WO2025149713A1

WO2025149713A1 - An injectable composition for controlled drug delivery

Info

Publication number: WO2025149713A1
Application number: PCT/FI2025/050013
Authority: WO
Inventors: Minna KELLOMÄKI; Vijay SINGH PARIHAR; Rasmus LATVALA; Seppo HOIVALA
Original assignee: Fysioline Oy
Current assignee: Fysioline Oy
Priority date: 2024-01-11
Filing date: 2025-01-13
Publication date: 2025-07-17
Anticipated expiration: 2026-07-11
Also published as: FI20245016A1

Abstract

The present invention relates to a nanoparticle system. In addition, the present invention relates to a nanoparticle drug system. The present invention relates also to an injectable composition comprising the nanoparticle system and a carrier, or the nanoparticle drug system and a carrier. Further, the present invention relates to a method of treating a degenerative and/or an inflammatory joint disorder in a subject, wherein the method comprises administering the injectable composition to the subject.

Description

An injectable composition for controlled drug delivery Field of the invention The present invention relates to a nanoparticle system. In addition, the present invention relates to a nanoparticle drug system. The present invention relates also to an injectable composition comprising the nanoparticle system and a carrier, or _{the nanoparticle drug system and a carrier. Further, the present invention relates to} _{a method of treating a degenerative and/or an inflammatory joint disorder in a} subject, wherein the method comprises administering the injectable composition to the subject. Background of the invention Degenerative and inflammatory joint disorders include typically osteoarthritis and arthritis. Arthritis is the most common musculoskeletal disorder causing pain and disabilities. Osteoarthritis is the second most common musculoskeletal condition with 595 million prevalent cases worldwide. Osteoarthritis can damage any joint, but the disorder most commonly affects feet, hands, shoulders, hips, knees, and spine. Osteoarthritis affects the entire joint as osteoarthritis progress the cartilage within a joint begins to break down and the underlying bone begins to change. However, in osteoarthritis the entire joint organ is affected, it causes deterioration of the connective tissues, ligaments and muscles, and inflammation of the joint lining. In advanced osteoarthritis synovial neovascularization and increased neuronal sprouting of bone nociceptors and sympathetic neurons within bone can been seen, and histopathological changes in the subchondral bone, including microdamage, bone marrow lesions, and bone cysts, emerge. It is common that patients with osteoarthritis cannot move properly, and a fear that physical activity will cause more pain and joint damage, will further limit physical activity. Sleep disturbances are associated with osteoarthritis pain, up to 70% of peoples with osteoarthritis have difficulties to fall or staying asleep, and many wake up earlier than desired. Lack of restoring restful sleep can cause depression and other psychological symptoms. In addition, inflammation of periarticular areas, areas in proximity of tendons as well as muscle and tendon insertions can be painful and limit physical activity of a subject. In modern medicine, analgesics are commonly used to relieve osteoarthritis and arthritis symptoms, primarily pain, pain caused by arthritis and inflammation of periarticular areas, synovium, areas in proximity of tendons as well as muscle and tendon insertions. Both non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are commonly used. If conservative treatments fail, surgery is performed. In joint replacement surgery damaged joint surfaces are removed and replaced with metal parts. NSAIDs are extensively used to suppress symptoms in osteoarthritis and arthritis, but they are associated with the risk of some serious adverse events like heart attacks and strokes, renal failure and gastrointestinal bleeding. Dizziness, nausea, vomiting, and constipation are the best-known adverse events of opioids, but they are also associated with potentially life-threatening adverse events like sedation, and respiratory depression. Opioids cause physical dependence and tolerance, which is a concern as the misuse of opioids and opioid-overdose deaths have increased dramatically during the last decades. Opioid analgesics use in osteoarthritis and arthritis can be decreased by intra- articular drug injections. Intra-articular drug injections commonly provide a highly effective but fairly short-lasting relief of symptoms. The therapeutic time is short as the drugs are dispersed out of the joint and/or adsorbed from the joint too fast. Therefore, it would be beneficial to have a sustained intra-articular release of drugs. Surgery rates have increased, in the OECD countries 174 per 100000 population having hip replacement and 137 per 100000 knee replacement, annually. However, not all patients benefit surgery; 15% of the patients with hip replacement and 23% of the patients with knee replacement have a decrease in their health-related quality of life at the 12-month follow-up. Moreover, the prevalence of persistent pain is 25- 30% after hip arthroplasty, 10-35% after knee arthroplasty and 18-25% after shoulder arthroplasty. There are some commercial intra-articular injection products in the market. It is a common practice to inject glucosaminoglycan gels, like hyaluronan, into the joint space. These have been shown to relief symptoms in most of the osteoarthritis patients. However, as the efficacy of current marketed products is relatively short, the injection may need to be repeated within a few weeks-time. Different commercial products have different dosing schedules, usually one injection per week for three or five weeks is proposed. The invention addresses this problem by lengthening the time the drugs and/or the active compounds stay active inside the joint. This is achieved through loading the