WO1989001777A1 - Lubricant composition for rheumatism - Google Patents

Lubricant composition for rheumatism Download PDF

Info

Publication number
WO1989001777A1
WO1989001777A1 PCT/AU1988/000322 AU8800322W WO8901777A1 WO 1989001777 A1 WO1989001777 A1 WO 1989001777A1 AU 8800322 W AU8800322 W AU 8800322W WO 8901777 A1 WO8901777 A1 WO 8901777A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition according
hyaluronic acid
phospholipid
joint
composition
Prior art date
Application number
PCT/AU1988/000322
Other languages
French (fr)
Inventor
Brian Andrew Hills
Original Assignee
Macnaught Pty. Limited
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 to US07/466,257 priority Critical patent/US5403592A/en
Application filed by Macnaught Pty. Limited filed Critical Macnaught Pty. Limited
Priority to AU23208/88A priority patent/AU620821B2/en
Priority to DE88907578T priority patent/DE3884622T2/en
Priority to AT88907578T priority patent/ATE95061T1/en
Publication of WO1989001777A1 publication Critical patent/WO1989001777A1/en

Links

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
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to lubricant compositions and in particular, compositions adapted for physiological use such as the lubrication of joints.
  • synovial fluid acts to effectively lubricate the surfaces of bones that are in frictional contact to form joints. Moreover, the synovial fluid is able to provide effective lubrication in joints such as the human knee, where the
  • the lubricant would desirably:-
  • synovial 30 fluid that is able to effectively lubricate joints. It has been recognised that one of the major components of synovial fluid is hyaluronic acid, which has a co-efficient of kinetic friction below 0.02.
  • the present inventor found phospholipids in pleural fluid and has shown that phospholipids can lubricate well as a layer adsorbed to such surfaces as glass or quartz when deposited onto those surfaces from solution in chloroform. Further, studies showed that these layers had high-load-bearing properties and that the same phospholipids are present in many other fluids adjacent to sliding tissue surfaces, for example, the pericardium, numerous visceral surfaces and the joints. Moreover, they are present in a surface active state which would be needed for them to be adsorbed to the sliding surfaces in vivo.
  • joint lubrication has the characteristics of boundary lubrication and yet coefficients of friction of a magnitude generally associated with hydrodynamic lubrication.
  • the present inventor has found that a composition having a suitably low coefficient of kinetic friction of the order of 0.003 - 0.010 may be prepared by the ultrasonication of surface active phospholipid in saline to produce a suspension of liposomes. It has further been found that lower coefficients of kinetic friction may be obtained when a surface active phospholipid is suspended in hyaluronic acid. Such compositions give suitably low coefficients of kinetic friction at relatively high loads.
  • the present invention relates to a lubricant composition comprised of at least one surface active phospholipid, hyaluronic acid or a water soluble salt thereof in saline solution.
  • the saline solution is 0.9% NaCl solution, optionally phosphate-buffered 0.9% NaCl solution.
  • the lubricant composition may optionally contain pharmaceutically acceptable excipients and/or additives.
  • a lubricant composition in accordance with the present invention, having a relatively high concentration of phospholipid in solution, said phospholipid being taken from either synovial fluid or from another site where lubrication of tissue takes place in the body, into the joint of an animal or a human leads to improved lubrication of the articular surfaces of said joint.
  • a higher degree of improved lubrication is obtained when the concentration of the phospholipid in the lubricant composition exceeds the normal concentration of phospholipid found in synovial fluid.
  • the adsorption of phospholipid onto the articular surfaces of a joint renders said surfaces hydrophobic and produces the aforesaid low coefficients of kinetic friction.
  • the increase in phospholipid concentration at a particular site, resulting from the introduction of a lubricant composition at said site, can also serve as a releasing agent, that is, prevent the sticking of a joint after standing when fluids can be "squeezed out".
  • the surface active phospholipid present in the lubricant composition can be used as a release agent when said c omposition is used in conjunction with the synovial fluid of a joint or of those sites of the body where surfaces are in contact. Such a use would result in increased mobility and decreased pain, if present, at the particular site.
  • the force of adhesion by a protein glue can be reduced by 90 to 99%.
