HK1118462A - Treatment of a condition in a mammal with administration of compounds and methods of use thereof - Google Patents

Description

Administration of compounds to treat conditions in mammals and methods of use thereof

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. provisional application serial No. 60/524,698, filed 24/11/2003, which is hereby incorporated by reference in its entirety.

Technical Field

[0002] The present invention relates to methods of treating, preventing, and lessening the severity of conditions or diseases selected from Osteoarthritis (OA), rheumatoid arthritis, synovitis, subchondral bone edema (subchondral bone edema), and cartilage degeneration (hereinafter, referred to as "OA and related disorders") by administering aminosugar derivative (aminosugar derivative) and pharmaceutically acceptable salts thereof.

Background

[0003] Osteoarthritis (OA) is a common joint disease with important social consequences (Lawrence et al, (1998) Arthritis Rheum.41: 778; Gabriel et al, (1997) J. Rheumatotol.24: 719; March et al, (1997) Baillieres Clin. Rheumatotol.11: 817). The classes of drugs used in the treatment of OA include acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS), injectable intra-articular corticosteroids (injectable intra-articular steroids), and hyaluronic acid. These drugs primarily reduce pain, but they have not been demonstrated to achieve true remission of the disease by slowing or otherwise arresting its progression (Altman et al, (1998) Osteoarthritis Cartisage 6 suppl. A: 22; Hochberg et al, (1995) Arthroritis Rheum.38: 1535; Hochberg et al, (1995) Arthroris Rheum.38: 1541). In addition, many of these treatments have adverse side effects.

[0004] Many forms of arthritis are initially treated with NSAIDS, sometimes with other analgesics. In the case where the disease cannot be adequately controlled with these agents, disease-modifying (remission-inducing) antirheumatic drugs (such as gold salts, D-penicillamine, antimalarial agents, and cytotoxic agents) that improve the disease can be used. Finally, glucocorticoids may be administered systemically or by intra-articular routes. However, in most patients none of these drugs is significantly effective in achieving true remission of the disease.

[0005] Bohne describes the use of glucosamine (GlcN) for the treatment of OA (Bohne (1969) Med. Welt 30: 1668). Since then, GlcN has become popular and is now commonly used as a supplement in treating OA patients. GlcN salts (sulfate and chloride) are believed to have properties that protect Cartilage (chondroprotective) or improve disease (disease-modifying) (Altman et al, Osteohrthritis Cartilage 6 suppl.A: 22; Lozada et al, (1997) Bull. Rheum. Dis.46: 5; Mevorach et al, (1994) Isr.J.Med.Sci.30: 928) and were originally proposed to promote repair of damaged Cartilage. Several studies have shown that cartilage from OA patients is characterized by accelerated turnover of cartilage matrix components (acellulated turn of the cartilagematrix components) and inappropriate repair (inadequate repair) (inot et al, (1978) biochem.j.169: 143; diappe et al, (1995) acta.ortho.scan (suppl.266) 66: 1). GlcN has been shown to provide anti-inflammatory activity through a number of different mechanisms. For example, GlcN has been shown to provide anti-inflammatory activity by inducing up-regulation of glycosaminoglycan (GAG) synthesis.

[0006] GlcN-induced upregulation of glycosaminoglycan synthesis represents a complex metabolic process that is potentially regulated by several mechanisms, such as direct GlcN entry into the GAG biosynthetic pathway, circumventing negative feedback control from uridine-diphosphate N-acetyl- α -D-glucosamine (Kornfeld et al, (1964) proc.natl.acad.sci.usa 52: 371), and upregulation of TGF α 1 production (Kolm-Litty et al, (1998) j.clin.invest.101: 160). Recently, a new mechanism of GIcN-mediated chondroprotection has been proposed, which involves the inhibition of aggrecanase (aggrecanase) activity in bovine cartilage explants and murine chondrosarcoma cells by the inhibition of glycosylphosphatidylinositol-linked proteins (Sandy et al, (1999) Arch. biochem. Biophys.367: 258) (Sandy et al, (1998) Arch. biochem. Biophys.335(Pt 1): 59).

[0007] GlcN inhibits phosphorylation events in the amplification of the interleukin-1 β (IL-1 β) signaling cascade, providing anti-inflammatory activity. One of the end products of the hexosamine pathway, UDP-N-acetyl-alpha-D-glucosamine, is shown to participate in the dynamic process of protein O-glycosylation, which utilizes serine or threonine residues as anchor sites (Haltiwanger et al, (1997) biochem. Biophys. Res. Commun.231: 237). Potentially, O-glycosylation of serine/threonine residues can compete with phosphorylation of the same residues, leading to a weakening of the intracellular signal transduction cascade (signal transduction cascades) (Chou et al, (1995) Proc. Natl. Acad. Sci. USA 92: 4417).

[0008] IL-1 β is known to induce Nitric Oxide (NO) production in cultured human articular chondrocytes (Geng et al, (1995) J.cell.physiol.163: 545). IL-1 β mediates induction of certain inflammatory mediators, including NO, cyclooxygenase-2 enzyme (COX-2) and interleukin-6 (IL-6), which is associated with the transfer of nuclear factor- κ B (NF- κ B) dimers from the cytoplasm to the nucleus where they bind to target genes and regulate their transcription (Chu et al, (1998) biochem. biophysis. Res. Commun.248: 871; Newton et al, (1997) FEBS Lett.418: 135; Parikh et al, (1997) 69: 139). The process of NF-. kappa.B activation depends on the phosphorylation of two serines (Ser-32 and Ser-36) in the kappa B.alpha.arrestin (I.kappa.B. alpha.) in the N-terminal regulatory domain of kappa B.beta.arrestin (I.kappa.B. beta.) (Karin (1999) J.biol.chem.274: 27339).

[0009] Anti-inflammatory mechanisms other than GlcN-induced upregulation of glycosaminoglycan synthesis may also result in GlcN's anti-arthritic activity. GlcN exhibits anti-inflammatory activity and protects rats from paw edema (paw edema) induced by bradykinin, serotonin and histamine (Setnikar et al, (1991) Arzneim-Forsch./Drug Res.41: 157). GlcN also protects animals from serositis induced by carrageenan, rat peritonitis induced by formalin, and mouse peritonitis induced by acetic acid (Setnikar et al, (1991) Arzneim-Forsch./drug Res.41: 157). GlcN does not inhibit cyclooxygenase or proteolytic enzymes in the inflamed mouse foot, but it inhibits peroxide production and lysosomal enzyme activity in the mouse liver (Setnikar et al, (1991) Arzneim-Forsch./drug Res.41: 157).

[0010] GlcN when administered orally also exhibits anti-inflammatory activity in murine kaolin or adjuvant-induced arthritis (Setnikar et al, (1991) Arzneim-Forsch./Drug Res.41: 542). However, GlcN has less anti-exudative (anti-inflammatory) or anti-inflammatory activity when administered orally than the corresponding activity of acetylsalicylic acid or indomethacin when administered orally.

[0011] Despite these advances in understanding the signaling pathways involved in OA and related disorders, however, the pathway(s) have not yet been fully disclosed. Thus, there is a need in the art for a better understanding of these mechanisms and, in turn, for a more accurate treatment of OA and related disorders with specific and specific aminosugars.

[0012] Many patents are directed to the use of GlcN and N-acetylglucosamine (GlcNAc) for the treatment of specific arthritic conditions. U.S. patent 3,683,076(Rovati) discloses the use of GlcN salts for the treatment of OA and rheumatoid arthritis; U.S. patent 4,870,061 (spec) discloses the use of GlcNAc for the treatment of degenerative joint diseases (degenerative joint diseases) by oral administration (buccal administration); us patent 5,840,715 and us patent 6,136,795 (both Florio) disclose the use of GlcNAc sulfate (as one of the components) as a nutritional supplement in dietary structure to provide relief from arthritis. However, there is a continuing need in the art to find additional compounds that are useful in the treatment of OA and related disorders.

[0013] The main drugs currently used for OA treatment include acetaminophen, NSAIDS, injectable intra-articular corticosteroids and hyaluronic acid. These drugs do not lead to true relief and have many negative side effects, which are discussed later. Therefore, there is a need for safer and effective OA treatments.

[0014] Acetaminophen is an analgesic used to treat pain caused by OA. Acetaminophen does not alter the underlying process of cartilage damage that occurs in OA and does not affect inflammation. One possible side effect of using acetaminophen includes liver damage, which results from prolonged use at high doses (greater than 4,000mg per day) or low doses in persons with chronic alcohol abuse or chronic liver disease.

[0015] NSAIDs, such as ibuprofen and naproxen, are used to reduce pain, inflammation and stiffness caused by OA. Side effects of NSAIDs may include asthma attacks, nausea, stomach pain, gastric bleeding, ulcers and other problems. Prolonged use of these drugs may injure the kidneys, resulting in secondary hypertension.

[0016] COX-2 inhibitors (e.g., Vioxx, Bextra, and Celebrex) are also NSAIDs and are used to reduce pain, inflammation, and stiffness caused by OA. Although they may not cause gastric ulcers as do other NSAIDs, some recent findings suggest that they may have some very serious side effects. After studies showed that long term use doubled the risk of heart attack and stroke, Vioxx was recently withdrawn from the market by the manufacturer Merck & co. Additionally, Pfizer recently disclosed that it would be possible to add a "black box" warning to the label of Bextra — this is one of the strongest warnings. According to Pfizer, Bextra may cause a rare, but sometimes fatal, drug response known as the s-jo syndrome, in which the skin, mouth, and eyes can blister severely. Other drugs including Celebrex may also cause this-however, it appears to be more common with Bextra than others. Patients taking Bextra who do so often do so in the first two weeks of treatment. Bextra is also associated with heart disease in high risk patients.