active compounds into bioactive nano/micro-carrier particles and embedding these particles in a saline solution, a gel, or a hydrogel. First, the particles release the drugs gradually and second the gel or hydrogel environment lengthens further the release time, keeping the active compounds in the joint for a sustained period, and thus prolonging the anti-inflammatory and/or analgesic effects of the compounds. Optimally, the selection of the components influence of the product is improving the performance of the composition more than the sum of the components i.e., supra- additive efficacy. Brief description of the invention After thorough intensive research, the inventors have surprisingly found that the nanoparticle system/the nanoparticle drug system of the present invention can be utilized in drug delivery, preferably in controlled drug delivery. Thus, the present invention relates to a nanoparticle system. In addition, the present invention relates to a nanoparticle drug system. Further, the present invention relates to an injectable composition that comprises the nanoparticle system or the nanoparticle drug system and a carrier. The injectable composition of the present invention can be used for drug delivery, preferably for controlled drug delivery to release pain caused by a degenerative and/or an inflammatory joint disorder or inflammation of a periarticular area, an area in proximity of tendons as well as a muscle and tendon insertion, and subchondral bone. Further, the present invention relates to a method of treating a _{degenerative and/or an inflammatory joint disorder in a subject, wherein the method} comprises administering the injectable composition to the subject. The present invention also relates to the injectable composition for use in a method of treating a _{degenerative and/or an inflammatory joint disorder in a subject.} The objects of the invention are achieved by the systems, compositions, uses and methods characterized by what is stated in the independent claims. The preferred embodiments of the invention are disclosed in the dependent claims. Other objects, details and advantages of the present invention will become apparent from the following detailed description. Brief description of the drawings Figure 1a and 1b show details of the formulation strategy. _{Figure 2 shows absorption based on TNBS assay for free hydrazide derivatives and} dexamethasone conjugated derivatives of hyaluronic acid (HA), heparin (HP) and chondroitin sulfate (CS). _{Figure 3 shows the drug release study for the lidocaine loaded HA-Dexamethasone,} HP-Dexamethasone and CS-Dexamethasone. _{Figure 4 shows a drug release study: represented in absorption of release drug with} time. Figure 5 shows the cell cytocompatibility for CS-Dexa-Lido, green dye indicates live cells and red dye indicates dead cells. Figure 6 shows the cell cytocompatibility for HP-Dexa-Lido, green dye indicates live cells and red dye indicates dead cells. Figure 7 shows the cell cytocompatibility for HA-Dexa-Lido, green dye indicates live cells, and red dye indicates dead cells. Figure 8 shows the particle size data of HA-Dexa-Lido nanoparticles. _{Figure 9 shows the particle size data of HP-Dexa-Lido nanoparticles.} Figure 10 shows the particle size data of CS-Dexa-Lido nanoparticles. Detailed description of the invention In the present specification the term “an inflammatory joint disorder” refers to arthritis, osteoarthritis, and/or inflammation of a periarticular area, an area in proximity of tendons as well as muscle and tendon insertions, and subchondral _{bone. In the present specification the term “a degenerative joint disorder” refers to} arthritis, osteoarthritis, and/or inflammation of the joint and the soft tissue surrounding the joint, and synovial neovascularization, nerve sprouting and histopathological changes in the subchondral bone. _{The present invention relates to nanoparticle systems as well as nanoparticle drug} _{systems. In addition, the present invention relates to injectable compositions} comprising the nanoparticle system and a carrier or the nanoparticle drug system _{and a carrier. Further, the present invention relates to a method of treating a} _{degenerative and/or an inflammatory joint disorder in a subject, wherein the method} comprises administering the injectable composition to the subject. In addition, the _{invention relates to an injectable composition comprising the nanoparticle system} and a carrier or the nanoparticle drug system and a carrier for use in a method of _{treating a degenerative join disorder and/or an inflammatory joint disorder in a} subject. The nanoparticle system of the present invention comprises a glycosaminoglycan and a glucocorticoid. The nanoparticle drug system of the present invention comprises a glycosaminoglycan, a glucocorticoid and an active pharmaceutical ingredient. The injectable composition of the present invention comprises the nanoparticle system or the nanoparticle drug system and a carrier. In the present invention, the glycosaminoglycan is or is selected from chondroitin sulfate (CS), hyaluronic acid (HA) or heparin (HP). In one embodiment, the glycosaminoglycan is chondroitin sulfate (CS). In one embodiment, the glycosaminoglycan is heparin (HP). In one embodiment, the glycosaminoglycan is hyaluronic acid (HA). The glucocorticoid acts as a hydrophobic component and helps in self-assembling to generate nanoparticles. The glucocorticoid is or is selected from prednisolone, triamcinolone or dexamethasone. In one embodiment, the glucocorticoid is prednisolone. In one embodiment, the glucocorticoid is triamcinolone. In one embodiment, the glucocorticoid is dexamethasone. _{In one embodiment, the nanoparticle system comprises chondroitin sulfate (CS) and} _{dexamethasone. In one embodiment, the nanoparticle system comprises} _{chondroitin sulfate (CS) and triamcinolone. In one embodiment, the nanoparticle} _{system comprises chondroitin sulfate (CS) and prednisolone. In one embodiment,} _{the nanoparticle system comprises hyaluronic acid (HA) and dexamethasone. In} _{one embodiment, the nanoparticle system comprises hyaluronic acid (HA) and} _{triamcinolone. In one embodiment, the nanoparticle system comprises hyaluronic} _{acid (HA) and prednisolone. In one embodiment, the nanoparticle system comprises} _{heparin (HP) and dexamethasone. In one embodiment, the nanoparticle system} _{comprises heparin (HP) and triamcinolone. In one embodiment, the nanoparticle} _{system comprises heparin (HP) and prednisolone.