated glycosaminoglycan having an average molecular weight in the range of 3,000 to 15,000 Daltons, a skin permeation agent, wherein the skin permeation agent promotes transdermal penetration of the sulfated glycosaminoglycan when applied to the intact skin surface, and a drug carrier for topical administration, wherein the drug carrier is mixed with the sulfated glycosaminoglycan and the skin permeation agent.

[0009] Another aspect of the present application relates to a method for treating pain, joint stiffness, soft tissue damage, connective tissue pathology and / or muscle soreness in a subject. The method includes selecting a subject in need of treatment for pain, joint stiffness, soft tissue damage, connective tissue pathology and / or muscle soreness; applying a storage-stable pharmaceutical composition to the selected subject, the storage-stable pharmaceutical composition comprising a sulfated glycosaminoglycan having an average molecular weight in the range of 3,000 to 15,000 Daltons, a skin permeation agent, wherein the skin permeation agent promotes transdermal penetration of the sulfated glycosaminoglycan when applied to an intact skin surface, and a drug carrier for topical administration, wherein the drug carrier is mixed with the sulfated glycosaminoglycan and the skin permeation agent. The administration is performed locally at a location near where the subject experiences pain, joint stiffness, soft tissue damage, connective tissue pathology and / or muscle soreness.

[0010] Another aspect of the present application relates to a storage-stable sulfated glycosaminoglycan having an average molecular weight in the range of 3,000 to 15,000 Daltons.

[0011] Another aspect of the present application relates to a storage-stable pharmaceutical composition comprising a sulfated glycosaminoglycan having an average molecular weight in the range of 3,000 to 15,000 Daltons and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is mixed with the sulfated glycosaminoglycan.

[0012] Another aspect of the present application relates to a method of treating a subject to obtain a medically observable improvement. The method comprises selecting a subject in need of treatment for a medically diagnosable condition, and administering a storage-stable pharmaceutical composition to the selected subject to facilitate treatment, the storage-stable pharmaceutical composition comprising a sulfated glycosaminoglycan having an average molecular weight in the range of 3,000 to 15,000 Daltons and a pharmaceutical carrier, wherein the pharmaceutical carrier is mixed with the sulfated glycosaminoglycan.

[0013] Another aspect of the present application relates to a method for producing storage-stable purified sulfated glycosaminoglycans. The method includes providing a sulfated glycosaminoglycan starting material containing a component less than 1,000 Daltons, subjecting the sulfated glycosaminoglycan starting material to tangential flow filtration under conditions that are effective to reduce the amount of the component less than 1,000 Daltons in the starting material to produce a purified sulfated glycosaminoglycan having an average molecular weight in the range of 3,000 to 15,000 Daltons, wherein the purified sulfated glycosaminoglycans include no more than 10% by weight of carbohydrates or other contaminants having a molecular weight less than 1,000 Daltons, and recovering the purified sulfated glycosaminoglycans.

[0014] The present application relates to compositions for treating various conditions, including treating joint pain, soft tissue damage, connective tissue pathology and muscle soreness in the human or animal body. The method comprises preparing a therapeutic composition from a mixture of polysulfated glycosaminoglycan fragments derived from chondroitin sulfate, in some cases with a skin penetrant. The method is also embodied in applying the therapeutic composition to the human or animal body, including applying it topically near the location where the human or animal feels discomfort or damage. In addition, the method comprises using a topical composition in the form of a cream, gel, excipient, transdermal tape and patch, ointment, gel, paste or collodion. Also disclosed are polysulfated glycosaminoglycan fragments and pharmaceutically acceptable free bases, salts, esters, ethers, or solvates of antibiotics, anti-infectives, antifungals, steroids, cannabinoids, antihistamines, anti-inflammatory agents, antiparasitic agents, immunomodulators, antisense agents, antiviral agents, therapeutic agents for treating hyperpigmentation and hypopigmentation of the skin, antipsoriatics, keratolytics, DNA synthesis inhibitors, cytotoxic agents, antithyroid agents, monoclonal antibody modulators, TNF Alpha antagonists, immunoglobulins, metabolic regulators, anti-angiogenic agents, protease inhibitors, anxiolytics, kinase regulators, cell growth regulators, enzymes, prostaglandins, peptides, analgesics, skin moisturizers, astringents, exfoliants, agents intended to protect the skin, change the appearance of the skin or increase the rate of skin healing and / or combinations thereof, including various active or synergistic ingredients such as lidocaine (and other local anesthetics), DMSO, glucosamine, diclofenac, capsaicin, salicylates, CBD, THC, menthol and combinations of other ingredients.

[0015] The method is also embodied as a process for purifying polysulfated glycosaminoglycan fragments to remove lower molecular weight byproducts and impurities by procedures such as ultrafiltration or diafiltration. This purification method produces purified polysulfated glycosaminoglycans that can be used to prepare therapeutic compositions with longer shelf life than preparations containing polysulfated glycosaminoglycans not prepared by the process.

[0016] Current treatments for these complaints are limited because they focus primarily on treating symptoms such as joint and / or muscle pain and stiffness, as well as limited range of motion. Often, these treatments, while effective in alleviating pain in the short term, can exacerbate disease progression, causing symptoms to worsen over time. Currently, there are no widely available pharmacological agents that are safe, easy to administer, and capable of slowing the progression of or preventing osteoarthritis.

[0017] Numerous studies on glycosaminoglycans have shown their potential role in alleviating pain and slowing disease progression in osteoarthritis. However, these high molecular weight compounds have shown beneficial effects only when administered by injection - because their molecular weight is very high and their ionic structures are highly charged. In addition, the process of preparing pharmaceutically acceptable sulfated glycosaminoglycans such as PSGAG is difficult to reproducible and results in contamination of the product with low molecular weight byproducts and impurities that limit the utility of this class of agents.

[0018] The present application discloses how to overcome these limitations by using PSGAGs within a defined molecular weight range. These can be effectively used to treat a variety of conditions by different means, including allowing patients to easily apply topical formulations containing skin penetration enhancers that help deliver such active ingredients through the skin barrier, allowing the active ingredients to reach the site of action without injection. DETAILED DESCRIPTION

[0019] One aspect of the present application relates to a storage-stable pharmaceutical composition comprising a sulfated glycosaminoglycan having an average molecular weight in the range of 3,000 to 15,000 Daltons, a skin permeation agent, wherein the skin permeation agent promotes transdermal penetration of the sulfated glycosaminoglycan when applied to the intact skin surface, and a drug carrier for topical administration, wherein the drug carrier is mixed with the sulfated glycosaminoglycan and the skin permeation agent.

[0020] In some embodiments, the sulfated glycosaminoglycan is selected from the group consisting of the following: chondroitin sulfate, polysulfated mucopolysaccharide, polysulfated glycosaminoglycan and / or a combination thereof. In some embodiments, the sulfated glycosaminoglycan includes chondroitin sulfate. In some embodiments, the sulfated glycosaminoglycan includes the chondroitin sulfate less than 5% by weight. For example, in some embodiments, the sulfated glycosaminoglycan includes the chondroitin sulfate less than 0.5% by weight, less than 1% by weight, less than 1.5% by weight, less than 2% by weight, less than 2.5% by weight, less than 3% by weight, less than 3.5% by weight, less than 4% by weight or less than 4.5% by weight of chondroitin sulfate. In some embodiments, the sulfated glycosaminoglycan includes polysulfated mucopolysaccharide. In other embodiments, the sulfated glycosaminoglycan includes polysulfated glycosaminoglycan.

[0021] As described herein, sulfated glycosaminoglycans include full-length naturally occurring sulfated glycosaminoglycans as well as sulfated fragments of these polysaccharides derived by chemical or enzymatic manipulation, wherein the sulfated glycosaminoglycan fragments have an average molecular weight of 3,000 to 15,000 Da. For example, in some embodiments, the average molecular weight of the sulfated glycosaminoglycan fragment is 3,000 to 4,000 Da, 3,000 to 5,000 Da, 3,000 to 6,000, 3,000 to 7,000 Da, 3,000 to 8,000 Da, 3,000 to 9,000 Da, 3,000 to 10,000 Da, 3,000 to 11,000 Da, 3,000 to 12,000 Da, 3,000 to 13,000 Da, 3,000 to 14,000 Da, 3,000 to 15,000 Da, 3,500 to 4,000 Da, 3,500 to 5,000 Da. , 3,500 to 6,000, 3,500 to 7,000 Da, 3,500 to 8,000 Da, 3,500 to 9,000 Da, 3,500 to 10,000 Da, 3,500 to 11,000 Da, 3,500 to 12,000 Da, 3,500 to 13,000 Da, 3,500 to 14,000 Da, 3,500 to 15,000 Da, 4,000 to 5,000 Da, 4,000 to 6,000, 4,000 to 7,000 Da, 4,000 to 8,000 Da, 4,000 to 9,000 Da, 4,000 to 10,000 Da. , 4,000 to 11,000 Da, 4,000 to 12,000 Da, 4,000 to 13,000 Da, 4,000 to 14,000 Da, 4,000 to 15,000 Da, 4,500 to 5,000 Da, 4,500 to 6,000 Da, 4,500 to 7,000 Da, 4,500 to 8,000 Da, 4,500 to 9,000 Da, 4,500 to 10,000 Da, 4,500 to 11,000 Da, 4,500 to 12,000 Da, 4,500 to 13,000 Da, 4,500 to 14,000 Da, 4,500 to 15,000 Da. 15,000 Da, 5,000 to 6,000 Da, 5,000 to 7,000 Da, 5,000 to 8,000 Da, 5,000 to 9,000 Da, 5,000 to 10,000 Da, 5,000 to 11,000 Da, 5,000 to 12,000 Da, 5,000 to 13,000 Da, 5,000 to 14,000 Da, 5,000 to 15,000 Da, 5,500 to 6,000 Da, 5,500 to 7,000 Da, 5,500 to 8,000 Da, 5,500 to 9,000 Da, 5,500 to 10,000 Da, 5,500 to 11,000 Da, 5,500 to 12,000 Da, 5,500 to 13,000 Da, 5,500 to 14,000 Da, 5,500 to 15,000 Da, 6,000 to 7,000 Da, 6,000 to 8,000 Da, 6,000 to 9,000 Da, 6,000 to 10,000 Da, 6,000 to 11,000 Da, 6,000 to 12,000 Da, 6,000 to 13,000 Da, 6,000 to 14,000 Da, 6,000 to 15,000 Da, 6,500 to 7,000 Da, 6,500 to 8,000 Da, 6,500 to 9,000 Da, 6 , 500 to 10,000 Da, 6,500 to 11,000 Da, 6,500 to 12,000 Da, 6,500 to 13,000 Da, 6,500 to 14,000 Da, 6,500 to 15,000 Da, 7,000 to 8,000 Da, 7,000 to 9,000, 7,000 to 9,500 Da, Da, 7,000 to 10,000 Da, 7,000 to 11,000 Da, 7,000 to 12,000 Da, 7,000 to 13,000 Da, 7,000 to 14,000 Da, 7,000 to 15,000 Da, 7,500 to 8,000 Da, 7,500 to 9,000 Da. , 7,500 to 10,000 Da, 7,500 to 11,000 Da, 7,500 to 12,000 Da, 7,500 to 13,000 Da, 7,500 to 14,000 Da, 7,500 to 15,000 Da, 8,000 to 9,000 Da, 8,000 to 10,000 Da, 8,000 to 11,000 Da, 8,000 to 12,000 Da, 8,000 to 13,000 Da, 8,000 to 14,000 Da, 8,000 to 15,000 Da. 00 Da, 8,500 to 13,000 Da, 8,500 to 14,000 Da, 8,500 to 15,000 Da, 9,000 to 10,000 Da, 9,000 to 11,000 Da, 9,000 to 12,000 Da, 9,000 to 13,000 Da, 9,000 to 14,000 Da, 9,000 to 15,000 Da, 9,500 to 10,000 Da, 9,500 to 11,000 Da, 9,500 to 12,000 Da, 9,500 to 13,000 Da, 9,500 to 14,000 Da, 9,500 to 15,000 Da, 10,000 to 11,000 Da, 10,10,000 to 12,000 Da, 10,000 to 13,000 Da, 10,000 to 14,000 Da, 10,000 to 15,000 Da, 10,500 to 11,000 Da, 10,500 to 12,000 Da, 10,500 to 13,000 Da, 10,500 to 14,000 Da, 10,500 to 15,000 Da, 11,000 to 12,000 Da, 11,000 to 13,000 Da, 11,000 to 14,000 Da, 11,000 to 15,000 Da, 11,500 to 12,000 Da, 11,500 to 13 ,000 Da, 11,500 to 14,000 Da, 11,500 to 15,000 Da, 12,000 to 13,000 Da, 12,000 to 14,000 Da, 12,000 to 15,000 Da, 12,500 to 13,000 Da, 12,500 to 14,000 Da, 12,500 to 15,000 Da, 13,000 to 14,000 Da, 13,000 to 15,000 Da, 13,500 to 14,000 Da, 13,500 to 15,000 Da, 14,000 to 15,000 Da, 14,500 to 15,000 Da. ,

[0022] In some embodiments, the sulfated glycosaminoglycans include no more than 10% by weight of carbohydrates or other contaminants having a molecular weight of less than 1,000 Daltons. In other embodiments, the sulfated glycosaminoglycans include no more than 1% by weight, no more than 2% by weight, no more than 3% by weight, no more than 4% by weight, no more than 5% by weight, no more than 6% by weight, no more than 7% by weight, no more than 8% by weight, or no more than 9% by weight of carbohydrates or other contaminants having a molecular weight of less than 1,000 Daltons.

[0023] In some embodiments, the sulfated glycosaminoglycans include no more than 20% by weight of carbohydrates or other contaminants having a molecular weight of less than 3,000 Daltons. In other embodiments, the sulfated glycosaminoglycans include no more than 1% by weight, no more than 2% by weight, no more than 3% by weight, no more than 4% by weight, no more than 5% by weight, no more than 6% by weight, no more than 7% by weight, no more than 8% by weight, or no more than 9% by weight, no more than 10% by weight, no more than 11% by weight, no more than 12% by weight, no more than 13% by weight, no more than 14% by weight, no more than 15% by weight, no more than 16% by weight, no more than 17% by weight, no more than 18% by weight, or no more than 19% by weight of carbohydrates or other contaminants having a molecular weight of less than 3,000 Daltons.

[0024] In some embodiments, the sulfated glycosaminoglycans include no more than 25% by weight of carbohydrates or other contaminants having a molecular weight of less than 5,000 Daltons. In other embodiments, the sulfated glycosaminoglycans include no more than 1% by weight, no more than 2% by weight, no more than 3% by weight, no more than 4% by weight, no more than 5% by weight, no more than 6% by weight, no more than 7% by weight, no more than 8% by weight, or no more than 9% by weight, no more than 10% by weight, no more than 11% by weight, no more than 12% by weight, no more than 13% by weight, no more than 14% by weight, no more than 15% by weight, no more than 16% by weight, no more than 17% by weight, no more than 18% by weight, or no more than 19% by weight, no more than 20% by weight, no more than 21% by weight, no more than 22% by weight, no more than 23% by weight, or no more than 24% by weight of carbohydrates or other contaminants having a molecular weight of less than 5,000 Daltons.

[0025] In some embodiments, the sulfated glycosaminoglycans contain less than 5,000 ppm of acetic acid. In some embodiments, the sulfated glycosaminoglycans contain less than 500 ppm, less than 1,000 ppm, less than 1,500 ppm, less than 2,000 ppm, less than 2,500 ppm, less than 3,000 ppm, less than 3,500 ppm, less than 4,000 ppm, or less than 4,500 ppm of acetic acid. In other embodiments, the sulfated glycosaminoglycans contain less than 5,000 ppm of acetic acid after storage at room temperature for at least 12 months after the start of storage. In some embodiments, the sulfated glycosaminoglycans contain less than 500 ppm, less than 1,000 ppm, less than 1,500 ppm, less than 2,000 ppm, less than 2,500 ppm, less than 3,000 ppm, less than 3,500 ppm, less than 4,000 ppm, or less than 4,500 ppm of acetic acid after storage at room temperature for at least 12 months after the start of storage. In some embodiments, the sulfated glycosaminoglycans contain less than 5,000 ppm acetic acid for at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months, or at least 24 months after the start of storage.

[0026] In some embodiments, the sulfated glycosaminoglycans remain white or off-white after being stored at room temperature for at least 6 months after the start of storage. In some embodiments, the sulfated glycosaminoglycans remain white or off-white after being stored at room temperature for at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months, or at least 24 months after the start of storage.