[0017] Although corticosteroids may be helpful in reducing inflammation, they have some unpleasant side effects, such as secondary hypertension (rapid onset hypertension, usually treatable and from identifiable causes), dyspepsia, increased appetite, weight gain, and nervousness or restlessness. Long-term use of corticosteroids may lead to cushing's syndrome. Cushing's syndrome is the result of an excess of cortisol, which may be derived from a drug, such as prednisone. Excess cortisol can cause many variations, including: increased fat deposition on the face (full moon face), neck and torso; emotional instability; weight gain; hypertension; frailty; diabetes mellitus; and osteoporosis. Furthermore, the use of corticosteroids, such as prednisone, cannot be abruptly stopped because the adrenal glands are inhibited by the long-term administration of prednisone, which makes the body a natural corticosteroid. If a patient has been taking a large dose of corticosteroid for a long period of time, the patient's body may take a year to adjust to the progressively decreasing dose.

[0018] Since there are many side effects of these current OA treatments, and they do not lead to true remission of OA, because they do not prevent or slow the progression of OA, there is a great need for safer and more effective treatments.

Summary of The Invention

[0019] The present invention relates to the discovery of structures useful for the treatment of OA and related disorders. The structure is an improvement over the prior art, wherein the therapeutic compound comprises the amino sugar glucosamine (GlcN) and N-acetyl-D-glucosamine (GlcNAc). The structures have specific moieties (moieties) that give them improved properties for the treatment of OA and related disorders. Structures of the present invention include, but are not limited to: derivatives of glucosamine, derivatives of galactosamine, derivatives of cyclitols and derivatives of iminocyclitols.

[0020] One embodiment of the present invention relates to the anti-inflammatory and cartilage protecting properties of the structures described in the technical field section above, and further relates to the anti-inflammatory and cartilage protecting properties of a subset of the structures in table 1, and further relates to the anti-inflammatory and cartilage protecting properties of a subset of the structures in table 2. According to the present embodiment, these amino sugars and glycoproteins may exhibit their anti-inflammatory and cartilage-protecting properties by interfering with cytokine-induced gene expression in chondrocytes. The structures have improved protein (including intracellular and extracellular receptors) binding, improved chondrocyte penetration, and increased hydrophobicity when compared to prior art compounds. Thus, the structures of the present invention are useful as novel treatments for OA and related disorders.

[0021] A preferred embodiment of the present invention relates to a method of treating, preventing, and reducing the severity of synovitis, subchondral bone edema (subchondral bone edema), and cartilage degeneration (cartilagedegradation) by administering to a patient a therapeutically effective amount of a compound selected from a compound of the structure of the present invention and pharmaceutically acceptable salts thereof, e.g., those compounds in tables 1 and 2, and pharmaceutically acceptable salts thereof. Preferably, a therapeutically effective amount of the structure is administered intra-articularly to a patient. More preferably, a therapeutically effective amount of a structured intra-articular administration is contained in a matrix as a controlled release formulation.

[0022] In another preferred embodiment of the invention, the intraarticular administration of the construct to a patient surprisingly shows an unexpected and significant retardation of cartilage degeneration in patients with less severe cartilage degeneration and a reduction in synovial inflammation both at macroscopic (macropic) and microscopic (microscopic) levels. The retardation of cartilage degeneration and the reduction in synovial inflammation seen following administration of the formulations of the invention make these formulations therapeutically useful, they may be used to treat synovitis, subchondral bone edema and cartilage degeneration in patients in need of such treatment.

[0023] In another preferred embodiment of the invention, the invention relates to a method comprising administering to a patient a composition comprising a therapeutically effective amount of a structure, alone or in combination with an existing anti-inflammatory agent or hexosaminidase inhibitor. Preferably, methods of administering the formulations of the present invention include, but are not limited to, intra-articular, topical, and intramuscular methods. More preferably, the controlled release formulations of said structures are administered intra-articularly to a patient in need of such treatment.

Detailed Description

Abbreviations and terms

[0024] In accordance with the present invention, and as used herein, the following terms and abbreviations are defined with the following meanings unless otherwise explicitly indicated. These explanations are for illustrative purposes only. These interpretations are not to be construed as limiting the terms as they are described or referred to throughout the specification. Rather, these interpretations are intended to include any additional aspect and/or example of the term, as described and claimed herein.

The following abbreviations are used herein:

BrdU ═ 5-bromo-2' -deoxyuridine;

GAGs ═ glycosaminoglycans;

GalNAc ═ N-acetylgalactosamine;

GlcN ═ glucosamine;

GlcNAc ═ N-acetylglucosamine;

HA ═ hyaluronic acid;

IL-1 β ═ interleukin-1 β;

IL-6 ═ interleukin-6;

MMP ═ matrix metalloproteinase;

NSAIDs are non-steroidal anti-inflammatory drugs;

OA is osteoarthritis;

PBS (phosphate buffered saline);

PEG ═ polyethylene glycol;

PMSF ═ phenylmethylsulfonyl fluoride;

RA ═ rheumatoid arthritis; and

SGAG ═ sulfated glycosaminoglycan (sulfated glycosaminoglycan)

[0025] The term "active ingredient" refers to a therapeutically effective amount of a drug or formulation thereof. Preferably, the active ingredients of the present invention are those compounds described in table 1, structures a-J and their derivatives.

[0026] The phrase "alginate gel" refers to a natural polysaccharide polymer comprising 1, 4-linked β -D-mannuronic acid and α -L-guluronic acid residues in varying proportions. Alginate is capable of forming stable gels, particularly in the presence of certain divalent cations, such as calcium, barium and strontium.

[0027] The phrase "amino acid derivative" refers to an amino acid that has been modified to include various substituents.

[0028]The term "aminosugar" refers to any synthetic or naturally occurring sugar in which one or more carbon atoms are replaced with an amino group (-NR)¹R²) And (4) substitution. Such substitution may occur regardless of the orientation or configuration of any asymmetric carbon present in the saccharide. Unless otherwise indicated, the term "aminosugar" refers to either anomer (α or β) of a cyclic or open chain aminosugar. The aminosugars may be N-substituted with alkyl or acyl groups, wherein one hydrogen atom of the pendant amino group is replaced by an alkyl or acyl moiety (-COR, where R ═ lower alkyl).

[0029] The expression "aminosugar derivative" refers to a derivative of a sugar having at least one amino substituent.

[0030] The word "arthritis" refers to any particular disease characterized by inflammation of the joints, although the cause of inflammation may differ in various conditions. Relatively common arthritic conditions include rheumatoid arthritis, juvenile arthritis, ankylosing spondylitis, psoriatic arthritis, and osteoarthritis. These are also called "degenerative joint diseases".

[0031] The words "articular cartilage" or "cartilage" refer to the substance that covers the ends of bone and forms the surface of the joint. Cartilage can withstand pressure and create a low friction surface for the sliding of joints. Articular cartilage includes chondrocytes and a matrix including proteins and glycosaminoglycan polysaccharides.

[0032] The term "cartilage degeneration" refers to degeneration in tissues including cartilage.

[0033] The expression "chitin (chitin)" refers to (poly) GlcNAc linked in a β -1, 4 manner. Chitin is widely found in nature, for example in the exoskeletons of insects and crustaceans.

[0034] The expression "chitosan (chitosan)" refers to deacetylated chitin or (poly) N-glucosamine linked in a β -1, 4 manner.

[0035] The term "chondrocyte" refers to a cell found in articular cartilage. Chondrocytes produce collagen, colloidal proteins and proteoglycans, which are glycosaminoglycans (also known as mucopolysaccharides) linked to proteins.

[0036] The term "conjugate" refers to a combination of two or more different molecules that are chemically bonded. The bond characteristics of the conjugates of the invention include, but are not limited to, amides, acetals, thioacetals, esters, and thioesters, or any such bond formed primarily by treatment of a reactive carbonyl component with a nucleophile.

[0037] The word "sustained release" is used only to describe a release profile that appears to be monophasic, with a smooth curvilinear release versus time profile. Those skilled in the art will appreciate that the release profile may actually correspond to an exponential or logarithmic time-release profile.

[0038] The term "cyclitol" refers to a cycloalkane containing one hydroxyl group on each of three or more ring atoms.

[0039] The phrase "derivative of a cyclitol" refers to a cyclitol that has been modified to include various substituents, including, but not limited to, amino groups.

[0040] The expression "iminocyclitol" refers to a sugar derivative in which the epoxy group is substituted by a nitrogen atom.

[0041] The expression "derivatives of iminocyclitols" refers to iminosugars which have been modified, including the iminocyclitols, which are inhibitors of hexosaminidases.

[0042] The phrase "derivative of galactosamine" refers to galactosamine that has been modified to include various substituents, including but not limited to N-acetylgalactosamine.

[0043] The phrase "derivative of glucosamine" refers to glucosamine that has been modified to include various substituents, including but not limited to N-acetylglucosamine.

[0044] The expression "encapsulation efficiency" refers to the amount of a compound or active ingredient that is contained, incorporated, loaded, associated, bound or otherwise embedded in an injectable polymer gel, liposome, microsphere, nanoparticle or the like. In general, "yield" is expressed as the encapsulation percentage of the active ingredient.

[0045] The terms "entrapped" or "encapsulated" refer to any method of formulating an active ingredient that limits, isolates, or otherwise inhibits the free dissolution of the active ingredient in a matrix, such as a solution or solid phase. Preferred examples of embedded or encapsulated active ingredients include, but are not limited to, formulations embedded in a matrix, wherein the matrix is selected from a granule, implant or gel.