  • the improved effects obtained through the administration of a lubricant composition can be maintained or readily re-established by irrigating the joint or site previously affected by a lubricant composition at regular intervals as required.
  • the present invention also relates to a method of use of a lubricant composition wherein said lubricant composition is introduced into the synovial fluid of a joint of an animal or a human resulting in the increased adsorption of phospholipids onto the articular surfaces of said joint such that the coefficient of kinetic friction between the articular surfaces and the synovial fluid and between the articular surfaces themselves is reduced.
  • the present invention relates to the use of a lubricant composition as a releasing agent when said lubricant composition is used in conjunction with the synovial fluid of a particular joint or at a particular site in a body where surfaces are in contact.
  • the present invention also provides a method for the treatment of osteoarthritis and related diseases of the joints of animals comprising administering to a disease affected joint an effective amount of a lubricant composition.
  • a preferred method of administering the inventive lubricant composition to a joint is by injection. Accordingly, the hyaluronic acid will need to be of a purity so as not to invoke an inflammatory response when injected into the joint.
  • surface active phospholipids refers to any one or more of the phospholipids selected from the sphingolipids and phosphoglycerides.
  • Surface active phospholipids which can be used in accordance with the present invention include phospholipids which may be naturally or artifically synthesized. Surface active phospholipids are preferably selected from the group comprised of phosphatidylcholine, phosphatidylethanolamine. phosphatidylserine, phosphatidylglycerol, y ⁇ - phosphatidylinositol, sphingomyelin and derivatives thereof. Additionally, mixtures of two or more of the aforementioned phospholipids may be used.
  • the surface active phospholipid is alpha-dipalmitoyl phosphatidylcholine (alpha-DPPC), most preferably, the racemic ⁇ DL) mixture of alpha-DPPC.
  • alpha-DPPC alpha-dipalmitoyl phosphatidylcholine
  • the racemic mixture provides enhanced effectiveness as a result of the 10 phospholipases found in vivo eventually break down the L form and thereby leaving the D form to continue to lubricate the surface. This would have the potential advantage of extending the period between irrigation of arthritic joints.
  • the DL alpha-DPPC is 15 synthetically derived and therefore its use would circumvent the risk of cross infection inherent in the use of L alpha DPPC derived from biological sources.
  • the concentration of surface active phospholipids in the lubricant composition is between 1 to 200 mg.ml " . 20
  • the compositions of the present invention being aqueous solutions, are readily usable and physiologically suitable for application in the lubrication of joints. In such cases it would appear that hyaluronic acid and phospholipids present in the joint act synergistically. 25 This may be the result of either hyaluronic acid facilitating the lubrication of the phospholipids or the phospholipids promoting the load bearing of the hyaluronic acid.
  • the hyaluronic acid of a lubricant composition may 30 be present as a water soluble salt, such as the sodium or potassium salt, or mixtures thereof. Further, a multivalent metal cation may be substituted for the sodium or potassium ion of the salt whereby hydrophobicity can be increased. Suitable cations for 35 this purpose include Ca 2+, Al3+ and Au4+
  • a lubricant composition would contain from 1 to 10 mg.ml " of hyaluronic acid, whilst in those compositions which include multivalent cations, the multivalent cation will be present in a concentration of 1 to 10 mM.
  • lubricant compositions in accordance with the invention have coeffecients of kinetic friction of the order of 0.003 to 0.008 at loads
  • the lubricant composition would be capable of providing sufficient lubrication even in such high load bearing joints as the human knee.
  • the present invention is able to provide effective lubricant compositions, particularly for use in physiological circumstances such as the lubrication of joints.
  • compositions of the present invention include use in the prevention of adhesion formation following abdominal surgery, particularly where make-up doses are given intraperitoneally, and as lubricants elsewhere in the body, for example, for "pleural rub”, “pericardial rub” and inter-fibre relaxation in muscular tissue. Note that. this latter use has implications for the treatment of fibrocytis.
  • membrane permeability such as the chorioamnionic sac.
  • membrane surfaces are also rendered hydrophobic. This property is also potentially useful in the treatment of arthritic joints since an impermeable hydrophobic articular surface is desirable even if joint lubrication is hydrodynamic.

