EP4084801A1 - Neuartige viskoelastische formulierung zur behandlung von osteoarthritis und verfahren zu ihrer herstellung - Google Patents
Neuartige viskoelastische formulierung zur behandlung von osteoarthritis und verfahren zu ihrer herstellungInfo
- Publication number
- EP4084801A1 EP4084801A1 EP20910352.2A EP20910352A EP4084801A1 EP 4084801 A1 EP4084801 A1 EP 4084801A1 EP 20910352 A EP20910352 A EP 20910352A EP 4084801 A1 EP4084801 A1 EP 4084801A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- gel
- viscoelastic
- mixture
- crosslinked
- production method
- Prior art date
- Legal status (The legal status 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 status listed.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 35
- 201000008482 osteoarthritis Diseases 0.000 title claims abstract description 35
- 238000009472 formulation Methods 0.000 title claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 12
- 238000011282 treatment Methods 0.000 title abstract description 11
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 78
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 78
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 78
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229920001287 Chondroitin sulfate Polymers 0.000 claims abstract description 27
- 229940059329 chondroitin sulfate Drugs 0.000 claims abstract description 27
- 208000002193 Pain Diseases 0.000 claims abstract description 15
- 210000001179 synovial fluid Anatomy 0.000 claims abstract description 11
- 230000003902 lesion Effects 0.000 claims abstract description 5
- 230000003247 decreasing effect Effects 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 210000000845 cartilage Anatomy 0.000 claims description 14
- 239000008055 phosphate buffer solution Substances 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 13
- HPILSDOMLLYBQF-UHFFFAOYSA-N 2-[1-(oxiran-2-ylmethoxy)butoxymethyl]oxirane Chemical compound C1OC1COC(CCC)OCC1CO1 HPILSDOMLLYBQF-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 210000003127 knee Anatomy 0.000 claims description 7
- 238000005461 lubrication Methods 0.000 claims description 7
- 238000004132 cross linking Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 238000011069 regeneration method Methods 0.000 claims description 6
- 239000008367 deionised water Substances 0.000 claims description 5
- 229910021641 deionized water Inorganic materials 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 4
- 230000003472 neutralizing effect Effects 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 210000003423 ankle Anatomy 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000001125 extrusion Methods 0.000 claims description 2
- 238000011049 filling Methods 0.000 claims description 2
- 238000005429 filling process Methods 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 230000001954 sterilising effect Effects 0.000 claims description 2
- 238000004659 sterilization and disinfection Methods 0.000 claims description 2
- 210000003857 wrist joint Anatomy 0.000 claims description 2
- 238000002347 injection Methods 0.000 description 19
- 239000007924 injection Substances 0.000 description 19
- 229920002385 Sodium hyaluronate Polymers 0.000 description 12
- 229940010747 sodium hyaluronate Drugs 0.000 description 12
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 12
- 210000000988 bone and bone Anatomy 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 230000003993 interaction Effects 0.000 description 8
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 210000001503 joint Anatomy 0.000 description 6
- 230000008569 process Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 4
- 230000002195 synergetic effect Effects 0.000 description 4
- 239000003431 cross linking reagent Substances 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229960005489 paracetamol Drugs 0.000 description 3
- 230000008929 regeneration Effects 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- 230000008961 swelling Effects 0.000 description 3
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 2
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 2
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 2
- 229920002683 Glycosaminoglycan Polymers 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 210000001188 articular cartilage Anatomy 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229960004544 cortisone Drugs 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- WCDDVEOXEIYWFB-VXORFPGASA-N (2s,3s,4r,5r,6r)-3-[(2s,3r,5s,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylic acid Chemical class CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O)[C@H](O)[C@H]1O WCDDVEOXEIYWFB-VXORFPGASA-N 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- -1 N-acetylamino group Chemical group 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 208000008558 Osteophyte Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 229940013181 advil Drugs 0.000 description 1
- 229940060515 aleve Drugs 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000011882 arthroplasty Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000001720 carbohydrates Chemical group 0.000 description 1
- 230000003846 cartilage breakdown Effects 0.000 description 1
- 230000022159 cartilage development Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000001612 chondrocyte Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 239000011243 crosslinked material Substances 0.000 description 1
- 229940029644 cymbalta Drugs 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229960002866 duloxetine Drugs 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 201000010934 exostosis Diseases 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000037219 healthy weight Effects 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 210000000281 joint capsule Anatomy 0.000 description 1
- 230000008407 joint function Effects 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- 230000003349 osteoarthritic effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 238000000554 physical therapy Methods 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000000518 rheometry Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940072651 tylenol Drugs 0.000 description 1
- 239000003190 viscoelastic substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
- C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
-
- 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
- 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
- A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
Definitions
- the present invention relates to a novel viscoelastic formulation developed to relieve pain caused by osteoarthritis (OA), to provide support to the synovial fluid whose effectiveness has decreased, and to treat osteochondral lesions, and a production method thereof.