[0046] The term "glycosaminoglycan" refers to a long heteropolysaccharide molecule containing a repeating disaccharide unit. The disaccharide unit can include a modified amino sugar: D-N-acetylgalactosamine or D-GlcNAc, and uronic acids, such as D-glucuronic acid or L-iduronic acid. GAGs are, among other functions, the lubricating fluid in the joints. Specific GAGs of physiological importance are hyaluronic acid, dermatan sulfate, chondroitin sulfate, heparin, heparan sulfate and keratan sulfate.

[0047] The term "hexosamine" refers to any amino sugar of a six carbon polyhydric alcohol containing an aldehyde or ketone group. The term hexosamine includes aldoses, deoxy aldoses and ketoses, regardless of the orientation or configuration of the asymmetric carbon bond. Preferred amino sugars are 2-, 3-, 5-or 6-deoxyketoses, preferably deoxyamino sugars, such as GlcN, mannosamine and galactosamine. More preferably, the amino sugar is N-acylated and is selected from the group consisting of deoxyacyl amino sugars, such as GlcNAc, N-acetylmannosamine, and GalNA.

[0048] The word "hexosaminidase" refers to any glycosidase that partially or completely hydrolyzes chitin or chitosan into their respective monosaccharide building blocks, e.g., GlcNAc and GlcN. Exemplary enzymes include exo-type β -D-gluconamides, β -N-acetylhexosaminidase, chitosanase (chitasanase), chitinase, lysozyme, and the like.

[0049] The phrase "hyaluronic acid (hyaluronan)" refers to a polymer of repeating molecules of N-acetylglucosamine and glucuronic acid.

[0050]The expression "hyaluronic acid" refers to a naturally occurring linear polysaccharide (long-chain biopolymer) formed by repeating a disaccharide unit composed of beta (1-3) N-acetyl-D-glucosamine-D-glucuronic acid linked by beta (1-4) glycosidic bonds. Hyaluronic acid is commercially available in several molecular weight ranges, from about 50,000 daltons to about 8 × 10⁶And D, dalton. Hyaluronic acid is also obtained as a sodium salt and is a dry, highly purified substance. Sodium hyaluronate may be stored with various preservatives known in the art including, but not limited to, alkyl substituted benzoates, alcohols, conjugates, blends, and mixtures thereof.

[0051] The word "IL-1 β" refers to interleukin-1 β, which is an immunomodulator that modulates a wide range of immune and inflammatory responses, including the modulation of B-cell and T-cell activation.

[0052] The word "IL-6" refers to interleukin-6, a multifunctional cytokine produced by a wide variety of cells. IL-6 functions as a regulator of immune response, acute phase response and hematopoiesis.

[0053] The phrase "injectable formulations" refers to sterile injectable compositions prepared as liquid solutions or suspensions. Solid forms suitable for dissolution or suspension in a liquid medium prior to injection may also be prepared. The preparation can also be emulsification or embedding of the active ingredient. Injectable formulations may also include various preservatives known in the art including, but not limited to, alkyl substituted benzoates, alcohols, conjugates, blends and mixtures thereof.

[0054] The expression "injectable polymer gel" refers to a polymer matrix carrier for embedding or encapsulating the active principle of the invention. Polymer-based injectable formulations allow the dosage and timing of the drug to be tailored by the selection and formulation of various active ingredient/polymer combinations. The total dose and release kinetics of the drug are variables that can be adjusted. For example, by varying the solvent content, copolymer ratio and copolymer molecular weight, and polymer solvent polarity, drug delivery parameters can be optimized. Polymer-based systems may also increase the useful life of the active ingredient. The use of polymer systems including polylactide and lactide-glycolide copolymers in formulations provides certain advantages, such as biocompatibility and biodegradability. The injectable polymer gel may be prepared, for example, processed, mixed, filtered, heated or sterilized according to processes known in the art.

[0055] The word intra-articular refers to a method of delivering drugs directly to the joint. Traditional drug delivery routes such as oral, intravenous or intramuscular administration rely on synovial vascular infusion (vasculerpusion) to transport drugs to the joint. This is inefficient because transsynovial transport of small molecules from synovial capillaries to the joint space typically occurs by passive diffusion, which becomes less effective as the size of the target molecule increases. Thus, the route of introducing molecules such as glucosamine (GlcN) into the joint space is essentially limited. Intra-articular injection or infusion of drugs overcomes these limitations.

[0056] The word "less severe" refers to a particular level of cartilage degeneration in a patient. Preferably, the less severe level is in the range of level 1 to level 3. More preferably, the less severe level is in the range of level 1 to level 2.

[0057] The expression "liposome" refers to a vesicle (vesicle) that forms spontaneously, for example when a phospholipid is dispersed in water or an aqueous medium, due to the hydrophilic interaction of lipid head groups (lipid head groups) with water and the production of single or multi-layered systems (vesicles) similar to biological membranes. In unilamellar liposomes, the bilayer structure forms a hollow sphere with a polar face facing the inner water chamber and the outer bulk water. Several acceptable methods of forming liposomes are known in the art. Generally, lipid bilayers are separated by an aqueous layer, forming multilamellar concentric bilayer vesicles. This onion-like structure is called multilamellar vesicles (MLV). Smaller unilamellar vesicles (unilamellar vesicles) can be produced by sonicating or compressing MLVs under appropriate conditions. Liposomes can be formulated with Chol to increase stability, and can include other materials, such as neutral lipids and surface modifiers, such as positively or negatively charged compounds. The preferred liposomes are small, monolayer bilayer spherical shells. Liposomes can encapsulate both lipophilic and hydrophilic drugs. When prepared by suitable methods, they can release the drug over an extended period of time. In addition, there is no toxicity associated with phospholipids. Many natural and synthetic phospholipids are commercially available and can be used to prepare liposomes. Examples known in the art and described by abbreviations include, but are not limited to, DSPC, DSPE-Con, DSPG, and DPPS.

[0058] The expression "matrix" refers to a solid, gel or liquid composition, which is capable of embedding therein the amino sugar and optionally further substances, such as anti-inflammatory drugs.

[0059] The expression "microsphere" refers to a polymeric matrix carrier for embedding or encapsulating the active principle of the invention. Microsphere-based formulations allow the dosage and timing of the drug to be tailored by the selection and formulation of various active ingredient/polymer combinations. The total dose and release kinetics of the drug are variables that can be adjusted. For example, by varying the copolymer ratio and copolymer molecular weight, drug delivery parameters can be optimized. Microsphere-based systems may also increase the useful life of the active ingredient. The use of microspheres comprising lactide-glycolide copolymers in the formulation provides certain advantages, such as biocompatibility and biodegradability. The microspheres may be prepared, for example, processed, machined, milled, ground or extruded according to processes known in the art.

[0060] The phrase "osteoarthritis related disorders" refers to the following conditions or diseases: osteoarthritis, rheumatoid arthritis, synovitis, subchondral bone edema, and cartilage degeneration.

[0061] The words "pharmaceutically acceptable" or "pharmacologically acceptable" refer to a formulation that does not produce an adverse, allergic, or other untoward reaction when administered to a mammal as appropriate (e.g., by a physician or veterinarian).

[0062]The words "polyethylene glycol" and "PEG" are meant to include the subunit HO- (CH)₂CH₂O)_nH, a water-soluble polymer. PEG may be end capped with an alkyl group.

[0063] The words "polymeric" or "polymeric carrier" refer to hyaluronic acid, polyethylene glycol, copolymers of polyethylene glycol and poly (lactic/glycolic acid), polymers of lactic acid and copolymers of poly (ethylene glycol-gamma- (DL-lactic-co-glycolic acid)), alginate gels, chitosan or pharmaceutically acceptable salts thereof.

[0064] The term "sustained release" refers to a period of time during which a drug is released to be available, or otherwise becomes physiologically absorbable. The time period of sustained release may be preceded by an induction period during which little or no drug is released, or the time period of sustained release may be biphasic, including an initial time period during which some drug is released and a second time period during which additional drug is released.

[0065] The word "synovitis" refers to inflammation of the joint lining. Synovitis is present in a variety of joint-related conditions including, but not limited to, osteoarthritis, physical or traumatic injuries, rheumatoid arthritis, and other autoimmune diseases.

[0066] The phrase "therapeutically effective amount" refers to the amount of biologically active substance necessary to cause the desired pharmacological effect. Depending on the potency of the particular active; age, weight, and response of the individual; as well as the nature and severity of the individual symptoms, which amount may vary widely. Thus, there is no strict upper or lower limit to the amount of active substance. A therapeutically effective amount for use in the present invention can be readily determined by one skilled in the art.

[0067] The present invention relates to methods of treating, preventing and lessening the severity of a condition or disease selected from Osteoarthritis (OA), rheumatoid arthritis, synovitis, subchondral bone edema and cartilage degeneration (hereinafter "OA and related disorders") by administering an amino sugar and pharmaceutically acceptable salts thereof.

[0068] The present invention relates to the discovery of structures useful for the treatment of OA and related disorders. The structures are an improvement over the prior art, wherein the therapeutic compounds include the amino sugar glucosamine (GlcN) and N-acetyl-D-glucosamine (GlcNAc). The structures have specific moieties that provide improved properties for the treatment of OA and related disorders. Structures of the present invention include, but are not limited to, derivatives of glucosamine, derivatives of galactosamine, derivatives of cyclitols, and derivatives of iminocyclitols. The related family of amino sugar structures shown below (hereinafter "structures") is of particular interest.

