Injectable solution for the treatment of cartilage lesions and osteoarthritis.

Description

1 / 9 Injectable solution for the treatment of cartilage lesions and osteoarthritis. Field of application

[001] This patent application relates to the development of a technology for incorporating ascorbic acid into an injectable solution containing hyaluronic acid (HA), standing out in the health field by promoting cartilage repair through the interaction between the patient's own cellular machinery and chondrogenic differentiation factors. State of the art

[002] In the search for the state of the art regarding technologies that treat osteoarthritis and cartilage damage, searches were carried out in the ESPACENET patent database. Initially, the combination used was the descriptors "ascorbic acid", in the title field, and "osteoarthritis", in the title or abstract field, where a single result was obtained referring to patent application number WO0228400A1, entitled THERAPEUTIC FORMULATION CONTAINING GLUCOSAMINE, METHYLSULFONIMETHANE AND POSSIBLY ASCORBIC ACID AND MANGANESE, however, the technology is a therapeutic formulation, for oral administration to equine or canine animals, for the treatment of osteoarthritis and the maintenance of joint function in animals, comprising 10 to 25% w / v of glucosamine and 6 to 20% w / v of methylsulfonylmethane.

[003] A search combining the terms “ascorbic acid” and “capsule” yielded 13 results, but none related to cartilage treatment. Most were focused on cosmetic applications.

[004] While searching for ascorbic acid injections, some results were found, such as process number JP2015189739A, which provides an ascorbic acid injection that can be used in bolus therapy using an ascorbic acid injection and can suppress, within an acceptable range, the discoloration of a liquid medication containing ascorbic acid with properties that are easily discolored. SOLUTION: the invention provides a Petition 870240109990, dated 12 / 24 / 2024, page 6 / 25 2 / 9 injection containing a stabilizer selected from 10% w / v or more of ascorbic acid or a salt thereof, 0.015% w / v or less of sulfite and 0.015% w / v or less of L-cysteine ​​or a salt thereof, or thioglycolic acid or a salt thereof. Titled LIQUID MEDICINE CONTAINING ASCORBIC ACID. However, the other large majority were for uses related to cancer treatment.

[005] INTRA-ARTICULAR VISCOSUPPLEMENTATION REGIME, EP1835923B, The present invention relates to methods of viscosupplementation for the treatment of osteoarthritis and joint injury with HA-based viscosupplements, particularly viscosupplements with an intra-articular residence half-life of less than 3 weeks. The viscosupplements for use in the invention methods may be further characterized by containing less than 20 mg / ml of HA, at least 5% (w / w) of which is in gel form, such as, for example, hylan GF 20 (Synvisc) administered in a single intra-articular injection of 6 ± 2 ml into the knee.

[006] In the patentscope, an oxidizable metal ion, such as the ferrous ion in the form of ferrous sulfate, and an ascorbate, such as ascorbic acid, have a synergistic effect on cartilage development. Therapeutic compositions comprising an oxidizable metal ion and an ascorbate are therefore useful in the treatment of osteoarthritis. The addition of a glucosamine, such as glucosamine hydrochloride, to the composition has an additional synergistic effect on cartilage production. Therapeutic compositions comprising an oxidizable metal ion, an ascorbate, and a glucosamine derivative are even more useful in the treatment of osteoarthritis, where the compositions can be administered orally, parenterally, intravenously, or by any other convenient method. Capsules for oral administration are preferred, number 2307079 and title COMPOSITIONS USEFUL FOR THE TREATMENT OF CONNECTIVE TISSUE DISEASES.

[007] Another title METHODS AND COMPOSITIONS FOR PREVENTION AND TREATMENT OF INFLAMMATION, OSTEOARTHRITIS AND Petition 870240109990, dated 12 / 24 / 2024, p. 7 / 25 3 / 9 OTHER DEGENERATIVE JOINT DISEASES where methods and compositions are provided to prevent and / or treat degenerative joint diseases, including osteoarthritis, as well as joint inflammation and to reduce associated pain. The formulation includes glucosamine, conjugated linoleic acid and ascorbic acid, with a daily oral dosage. Treatment methods are also provided. The compositions and methods may be provided as an over-the-counter medicine, a nutritional supplement, a prescription medicine or a component thereof, or a functional or medical food or a component thereof, and has the number 6838451, having been granted in 2005.

