EP4084801A1 - Nouvelle formulation viscoélastique pour le traitement de l'arthrose et son procédé de production - Google Patents
Nouvelle formulation viscoélastique pour le traitement de l'arthrose et son procédé de productionInfo
- 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
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- 201000008482 osteoarthritis Diseases 0.000 title claims abstract description 35
- 238000009472 formulation Methods 0.000 title claims abstract description 15
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- 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
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
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- 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
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- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 2
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- 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
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- 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
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- 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
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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).
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Abstract
La présente invention concerne une nouvelle formulation viscoélastique mise au point pour le traitement de l'arthrose, et son procédé de production. L'objectif de la présente invention est de fournir un gel viscoélastique comprenant de l'acide hyaluronique réticulé, du sulfate de chondroïtine et de l'acide hyaluronique non réticulé (AH linéaire) à utiliser dans des applications intra-articulaires en vue de soulager la douleur provoquée par l'arthrose, pour fournir un support pour le liquide synovial dont l'efficacité a diminué, et pour traiter des lésions ostéochondrales.
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 (fr) | 2019-12-31 | 2020-12-31 | Nouvelle formulation viscoélastique pour le traitement de l'arthrose et son procédé de production |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP4084801A1 true EP4084801A1 (fr) | 2022-11-09 |
| EP4084801A4 EP4084801A4 (fr) | 2024-04-17 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP20910352.2A Pending EP4084801A4 (fr) | 2019-12-31 | 2020-12-31 | Nouvelle formulation viscoélastique pour le traitement de l'arthrose et son procédé de production |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP4084801A4 (fr) |
| TR (2) | TR201922945A2 (fr) |
| WO (1) | WO2021137837A1 (fr) |
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 |
| US8394782B2 (en) * | 2007-11-30 | 2013-03-12 | Allergan, Inc. | Polysaccharide gel formulation having increased longevity |
| US20090143348A1 (en) * | 2007-11-30 | 2009-06-04 | Ahmet Tezel | Polysaccharide gel compositions and methods for sustained delivery of drugs |
| 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 |
| MX2017010383A (es) * | 2015-02-13 | 2018-11-12 | Endo Derma Co Ltd | Microestructura usando hidrogel de ácido hialurónico reticulado y método para preparar el mismo. |
| TWI675666B (zh) * | 2016-06-16 | 2019-11-01 | 南韓商安道德瑪股份有限公司 | 溶解特性優秀的透明質酸微結構體 |
| KR20180035032A (ko) * | 2016-09-28 | 2018-04-05 | 주식회사 파마리서치프로덕트 | 가교 히알루론산을 포함하는 주사용 조성물 |
-
2019
- 2019-12-31 TR TR2019/22945A patent/TR201922945A2/tr unknown
- 2019-12-31 TR TR2019/22907A patent/TR201922907A2/tr unknown
-
2020
- 2020-12-31 EP EP20910352.2A patent/EP4084801A4/fr active Pending
- 2020-12-31 WO PCT/TR2020/051471 patent/WO2021137837A1/fr unknown
Also Published As
| Publication number | Publication date |
|---|---|
| TR201922907A2 (tr) | 2021-07-26 |
| WO2021137837A1 (fr) | 2021-07-08 |
| EP4084801A4 (fr) | 2024-04-17 |
| TR201922945A2 (tr) | 2021-07-26 |
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