[0027] All cells and many macromolecules in nature carry a series of covalently attached sugars (monosaccharides) or sugar chains (oligosaccharides (usually less than twelve monosaccharides) or polysaccharides (usually more than twelve monosaccharides)), which are collectively called glycans. Sometimes glycans can be independent entities. Many glycans are on the external surface of cells and secreted macromolecules and can regulate or mediate many events in cell-cell, cell-matrix and cell-molecule interactions that are critical for the development and function of complex multicellular organisms.

[0028] Most cell surface polysaccharides present in animals belong to a class of polysaccharides known as glycosaminoglycans (GAGs). Glycosaminoglycans are complex polysaccharides present on the cell surface and free in the extracellular matrix, belonging to a highly heterogeneous class of macromolecules. GAGs (formerly known as mucopolysaccharides) are linear macromolecules with a molecular mass of >15,000 Daltons (Da). These linear polysaccharides contain repeating disaccharide units, which typically contain an amino sugar residue (i.e., glucosamine or galactosamine) and a uronic acid residue containing glucuronic acid or iduronic acid. Amino-substituted sugars can be attached to hexuronic acid residues. Modifications to sugar residues are common, especially sulfation of hydroxyl groups or amino groups. Sulfate groups and hexuronic acid carboxylate groups are negatively charged under physiological conditions. C 2 , C 3 , C 4 and C 6 The hydroxyl group and C 2The amino groups on the GAGs can be replaced by sulfate groups. Representative compounds of GAGs are: heparin, heparan sulfate, dermatan sulfate, hyaluronic acid, chondroitin sulfate and keratan sulfate. These GAGs differ in the structure of their disaccharide repeating units (structural units). These complex carbohydrate macromolecules are present in humans and animals, some of which are located in tissues and fluids. GAGs are responsible for carrying out and regulating a large number of essential cellular functions, and for soft tissues, they play a key role in promoting healing and / or reducing coagulation. GAGs mainly exhibit biological functions through their interactions with hundreds of GAG-binding proteins present on the cell surface and in the extracellular space. Structural factors that affect the strength and specificity of binding are key to triggering appropriate biological responses. Polysaccharides have a variety of protective, stabilizing, organizing and barrier functions. Glycosaminoglycans (GAGs) are signaling polysaccharides because they interact with receptor tyrosine kinases and / or their ligands and promote changes in cell behavior.

[0029] Chondroitin sulfate is a sulfated GAG composed of alternating sugar (N-acetylgalactosamine and glucuronic acid) chains with an average molecular weight of 20,000-30,000Da. It comes from multiple species, including mammals and fish. Each monosaccharide can be unsulfated, sulfated once or sulfated twice. The most common pattern is that the hydroxyl groups at positions 4 and 6 of N-acetyl-galactosamine are sulfated, and position 2 of the glucuronic acid of some chains is sulfated. Chondroitin chains can have more than 100 individual sugars, each of which can be sulfated at different positions and in different quantities. Chondroitin sulfate is an important structural component of cartilage and provides great resistance to compression. Chondroitin sulfate is usually mixed with glucosamine to make an orally administered therapeutic agent.

[0030] Mucopolysaccharide polysulfate (MPS) is a naturally occurring organic heparinoid compound. MPS consists of long, unbranched polysaccharides with repeating disaccharide units. Its chemical structure allows for the formation of numerous hydrogen bonds with adjacent water molecules, thereby effectively hydrating the surrounding tissues through its water-retaining properties (Pichotka et al., "Experimental Studies on Percutaneous Efficacy of Anticoagulative Substances; Potentiation of Intravenously Administered Heparin by Percutaneous Hirudoid," Arzneimittel-Forschung 4(4):277-282 (1954); Buchtela et al., "The Percutaneous Resportion of an S35-labelled Mucopolysaccharide Polysulfuric Acid Ester," Arzneimittel-Forschung 17(5):591-593 (1967); and Larsson et al., "Percutaneous Treatment With a Mucopolysaccharide Polysulphate of Experimentally Induced Subcutaneous Haematomas in Man," Thrombosis and Haemostasis 53(3):343-345 (1985), which is hereby incorporated by reference in its entirety). MPS is described solely as a semisynthetic glycosaminoglycan with an average molecular mass of 9700 Da, which has a variety of roles.

[0031] The chemical properties of polysulfated glycosaminoglycans (PSGAGs) are similar to those of natural mucopolysaccharides present in cartilage tissue. It is composed of repeated disaccharide units (including hexosamine and hexuronic acid), and because it is similar to GAGs already present in cartilage; therefore, PSGAGs are easily integrated into itself (Wanamaker et al., "Applied Pharmacology for Veterinary Technicians-E-Book," Elsevier Health Sciences, p. 392. ISBN9780323291705 (2014-03-25); and White "Adequan: A Review for the Practicing Veterinarian," J. Equine Vet. Sci. 8 (6): 463-468 (1988), both of which are hereby incorporated by reference in their entirety). PSGAGs are prepared from chondroitin sulfate by extensive sulfation, fragmentation and purification processes. The molecular weight of chondroitin sulfate is generally in the range of 20,000 to 30,000 Da, while PSGAG according to the present application is generally prepared to have a molecular weight in the range of 3,000 to 15,000 Da.

[0032] The specific mechanism of action in canine joints is unclear. PSGAG is characterized as a "condition-modifying osteoarthritis drug". Experiments conducted in vitro have shown that PSGAG can inhibit certain catabolic enzymes whose activity increases in inflamed joints and enhance the activity of some anabolic enzymes. For example, PSGAG has been shown to significantly inhibit serine proteases. It has been shown that serine proteases can play a role in interleukin-1-mediated degradation of cartilage proteoglycans and collagen. PSGAG is reported to be an inhibitor of prostaglandin E2 (PGE2) synthesis. PGE2 has been shown to increase the loss of proteoglycans from cartilage. PSGAG is reported to inhibit some catabolic enzymes, such as elastase, matrix lysin, metalloproteinase, cathepsin B1 and hyaluronidase, which degrade collagen, proteoglycans and hyaluronic acid in degenerative joint diseases. The anabolic effects studied include the ability to stimulate the synthesis of proteins, collagen, proteoglycans and hyaluronic acid in various cells and tissues in vitro. Cultured human and rabbit chondrocytes have shown increased synthesis of proteoglycans and hyaluronan in the presence of PSGAG.PSGAG has shown a specific enhancing effect on hyaluronan synthesis by synoviocytes in vitro.

[0033] The absorption, distribution, metabolism and excretion of PS GAGs following intramuscular injection have been studied in several species including rats, rabbits, humans, horses and dogs.

[0034] Studies in rabbits have shown that PSGAG reaches maximum blood concentrations following intramuscular injection within 20 to 40 minutes after injection and the drug is distributed to all tissues studied, including articular cartilage, synovial fluid, adrenal glands, thyroid gland, peritoneal fluid, lung, eye, spinal cord, kidney, brain, liver, spleen, bone marrow, skin, and heart.

[0035] It was found that after intramuscular injection of PSGAG in humans, the drug binds to serum proteins. PSGAG binds to albumin as well as χ-globulin and β-globulin with an expected degree of binding of 30% to 40%. Therefore, the drug can be present in the bloodstream in both bound and free forms. The synovium is not a significant barrier to the distribution of PSGAG from the bloodstream to the synovial fluid. Distribution from the synovial fluid to the cartilage occurs by diffusion. In articular cartilage, the drug is deposited in the cartilage matrix.

[0036] The serum and synovial fluid distribution profiles of PSGAG have been studied in dogs and found to be similar to those in humans and rabbits.

[0037] As used herein, "skin," "skin surface," "dermis," "epidermis," and similar terms are used interchangeably to refer not only to the outer layer of the subject's skin, including the epidermis, but also to the underlying layers and mucosal surfaces. The skin site is intact (e.g., normal skin) as opposed to damaged (i.e., damaged or lacking at least a portion of the stratum corneum (e.g., skin damaged by exposure to a relevant agent, radiation exposure, other agents, the presence of a pathological condition such as a rash or contact dermatitis, physical trauma such as a cut, wound, or abrasion, skin hypoplasia such as that present in premature infants, situations where all or part of the epidermis is exposed, situations where part of the dermis is removed such as partial thickness wounds encountered in skin resurfacing procedures such as chemical peels, dermabrasion, and laser resurfacing, etc.)).

[0038] In order for topical administration of an active pharmaceutical ingredient (API) to be effective, the active ingredient needs to penetrate the stratum corneum (SC), the outermost layer of the skin, to reach the lower layers of the epidermis. The barrier function of the skin must be overcome to achieve transdermal delivery of the active ingredient. A common method of penetrating the skin barrier is to use additive chemicals that act as penetration enhancers. These chemical penetration enhancers are molecules that increase subcutaneous permeability. The effects and mechanisms of several chemical enhancers are summarized in Kim et al., "Transdermal Delivery Systems in Cosmetics," Biomedl Dermatol. 4(10): 1-12 (2020), which is hereby incorporated by reference in its entirety.

[0039] As used herein, "transdermal penetration" refers to administration through the skin. Transdermal administration is generally applied when systemic delivery of an active substance is desired, although it can also be used to deliver an active substance to tissues beneath the skin with minimal systemic absorption.

[0040] In some embodiments, skin permeation agents include penetration enhancers. As used herein, the term "penetration enhancer" refers to a chemical substance that is delivered together with the intended drug, or before drug administration, to promote the transdermal penetration of the administered drug at the skin surface. Penetration enhancers have been used to increase the rate at which drugs penetrate the skin. Ideally, such chemical enhancers are passive and harmless, and only promote the diffusion of the intended drug through the stratum corneum, where the intended drug can diffuse through the extracellular matrix to reach the site of action.

[0041] Suitable skin penetration enhancers can be, for example, sulfoxides, alcohols, fatty acids, esters of saturated or unsaturated fatty acids, polyols, amides, surfactants, terpenes and terpenoids, alkanones, organic acids and esters, cyclodextrins, water, vitamin E, phospholipids, essential oils and their terpene components, plant carrier oils, alcohols, isomers of aliphatic diols and aliphatic triols, urea or other amide derivatives, tocopherol acetate, aloe derivatives, silicon derivatives, chelating agents, water, emulsifiers, polyoxyethers of fatty acids, vitamins, antioxidants, antimicrobial preservatives, and combinations thereof. To date, more than 350 chemical substances have been shown to enhance skin permeability (Karande et al., "Discovery of Transdermal Penetration Enhancers by High-throughput Screening," Nat Biotechnol. 22: 192-197 (2004), which is hereby incorporated by reference in its entirety), including terpenes, sulfoxides, lauryl nitrogen, and hydroxyethyl esters. Ketones, pyrrolidones, fatty acids, fatty alcohols, alcohols such as ethylene glycol, surfactants, and urea (Chen et al., "Novel Chemical Permeation Enhancers for Transdermal Drug Delivery," Asian J Pharm Sci. 9(2):51-64 (2014), which is hereby incorporated by reference in its entirety). Urea has long been used in topical and transdermal preparations and has been widely described for its moisturizing, keratolytic, and penetration enhancing activities.

[0042] In some embodiments, the skin penetrant is selected from the group consisting of acetone, acyl lactylates, acyl peptides, acyl sarcosinates, alkanolamine salts of fatty acids, alkyl benzenesulfonates, alkyl ether sulfates, alkyl sulfates, anionic surfactants, benzyl benzoate, benzyl salicylate, butane-1,4-diol, butyl benzoate, butyl laurate, butyl myristate, butyl stearate, cationic surfactants, citric acid, cocamidopropyl betaine, decyl methyl sulfoxide, oleic acid Decyl ester, dibutyl azelate, dibutyl phthalate, dibenzyl sebacate, dibutyl sebacate, dibutyl suberate, dibutyl succinate, dioctyl adipate, didecyl phthalate, diethylene glycol, diethyl sebacate, diethyl m-toluamide, di(2-hydroxypropyl) ether, diisopropyl adipate, diisopropyl sebacate, N,N-dimethylacetamide, dimethyl azelate, N,N-dimethylformamide, 1,5-dimethyl-2-pyrrolidone, dimethyl sebacate, di Methyl sulfoxide, dioctyl adipate, dioctyl azelate, dioctyl sebacate, 1,4-dioxane, 1-dodecylazacycloheptan-2-one, dodecyl dimethylamine oxide, ethyl decanoate, ethyl hexanoate, ethyl octanoate, 2-ethyl-hexyl nonanoate, ethyl-2-hydroxypropionate, ethyl laurate, ethyl myristate, 1-ethyl-2-pyrrolidone, ethyl salicylate, hexyl laurate, 2-hydroxyoctanoic acid, 2-hydroxypropionic acid, 2-hydroxypropionic acid, isosulfate, isopropyl isostearate , isopropyl palmitate, guar hydroxypropyltrimonium chloride, hexane-2,5-diol, khellin, lamepons, lauryl alcohol, maypons, metal salts of fatty acids, methyl nicotinate, 2-methylpropane-2-ol, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, methyl taurine, miranol surfactant nonionic surfactant octanol, octylphenoxypolyethoxyethanol, oleic acid, ethanolamine, oleyl alcohol, pentyl-2,4-diol, phenoxyethanol, phosphatidylcholine, phosphine oxide, polyalkoxylated ether glycolate, poly(diallylpiperidinium chloride), poly(dipropyldiallylammonium chloride), polyglycerol esters, polyoxyethylene lauryl ether, polyoxy: polyoxyethylene stearate, polyoxypropylene 15 stearyl ether, poly(vinylpyridinium chloride), propan-1-ol, propan-2-ol, propylene glycol dipelargonate, pyroglutamic acid, 2-pyrrolidone, pyruvic acid, quaternium 5, quaternium 18, quaternium 19, quaternium 23, quaternium 31, quaternium 40, quaternium 57, quaternary ammonium salt, quaternized poly(dimethylaminoethyl methacrylate), quaternized poly(vinyl alcohol), chromamine hydrochloride, sodium cocoaminopropionate, di Sodium octyl sulfosuccinate, sodium laurate, sodium lauryl ether sulfate, sodium lauryl sulfate, sugar esters, sulfosuccinates, tetrahydrofuran, tetrahydrofurfuryl alcohol, transcutol, triethanolamine dodecylbenzene sulfonate, triethanolamine oleate, water and derivatives, salts, essential oils and their terpene components, vegetable carrier oils, emulsifiers, ethanol, dimethyl sulfoxide, dimethyl isosorbide, isopropyl myristate, propylene glycol, sodium lauryl sulfate, lauryl amine oxide, vitamin E, lower alcohols, alcohols, isomers of aliphatic diols and aliphatic triols, urea or other amide derivatives, primary and secondary alcohols, fatty acids, fatty acid esters, polyols, amides, surfactants, terpenes and terpenoids, alkanones, organic acids and esters, cyclodextrins, phospholipids and combinations thereof. ,

[0043] Essential oils include eucalyptus oil, eucalyptol, clove oil, turpentine and peppermint oil. Plant carrier oils are natural fixed oils squeezed mainly from seeds and constitute common ingredients of topical pharmaceutical preparations. They are mixtures of heterogeneous lipids (mainly consisting of triglycerides) and lower concentrations of components (such as free fatty acids (saturated and unsaturated fatty acids), monoglycerides and diglycerides, sterols, phospholipids, fatty alcohols and fat-soluble vitamins).

[0044] Suitable alcohols include alkanols such as ethanol, propanol, butanol, pentanol, hexanol, octanol, n-octanol, nonanol, decanol, 2-butanol, 2-pentanol and benzyl alcohol; fatty alcohols such as octanol, decanol, lauryl alcohol, 2-lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol and linolenic alcohol; isopropanol and 2-(2-ethoxy)ethanol.

[0045] Examples of suitable fatty acids include straight chain fatty acids such as valeric acid, heptanoic acid, nonanoic acid, caproic acid, capric acid, lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid and caprylic acid; and branched chain fatty acids such as isovaleric acid, neopentanoic acid, neoheptanoic acid, neononanoic acid, trimethylhexanoic acid, neodecanoic acid and isostearic acid.

[0046] Examples of suitable fatty acid esters include aliphatic fatty acid esters such as isopropyl n-butyrate, isopropyl n-hexanoate, isopropyl n-decanoate, isopropyl myristate, isopropyl palmitate and octyldodecyl myristate; fatty acid alkyl esters such as ethyl acetate, butyl acetate, methyl valerate, methyl propionate, diethyl sebacate and ethyl oleate and diisopropyl adipate.

[0047] Examples of suitable polyols include propylene glycol, propylene glycol monolaurate, butylene glycol, polyethylene glycol, ethylene glycol, diethylene glycol, triethylene glycol, dipropylene glycol, ethoxydiglycol, pentylene glycol, glycerine, propanediol, butylene glycol, pentylene glycol, hexanetriol and glycerol.