[008] The patent granted in 2018 entitled STRONTIUM-BASED COMPOSITION, PRODUCT AND METHOD OF USE THEREOF TO CONTROL THE PROGRESSION OF OSTEOARTHRITIS, OSTEOPOROSIS AND DENTAL CARIES, number 09974804, presents a strontium-based composition to control the progression of osteoarthritis, osteoporosis and dental caries. The composition may include a mixture of ingredients including: at least 500 mg of strontium carbonate; citric acid; ascorbic acid; malic acid; folic acid; vitamin D3; magnesium citrate; natural sweetener; and flavoring. The blend of all-natural ingredients based on strontium is simply delivered into the oral cavity, where a chemical reaction occurs "in vivo," resulting in the direct exposure of the tooth and dentin to facilitate the direct benefits of strontium in preventing tooth decay and reducing sensitivity.The mixture of ingredients is then swallowed to establish intestinal transit and absorption, allowing for targeted systemic absorption benefits in the bone and joint areas.

[009] FACILITATED TRANSPORT OF BISPHOSPHONATES BY VITAMIN C is a patent application describing compounds of the formula: wherein: A1 is ascorbic acid, dehydroascorbic acid, ascorbyl-2-phosphate, an analogue thereof, or a salt thereof; L is a linking group coupled to A1 at its C5 or C6 position; and B1 is an active agent such as an imaging agent or a therapeutic agent (e.g., a bisphosphonate). Petition 870240109990, dated 12 / 24 / 2024, page 8 / 25 4 / 9 together with their pharmaceutically acceptable salts and prodrugs. The compounds are useful, among other things, for improving cartilage absorption of active agents administered for joint diseases such as osteoarthritis and rheumatoid arthritis, and for improving the gastrointestinal absorption of bisphosphonates.

[0010] METHODS AND COMPOSITIONS FOR TREATING OSTEOARTHRITIS AND PROMOTING CARTILAGE FORMATION; the invention provides methods and compositions for treating or inhibiting the development of osteoarthritis in an individual with osteoarthritis or at risk of developing osteoarthritis and for stimulating or increasing cartilage production or formation in an individual. The methods involve administering to the subject a therapeutically effective amount of a composition comprising one or more agents among adenosine, an adenosine receptor agonist and an agent that positively regulates or increases the amount or biological activity of adenosine, or an analogue or derivative thereof. The adenosine receptor may be an A1, A2A, A2B and A3-adenosine receptor. The agent that positively regulates or increases the amount or biological activity of adenosine may be dipyridamole or ticagrelor.The composition can be administered via intra-articular injection, such as injection into the synovial fluid of a joint. The composition may be effective in reducing or inhibiting cartilage degeneration or damage, or in stimulating or increasing cartilage production or formation. The composition may be a liposomal composition or contain a liposome. 20180036238 is the publication number.

[0011] ANTI-INFLAMMATORY ANALGESIC PREPARATIONS COMPRISING 3-O-ASCORBIC ACID DERIVATIVES This is an anti-inflammatory analgesic preparation containing a specific 3O-substituted ascorbic acid as the active ingredient, exhibiting excellent anti-inflammatory analgesic effects and being excellent in terms of shelf life, skin safety and endermic absorption of the active ingredient. Petition 870240109990, dated 12 / 24 / 2024, page 9 / 25 5 / 9

[0012] In the INPI database, process number BR 11 2022 026725 was found, which refers to the use of a caspase inhibitor to relieve or treat osteoarthritis, whose title is PHARMACEUTICAL COMPOSITION TO RELIEVE OR TREAT OSTEOARTHRITIS.

[0013] Another process was number BR 11 2019 011418 1, entitled COMPOSITION FOR THE TREATMENT OF OSTEOARTHRITIS, which refers to a composition for use in the treatment of osteoarthritis (OA), wherein said composition comprises 5 to 40 mg of sodium clodronate, or an equivalent amount of clodronic acid, or other pharmaceutically acceptable salts thereof, and wherein said composition is administered intraocularly in a single-dose form once a month, once every two weeks or once a week. Single-dose medications and kits comprising the same are also described.