Formula I

[0069] The compounds claimed herein include those of formula I wherein:

[0070]R¹the method comprises the following steps: CHO, CH₂OH or CO₂H；

[0071]R²The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

[0072]R³the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R²，R³＝O；

[0073]R⁴The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Is cyclic or acyclic alkyl, aryl, linked by ether bondsRadical, heterocyclic radical), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

[0074]R⁵the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁴，R⁵＝O；

[0075]R⁶The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

[0076]R⁷the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁶，R⁷＝O；

[0077]R⁸The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

[0078]R⁹the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁸，R⁹＝O；

[0079]R¹⁰The method comprises the following steps: H. CH (CH)₃、CH₂OH、CH₂OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), CH₂Cl、CH₂Br、CH₂F、CH₂SH、CH₂SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂NH₂、CH₂NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or CH₂NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative); and

[0080]when the compound has R¹When R is CHO, if⁸Is OH, SH, NH₂Or NHR¹⁴Or R is⁶Is OH, SH, NH₂Or NHR¹⁴The compound may be present in cyclic form.

Formula II

[0081] The compounds claimed herein include those of formula II, wherein:

[0082]x is: o, S, CH₂NH or NR²⁰(wherein R is²⁰Is a cyclic or acyclic alkyl, aryl, heterocyclic group);

[0083]y is: o, S, CH₂Or NH;

[0084]R¹⁷the method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH²、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

[0085]R²the method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

[0086]R³the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R²，R³＝O；

[0087]R⁴The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivativeProduct), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

[0088]R⁵the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁴，R⁵＝O；

[0089]R⁶The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

[0090]R⁷the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁶，R⁷＝O；

[0091]R⁹The method comprises the following steps: H. c-linked cyclic or acyclic alkyl, aryl, or heterocyclic groups; and

[0092]R¹⁰the method comprises the following steps: H. CH (CH)₃、CH₂OH、CH₂OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), CH₂Cl、CH₂Br、CH₂F、CH₂SH、CH₂SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂NH₂、CH₂NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or CH₂NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative).

Formula III

[0093] Compounds claimed herein include those of formula III wherein:

[0094]x is: o, S, CH₂NH or NR²⁰(wherein R is²⁰Is a cyclic or acyclic alkyl, aryl, heterocyclic group);

[0095]y is: o, S, CH₂Or NH;

[0096]R¹⁷the method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH²、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

[0097]R²the method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is in the form of a ringOr without cycloalkyl, aryl, heterocyclic or amino acid derivatives), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

[0098]R³the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R²，R³＝O；

[0099]R⁴The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

[0100]R⁵the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁴，R⁵＝O；

[0101]R⁷The method comprises the following steps: h, a C-linked cyclic or acyclic alkyl, aryl, or heterocyclic group;

[0102]R⁸the method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Is a cyclic or acyclic alkyl, aryl, heterocyclic radical linked by ether bondsCluster), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

[0103]R⁹the method comprises the following steps: h, a C-linked cyclic or acyclic alkyl, aryl, or heterocyclic group; and

[0104]R¹⁰the method comprises the following steps: H. CH (CH)₃、CH₂OH、CH₂OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), CH₂Cl、CH₂Br、CH₂F、CH₂SH、CH₂SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂NH₂、CH₂NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or CH₂NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative).

Formula IV

[0105] The compounds claimed herein include those of formula IV wherein:

[0106]y is: o, S, CH₂Or NH;

[0107]R¹⁷the method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH²、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

[0108]R¹⁸the method comprises the following steps: H. o, NH or NR¹⁹(wherein R is¹⁹Is a cyclic or acyclic alkyl, aryl, heterocyclic group, or an acyl-linked cyclic or acyclic alkyl, aryl, or heterocyclic group);

[0109]R²the method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

[0110]R³the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R²，R³＝O；

[0111]R⁴The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

[0112]R⁵the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁴，R⁵＝O；

[0113]R⁶The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

[0114]R⁷the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁶，R⁷＝O；

[0115]R⁸The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

[0116]R⁹the method comprises the following steps: h, C-linked cyclic or acyclic alkanesA radical, an aryl radical, a heterocyclic radical, or R⁸，R⁹O; and

[0117]R¹⁰the method comprises the following steps: H. CH (CH)₃、CH₂OH、CH₂OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), CH₂C1、CH₂Br、CH₂F、CH₂SH、CH₂SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂NH₂、CH₂NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or CH₂NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative).

[0118]Having Y-R¹⁷May be prepared by reacting a compound of (A) with a compound of (B)¹⁷Functional group-linked monomeric, oligomeric or polymeric forms. By reaction with R¹⁷The moieties act as linkers, and these compounds may be covalently coupled to another molecule, including a peptide, protein or particle. By reaction with R¹⁷Partly as anchors (anchors), these compounds can also be bound non-covalently in the form of liposomes or particles.

[0119] One embodiment of the present invention relates to the anti-inflammatory and cartilage protecting properties of the above structures and further to the anti-inflammatory and cartilage protecting properties of the subset of structures in table 1 and also to the anti-inflammatory and cartilage protecting properties of the subset of structures in table 2. According to this embodiment, these amino sugars and glycoproteins may exhibit anti-inflammatory and cartilage-protective properties by interfering with cytokine-induced gene expression in chondrocytes. The structures have improved protein (including intracellular and extracellular receptors) binding, improved chondrocyte penetration, and increased hydrophobicity when compared to prior art compounds. Thus, the structures of the present invention are useful as novel treatments for OA and related disorders.

[0120] A preferred embodiment of the present invention relates to a method of treating, preventing and reducing synovitis, subchondral bone edema and cartilage degeneration by administering to a patient a therapeutically effective amount of a compound selected from the group consisting of compounds of the structures of the present invention and pharmaceutically acceptable salts thereof, such as those in tables 1 and 2, and pharmaceutically acceptable salts thereof. Preferably, a therapeutically effective amount of the construct is administered intra-articularly to the patient. More preferably, a therapeutically effective amount of the construct is administered intra-articularly as a controlled release formulation contained within a matrix.

[0121] In another preferred embodiment of the invention, the structure administered intra-articularly to a patient surprisingly exhibits an unexpected and significant retardation of cartilage degeneration in patients with less severe cartilage degeneration and a reduction in synovial inflammation at macroscopic and microscopic levels. The retardation of cartilage degeneration and the reduction in synovial inflammation seen following administration of the formulations of the invention make them therapeutically useful in treating conditions such as synovitis, subchondral bone edema, and cartilage degeneration in patients in need of such treatment.

[0122] In another preferred embodiment of the invention, the invention relates to a method comprising administering to a patient a composition comprising a therapeutically effective amount of a structure, alone or in combination with an existing anti-inflammatory agent or hexosaminidase inhibitor. Preferably, methods of administering the formulations of the present invention include, but are not limited to, intra-articular, topical, and intramuscular methods. More preferably, the controlled release formulations of said structures are administered intra-articularly to a patient in need of such treatment.

Formulations and methods

[0123] The present invention relates to the use of novel amino sugars based on their anti-inflammatory properties. Thus, the following discussion details the experiments designed to determine the cause of the cartilage protective and anti-inflammatory properties of these aminosugars. Based on the studies, novel structures for the treatment of OA and related disorders are obtained. Without limiting the scope of applicants' invention, related families of structures shown below are particularly useful as compounds of the invention.

Formula V formula VI

Wherein X may be O, NH or CH₂

These compounds of formulae V and VI (subsets a-J of structures) are defined by their particular pattern of substituents as shown in table 1 and described with reference to above.

Subset of the structures of Table 1 (A-J)

[0124] Methods of screening compounds and analytical measurement methods are disclosed or well known in the art. See, for example, PCT publication WO 02/078445a1, which is incorporated herein by reference in its entirety. The structures of the present invention will be similarly screened to elucidate their improved properties. The following examples section lists various analytical methods that can be performed to screen the structures of the present invention.

[0125] Various modifications and alterations of this invention will be apparent to those skilled in the art without departing from the spirit and scope of this invention. For example, it should be noted that the steps described in any method need not be performed in the order in which they are recited. Those skilled in the art will recognize variations when performing the steps in the order in which they are recited. For further example, in certain embodiments, the steps may be performed simultaneously. The foregoing methods should be constructed with these principles in mind.

[0126] Studies have revealed specific structures that can be used as pharmaceutical compositions to treat OA and related disorders. Without being bound by any theory, the structures and their derivatives have improvements over the prior art compounds in the following respects: the structures have improved hydrophobicity, improved hydrolytic characteristics, improved cell penetration, enhanced protein and receptor (intracellular and extracellular) binding, and improved structures. Furthermore, the structures are useful for elucidating signaling pathways involved in the treatment of OA and related disorders with aminosugars, which in turn allows for the customized selection of specific structures for more precise treatment of OA or related disorders in patients.

[0127] Merely by way of example, the following class 5 specific structures are of particular interest.

TABLE 2 subset of structures (classes 1-5)

Class 1: simple alkyl glycosides of GlcNAc/GalNAc

Class 2: n-acyl derivatives of glucosamine (GlcNH)₂)

Class 3: substrates of hexosaminidases

Class 4: multivalent forms of GlcNAc

Class 5: GlcNAc-like molecules (sugar derivatives)

Pharmaceutical formulations and administration

[0128]The aminosugars or derivatives thereof as active ingredients may be formulated into pharmaceutically acceptable preparations, such as those described in Remington's Pharmaceutical Sciences, 18^thed., Mack Publishing Co., Easton, Pa (1990), which is incorporated herein by reference, and is used for the specific treatment of a disease or pathological condition with little or no effect on healthy tissue. The preparation of a pharmaceutical composition comprising an active ingredient dissolved or dispersed therein is not necessarily limited based on the formulation. Such compositions may be prepared as injectable liquid solutions or suspensions. However, solid forms suitable for dissolution or resuspension in a liquid prior to use can also be prepared. The preparation may also be emulsified.