[0048] Examples of suitable amides include urea, dimethylacetamide, diethyltoluamide, dimethylformamide (DMF), dimethyloctanamide, dimethyldecanamide, biodegradable cyclic ureas (e.g., 1-alkyl-4-imidazolin-2-ones), pyrrolidone derivatives, biodegradable pyrrolidone derivatives (e.g., fatty acid esters of N-(2-hydroxyethyl)-2-pyrrolidone), cyclic amides, hexamethylene lauramide and its derivatives, diethanolamine, and triethanolamine. Examples of pyrrolidone derivatives include 1-methyl-2-pyrrolidone, N-methyl-2-pyrrolidone, 2-pyrrolidone, 1-lauryl-2-pyrrolidone, 1-methyl-4-carboxy-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, 1-hexyl-4-carboxy-2-pyrrolidone, 1-lauryl-4-carboxy-2-pyrrolidone, 1-methyl-4-methoxycarbonyl-2-pyrrolidone, 1-hexyl-4-methoxycarbonyl-2-pyrrolidone, 1-lauryl-4-methoxycarbonyl-2-pyrrolidone, N-cyclohexylpyrrolidone, N-dimethylaminopropylpyrrolidone, N-coconut oil alkylpyrrolidone, N-tallow alkylpyrrolidone and N-methylpyrrolidone. Examples of cyclic amides include 1-dodecylazacycloheptan-2-one (e.g., Azone TM (e.g., Syntec Pharma Corp, Farmingdale, NY)), 1-geranylazacycloheptan-2-one, 1-farnesylazacycloheptan-2-one, 1-geranylgeranylazacycloheptan-2-one, 1-(3,7-dimethyloctyl)azepan-2-one, 1-(3,7,11-trimethyldodecyl)azepan-2-one, 1-geranylazacyclohexan-2-one, 1-geranylazacyclopentan-2,5-dione and 1-farnesylazacyclopentan-2-one.

[0049] Suitable surfactants include anionic surfactants such as sodium laurate, sodium lauryl sulfate, and the like; cationic surfactants such as benzalkonium chloride, dodecyltrimethylammonium chloride, cetyltrimethylammonium bromide; nonionic surfactants such as propoxylated polyoxyethylene ethers, for example, poloxamer 231, poloxamer 182, poloxamer 184, polyoxyethylene esters, sorbitan mono-9-octadecenoate, ethoxylated fatty acids, for example, Tween 20, Myrj 45, sorbitan derivatives, for example, Tween 40, Tween 60, Tween 80, Span 60, ethoxylated alcohols, for example, polyoxyethylene (4) lauryl ether ( 30), polyoxyethylene (2) oleyl ether, caprylocaproyl polyoxy-8 glyceride, polyglycerol oleate, polyoxyethylated glycolytic glycerides, polysorbate, monoglyceride, lecithin and lecithin derivatives.

[0050] Suitable terpenes and terpenoids include D-limonene, pinene, p-carene, terpineol, carveol, carvone, menthone, limonene oxide, pinene oxide, eucalyptus oil, terpineol and menthol.

[0051] Examples of suitable organic acids and esters include salicylic acid, methyl salicylate, citric acid, lauryl lactate and succinic acid.

[0052] Other examples of suitable penetration enhancers include glycerol monoethyl ether, beta-cyclodextrin, and polyglycosylated glycerides.

[0053] In some embodiments, the skin penetration enhancer is one or more of the following: Laurogicol TM 90. (diethylene glycol monoethyl ether) (Gattefossé Corporation, Paramus, NJ), (PEG-8 Caprylic / Capric Glycerides) (Gattefoss6 Corporation, Paramus, NJ), Oleique (polyglyceryl-3 oleate) (Gattefossé Corporation, Paramus, NJ), 2125cs (Gattefossé Corporation, Paramus, NJ), oleic acid, HPbCD, (Fagron, Inc., St. Paul, Minn.), Plus (Fagron, Inc., St. Paul, Minn.), Phytobase TM (Fagron, Inc., St. Paul, Minn.), (Fagron, Inc., St. Paul, Minn.) and Pluronic lecithin organogel (PLO), Humco HRT Heavy TM and HRT Botanical TM (Humco, Texarkana, Tex.), Fagron HRT Heavy TM (Fagron, Inc., St. Paul, Minn.), Fagron HRTBotanical TM (Fagron, Inc., St. Paul, Minn.), Letco HRT Cream (Letco Medical, Decatur, Ala.), Medisca PenDerm TM (Medisca Inc., Pittsburgh, NY), (1-dodecylazacycloheptan-2-one), (cyclopentadecalactone), (alkyl-2-(N,N-disubstituted amino)-alkanoate), (2-(n-nonyl)-1,3-dioxolane), (Professional Compounding Centers of America, Inc., Houston, Tex.), Humco Salt Stable, Medica Salt Stable, etc., lecithin palmitate isopropyl ester (LIPS), and penetration enhancers such as those shown in U.S. Pat. Nos. 3,909,816, 4,405,616, 4,801,586, 4,861,764, 4,886,783, 4,983,396, 5,118,845, and 5,196,410, each of which is hereby expressly incorporated herein by reference in its entirety.

[0054] According to reports, Contains ethoxydiglycol, water, glycerin, C12-C15 alkyl benzoate, glyceryl stearate, dimethicone, cetearyl alcohol, cetearyl glucoside, polyacrylamide, cetyl alcohol, magnesium aluminum silicate, xanthan gum, aloe barbadensis, tocopheryl acetate, apricot kernel oil, grape seed extract, wheat germ oil, vitamin A palmitate, vitamin C palmitate, ProLipo multi-emulsion liposomal system, tetrasodium EDTA, phenoxyethanol and sodium hydroxymethylglycinate.

[0055] It contains fatty acid alcohols, acids, esters, phospholipids, antioxidants, skin feel enhancers, natural moisturizers, natural preservatives, nonionic emulsifiers, anionic emulsifiers and buffers. It is a transdermal functional bioactive oil-in-water emulsion containing a phospholipid matrix and pharmacologically acceptable active substances. Gels are emollients that soften and moisturize the skin. Emollients can be used as lubricants to treat or prevent dry skin, itching, and minor skin irritations. Skin penetration topical compositions can also be formulations consisting of about 80% by weight of pluronic gel and about 20% by weight of lipid oil.

[0056] The commercially available carriers listed above represent effective skin penetration enhancers; however, those skilled in the art will recognize that topical carriers that meet the specific chemical requirements of individual drugs can be formulated to achieve maximum efficiency of topical delivery. In addition to using commercially available matrices such as these, components similar to those present in these matrices can also be used to form new matrices that can be used for therapeutic compositions herein. For example, other fatty alcohols, oils, lipids, gums, polymers, etc. can be compounded to produce therapeutic compositions within the scope of the present disclosure.

[0057] In some cases, the skin penetration enhancer can also serve as a solvent. For example, the preparation of the present disclosure can include a solvent such as water, purified water, hexylene glycol, propylene glycol, oleyl alcohol, propylene carbonate, dimethyl sulfoxide, N-methyl-pyrrolidone and mineral oil. Sometimes, the solvent also serves as a skin penetration enhancer. In other cases, the solvent cannot serve as a skin penetration enhancer.

[0058] In some embodiments, the carrier is selected from the group consisting of: transdermal tapes, transdermal patches, ointments, creams, gels, pastes, collodion compositions, foams, fast dissolving solids, and lotions. As used herein, "carrier" and "drug carrier" are used interchangeably and refer to any liquid, gel, ointment, solvent, liquid, diluent, fluid ointment base, liposome, micelle, macromicelle, etc., which is suitable for contact with a subject or its tissue without causing adverse physiological reactions and does not interact with other components of the composition in a harmful manner. A variety of carrier ingredients are known to be useful in preparing topical preparations, such as gelatin, polymers, fats and oils, lecithin, collagen, alcohol, water, etc.

[0059] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically active agent selected from the group consisting of: a pharmaceutically acceptable free base, salt, ester, ether, or solvate of an antibiotic, an anti-infective, an antifungal, a steroid, a cannabinoid, an antihistamine, an anti-inflammatory, an antiparasitic, an immunomodulator, an antisense agent, an antiviral agent, a therapeutic agent for treating hyperpigmentation and hypopigmentation conditions of the skin, an antipsoriatic, a keratolytic, a DNA synthesis inhibitor, a cytotoxic agent, an antithyroid agent, a monoclonal antibody modulator, a TNFα antagonist, an immunoglobulin, a metabolic regulator, an anti-angiogenic agent, a protease inhibitor, an anxiolytic, a kinase regulator, a cell growth regulator, an enzyme, a prostaglandin, a peptide, an analgesic, a skin moisturizer, a astringent, an exfoliant, an agent intended to protect the skin or change the appearance of the skin or increase the rate of skin healing, and combinations thereof.

[0060] In some embodiments, the pharmaceutical composition further comprises an additive selected from the group consisting of: adjuvants, gelling agents, thickeners, solvents, preservatives, pH regulators, colorants, spices, flavors, propellants, absorbents, adsorbents, antioxidants, antimicrobial preservatives and / or combinations thereof. In some embodiments, the additive is selected from the group consisting of: tocopherol acetate, aloe derivatives, silicon derivatives, chelating agents, emulsifiers, polyols, water and combinations thereof.

[0061] The gelling agent may be selected from the group consisting of hydroxyethylcellulose, hyaluronic acid, Natrasol, pectines, agar, alginic acid and its salts, guar gum, pectin, polyvinyl alcohol, polyethylene oxide, cellulose and its derivatives, propylene carbonate, polyethylene glycol, sodium hexylene glycol carboxymethyl cellulose, polyacrylates, polyoxyethylene-polyoxypropylene block copolymers, pluronics, wood wax alcohols and tyloxapol.

[0062] In some embodiments, the composition comprises 0.1 wt % to 25 wt % of sulfated glycosaminoglycans, 20 wt % to 60 wt % of a skin permeation agent, and 20 wt % to 80 wt % of a carrier and a gelling agent / thickening agent. For example, in some embodiments, the sulfated glycosaminoglycans are present in an amount of about 0.1 wt % to 1 wt %, 0.1 wt % to 5 wt %, 0.1 wt % to 10 wt %, 0.1 wt % to 15 wt %, 0.1 wt % to 20 wt %, 0.1 wt % to 25 wt %, 0.5 wt % to 1 wt %, 0.5 wt % to 5 wt %, 0.5 wt % to 10 wt %, 0.5 wt % to 15 wt %, 0.5 wt % to 20 wt %, 0.5 wt % to 25 wt %. %, 1 wt % to 5 wt %, 1 wt % to 10 wt %, 1 wt % to 15 wt %, 1 wt % to 20 wt %, 1 wt % to 25 wt %, 5 wt % to 10 wt %, 5 wt % to 15 wt %, 5 wt % to 20 wt %, 5 wt % to 25 wt %, 10 wt % to 15 wt %, 10 wt % to 20 wt %, 10 wt % to 25 wt %, 15 wt % to 20 wt %, 15 wt % to 25 wt %, 20 wt % to 25 wt %. In some embodiments, the skin penetrant is present in the formulation in an amount ranging from about 20% to 30%, 20% to 40%, 20% to 50%, 20% to 60%, 25% to 30%, 25% to 40%, 25% to 50%, 25% to 60%, 30% to 40%, 30% to 50%, 30% to 60%, 35% to 40%, 35% to 50%, 35% to 60%, 40% to 50%, 40% to 60%, 45% to 50%, 45% to 60%, 50% to 60%, 55% to 60% by weight based on the weight of the composition.In some embodiments, the carrier is present in the formulation in an amount ranging from about 20% to 30%, 20% to 40%, 20% to 50%, 20% to 60%, 20% to 70%, 20% to 80%, 30% to 40%, 30% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 40% to 50%, 40% to 60%, 40% to 70%, 40% to 80%, 50% to 60%, 50% to 70%, 50% to 80%, 60% to 70%, 60% to 80%, 70% to 80% by weight based on the weight of the composition.

[0063] In some embodiments, the composition comprises 5 wt % to 16 wt % of the sulfated glycosaminoglycan, 25 wt % to 55 wt % of the skin permeating agent, and 25 wt % to 75 wt % of the carrier. For example, in some embodiments, the sulfated glycosaminoglycan is present in an amount of about 5 wt % to 6 wt %, 5 wt % to 7 wt %, 5 wt % to 8 wt %, 5 wt % to 9 wt %, 5 wt % to 10 wt %, 5 wt % to 11 wt %, 5 wt % to 12 wt %, 5 wt % to 13 wt %, 5 wt % to 14 wt %, 5 wt % to 15 wt %, 5 wt % to 16 wt %, 7 wt % to 8 wt %, 7 wt % to 9 wt %, 7 wt % to 10 wt %, 7 wt % to 11 wt %, 7 wt % to 12 wt %, 7 wt % to 13 wt %, 7 wt % to 14 wt %, 7 wt % to 15 wt %. %, 7 wt % to 16 wt %, 9 wt % to 10 wt %, 9 wt % to 11 wt %, 9 wt % to 12 wt %, 9 wt % to 13 wt %, 9 wt % to 14 wt %, 9 wt % to 15 wt %, 9 wt % to 16 wt %, 11 wt % to 12 wt %, 11 wt % to 13 wt %, 11 wt % to 14 wt %, 11 wt % to 15 wt %, 11 wt % to 16 wt %, 13 wt % to 14 wt %, 13 wt % to 15 wt %, 13 wt % to 16 wt %, 14 wt % to 16 wt %, 14 wt % to 15 wt %, and 15 wt % to 16 wt %. In some embodiments, the skin penetrant is present in the formulation in an amount ranging from about 25% to 30%, 25% to 35%, 25% to 40%, 25% to 45%, 25% to 50%, 25% to 55%, 30% to 35%, 30% to 40%, 30% to 45%, 30% to 50%, 30% to 55%, 35% to 40%, 35% to 45%, 35% to 50%, 35% to 55%, 40% to 45%, 40% to 50%, 40% to 55%, 45% to 50%, 45% to 55%, 50% to 55% by weight based on the weight of the composition.In some embodiments, the carrier is present in an amount of about 25% to 30%, 25% to 35%, 25% to 40%, 25% to 45%, 25% to 50%, 25% to 55%, 25% to 60%, 25% to 65%, 25% to 70%, 25% to 75%, 30% to 35%, 30% to 40%, 30% to 50%, 25% to 55%, 25% to 60%, 25% to 65%, 25% to 70%, 25% to 75%, 30% to 35%, 30% to 40%, 30% to % to 45 wt%, 30 wt% to 50 wt%, 30 wt% to 55 wt%, 30 wt% to 60 wt%, 30 wt% to 65 wt%, 30 wt% to 70 wt%, 30 wt% to 75 wt%, 35 wt% to 40 wt%, 35 wt% to 45 wt%, 35 wt% to 50 wt%, 35 wt% to 55 wt%, 35 wt% to 60 wt%, 35 wt% to 65 wt%, 35 wt% to 70 wt%, 35 wt% to 75 wt%, 40% to 45% by weight, 40% to 50% by weight, 40% to 55% by weight, 40% to 60% by weight, 40% to 65% by weight, 40% to 70% by weight, 40% to 75% by weight, 45% to 50% by weight, 45% to 55% by weight, 45% to 60% by weight, 45% to 65% by weight, 45% to 70% by weight, 45% to 75% by weight, 50% to 55% by weight, 50% to 50% by weight % to 70 wt %, 50 wt % to 75 wt %, 55 wt % to 60 wt %, 55 wt % to 65 wt %, 55 wt % to 70 wt %, 55 wt % to 75 wt %, 60 wt % to 65 wt %, 60 wt % to 70 wt %, 60 wt % to 75 wt %, 65 wt % to 70 wt %, 65 wt % to 75 wt %, 70 wt % to 75 wt %.

[0064] Another aspect of the present application relates to a method for treating pain, joint stiffness, soft tissue damage, connective tissue pathology and / or muscle soreness in a subject by administering a pharmaceutical composition disclosed herein. The method comprises selecting a subject in need of treatment for pain, joint stiffness, soft tissue damage, connective tissue pathology and / or muscle soreness; administering a storage-stable pharmaceutical composition to the selected subject, the storage-stable pharmaceutical composition comprising a sulfated glycosaminoglycan having an average molecular weight in the range of 3,000 to 15,000 Daltons, a skin permeation agent, wherein the skin permeation agent promotes transdermal penetration of the sulfated glycosaminoglycan when applied to an intact skin surface, and a drug carrier for topical administration, wherein the drug carrier is mixed with the sulfated glycosaminoglycan and the skin permeation agent. The administration is performed locally at a location near where the subject experiences pain, joint stiffness, soft tissue damage, connective tissue pathology and / or muscle soreness.