} The nanoparticle systems of the present invention can be synthetized using a two- step modification on the glycosaminoglycan’s (heparin (HP), chondroitin sulfate (CS), hyaluronic acid (HA)) backbone i.e., carbohydrazide modification followed by _{conjugation of the glucocorticoid i.e., with dexamethasone, triamcinolone, or} prednisolone, with a hydrazone linkage (hydrazone bond(s)). There are also other routes for particle formation but the above described way involves minimum chemical modifications possible and is thus advantageous in several aspects. In the nanoparticle drug systems, the nanoparticles serve as carriers for drug molecules, which are typically encapsulated or attached to the surface of the nanoparticles. The drug molecules are trapped in and self-assembled as particles due to supramolecular interactions, such as van der Waals forces and hydrogen bonds. The hydrodynamic size of the nanoparticles was measured using a zetasizer instrument. The hydrodynamic size of the nanoparticles ranges between 290-760 nm. In one embodiment the size ranges between 380-600 nm. In one embodiment the size ranges between 400-600 nm. In one embodiment the size ranges between 290-400 nm. The nanoparticle drug system of the present invention comprises a glycosaminoglycan, a glucocorticoid, and an active pharmaceutical ingredient. In one embodiment, the active pharmaceutical ingredient is not the same glucocorticoid as the glucocorticoid of the nanoparticle. In one embodiment, the active pharmaceutical ingredient is not a glucocorticoid. The active pharmaceutical ingredient can be a local anesthetic, an opioid, a non-steroidal anti-inflammatory drug (NSAID), a calcium channel blocker, a transient receptor potential vanilloid 1 (TRPV1) agonist, a corticosteroid, α2-adrenergic agonist, or a gamma-aminobutyric acid agonist/analog. The local anesthetic drug is, for example, lidocaine or bupivacaine. The opioid is, for example, morphine, oxycodone, or tramadol. The NSAID is, for example, ketorolac, ketoprofen or indomethacin. The calcium channel blocker is, for example, verapamil or nifedipine. The TRPV1 agonist is for example, capsaicin. The corticosteroid is, for example, dexamethasone, triamcinolone, or prednisolone. The α2-adrenergic agonist is, for example, clonidine or dexmedetomidine. The gamma-aminobutyric acid agonist/analog is, for example, diazepam, midazolam, baclofen, pregabalin or gabapentin. Thus, in one _{embodiment, the nanoparticle drug system comprises hyaluronic acid (HA),} _{dexamethasone and lidocaine. In one embodiment, the nanoparticle drug system} _{comprises hyaluronic acid (HA), triamcinolone and lidocaine. In one embodiment,} _{the nanoparticle drug system comprises hyaluronic acid (HA), prednisolone and} _{lidocaine. In one embodiment, the nanoparticle drug system comprises heparin} _{(HP), dexamethasone and lidocaine. In one embodiment, the nanoparticle drug} _{system comprises heparin (HP), triamcinolone and lidocaine. In one embodiment,} _{the nanoparticle drug system comprises heparin (HP), prednisolone and lidocaine.} _{In one embodiment, the nanoparticle drug system comprises chondroitin sulfate} _{(CS), dexamethasone and lidocaine. In one embodiment, the nanoparticle drug} _{system comprises chondroitin sulfate (CS), triamcinolone and lidocaine. In one} _{embodiment, the nanoparticle drug system comprises hyaluronic acid (HA)} _{dexamethasone and tramadol. In one embodiment, the nanoparticle drug system} _{comprises hyaluronic acid (HA), triamcinolone and tramadol. In one embodiment,} _{the nanoparticle drug system comprises hyaluronic acid (HA), prednisolone and} _{tramadol. In one embodiment, the nanoparticle drug system comprises heparin} _{(HP), dexamethasone and tramadol. In one embodiment, the nanoparticle drug} _{system comprises heparin (HP), triamcinolone and tramadol. In one embodiment,} _{the nanoparticle drug system comprises heparin (HP), prednisolone and tramadol.} _{In one embodiment, the nanoparticle drug system comprises chondroitin sulfate} _{(CS), dexamethasone and tramadol. In one embodiment, the nanoparticle drug} _{system comprises chondroitin sulfate (CS), triamcinolone and tramadol.} In the nanoparticle drug systems, the nanoparticles serve as carriers for drug molecules, which are typically encapsulated or attached to the surface of the nanoparticles. The drug molecules are trapped in and self-assembled as particles due to supramolecular interactions, such as van der Waals forces and hydrogen bonds. The hydrodynamic size of the nanoparticles was measured using a zetasizer instrument. The hydrodynamic size of the nanoparticles ranges between 290-760 nm. In one embodiment the size ranges between 380-600 nm. In one embodiment the size ranges between 400-600 nm. In one embodiment the size ranges between 290-400 nm. In one embodiment, the hydrodynamic size of the nanoparticles having chondroitin sulfate as the glycosaminoglycan ranges between 400-500 nm. In one embodiment, the hydrodynamic size of the of the nanoparticles having heparin as the glycosaminoglycan ranges between 290-450 nm. In one embodiment, the hydrodynamic size of the nanoparticles having hyaluronic acid as the glycosaminoglycan ranges between 700-760 nm. The chemical structures of the glucocorticoids are very similar, thus the sizes of the nanoparticles having either _{prednisolone, triamcinolone or dexamethasone as the glucocorticoid