WO2024080954A1 - Gel intra-articulaire pour la régénération tissulaire et cartilagineuse - Google Patents

Gel intra-articulaire pour la régénération tissulaire et cartilagineuse Download PDF

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Publication number
WO2024080954A1
WO2024080954A1 PCT/TR2023/050964 TR2023050964W WO2024080954A1 WO 2024080954 A1 WO2024080954 A1 WO 2024080954A1 TR 2023050964 W TR2023050964 W TR 2023050964W WO 2024080954 A1 WO2024080954 A1 WO 2024080954A1
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WO
WIPO (PCT)
Prior art keywords
articular
intra
gel
formulation
glycine
Prior art date
Application number
PCT/TR2023/050964
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English (en)
Inventor
Süleyman Patir
Original Assignee
Patir Sueleyman
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from TR2022/015493 external-priority patent/TR2022015493A2/tr
Application filed by Patir Sueleyman filed Critical Patir Sueleyman
Publication of WO2024080954A1 publication Critical patent/WO2024080954A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/06—Materials or treatment for tissue regeneration for cartilage reconstruction, e.g. meniscus

Definitions

  • the present invention relates to an intra-articular gel composition which provides tissue and cartilage regeneration and to a gel formulation wherein the gel composition is presented in a carrier fluid. More particularly, the present invention relates to a composition and a formulation of an intra-articular gel with greatly improved pH stability.
  • Osteoarthritis is a degenerative joint disease thataffects the bone and soft tissues of the joint. Osteoarthritis, which belongs to the group of rheumatic diseases, is characterized as a type of arthritis (joint inflammation/arthritis) within this category. Osteoarthritis (OA) is a chronic and progressive disease that causes significant pain and difficulty in movement in patients.
  • Cartilage is a hard and slippery tissue that allows almost frictionless joint movement with the help of synovial fluid. Osteoarthritis is caused by the wear of the cartilage that acts as a shock absorber at the ends of the bones in the joints. In other words, in patients with osteoarthritis, wear and tear of the cartilage occurs and the cartilage tissue deteriorates over time. This leads to changes in the bone structure and degeneration of the connective tissues that hold the joint together and connect the muscles to the bone. In addition, inflammation of the joint capsule occurs.
  • Synovial fluid is a lubricating substance secreted by the synovial membrane that surrounds the area where two bones meetin the joints. This lubricating substance allows the jointto move easily.
  • the pH of the synovial fluid is alkaline and ranges from about 7.3 to 7.6.
  • the pH of the synovial fluid moves towards the acidic range and can sometimes drop as low as 6.0 (Jin, T., et al. (2020).
  • Intraarticular injections for the treatment of osteoarthritis focus on the clinical use of hyaluronic acid. Drugs in R&D, 11(1), 13-27).
  • intra-articular fluid supplements commonly used in the early stage of cartilage degeneration include; mixtures comprising hyaluronic acid-sodium, hyaluronic acid- sodium/chondroitin sulfate or hyaluronic acid-sodium/chondroitin sulfate/N-acetylglucosamine.
  • Hyaluronate (also known as hyaluronic acid and hyaluronan) is a high molecular mass polysaccharide found naturally in the extracellular space of higher animals, especially in soft connective tissues. It is a linear polymer consisting of repeating monomers of n-acetyl glucosamine and glucuronic acid. Hyaluronate plays an important role in protecting the synovial joint by contributing to joint lubrication by buffering load transfer across articular surfaces (Schiavinato, A., Finesso, M., Cortivo, R., & Abatangelo, G. (2002). Comparison of the effects of intraarticular injections of Hyaluronan and its chemically cross-linked derivative (Hylan G-F20) in normal rabbit knee joints. Clinical and experimental rheumatology, 20(4), 445-454).
  • hyaluronate which is used for tissue regeneration in the treatment of osteoarthritis, is its sodium salt, sodium hyaluronate.
  • Sodium hyaluronate is injected into the joint as part of osteoarthritis treatment to act as both a shock absorber and lubricant for the joint.
  • Sodium hyaluronate has the following chemical structure:
  • N- Acetyl glucosamine (GlcNAc), whose chemical structure is given below, is an amide derivative of the monosaccharide glucose. It is a secondary amide between glucosamine and acetic acid.
  • GlcNAc N- Acetyl glucosamine
