WO2011160146A1 - Pharmaceutical preparation containing dextran and sodium hyaluronate for the treatment of joint disorders - Google Patents
Pharmaceutical preparation containing dextran and sodium hyaluronate for the treatment of joint disorders Download PDFInfo
- Publication number
- WO2011160146A1 WO2011160146A1 PCT/AT2011/000269 AT2011000269W WO2011160146A1 WO 2011160146 A1 WO2011160146 A1 WO 2011160146A1 AT 2011000269 W AT2011000269 W AT 2011000269W WO 2011160146 A1 WO2011160146 A1 WO 2011160146A1
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- WO
- WIPO (PCT)
- Prior art keywords
- molecular weight
- dextran
- sodium hyaluronate
- average molecular
- pharmaceutical preparation
- 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.)
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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
- A61K31/70—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
- A61K31/716—Glucans
- A61K31/721—Dextrans
-
- 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
- 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
Definitions
- the present invention is directed to a pharmaceutical preparation for intraarticular injection for treating inflammatory and degenerative joint disorders.
- Osteoarthritis also known as degenerative arthritis, degenerative joint disease
- OA is a group of diseases and mechanical abnormalities involving degradation of joints, including articular cartilage and the subchondral bone next to it.
- OA OA-related diseases
- a variety of potential forces— hereditary, developmental, metabolic, and mechanical— may initiate processes leading to loss of cartilage ⁇ a strong protein matrix that lubricates and cushions the joints.
- OA is the most common form of arthritis.
- joint disorders such as rheumatoid arthritis can lead to degradation of articular cartilage structures caused by chronic inflammation of synovial tissues.
- Anti-inflammatory agents which are orally ingested, are used to temporarily treat pain and inflammation of the joint. Corticosteroids are also used for local treatment
- the replacement of sodium hyaluronate (a natural component of the synovial fluid) via local injection alleviates symptoms of OA by increasing lubrication and cushioning within the synovial cavity. This treatment is not always effective and does not have any positive influence on inflammatory processes.
- EP 1 066 044 Bl describes the use of a composition for intraarticular injection containing clinical grade dextran (a biocompatible colloid) with a bimodal molecular weight distribution: 0.2% to 32% (m/v) dextran with an average molecular weight between 30,000 and 110,000 Da (e.g. dextran 70 for injection with an average molecular weight of 70,000 Da; as described in the European Pharmacopoeia) and 0.2% to 6% (m/v) dextran with an average molecular weight between 500 and 3,000 Da.
- dextran 70 for injection with an average molecular weight of 70,000 Da as described in the European Pharmacopoeia
- 0.2% to 6% (m/v) dextran with an average molecular weight between 500 and 3,000 Da.
- the combination of both dextrans was shown to provide almost immediate and sustained pain relief after injection. This effect was attributed to the addition of the smaller dextran to the formulation, which diffuses into surrounding tissues much faster than the larger molecular weight dextran.
- Dextrans with an average molecular weight between 30,000 and 110,000 Da e.g. dextran 70
- DIAR Dextran Induced Anaphylactic Reactions
- the inventive pharmaceutical preparation for intraarticular injection for treating inflammatory and degenerative joint disorders contains 0.2-32% (m/v) dextran with an average molecular weight of 500 to 3,000 Da and 0.1-10% sodium hyaluronate with an average molecular weight of 500,000 to 3500,000 Da, with the proviso that no further dextran having an average molecular weight in the range of 30,000 and 110,000 Da is contained.
- the invention is based on the finding that a colloidal viscoelastic formulation containing only low molecular weight dextran (e.g. dextran 1 for injection with an average molecular weight of 1000 Da; as listed in the European Pharmacopoeia), i.e. no further dextran having an average molecular weight in the range of 30,000 and 110,000 Da, and sodium hyaluronate has the same unexpected positive effects which are described in EP1 066 044 Bl using dextran with a bimodal distribution of the molecular weight, i.e. rapid onset of pain relief and improved joint mobility and extension of pain relief to adjacent tissues.
- the invention provides a physiologically acceptable composition for intraarticular injection without the risk of serious side effects.
- the formulation additionally contains physiologically acceptable salts, buffer substances, additional lubricants, substances to enhance viscosity, substances to adjust osmolality; is administered via intraarticular injection; contains a volume suitable for the intraarticular space; is sterile.
- Preferred embodiment 0.2-32% (m/v) injection grade low mol. weight fraction of dextran with an average molecular weight of 500 to 3,000 Da and 0,1-10% sodium hyaluronate with an average molecular weight of 500,000 to 3500,000 Da.