will be in the} same range. The drug molecules will not affect the size as they are small molecules encapsulated therein. The nanoparticle drug systems of the present invention can be synthetized using a two-step modification on the glycosaminoglycan’s (chondroitin sulfate (CS), hyaluronic acid (HA, heparin (HP)) backbone i.e., carbohydrazide modification _{followed by conjugation of the glucocorticoid i.e., with prednisolone, triamcinolone} _{or dexamethasone, with a hydrazone linkage. The glucocorticoid contributing as a} hydrophobic component, helps in self-assembling to generate nanoparticles. During the self-assembling process, the drug molecules trap inside the nanoparticle. This is shown in Figures 1a and 1b. The nanoparticle drug system provides a prolonged or sustained release for the drug molecules. The sustained release of the drug was found to be over ten days without burst release in the beginning. Figures 3 and 4 show the release characteristics of the nanoparticle drug system of the present invention. In one embodiment, the injectable composition comprises the nanoparticle drug system of the present invention and a carrier. In another embodiment of the present invention, the injectable composition comprises the nanoparticle system of the present invention and a carrier. In one embodiment, the carrier is a hydrogel. In one embodiment, the carrier is a gel. In one embodiment, the carrier is saline solution. In one embodiment, the carrier is a hydrogel. The hydrogel matrix is typically composed of or formed from one or more hydrophilic polymers that can absorb and retain a substantial amount of water. The hydrogels are crosslinked to modify and control the density of the molecular network. The hydrogel serves as a reservoir for the drug nanoparticle systems, controlling the release of the active pharmaceutical ingredient. The molecules of the active pharmaceutical ingredient gradually diffuse through the hydrogel, and the release rate can be controlled by altering the properties of the hydrogel, such as its composition, crosslinking type and density. This delivery system offers localized drug delivery, meaning the drug is primarily released at the site of application. Additionally, the hydrogel can provide a prolonged release of the drug over an extended period. In one embodiment, the hydrogel is formed from chondroitin sulphate (CS), hyaluronic acid (HA), heparin (HP) or a mixture thereof. In one embodiment, the hydrogel is formed from compounds that support the metabolism of a cartilage. In one embodiment, the compound that support the metabolism of a cartilage is hyaluronic acid (HA) or chondroitin sulphate (CS), or a mixture thereof. In one embodiment, the carrier is a gel. The gel matrix is typically formed of one or more gels, namely hydrophilic polymers. The drug nanoparticle systems are administered in a gel, or a mixture of gels and the molecules of gel(s) are causing the active pharmaceutical ingredient released from the nanoparticles to diffuse out from the gel more slowly than in the case of the water-based saline solution. The molecules of the active pharmaceutical ingredient gradually diffuse through the gel(s), and the release rate can be controlled e.g., by viscosity of gel(s). This delivery system offers localized drug delivery, meaning the active pharmaceutical ingredient is primarily released at the site of application. Additionally, the gel(s) can provide slightly prolonged release rate of the active pharmaceutical ingredient. In one embodiment, the gel is formed from compounds that support the metabolism of a cartilage. In one embodiment, the compound that support the metabolism of a cartilage is hyaluronic acid (HA) or chondroitin sulphate (CS), or a mixture thereof. In one embodiment, the glycosaminoglycan of the nanoparticle system or the nanoparticle drug system and the glycosaminoglycan of the gel or the hydrogel is the same glycosaminoglycan. In one embodiment, the carrier is a saline solution. In this embodiment, the nanoparticle system or the nanoparticle drug system in a saline solution can be injected to the target tissue. Thus, the present invention relates to an injectable composition comprising (a1) a nanoparticle drug system which comprises: - a glycosaminoglycan, - a glucocorticoid; and - an active pharmaceutical agent; or (a2) a nanoparticle system which comprises: - a glycosaminoglycan, - a glucocorticoid; and (b) a carrier selected from a gel or a hydrogel, which comprises or is formed from at least one glycosaminoglycan, or saline solution. In one embodiment, the glycosaminoglycan is selected is from chondroitin sulfate (CS), hyaluronic acid (HA), or heparin (HP). In one embodiment, the glucocorticoid is selected from prednisolone, triamcinolone or dexamethasone. Accordingly, the present invention relates to an injectable composition comprising (a1) a nanoparticle drug system which comprises: - a glycosaminoglycan which is chondroitin sulfate (CS), hyaluronic acid (HA), or heparin (HP), - a glucocorticoid which is prednisolone, triamcinolone or dexamethasone; and - an active pharmaceutical agent; or (a2) a nanoparticle system which comprises: - a glycosaminoglycan which is chondroitin sulfate (CS), hyaluronic acid (HA), or heparin (HP), and - a glucocorticoid which is prednisolone, triamcinolone or dexamethasone; and _{(b) a carrier which is a gel or a hydrogel, which comprises or is formed from a} glycosaminoglycan selected from chondroitin sulphate (CS), hyaluronic acid (HA) or heparin (HP) or any mixture thereof, or a saline solution. The injectable compositions of the present invention provide extension for the time the drugs and/or the active compounds stay active inside the joint. This is achieved through loading the active compounds into/onto the nanoparticles and embedding these particles in a saline solution, a gel, or a hydrogel. First, the particles release the drugs gradually and second the gel or hydrogel environment lengthens further the release time, keeping the active compounds in the joint for a sustained period, and thus prolonging the anti-inflammatory and/or analgesic effects of the compounds. In one embodiment, the injectable composition of the present invention provides controlled drug delivery and/or prolonged release of the active pharmaceutical ingredient(s). The nanoparticle drug system design prolongs the time the active pharmaceutical ingredient(s) stay(s) in the joint compared to the active pharmaceutical ingredient as such. The carrier design prolongs further the duration of action of the active pharmaceutical ingredient(s) in the joint. Thus, one key point with the carrier design is that the carrier molecules in the gel or hydrogel form will slowly be hydrolyzed and that the hydrolyzed parts (i.e., the nanoparticle system or _{the nanoparticle drug system) per se, will be active components.