Landscapes

  • 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)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (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)
  • Materials For Medical Uses (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

A composition comprised of at least one surface active phospholipid, hyaluronic acid or a water soluble salt thereof in saline solution for use as a lubricant, in particular, for physiological use such as the lubrication of joints. The composition can be used to reduce the coefficient of kinetic friction between surfaces in contact with each other, in particular load-bearing surfaces.

Description

LUBRICANT COMPOSITION FOR RHEUMATISM
--~*- This invention relates to lubricant compositions and in particular, compositions adapted for physiological use such as the lubrication of joints.
In man and other animals it is known that synovial
5 fluid acts to effectively lubricate the surfaces of bones that are in frictional contact to form joints. Moreover, the synovial fluid is able to provide effective lubrication in joints such as the human knee, where the
_2 normal applied load is about 3 kg. cm
10 Due to the widespread and debilitating effects of osteoarthritis and other rheumatic diseases, considerable attention has been paid to developing a lubricant effective for irrigating arthritic joints. Such a lubricant would help to keep the joint mobile and reduce
15 mechanical stress causing pain during movement. Additionally, the lubricant would desirably:-
1. reduce wear of the articular surfaces;
2. facilitate release of surfaces in initiating motion; and
20 3. render the surfaces hydrophobic and, hence, less permeable to fluid whose expression from the joint can contribute to the hydration of cartilage which is a common finding in arthritis. It is to be noted that a lubricant of the 25 aforementioned type would also be effective in other tissues where surfaces are in sliding contact such as the heart, lungs and in muscle fibres.
Accordingly, attention has been directed towards identifying an "active ingredient" present in synovial 30 fluid that is able to effectively lubricate joints. It has been recognised that one of the major components of synovial fluid is hyaluronic acid, which has a co-efficient of kinetic friction below 0.02.
However, its lubricating ability fails when it is loaded 35 above about 0.5-1 kg.cm -2. It would therefore fail
_2 well below the normal load of about 3 kg. cm borne by the knee joints of man.
The finding of the failure of hyaluronic acid to effectively lubricate under such loads has raised the question as to the nature of the surface active ingredient which would normally be present in a joint rendering the articular surfaces of the joint hydrophobic. It has further been observed that good lubrication of joints is achieved when synovial fluid is replaced by saline thus suggesting that the active ingredient is adsorbed onto the articular surfaces.
In studying the sliding of the pleura1 surfaces in the lung, the present inventor found phospholipids in pleural fluid and has shown that phospholipids can lubricate well as a layer adsorbed to such surfaces as glass or quartz when deposited onto those surfaces from solution in chloroform. Further, studies showed that these layers had high-load-bearing properties and that the same phospholipids are present in many other fluids adjacent to sliding tissue surfaces, for example, the pericardium, numerous visceral surfaces and the joints. Moreover, they are present in a surface active state which would be needed for them to be adsorbed to the sliding surfaces in vivo.
The results of those experiments have shown that layers of certain phospholipids, especially the disaturated phosphatidylcholines (lecithins), can give coefficients of kinetic friction of less than 0.01 and sometimes as low as 0.002 when deposited by evaporation from solution in chloroform. Moreover, such low values for coefficient of kinetic friction may be obtained for
_2 loads as high as 13 kg. cm . These findings may explain why joint lubrication has the characteristics of boundary lubrication and yet coefficients of friction of a magnitude generally associated with hydrodynamic lubrication.
The present inventor has found that a composition having a suitably low coefficient of kinetic friction of the order of 0.003 - 0.010 may be prepared by the ultrasonication of surface active phospholipid in saline to produce a suspension of liposomes. It has further been found that lower coefficients of kinetic friction may be obtained when a surface active phospholipid is suspended in hyaluronic acid. Such compositions give suitably low coefficients of kinetic friction at relatively high loads. The present invention relates to a lubricant composition comprised of at least one surface active phospholipid, hyaluronic acid or a water soluble salt thereof in saline solution. The saline solution is 0.9% NaCl solution, optionally phosphate-buffered 0.9% NaCl solution. The lubricant composition may optionally contain pharmaceutically acceptable excipients and/or additives.
The introduction of a lubricant composition, in accordance with the present invention, having a relatively high concentration of phospholipid in solution, said phospholipid being taken from either synovial fluid or from another site where lubrication of tissue takes place in the body, into the joint of an animal or a human leads to improved lubrication of the articular surfaces of said joint. A higher degree of improved lubrication is obtained when the concentration of the phospholipid in the lubricant composition exceeds the normal concentration of phospholipid found in synovial fluid. The adsorption of phospholipid onto the articular surfaces of a joint renders said surfaces hydrophobic and produces the aforesaid low coefficients of kinetic friction.