  • EP2886104A1 discloses an intra-articular gel formulation comprising sodium hyaluronate, N- acetyl glucosamine and chondroitin sulfate for the treatment of osteoarthritis.
  • Glycine has the chemical formula NH2-CH2-COOH and is the simplest stable amino acid. Glycine can be used in pharmaceutical formulations as a buffering agent, wetting agent, bulking agent, dietary supplement, tablet disintegrant and freeze-drying agent (Raymond C Rowe, Paul J, Sheskey & Marian E, Quinn (2009). Handbook of Pharmaceutical Excipients, 6th ed. RPS Publishing).
  • EP3544616A1 discloses that proline, another amino acid, is comprised in the formulation in order to stabilize the lyophilized formulation containing dalbavansin.
  • the amino acids glycine and proline are important building blocks for collagen synthesis in joints. Osteoarthritis patients require large amounts of glycine, proline and lysine to restore normal levels of collagen synthesis, which is reduced due to osteoarthritis (de Paz-Lugo, P., et al. (2016), High glycine concentration increases collagen synthesis by articular chondrocytes in vitro: acute glycine deficiency could be an important cause of osteoarthritis. Amino acids, 50(10), 1357-1365).
  • EP1713464A2 relates to a method for increasing the flexibility of cartilage in an animal in need of such increase.
  • the method involves administering to a mammal an effective amount of at least one of glycine and proline in order to increase cartilage flexibility.
  • EP2515897B1 relates to the use of an intra-articular gel containing a combination of glycine and proline in the treatment of osteoarthritis.
  • the combination may also comprise a natural or synthetic viscosity-controlling polymer.
  • intra-articular gel formulations for the treatment of osteoarthritis are known in the relevant field.
  • the present invention provides an intra-articular gel formulation having a stable pH that is compatible with the pH range of the synovial fluid observed in osteoarthritis patients. Said formulation increases patient compliance by preventing irritation and pain that may occur during and following administration.
  • the present invention provides a composition and a formulation with high stability and thus extended shelflife. The compositions and formulations of the present invention are therefore advantageous in that they provide pH-stable products that maintain the efficacy and stability of the active ingredient and minimize the side effects.
  • the invention provides an intra-articular gel composition, wherein said composition comprises the following components by weight:
  • the intra-articular gel composition of the invention preferably comprises the following components by weight:
  • the intra-articular gel composition of the invention comprises the following components by weight:
  • the intra-articular gel composition of the invention may further be mixed with a carrier fluid, more preferably with water for injection, to form suitable formulations.
  • the intra-articular gel formulation of the invention preferably comprises between 5 mg and 40 mg of sodium hyaluronate in 1 ml of water. More preferably, the amount of sodium hyaluronate is 15 mg.
  • amino acids proline and glycine comprised in the intra-articular gel composition or formulation of the invention are preferably in the L configuration.
  • the invention provides the intra-articular gel formulation of the invention for use in the prevention and/or treatment of tissue and/or cartilage degeneration in humans or animals.
  • Said tissue and/or cartilage degeneration is preferably tissue and/or cartilage degeneration due to osteoarthritis.
  • the present invention relates to an intra-articular gel formulation with high pH stability.
  • Said formulation comprises NaH 2 PO 4 (monosodium phosphate), Na 2 HPO 4 (disodium phosphate), NaCl (sodium chloride), N-acetyl-D- glucosamine, glycine, proline and sodium hyaluronate.
  • the intra- articular gel formulation of the invention is effective in the prevention and/or treatment of cartilage degeneration, in particular in the treatment of osteoarthritis.
  • the present invention provides an intra-articular gel formulation, said formulation comprises the following components by weight:
  • the formulation of the invention preferably comprises said components in the following percentages by weight:
  • the formulation of the invention more preferably comprises said components in the following percentages by weight:
  • composition or formulation according to the present invention is intended to provide a product with high pH stability.