} The present invention relates also to a method of treating a degenerative joint disorder and/or an inflammatory joint disorder in a subject, wherein the method comprises administering the injectable composition comprising the nanoparticle system and a carrier, or the nanoparticle drug system and a carrier to the subject. _{Specifically, the invention relates to a method of treating a degenerative joint} disorder and/or an inflammatory joint disorder in a subject, wherein the method comprises injecting the injectable composition to a damaged joint of the subject. In one embodiment, the degenerative and/or an inflammatory joint disorder is osteoarthritis. In one embodiment, the degenerative and/or an inflammatory joint _{disorder is arthritis. In one embodiment, the degenerative and/or an inflammatory} joint disorder is inflammation of the joint and the soft tissue surrounding the joint. In one embodiment, the present invention relates to an injectable composition comprising the nanoparticle drug system and a carrier, or the nanoparticle system and a carrier, for use in a method of treating a degenerative joint disorder in a subject. Specifically, the invention relates to an injectable composition comprising the nanoparticle system and a carrier, or the nanoparticle drug system and a carrier _{for use in a method of treating a degenerative joint disorder, wherein the method} comprises injecting the injectable composition to a damaged joint of the subject. In one embodiment, the degenerative joint disorder is osteoarthritis. In one _{embodiment, the degenerative joint disorder is arthritis. In one embodiment, the} degenerative joint disorder is inflammation of the joint and the soft tissue surrounding the joint. _{The present invention relates further to a method of treating an inflammatory joint} _{disorder in a subject, wherein the method comprises administering the injectable} composition comprising the nanoparticle system and a carrier, or the nanoparticle drug system and a carrier to the subject. Specifically, the invention relates to a _{method of treating an inflammatory joint disorder in a subject, wherein the method} comprises injecting the injectable composition to a damaged joint of the subject. In _{one embodiment, the inflammatory joint disorder is arthritis. In one embodiment, the} _{inflammatory joint disorder is osteoarthritis. In one embodiment, the inflammatory} joint disorder is an inflammation of a periarticular area. In one embodiment, the inflammatory joint disorder is inflammation in an area in proximity of tendons. In one _{embodiment, the inflammatory joint disorder is inflammation in muscle and tendon} insertions. In one embodiment, the present invention relates to an injectable composition comprising the nanoparticle drug system and a carrier, or the nanoparticle system and a carrier for use in a method of treating an inflammatory joint disorder in a subject. Specifically, the invention relates to an injectable composition comprising the nanoparticle system and a carrier, or the nanoparticle drug system and a carrier _{for use in a method of treating an inflammatory joint disorder, wherein the method} comprises injecting the injectable composition to a damaged joint of the subject. In _{one embodiment, the inflammatory joint disorder is arthritis. In one embodiment, the} _{inflammatory joint disorder is osteoarthritis. In one embodiment, the inflammatory} joint disorder is an inflammation of a periarticular area. In one embodiment, the inflammatory joint disorder is inflammation in an area in proximity of tendons. In one _{embodiment, the inflammatory joint disorder is inflammation in muscle and tendon} insertions. In one embodiment, the present invention relates to a method of releasing pain caused by a degenerative joint disorder in a subject, wherein the method comprises administering the injectable composition comprising the nanoparticle system and a carrier or the nanoparticle drug system and a carrier to the subject. Specifically, the _{invention relates to a method of releasing pain caused by a degenerative joint} disorder in a subject, wherein the method comprises injecting the injectable _{composition to a damaged joint of the subject. In one embodiment, the degenerative} _{joint disorder is osteoarthritis. In one embodiment, the degenerative joint disorder is} _{arthritis. In one embodiment, the degenerative joint disorder is inflammation of the} joint and the soft tissue surrounding the joint. _{In one embodiment, the present invention relates to an injectable composition} comprising the nanoparticle system and a carrier, or the nanoparticle drug system and a carrier for use in a method of releasing pain caused by a degenerative joint disorder. Specifically, the invention relates to an injectable composition comprising the nanoparticle system and a carrier or the nanoparticle drug system and a carrier _{for use in a method of treating a degenerative joint disorder, wherein the method} comprises injecting the injectable composition to a damaged joint of the subject. In one