The increase in phospholipid concentration at a particular site, resulting from the introduction of a lubricant composition at said site, can also serve as a releasing agent, that is, prevent the sticking of a joint after standing when fluids can be "squeezed out". Thus, the surface active phospholipid present in the lubricant composition can be used as a release agent when said c omposition is used in conjunction with the synovial fluid of a joint or of those sites of the body where surfaces are in contact. Such a use would result in increased mobility and decreased pain, if present, at the particular site. In some cases where the composition is used as a release agent the force of adhesion by a protein glue can be reduced by 90 to 99%.
The improved effects obtained through the administration of a lubricant composition can be maintained or readily re-established by irrigating the joint or site previously affected by a lubricant composition at regular intervals as required.
Thus, the present invention also relates to a method of use of a lubricant composition wherein said lubricant composition is introduced into the synovial fluid of a joint of an animal or a human resulting in the increased adsorption of phospholipids onto the articular surfaces of said joint such that the coefficient of kinetic friction between the articular surfaces and the synovial fluid and between the articular surfaces themselves is reduced.
In addition, the present invention relates to the use of a lubricant composition as a releasing agent when said lubricant composition is used in conjunction with the synovial fluid of a particular joint or at a particular site in a body where surfaces are in contact.
The present invention also provides a method for the treatment of osteoarthritis and related diseases of the joints of animals comprising administering to a disease affected joint an effective amount of a lubricant composition. A preferred method of administering the inventive lubricant composition to a joint is by injection. Accordingly, the hyaluronic acid will need to be of a purity so as not to invoke an inflammatory response when injected into the joint.
As referred to in this specification, surface active phospholipids refers to any one or more of the phospholipids selected from the sphingolipids and phosphoglycerides. Surface active phospholipids which can be used in accordance with the present invention include phospholipids which may be naturally or artifically synthesized. Surface active phospholipids are preferably selected from the group comprised of phosphatidylcholine, phosphatidylethanolamine. phosphatidylserine, phosphatidylglycerol, y~- phosphatidylinositol, sphingomyelin and derivatives thereof. Additionally, mixtures of two or more of the aforementioned phospholipids may be used. 5 In a particularly preferred embodiment the surface active phospholipid is alpha-dipalmitoyl phosphatidylcholine (alpha-DPPC), most preferably, the racemic <DL) mixture of alpha-DPPC. The racemic mixture provides enhanced effectiveness as a result of the 10 phospholipases found in vivo eventually break down the L form and thereby leaving the D form to continue to lubricate the surface. This would have the potential advantage of extending the period between irrigation of arthritic joints. Preferably, the DL alpha-DPPC is 15 synthetically derived and therefore its use would circumvent the risk of cross infection inherent in the use of L alpha DPPC derived from biological sources. The concentration of surface active phospholipids in the lubricant composition is between 1 to 200 mg.ml" . 20 The compositions of the present invention, being aqueous solutions, are readily usable and physiologically suitable for application in the lubrication of joints. In such cases it would appear that hyaluronic acid and phospholipids present in the joint act synergistically. 25 This may be the result of either hyaluronic acid facilitating the lubrication of the phospholipids or the phospholipids promoting the load bearing of the hyaluronic acid.
The hyaluronic acid of a lubricant composition may 30 be present as a water soluble salt, such as the sodium or potassium salt, or mixtures thereof. Further, a multivalent metal cation may be substituted for the sodium or potassium ion of the salt whereby hydrophobicity can be increased. Suitable cations for 35 this purpose include Ca 2+, Al3+ and Au4+
Typically, a lubricant composition would contain from 1 to 10 mg.ml" of hyaluronic acid, whilst in those compositions which include multivalent cations, the multivalent cation will be present in a concentration of 1 to 10 mM.
In preferred forms, lubricant compositions in accordance with the invention have coeffecients of kinetic friction of the order of 0.003 to 0.008 at loads
_2 as high as 13 kg.cm . It will therefore be realised that the lubricant composition would be capable of providing sufficient lubrication even in such high load bearing joints as the human knee.
From the foregoing, it is evident that the present invention is able to provide effective lubricant compositions, particularly for use in physiological circumstances such as the lubrication of joints.
Some other physiological uses for the compositions of the present invention include use in the prevention of adhesion formation following abdominal surgery, particularly where make-up doses are given intraperitoneally, and as lubricants elsewhere in the body, for example, for "pleural rub", "pericardial rub" and inter-fibre relaxation in muscular tissue. Note that. this latter use has implications for the treatment of fibrocytis.
An additional use is the reduction of membrane permeability such as the chorioamnionic sac. Such membrane surfaces are also rendered hydrophobic. This property is also potentially useful in the treatment of arthritic joints since an impermeable hydrophobic articular surface is desirable even if joint lubrication is hydrodynamic.
It will be recognised by persons skilled in the art that, in respect of the invention as described, numerous variations and modifications are possible without departing from the spirit or scope thereof.