- sodium hyaluronate is partially crosslinked, preferably via disulfide bonds.
- European Pharmacopoeia with an average molecular weight of 1,000 Da; dextran 70 for injection (as listed in the European Pharmacopoeia) with an average molecular weight of 70,000 Da; sodium hyaluronate with an average molecular weight in the range of 2200,000 to 2700,000 Da.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Immunology (AREA)
- Dermatology (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Pharmaceutical preparation for intraarticular injection for treating inflammatory and degenerative joint disorders containing 0.2-32% (m/v) dextran with an average molecular weight of 500 to 3,000 Da and 0.1-10% sodium hyaluronate with an average molecular weight of 500,000 to 3500,000 Da, with the proviso that no further dextran having an average molecular weight in the range of 30,000 and 110,000 Da is contained.
Description
PHARMACEUTICAL PREPARATION CONTAINING DEXTRAN AND SODIUM HYALURONATE FOR THE TREATMENT OF JOINT DISORDERS
The present invention is directed to a pharmaceutical preparation for intraarticular injection for treating inflammatory and degenerative joint disorders.
Introduction
Osteoarthritis (OA, also known as degenerative arthritis, degenerative joint disease), is a group of diseases and mechanical abnormalities involving degradation of joints, including articular cartilage and the subchondral bone next to it. Clinical
manifestations of OA may include joint pain, tenderness, stiffness, creaking, locking of joints, and sometimes local inflammation. In OA, a variety of potential forces— hereditary, developmental, metabolic, and mechanical— may initiate processes leading to loss of cartilage ~ a strong protein matrix that lubricates and cushions the joints. The patient increasingly experiences pain upon weight bearing, including walking and standing. OA is the most common form of arthritis. In addition, joint disorders such as rheumatoid arthritis can lead to degradation of articular cartilage structures caused by chronic inflammation of synovial tissues.
State of the art
Anti-inflammatory agents, which are orally ingested, are used to temporarily treat pain and inflammation of the joint. Corticosteroids are also used for local treatment
(intraarticular injection), which reduces systemic side effects for the patient. It is however well known that in the long term corticosteroids accelerate the degenerative processes in OA and their effect on pain and inflammation is only short lived.
The replacement of sodium hyaluronate (a natural component of the synovial fluid) via local injection alleviates symptoms of OA by increasing lubrication and cushioning within the synovial cavity. This treatment is not always effective and does not have any positive influence on inflammatory processes.
There is a longfelt need for safe and effective treatment options to treat pain and inflammation in patients suffering from inflammatory and degenerative joint disorders. EP 1 066 044 Bl describes the use of a composition for intraarticular injection containing clinical grade dextran (a biocompatible colloid) with a bimodal molecular weight distribution: 0.2% to 32% (m/v) dextran with an average molecular weight
between 30,000 and 110,000 Da (e.g. dextran 70 for injection with an average molecular weight of 70,000 Da; as described in the European Pharmacopoeia) and 0.2% to 6% (m/v) dextran with an average molecular weight between 500 and 3,000 Da. The combination of both dextrans was shown to provide almost immediate and sustained pain relief after injection. This effect was attributed to the addition of the smaller dextran to the formulation, which diffuses into surrounding tissues much faster than the larger molecular weight dextran.
Dextrans with an average molecular weight between 30,000 and 110,000 Da (e.g. dextran 70) however are known to cause severe anaphylactic reactions (so-called Dextran Induced Anaphylactic Reactions, DIAR). The co-administration of low mol. weight dextran only reduces the risk of these potentially life-threatening side effects without completely eliminating it (Ljungstrom et al. 1988, Ljungstrom et al. 1993). The risk-benefit ratio for this treatment strategy is consequently not acceptable.
Invention
The inventive pharmaceutical preparation for intraarticular injection for treating inflammatory and degenerative joint disorders contains 0.2-32% (m/v) dextran with an average molecular weight of 500 to 3,000 Da and 0.1-10% sodium hyaluronate with an average molecular weight of 500,000 to 3500,000 Da, with the proviso that no further dextran having an average molecular weight in the range of 30,000 and 110,000 Da is contained.
The invention is based on the finding that a colloidal viscoelastic formulation containing only low molecular weight dextran (e.g. dextran 1 for injection with an average molecular weight of 1000 Da; as listed in the European Pharmacopoeia), i.e. no further dextran having an average molecular weight in the range of 30,000 and 110,000 Da, and sodium hyaluronate has the same unexpected positive effects which are described in EP1 066 044 Bl using dextran with a bimodal distribution of the molecular weight, i.e. rapid onset of pain relief and improved joint mobility and extension of pain relief to adjacent tissues. The invention provides a physiologically acceptable composition for intraarticular injection without the risk of serious side effects.