embodiment, the degenerative joint disorder is osteoarthritis. In one _{embodiment, the degenerative joint disorder is arthritis. In one embodiment, the} degenerative joint disorder is inflammation of the joint and the soft tissue surrounding the joint. In one embodiment, the present invention relates to a method of releasing pain _{caused by an inflammatory joint disorder, wherein the method comprises} administering the injectable composition comprising the nanoparticle system and a _{carrier, or the nanoparticle drug system and a carrier to the subject. Specifically, the} _{invention relates to a method of releasing pain caused by an inflammatory joint} disorder in a subject, wherein the method comprises injecting the injectable _{composition to a damaged joint of the subject. In one embodiment, the inflammatory} _{joint disorder is arthritis. In one embodiment, the inflammatory joint disorder is} _{osteoarthritis. In one embodiment, the inflammatory joint disorder is an inflammation} _{of a periarticular area. In one embodiment, the inflammatory joint disorder is} inflammation in an area in proximity of tendons. In one embodiment, the inflammatory joint disorder is inflammation in muscle and tendon insertions. In one embodiment, the present invention relates to a method of treating and/or _{alleviating inflammation caused by a degenerative joint disorder, wherein the} method comprises administering the injectable composition comprising the nanoparticle system and a carrier, or the nanoparticle drug system and a carrier to the subject. Specifically, the invention relates to a method of treating and/or _{alleviating inflammation caused by a degenerative joint disorder in a subject,} wherein the method comprises injecting the injectable composition to a damaged _{joint of the subject. In one embodiment, the degenerative joint disorder is} _{osteoarthritis. In one embodiment, the degenerative joint disorder is arthritis. In one} embodiment, the degenerative joint disorder is inflammation of the joint and the soft tissue surrounding the joint. In one embodiment, the present invention relates to an injectable composition comprising the nanoparticle system and a carrier, or the nanoparticle drug system and a carrier for use in a method of treating and/or alleviating inflammation caused by a degenerative joint disorder. Specifically, the invention relates to an injectable composition comprising the nanoparticle system and a carrier, or the nanoparticle _{drug system and a carrier for use in a method of treating and/or alleviating} _{inflammation caused by a degenerative joint disorder, wherein the method} comprises injecting the injectable composition to a damaged joint of the subject. In one embodiment, the degenerative joint disorder is osteoarthritis. In one _{embodiment, the degenerative joint disorder is arthritis. In one embodiment, the} degenerative joint disorder is inflammation of the joint and the soft tissue surrounding the joint. In one embodiment, the present invention relates to a method of treating and/or _{alleviating inflammation caused by an inflammatory joint disorder, wherein the} method comprises administering the injectable composition comprising the nanoparticle system and a carrier, or the nanoparticle drug system and a carrier to the subject. Specifically, the invention relates to a method of treating and/or _{alleviating inflammation caused by an inflammatory joint disorder in a subject,} wherein the method comprises injecting the injectable composition to a damaged _{joint of the subject. In one embodiment, the inflammatory joint disorder is arthritis.} _{In one embodiment, the inflammatory joint disorder is osteoarthritis. In one} _{embodiment, the inflammatory joint disorder is an inflammation of a periarticular} _{area. In one embodiment, the inflammatory joint disorder is inflammation in an area} _{in proximity of tendons. In one embodiment, the inflammatory joint disorder is} inflammation in muscle and tendon insertions. _{In one embodiment, the present invention relates to an injectable composition} comprising the nanoparticle system and a carrier, or the nanoparticle drug system and a carrier for use in a method of treating and/or alleviating inflammation caused by an inflammatory joint disorder. Specifically, the invention relates to an injectable composition comprising the nanoparticle system and a carrier, or the nanoparticle _{drug system and a carrier for use in a method of treating and/or alleviating} _{inflammation caused by an inflammatory joint disorder, wherein the method} comprises injecting the injectable composition to a damaged joint of the subject. In _{one embodiment, the inflammatory joint disorder is arthritis. In one embodiment, the} _{inflammatory joint disorder is osteoarthritis. In one embodiment, the inflammatory} joint disorder is an inflammation of a periarticular area. In one embodiment, the inflammatory joint disorder is inflammation in an area in proximity of tendons. In one _{embodiment, the inflammatory joint disorder is inflammation in muscle and tendon} insertions. The following examples are given to further illustrate the invention without, however, restricting the invention thereto. EXAMPLES Example 1 Synthesis of glycosaminoglycan (GAG)-Dexamethasone conjugate: The synthetic strategy involved two-step modification on the glycosaminoglycans (heparin (HP), chondroitin sulfate (CS) and hyaluronic acid (HA)) backbone i.e., carbohydrazide modification followed by dexamethasone conjugation. The goal was to achieve the dexamethasone conjugation on GAGs molecules under mild reaction condition via hydrazide coupling reaction. In short, the HP (600 mg), CS (500 mg) and HA (400 mg), 1 mmole, based on the molar mass of the repeating unit in the polymer chain was dissolved in the 120 mL of deionized (DI) water followed by the addition of 1 hydroxybenzotriazole hydrate (HOBt, 153 mg 1 mmol) to the reaction mixture. To the above stirred solution, carbohydrazide (CDH, 91 mg, 1 mmol) was added and the pH of the solution was adjusted between 4.7 and 4.8. Finally, 1-Ethyl- 3-(3-dimethylaminopropyl)carbodiimide (EDC, 38.4 mg, 0.2 mmol) was added and the reaction mixture was stirred at room temperature (RT) for 12 hours. Example 2 Purification and characterization of the products: The crude reaction mixtures of the carbohydrazide coupling reaction were transferred into the dialysis bag (Spectra Por-3, MWCO 3500) and dialyzed against DI water in an acidic condition (dilute HCl, pH = 3-4) containing 120 mM NaCl for 24 hours followed by dialysis in acidic condition (HCl, pH 3-4, 24 h) and then dialyzed against DI water for 24 h. The dialyzed reaction solutions were lyophilized to obtain dried GAGs-CDH products. The degree of hydrazide modifications was determined by trinitrobenzene sulfonic acid (TNBS) assay. Example 3 Synthesis of GAGs-Dexamethasone conjugates: The conjugation of dexamethasone on the CDH derivatives of GAGs, heparin (HP- CDH), chondroitin sulfate (CS-CDH), and hyaluronic acid (HA-CDH) were achieved by hydrazone formation reaction. In short, the HP (150 mg), CS (125 mg) and HA (100 mg), 0.25 mmole, were dissolved in 50 mL of DI water. Dexamethasone (12 mg, 0.3 mmol) was dissolved in 20 mL of dimethyl sulfoxide was added to above solutions. The pH of the reaction mixture solutions was adjusted by using acetic acid (HP-CDH, pH= 4.75; CS-CDH, pH= 3.20; HA-CDH, pH= 4.5) and kept for stirring overnight at 50^°C. The reaction mixtures were purified upon dialysis against DI water (48 h). The solutions were lyophilized, and the degree of dexamethasone conjugation was determined using UV–Vis spectroscopy, by estimating the unreacted hydrazide residue through TNBS assay. The conjugation of dexamethasone was estimated from the reduced absorption in TNBS assay due to reduction in the free hydrazide groups as shown in Figure 2. The dexamethasone conjugation was further confirmed by performing proton NMR spectroscopy. Following the same protocol as for GAGs-Dexamethasone, prednisolone and triamcinolone were conjugated to the GAGs-CDH via hydrazone formation and the percentage conjugation obtained was 5-6%. Example 4 Drug loading on the GAGs-Dexamethasone conjugates and release study: 50 mg of HA-Dexamethasone, CS-Dexamethasone and HP-Dexamethasone were dissolved in the 40 mL of DMSO:H₂O (5:3) and stirred at RT for 1 hour.5 mg of lidocaine was dissolved separately in 5 mL of DMSO and added to reaction mixtures and stirred at RT for 6 hours. 30 mL of DI water was added to all three reaction mixtures and stirred at RT overnight. The reaction mixtures were loaded into dialysis bag (Spectra Por 3.5 kDa) and dialyzed against DI water for 24 hours. The purified reaction mixtures were lyophilized which affords the white solid products. The lidocaine loading was 4.9% for HA-Dex, 5.1% for CS-Dex and 4.7% for HP-Dex by weight and was determined from UV-Vis spectroscopy. The relative drug release kinetics were examined using a mini-dialysis device. The drug-loaded samples were kept in simulated body fluid (SBF) at pH 7.4, 37°C, to mimic the physiological conditions. The experiments indicated the slow and sustained release of lidocaine over a period of 10 days. The amount of the drug released over time was 11-12% of the percentage loading of a drug by weight and release attain near zero-order kinetics as compared to free drug in 10 days. The results are shown in Figures 3 and 4. Example 5 Cell Cytocompatibility The cell cytocompatibility was tested for CS-Dexa-Lido (Chondroitin Sulfate- Dexamethasone-Lidocaine), HP-Dexa-Lido (Heparin- Dexamethasone-Lidocaine), and HA-Dexa-Lido (Hyaluronic Acid-Dexamethasone-Lidocaine) nanoparticle drug systems to bone marrow stromal cells (BMSC) at three different concentrations (10 mg/mL, 20 mg/mL and 40 mg/mL) of drug loaded polymeric nano/micro particles. The preliminary cell cytocompatibility results indicate that the cells remained viable (cells stained green) for both Day 1 and Day 3 of the experiment in all tested concentrations of materials. Cells were stained using live-dead -staining by means _{of LIVE/DEAD™ Viability/Cytotoxicity Kit, for mammalian cells (Invitrogen™).} The results are shown in Figures 5-7. Example 6 Preparation of an injectable formulations The drug-loaded nanoparticles were dispersed in saline solution at three different concentrations (10 mg/mL, 20 mg/mL, and 40 mg/mL) to formulate a saline-based injectable system. Similarly, the drug-loaded nanoparticles were separately dispersed in simulated body fluid (SBF) at concentrations of 10 mg/mL, 20 mg/mL, and 40 mg/mL. These solutions were then mixed with an injectable gel system to achieve the desired formulation. For the drug-loaded injectable hydrogel system, the drug-loaded nanoparticles were dispersed in hydrogel precursor at concentrations of 10 mg/mL, 20 mg/mL, and 40 mg/mL. Subsequently, hydrogel crosslinking was performed utilizing hydrazone chemistry to trap the particles within the hydrogel matrix, facilitating sustained release. Example 7 Particle size determination The particle sizes of the nanoparticles HA-Dexa-L, HP-Dexa-L and CS-Dexa-L were measured with the Zetasizer Nano ZS, Malvern, UK at 25 °C using disposable cells. The particle size of HA-Dexa-L particles (Hyaluronic acid-Dexamethasone- Lidocaine) was found to be in the range of 706 nm to 758 nm (please figure 8). The particle size of HP-Dexa-L particles (Heparin-Dexamethasone-Lidocaine) was found to be in the range of 290 nm to 440 nm (please figure 9). The particle size of CS-Dexa-L particles (Chondroitin sulfate-Dexamethasone- Lidocaine) was found to be in the range of 400 nm to 477 nm (please figure 10). The particle sizes we measured with dexamethasone as the glucocorticoid, but the sizes for the other glucocorticoids will be in the same range as their chemical structures are very similar. The drug molecules will not affect the size as they are small molecules encapsulated therein.