[0129] In a preferred embodiment, the composition is contained in a container that includes a label stating the effectiveness of the composition as approved by the U.S. FDA for treatment of a disease or condition described herein (or an equivalent label in other countries). Such a container will provide a therapeutically effective amount of the active ingredient to be administered to the host.

[0130] The particular aminosugars that are effective for the condition of interest may be administered to the mammal, alone or in admixture with suitable carrier(s) or excipient(s), in the form of a pharmaceutical composition. In treating a mammal exhibiting a condition of interest, a therapeutically effective amount of one or more agents, such as one of the structures of the present invention (including but not limited to derivatives of glucosamine, derivatives of galactosamine, derivatives of cyclitols, or derivatives of mesoiminocyclitols) is administered. The active ingredient may be mixed with excipients that are pharmaceutically acceptable and compatible with the active ingredient in amounts suitable for use in the methods of treatment described herein.

[0131] Pharmaceutically acceptable salts may be prepared by standard techniques. For example, the free base form of the compound is first dissolved in a suitable solvent, such as an aqueous or hydro-alcoholic solution containing a suitable acid. The salt is then isolated by evaporating the solution. In another embodiment, the salt is prepared by reacting a free base and an acid in an organic solvent.

[0132] The carrier or excipient may be used to facilitate administration of the compound, for example, to increase the solubility of the compound. Examples of carriers and excipients include calcium carbonate, calcium phosphate, various sugars or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, water, saline, dextrose, glycerol, ethanol, and physiologically compatible solvents.

[0133] Pharmaceutically acceptable salts of the components may be included in the compositions of the present invention. Such pharmaceutically acceptable salts include the acid addition salts (formed with any of the free amino groups of the amino sugar) formed with inorganic acids such as hydrochloric or phosphoric acid, sulfuric acid and the like, or with organic acids such as acetic, tartaric, mandelic and the like. Salts formed with the free carboxyl groups of the amino sugars can also be derived from inorganic bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, or ferric hydroxide and organic bases such as isopropylamine, trimethylamine, 2-aminoethanol, histidine, procaine and the like.

[0134] Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by measuring LD50 (the lethal dose of 50% of the population) and ED50 (the therapeutically effective dose in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50/ED 50. Compounds that exhibit large therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used to formulate a range of doses for use in humans. The dosage of such compounds is preferably within a range of circulating concentrations that includes ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

[0135] For any aminosugar compound used in the methods of the present invention, the therapeutically effective dose may be initially estimated based on cell culture assays. For example, the dose can be formulated to achieve a circulating plasma concentration range in animal models that includes IC50 (i.e., the concentration of the test compound that achieves half-maximal lysis of the protein complex (half-maximal lysis), or half-maximal inhibition of the intracellular level and/or activity of a component of the complex (half-maximal inhibition)) as determined in cell culture. Such information can be used to more accurately determine useful dosages in humans. Levels in plasma can be measured by, for example, HPLC.

[0136] Another preferred embodiment of the invention relates to an improved preparation of the active ingredient GlcNAc. GlcNAc is encapsulated or embedded in liposomes or other encapsulating agents (entropping agents), which will alter its pharmacokinetic profile when injected intra-articularly. Preferably, the GlcNAc is embedded in the matrix. More preferably, the GlcNAc is embedded in a matrix selected from a particle, an implant or a gel.

[0137] The exact formulation, route of administration and dosage can be selected by the individual physician, depending on the condition of the mammal. (see, for example, Fingl et al, in The Pharmacological Basis of Therapeutics, 1975, Ch.1p.1). It should be noted that the attending physician knows how and when to terminate, interrupt or adjust administration in view of toxicity or organ dysfunction. Conversely, if the clinical response is inadequate (to preclude toxicity), the attending physician will also know to adjust the treatment to higher levels. In the treatment of a condition of interest, the number of doses administered will vary with the severity of the condition to be treated and the route of administration. For example, partial assessment of the severity of a condition can be made by standard prognostic evaluation methods. Moreover, the dosage and possibly the frequency of dosage will also vary according to the age, weight and response of the individual animal. In veterinary medicine, a procedure similar to the one described above may be used.

[0138]Such agents may be formulated and administered systemically or locally depending on the particular condition being treated. In Remington's Pharmaceutical Sciences, 18^thed., Mack Publishing Co., Easton, Pa. (1990), which is incorporated herein by reference.

[0139] For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers, such as Hanks's solution, Ringer's solution, or physiological saline buffer.

[0140] It is within the scope of the present invention to formulate the compounds disclosed herein for use in the practice of the present invention as dosages suitable for systemic administration (systemic administration) using a pharmaceutically acceptable carrier. By appropriate choice of carrier and appropriate manufacturing practice, the compositions of the present invention, particularly those formulated as solutions, can be administered parenterally, for example by intravenous injection.

[0141] Pharmaceutical compositions suitable for use in the present invention include compositions comprising an effective amount of the active ingredient to achieve its intended purpose. Determination of an effective amount is within the ability of those skilled in the art, particularly in view of the detailed disclosure provided herein. In addition to the active ingredient, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. The pharmaceutical compositions of the invention can be manufactured in a manner known per se, for example by means of conventional mixing, dissolving, granulating, dragee-making, levitating, emulsifying, encapsulating, entrapping or lyophilizing processes.

[0142] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Alternatively, suspensions of the active compounds can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, for example sodium carboxymethyl cellulose, sorbitol or dextran. Alternatively, the suspension may contain suitable stabilizers or agents that increase the solubility of the compounds to produce highly concentrated solutions.

[0143] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gum, polyethylene glycol and/or titanium dioxide, lacquer solutions (lacquer solutions) and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the tablets or dragee coatings for the purpose of identifying or characterizing different combinations of active compound doses.

Examples

[0144] The following examples are provided by way of illustration of specific embodiments of the invention and are not intended to limit the scope of the invention in any way.

Example 1

Treatment of cultured osteoarthritic human articular chondrocytes with aminosugars

[0145] Following conventional total knee replacement, human osteoarthritic cartilage is harvested from a donor who has been informed. Articular cartilage from femoral condyles and tibial plateaus (tibial plateaus) was aseptically dissected. The cartilage scrapings were harvested and placed in tissue culture medium (DMEM, 10% FBS, penicillin, streptomycin) and stored at 4 ℃ until they were processed.

[0146]After digestion sequentially with pronase (Roche, 10g/l) for 30 minutes and collagenase type IV (Sigma, 1g/l) for 6 hours, both in 0.9% NaCl, chondrocytes were isolated from cartilage. In DMEM (BioWhittaker) supplemented with 10% fetal bovine serum (BioWhittaker), 60U/ml penicillin, 60. mu.g/ml streptomycin and 2mmol/l glutamine (BioWhittaker), 5% CO was present at 37 deg.C₂In the case of (3), chondrocytes are allowed to grow to confluence.

[0147] Assays were performed with either primary or secondary generation cells. Chondrocyte proliferation and apoptosis were determined after incubation of human chondrocytes with different levels of various aminosugar derivatives of the present invention, including but not limited to derivatives of glucosamine, derivatives of galactosamine, derivatives of cyclitols and derivatives of iminocyclitols. Where indicated, cells were preincubated with equimolar concentrations of each structure. Cell morphology and survival were assessed macroscopically by staining observations and biochemically with BrdU staining.

Example 2

Effect of aminosugars on IL-1 beta-induced NO in cultured chondrocytes

[0148] IL-1. beta. induced inflammatory mediator NO was measured by protein ELISA (R & D Systems, Minneapolis, MN) according to the method of the Griess reaction (level, et. al. methods enzymol.233: 250).

[0149] Amino sugars such as GlcN and GlcNAc are known to inhibit IL-1 β and TNF α -induced nitric oxide (. NO) production in osteoarthritic human articular chondrocytes (PCT publication WO 02/078445A 1). Therefore, the influence of the aminosugar derivatives of the present invention including, but not limited to, derivatives of glucosamine, derivatives of galactosamine, derivatives of cyclitol, and derivatives of iminocyclitol on IL-1 β -induced production of NO will be measured and compared according to the method of Griess reaction.

[0150]In oxygenated solutions, NO decomposes to form NO₂ ^-And NO₃ ^-As shown in formulas (1) to (3).

2·NO+O₂→2·NO₂ (1)

H₂O

·NO+·NO₂→N₂O₃→2NO₂ ^- (2)

H₂O

2·NO₂→N₂O₄→NO₂ ^-+NO₃ ^- (3)

[0151]These stable end products can be detected using a discontinuous spectrophotometric assay. By observing the presence of NO₂ ^-And a Griess reagent can directly detect the nitrite. On the other hand, if an in-line low pressure pumping system is used, the NO must first be pumped using nitrate reductase or copper cadmium plated columns₃ ^-Reduction to NO₂ ^-. The automated system (Green et al. anal. biochem. 126: 131) has been described in detail elsewhere, but certain aspects of the system are discussed below.

[0152]Cultured cells such as osteoarthritic human articular chondrocytes described in example 1 above, can be plated in 96-well plates at 40,000 cells/well in the presence of 1% FBS. After 48 hours, moreChange medium (the medium should not contain phenol red, because phenol red absorbs in the same region as the Griess reaction product). Cells were then stimulated with 5ng/ml IL-1 β for 24 hours in the presence of the above amino sugar of the invention. Production of NO will be detected as NO in cell culture supernatant₂ ^-And (4) accumulating.