Claims

THE CLAIMS :
1. A lubricant composition comprised of at least one surface active phospholipid, hyaluronic acid or a water soluble salt thereof in saline solution, and optionally pharmaceutically acceptable excipients and/or additives.
2. A composition according to claim 1, wherein the concentration of the surface active phospholipid is between 1 to 200 mg.ml" .
3. A composition according to claim 1, wherein the concentration of hyaluronic acid is from 1 to 10 mg. l .
4. A composition according to claim 1, wherein the hyaluronic acid salt is selected from sodium, potassium, calcium, aluminium or gold salts of hyaluronic acid.
5. A composition according to claim 1, wherein the concentration of the hyaluronic acid or salt thereof containing a monovalent cation is from 1 to 10 mg.ml- .
6. A composition according to claim 1, wherein the concentration of the hyaluronic salt containing a multivalent cation is from 1 to 10 mM.
7. A composition according to claim 1, wherein said phospholipid is selected from the group comprised of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinosital, sphingomyelin and derivatives thereof.
8. A composition according to claim 1, wherein the phospholipid is alpha-dipalmitoyl phosphatidylcholine.
9. A composition according to claim 1, wherein the phospholipid is a racemic mixture of D-alpha-dipalmitoyl phosphatidylcholine and L-alpha-dipalmitoyl phosphatidylcho1ine.
10. A composition according to any one of claims 1 to
9, wherein the surface active phospholipid is suspended in the hyaluronic acid or salts thereof.
11. A composition according to any one of claims 1 to
10, when introduced into a joint of an animal or a human.
12. A composition according to any one of claims 1 to 10, when used to reduce the coefficient of kinetic friction imparted to the boundary surfaces of a joint upon articulation to a value of between 0.003 to 0.05.
13. A method according to claim 12, wherein the reduced coefficient of kinetic friction occurs at loading values
_2 on said surfaces up to 20 kg.cm .
14. A composition according to any one of claims 1 to 10, when used as a release agent.
15. A method for improving lubrication of surfaces and in particular surfaces in the joints of animals and humans comprising the steps of:
(a) administering to an affected joint a lubricant composition comprised of at least one surface active phospholipid, hyaluronic acid or a water soluble salt thereof in saline solution and optionally,
(b) irrigating said joint at regular intervals with said lubricant composition as required in order to maintain or re-establish the improved lubrication of the surface and reduced coefficient of kinetic friction resulting from (a) .
16. A method according to any one of claims 11 to 15, wherein the composition is administered by injection.
17. A composition according to any one of claims 1 to 10, when used in the treatment of arthritic joints.
18. A composition according to any one of claims 1 to 10, when used in the treatment of joints affected by osteoarthitis or rheumatic disease.
19. A composition according to any one of claims 1 to 10, when used as a lubricant between tissue surfaces in contact with each other.
20. A composition according to claim 1, or a method according to any one of claims 11 to 19, substantially as herein described.
PCT/AU1988/000322 1987-08-25 1988-08-25 Lubricant composition for rheumatism WO1989001777A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US07/466,257 US5403592A (en) 1987-08-25 1987-08-25 Lubricant composition for rheumatism
AU23208/88A AU620821B2 (en) 1987-08-25 1988-08-25 Hyaluronic acid lubricating compounds
DE88907578T DE3884622T2 (en) 1987-08-25 1988-08-25 LUBRICANT PREPARATION FOR TREATING RHEUMA.
AT88907578T ATE95061T1 (en) 1987-08-25 1988-08-25 LUBRICANT PREPARATION FOR THE TREATMENT OF RHEUMA.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPI3944 1987-08-25
AUPI394487 1987-08-25

Publications (1)

Publication Number Publication Date
WO1989001777A1 true WO1989001777A1 (en) 1989-03-09

Family

ID=3772410

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU1988/000322 WO1989001777A1 (en) 1987-08-25 1988-08-25 Lubricant composition for rheumatism

Country Status (7)

Country Link
US (1) US5403592A (en)
EP (1) EP0387252B1 (en)
JP (1) JPH03501250A (en)
CN (1) CN1027134C (en)
CA (1) CA1325595C (en)
DE (1) DE3884622T2 (en)
WO (1) WO1989001777A1 (en)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0505817A1 (en) * 1991-03-15 1992-09-30 FIDIA S.p.A. Use of phosphatidylserine and its derivatives for the manufacture of a medicament for the treatment of degenerative pathologies also associated with immune disfunctions
EP0516685A1 (en) * 1990-02-22 1992-12-09 Macnaught Pty. Limited Artificial tears
WO1992021981A1 (en) * 1991-05-29 1992-12-10 Baxter International Inc. Methods and compositions for the prevention, diagnosis, and treatment of inflammatory serosal disease and related conditions
US5411743A (en) * 1990-12-03 1995-05-02 Vestar, Inc. Prevention of synovial adhesions
WO1998014538A1 (en) * 1996-10-03 1998-04-09 Klüber Lubrication Benelux Lubricant with phospholipid and a basic compound base
EP0868190A1 (en) * 1995-12-19 1998-10-07 MacNaught Medical Pty. Limited Phospholipid and propylene glycol based lubricant
WO1998053800A1 (en) * 1997-05-29 1998-12-03 Applied Biotechnologies, Inc. Compositions and methods for preventing adhesion
EP1044691A2 (en) * 1999-01-28 2000-10-18 Tokyo Medical and Dental University Use of glycosaminoglycan lipid conjugates for inducing osteogenesis
WO2001085179A2 (en) * 2000-05-11 2001-11-15 Clemson University Biological joint lubricant composition and method of applying
WO2003000344A1 (en) * 2001-06-25 2003-01-03 Britannia Pharmaceuticals Limited Use of phospholipids for the prevention 0f surgical adhesions
WO2005084684A1 (en) * 2004-03-05 2005-09-15 Synthes Ag Chur Use of a mixture for the production of an agent for treating defective or degenerated cartilage in the production of natural cartilage replacement in vitro
WO2006067608A1 (en) * 2004-12-22 2006-06-29 Laboratoire Medidom S.A. Aqueous formulations based on sodium hyaluronate for parenteral use
EP1680477A2 (en) * 2003-09-10 2006-07-19 M-I L.L.C. Phospholipid lubricating agents in aqueous based drilling fluids
EP1839685A3 (en) * 2006-03-31 2008-01-02 DePuy Products, Inc. Bearing material for a medical implant
US7906139B2 (en) 2002-04-03 2011-03-15 Lamellar Therapeutics Limited Compositions and methods of using lamellar bodies for therapeutic purposes
WO2011138228A1 (en) * 2010-05-04 2011-11-10 Trb Chemedica Ag Aqueous composition for ophthalmic or dermal use
US9173901B2 (en) 2003-09-25 2015-11-03 Lamellar Therapeutics Limited Compositions and methods of using lamellar bodies for modifying linear biological macromolecules
US10888580B2 (en) 2015-09-24 2021-01-12 Matrix Biology Institute High elasticity hyaluronan compositions and methods of use thereof
US10933085B2 (en) 2013-07-10 2021-03-02 Matrix Biology Institute Compositions of hyaluronan with high elasticity and uses thereof