[0065] Suitable pharmaceutical compositions are pharmaceutical compositions of the present disclosure as described herein.

[0066] The terms "treat", "treatment of", "treating", and the like refer to both therapeutic treatment and prophylactic or preventative measures, wherein the purpose is to prevent (partially or completely) or mitigate (e.g., to alleviate or delay the onset of) an undesirable physiological disorder, condition, or disease, or to obtain a beneficial or desired clinical result, such as partial or complete restoration or inhibition of the decline of a parameter, value, function, or result that has become or is about to become abnormal. For example, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; reduction of the extent, activity, or rate of development of a disorder, condition, or disease; stabilization of the state of a disorder, condition, or disease (i.e., not worsening); delaying the onset of a disorder, condition, or disease or slowing the progression of a disorder, condition, or disease; ameliorating a disorder, condition, or disease state; and relieving (partially or completely) a disorder, condition, or disease, whether or not it means an immediate alleviation of actual clinical symptoms, or an enhancement or amelioration of a disorder, condition, or disease. Treatment is intended to induce a clinically significant response without excessive side effects.

[0067] In some embodiments, the pain of the selected subject is treated. Pain sensations include sharp pain, dull pain, dull pain, and other forms of pain sensations. Pain is a sensation that can vary in intensity and duration and may be caused by a variety of reasons. For example, pain can be acute, for example, due to injury, illness, or trauma; can be chronic, for example, due to chronic disease or illness, inflammation, cancer, or other reasons; can be localized or diffuse; and can be low intensity, moderate intensity, or high intensity. Therefore, pain is a diverse sensation that includes, for example, acute pain, chronic pain, visceral pain, surgical pain, joint pain, bone pain, back pain, headache, neuropathic pain, phantom limb pain, and other forms and experiences of pain.

[0068] In some embodiments, the selected subject is treated for joint stiffness. Joints are formed where two bones meet. Healthy joint bones are lined with spongy cartilage, which acts as a shock absorber, and the synovial fluid secreted by the synovial membrane lining the joint cavity acts as a lubricant to prevent friction. Joint function can be measured by evaluating parameters such as range of motion and whether there is discomfort or pain during exercise. Common joint conditions include osteoarthritis, rheumatoid arthritis, gout, lupus, tendinitis, bursitis, carpal tunnel syndrome, sprains, etc.

[0069] In some embodiments, osteoarthritis pain is treated in the selected subject. Osteoarthritis (OA) is a condition that occurs due to the progressive degeneration and wear of cartilage (cushioning pads between joints), especially in large joints such as the hip and knee. This is a normal degenerative process associated with age that occurs gradually after normal wear and tear. OA begins with cartilage destruction, leading to joint pain, inflammation, and progressive stiffness.

[0070] Osteoarthritis pain can have one or both of inflammatory and non-inflammatory components. Non-inflammatory osteoarthritis pain is a specific type of non-inflammatory musculoskeletal pain, usually caused by the effects of osteoarthritis-related morphological changes, such as cartilage degradation, changes in bone to sensory neurons, and vascularization of bone remodeling. It is usually characterized as a deep, dull pain sensation that worsens with activity. It is usually intermittent and usually mild, but may be persistent and severe. Bone crepitus is usually present in the affected joints. Inflammatory osteoarthritis pain is usually caused by synovial inflammation following cartilage and bone pathological processes, involving tissue damage and macrophage infiltration (causing edema) associated with classical immune system responses. When the pain relief composition is applied to the subject's knee, hip, elbow, shoulder, wrist, ankle, back, finger joints, or other joints that exhibit pain and stiffness due to osteoarthritis, the pharmaceutical composition of the present disclosure is particularly suitable for relieving joint pain associated with OA.

[0071] In some embodiments, a soft tissue injury is treated in a selected subject. Soft tissue injuries may be caused by sports-induced injuries (such as sprains, tennis elbow, or runner's knee) and refer to chronic and acute injuries of soft tissues (including muscles, ligaments, tendons, tendon sheaths, and cartilage). Ligaments are bands of tissue that connect bones. Tendons are bands of tissue that connect muscles and bones. Tendon sheaths are tissues that surround and lubricate tendons. Injuries to any of these soft tissues may cause inflammation, pain, and stiffness.

[0072] In some embodiments, the selected subject is treated for muscle soreness.

[0073] In some embodiments, the connective tissue pathology of the selected subject is treated. Connective tissue is composed of two proteins (collagen and elastin). Collagen is present in tendons, ligaments, skin, cornea, cartilage, bones and blood vessels; elastin is the main component of ligaments and skin. When these connective tissues are inflamed, connective tissue pathology will result. There are more than 200 pathologies that affect connective tissue. They can be hereditary, caused by environmental factors, or in the most common cases, the cause of the pathology is unknown. Connective tissue diseases include, but are not limited to, rheumatoid arthritis, scleroderma, granulomatosis with polyangiitis, Churg-Strauss syndrome, Ehlers-Danlos syndrome, lupus, microscopic polyangiitis, polymyositis / dermatomyositis, Marfan syndrome, mixed connective tissue disease, undifferentiated connective tissue disease. The parts of the body that may be affected include bones, joints, skin, heart and blood vessels, and lungs, and the symptoms may vary depending on the affected area.

[0074] "Subjects" (or "patients") treated using the methods and compositions disclosed herein include human subjects and animal subjects for veterinary purposes (e.g., dogs, cats, horses, monkeys, etc.). In some embodiments, the selected subject is a mammal. In some embodiments, the selected subject is a human.

[0075] Another aspect of the present application relates to a storage-stable sulfated glycosaminoglycan having an average molecular weight in the range of 3,000 to 15,000 Daltons.The storage-stable sulfated glycosaminoglycan is a storage-stable sulfated glycosaminoglycan of the present disclosure as described herein.

[0076] Another aspect of the present application relates to a storage-stable pharmaceutical composition comprising a sulfated glycosaminoglycan having an average molecular weight in the range of 3,000 to 15,000 Daltons and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is mixed with the sulfated glycosaminoglycan.

[0077] Suitable pharmaceutical compositions are pharmaceutical compositions of the present disclosure as described herein.

[0078] In some embodiments, the pharmaceutical carrier is an injectable liquid, solution or emulsion capable of dissolving the purified sulfated glycosaminoglycan.

[0079] In some embodiments, the composition comprises 0.1 wt % to 25 wt % of the sulfated glycosaminoglycan and 75 wt % to 99 wt % of the carrier. For example, in some embodiments, the sulfated glycosaminoglycan is present in an amount of about 0.1 wt % to 1 wt %, 0.1 wt % to 5 wt %, 0.1 wt % to 10 wt %, 0.1 wt % to 15 wt %, 0.1 wt % to 20 wt %, 0.1 wt % to 25 wt %, 0.5 wt % to 1 wt %, 0.5 wt % to 5 wt %, 0.5 wt % to 10 wt %, 0.5 wt % to 15 wt %, 0.5 wt % to 20 wt %, 0.5 wt % to 25 wt %. %, 1 wt % to 5 wt %, 1 wt % to 10 wt %, 1 wt % to 15 wt %, 1 wt % to 20 wt %, 1 wt % to 25 wt %, 5 wt % to 10 wt %, 5 wt % to 15 wt %, 5 wt % to 20 wt %, 5 wt % to 25 wt %, 10 wt % to 15 wt %, 10 wt % to 20 wt %, 10 wt % to 25 wt %, 15 wt % to 20 wt %, 15 wt % to 25 wt %, 20 wt % to 25 wt %. In some embodiments, the carrier is present in the formulation in an amount ranging from about 75% to 80%, 75% to 85%, 75% to 90%, 75% to 95%, 75% to 99%, 80% to 85%, 80% to 90%, 80% to 95%, 80% to 99%, 85% to 90%, 85% to 95%, 85% to 99%, 90% to 95%, 90% to 99%, or 95% to 99% by weight based on the weight of the composition.

[0080] In some embodiments, the composition comprises 5 wt % to 16 wt % of the sulfated glycosaminoglycan and 84 wt % to 95 wt % of the carrier. For example, in some embodiments, the sulfated glycosaminoglycan is present in an amount of about 5 wt % to 6 wt %, 5 wt % to 7 wt %, 5 wt % to 8 wt %, 5 wt % to 9 wt %, 5 wt % to 10 wt %, 5 wt % to 11 wt %, 5 wt % to 12 wt %, 5 wt % to 13 wt %, 5 wt % to 14 wt %, 5 wt % to 15 wt %, 5 wt % to 16 wt %, 7 wt % to 8 wt %, 7 wt % to 9 wt %, 7 wt % to 10 wt %, 7 wt % to 11 wt %, 7 wt % to 12 wt %, 7 wt % to 13 wt %, 7 wt % to 14 wt %, 7 wt % to 15 wt %. %, 7 wt % to 16 wt %, 9 wt % to 10 wt %, 9 wt % to 11 wt %, 9 wt % to 12 wt %, 9 wt % to 13 wt %, 9 wt % to 14 wt %, 9 wt % to 15 wt %, 9 wt % to 16 wt %, 11 wt % to 12 wt %, 11 wt % to 13 wt %, 11 wt % to 14 wt %, 11 wt % to 15 wt %, 11 wt % to 16 wt %, 13 wt % to 14 wt %, 13 wt % to 15 wt %, 13 wt % to 16 wt %, 14 wt % to 16 wt %, 14 wt % to 15 wt %, and 15 wt % to 16 wt %. In some embodiments, the carrier is present in the formulation in an amount ranging from about 84% to 90%, 84% to 91%, 84% to 92%, 84% to 93%, 84% to 94%, 84% to 95%, 86% to 90%, 86% to 91%, 86% to 92%, 86% to 93%, 86% to 94%, 86% to 95%, 88% to 91%, 88% to 92%, 88% to 93%, 88% to 94%, 88% to 95%, 90% to 91%, 90% to 92%, 90% to 93%, 90% to 94%, or 90% to 95% by weight based on the weight of the composition.

[0081] Another aspect of the present application relates to a method of treating a subject to obtain a medically observable improvement. The method comprises selecting a subject in need of treatment for a medically diagnosable condition, and administering a storage-stable pharmaceutical composition to the selected subject to facilitate treatment, the storage-stable pharmaceutical composition comprising a sulfated glycosaminoglycan having an average molecular weight in the range of 3,000 to 15,000 Daltons and a pharmaceutical carrier, wherein the pharmaceutical carrier is mixed with the sulfated glycosaminoglycan.

[0082] Suitable pharmaceutical compositions are pharmaceutical compositions of the present disclosure as described herein.

[0083] In some embodiments, the subject is treated for pain, joint stiffness, soft tissue injury, connective tissue condition, and / or muscle soreness.

[0084] Suitable subjects are subjects of the present disclosure as described herein.

[0085] The pain, joint stiffness, soft tissue injury, connective tissue condition and / or muscle aches are pain, joint stiffness, soft tissue injury, connective tissue condition and / or muscle aches of the present disclosure as described herein.

[0086] In some embodiments, administration is ear administration, oral administration, ocular administration, nasal administration, rectal administration, urethral administration, vaginal administration, parenteral administration (including subcutaneous administration, intradermal administration, intramuscular administration, intravenous administration and intraarticular administration), rectal administration and topical administration (including dermal administration, buccal administration, sublingual administration and intraocular administration) and / or a combination thereof. The most suitable route may depend on the condition and symptom of the recipient.

[0087] Treatment can continue as long as desired or as short as possible. The composition can be administered in a regimen of, for example, one to four times a day or more. A suitable treatment period can be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about 1 year, or unlimited. When the desired result (e.g., partial or complete alleviation of symptoms) is achieved, the treatment period can terminate.

[0088] In some embodiments, the storage-stable pharmaceutical composition is in the form of an aerosol, a chewable stick, a bead, a capsule, a honeycomb tablet, a chewable gel, a cloth, a concentrate, a cream, a crystal, a disk, an irrigator, a dressing, a drug eluting contact lens, an elixir, an emulsion, an enema, an extract, an extended release fiber, a film, a gas, a gel, a pellet, a granule, a chewing gum, an implant, an inhaler, an injection, an insert, an intrauterine device, a syringe ... An IUD, a rinse, a jelly, a kit, a rub, a lip balm, a liquid, a lotion, a lozenge, a mouthwash, an oil, an ointment, a paste, a pastille, a patch, a pellet, a pill, a plaster, a poultice, a powder, a ring, a rinse, a salves, a shampoo, a soap, a solution, a sponge, a spray, a stick, a strip, a suppository, a suspension, a swab, a syrup, a tablet, a tampon, a tape, a tincture, a lozenge, a wafer, and / or a combination thereof.

[0089] The preparation can be conveniently presented in unit dosage form and can be prepared by any method known in the pharmaceutical field. Such methods include the step of combining the compound of the present application or its pharmaceutically acceptable salt or solvate ("active ingredient") with a carrier (constituting one or more accessory ingredients). In general, the preparation is prepared in the following manner: the active ingredient is uniformly and closely combined with a liquid carrier or a finely divided solid carrier or both, and then the product is shaped into a desired preparation as required.

[0090] Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

[0091] Tablets can be prepared optionally with one or more auxiliary ingredients by compression or molding. Compressed tablets can be prepared in the following manner: the active ingredient in a free-flowing form (such as a powder or granules) is compressed in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, lubricant, surfactant or dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or scored, and can be formulated to provide a sustained, delayed or controlled release of the active ingredient therein.

[0092] The pharmaceutical composition may contain a "pharmaceutically acceptable inert carrier," and the expression is intended to include one or more inert excipients including, for example, but not limited to, starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrants, and the like. Tablet dosages of the disclosed compositions may be coated, if desired, by standard aqueous or nonaqueous techniques. "Pharmaceutically acceptable carrier" also encompasses controlled release devices.

[0093] The pharmaceutical composition may optionally include other therapeutic ingredients, anti-caking agents, preservatives, sweeteners, colorants, flavors, desiccants, plasticizers, dyes, etc. Any such optional ingredients must be compatible with the compounds of the present application to ensure the stability of the formulation. The composition may contain other additives as needed, including, for example, lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, inositol, etc. and their hydrates, and amino acids, for example, alanine, glycine and betaine, and peptides and proteins, for example, albumin.

[0094] Examples of excipients used as pharmaceutically acceptable carriers and pharmaceutically acceptable inert carriers as well as the aforementioned additional ingredients include, but are not limited to, binders, fillers, disintegrants, lubricants, antimicrobial agents and coating agents.

[0095] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. Except for the subject composition, the liquid dosage form may include inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents, and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuran alcohol, polyethylene glycol, and fatty acid esters of sorbitan, cyclodextrins, and mixtures thereof.

[0096] Suspensions, in addition to the subject compositions, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0097] Formulations for rectal or vaginal administration may be presented as suppositories, which may be prepared by mixing the subject composition with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylates, and which are solid at room temperature but liquid at body temperature and therefore will melt in the body cavity and release the active agent.

[0098] Pharmaceutical compositions suitable for parenteral administration include combinations of the subject compositions with one or more of the following: pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, sterile powders to be reconstituted into sterile injectable solutions or dispersions prior to use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0099] Examples of suitable aqueous and non-aqueous carriers that can be employed in pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate) and cyclodextrins. Appropriate fluidity can be maintained, for example, by using coating materials (such as lecithin), by maintaining the desired particle size in the case of dispersions, and by using surfactants.

[0100] Dosage forms for transdermal administration of the subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be necessary.

[0101] In addition to the subject composition, the ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0102] In addition to the subject composition, powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may additionally contain conventional propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (such as butane or propane).

[0103] Alternatively, compositions and compounds can be administered by aerosol. This is accomplished by preparing aqueous aerosols, liposome preparations or solid particles containing the compound. Non-aqueous (e.g., fluorocarbon propellants) suspensions can be used. Sonic wave sprayers can be used because they minimize the exposure of the reagent to shear, which may cause degradation of the compound contained in the subject composition. Typically, aqueous aerosols are prepared by preparing an aqueous solution or suspension of the subject composition with conventional pharmaceutically acceptable carriers and stabilizers. The carrier and stabilizer are different due to the requirements of the specific subject composition, but generally include nonionic surfactants (tweens, pluronics or polyethylene glycols), harmless proteins (such as serum albumin), sorbitan esters, oleic acid, lecithin, amino acids (such as glycine), buffers, salts, sugars or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0104] The dosage range for adults may vary. The exact amount of compound administered to a patient will be the responsibility of the attending physician. However, the dosage employed will depend on a number of factors, including the age and sex of the patient, the exact condition being treated and its severity. Dosages for animals (including non-human mammals) also need to be adopted in conjunction with similar considerations.

