AU620821B2 - Hyaluronic acid lubricating compounds - Google Patents

Description

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AUTRALIA (51)

PATENT

(43) A-A-23208/88 WORLD INTELLECTUAL PROPERTY ORGANIZATION International Bureau

PCT

INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 4 (11) International Publication Number: W 89/ 01777 A61K 31/725, 31/685, 31/66 Al (43) InternatI ic o D arcj989 (09.03.89) (21) International Application Number: PCT/AU88/00322 (81) Designated States: AT, AT (European patent), AU, BB, BE (European patent), BG, BJ (OAPI patent), BR, (22) International Filing Date: 25 August 1988 (25.08.88) CF (OAPI patent), CG (OAPI patent), CH, CH (European patent), CM (OAPI patent), DE, DE (European patent), DK, FI, FR (European patent), GA (31) Priority Application Number: PI 3944 (OAPI patent), GB, GB (European patent), HU, IT (European patent), JP, KP, KR, LK, LU, LU (Euro- (32) Priority Date: 25 August 1987 (25.08.87) pean patent), MC, MG, ML (OAPI patent), MR (OA- P. patent), MW, NL, NL (European patent), NO, (33) Priority Country: AU RO, SD, SE, SE (European patent), SN (OAPI patent), SU, TD (OAPI patent), TG (OAPI patent), US.

(71) Applicant (for all designated States except US): MAC- NAUGHT PTY. LIMITED [AU/AU]; 47-49 Henderson Street, Turrella, NSW 2205 Published With international search report.

(72) Inventor; and With amended claims and statement.

Inventor/Applicant (for US only) HILLS, Brian, Andrew [AU/AU]; "West Tree", Dumaresq Road, Dumaresq via Armidale, NSW 2350 (AU).

P 11 MAY 1989 (74) Agent: TAYLOR, Paul, Robert; Arthur S. Cave Co., A Level 10, 10 Barrack Street, Sydney, NSW 2000

AUSTRALIAN

31 MAR 1989 PATENT OFFICE i: (54) Title: (57) Abstract 1yq/orcnic acid 1tUbtca- iY 9 coEtos&O'1lS i

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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 w'ith each other, in particular loadbearing surfaces.

WO 89/01777 1 PCT/AU88/00322 Hyc ror c c'cic/ (ub'rica-4iry c s Aci.s 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 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 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 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 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 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 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 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 F a S.

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2 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 pleural 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 loads as high as 13 kg.

-2 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 aqueous solution saline) to produce a suspension of liposomes. It has further been found that lower coefficients of kinetic friction may be *c 5555

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0098e/VMJ 3 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 comprising an aqueous solution or emulsion of at least one surface active phospholipid, and hyaluronic acid or a water soluble salt thereof. Preferably the composition is in saline solution. The saline solution may be 0.9% NaCl solution, for example, 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 S concentration of the phospholipid in the lubricant composition exceeds the normal concentration of phospholipid found in synovial fluid. The adsorption of phospholipid onto the e. 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 composition 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%.

0098e/VMJ ~e I 1 1111111 Il kl III 1 ~e~l~g C r c PCT./AU 88 0 0 4 RECEIVED 2 5 JUL 1989 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 reduces.

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 and claims, 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 artificially synthesized. Surface active phospholipids are preferably selected from the group comprised of phosphatidylcholine, phosphatidylethanolamine, 1 2 2 e 5 phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, sphingomyelin and derivatives thereof.

Additionally, mixures of two or more of the aforementioned phospholipids may be used.

In a particularly preferred embodiment the surface active phospholipid is alpha-dipalmitoyl phosphatidycholine (alpha-DPPC), most preferably, the racemic (DL) mixture of alpha-DPPC). The racemic mixture provides enhanced effectiveness as a result of the 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 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 The compositions of the present invention, being aqueous solutions or emulsions, 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. 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 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 this purpose include Ca 2 A3+ and 4+ SAu Typically, a lubricant composition would contain from 1 to 10 mg.ml 1 of hyaluronic acid, whilst in those compositions which include multivalent cations, the multivalent cation will be present in a concentration of 1 to mM.

i098e/VMJ 6 In preferred forms, lubricant compositions in accordance with the invention have coefficients of kinetic friction of -2 the order of 0.003 to 0.008 at loads as high as 13 kg.cm 2 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.