Claims

CLAIMS: 1. An injectable composition comprising (a1) a nanoparticle drug system which comprises: - a glycosaminoglycan which is chondroitin sulfate (CS), hyaluronic acid (HA), or heparin (HP), - a glucocorticoid which is prednisolone, triamcinolone or dexamethasone; and - an active pharmaceutical agent; or (a2) a nanoparticle system which comprises: - a glycosaminoglycan which is chondroitin sulfate (CS), hyaluronic acid (HA), or heparin (HP), and - a glucocorticoid which is prednisolone, triamcinolone or dexamethasone; and _{(b) a carrier which is a gel or a hydrogel, which comprises or is formed from a} glycosaminoglycan selected from chondroitin sulphate (CS), hyaluronic acid (HA) or heparin (HP) or any mixture thereof, or a saline solution. 2. The injectable composition of claim 1, wherein the carrier is a gel or a hydrogel. 3. The injectable composition of claim 2, wherein the glycosaminoglycan of the nanoparticle drug system or the nanoparticle system and the glycosaminoglycan of the gel or the hydrogel is the same glycosaminoglycan. 4. The injectable composition of any one of claims 1- 3, wherein the glycosaminoglycan is chondroitin sulfate (CS). 5. The injectable composition of any one of claims 1- 3, wherein the glycosaminoglycan is heparin (HP). 6. The injectable composition of any one of claims 1- 3, wherein the glycosaminoglycan is hyaluronic acid (HA). 7. The injectable composition of any one of claims 1-6, wherein the glucocorticoid is prednisolone.

8. The injectable composition of any one of claims 1-6, wherein the glucocorticoid is triamcinolone. 9. The injectable composition of any one of claims 1-6, wherein the glucocorticoid is dexamethasone. 10. The injectable composition of any one of claims 1-10, wherein the active _{pharmaceutical ingredient is a local anesthetic, an opioid, a non-steroidal anti-} inflammatory drug (NSAID), a calcium channel blocker, a transient receptor potential vanilloid 1 (TRPV1) agonist, a corticosteroid, α2-adrenergic agonist, or a gamma- aminobutyric acid agonist/analog. 11. The injectable composition of claim 10, wherein the active pharmaceutical ingredient is a local anesthetic, such as lidocaine. 12. The injectable composition of claim 10, wherein the active pharmaceutical ingredient is an opioid, such as tramadol. 13. The injectable composition of claim 10, wherein the active pharmaceutical ingredient is an NSAID, such as indomethacin. 14. The injectable composition of any one of claims 1-13 for use in a method for _{treating an inflammatory joint disorder in a subject.} _{15. The injectable composition of any one of claims 1-13 for use in a method of} _{releasing pain caused by an inflammatory joint disorder in a subject.} _{16. The injectable composition of any one of claims 1-13 for use in a method of} _{treating and/or alleviating inflammation caused by an inflammatory joint disorder in} a subject. 17. The injectable composition for use of any one of claims claim 14-16, wherein the _{inflammatory joint disorder is arthritis, osteoarthritis, inflammation in a periarticular} area, inflammation in an area in proximity of tendons or inflammation in muscle and tendon insertions.

18. The injectable composition of any one of claims 1-13 for use in a method for treating a degenerative joint disorder in a subject. 19. The injectable composition of any one of claims 1-13 for use in a method of releasing pain caused by a degenerative joint disorder in a subject. _{20. The injectable composition of any one of claims 1-13 for use in a method of} _{treating and/or alleviating inflammation caused by a degenerative joint disorder in a} subject. 21. The injectable composition for use of any one of claims 18-20, wherein the degenerative joint disorder is osteoarthritis, arthritis or inflammation of the joint and the soft tissue surrounding the joint. _{22. A nanoparticle system comprising a glycosaminoglycan selected from} chondroitin sulfate (CS), hyaluronic acid (HA), and heparin (HP), and a glucocorticoid selected from dexamethasone, triamcinolone, and prednisolone. 23. A nanoparticle drug system comprising a glycosaminoglycan selected from chondroitin sulfate (CS), hyaluronic acid (HA) and heparin (HP), and a glucocorticoid selected from prednisolone, triamcinolone, and dexamethasone, and an active pharmaceutical ingredient. 24. The nanoparticle system of claim 22 or the nanoparticle drug system of claim 23, wherein the glycosaminoglycan is chondroitin sulfate (CS), and the glucocorticoid is prednisolone, triamcinolone or dexamethasone. 25. The nanoparticle system of claim 22 or the nanoparticle drug system of claim 23, wherein the glycosaminoglycan is heparin (HP), and the glucocorticoid is prednisolone, triamcinolone or dexamethasone. 26. The nanoparticle system of claim 23 or the nanoparticle drug system of claim 24, wherein the glycosaminoglycan is hyaluronic acid (HA) and the glucocorticoid is prednisolone, triamcinolone or dexamethasone.

27. The nanoparticle drug system of any one of claims 23-26, wherein the active pharmaceutical ingredient is a local anesthetic, an opioid, a non-steroidal anti- inflammatory drug (NSAID), a calcium channel blocker, a transient receptor potential vanilloid 1 (TRPV1) agonist, a corticosteroid, α2-adrenergic agonist, or a gamma- aminobutyric acid agonist/analog. 28. The nanoparticle drug system of claim 27, wherein the active pharmaceutical ingredient is a local anesthetic, such as lidocaine. 29. The nanoparticle drug system of claim 27, wherein the active pharmaceutical ingredient is an opioid, such as tramadol. 30. The nanoparticle drug system of claim 27, wherein the active pharmaceutical ingredient is an NSAID, such as indomethacin.