[0105] A daily dosage unit (e.g., an oral dosage unit) can contain, for example, 1 to 30 mg, 1 to 40 mg, 1 to 100 mg, 1 to 300 mg, 1 to 500 mg, 1 to 1,000 mg, 1 to 1,500 mg, 1 to 2,000 mg, 1 to 2,500 mg, 1 to 3,000 mg, 1 to 3,500 mg, 1 to 4,000 mg, 1 to 4,500 mg, 1 to 5,000 mg, 100 to 1,000 mg, 100 to 1,500 mg, 100 to 2,000 mg, 100 to 2,500 mg, 100 to 3,000 mg, 100 to 3,500 mg, 100 to 4,000 mg, 100 to 4,500 mg, 100 to 5,000 mg, 500 to 1,000 mg, 500 to 1,500 mg, 500 to 2,000 mg, 500 to 2,500 mg, 500 to 3,000 mg, 500 to 3,500 mg, 500 to 4,000 mg, 500 to 4,5 00mg, 500 to 5,000mg, 1,000 to 1,500mg, 1,000 to 2,000mg, 1,000 to 2,500mg, 1,000 to 3,000mg, 1,000 to 3,500mg, 1,000 to 4,000mg, 1,000 to 4,500mg, 1,000 to 5,000mg, 1,500 to 2,000mg, 1,500 to 2,500mg, 1,500 to 3,000mg, 1, 500 to 3,500mg, 1,500 to 4,000mg, 1,500 to 4,500mg, 1,500 to 5,000mg, 2,000 to 2,500mg, 2,000 to 3,000mg, 2,000 to 3,500mg, 2,000 to 4,000mg, 2,000 to 4,500mg, 2,000 to 5,000mg, 2,500 to 3,000mg, 2,500 to 3,500mg, 2,500 to 4,000mg.0 mg, 2,500 to 4,500 mg, 2,500 to 5,000 mg, 3,000 to 3,500 mg, 3,000 to 4,000 mg, 3,000 to 4,500 mg, 3,000 to 5,000 mg, 3,500 to 4,000 mg, 3,500 to 4,500 mg, 3,500 to 5,000 mg, 4,000 to 4,500 mg, 4,000 to 5,000 mg, 4,500 to 5,000 mg, 2 to 500 mg, 3 to 100 mg, 5 to 20 mg, 5 to 100 mg (e.g., 1 mg, 2 mg, 3 , 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 1,000mg, 1,500mg, 2,000mg, 2,500mg, 3,000mg, 3,500mg, 4,000mg, 4,500mg, 5,000mg) of a compound described herein.

[0106] Additional information regarding pharmaceutical compositions and their formulations is described in Remington: The Science and Practice of Pharmacy, 20th Edition, 2000, which is hereby incorporated by reference in its entirety.

[0107] The present disclosure includes pharmaceutical or dermatological compositions containing storage-stable purified PSGAG for administration to humans or mammals in therapeutic or subtherapeutic doses in a suitable delivery system, wherein administration of the dose produces a physiological or therapeutic response. These compositions include any of the medicaments of the categories described herein, including storage-stable medicaments prepared as described herein, and an acceptable carrier. The carrier is preferably in the form of a lotion, cream, gel, emulsion, ointment, solution, suspension, foam or paste. The composition can be applied to an area of ​​the skin by spraying or atomizing the solution or suspension onto the area of ​​the skin, or applying the lotion, cream, gel, emulsion, ointment, foam or paste onto the area of ​​the skin.

[0108] Unless the context indicates otherwise, preferences and options for a given aspect, feature, embodiment or parameter should be considered to be disclosed in conjunction with any and all preferences and options for all other aspects, features, embodiments and parameters described in the present application.

[0109] Another aspect of the present application relates to a method for producing storage-stable purified sulfated glycosaminoglycans. The method includes providing a sulfated glycosaminoglycan starting material containing a component less than 1,000 Daltons, subjecting the sulfated glycosaminoglycan starting material to tangential flow filtration under conditions that are effective to reduce the amount of the component less than 1,000 Daltons in the starting material to produce a purified sulfated glycosaminoglycan having an average molecular weight in the range of 3,000 to 15,000 Daltons, wherein the purified sulfated glycosaminoglycans include no more than 10% by weight of carbohydrates or other contaminants having a molecular weight less than 1,000 Daltons, and recovering the purified sulfated glycosaminoglycans.

[0110] Lower molecular weight byproducts and impurities can be removed by ultrafiltration or diafiltration. These lower molecular weight impurities and byproducts are known to cause discoloration of formulations containing the active ingredient and to result in a shortened shelf life and reduced commercial stability of formulations containing sulfated glycosaminoglycans that are prepared without this addition process. In addition, this treatment also allows the preparation of specific molecular ranges of these sulfated fragments obtained from naturally occurring glycosaminoglycans.

[0111] In some embodiments, tangential flow filtration is performed by ultrafiltration. Ultrafiltration involves separating components based on molecular weight and size to separate the molecular weight component of interest. External pressure pushes the liquid through a semipermeable membrane that is able to remove low molecular weight solutes. Ultrafiltration membranes are only suitable for small molecules and are defined by the molecular weight cutoff of the membrane used. Suspended solids and high molecular weight solutes remain in the retentate, while water and low molecular weight solutes pass through the membrane into the filtrate. This separation process is commonly used to purify and concentrate large molecules (10 3 -10 6 Da) solution.

[0112] In some embodiments, tangential flow filtration is performed by diafiltration. Diafiltration is a dilution process that involves using a micromolecular permeability filter to remove or separate components of a solution according to molecular size to obtain a desired molecular weight range. The term "diafiltration" means a combination of "dilution" and "filtration" and involves using a tangential flow filtration system. A buffer solution or demineralized water is added to the concentrate or retentate to replenish the infiltration water lost during the filtration, so that the concentration of the repellent compound (i.e., the target product) can be kept constant while diluting unwanted small molecular weight compounds so that they are gradually "washed out" by the filtration cycle.

[0113] Diafiltration is usually carried out using a batch of feed water, the permeate is recycled back to the feed tank for further processing, and a buffer solution or demineralized water is added to the feed tank as a diluent. The diluent can be added in a continuous or discontinuous manner. The advantage of continuous diafiltration is the ability to maintain a stable concentration of the target product in the retentate, as concentration changes may cause molecular interactions, resulting in product losses. In this continuous diafiltration mode, the diluent is added at the same flow rate as the permeate, and when the permeate volume produced reaches the same as the initial feed volume, one diafiltration volume or one diafiltration cycle is performed. It is important to choose a membrane with an appropriate molecular weight cutoff (MWCO). The MWCO of a membrane is considered to be the molecular weight (MW) of a specific polymer compound that has a 90% rejection rate on this membrane.

[0114] In some embodiments, tangential flow filtration is performed by a size exclusion membrane or another porous membrane. The porous membrane is composed of a solid matrix with a defined hole of a specific size, which can be used to separate solutes or particles by size. The separation of solutes by porous membranes depends mainly on the size of the molecule and the membrane pore size. When the size of the target solute or particle is relatively larger than the size of the membrane pore, high selectivity can be obtained. Porous membranes with an average pore size greater than 50nm are classified as macroporous membranes, while porous membranes with an average pore size between 2nm and 0.2nm are classified as microporous membranes. Membranes with a pore size less than 0.2nm are classified as non-porous membranes or dense membranes.

[0115] The filtration process is capable of producing a purified PSGAG as described herein above, which contains less than 5,000 ppm, and preferably less than 1,000 ppm, of acetic acid when manufactured. The purified PSGAG produced is stable when stored at room temperature in a suitable primary or secondary container, or a combination thereof, wherein the container is composed of plastic, paper, cardboard or metal. In addition, the storage container can be treated to remove or reduce residual air or oxygen.

[0116] In some embodiments, the purified sulfated glycosaminoglycans include no more than 1 wt%, no more than 2 wt%, no more than 3 wt%, no more than 4 wt%, no more than 5 wt%, no more than 6 wt%, no more than 7 wt%, no more than 8 wt%, or no more than 9 wt% of carbohydrates having a molecular weight less than 1,000 Daltons or other contaminants.

[0117] In some embodiments, the purified sulfated glycosaminoglycans include no more than 20% by weight of carbohydrates or other contaminants having a molecular weight of less than 3,000 Daltons. In other embodiments, the purified sulfated glycosaminoglycans include no more than 1% by weight, no more than 2% by weight, no more than 3% by weight, no more than 4% by weight, no more than 5% by weight, no more than 6% by weight, no more than 7% by weight, no more than 8% by weight, or no more than 9% by weight, no more than 10% by weight, no more than 11% by weight, no more than 12% by weight, no more than 13% by weight, no more than 14% by weight, no more than 15% by weight, no more than 16% by weight, no more than 17% by weight, no more than 18% by weight, or no more than 19% by weight of carbohydrates or other contaminants having a molecular weight of less than 3,000 Daltons.

[0118] In some embodiments, the purified sulfated glycosaminoglycans include no more than 25% by weight of carbohydrates or other contaminants having a molecular weight of less than 5,000 Daltons. In other embodiments, the purified sulfated glycosaminoglycans include no more than 1% by weight, no more than 2% by weight, no more than 3% by weight, no more than 4% by weight, no more than 5% by weight, no more than 6% by weight, no more than 7% by weight, no more than 8% by weight, or no more than 9% by weight, no more than 10% by weight, no more than 11% by weight, no more than 12% by weight, no more than 13% by weight, no more than 14% by weight, no more than 15% by weight, no more than 16% by weight, no more than 17% by weight, no more than 18% by weight, or no more than 19% by weight, no more than 21% by weight, no more than 22% by weight, no more than 23% by weight, or no more than 24% by weight of carbohydrates or other contaminants having a molecular weight of less than 5,000 Daltons.

[0119] In some embodiments, the purified sulfated glycosaminoglycans contain less than 5,000 ppm of acetic acid. In some embodiments, the purified sulfated glycosaminoglycans contain less than 500 ppm, less than 1,000 ppm, less than 1,500 ppm, less than 2,000 ppm, less than 2,500 ppm, less than 3,000 ppm, less than 3,500 ppm, less than 4,000 ppm, or less than 4,500 ppm of acetic acid. In other embodiments, the purified sulfated glycosaminoglycans contain less than 5,000 ppm of acetic acid after storage at room temperature for at least 12 months after the start of storage. In some embodiments, the purified sulfated glycosaminoglycans contain less than 500 ppm, less than 1,000 ppm, less than 1,500 ppm, less than 2,000 ppm, less than 2,500 ppm, less than 3,000 ppm, less than 3,500 ppm, less than 4,000 ppm, or less than 4,500 ppm of acetic acid after storage at room temperature for at least 12 months after the start of storage. In some embodiments, the purified sulfated glycosaminoglycans contain less than 5,000 ppm acetic acid for at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months, or at least 24 months after the start of storage.

[0120] In some embodiments, the purified sulfated glycosaminoglycans remain white or off-white after being stored at room temperature for at least 6 months after the start of storage. In some embodiments, the purified sulfated glycosaminoglycans remain white or off-white after being stored at room temperature for at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months, or at least 24 months after being stored at room temperature.

[0121] In some embodiments, the process further comprises storing the purified sulfated glycosaminoglycans at room temperature for at least 12 months. In some embodiments, the process comprises storing the purified sulfated glycosaminoglycans at room temperature for at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months or at least 24 months. In some embodiments, the purified sulfated glycosaminoglycans contain less than 5,000 ppm of acetic acid within at least 12 months of storage at room temperature. In some embodiments, the purified sulfated glycosaminoglycans contain less than 500 ppm, less than 1,000 ppm, less than 1,500 ppm, less than 2,000 ppm, less than 2,500 ppm, less than 3,000 ppm, less than 3,500 ppm, less than 4,000 ppm or less than 4,500 ppm of acetic acid within at least 12 months of storage at room temperature.

[0122] In some embodiments, the purified sulfated glycosaminoglycans are stored in containers composed of plastic, paper, cardboard or metal. In some embodiments, the container is treated before, during or after said storage to remove residual oxygen or air.

[0123] The above disclosure is general. It will be described in more detail below by the following examples. The description of the embodiments is for illustrative purposes only and is not intended to limit the scope of the present application. Depending on the suggestion or convenience of the situation, it is contemplated to change the form or replace equivalents. Although specific terms have been adopted herein, these terms are only used for descriptive purposes and are not intended to be used for limiting purposes.

[0124] Example

[0125] The following examples are provided to illustrate various aspects of the present application but are not intended to limit the scope of the claimed application.

[0126] Example 1 - Production of polysulfated glycosaminoglycans

[0127] GAGs are prepared from tracheal cartilage extracted from domesticated animals. Alternatively, GAGs can be readily obtained from a number of commercial sources.

[0128] Step 1. Dissolving GAGs: To dissolve GAGs, about 5 Kg of glycosaminoglycan chondroitin sulfate (purchased from Bioiberica) was dissolved in 25 L of formamide at 60° C. in reactor 01. The resulting solution was stirred for about 3 hours.

[0129] Step 2. Sulfonation reaction: To sulfonate glycosaminoglycans, about 7.5 L of chlorosulfonic acid dissolved in 15 L of formamide was premixed in reactor 02 and then slowly added to the GAG ​​solution under stirring while keeping the temperature below 30° C. The mixture was then stirred in reactor 01 at 30° C. for 16 hours.

[0130] Step 3. Termination of the sulfonation reaction: To terminate the sulfonation reaction, the reaction liquid was poured into 4 times the volume of ethanol in a plastic bucket under stirring, wherein a white precipitate was produced.

[0131] Step 4. Dissolve the precipitate with water: After removing the supernatant, the precipitate from step 3 was transferred to reactor 01 and then dissolved in 50 L of purified water. The temperature was maintained below 20°C.

[0132] Step 5. Neutralization: To neutralize the solution from step 4, it was immediately treated with 20% NaOH solution in reactor 01, and the pH value of the resulting solution was 9.0.

[0133] Steps 6 to 12. Repeat fractional precipitation: Transfer the solution in step 5 to a plastic bucket. Add about four times the volume of ethanol to the solution under stirring, and then let the solution stand for 12 hours. Remove the supernatant and then dissolve the precipitate in 50L of purified water. Add four times the volume of ethanol to the solution under stirring, and then let the mixture stand for 12 hours. Repeat this process three times. The precipitate obtained in step 12 is the intermediate. Take out a sample for analysis and measure the ratio of sulfate to carboxylate and the molecular weight. The ratio of sulfate to carboxylate should be between 3 and 4. The average molecular weight should be between 6,500Da and 12,000Da.

[0134] Step 13. Dissolve the precipitate with water; dissolve the precipitate in 50 L of purified water.

[0135] Step 14. Decolorization: To decolorize the solution, adjust the pH to 10 with 20% NaOH solution, then add hydrogen peroxide to produce a solution with a final hydrogen peroxide concentration of about 0.5%. Then let the mixture stand at room temperature for three hours. Remove a sample and check the color. If the color of the sample does not meet the specification (colorless to light yellow), repeat the bleaching step.

[0136] Step 15. Removal of excess formamide: To remove formamide, the solution from step 14 was transferred to reactor 01, the pH value was adjusted to 10 with 20% sodium carbonate solution, and then the solution was heated to 60° C. in reactor 01 with stirring for about 6 hours.

[0137] Steps 16 to 18. Repeat fractional precipitation: Transfer the solution in step 15 to a plastic bucket. Add about 4 volumes of ethanol to the solution while stirring, and then let the mixture stand for 12 hours. Repeat this process two more times.

[0138] Step 19. Dissolve the precipitate with water: remove the supernatant in the plastic bucket, and dissolve the precipitate in 50 L of purified water.

[0139] Step 20. Microfiltration: Adjust the pH of the solution to 7.0 with 20% NaOH solution and then filter through a 0.45 micron membrane using filter 01. Collect the filtrate into a plastic bucket.

[0140] Step 21. Precipitate with ethanol: Add about 3 volumes of ethanol to the filtrate, and allow the filtrate to stand in a plastic bucket for about 12 hours.

[0141] Step 22. Dehydration and drying: To dehydrate the precipitate, collect it and wash it several times with absolute ethanol. Then dry the precipitate under vacuum at 60°C for 12 to 24 hours. Take a sample (Intermediate 2) for laboratory testing as described in Example 2. If the loss on drying is less than 8%, the precipitate is blended and sieved with a grinder mixer (100 mesh screen).

[0142] Step 23. Packaging: The product is packaged in double-layer polyethylene sterile bags under sterile conditions and then placed in airtight aluminum containers.

[0143] Example 2 - Production of storage-stable purified polysulfated glycosaminoglycans.