Due to this beneficial safety profile repeated injections are possible if they are needed in some cases to achieve a long term effect on pain relief.
Combination therapies with additional supplementation of sodium hyaluronate
(unmodified or cross-linked form for longer residence time and higher viscoelasticity) are possible as well to improve joint lubrication additionally after achieving pain relief with the first injection of low mol. weight dextran and sodium hyaluronate
combination.
The formulation additionally contains physiologically acceptable salts, buffer substances, additional lubricants, substances to enhance viscosity, substances to adjust osmolality; is administered via intraarticular injection; contains a volume suitable for the intraarticular space; is sterile.
Preferred embodiment: 0.2-32% (m/v) injection grade low mol. weight fraction of dextran with an average molecular weight of 500 to 3,000 Da and 0,1-10% sodium hyaluronate with an average molecular weight of 500,000 to 3500,000 Da. In another embodiment sodium hyaluronate is partially crosslinked, preferably via disulfide bonds.
Example
Physical-chemical characterisation (measurement of pH value, osmolality and rheological properties) revealed that the formulation described in this invention has comparable physical-chemical properties to the invention claimed in EP 1 066 044 Bl. The following raw materials were used: dextran 1 for injection (as listed in the
European Pharmacopoeia) with an average molecular weight of 1,000 Da; dextran 70 for injection (as listed in the European Pharmacopoeia) with an average molecular weight of 70,000 Da; sodium hyaluronate with an average molecular weight in the range of 2200,000 to 2700,000 Da.
Claims
1. Pharmaceutical preparation for intraarticular injection for treating inflammatory and degenerative joint disorders containing 0.2-32% (m/v) dextran with an average molecular weight of 500 to 3,000 Da and 0.1-10% sodium hyaluronate with an average molecular weight of 500,000 to 3500,000 Da, with the proviso that no further dextran having an average molecular weight in the range of 30,000 and 110,000 Da is contained.
2. Pharmaceutical preparation according to claim 1, additionally comprising 0.01% - 10% sodium hyaluronate which is chemically crosslinked.
3. Pharmaceutical preparation according to claim 1 or 3, additionally comprising one or more out of the group consisting of antibiotics, anti-inflammatory agents, vitamins, local anesthetics, cell nutrients and natural ingredients of the synovial fluid.
4. Use of dextran with an average molecular weight of 500 to 3,000 Da and sodium hyaluronate with an average molecular weight of 500,000 to 3500,000 Da for the production of a pharmaceutical preparation for the treatment of inflammatory and degenerative joint disorders, wherein first said dextran and said sodium hyaluronate is applied and subsequently one of more injections of sodium hyaluronate is applied.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT10552010 | 2010-06-23 | ||
| ATA1055/2010 | 2010-06-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2011160146A1 true WO2011160146A1 (en) | 2011-12-29 |
Family
ID=44343855
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/AT2011/000269 Ceased WO2011160146A1 (en) | 2010-06-23 | 2011-06-16 | Pharmaceutical preparation containing dextran and sodium hyaluronate for the treatment of joint disorders |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2011160146A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20190065771A (en) * | 2017-12-04 | 2019-06-12 | 이일훈 | Compositions for treating joint or connective tissue disease comprising dextran or poloxamer |
| KR20200015671A (en) * | 2020-02-04 | 2020-02-12 | 이일훈 | Compositions for treating joint or connective tissue disease comprising dextran or poloxamer |
| KR20200126948A (en) * | 2020-02-04 | 2020-11-09 | 메디슨파크 주식회사 | Compositions for treating joint or connective tissue disease comprising dextran or poloxamer |
| KR20210127909A (en) * | 2020-10-26 | 2021-10-25 | 메디슨파크 주식회사 | Compositions for treating joint or connective tissue disease comprising dextran or poloxamer |
Citations (3)
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|---|---|---|---|---|
| WO2003000191A2 (en) * | 2001-06-25 | 2003-01-03 | Depuy | Composition comprising glycosaminogycans and hyaluronidase inhibitors for the treatment of arthritic joints |