- OA osteoarthritis
- Osteoarthritis is the most common chronic (long-term) joint disease affecting millions of people worldwide. OA is also called degenerative joint disease, degenerative arthritis, and wear and tear arthritis. The joint is where two bones come together and the ends of these bones are covered with a protective tissue called cartilage. Cartilage is a durable and slippery tissue that allows joint movement to occur almost without friction. Synovial fluid which provides lubrication between the bone ends and the cartilage is comprised of Hyaluronic Acid (HA) that is naturally present in the body. The viscosity, lubrication and shock absorbing properties of the said synovial fluid decrease over time due to mechanical effects and the cartilages begin to rub against each other and break down.
- HA Hyaluronic Acid
- OA affects the entire joint, as well as cartilage breakdown. It causes changes in the bone structure and the deterioration of the connective tissues that hold the joint together and connect the muscles to the bone; and also causes inflammation of the joint capsule.
- OA Even though OA is usually seen in old ages, it can sometimes be seen also in young people. OA symptoms develop over time and they worsen as it progresses. Symptoms of OA include pain, stiffness, tenderness, loss of flexibility, crepitus, osteophyte formation, and swelling.
- Acetaminophen It is known that acetaminophen (Tylenol and others) helps patients with osteoarthritis suffering from mild to moderate pain. Intake of acetaminophen more than the recommended dose may cause liver damage.
- Non-steroidal anti-inflammatory drugs NSAIDs
- NS A TPs such as Advil (ibuprofen) and Aleve (naproxen) reduce swelling as well as pain.
- Duloxetine (Cymbalta): This drug which is normally used as an antidepressant is also used to treat chronic pain, including osteoarthritis pain.
- Corticosteroid drug injections may relieve the pain in the joint. During this procedure, the doctor checks the area around the joint, and then inserts a needle into the cavity in the joint and injects the drug. The number of cortisone injections which can be taken per year is generally limited to three or four injections since the drug worsens joint damage over time.
- Viscoelastic injections may relieve pain by means of providing an amount of cushioning in the knee. Normally, hyaluronic acid is a component that naturally exists in joint fluid. • Realigning the bones: In knee osteotomy, a surgeon cuts the bone above or below the knee and then removes or inserts a wedge bone. This takes the body weight away from the worn part of the knee.
- HA In the knee with OA, the concentration of HA decreases approximately to half of the normal level. Changes in the viscous and elastic properties of HA decrease the joint's ability to withstand tensile and shear forces. HA injections can help recover the normal levels of synovial fluid. These injections not only lubricate the joint, they can also reduce inflammation and protect the cartilage from further wear and tear.
- the injections are made in weekly periods by a doctor or healthcare professional.
- the number of injections to be made may vary depending on the HA concentration.
- the doctor can perform aspiration by taking some of the fluid from the knee joint with a needle in order to reduce swelling.
- HA hyaluronic acid which is not crosslinked
- HA is subjected to crosslinking processes with crosslinking agents such as ethyldimethylaminopropyl carbodiimide (EDC), butanediol diglycidylether (BDDE) or divinyl sulfone (DVS) in order to improve its viscoelastic properties and increase its permanence.