[0144] Formamide was added to a suitable reaction vessel and heated to 60°C. Chondroitin sulfate (1.00 kg) was added at this time. The solution was then cooled to 10°C and chlorosulfonic acid (2.63 kg) was added. After the addition was complete, the reaction was heated at 40°C for approximately 20 hours.

[0145] After this, the reactant was cooled and its pH was adjusted to 3 by adding 50% aqueous sodium hydroxide solution. The resulting material was then poured into ethanol and the mixture was stirred rapidly and then filtered. The filter cake was washed with ethanol and dissolved in water. The pH was adjusted to 8.5 with another 50% aqueous sodium hydroxide solution. Hydrogen peroxide was then added and the mixture was stirred for another 18 hours. The reactant was diluted with water and the remaining hydrogen peroxide was neutralized by adding sodium sulfite in batches. The mixture was then filtered through diatomaceous earth and the filter cake was washed twice with water.

[0146] The resulting filtrate was added to the retentate tank and diluted with fresh deionized water. The solution was purified by tangential flow filtration (TFF) to remove ionic salts and low molecular weight substances. The filtration system consisted of a 0.5 m2 The surface area of ​​the Pall Centrasette II 1K Da cut-off box is composed of a Pall Centrasette 5TFF box clip. A Masterflex I / P peristaltic pump running at 1-3L / min is used to establish a circulating flow for the filtration process. The transmembrane pressure is maintained between 20-40psi, and the filtrate containing salts and low molecular weight compounds is collected at a rate of approximately 15-30min / L. During the filtration process, fresh deionized water is added to the retentate tank at a rate approximately equal to the filtrate collection to maintain a fixed volume. Once the retentate is free of low molecular weight impurities, the resulting solution is evaporated to a volume of 5L at 55°C. Sodium chloride is added to the solution and the mixture is stirred until uniform. Methanol is then added, followed by activated carbon. After stirring for 30 minutes, the mixture is filtered and the pH value of the filtrate is adjusted to 6-7 with 50% sodium hydroxide.

[0147] Additional methanol was then added to the solution in a steady stream and the mixture was heated to 60-65° C. The resulting white suspension was filtered after cooling to 20-25° C. The filter cake was washed with methanol and dried under vacuum to give 700-800 g of PSGAG.

[0148] Example 3 - Characterization of PSGAG compounds

[0149] The unique polyanionic properties of polysulfated glycosaminoglycans (PSGAG) were determined by electrophoresis. A 70 mm cellulose acetate (CA) membrane saturated with 0.2 N hydrochloric acid was suspended through the contact point between the cathode and anode of the electrophoresis chamber. A test solution containing about 1 microgram of PSGAG was applied to the cathode end of the strip. A current of about 65 mA was applied for 65 minutes. The CA membrane was removed from the tank and then stained with a 0.1% toluidine blue solution for 5 minutes. The CA membrane was rinsed with enough water to remove excess toluidine blue. On the strip, PSGAG appeared only as a purple-blue spot, about 3 cm from its starting point.

[0150] The cathode is the negative end of the electrophoresis chamber. Anionic compounds such as PSGAG will migrate toward the anode of the chamber (i.e., its positive end) under an applied current. The polyanionic properties of PSGAG were compared with hyaluronic acid, chondroitin sulfate A, chondroitin sulfate B (dermatan sulfate), chondroitin sulfate C, heparin sulfate, and keratan sulfate using electrophoresis. The results are as follows:

[0151] substance Distance(CM) PSGAG 3.1±0.3(n＝12) Hyaluronic acid 1.1±0.1(n＝2) Chondroitin sulfate A 2.1±0.0(n＝2) Dermatan sulfate 1.7±0.0(n＝2) Chondroitin Sulfate C 2.0±0.3(n＝2) Heparin sulfate 2.3±0.0(n＝2) Keratin sulfate 2.5±0.1(n＝2)

[0152] The results showed that the anionic nature of PSGAG is significantly greater than that of hyaluronic acid, chondroitin sulfate A, dermatan sulfate, chondroitin sulfate C, heparan sulfate, and keratan sulfate. The strong negative charge of PSGAG enables it to bind to the positively charged parts of proteins.

[0153] The molecular weight distribution of PSGAG is determined by high pressure gel permeation chromatography (HP-GPC). The HP-GPC system uses an efficient gel filtration column filled with a bonded diol-coated silica gel with a particle size of 7 microns. The molecular weight range of the column is between 100 and 50,000 daltons. The mobile phase consisting of a dilute sodium sulfate solution (0.05M) is pumped through the column at a constant flow rate, pressure and temperature. The PSGAG sample is diluted to 5 mg / mL using the mobile phase, and then a portion of the resulting solution (10 g / L) is sampled into the HP-GPC system.

[0154] As each separated species is eluted, the refractive index detector measures the peak response of that species, which is proportional to the concentration of the species. A computerized GPC software program interprets the data and calculates the relative weight average molecular weight (Mw), number average molecular weight (Mn), and polydispersity index (Mw / Mn) of the sample. These values ​​are based on commercially available molecular weight standards ranging from 1,000 to 47,300 Daltons, which are used to calibrate the system immediately prior to sample analysis.

[0155] Example 4 - Preparation of Formulations for Drug Products

[0156] As a preliminary step in preparing the pain relief composition of the present disclosure, each of the components is subjected to a subjective quality control evaluation in which color, odor, and weight are evaluated. These results are then compared to previous samples of the same component to ensure that each sample is of the same quality as the previously used component.

[0157] Each of the components is then filtered individually to remove any particulate matter contained therein. Filtering is preferably accomplished by passing the components through a 2-stage filter.

[0158] Method for preparing 100g 15% PSGAG product:

[0159] Step 1: Weigh out 15 g of active ingredient (PSGAG).

[0160] Step 2: Weigh out 15g of HRT Supreme or HRT Heavy Cream or Gel Base.

[0161] Step 3: Measure out 50 mL of USP water or equivalent purified water.

[0162] Step 4: Add water to the beaker and slowly heat from room temperature to 72°F.

[0163] Step 5: Add water to the appropriately sized unguator tank.

[0164] Step 6: Add PSGAG to the unguator jar, cover with lid, and mix for 15 min at mixer setting (approximately 3000 rpm).

[0165] Step 7: After mixing is complete, open and confirm that the PSGAG is completely dissolved in the solution. If the water is not hot enough, repeat the mixing process until dissolved. The color of the solution will be light amber to clear.

[0166] Step 8: Add 15 g of a gelling agent / thickener, such as Fagron (Fagron, Inc., St. Paul, Minn.) was added to the solution and then mixed for an additional five minutes using the same mixer settings. The concentrate was inspected and should be smooth and viscous in nature, similar to a thick emulsion.

[0167] Step 9: Add 15 g of cream base (step 2) to the concentrate and repeat mixing once more using the gel setting for 15 minutes.

[0168] Step 10: After mixing is complete, the cream should be white in color and smooth to the touch. There should be no particles or grains in the cream at this point. More gelling agent may be added and mixed at this point until a cream consistency is achieved, but do not exceed 10% of the total weight / volume to avoid dilution.

[0169] Example 5 - 10% PSGAG with 0.5% Lidocaine

[0170] 10 grams of PSGAG powder was dissolved in water according to the procedure in Example 4. To this solution, 0.5 grams of lidocaine hydrochloride was added and mixed until completely dissolved to obtain an aqueous solution with a pH of 6.17. To this solution, a gelling agent and a cream base were added to obtain 100 grams of 10% PSGAG containing 0.5% lidocaine hydrochloride.

[0171] Example 6 - 10% PSGAG with 10% Methyl Salicylate

[0172] 10 grams of PSGAG powder was dissolved in water following the procedure in Example 4. 10 grams of methyl salicylate was added to the solution and mixed until completely dissolved to give an aqueous solution with a pH of 6.35. A gelling agent and a cream base were added to the solution to give 100 grams of 10% PSGAG containing 10% methyl salicylate.

[0173] Example 7 - 15% PSGAG with 0.1% BHT

[0174] 15 grams of PSGAG powder was dissolved in water following the procedure in Example 4. To this solution was added 0.1 g of BHT and mixed until completely dissolved to give an aqueous solution with a pH of 6.03. To this solution was added a gelling agent and a cream base to give 100 g of PSGAG containing 0.1% BHT.

[0175] Example 8 - 15% PSGAG with 0.2% Sodium Thiosulfate

[0176] 15 grams of PSGAG powder was dissolved in water following the procedure in Example 4. To this solution was added 0.2 g of sodium thiosulfate and mixed until completely dissolved to give an aqueous solution with a pH of 6.13. To this solution was added a gelling agent and a cream base to give 100 g of PSGAG containing 0.1% BHT.

[0177] Example 9. Anesthetic Composition

[0178]

[0179] The ingredients are ground into the matrix by serial dilution technique.

[0180] Example 10 - Anti-inflammatory Composition

[0181]

[0182] Mix PSGAG with water. Incorporate into cream base while mixing. Mix until homogeneous. Mix in hydrocortisone and mix until homogeneous in appearance.

[0183] Example 11 - Parenteral Compositions

[0184] Ingredients %W / W

[0185] PSGAG 10.0

[0186] Water 20.0

[0187] Dissolve PSGAG in water, pass through a suitable sterile 0.22 micron membrane filter and aseptically fill into suitable sterile containers.

[0188] Example 12. Topical Moisturizer Composition

[0189]

[0190] 1. Combine water and urea to prepare the aqueous phase. Then add ethanol, polysorbate 80 and dimethicone copolyol to this mixture while mixing.

[0191] 2. In a separate container, prepare an oil phase by combining canola oil and sorbitan sesquioleate.

[0192] 3. The oil phase is then added to the water mixture and blended to form the composition.

[0193] Example 13. Aerosol Foam Composition

[0194]

[0195] 1. Combine materials except propellant.

[0196] 2. The concentrated mixture is then added to an aerosol container such as an aluminum tube.

[0197] 3. The propellant is then added by conventional procedures such as by valve or under-the-cup filling methods.

[0198] Embodiment 14

[0199] A 66-year-old Caucasian male retiree presented with increasing hip pain from long-standing osteoarthritis in both hips. The man was considering hip replacement surgery as it was an increasingly likely option. His symptoms were pain, stiffness, and limited mobility. He applied the 15% PSGAG cream mixture topically to the hip joint and then rubbed it into the area causing the pain. After this treatment once a day, the pain was quickly reduced and his quality of life was greatly improved. The patient applied the cream once a day for the first two weeks and then gradually reduced the usage to every other day or less as needed.

[0200] Embodiment 15

[0201] A 65-year-old Caucasian woman had a curved meniscus in her left knee that occasionally caused severe pain (rated as 9 out of 10 on a scale of 1 to 10). She applied the 15% PSGAG cream mixture to the area over and around the knee joint and rubbed it in. After treatment, the woman reported that the pain was gone within a few hours and that she could occasionally treat it as needed.

[0202] Example 16

[0203] The 65-year-old woman in Example 15 also suffered from hemorrhoidal attacks, which caused severe pain, irritation and embarrassment. The woman applied a small amount of the 15% PSGAG cream mixture to the painful area once a day for 2-3 days, and the hemorrhoidal attacks subsided and the pain was completely relieved.

[0204] Embodiment 17

[0205] A 57-year-old man with chronic knee pain that occasionally required cortisone injections treated his knees with 15% PSGAG cream mixture daily and experienced relief of pain and stiffness. The man continued to use the cream as needed.

[0206] Embodiment 18

[0207] A 28-year-old male jockey presented with severe pain in his elbow due to a fracture sustained during horse racing. The previous injury resulted in chronic pain and joint stiffness. The patient was unable to find effective treatment to relieve the pain. After daily treatment, 15% PSGAG cream mixture was applied to the elbow and surrounding area, and the pain was significantly reduced and the range of motion was improved.

[0208] Embodiment 19

[0209] A 65-year-old Caucasian male in good health had calcified, discolored, and hardened toenails. Topical application of 15% PSGAG cream mixture once daily for two weeks resulted in improved toenail color, new cuticle growth, and reduced calcification, which improved blood flow to the extremities. Shortly after application, the skin developed slight redness and became smoother due to increased blood flow.

[0210] Embodiment 20

[0211] A 46-year-old Caucasian female in good health had undergone an ACL meniscus repair. Walking was observed before and after application of the cream. After surgery, a 15% PSGAG cream mixture was applied to the knee joint before walking and observed increased activity and decreased pain during and after exercise.

[0212] Embodiment 21

[0213] A 70-year-old Caucasian male in good health applied 15% PSGAG cream mixture to relieve arthritis pain in his hands and thumbs. Activity increased and pain decreased shortly thereafter.

[0214] Embodiment 22

[0215] A 65-year-old Caucasian male in good health applied a 15% PSGAG cream mixture to the shoulder and knee areas after playing ball. Activity increased and pain decreased shortly thereafter.

[0216] Embodiment 23

[0217] A middle-aged woman diagnosed with Ehlers-Danlos syndrome had pain in her neck, hands, and elbows, and a labral tear in her hip. After applying 15% PSGAG cream to the affected area, she noticed a great improvement in her hands and hips, with much less pain, and a great improvement in her elbows, which were almost pain-free. Her neck condition also improved.

[0218] Embodiment 24

[0219] A 65-year-old male, a professional metal artist, experienced swelling and stiffness in the finger joints and wrists after strenuous activity. After applying 15% PSGAG cream topically to the affected areas with the "fingertips", he felt relief within 15 minutes.

[0220] Embodiment 25

[0221] A 31-year-old female, professional web service worker, presented with pain and swelling in the finger joints and wrists after keyboarding activities. She was diagnosed with "joint hypermobility" by an orthopedic surgeon 6 months prior to application. After applying 15% PSGAG cream topically to the affected areas, she felt relief within 15-30 minutes. Better range of motion and reduced joint stiffness and pain were observed during follow-up visits by the orthopedic surgeon.

[0222] Embodiment 26

[0223] A 45-year-old female, a professional nonprofit administrator, presented with lower back pain and stiffness. She observed relief within 15 minutes after applying 15% PSGAG cream topically to the affected area.

[0224] Embodiment 27

[0225] A 62-year-old retired female presented with severe bruising on her right thigh due to a fall. After applying 15% PSGAG cream topically to half of the affected area, the bruise was less severe after 24 hours and disappeared after 72 hours. After 72 hours, the untreated area was still dark purple.

[0226] Embodiment 28

[0227] A 62-year-old retired female presented with arthritis in her fingers. After applying 15% PSGAG cream topically to the affected areas, she observed improved movement and reduced stiffness.

[0228] While preferred embodiments have been depicted and described herein in detail, it will be apparent to those skilled in the relevant arts that various modifications, additions, substitutions etc. are possible without departing from the spirit of the invention and these are therefore deemed to be within the scope of the invention as defined by the following claims.

Claims

1. A storage-stable pharmaceutical composition, comprising: sulfated glycosaminoglycans having an average molecular weight in the range of 3,000 to 15,000 Daltons; a skin penetrant, wherein the skin penetrant promotes transdermal penetration of the sulfated glycosaminoglycan when applied to the intact skin surface; as well as A drug carrier for topical administration, wherein the drug carrier is mixed with the sulfated glycosaminoglycan and the skin permeation agent.

2. The storage-stable pharmaceutical composition of claim 1, wherein the sulfated glycosaminoglycan has an average molecular weight in the range of 7,000 to 9,500 Daltons.

3. The storage-stable pharmaceutical composition of claim 1, wherein the sulfated glycosaminoglycan is selected from the group consisting of chondroitin sulfate, polysulfated mucopolysaccharide, polysulfated glycosaminoglycan, and combinations thereof.

4. The storage-stable pharmaceutical composition of claim 3, wherein the sulfated glycosaminoglycan comprises chondroitin sulfate.

5. The storage-stable pharmaceutical composition of claim 4, wherein the sulfated glycosaminoglycan comprises less than 5% by weight of chondroitin sulfate.

6. The storage-stable pharmaceutical composition of claim 3, wherein the sulfated glycosaminoglycan comprises a polysulfated glycosaminoglycan.

7. The storage-stable pharmaceutical composition of claim 3, wherein the sulfated glycosaminoglycan comprises polysulfated mucopolysaccharide.

8. The storage-stable pharmaceutical composition of claim 1, wherein the sulfated glycosaminoglycan comprises no more than 10% by weight of carbohydrates or other contaminants having a molecular weight of less than 1,000 Daltons.

9. The storage-stable pharmaceutical composition of claim 1, wherein the sulfated glycosaminoglycan comprises no more than 20% by weight of carbohydrates or other contaminants having a molecular weight of less than 3,000 Daltons.

10. The storage-stable pharmaceutical composition of claim 1, wherein the sulfated glycosaminoglycan comprises no more than 25% by weight of carbohydrates or other contaminants having a molecular weight of less than 5,000 Daltons.