  • Inventors of the present application have realized that combining the components of the composition in the percentages given above allows to obtain a product with high pH stability, as will be described in more detail below.
  • composition of the present invention may comprise NaH 2 P04, Na2HP04, NaCl, N- acetyl-D-glucosamine, glycine, proline and sodium hyaluronate in any percentage within the above-mentioned weight percentage ranges, as to add up to 100%.
  • the intraarticular gel composition of the invention may comprise, by weight:
  • composition of the present invention may further be mixed with a carrier fluid, more preferably with water for injection, to obtain formulations of the invention.
  • a carrier fluid more preferably with water for injection
  • the amount of water for injection in which the components of the formulation are dissolved is preferably 1 ml.
  • amino acids proline and glycine comprised in the intra-articular gel composition of the invention are preferably in the L configuration.
  • the invention provides the intra-articular gel composition or formulation according to the invention for use in the prevention and/or treatment of tissue and/or cartilage degeneration in humans or animals.
  • Said tissue and/or cartilage degeneration is preferably tissue and/or cartilage degeneration due to osteoarthritis.
  • the molecular weight of the sodium hyaluronate comprised in the intra-articular gel composition of the invention is preferably in the range of 800 kDa to 3 MDa, more preferably in the range of 1 MDa to 2.5 MDa.
  • the molecular weight of the sodium hyaluronate comprised in the formulation of the invention may be, for example, 800 kDa, 1 MDa, 1.5 MDa, 2 MDa, 2.5 MDa or 3 MDa.
  • the amount of sodium hyaluronate in 1 ml of the intra-articular gel formulation of the invention is preferably in the range of 5 mg to 40 mg, more preferably in the range of 7.5 mg to 30 mg. More specifically, the amount of sodium hyaluronate in 1 ml of water for injection is in the range of 10 mg to 20 mg.
  • the amount of sodium hyaluronate in 1 ml of water for injection may be, for example, 10 mg, 13 mg, 15 mg, 18 mg or 20 mg.
  • the amount of sodium hyaluronate in 1 ml of water for injection is most preferably 15 mg.
  • the amount of glycine in 1 ml of the intra-articular gel formulation of the invention is preferably in the range of 1 mg to 15 mg, more preferably in the range of 2.25 mg to 12.5 mg. More specifically, the amount of glycine in 1 ml of water for injection is in the range of 5 mg to 10 mg.
  • the amount of glycine in 1 ml of water for injection may be, for example, 5 mg, 6 mg, 7.5 mg, 9 mg or 10 mg.
  • the amount of glycine in 1 ml of water for injection is most preferably 7.5 mg.
  • Said glycine is preferably L-glycine.
  • the amount of proline in 1 ml of the intra-articular gel formulation of the invention is preferably in the range of 1 mg to 12.5 mg, more preferably in the range of
  • the amount of proline in 1 ml of water for injection is in the range of 3.75 mg to 6.5 mg.
  • the amount of proline in 1 ml of water for injection may be, for example, 3.75 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg or 6.5 mg.
  • the amount of proline in 1 ml of water for injection is most preferably 5 mg.
  • Said proline is preferably L-proline.
  • the amount of N-acetyl-D-glucosamine in 1 ml of the intra-articular gel formulation of the invention is preferably in the range of 5 mg to 30 mg, more preferably in the range of 7.5 mg to 25 mg. More specifically, the amount of N-acetyl-D- glucosamine in 1 ml of water for injection is in the range of 10 mg to 20 mg.
  • the amount of N- acetyl-D-glucosamine in 1 ml of water for injection may be, for example, 10 mg, 12.5 mg, 15 mg,
  • N-acetyl-D-glucosamine 17.5 mg.
  • the amount of N-acetyl-D-glucosamine in 1 ml of water for injection is most preferably 15 mg.
  • Said N-acetyl-D-glucosamine may be synthetic.
  • the amount of NalkPC (monosodium phosphate) in 1 ml of the intra-articular gel formulation of the invention is preferably in the range of 0.25 mg to 0.75 mg, more preferably in the range of 0.35 mg to 0.60 mg.
  • the amount of NalkPC in 1 ml of water for injection is most preferably 0.45 mg.
  • the amount of Na2HPC>4 (disodium phosphate) in 1 ml of the intra-articular gel formulation of the invention is preferably in the range of 0.5 mg to 5 mg, more preferably in the range of 1 mg to 3.5 mg.
  • the amount of Na2HPC>4 in 1 ml of water for injection is most preferably 2 mg.
  • the amount of NaCl (sodium chloride) in 1 ml of the intra-articular gel formulation of the invention is preferably in the range of 2.5 mg to 7.5 mg, more preferably in the range of 3.5 mg to 6 mg.
  • the amount of Naf ⁇ PC in 1 ml of water for injection is most preferably 4.5 mg.