[0153]Fresh Griess reagent should be prepared by mixing equal volumes of 0.1% naphthylethylenediamine dihydrochloride (NEDD) and 1% sulfanilamide in 5% phosphoric acid. Nitrate reductase (Aspergillus species) and L-glutamate dehydrogenase (Candida utilis) are commercially available. Cadmium powder (100 mesh) is available from Aldrich (Milwaukee, Wis.) and should be processed as described in Green et al, with the following modifications. A small amount of cadmium (2-3g) was washed with water in a 250ml conical flask to remove fines. Then the cadmium is added with 2 percent CuSO₄·H₂And washing twice with water. The washing should be done quickly because if left in solution for too long, the cadmium will turn reddish brown, resulting in a reduction in reducing power. The copper-plated cadmium was gently emptied and washed thoroughly with water, and then washed with 1% phosphoric acid. The copper-plated cadmium was stored in 1% phosphoric acid with as little headspace as possible.

[0154]In a disposable semimicroscale colorimetric cell, the following were combined: 210 μ l cell culture supernatant, 60 milliunits (milliunits) nitrate reductase and 25 μm NADPH. The samples were incubated for 30 minutes at room temperature to allow for NO₃ ^-Reduction to NO₂ ^-Then the following were added: 200 milliunits of L-glutamate dehydrogenase, 100mM NH₄Cl and 4mM freshly prepared alpha-ketoglutaric acid. The samples were then incubated at room temperature for an additional 10 minutes to allow any residual NADPH to be consumed as NADPH interferes with the Griess reaction. Then, 250. mu.l of Griess reagent was added to bring the total reaction volume to 500. mu.l. The samples were incubated at 37 ℃ for 5 minutes. The absorbance at 543mm was then recorded relative to the blank, which should contain buffer and Griess reagent. Using a mixture of NO at known concentrations₂ ^-And NO₃ ^-The generated standard curve can determine NO in the sample₂ ^-And NO₃ ^-The concentration of (c).

Example 3

Effect of amino sugars on IGF-stimulated sulfated glycosaminoglycan (SGAG) Synthesis

[0155]Both basic sulfated glycosaminoglycan (SGAG) synthesis and IGF-stimulated sulfated glycosaminoglycan (SGAG) synthesis in vitro and in vivo can be determined by methods similar to those described elsewhere (Scharstuhl et al. Can be assayed in the extracellular fraction³⁵Sodium S-sulfate (ICN Radiochemicals, Irvine, Calif.) was incorporated at the level of SAGA. This can be done in the presence or absence of amino sugar derivatives of the present invention including, but not limited to, derivatives of glucosamine, derivatives of galactosamine, derivatives of cyclitols, and derivatives of iminocyclitols.

In vivo SGAG synthesis:

[0156] the right knee joint of mice aged 3 months to 18 months can be injected with IGF in PBS supplemented with 0.1% bovine serum albumin and amino sugar derivatives of the present invention including, but not limited to, derivatives of glucosamine, derivatives of galactosamine, derivatives of cyclitols, and derivatives of iminocyclitols. Three injections may be given on alternate days (1, 3 and 5 days). Both left knee joints can be injected with IGF in PBS supplemented with 0.1% bovine serum albumin as an internal control.

[0157]The synthesis of SGAG can be measured ex vivo one day after the last injection. Mice were sacrificed and patella with standard amounts of surrounding tissue dissected away as described elsewhere (van den Berg et al. Reumatol. int.6: 273). Then use³⁵The patella was pulse-labeled with S-sulfate (20. mu. Ci, 2 hours, 37 ℃). The patella was then washed thoroughly with saline and fixed in 96% ethanol at room temperature for 24 hours. Thereafter, the patella was decalcified in 5% formic acidAnd was carried out at room temperature for 4 hours. Articular cartilage was then stripped from The bottom bone and dissolved in Lumasolve (Lumac, Groningen, The Netherlands) at 60 ℃. For each patella, measurements were made separately using a liquid scintillation counter³⁵And (4) doping S.

In vitro SGAG synthesis:

[0158]mice between 3 and 5 months or 12 and 21 months of age were sacrificed. The patella with surrounding tissue was dissected in a standard manner and placed in RPMI1640 medium (Dutchmodification, flowaberrators, Irvine, UK). The patella was divided into 6 treatment groups (minimum six patella per group): (1) no treatment, (2) IGF, (3) IGF + glucosamine derivatives, (4) IGF + galactosamine derivatives, (5) IGF + cyclitol derivatives, and (6) IGF + iminocyclitol derivatives. The tissue culture medium was changed every 24 hours. After 48 hours of treatment, the patella was treated in RPMI1640(Dutchmodification) supplemented with gentamicin (50mg/L) and 2 mM/L-glutamine at 37 ℃ and 5% CO₂And labeled with 20. mu. Ci of radioactive sulfate for 2 hours. The remaining labeling steps were performed as described above. All absorbances and³⁵s incorporation levels can be converted to percentages relative to control treatment (═ 100%). The results can be statistically analyzed by analysis of variance (ANOVA).

Example 4

[0159] Effect of amino sugars on IL-1 induced IL-6 and Matrix Metalloproteinases (MMPs) in cultured chondrocytes

Measurement of IL-6 in cultured chondrocytes by protein ELISA:

[0160] cultured cells, such as osteoarthritic human articular chondrocytes described in example 1 above, can be plated in 96-well plates at 40,000 cells/well in the presence of 1% FBS. After 48 hours, the medium was changed. The cells were then stimulated with 5ng/ml IL-1 for 24 hours in the presence of amino sugar derivatives of the present invention including, but not limited to, derivatives of glucosamine, derivatives of galactosamine, derivatives of cyclitols and derivatives of iminocyclitols. IL-6 levels in culture supernatants were measured by protein ELISA (R & D Systems, Minneapolis, MN) according to the supplier's protocol. The results were read at 450 nm.

MMPs in cultured chondrocytes were measured by protein ELISA:

[0161] interleukin 1(IL1) is considered to be one of the most important catabolic factors in joint disease. In OA, large amounts of IL1 are produced by chondrocytes, resulting in the production of cartilage degeneration Matrix Metalloproteinases (MMPs).

[0162] Cultured cells, such as osteoarthritic human articular chondrocytes described in example 1 above, can be plated in 96-well plates at 40,000 cells/well in the presence of 1% FBS. After 48 hours, the medium was changed. The cells were then stimulated with 5ng/ml IL-1 for 24 hours in the presence of amino sugar derivatives of the present invention including, but not limited to, derivatives of glucosamine, derivatives of galactosamine, derivatives of cyclitols and derivatives of iminocyclitols. IL-1 induced MMP-1 to-13, and of particular interest MMP-3 and MMP-13, were measured by protein ELISA (Amersham biosciences).

Other embodiments

[0163] All references discussed above are incorporated herein in their entirety for all purposes. While the present invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (92)

1. A method of treating an osteoarthritis-related condition in a mammal comprising administering to said mammal a compound, wherein said compound further comprises a therapeutically effective amount of an aminosugar derivative, wherein said aminosugar derivative is selected from the group consisting of derivatives of glucosamine, derivatives of galactosamine, derivatives of cyclitols, derivatives of iminocyclitols, and pharmaceutically acceptable salts thereof.

2. The method of claim 1, wherein the osteoarthritis-associated condition is selected from osteoarthritis, rheumatoid arthritis, synovitis, subchondral bone edema, and cartilage degeneration.

3. The method of claim 2, wherein the osteoarthritis-associated condition is osteoarthritis.

4. The method of claim 2, wherein the osteoarthritis-associated condition is rheumatoid arthritis.

5. The method of claim 2, wherein the osteoarthritis-associated condition is synovitis.

6. The method of claim 2, wherein the osteoarthritis-associated condition is subchondral bone edema.

7. The method of claim 2, wherein the osteoarthritis-associated condition is cartilage degeneration.

8. The method of claim 1, wherein the aminosugar derivative is a derivative of glucosamine or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein the derivative of glucosamine is selected from compounds of formula V, wherein:

x is O;

R₁selected from: methoxy, benzyloxy, p-nitrophenyloxy, hydroxy, 5-bromo-4-chloro-indolyl, tetradecanoyl-BSA, and aminitol;

R₂selected from: acetyl, benzoyl, trifluoroacetyl, aminoacetyl andbutyryl; and

R₃selected from: hydroxy, (R) -1-carboxyethyl and 1-carboxyethoxy.

10. The method of claim 8, wherein the derivative of glucosamine is a derivative of N-acetylglucosamine or a pharmaceutically acceptable salt thereof.

11. The method of claim 10, wherein the derivative of N-acetylglucosamine is selected from compounds of formula V, wherein:

x is O;

R₁selected from: methoxy, benzyloxy, p-nitrophenyloxy, hydroxy, 5-bromo-4-chloro-indolyl, tetradecanoyl-BSA, and aminitol;

R₂selected from: acetyl, benzoyl, trifluoroacetyl, aminoacetyl and butyryl; and

R₃selected from: hydroxy, (R) -1-carboxyethyl and carboxyethoxy.

12. The method of claim 1, wherein the aminosugar derivative is a derivative of a cyclitol or a pharmaceutically acceptable salt thereof.

13. The process of claim 12, wherein the derivative of the cyclitol is selected from compounds of formula V, wherein:

x is CH₂；

R₁Selected from: methoxy, benzyloxy, p-nitrophenyloxy, hydroxy, 5-bromo-4-chloro-indolyl, tetradecylalkanoyl-BSA and aminitol;

R₂selected from: acetyl, benzoyl, trifluoroacetyl, aminoacetyl and butyryl; and

R₃selected from: hydroxy, (R) -1-carboxyethyl and 1-carboxyethoxy.