- crosslinking reaction is an intramolecular and intermolecular esterification reaction that is performed using several reagents. It has been envisaged that by means of using this technique, the residence time of the HA formulation in the joint can be increased.
- the physical, chemical and biological properties of HA change significantly by increasing the degree of crosslinking.
- the gel suspension of crosslinked HA has different rheological properties than the linear HA.
- the low frequency modulus of crosslinked HA is higher than the non-crosslinked HA, which indicates that a network structure has been formed for crosslinked materials.
- the constant shear viscosity or elastic modulus is not higher than non-crosslinked HA.
- the residence time in the body of the linear HA viscoelastic material against the mechanical effect of the joint is shorter than the crosslinked HA.
- the mechanical strength of the crosslinked HA is higher than that of linear chains. While the specialist applying the treatment carries out the non-crosslinked HA (Linear HA) injection at weekly intervals, this period is longer for viscoelastics comprising crosslinked HA. For this reason, the specialist physician generally prefers injections also including crosslink having a longer residence time in the body and higher mechanical strength. It has been observed that the crosslinked viscoelastic exhibits effective results even with a single injection.
- European patent document no EP1443945B1 an application known in the state of the art, discloses synergistic effect of sodium hyaluronate and chondroitin sulfate mixture on the lubrication and regeneration of articular cartilage damaged by stage I and stage II osteoarthritis of human joints.
- the combination of linear HA and chondroitin sulfate was used in the treatment of osteoarthritis.
- the objective of the present invention is to provide a novel viscoelastic gel to be used in intra-articular applications in order to relieve pain caused by Osteoarthritis (OA), to provide support to the synovial fluid whose effectiveness has decreased and to treat osteochondral lesions.
- Another objective of the present invention is to create a synergistic effect by means of mixing chondroitin sulfate, which is a suitable substance for the regeneration of cartilage, with sodium hyaluronate.
- a further objective of the present invention is to increase the residence time of chondroitin sulfate in the tissue due to its good adhesion to the tissue with positive charge due to its negative charge provided by the sulfate groups that are densely present in its structure.
- Another objective of the present invention is to increase mechanical strength and residence time of the gel by means of the crosslinked HA present in the mixture.
- the viscoelastic gel of the present invention has been developed to be used in intra-articular applications for the treatment of osteochondral lesions caused by Osteoarthritis (OA) and comprises a novel viscoelastic gel formulation comprised of three active ingredients. These ingredients are as follows: i. Crosslinked hyaluronic acid ii. Chondroitin sulfate iii. Non-crosslinked hyaluronic acid (Linear HA) The ingredients in the viscoelastic gel formulation of the present invention are prepared within the scope of the ratios in Table 1, and the concentrations of the active ingredients in the formulation described above are (preferably) in the following range: - Crosslinked HA : 2-12 mg/ml
- Non-crosslinked HA 6-20 mg/ml Table 1 Combination ratios (%) of components by weight required for crosslinked HA reaction/synthesis only
- the production method of the viscoelastic gel developed within the scope of the invention is comprised of the following steps:
- the viscoelastic gel of the present invention can be specifically used for human joints suffering from stage I and stage II osteoarthritis (application site including knee, shoulder, sacroiliac, hip, ankle, elbow, interphalangeal and wrist joints) for lubrication of the joint and self-regeneration of the cartilage.
- stage I and stage II osteoarthritis application site including knee, shoulder, sacroiliac, hip, ankle, elbow, interphalangeal and wrist joints
- it is aimed to create a synergistic effect by means of mixing chondroitin sulfate, which is a suitable substance for the regeneration of cartilage, with sodium hyaluronate.
- the crosslinked HA in the mixture enables to increase the mechanical strength of the gel and its residence time in the body.
- the considerable efficacy of the treatment provided by the viscoelastic gel of the present invention can be associated with the stimulation of chondrogenesis synergistically combined with the known benefits of viscoelastic treatment.