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6743774B1 (en) * 1999-04-23 2004-06-01 Rhode Island Hospital Tribonectins
GB0007150D0 (en) * 2000-03-24 2000-05-17 Lamellar Therapeutics Limited Immunotherapeutic methods and compositions
US20020172712A1 (en) * 2001-03-19 2002-11-21 Alan Drizen Antiemetic, anti-motion sustained release drug delivery system
WO2003000190A2 (en) * 2001-06-25 2003-01-03 Depuy Liposomal encapsulation of glycosaminoglycans for the treatment of arthritic joints
WO2005000331A2 (en) * 2003-06-04 2005-01-06 Mucosal Therapeutics, Inc. Compositions for the treatment and prevention of degenerative joint disorders
CN102924584A (en) * 2003-08-14 2013-02-13 惠氏公司 Recombinant lubricin molecules and uses thereof
US10543094B2 (en) 2004-01-30 2020-01-28 Beamalloy Reconstructive Medical Products, Llc Orthopaedic implants having self-lubricated articulating surfaces designed to reduce wear, corrosion, and ion leaching
US9523144B2 (en) * 2004-01-30 2016-12-20 Beamalloy Reconstructive Medical Products, Llc Orthopaedic implants having self-lubricated articulating surfaces designed to reduce wear, corrosion, and ion leaching
US20090155200A1 (en) * 2004-04-20 2009-06-18 Jay Gregory D Methods of promoting cartilage healing or cartilage integration
US20080287369A1 (en) * 2004-07-23 2008-11-20 Jay Gregory D Compositions and Methods for Viscosupplementation
CN1319606C (en) * 2004-10-15 2007-06-06 凌沛学 Lubricant for human body containing extract product form soybean and hyaluronic acid and preparation method
EP1827478A4 (en) * 2004-12-03 2009-08-05 Mucosal Therapeutics Llc Methods of treatment for injured or diseased joints
US20070111327A1 (en) * 2005-05-05 2007-05-17 Jay Gregory D Methods of detecting lubricin
JP5660561B2 (en) * 2006-09-28 2015-01-28 ハダシット メディカルリサーチサービセス アンド ディベロップメント リミテッド Use of glycerophospholipids for joint lubrication
US20090068247A1 (en) * 2007-09-12 2009-03-12 Mucosal Therapeutics Biocompatible devices coated with a tribonectin and methods for their production
CN102552989A (en) * 2010-12-07 2012-07-11 宁小静 Multifunctional personal lubricant
CN103083733A (en) * 2013-02-19 2013-05-08 华熙福瑞达生物医药有限公司 Medical water-based lubricant for introducing instrument into body cavity
EP3154550B1 (en) * 2014-06-15 2021-08-04 Yeda Research and Development Co. Ltd. Surface treatment by water-soluble polymers and lipids/liposomes
GB201511058D0 (en) * 2015-06-23 2015-08-05 Lamellar Biomedical Ltd Compositions and methods for using lamellar bodies for therapeutic purposes
IL272630B2 (en) 2017-08-22 2023-09-01 Moebius Medical Ltd Liposomal formulation for joint lubrication

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4141973A (en) * 1975-10-17 1979-02-27 Biotrics, Inc. Ultrapure hyaluronic acid and the use thereof
AU3580784A (en) * 1983-11-25 1985-05-30 Miles Laboratories Inc. The use of ultrapure hyaluronic acid to improve animal joint function
EP0161887A2 (en) * 1984-05-04 1985-11-21 Seikagaku Kogyo Co. Ltd. Crosslinked hyaluronic acid and its use
WO1986005984A1 (en) * 1985-04-09 1986-10-23 Pharmacia Ab Hyaluronic acid preparation to be used for treating inflammations of skeletal joints
EP0265116A2 (en) * 1986-10-13 1988-04-27 FIDIA S.p.A. Cross-linked esters of hyaluronic acid