| EP1066044B1 (en) | 1998-03-27 | 2004-03-10 | Glenpharma | Dextran formulations for treatment of inflammatory joint disorders |
| WO2005110278A2 (en) * | 2003-04-29 | 2005-11-24 | Musculoskeletal Transplant Foundation | Cartilage repair mixture containing allograft chondrocytes |
-
2011
- 2011-06-16 WO PCT/AT2011/000269 patent/WO2011160146A1/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1066044B1 (en) | 1998-03-27 | 2004-03-10 | Glenpharma | Dextran formulations for treatment of inflammatory joint disorders |
| WO2003000191A2 (en) * | 2001-06-25 | 2003-01-03 | Depuy | Composition comprising glycosaminogycans and hyaluronidase inhibitors for the treatment of arthritic joints |
| WO2005110278A2 (en) * | 2003-04-29 | 2005-11-24 | Musculoskeletal Transplant Foundation | Cartilage repair mixture containing allograft chondrocytes |
Non-Patent Citations (1)
| Title |
|---|
| ALY M N S: "Intra-articular drug delivery: A fast growing approach", RECENT PATENTS ON DRUG DELIVERY & FORMULATION, BENTHAM SCIENCE PUBLISHERS LTD, NL, vol. 2, no. 3, 1 November 2008 (2008-11-01), pages 231 - 237, XP009151166, ISSN: 1872-2113 * |
Cited By (18)
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| JP2023089978A (en) * | 2017-12-04 | 2023-06-28 | メディシン、パーク、カンパニー、リミテッド | Composition for treatment of joint or connective tissue disease comprising dextran or poloxamer |
| US11801260B2 (en) | 2017-12-04 | 2023-10-31 | Medicine Park Co., Ltd | Compositions for treating joint or connective tissue disease comprising dextran or poloxamer |
| KR102075596B1 (en) * | 2017-12-04 | 2020-02-10 | 이일훈 | Compositions for treating joint or connective tissue disease comprising dextran or poloxamer |
| JP7796077B2 (en) | 2017-12-04 | 2026-01-08 | メディシン、パーク、カンパニー、リミテッド | Compositions for treating joint or connective tissue diseases, comprising dextran or poloxamer - Patent Application 20070122997 |
| CN111491640A (en) * | 2017-12-04 | 2020-08-04 | 医药产业园有限公司 | Composition for treating joint disease or connective tissue disease comprising glucan or poloxamer |
| EP4588514A3 (en) * | 2017-12-04 | 2025-10-15 | Medicine Park Co., Ltd. | Composition for treating joint disease or connective tissue disease containing dextran or poloxamer |
| CN111491640B (en) * | 2017-12-04 | 2025-05-30 | 医药产业园有限公司 | Composition for treating joint diseases or connective tissue diseases comprising dextran or poloxamer |
| JP2021505680A (en) * | 2017-12-04 | 2021-02-18 | メディシン、パーク、カンパニー、リミテッドＭｅｄｉｃｉｎｅ Ｐａｒｋ Ｃｏ．， Ｌｔｄ． | A therapeutic composition for joint or connective tissue diseases, including dextran or poloxamer. |
| WO2019112291A1 (en) * | 2017-12-04 | 2019-06-13 | 이일훈 | Composition for treating joint diseases or connective tissue diseases, containing dextran or poloxamer |
| US11278565B2 (en) | 2017-12-04 | 2022-03-22 | Medicine Park Co., Ltd. | Compositions for treating joint or connective tissue disease comprising dextran or poloxamer |
| JP7674103B2 (en) | 2017-12-04 | 2025-05-09 | メディシン、パーク、カンパニー、リミテッド | Compositions for treating joint or connective tissue diseases comprising dextran or poloxamer - Patent Application 20070229333 |
| KR20190065771A (en) * | 2017-12-04 | 2019-06-12 | 이일훈 | Compositions for treating joint or connective tissue disease comprising dextran or poloxamer |
| KR102316719B1 (en) * | 2020-02-04 | 2021-10-25 | 메디슨파크 주식회사 | Compositions for treating joint or connective tissue disease comprising dextran or poloxamer |
| KR20200126948A (en) * | 2020-02-04 | 2020-11-09 | 메디슨파크 주식회사 | Compositions for treating joint or connective tissue disease comprising dextran or poloxamer |
| KR102172290B1 (en) | 2020-02-04 | 2020-10-30 | 메디슨파크 주식회사 | Compositions for treating joint or connective tissue disease comprising dextran or poloxamer |
| KR20200015671A (en) * | 2020-02-04 | 2020-02-12 | 이일훈 | Compositions for treating joint or connective tissue disease comprising dextran or poloxamer |
| KR102468374B1 (en) * | 2020-10-26 | 2022-11-17 | 메디슨파크 주식회사 | Compositions for treating joint or connective tissue disease comprising dextran or poloxamer |
| KR20210127909A (en) * | 2020-10-26 | 2021-10-25 | 메디슨파크 주식회사 | Compositions for treating joint or connective tissue disease comprising dextran or poloxamer |
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