- Implantation of matrix of chondroitin sulfate and sodium hyaluronate can increase the continuity of naturally occurring chondrocytes and enable the damaged cartilage to self-regenerate by reconstituting its original state.
- chondroitin sulfate perfectly absorbs the positively charged tissue with the negatively charged sulfate groups inherent therein and the residence time is prolonged and therefore patient comfort is prolonged.
- combining cross-linked HA with chondroitin sulfate provides a longer duration of effectiveness compared to combinations comprising linear HA.
- Chondroitin sulfate which is also present in the synovial fluid and extracellular matrix, mechanically surrounds the cartilage tightly and with highly negatively charged sulfate groups therein, it has the ability to bind water and cations (Na + ) to form a flexible layer to create electrostatic repulsion providing most of the resistance which causes the elasticity of compression of the cartilage.
- Both chondroitin sulfate and sodium hyaluronate are glycosaminoglycans, which are generally known as mucopolysaccharides. It has been seen that upon mixing of chondroitin sulfate and sodium hyaluronate in an aqueous solution, they align and attract each other by hydrogen bonding at N-acetylamino group for a part of the molecular units. The hydrogen bonding interaction is only one of several possible interactions for chondroitin sulfate and sodium hyaluronate. Chondroitin sulfate derivative beads and hyaluronate derivative beads have the ability to interact with each other and it is assumed that this interaction takes place among the carbohydrate chains of the polymers.
- Adding chondroitin sulfate to sodium hyaluronate in aqueous solution significantly increases the viscosity of the mixture. It is seen that this increase in viscosity is essentially due to an increase in molecular weight rather than an increase in solute concentration.
- the viscosity of the solute- solvent is a function of molecular weight and solute concentration.
- the hydrogen bonding interaction between chondroitin sulfate and sodium hyaluronate will cause the molecular size to expand effectively. Therefore, the viscosity of the mixture will increase.
- the interaction between chondroitin sulfate and sodium hyaluronate can also occur at any concentration. However, the synergistic viscosity effect is more apparent at higher concentration due to the concentration effect and interaction affinity of the molecules. All these interactions show the effect of chondroitin sulfate in the formulation on non-crosslinked HA (Linear HA).
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Polymers & Plastics (AREA)
- Molecular Biology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Dispersion Chemistry (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Materials Engineering (AREA)
- Rheumatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Materials For Medical Uses (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2019/22907A TR201922907A2 (tr) | 2019-12-31 | 2019-12-31 | Osteoartri̇t tedavi̇si̇ i̇çi̇n yeni̇ bi̇r vi̇skoelasti̇k formülasyonu ve bunun üreti̇m yöntemi̇ |
| PCT/TR2020/051471 WO2021137837A1 (en) | 2019-12-31 | 2020-12-31 | A novel viscoelastic formulation for osteoarthritis treatment and a production method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP4084801A1 true EP4084801A1 (de) | 2022-11-09 |
| EP4084801A4 EP4084801A4 (de) | 2024-04-17 |
Family
ID=76687210
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP20910352.2A Pending EP4084801A4 (de) | 2019-12-31 | 2020-12-31 | Neuartige viskoelastische formulierung zur behandlung von osteoarthritis und verfahren zu ihrer herstellung |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP4084801A4 (de) |
| TR (2) | TR201922907A2 (de) |