14. The method of claim 1, wherein the aminosugar derivative is a derivative of galactosamine or a pharmaceutically acceptable salt thereof.

15. The method of claim 14 wherein the derivative of galactosamine is selected from the group consisting of compounds of formula VI wherein:

x is O;

R₁selected from: methoxy, benzyloxy, p-nitrophenyloxy, hydroxy, 5-bromo-4-chloro-indolyl, tetradecanoyl-BSA, and aminitol;

R₂selected from: acetyl, benzoyl, trifluoroacetyl, aminoacetyl and butyryl; and

R₃selected from: hydroxy, (R) -1-carboxyethyl and 1-carboxyethoxy.

16. The method of claim 1, wherein the aminosugar derivative is a derivative of an iminocyclitol or a pharmaceutically acceptable salt thereof.

17. The process of claim 16, wherein the derivative of the iminocyclitol is selected from compounds of formula V, wherein:

x is NH;

R₁selected from: methoxy, benzyloxy, p-nitrophenyloxy, hydroxy, 5-bromo-4-chloro-indolyl, tetradecanoyl-BSA, and aminitol;

R₂selected from: acetyl, benzoyl, trifluoroacetyl, aminoacetyl and butyryl; and

R₃selected from: hydroxy, (R) -1-carboxyethyl and 1-carboxyethoxy.

18. The method of claim 1, wherein the aminosugar derivative is selected from formula I, wherein:

R¹the method comprises the following steps: CHO, CH₂OH or CO₂H；

R²The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R³the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R²，R³＝O；

R⁴The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Is cyclic connected by an ether bondOr without cycloalkyl, aryl, heterocyclic groups), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R⁵the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁴，R⁵＝O；

R⁶The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R⁷the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁶，R⁷＝O；

R⁸The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R⁹the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁸，R⁹O; and

R¹⁰the method comprises the following steps: H. CH (CH)₃、CH₂OH、CH₂OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), CH₂Cl、CH₂Br、CH₂F、CH₂SH、CH₂SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂NH₂、CH₂NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or CH₂NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative).

19. The method of claim 1, wherein the aminosugar derivative is selected from formula II, wherein:

x is: o, S, CH₂NH or NR²⁰(wherein R is²⁰Is a cyclic or acyclic alkyl, aryl, heterocyclic group);

y is: o, S, CH₂Or NH;

R¹⁷the method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R²the method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R³the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R²，R³＝O；

R⁴The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R⁵the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁴，R⁵＝O；

R⁶The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Is cyclic or acyclic alkyl linked by ether bondsAryl, heterocyclic group), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R⁷the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁶，R⁷＝O；

R⁹The method comprises the following steps: h, a C-linked cyclic or acyclic alkyl, aryl, or heterocyclic group; and

R¹⁰the method comprises the following steps: H. CH (CH)₃、CH₂OH、CH₂OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), CH₂Cl、CH₂Br、CH₂F、CH₂SH、CH₂SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂NH₂、CH₂NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or CH₂NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative).

20. The method of claim 1, wherein the aminosugar derivative is selected from formula III, wherein:

x is: o, S, CH₂NH or NR²⁰(wherein R is²⁰Is a cyclic or acyclic alkyl, aryl, heterocyclic group);

y is: o, S, CH₂Or NH;

R¹⁷the method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R²the method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R³the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R²，R³＝O；

R⁴The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is cyclic or acyclic alkyl, aryl, heteroCyclic or amino acid derivatives);

R⁵the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁴，R⁵＝O；

R⁷The method comprises the following steps: h, a C-linked cyclic or acyclic alkyl, aryl, or heterocyclic group;

R⁸the method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R⁹the method comprises the following steps: h, a C-linked cyclic or acyclic alkyl, aryl, or heterocyclic group; and

R¹⁰the method comprises the following steps: H. CH (CH)₃、CH₂OH、CH₂OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), CH₂Cl、CH₂Br、CH₂F、CH₂SH、CH₂SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂NH₂、CH₂NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or CH₂NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative).

21. The method of claim 1, wherein the aminosugar derivative is selected from formula IV, wherein:

y is: o, S, CH₂Or NH;

R¹⁷the method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R¹⁸the method comprises the following steps: H. o, NH or NR¹⁹(wherein R is¹⁹Is a cyclic or acyclic alkyl, aryl, heterocyclic group, or an acyl-linked cyclic or acyclic alkyl, aryl, or heterocyclic group);

R²the method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R³the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R²，R³＝O；

R⁴The method comprises the following steps: H. OH group、OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R⁵the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁴，R⁵＝O；

R⁶The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R⁷the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁶，R⁷＝O；

R⁸The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or a ring linked by an ether bondCyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R⁹the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁸，R⁹O; and

R¹⁰the method comprises the following steps: H. CH (CH)₃、CH₂OH、CH₂OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), CH₂Cl、CH₂Br、CH₂F、CH₂SH、CH₂SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂NH₂、CH₂NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or CH₂NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative).

22. The method of claim 1, wherein the aminosugar derivative further comprises anti-inflammatory properties.

23. The method of claim 22, wherein the anti-inflammatory property of the aminosugar derivative is a result of interference of the aminosugar derivative with cytokine-induced gene expression in chondrocytes.

24. The method of claim 1, wherein the aminosugar derivative further comprises cartilage protecting properties.

25. The method of claim 24, wherein the cartilage protecting property of the aminosugar derivative is a result of interference of the aminosugar derivative with cytokine-induced gene expression in chondrocytes.

26. The method of claim 1, wherein the aminosugar derivative further comprises improved protein binding.

27. The method of claim 26, wherein the protein is an intracellular receptor.

28. The method of claim 26, wherein the protein is an extracellular receptor.

29. The method of claim 1, wherein the aminosugar derivative further comprises improved chondrocyte penetration.

30. The method of claim 1, wherein the aminosugar derivative further comprises increased hydrophobicity.

31. The method of claim 1 wherein the amino derivative is administered to the mammal by a mode selected from the group consisting of intra-articular administration, topical administration, and intramuscular administration.

32. The method of claim 31, wherein said administration of said aminosugar derivative is by intra-articular administration.

33. The method of claim 32, wherein said administration of said aminosugar derivative is intra-articular administration as a controlled release formulation.

34. The method of claim 33, wherein the aminosugar derivative is administered as a controlled release formulation comprised within a matrix by intra-articular administration.

35. The method of claim 32, wherein said intra-articular administration of said aminosugar derivative results in a retardation of cartilage degeneration.

36. The method of claim 32, wherein said intra-articular administration of said aminosugar derivative results in a reduction of synovial inflammation.

37. The method of claim 36, wherein the reduction in synovial inflammation occurs at a macroscopic level.

38. The method of claim 36, wherein the reduction in synovial inflammation occurs at microscopic levels.

39. The method of claim 31, wherein said administration of said aminosugar derivative is by topical administration.

40. The method of claim 31, wherein said administration of said aminosugar derivative is by intramuscular administration.

41. The method of claim 1, wherein the aminosugar derivative is administered in combination with an anti-inflammatory agent.

42. The method of claim 1, wherein the aminosugar derivative is administered in combination with an hexosaminidase inhibitor.

43. The method of claim 1, wherein the method of treating the condition is selected from treating the condition, preventing the condition, and lessening the severity of the condition.

44. The method of claim 43, wherein said method of treating said condition consists of treating said condition.

45. The method of claim 43, wherein said method of treating said condition consists of preventing said condition.

46. The method of claim 43, wherein said method of treating said condition consists of reducing the severity of said condition.

47. A formulation for use in the treatment of an osteoarthritis-related condition comprising a compound, wherein the compound further comprises a therapeutically effective amount of an aminosugar derivative, wherein the aminosugar derivative is selected from the group consisting of derivatives of glucosamine, derivatives of galactosamine, derivatives of cyclitols, derivatives of iminocyclitols, and pharmaceutically acceptable salts thereof.

48. The formulation of claim 47, wherein the osteoarthritis-associated condition is selected from osteoarthritis, rheumatoid arthritis, synovitis, subchondral bone edema, and cartilage degeneration.

49. The formulation of claim 48, wherein the osteoarthritis-associated condition is osteoarthritis.

50. The formulation of claim 48, wherein the osteoarthritis-associated condition is rheumatoid arthritis.

51. The formulation of claim 48, wherein the osteoarthritis-associated condition is synovitis.

52. The formulation of claim 48, wherein the osteoarthritis-associated condition is subchondral bone edema.

53. The formulation of claim 48, wherein the osteoarthritis-associated condition is cartilage degeneration.

54. The formulation of claim 47, wherein the aminosugar derivative is a derivative of glucosamine or a pharmaceutically acceptable salt thereof.

55. The formulation of claim 54, wherein the derivative of glucosamine is selected from compounds of formula V, wherein:

x is O;

R₁selected from: methoxy, benzyloxy, p-nitrophenyloxy, hydroxy, 5-bromo-4-chloro-indolyl, tetradecanoyl-BSA, and aminitol;

R₂selected from: acetyl, benzoyl, trifluoroacetyl, aminoacetyl and butyryl; and

R₃selected from: hydroxy, (R) -1-carboxyethyl and 1-carboxyethoxy.

56. The formulation of claim 54, wherein the derivative of glucosamine is a derivative of N-acetylglucosamine or a pharmaceutically acceptable salt thereof.