[0014] The process in which compositions and methods for the treatment of osteoarthritis are provided, including the intra-articular administration of a compound of Formula (I) including its amorphous and polymorphic forms, entitled OSTEOARTHRITIS TREATMENT, is number BR 11 2018 009252 5, also found in the INPI database.

[0015] Entitled 2-(2-METHYLAMINO-PYRIMIDIN-4-YL)-1HINDOL-5-CARBOXYLIC ACID [(S)-1-CARBAMOYL-2-(PHENYL-PYRIMIDIN-2-YLAMINO)-ETHYL]-AMIDE FOR USE IN THE TREATMENT OF PAIN ASSOCIATED WITH OSTEOARTHRITIS, the aforementioned patent application refers to the use in the treatment of pain associated with osteoarthritis in the knee, also identified with the number BR 11 2016 029044 5.

[0016] BR 11 2016 013834 1, PHARMACEUTICAL COMBINATION, PHARMACEUTICAL COMPOSITION IN THE FORM OF AN INJECTABLE LIQUID SOLUTION AND PRE-FILLED SYRINGE, refers to an injectable combination of two specific glycosaminoglycans, hyaluronic acid and chondroitin sulfate, with cyclodextrins and to the use of the combination for the treatment of diseases related to the skeletal systems, particularly in intra-articular treatment, as well as in intradermal treatment. Petition 870240109990, dated 12 / 24 / 2024, page 10 / 25 6 / 9

[0017] COMPOSITION FOR REPAIRING CARTILAGE TISSUE, METHOD FOR PREPARATION AND USE THEREOF, under number BR 11 2014 028193 9 B1, refers to a composition for repairing cartilage tissue, and a method for its production and use. The present invention provides a composition for repairing cartilage tissue, which is obtained by mixing collagen and hyaluronic acid using a two-way syringe or a mixer, where the collagen has a diluted concentration of 5-60 mg / mL excluding water or physiological phosphate buffer solution and the hyaluronic acid has a diluted concentration of 5-20 mg / mL excluding water or physiological phosphate buffer solution.

[0018] THERAPEUTIC METHOD FOR THE TREATMENT OF A JOINT SHOWING DEGENERATION OF ARTICULAR CARTILAGE, USE OF A STABLE, VISCOUS, BUFFERED AQUEOUS SOLUTION, METHOD FOR REPAIRING OR REGENERATING CARTILAGE IN A MAMMALIAN JOINT, AND USE OF A MIXTURE OF CHONDROITIN SULFATE AND HYALURONIC ACID OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, activated with the use of the composition formed by sodium hyaluronate and sodium chondroitin sulfate for the treatment of chondral lesions in osteoarthritis, and to the use of this composition in the manufacture of a product for this treatment, PI 0214032-2. Description of the technology: Reagents and solutions

[0019] Process of incorporating ascorbic acid into an injectable solution containing hyaluronic acid (HA), standing out in the health field for promoting cartilage repair through the interaction between the patient's own cellular machinery and chondrogenic differentiation factors with the reagents: ascorbic acid, L-ascorbic acid (L-threo-2-hexenone-1,4-lactone), L-threo-2,3,4,5,6-pentahydroxyhex-2-acidoenoic-4-lactone, L-dehydroascorbic acid, 2,3-diketogulonic acid with a biopolymer formed by the acid Petition 870240109990, dated 12 / 24 / 2024, page 11 / 25 7 / 9 glucuronic acid and N-acetylglucosamine or sodium hyaluronate were sourced from Sigma, Merck and Labsynth Ltd, of Aldrich Chemical Co.

[0020] Other solvents used, such as: ethyl alcohol, absolute methyl alcohol and DMF; as well as imidazole were sourced from Merck. Acetone and diethyl ether were sourced from Sigma, Merck and Labsynth Ltd, of Aldrich Chemical Co.

[0021] The other reagents were obtained from different sources, with analytical grade.