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1523965A (en) * 1976-03-19 1978-09-06 Ici Ltd Pharmaceutical compositions containing steroids
US4466958A (en) * 1981-03-18 1984-08-21 Morrison L M Food supplement
JPS59210013A (en) * 1983-05-04 1984-11-28 Ajinomoto Co Inc Active substance-containing liposome
JPS601122A (en) * 1983-06-20 1985-01-07 Green Cross Corp:The Fat emulsion of biphenylylpropionic acid derivative
JPS6245336A (en) * 1985-08-21 1987-02-27 Toyo Biyuut Kk Emulsified composition
IN166447B (en) * 1985-11-27 1990-05-12 Ethicon Inc
JPH07116010B2 (en) * 1986-03-10 1995-12-13 株式会社コーセー Cosmetics
US4946683A (en) * 1987-11-18 1990-08-07 Vestar, Inc. Multiple step entrapment/loading procedure for preparing lipophilic drug-containing liposomes

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4141973A (en) * 1975-10-17 1979-02-27 Biotrics, Inc. Ultrapure hyaluronic acid and the use thereof
US4141973B1 (en) * 1975-10-17 1989-08-08
AU3580784A (en) * 1983-11-25 1985-05-30 Miles Laboratories Inc. The use of ultrapure hyaluronic acid to improve animal joint function
EP0161887A2 (en) * 1984-05-04 1985-11-21 Seikagaku Kogyo Co. Ltd. Crosslinked hyaluronic acid and its use
WO1986005984A1 (en) * 1985-04-09 1986-10-23 Pharmacia Ab Hyaluronic acid preparation to be used for treating inflammations of skeletal joints
EP0265116A2 (en) * 1986-10-13 1988-04-27 FIDIA S.p.A. Cross-linked esters of hyaluronic acid

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN, C 167, page 36, JP,A, 58-37001 (Midori Juji K.K.) 4 March 1983 (04.03.83) *
See also references of EP0387252A4 *

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0516685A1 (en) * 1990-02-22 1992-12-09 Macnaught Pty. Limited Artificial tears
EP0516685A4 (en) * 1990-02-22 1993-03-17 Macnaught Pty. Limited Artificial tears
US5411743A (en) * 1990-12-03 1995-05-02 Vestar, Inc. Prevention of synovial adhesions
EP0505817A1 (en) * 1991-03-15 1992-09-30 FIDIA S.p.A. Use of phosphatidylserine and its derivatives for the manufacture of a medicament for the treatment of degenerative pathologies also associated with immune disfunctions
WO1992021981A1 (en) * 1991-05-29 1992-12-10 Baxter International Inc. Methods and compositions for the prevention, diagnosis, and treatment of inflammatory serosal disease and related conditions
EP0868190A1 (en) * 1995-12-19 1998-10-07 MacNaught Medical Pty. Limited Phospholipid and propylene glycol based lubricant
EP0868190A4 (en) * 1995-12-19 2001-02-14 Macnaught Med Pty Ltd Phospholipid and propylene glycol based lubricant
WO1998014538A1 (en) * 1996-10-03 1998-04-09 Klüber Lubrication Benelux Lubricant with phospholipid and a basic compound base
WO1998053800A1 (en) * 1997-05-29 1998-12-03 Applied Biotechnologies, Inc. Compositions and methods for preventing adhesion
EP1044691A2 (en) * 1999-01-28 2000-10-18 Tokyo Medical and Dental University Use of glycosaminoglycan lipid conjugates for inducing osteogenesis
EP1044691A3 (en) * 1999-01-28 2003-06-11 Tokyo Medical and Dental University Use of glycosaminoglycan lipid conjugates for inducing osteogenesis
US7867985B2 (en) 2000-05-11 2011-01-11 Clemson University Research Foundation Biological lubricant composition and method of applying lubricant composition
WO2001085179A2 (en) * 2000-05-11 2001-11-15 Clemson University Biological joint lubricant composition and method of applying
WO2001085179A3 (en) * 2000-05-11 2002-03-21 Univ Clemson Biological joint lubricant composition and method of applying
WO2003000344A1 (en) * 2001-06-25 2003-01-03 Britannia Pharmaceuticals Limited Use of phospholipids for the prevention 0f surgical adhesions
US7906139B2 (en) 2002-04-03 2011-03-15 Lamellar Therapeutics Limited Compositions and methods of using lamellar bodies for therapeutic purposes
EP1680477A4 (en) * 2003-09-10 2007-10-10 Mi Llc Phospholipid lubricating agents in aqueous based drilling fluids
EP1680477A2 (en) * 2003-09-10 2006-07-19 M-I L.L.C. Phospholipid lubricating agents in aqueous based drilling fluids
US9750766B2 (en) 2003-09-25 2017-09-05 Lamellar Biomedical Limited Compositions and methods of using lamellar bodies for modifying linear biological macromolecules
US9173901B2 (en) 2003-09-25 2015-11-03 Lamellar Therapeutics Limited Compositions and methods of using lamellar bodies for modifying linear biological macromolecules
WO2005084684A1 (en) * 2004-03-05 2005-09-15 Synthes Ag Chur Use of a mixture for the production of an agent for treating defective or degenerated cartilage in the production of natural cartilage replacement in vitro
WO2006067608A1 (en) * 2004-12-22 2006-06-29 Laboratoire Medidom S.A. Aqueous formulations based on sodium hyaluronate for parenteral use
EP1839685A3 (en) * 2006-03-31 2008-01-02 DePuy Products, Inc. Bearing material for a medical implant
US7812098B2 (en) 2006-03-31 2010-10-12 Depuy Products, Inc. Bearing material of medical implant having reduced wear rate and method for reducing wear rate
WO2011138228A1 (en) * 2010-05-04 2011-11-10 Trb Chemedica Ag Aqueous composition for ophthalmic or dermal use
US10933085B2 (en) 2013-07-10 2021-03-02 Matrix Biology Institute Compositions of hyaluronan with high elasticity and uses thereof
US11524027B2 (en) 2013-07-10 2022-12-13 Matrix Biology Institute Compositions of hyaluronan with high elasticity and uses thereof
US10888580B2 (en) 2015-09-24 2021-01-12 Matrix Biology Institute High elasticity hyaluronan compositions and methods of use thereof
US11583549B2 (en) 2015-09-24 2023-02-21 Matrix Biology Institute High elasticity hyaluronan compositions and methods of use thereof