11. The storage-stable pharmaceutical composition of claim 1, wherein the sulfated glycosaminoglycan contains less than 5,000 ppm of acetic acid.

12. The storage-stable pharmaceutical composition of claim 1, wherein the sulfated glycosaminoglycan contains less than 5,000 ppm of acetic acid after storage at room temperature for at least 12 months after the initiation of storage.

13. The storage-stable pharmaceutical composition of claim 1, wherein the sulfated glycosaminoglycan remains white or off-white after storage at room temperature for at least 6 months after the start of storage.

14. The storage-stable pharmaceutical composition of claim 1, wherein the sulfated glycosaminoglycan remains white or off-white after storage at room temperature for at least 12 months after the start of storage.

15. The storage-stable pharmaceutical composition of claim 1, wherein the sulfated glycosaminoglycan is prepared by the following process, comprising A sulfated glycosaminoglycan starting material containing components less than 1,000 Daltons is subjected to tangential flow filtration under conditions effective to reduce the amount of components less than 1,000 Daltons in the starting material to produce purified sulfated glycosaminoglycans having an average molecular weight in the range of 3,000 to 15,000 Daltons, wherein the purified sulfated glycosaminoglycans include no more than 10% by weight of carbohydrates or other contaminants having a molecular weight less than 1,000 Daltons.

16. The storage-stable pharmaceutical composition of claim 1, wherein the skin penetrant is selected from the group consisting of acetone, acyl lactylates, acyl peptides, acyl sarcosinates, alkanolamine salts of fatty acids, alkyl benzenesulfonates, alkyl ether sulfates, alkyl sulfates, anionic surfactants, benzyl benzoate, benzyl salicylate, butane-1,4-diol, butyl benzoate, butyl laurate, butyl myristate, butyl stearate, cationic surfactants, citric acid, cocamide Propyl betaine, decyl methyl sulfoxide, decyl oleate, dibutyl azelate, dibutyl phthalate, dibenzyl sebacate, dibutyl sebacate, dibutyl suberate, dibutyl succinate, dioctyl adipate, didecyl phthalate, diethylene glycol, diethyl sebacate, diethyl m-toluamide, di(2-hydroxypropyl) ether, diisopropyl adipate, diisopropyl sebacate, N,N-dimethylacetamide, dimethyl azelate, N,N-dimethylformamide, 1,5-dimethyl-2-pyridine Pyrrolidone, dimethyl sebacate, dimethyl sulfoxide, dioctyl adipate, dioctyl azelaic acid, dioctyl sebacate, 1,4-dioxane, 1-dodecylazacycloheptan-2-one, dodecyl dimethylamine oxide, ethyl decanoate, ethyl hexanoate, ethyl octanoate, 2-ethyl-hexyl nonanoate, ethyl-2-hydroxypropionate, ethyl laurate, ethyl myristate, 1-ethyl-2-pyrrolidone, ethyl salicylate, hexyl laurate, 2-hydroxyoctanoic acid, 2-hydroxypropionic acid, 2-hydroxypropionic acid, isothioic acid Acid esters, isopropyl isostearate, isopropyl palmitate, guar hydroxypropyltrimonium chloride, hexane-2,5-diol, kaolin, lamepons, lauryl alcohol, maypons, metal salts of fatty acids, methyl nicotinate, 2-methylpropane-2-ol, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, methyl taurine, miranol surfactants nonionic surfactants octanol, octylphenoxy polyethoxyethanol, oleic acid, ethanolamine, oleyl alcohol, amyl-2,4-diol, phenoxyethanol, phosphatidylcholine, phosphine oxide, polyalkoxylated ether glycolate, poly(diallylpiperidinium chloride), poly(dipropyldiallylammonium chloride), polyglycerol esters, polyoxyethylene lauryl ether, polyoxy: polyoxyethylene stearate, polyoxypropylene 15 stearyl ether, poly(vinylpyridinium chloride), propan-1-ol, propan-2-ol, propylene glycol dipelargonate, pyroglutamic acid, 2-pyrrolidone, pyruvic acid, quaternary ammonium salt 5, quaternary ammonium salt 18, quaternary ammonium salt 19, quaternary ammonium salt 23, quaternary ammonium salt 31, quaternary ammonium salt 40, quaternary ammonium salt 57, quaternary ammonium salt, quaternized poly(dimethylaminoethyl methacrylate), quaternized poly(vinyl alcohol), chromamine hydrochloride, sodium cocoaminopropionate, dioctyl sulfosuccinate Sodium lauryl sulfate, sodium laurate, sodium lauryl ether sulfate, sodium lauryl sulfate, sugar esters, sulfosuccinates, tetrahydrofuran, tetrahydrofurfuryl alcohol, transcutol, triethanolamine dodecylbenzene sulfonate, triethanolamine oleate, water and derivatives, salts, essential oils and their terpene components, plant carrier oils, emulsifiers, ethanol, dimethyl sulfoxide, dimethyl isosorbide, isopropyl myristate, propylene glycol, sodium lauryl sulfate, lauryl amine oxide, vitamin E, lower alcohols, alcohols, isomers of aliphatic diols and aliphatic triols, urea or other amide derivatives, primary and secondary alcohols, fatty acids, fatty acid esters, polyols, amides, surfactants, terpenes and terpenoids, alkanones, organic acids and esters, cyclodextrins, phospholipids and combinations thereof.

17. The storage-stable pharmaceutical composition of claim 1, wherein the skin penetrant is selected from the group consisting of primary or secondary alcohols, polyoxyethers of fatty acids, vitamins, antioxidants, antimicrobial preservatives, fatty acid esters, and combinations thereof.

18. The storage-stable pharmaceutical composition of claim 1, wherein the skin penetrant is selected from the group consisting of tocopherol acetate, aloe derivatives, silicon derivatives, chelating agents, emulsifiers, polyols, water, and combinations thereof.

19. The storage-stable pharmaceutical composition of claim 1, further comprising: Pharmaceutically active agents.

20. The storage-stable pharmaceutical composition of claim 19, wherein the pharmaceutically active agent is selected from the group consisting of a pharmaceutically acceptable free base, salt, ester, ether, or solvate of an antibiotic, an anti-infective, an anti-fungal, a steroid, a cannabinoid, an antihistamine, an anti-inflammatory, an anti-parasitic, an immunomodulator, an antisense agent, an antiviral agent, a therapeutic agent for treating hyperpigmentation and hypopigmentation conditions of the skin, an anti-psoriatic, a keratolytic, a DNA synthesis inhibitor, a cytotoxic agent, an anti-thyroid agent, a monoclonal antibody modulator, a TNFα antagonist, an immunoglobulin, a metabolic modulator, an anti-angiogenic agent, a protease inhibitor, an anxiolytic, a kinase modulator, a cell growth regulator, an enzyme, a prostaglandin, a peptide, an analgesic, a skin moisturizer, an astringent, an exfoliant, an agent intended to protect the skin or change the appearance of the skin or increase the rate of skin healing, and combinations thereof.

21. The storage-stable pharmaceutical composition of claim 1, further comprising: An additive selected from the group consisting of adjuvants, gelling agents, thickeners, solvents, preservatives, pH adjusters, colorants, fragrances, flavors, propellants, absorbents, adsorbents, antioxidants, antimicrobial preservatives, and combinations thereof.

22. The storage-stable pharmaceutical composition of claim 1, wherein the carrier is selected from the group consisting of a transdermal tape, a transdermal patch, an ointment, a cream, a gel, a paste, a collodion composition, a foam, a fast dissolving solid, and a lotion.

23. The storage-stable pharmaceutical composition of claim 1, wherein the storage-stable pharmaceutical composition comprises 0.1 wt% to 25 wt% of the sulfated glycosaminoglycan, 20 wt% to 60 wt% of the skin permeation agent, and 20 wt% to 80 wt% of the carrier.

24. The storage-stable pharmaceutical composition of claim 1, wherein the storage-stable pharmaceutical composition comprises 5 to 16 wt% of the sulfated glycosaminoglycan, 25 to 55 wt% of the skin permeation agent, and 25 to 75 wt% of the carrier.

25. A method of treating pain, joint stiffness, soft tissue injury, connective tissue pathology and / or muscle soreness in a subject, the method include: Select subjects who need treatment for pain, joint stiffness, soft tissue injuries, connective tissue conditions and / or muscle soreness, and administering to a selected subject a storage-stable pharmaceutical composition comprising: sulfated glycosaminoglycans having an average molecular weight in the range of 3,000 to 15,000 Daltons; a skin penetrant, wherein the skin penetrant promotes transdermal penetration of the sulfated glycosaminoglycan when applied to the intact skin surface; as well as A pharmaceutical carrier for topical administration, the pharmaceutical carrier being mixed with the sulfated glycosaminoglycan and the skin permeation agent, wherein the administration is performed locally near a location where the subject experiences pain, joint stiffness, soft tissue injury, connective tissue pathology, and / or muscle soreness.

26. The method of claim 25, wherein the sulfated glycosaminoglycan has an average molecular weight in the range of 7,000 to 9,500 Daltons.

27. The method of claim 25, wherein the sulfated glycosaminoglycan is selected from the group consisting of chondroitin sulfate, polysulfated mucopolysaccharide, polysulfated glycosaminoglycan, and combinations thereof.

28. The method of claim 27, wherein the sulfated glycosaminoglycan comprises chondroitin sulfate.

29. The method of claim 28, wherein the sulfated glycosaminoglycan comprises less than 5% by weight chondroitin sulfate.

30. The method of claim 27, wherein the sulfated glycosaminoglycan comprises a polysulfated glycosaminoglycan.

31. The method of claim 27, wherein the sulfated glycosaminoglycan comprises polysulfated mucopolysaccharide.

32. The method of claim 25, wherein the sulfated glycosaminoglycans include no more than 10% by weight of carbohydrates or other contaminants having a molecular weight less than 1,000 Daltons.

33. The method of claim 25, wherein the sulfated glycosaminoglycans include no more than 20% by weight of carbohydrates or other contaminants having a molecular weight less than 3,000 Daltons.

34. The method of claim 25, wherein the sulfated glycosaminoglycans include no more than 25% by weight of carbohydrates or other contaminants having a molecular weight less than 5,000 Daltons.

35. The method of claim 25, wherein the sulfated glycosaminoglycan contains less than 5,000 ppm acetic acid.

36. The method of claim 35, wherein the sulfated glycosaminoglycan contains less than 5,000 ppm acetic acid after storage at room temperature for at least 12 months after the initiation of storage.

37. The method of claim 25, wherein the sulfated glycosaminoglycan remains white or off-white after storage at room temperature for at least 6 months after the start of storage.

38. The method of claim 25, wherein the sulfated glycosaminoglycan remains white or off-white after storage at room temperature for at least 12 months after the start of storage.

39. The method of claim 25, wherein the skin penetrant is selected from the group consisting of acetone, acyl lactylates, acyl peptides, acyl sarcosinates, alkanolamine salts of fatty acids, alkyl benzenesulfonates, alkyl ether sulfates, alkyl sulfates, anionic surfactants, benzyl benzoate, benzyl salicylate, butane-1,4-diol, butyl benzoate, butyl laurate, butyl myristate, butyl stearate, cationic surfactants, citric acid, cocamidopropyl betaine , decyl methyl sulfoxide, decyl oleate, dibutyl azelate, dibutyl phthalate, dibenzyl sebacate, dibutyl sebacate, dibutyl suberate, dibutyl succinate, dioctyl adipate, didecyl phthalate, diethylene glycol, diethyl sebacate, diethyl m-toluamide, di(2-hydroxypropyl) ether, diisopropyl adipate, diisopropyl sebacate, N,N-dimethylacetamide, dimethyl azelate, N,N-dimethylformamide, 1,5-dimethyl-2-pyrrolidone , dimethyl sebacate, dimethyl sulfoxide, dioctyl adipate, dioctyl azelaic acid, dioctyl sebacate, 1,4-dioxane, 1-dodecylazacycloheptan-2-one, dodecyl dimethylamine oxide, ethyl decanoate, ethyl hexanoate, ethyl octanoate, 2-ethyl-hexyl nonanoate, ethyl-2-hydroxypropionate, ethyl laurate, ethyl myristate, 1-ethyl-2-pyrrolidone, ethyl salicylate, hexyl laurate, 2-hydroxyoctanoic acid, 2-hydroxypropionic acid, 2-hydroxypropionic acid, isosulfate Esters, isopropyl isostearate, isopropyl palmitate, guar hydroxypropyltrimonium chloride, hexane-2,5-diol, kaolin, lamepons, lauryl alcohol, maypons, metal salts of fatty acids, methyl nicotinate, 2-methylpropane-2-ol, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, methyl taurine, miranol surfactants nonionic surfactants octanol, octylphenoxy polyethoxyethanol, oleic acid, ethanolamine, oleyl alcohol, amyl-2,4-diol, phenoxyethanol, phosphatidylcholine, phosphine oxide, polyalkoxylated ether glycolate, poly(diallylpiperidinium chloride), poly(dipropyldiallylammonium chloride), polyglycerol esters, polyoxyethylene lauryl ether, polyoxy: polyoxyethylene stearate, polyoxypropylene 15 stearyl ether, poly(vinylpyridinium chloride), propan-1-ol, propan-2-ol, propylene glycol dipelargonate, pyroglutamic acid, 2-pyrrolidone, pyruvic acid, quaternary ammonium salt 5, quaternary ammonium salt 18, quaternary ammonium salt 19, quaternary ammonium salt 23, quaternary ammonium salt 31, quaternary ammonium salt 40, quaternary ammonium salt 57, quaternary ammonium salt, quaternized poly(dimethylaminoethyl methacrylate), quaternized poly(vinyl alcohol), chromamine hydrochloride, sodium cocoaminopropionate, dioctyl sulfosuccinate Sodium lauryl sulfate, sodium laurate, sodium lauryl ether sulfate, sodium lauryl sulfate, sugar esters, sulfosuccinates, tetrahydrofuran, tetrahydrofurfuryl alcohol, transcutol, triethanolamine dodecylbenzene sulfonate, triethanolamine oleate, water and derivatives, salts, essential oils and their terpene components, plant carrier oils, emulsifiers, ethanol, dimethyl sulfoxide, dimethyl isosorbide, isopropyl myristate, propylene glycol, sodium lauryl sulfate, lauryl amine oxide, vitamin E, lower alcohols, alcohols, isomers of aliphatic diols and aliphatic triols, urea or other amide derivatives, primary and secondary alcohols, fatty acids, fatty acid esters, polyols, amides, surfactants, terpenes and terpenoids, alkanones, organic acids and esters, cyclodextrins, phospholipids and combinations thereof.

40. The method of claim 25, wherein the skin penetrant is selected from the group consisting of primary or secondary alcohols, polyoxyethers of fatty acids, vitamins, antioxidants, antimicrobial preservatives, fatty acid esters, and combinations thereof.

41. The method of claim 25, wherein the skin penetrant is selected from the group consisting of tocopherol acetate, aloe derivatives, silicon derivatives, chelating agents, emulsifiers, polyols, water, and combinations thereof.

42. The method of claim 25, wherein the selected subject is treated for pain.

43. The method of claim 25, wherein the selected subject is treated for joint stiffness.

44. The method of claim 25, wherein the selected subject is treated for soft tissue damage.

45. The method of claim 25, wherein the selected subject is treated for muscle soreness.

46. ​​The method of claim 25, wherein the selected subject is treated for osteoarthritis pain.

47. The method of claim 25, wherein the selected subject is treated for a connective tissue condition.

48. The method of claim 25, wherein the selected subject is a mammal.

49. The method of claim 25, wherein the selected subject is a human.

50. The method of claim 25, wherein the storage-stable pharmaceutical composition further comprises: Pharmaceutically active agents.

51. The method of claim 50, wherein the pharmaceutically active agent is selected from the group consisting of a pharmaceutically acceptable free base, salt, ester, ether, or solvate of an antibiotic, an anti-infective, an anti-fungal, a steroid, a cannabinoid, an antihistamine, an anti-inflammatory, an anti-parasitic, an immunomodulator, an antisense agent, an antiviral agent, a therapeutic agent for treating hyperpigmentation and hypopigmentation conditions of the skin, an anti-psoriatic, a keratolytic, a DNA synthesis inhibitor, a cytotoxic agent, an anti-thyroid agent, a monoclonal antibody modulator, a TNFα antagonist, an immunoglobulin, a metabolic modulator, an anti-angiogenic agent, a protease inhibitor, an anxiolytic, a kinase modulator, a cell growth regulator, an enzyme, a prostaglandin, a peptide, an analgesic, a skin moisturizer, a astringent, an exfoliant, an agent intended to protect the skin or change the appearance of the skin or increase the rate of skin healing, and combinations thereof.