  • the formulation according to the invention may comprise any combination of amounts of the components of the formulation corresponding to the ranges of amounts given above.
  • the inventors have found that combining the components of the formulation in these ranges of amounts advantageously allows for both the high efficacy of the active ingredient and the high pH stability of the formulation.
  • Example 1 Intra-Articular Gel Formulation in 1 ml of Water for Injection
  • the intra-articular gel formulation according to a preferred embodiment of the present invention is given in Table 1 below.
  • the gel of Example 1 is an intra-articular matrix gel for the treatment of osteoarthritis, degenerative joint diseases and degenerative meniscal tears due to synovial fluid deficiency and for the promotion of cartilage regeneration. Said gel is administered into the joint by injection. pH Stability Studies
  • Table 2 shows that the pH values of the gel formulations without glycine and proline were measured in the range of 6.92 to 7.28 before sterilization, wherein the formulations containing 10 mg/ml, 18 mg/ml and 20 mg/ml Hyaluronate were around 7.0. However, after autoclaving at 121°C for 15 minutes, a major deviation was observed in pH values for all concentrations and pH values even exceeded 7.4 for some concentrations.
  • Table 3 shows that the pH values of the gel formulations containing glycine and proline proved a high stability around pH 7.0 both before and after sterilization.
  • the gel formulation samples of the invention maintain their pH stability to a great extent before and after sterilization (autoclave) in case they contain glycine and proline.
  • intra-articular compositions with a pH of 7.4 or higher may cause various adverse effects such as post-injection pain, flare-ups, skin pigment changes, fat atrophy and joint infection by activating the inflammatory enzymes, and adversely affect drug stabilization (lannitti, T., Lodi, D., & Palmieri, B. (2011).
  • Intra-articular injections for the treatment of osteoarthritis focus on the clinical use of hyaluronic acid. Drugs in R&D, 11(1), 13-27). Therefore, the formulations of the present invention, which have a highly stable pH value due to the glycine and proline components and their specific percentages in the formulation, increase patient compliance and allow the active ingredient to be injected with maximum efficiency due to their pH stability.
  • the intra-articular gel formulation of the present invention is stable due to its components and their specific weight percentages, the pH level of the formulation is substantially maintained around 7.0 and thus the formulation can be safely injected into the synovial fluid without causing irritation or pain to the patient.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Dermatology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Molecular Biology (AREA)
  • Transplantation (AREA)
  • Dispersion Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition de gel intra-articulaire qui favorise la régénération tissulaire et cartilagineuse et une formulation de gel dans laquelle la composition de gel est placée dans un fluide porteur. Ladite composition et ladite formulation comprennent du hyaluronate de sodium ainsi que les acides aminés glycine et proline.
PCT/TR2023/050964 2022-10-11 2023-09-15 Gel intra-articulaire pour la régénération tissulaire et cartilagineuse WO2024080954A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2022/015493 TR2022015493A2 (tr) 2022-10-11 Doku ve kikirdak rejenerasyonu i̇çi̇n eklem i̇çi̇ jel
TR2022015493 2022-10-11

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WO2024080954A1 true WO2024080954A1 (fr) 2024-04-18

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020068718A1 (en) * 2000-10-03 2002-06-06 Pierce Scott W. Chondroprotective/restorative compositions and methods of use thereof
WO2004034980A2 (fr) * 2002-10-16 2004-04-29 Marcum Frank D Traitement de la synovite traumatique et des lesions du cartilage articulaire
US20050234012A1 (en) * 2001-12-21 2005-10-20 Jafari Masoud R Combinations of viscoelastics for use during surgery

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020068718A1 (en) * 2000-10-03 2002-06-06 Pierce Scott W. Chondroprotective/restorative compositions and methods of use thereof
US20050234012A1 (en) * 2001-12-21 2005-10-20 Jafari Masoud R Combinations of viscoelastics for use during surgery
WO2004034980A2 (fr) * 2002-10-16 2004-04-29 Marcum Frank D Traitement de la synovite traumatique et des lesions du cartilage articulaire

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