| WO (1) | WO2021137837A1 (de) |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5827937A (en) * | 1995-07-17 | 1998-10-27 | Q Med Ab | Polysaccharide gel composition |
| US20090143348A1 (en) * | 2007-11-30 | 2009-06-04 | Ahmet Tezel | Polysaccharide gel compositions and methods for sustained delivery of drugs |
| US8394782B2 (en) * | 2007-11-30 | 2013-03-12 | Allergan, Inc. | Polysaccharide gel formulation having increased longevity |
| ITPD20120098A1 (it) * | 2012-03-30 | 2013-10-01 | Fidia Farmaceutici | "nuove formulazioni faramaceutiche contenenti condroitin solfato e derivati dell'acido ialuronico" |
| KR101459070B1 (ko) * | 2013-12-09 | 2014-11-17 | (주) 뉴메딕 | 지속성을 갖는 히알루론산 겔 조성물 |
| CA2975076C (en) * | 2015-02-13 | 2021-07-20 | Endo Derma Co.,Ltd. | Microstructure using crosslinked hyaluronic acid hydrogel and method for preparing the same |
| WO2017217818A1 (ko) * | 2016-06-16 | 2017-12-21 | 주식회사 엔도더마 | 용해 특성이 우수한 히알루론산 마이크로구조체 |
| KR20180035032A (ko) * | 2016-09-28 | 2018-04-05 | 주식회사 파마리서치프로덕트 | 가교 히알루론산을 포함하는 주사용 조성물 |
-
2019
- 2019-12-31 TR TR2019/22907A patent/TR201922907A2/tr unknown
- 2019-12-31 TR TR2019/22945A patent/TR201922945A2/tr unknown
-
2020
- 2020-12-31 EP EP20910352.2A patent/EP4084801A4/de active Pending
- 2020-12-31 WO PCT/TR2020/051471 patent/WO2021137837A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP4084801A4 (de) | 2024-04-17 |
| TR201922945A2 (tr) | 2021-07-26 |
| WO2021137837A1 (en) | 2021-07-08 |
| TR201922907A2 (tr) | 2021-07-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20210085827A1 (en) | Preventative therapy for post-traumatic osteoarthritis | |
| EP1066044B1 (de) | Dextran formulierungen zur behandlung entzündlicher gelenkerkrankungen | |
| JP6359599B2 (ja) | 関節を治療する組成物 | |
| US10821131B2 (en) | Pharmaceutical formulations comprising chondroitin sulfate and hyaluronic acid derivatives | |
| US7119062B1 (en) | Methods and compositions for improved articular surgery using collagen | |
| EP2170055B1 (de) | Zusammensetzung in der verwendung zur behandlung von bindegewebsschäden | |
| MXPA01011542A (es) | Regeneracion del cartilago articular da°ado por la osteoartritis de grado i y ii, mediante la aplicacion intra-articular de una mezcla de hialuronato de sodio y de condroitin sulfato en un vehiculo de gel. | |
| CN101065106A (zh) | 三元天然聚合物粘弹性组合物 | |
| Balazs | Therapeutic use of hyaluronan | |
| JP4990446B2 (ja) | 関節症治療用注入剤 | |
| US20240050628A1 (en) | Injectable photocrosslinked hyaluronic acid hydrogels, production method thereof and their use for the treatment of osteoarthritis | |
| EP4084801A1 (de) | Neuartige viskoelastische formulierung zur behandlung von osteoarthritis und verfahren zu ihrer herstellung | |
| JP7506431B2 (ja) | ヒアルロン酸とプルロニックを含む関節及び軟骨損傷の予防又は治療用組成物 | |
| JP2007507516A (ja) | アミノ糖投与による哺乳動物の障害の治療及びアミノ糖の使用 | |
| RU2815871C1 (ru) | Способ лечения деформирующего остеоартрита коленного сустава | |
| JP2020510088A (ja) | 新規な粘弾性溶液及びそのリウマチ学における使用 | |
| TW201739457A (zh) | 組成物在製備治療動物或人的受傷肌腱之藥物的用途與套組 | |
| More et al. | Mechanical Properties of Human Synovial Fluid: An Approach for Osteoarthritis Treatment | |
| WO2023239695A1 (en) | Prophylaxis and treatment of degraded cartilage |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
| 17P | Request for examination filed |
Effective date: 20220725 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
| DAV | Request for validation of the european patent (deleted) | ||
| DAX | Request for extension of the european patent (deleted) | ||
| A4 | Supplementary search report drawn up and despatched |
Effective date: 20240315 |
|
| RIC1 | Information provided on ipc code assigned before grant |
Ipc: A61P 19/02 20060101ALI20240311BHEP Ipc: A61K 31/737 20060101ALI20240311BHEP Ipc: A61K 31/728 20060101AFI20240311BHEP |