[0022] The water for preparing all solutions was deionized using a Barnstead D 4700 apparatus. The deionizing system consists of a circuit of 4 cylindrical filters, containing resin for ion capture and activated carbon for organic material capture. Chondro-induction synthesis or chondro-inducing biomolecule

[0023] Complexes and solutions were reprepared, and some syntheses were reproduced, whether from chondro-induction environments or from chondro-inducing biomolecules previously performed or done by the group. Tridentate and tetradentate ligands were used; some of the Schiff base type were obtained from carbonyl compounds and amines. The compounds were prepared according to the described procedures, introducing some modifications, mainly regarding the addition of reagents, pH, and the use or not of an inert atmosphere, in order to obtain better results.

[0024] Chemical and structural characterization was carried out using different techniques to obtain chemical and structural parameters. The study began with the use of ascorbic acid, L-ascorbic acid (L-threo-2hexenone-1,4-lactone), L-threo-2,3,4,5,6-pentahydroxyhex-2-acidoenoic-4-lactone, L-dehydroascorbic acid, 2,3-diketogulonic acid, pure or in a form protected by encapsulation with organic molecules of varying or constant molecular weight of encapsulators with a biopolymer formed by glucuronic acid and N-acetylglucosamine or sodium hyaluronate, or in their absence, in the constitution of either the chondro-induction environment or Petition 870240109990, dated 12 / 24 / 2024, page 12 / 25 8 / 9 of chondroinductive biomolecules. Therefore, the body's healing potential to regenerate human cartilage, mainly in articular regions. Concentrations of molecules from 1.00 x 10-6 mg / Kg to 12000 mg / Kg of both L-ascorbic acid (L-threo-2-hexenone-1,4-lactone) or L-threo2,3,4,5,6-pentahydroxyhex-2-acidoenoic-4-lactone, L-dehydroascorbic acid, 2,3-diketogulonic acid, and the biopolymer formed by glucuronic acid and N-acetylglucosamine or sodium hyaluronate were tested not only in mixture form but also in solution form and exhibited the environmental properties of chondroinduction or chondroinductive biomolecules. In preparing solutions, the glassware used was the volumetric pipette or micropipette, or the graduated pipette or micropipette, and the volumetric flask, the latter having a calibration mark located on the neck, which determines the limit of its capacity.The solute was weighed using an analytical and semi-analytical balance; the solute was dissolved in a beaker using a small amount of solvent, quantitatively transferred to a volumetric flask, the volume was completed with solvent, and the solution was homogenized, not necessarily in the order presented. The following equipment was used: ultrasound, vortex mixer, glass rod, microwave oven, mechanical stirrers, Kline shaker, microplates and tubes, mechanical stirrer for creams and viscous solutions, magnetic stirrers, heating plate, and watch glass.

[0025] Encapsulated or non-encapsulated ascorbic acid may be combined with other solutions or molecules, in a preparation and mixing process, comprising stem cells from dental pulp fragments and may be combined with biomaterials that possess factors that improve the structural and mechanical properties of the cartilage tissue bioengineering kit, including but not limited to: type II collagen, collagen sponges, collagen membranes, nanofiber scaffolds, scaffold-free technologies, hyaluronates, chondroitin sulfate, glycosaminoglycan sulfate (sGAG), polyethylene terephthalate, polyethylene glycol (PEG), cellulose acetate, chitosan, alginate, platelet-rich plasma (PRP) derived scaffolds, hydrogels, gelatins, chitin and polycaprolactone, acid Petition 870240109990, dated 12 / 24 / 2024, page 13 / 25 9 / 9 polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), hydroxyapatite, α-tricalcium phosphate, β-tricalcium phosphate and ceramics, and may also be combined with growth factors, increasing differentiation and cell viability, including but not limited to: TGF-β, bone morphogenic protein (BMP), IGF, PDGF, bFGF, VEGF, PRP. Petition 870240109990, dated 12 / 24 / 2024, page 14 / 25