Also Published As

Publication number Publication date
CN1033239A (en) 1989-06-07
EP0387252A1 (en) 1990-09-19
CA1325595C (en) 1993-12-28
US5403592A (en) 1995-04-04
DE3884622D1 (en) 1993-11-04
CN1027134C (en) 1994-12-28
JPH03501250A (en) 1991-03-22
EP0387252A4 (en) 1990-12-05
DE3884622T2 (en) 1994-04-28
EP0387252B1 (en) 1993-09-29

Similar Documents

Publication Publication Date Title
EP0387252B1 (en) Lubricant composition for rheumatism
US6133249A (en) Phospholipid and propylene glycol based lubricant
Pearson et al. Cyclical etidronate: its effect on bone density in patients with acute spinal cord injury
JP2002509890A (en) Dextran composition for treating inflammatory joint disease and method of treatment
US5015634A (en) Method of treating tissue damage with inositol triphosphate
JP2016185989A (en) Methods for treating acute and overuse sprain and strain using hyaluronic acid
WO2001085179A3 (en) Biological joint lubricant composition and method of applying
JPH05502857A (en) Fluorocarbon emulsion and buffer system with amino acid-based anti-inflammatory agents
Hills Gastric surfactant and the hydrophobic mucosal barrier.
PL189526B1 (en) Application of zinc hyaluronate against a peptic ulcer
AU620821B2 (en) Hyaluronic acid lubricating compounds
JP4990446B2 (en) Injection for treatment of arthropathy
EP3672653B1 (en) Liposomal formulation for joint lubrication
WO1991012026A1 (en) Means of reducing surgical adhesions
CA2110110A1 (en) Use of certain methanebisphosphonic acid derivatives in fracture healing
WO2005027933A1 (en) Unsaturated phosphatidylcholines and uses thereof
Bullen et al. Cefuroxime levels attained in tissues and wound exudates from severely ischaemic limbs
Butcher Mokha et al. Glucosamine and Its Effects on Articular Cartilage and Osteoarthritis.
AU699375B2 (en) Phospholipid and propylene glycol based lubricant
EA042384B1 (en) LIPOSOMAL COMPOSITION TO PROVIDE A JOINT LUBRICANT
NZ761298B2 (en) Liposomal formulation for joint lubrication
TW202029966A (en) Liposomal formulation for joint lubrication
Carden et al. Effects of oral glucosamine sulfate supplementation on gait parameters and blood oxidative status in the aged horse
Madonick tree by coughing, additional measures must be employed. The
EA199800848A1 (en) HYPOLIPIDEMIC AND ANTI-ATEROSCLEROTIC MEANS

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AT AU BB BG BR CH DE DK FI GB HU JP KP KR LK LU MC MG MW NL NO RO SD SE SU US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE BJ CF CG CH CM DE FR GA GB IT LU ML MR NL SE SN TD TG

CR1 Correction of entry in section i

Free format text: IN PAT.BUL.06/89,UNDER PUBLISHED ADD AND STATEMENT AFTER"WITH AMENDED CLAIMS"

WWE Wipo information: entry into national phase

Ref document number: 1988907578

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1988907578

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 1988907578

Country of ref document: EP