57. The formulation of claim 56, wherein the derivative of N-acetylglucosamine is selected from compounds of formula V, wherein:

x is O;

R₁selected from: methoxy, benzyloxy, p-nitrophenyloxy, hydroxy, 5-bromo-4-chloro-indolyl, tetradecanoyl-BSA, and aminitol;

R₂selected from: acetyl, benzoyl, trifluoroacetyl, aminoacetyl and butyryl; and

R₃selected from: hydroxy, (R) -1-carboxyethyl and carboxyethoxy.

58. The formulation of claim 47, wherein the aminosugar derivative is a derivative of a cyclitol or a pharmaceutically acceptable salt thereof.

59. The formulation of claim 58, wherein the derivative of the cyclitol is selected from compounds of formula V, wherein:

x is CH₂；

R₁Selected from: methoxy, benzyloxy, p-nitrophenyloxy, hydroxy, 5-bromo-4-chloro-indolyl, tetradecanoyl-BSA, and aminitol;

R₂selected from: acetyl, benzoyl, trifluoroacetyl, aminoacetyl and butyryl; and

R₃selected from: hydroxy, (R) -1-carboxyethyl and 1-carboxyethoxy.

60. The formulation of claim 47, wherein the aminosugar derivative is a derivative of galactosamine or a pharmaceutically acceptable salt thereof.

61. The formulation of claim 60 wherein the derivative of galactosamine is selected from the group consisting of compounds of formula VI wherein:

x is O;

R₁selected from: methoxy, benzyloxy, p-nitrophenyloxy, hydroxy, 5-bromo-4-chloro-indolyl, tetradecanoyl-BSA, and aminitol;

R₂selected from acetyl, benzoyl, trifluoroacetyl, aminoacetyl and butyryl; and

R₃selected from: hydroxy, (R) -1-carboxyethyl and 1-carboxyethoxy.

62. The method of claim 1, wherein the aminosugar derivative is a derivative of an iminocyclitol or a pharmaceutically acceptable salt thereof.

63. The process of claim 12, wherein the derivative of the iminocyclitol is selected from compounds of formula V, wherein:

x is NH;

R₁selected from: methoxy, benzyloxy, p-nitrophenyloxy, hydroxy, 5-bromo-4-chloro-indolyl, tetradecanoyl-BSA, and aminitol;

R₂selected from: acetyl, benzoyl, trifluoroacetyl, aminoacetyl and butyryl; and

R₃selected from: hydroxy, (R) -1-carboxyethyl and 1-carboxyethoxy.

64. The formulation of claim 47, wherein the aminosugar derivative is selected from formula I, wherein:

R¹the method comprises the following steps: CHO, CH₂OH or CO₂H；

R²The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Is an etherLinked cyclic or acyclic alkyl, aryl, heterocyclic groups), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R³the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R²，R³＝O；

R⁴The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R⁵the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁴，R⁵＝O；

R⁶The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group)Or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R⁷the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁶，R⁷＝O；

R⁸The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R⁹the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁸，R⁹O; and

R¹⁰the method comprises the following steps: H. CH (CH)₃、CH₂OH、CH₂OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), CH₂Cl、CH₂Br、CH₂F、CH₂SH、CH₂SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂NH₂、CH₂NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or CH₂NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative).

65. The formulation of claim 47, wherein the aminosugar derivative is selected from formula II, wherein:

x is: o, S, CH₂NH or NR²⁰(wherein R is²⁰Is a cyclic or acyclic alkyl, aryl, heterocyclic group);

y is: o, S, CH₂Or NH;

R¹⁷the method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R²the method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R³the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R²，R³＝O；

R⁴The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Is cyclic connected by an ether bondOr without cycloalkyl, aryl, heterocyclic groups), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R⁵the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁴，R⁵＝O；

R⁶The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R⁷the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁶，R⁷＝O；

R⁹The method comprises the following steps: h, a C-linked cyclic or acyclic alkyl, aryl, or heterocyclic group; and

R¹⁰the method comprises the following steps: H. CH (CH)₃、CH₂OH、CH₂OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), CH₂Cl、CH₂Br、CH₂F、CH₂SH、CH₂SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂NH₂、CH₂NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or CH₂NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative).

66. The formulation of claim 47, wherein the aminosugar derivative is selected from formula III, wherein:

x is: o, S, CH₂NH or NR²⁰(wherein R is²⁰Is a cyclic or acyclic alkyl, aryl, heterocyclic group);

y is: o, S, CH₂Or NH;

R¹⁷the method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH²、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R²the method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Is a cyclic or acyclic alkyl, aryl, heterocyclic radical linked by ether bondsCluster), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R³the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R²，R³＝O；

R⁴The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R⁵the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁴，R⁵＝O；

R⁷The method comprises the following steps: h, a C-linked cyclic or acyclic alkyl, aryl, or heterocyclic group;

R⁸the method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative); and

R⁹the method comprises the following steps:H. c-linked cyclic or acyclic alkyl, aryl, or heterocyclic groups; and

R¹⁰the method comprises the following steps: H. CH (CH)₃、CH₂OH、CH₂OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), CH₂Cl、CH₂Br、CH₂F、CH₂SH、CH₂SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂NH₂、CH₂NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or CH₂NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative).

67. The formulation of claim 47, wherein the aminosugar derivative is selected from formula IV, wherein:

y is: o, S, CH₂Or NH;

R¹⁷the method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R¹⁸the method comprises the following steps: H. o, NH or NR¹⁹(wherein R is¹⁹Is a cyclic or acyclic alkyl, aryl, heterocyclic group, or an acyl-linked cyclic or acyclic alkyl, aryl, or heterocyclic group);

R²the method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R³the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R²，R³＝O；

R⁴The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R⁵the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁴，R⁵＝O；

R⁶The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or aminoAcid derivatives), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R⁷the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁶，R⁷＝O；

R⁸The method comprises the following steps: H. OH, OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), Cl, Br, F, SH, SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), NH₂、NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heterocyclic group) or NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative);

R⁹the method comprises the following steps: h, C-linked cyclic or acyclic alkyl, aryl, heterocyclic group, or R⁸，R⁹O; and

R¹⁰the method comprises the following steps: H. CH (CH)₃、CH₂OH、CH₂OR¹¹(wherein R is¹¹Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂OCOR¹²(wherein R is¹²Is cyclic or acyclic alkyl, aryl, heterocyclic or amino acid derivative), CH₂Cl、CH₂Br、CH₂F、CH₂SH、CH₂SR¹³(wherein R is¹³Cyclic or acyclic alkyl, aryl, heterocyclic groups linked by ether linkages), CH₂NH₂、CH₂NR¹⁴R¹⁵(wherein R is¹⁴Or R¹⁵Is H or an ether-linked cyclic or acyclic alkyl, aryl, heteroCyclic group) or CH₂NHCOR¹⁶(wherein R is¹⁶Is a cyclic or acyclic alkyl, aryl, heterocyclic, or amino acid derivative).

68. The formulation of claim 47, wherein the aminosugar derivative further comprises anti-inflammatory properties.

69. The formulation of claim 68, wherein the anti-inflammatory properties of the aminosugar derivative are a result of interference of the aminosugar with cytokine-induced gene expression in chondrocytes.

70. The formulation of claim 47, wherein the aminosugar derivative further comprises cartilage protecting properties.

71. The formulation of claim 70, wherein the cartilage protecting property of the aminosugar derivative is a result of interference of the aminosugar with cytokine induced gene expression in chondrocytes.

72. The formulation of claim 47, wherein the aminosugar derivative further comprises improved protein binding.

73. The formulation of claim 72, wherein the protein is an intracellular receptor.

74. The formulation of claim 72, wherein the protein is an extracellular receptor.

75. The formulation of claim 47, wherein the aminosugar derivative further comprises improved chondrocyte penetration.

76. The formulation of claim 47, wherein the aminosugar derivative further comprises increased hydrophobicity.

77. The formulation of claim 47, wherein the amino derivative is administered to the mammal by a mode selected from the group consisting of intra-articular administration, topical administration, and intramuscular administration.

78. The formulation of claim 77, wherein said administration of said aminosugar derivative is by intra-articular administration.

79. The formulation of claim 78, wherein said administration of said aminosugar derivative is intra-articular administration as a controlled release formulation.

80. A formulation as claimed in claim 79 wherein the aminosugar derivative is contained within a matrix for administration by intra-articular administration as a controlled release formulation.

81. The formulation of claim 78, wherein the intra-articular administration of the aminosugar derivative results in a retardation of cartilage degeneration.

82. The formulation of claim 78, wherein the intra-articular administration of the aminosugar derivative results in a reduction of synovial inflammation.

83. The formulation of claim 82, wherein the reduction in synovial inflammation occurs at a macroscopic level.

84. The formulation of claim 82, wherein the reduction in synovial inflammation occurs at microscopic levels.

85. The formulation of claim 77, wherein said administration of said aminosugar derivative is by topical administration.

86. The formulation of claim 77, wherein said administration of said aminosugar derivative is by intramuscular administration.

87. The formulation of claim 47, wherein the aminosugar derivative is administered in combination with an anti-inflammatory agent.

88. The formulation of claim 47, wherein the aminosugar derivative is administered in combination with an hexosaminidase inhibitor.

89. The formulation of claim 47, wherein the treatment of the osteoarthritis-associated condition is selected from the group consisting of treating the osteoarthritis-associated condition, preventing the osteoarthritis-associated condition, and reducing the severity of the osteoarthritis-associated condition.

90. The formulation of claim 89, wherein the treatment consists of treating the osteoarthritis-associated condition.

91. The formulation of claim 89, wherein the treatment consists of preventing the osteoarthritis-associated condition.

92. The formulation of claim 89, wherein the treatment consists of reducing the severity of the osteoarthritis-associated condition.