Claims

1 / 3 CLAIMS 1) INJECTABLE SOLUTION FOR THE TREATMENT OF CARTILAGE LESIONS AND OSTEOARTHRITIS Characterized by the incorporation of ascorbic acid in an injectable solution containing hyaluronic acid (HA) with chondrogenic differentiation factors containing the reagents ascorbic acid, L-ascorbic acid (L-threo-2-hexenone-1,4-lactone), L-threo-2,3,4,5,6-pentahydroxyhex-2-acidoenoic-4-lactone, L-dehydroascorbic acid, 2,3-diketogulonic acid with a biopolymer formed by glucuronic acid and N-acetylglucosamine or sodium hyaluronate, as well as the solvents ethyl alcohol, absolute methyl alcohol and DMF;as well as imidazole and water for deionized preparation in a Barnstead apparatus, model D 4700, where the deionizing system consists of a circuit of 4 cylindrical filters, containing resin for ion capture and activated carbon for organic material capture, with complex preparations, solutions and reproduced some syntheses, whether from the chondro-induction environment or from chondro-inducing biomolecules previously performed or made by the group, tridentate and tetradentate ligands were used, some of the Schiff base type were obtained from carbonyl compounds and amines, the compounds were prepared according to the procedures described, introducing some modifications, mainly with regard to the addition of reagents, pH, use or not of an inert atmosphere; 2) INJECTABLE SOLUTION FOR THE TREATMENT OF CARTILAGE LESIONS AND OSTEOARTHRITIS characterized by the use of chemical and structural techniques to obtain chemical and structural parameters, based, according to Claim 1, on the use of ascorbic acid, L-ascorbic acid (L-threo-2-hexenone-1,4-lactone), L-threo-2,3,4,5,6-pentahydroxyhex-2-acidoenoic-4-lactone, L-dehydroascorbic acid, 2,3-diketogulonic acid, in protein form, as per Petition 870250057711, dated 07 / 07 / 2025, page 1. 5 / 7 2 / 3 encapsulation by organic molecules of varying or constant molecular weight of encapsulators with biopolymer formed by glucuronic acid and N-acetylglucosamine or sodium hyaluronate, or in their absence, in the constitution of either the chondro-induction environment or the chondro-inducing biomolecule; 3) INJECTABLE SOLUTION FOR THE TREATMENT OF CARTILAGE INJURIES AND OSTEOARTHRITIS, according to Claim 1, characterized by the body's healing potential to regenerate human cartilage, mainly in articular regions, containing concentrations of molecules from 1.00 x 10-6 mg / Kg to 12000 mg / Kg of both L-ascorbic acid (L-threo-2-hexenone-1,4-lactone) or L-threo-2,3,4,5,6-pentahydroxyhex-2-acidoenoic-4-lactone, L-dehydroascorbic acid, 2,3-diketogulonic acid, and the biopolymer formed by glucuronic acid and N-acetylglucosamine or sodium hyaluronate, which exhibited the environmental properties of chondroinduction or chondroinducing biomolecules; 4) INJECTABLE SOLUTION FOR THE TREATMENT OF CARTILAGE LESIONS AND OSTEOARTHRITIS characterized by a mixture preparation process with encapsulated or non-encapsulated ascorbic acid, combined with other solutions or molecules comprising stem cells from dental pulp fragments and possibly combined with biomaterials that possess factors that improve the structural and mechanical properties of the cartilage tissue bioengineering kit, including, but not limited to, type II collagen, collagen sponges, collagen membranes, nanofiber scaffolds, "scaffold-free" technologies, hyaluronates, chondroitin sulfate, glycosaminoglycan sulfate (sGAG), polyethylene terephthalate, polyethylene glycol (PEG), cellulose acetate, chitosan, alginate, platelet-rich plasma (PRP) derived scaffolds, hydrogels, gelatins, chitin and polycaprolactone, polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), hydroxyapatite, α-tricalcium phosphate,β-tricalcium phosphate and ceramics Petition 870250057711, dated 07 / 07 / 2025, page 6 / 7 3 / 3 and may also be combined with growth factors, increasing differentiation and cell viability, and may include, but not limited to: TGF-β, bone morphogenic protein (BMP), IGF, PDGF, bFGF, VEGF, PRP. Petition 870250057711, dated 07 / 07 / 2025, page 7 / 7,