52. The method of claim 25, wherein the storage-stable pharmaceutical composition further comprises: An additive selected from the group consisting of adjuvants, gelling agents, thickeners, solvents, preservatives, pH adjusters, colorants, fragrances, flavors, propellants, absorbents, adsorbents, antioxidants, antimicrobial preservatives, and combinations thereof.

53. The method of claim 25, wherein the storage-stable pharmaceutical composition further comprises: An additive selected from the group consisting of tocopherol acetate, aloe derivatives, silicon derivatives, chelating agents, emulsifiers, polyols, water, and combinations thereof.

54. The method of claim 25, wherein the carrier is selected from the group consisting of a transdermal tape, a transdermal patch, an ointment, a cream, a gel, a paste, a collodion, a foam, a paste, a fast dissolving solid, and a lotion.

55. The method of claim 25, wherein the storage-stable pharmaceutical composition comprises 0.1 wt% to 25 wt% of the sulfated glycosaminoglycan, 20 wt% to 60 wt% of the skin permeation agent, and 20 wt% to 80 wt% of the drug carrier.

56. The method of claim 25, wherein the storage-stable pharmaceutical composition comprises 5 to 16 wt% of the sulfated glycosaminoglycan, 25 to 55 wt% of the skin permeation agent, and 25 to 75 wt% of the drug carrier.

57. A storage-stable sulfated glycosaminoglycan having an average molecular weight in the range of 3,000 to 15,000 Daltons.

58. The storage-stable sulfated glycosaminoglycan of claim 57, wherein the sulfated glycosaminoglycan has an average molecular weight in the range of 7,000 to 9,500 Daltons.

59. The storage-stable sulfated glycosaminoglycan of claim 57, wherein the sulfated glycosaminoglycan is selected from the group consisting of chondroitin sulfate, polysulfated mucopolysaccharide, polysulfated glycosaminoglycan, and combinations thereof.

60. The storage-stable sulfated glycosaminoglycan of claim 59, wherein the sulfated glycosaminoglycan comprises chondroitin sulfate.

61. The storage-stable sulfated glycosaminoglycan of claim 60, wherein the sulfated glycosaminoglycan comprises less than 5% by weight chondroitin sulfate.

62. The storage-stable sulfated glycosaminoglycan of claim 59, wherein the sulfated glycosaminoglycan comprises polysulfated glycosaminoglycan.

63. The storage-stable sulfated glycosaminoglycan of claim 59, wherein the sulfated glycosaminoglycan comprises a polysulfated mucopolysaccharide.

64. The shelf-stable sulfated glycosaminoglycan of claim 57, wherein the sulfated glycosaminoglycan comprises no more than 10% by weight of carbohydrates or other contaminants having a molecular weight less than 1,000 Daltons.

65. The shelf-stable sulfated glycosaminoglycan of claim 57, wherein the sulfated glycosaminoglycan comprises no more than 20% by weight of carbohydrates or other contaminants having a molecular weight less than 3,000 Daltons.

66. The shelf-stable sulfated glycosaminoglycan of claim 57, wherein the sulfated glycosaminoglycan comprises no more than 25% by weight of carbohydrates or other contaminants having a molecular weight less than 5,000 Daltons.

67. The shelf-stable sulfated glycosaminoglycan of claim 57, wherein the sulfated glycosaminoglycan contains less than 5,000 ppm acetic acid.

68. The shelf-stable sulfated glycosaminoglycan of claim 57, wherein the sulfated glycosaminoglycan contains less than 5,000 ppm acetic acid after storage at room temperature for at least 12 months after the initiation of storage.

69. The storage-stable sulfated glycosaminoglycan of claim 57, wherein the storage-stable sulfated glycosaminoglycan remains white or off-white after storage at room temperature for at least 6 months after the start of storage.

70. The storage-stable sulfated glycosaminoglycan of claim 57, wherein the storage-stable sulfated glycosaminoglycan remains white or off-white after storage at room temperature for at least 12 months after the start of storage.

71. The storage-stable sulfated glycosaminoglycan of claim 57, wherein the sulfated glycosaminoglycan is prepared by a process comprising A sulfated glycosaminoglycan starting material containing components less than 1,000 Daltons is subjected to tangential flow filtration under conditions effective to reduce the amount of components less than 1,000 Daltons in the starting material to produce purified sulfated glycosaminoglycans having an average molecular weight in the range of 3,000 to 15,000 Daltons, wherein the purified sulfated glycosaminoglycans include no more than 10% by weight of carbohydrates or other contaminants having a molecular weight less than 1,000 Daltons.

72. A storage-stable pharmaceutical composition, comprising: sulfated glycosaminoglycans having an average molecular weight in the range of 3,000 to 15,000 Daltons; and A drug carrier is mixed with the sulfated glycosaminoglycan.

73. The storage-stable pharmaceutical composition of claim 72, wherein the sulfated glycosaminoglycan has an average molecular weight in the range of 7,000 to 9,500 Daltons.

74. The storage-stable pharmaceutical composition of claim 72, wherein the sulfated glycosaminoglycan is selected from the group consisting of chondroitin sulfate, polysulfated mucopolysaccharide, polysulfated glycosaminoglycan, and combinations thereof.

75. The storage-stable pharmaceutical composition of claim 74, wherein the sulfated glycosaminoglycan comprises chondroitin sulfate.

76. The storage-stable pharmaceutical composition of claim 75, wherein the sulfated glycosaminoglycan comprises less than 5% by weight chondroitin sulfate.

77. The storage-stable pharmaceutical composition of claim 74, wherein the sulfated glycosaminoglycan comprises a polysulfated glycosaminoglycan.

78. The storage-stable pharmaceutical composition of claim 74, wherein the sulfated glycosaminoglycan comprises a polysulfated mucopolysaccharide.

79. The storage-stable pharmaceutical composition of claim 72, wherein the sulfated glycosaminoglycan comprises no more than 10% by weight of carbohydrates or other contaminants having a molecular weight less than 1,000 Daltons.

80. The storage-stable pharmaceutical composition of claim 72, wherein the sulfated glycosaminoglycan comprises no more than 20% by weight of carbohydrates or other contaminants having a molecular weight less than 3,000 Daltons.

81. The storage-stable pharmaceutical composition of claim 72, wherein the sulfated glycosaminoglycan comprises no more than 25% by weight of carbohydrates or other contaminants having a molecular weight less than 5,000 Daltons.

82. The storage-stable pharmaceutical composition of claim 72, wherein the sulfated glycosaminoglycan contains less than 5,000 ppm acetic acid.

83. The storage-stable pharmaceutical composition of claim 72, wherein the sulfated glycosaminoglycan contains less than 5,000 ppm of acetic acid after storage at room temperature for at least 12 months after initiation of storage.

84. The storage-stable pharmaceutical composition of claim 72, wherein the sulfated glycosaminoglycan remains white or off-white after storage at room temperature for at least 6 months after the start of storage.

85. The storage-stable pharmaceutical composition of claim 72, wherein the sulfated glycosaminoglycan remains white or off-white after storage at room temperature for at least 12 months after the initiation of storage.

86. The storage-stable pharmaceutical composition of claim 72, wherein the sulfated glycosaminoglycan is prepared by a process comprising A sulfated glycosaminoglycan starting material containing components less than 1,000 Daltons is subjected to tangential flow filtration under conditions effective to reduce the amount of components less than 1,000 Daltons in the starting material to produce purified sulfated glycosaminoglycans having an average molecular weight in the range of 3,000 to 15,000 Daltons, wherein the purified sulfated glycosaminoglycans include no more than 10% by weight of carbohydrates or other contaminants having a molecular weight less than 1,000 Daltons.

87. The storage-stable pharmaceutical composition of claim 72, further comprising: Pharmaceutically active agents.

88. A storage-stable pharmaceutical composition as described in claim 87, wherein the pharmaceutically active agent is selected from the group consisting of: a pharmaceutically acceptable free base, salt, ester, ether, or solvate of an antibiotic, an anti-infective, an antifungal, a steroid, a cannabinoid, an antihistamine, an anti-inflammatory, an antiparasitic, an immunomodulator, an antisense agent, an antiviral agent, a therapeutic agent for treating hyperpigmentation and hypopigmentation conditions of the skin, an antipsoriatic, a keratolytic, a DNA synthesis inhibitor, a cytotoxic agent, an antithyroid agent, a monoclonal antibody modulator, a TNFα antagonist, an immunoglobulin, a metabolic regulator, an anti-angiogenic agent, a protease inhibitor, an anxiolytic, a kinase regulator, a cell growth regulator, an enzyme, a prostaglandin, a peptide, an analgesic, a skin moisturizer, a astringent, an exfoliant, an agent intended to protect the skin or change the appearance of the skin or increase the rate of skin healing, and combinations thereof.

89. The storage-stable pharmaceutical composition of claim 72, further comprising: An additive selected from the group consisting of adjuvants, gelling agents, thickeners, solvents, preservatives, pH adjusters, colorants, fragrances, flavors, propellants, absorbents, adsorbents, antioxidants, antimicrobial preservatives, and combinations thereof.

90. The storage-stable pharmaceutical composition of claim 72, further comprising: An additive selected from the group consisting of tocopherol acetate, aloe derivatives, silicon derivatives, chelating agents, emulsifiers, polyols, water, and combinations thereof.

91. The storage-stable pharmaceutical composition of claim 72, wherein the pharmaceutical carrier is an injectable liquid, solution or emulsion capable of dissolving the purified sulfated glycosaminoglycan.

92. The storage-stable pharmaceutical composition of claim 72, wherein the storage-stable pharmaceutical composition comprises 0.1 wt% to 25 wt% of the sulfated glycosaminoglycan and 75 wt% to 99 wt% of the carrier.

93. The storage-stable pharmaceutical composition of claim 72, wherein the storage-stable pharmaceutical composition comprises 5 to 16 wt% of the purified sulfated glycosaminoglycan and 84 to 95 wt% of the carrier.

94. A method of treating a subject to obtain a medically observable improvement, the method include: Selecting subjects in need of treatment for medically diagnosable conditions, and administering to a selected subject to facilitate treatment a storage-stable pharmaceutical composition comprising: sulfated glycosaminoglycans having an average molecular weight in the range of 3,000 to 15,000 Daltons, and A drug carrier is mixed with the sulfated glycosaminoglycan.

95. The method of claim 94, wherein the sulfated glycosaminoglycan is selected from the group consisting of chondroitin sulfate, polysulfated mucopolysaccharides, polysulfated glycosaminoglycans, and combinations thereof.

96. The method of claim 94, wherein the sulfated glycosaminoglycans include no more than 10% by weight of carbohydrates or other contaminants having a molecular weight less than 1,000 Daltons.

97. The method of claim 94, wherein the sulfated glycosaminoglycans include no more than 20% by weight of carbohydrates or other contaminants having a molecular weight less than 3,000 Daltons.

98. The method of claim 94, wherein the sulfated glycosaminoglycans include no more than 25% by weight of carbohydrates or other contaminants having a molecular weight less than 5,000 Daltons.

99. The method of claim 94, wherein the sulfated glycosaminoglycan contains less than 5,000 ppm acetic acid.

100. The method of claim 94, wherein the sulfated glycosaminoglycan remains white or off-white after storage at room temperature for at least 6 months after the initiation of storage.

101. The method of claim 94, wherein the sulfated glycosaminoglycan remains white or off-white after storage at room temperature for at least 12 months after the initiation of storage.

102. The method of claim 94, wherein the selected subject is a mammal.

103. The method of claim 94, wherein the selected subject is a human.

104. The method of claim 94, wherein the storage-stable pharmaceutical composition further comprises: Pharmaceutically active agents.

105. The method of claim 104, wherein the pharmaceutically active agent is selected from the group consisting of a pharmaceutically acceptable free base, salt, ester, ether, or solvate of an antibiotic, an anti-infective, an anti-fungal, a steroid, a cannabinoid, an antihistamine, an anti-inflammatory, an anti-parasitic, an immunomodulator, an antisense agent, an antiviral agent, a therapeutic agent for treating hyperpigmentation and hypopigmentation conditions of the skin, an anti-psoriatic, a keratolytic, a DNA synthesis inhibitor, a cytotoxic agent, an anti-thyroid agent, a monoclonal antibody modulator, a TNFα antagonist, an immunoglobulin, a metabolic modulator, an anti-angiogenic agent, a protease inhibitor, an anxiolytic, a kinase modulator, a cell growth regulator, an enzyme, a prostaglandin, a peptide, an analgesic, a skin moisturizer, a astringent, an exfoliant, an agent intended to protect the skin or change the appearance of the skin or increase the rate of skin healing, and combinations thereof.

106. The method of claim 94, wherein the storage-stable pharmaceutical composition further comprises: An additive selected from the group consisting of adjuvants, gelling agents, thickeners, solvents, preservatives, pH adjusters, colorants, fragrances, flavors, propellants, absorbents, adsorbents, antioxidants, antimicrobial preservatives, and combinations thereof.

107. The method of claim 94, wherein the storage-stable pharmaceutical composition further comprises: An additive selected from the group consisting of tocopherol acetate, aloe derivatives, silicon derivatives, chelating agents, emulsifiers, polyols, water, and combinations thereof.

108. The method of claim 94, wherein the storage-stable pharmaceutical composition comprises 0.1 wt% to 25 wt% of the sulfated glycosaminoglycan and 75 wt% to 99 wt% of the carrier.

109. The method of claim 94, wherein the storage-stable pharmaceutical composition comprises 5% to 16% by weight of the purified sulfated glycosaminoglycan and 84% to 95% by weight of the carrier.

110. The method of claim 94, wherein the selected subject is treated for pain, joint stiffness, soft tissue injury, connective tissue condition, wound and / or muscle soreness.

111. The method of claim 94, wherein the administration is otic, oral, ocular, nasal, rectal, urethral, ​​vaginal, parenteral, topical, and combinations thereof.

112. A method for producing storage-stable purified sulfated glycosaminoglycans, the method include: providing a sulfated glycosaminoglycan starting material containing components less than 1,000 Daltons; subjecting the sulfated glycosaminoglycan starting material to tangential flow filtration under conditions effective to reduce the amount of components less than 1,000 Daltons in the starting material to produce purified sulfated glycosaminoglycans having an average molecular weight in the range of 3,000 to 15,000 Daltons, wherein the purified sulfated glycosaminoglycans include no more than 10% by weight of carbohydrates or other contaminants having a molecular weight less than 1,000 Daltons; as well as The purified sulfated glycosaminoglycans are recovered.

113. The method of claim 112, wherein the purified sulfated glycosaminoglycans comprise no more than 20% by weight of carbohydrates or other contaminants having a molecular weight less than 3,000 Daltons.

114. The method of claim 112, wherein the purified sulfated glycosaminoglycans comprise no more than 25% by weight of carbohydrates or other contaminants having a molecular weight less than 5,000 Daltons.

115. The method of claim 112, wherein the purified sulfated glycosaminoglycans contain less than 5,000 ppm acetic acid.

116. The method of claim 112, wherein the purified sulfated glycosaminoglycans contain less than 1,000 ppm acetic acid.

117. The method of claim 112, wherein the purified sulfated glycosaminoglycans contain less than 5,000 ppm acetic acid after storage at room temperature for at least 12 months after initiation of storage.

118. The method of claim 112, wherein the purified sulfated glycosaminoglycan remains white or off-white after storage at room temperature for at least 6 months after the start of storage.

119. The method of claim 112, wherein the purified sulfated glycosaminoglycan remains white or off-white after storage at room temperature for at least 12 months after the start of storage.

120. The method of claim 112, wherein the tangential flow filtration is performed by ultrafiltration.

121. The method of claim 112, wherein the tangential flow filtration is performed by diafiltration.

122. The method of claim 112, wherein the tangential flow filtration is performed through a size exclusion membrane or another porous membrane.

123. The method of claim 112, further comprising: include: The purified sulfated glycosaminoglycans were stored at room temperature for at least 12 months.

124. The method of claim 123, wherein the purified sulfated glycosaminoglycan contains less than 5,000 ppm acetic acid when stored at room temperature for at least 12 months.

125. The method of claim 123, wherein the purified sulfated glycosaminoglycans are stored in a container comprised of plastic, paper, cardboard or metal.

126. The method of claim 125, wherein the container is treated to remove residual oxygen or air before, during or after the storage.

127. The method of claim 112, wherein the purified sulfated glycosaminoglycans have an average molecular weight in the range of 7,000 to 9,500 Daltons.

128. The method of claim 112, wherein the purified sulfated glycosaminoglycan is selected from the group consisting of chondroitin sulfate, polysulfated mucopolysaccharides, polysulfated glycosaminoglycans, and combinations thereof.

129. A product produced by the method of claim 112.

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