The invention is now described with reference to various examples.

Example 1 DLa-Dipalmitoyl phosphatidylcholine (DPPC) from the Sigma Chemical Company (Product #P6138) was 'softened' by dissolving it g) in chloroform (30 ml) and then using nitrogen to evaporate off the solvent, leaving finely powdered DPPC. 10 mg of this fine powder was then added to 10 ml of a solution of hyaluronic acid (HA) in saline at 4 0 C. The HA was derived from rooster comb (Sigma product H5388) and dissolved to a concentration of 3 mg/ml saline. The suspension of DPPC was vortexed and then ultrasonicated for 1- hours with 0098e/VMJ 7 intermittent vortexing using an ultrasonicator from Laboratory supplies Co. Inc. of Hicksville, N.Y. (Model #GllZSPIT).

The suspension was placed between two horizontal flat quartz plates of which the bottom one was fixed to a traveller and the upper one to a force transducer orientated to measure a horizontal force. After two hours the top plate was loaded to exert a pressure of 2.1 Kg/cm 2 on the lower plate which was then moved at a uniform speed of 2 cm/min. The coefficient of kinetic friction was then measured from the ratio of the horizontal force to the vertical load. The first pass gave a value for p of 0.021 and the second 0.020.

After a further 30 cycles, the friction was reduced to 0.002 and 0.005 after 70 cycles.

Example 2 Following the same procedures as above 'softened' DPPC was dispersed (3 mg/ml) in HA solution (10 mg/ml) containing 1 mM auric (gold) chloride. After 4 hours with the plates in contact, the first pass gave p 0.026, the second 0.014 while the 15th and 16th passes both gave p 0.004.

Example 3 Following essentially the same procedure 10 mg/ml of La-dipalmitoyl phosphatidylcholine (Sigma P6267) was ultrasonicated in HA solution (1 mg HA in 1 ml saline) for minutes. At a load of 3 Kg/cm 2 and after 5 minutes contact of the plates, the average coefficient of kinetic friction for the first 8 passes was 0.009+ 0.001.

It will be recognised by persons skilled in the art that, in respect of the invention as described, numerous Svariations and modifications are possible without departing from the spirit or scope thereof.

t 0098e/VMJ

Claims (17)

1. A water based lubricant and/or release composition for physiological use comprising at least one surface active phospholipid selected from sphingolipids or phosphoglycerides, and hyaluronic acid or a water soluble salt thereof, and the composition optionally further comprising pharmaceutically acceptable excipients and/or additives.

2. A composition according to claim 1 which further comprises saline.

3. A composition according to claim 1, wherein the concentration of the surface active phospholipid is between 1 to 200 mg ml

4. A composition according to claim 1 wherein the concentration of hyaluronic acid is from 1 to 10 mg ml-" 1

5. A composition according to claim 1, wherein the hyaluronic acid salt is selected from sodium, potassium, calcium, aluminium or gold salts of hyaluronic acid.

6. 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

7. A composition according to claim 1, wherein the concentration of the hyaluronic salt containing a multivalent cation is from 1 to 10 mM.

8. 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.

9. A composition according to claim 1, wherein the phospholipid is alpha-dipalmitoyl phosphatidylcholine. A composition according to claim 1, wherein the phospholipid is a racemic mixture of D-alpha-dipalmitoyl phosphatidylcholine and L-alpha-dipalmitoyl phosphatidylcholine. 0098e/VMJ 9

11. A composition according to any one of claims 1 to wherein the surface active phospholipid is suspended in the hyaluronic acid or salts thereof.

12. A composition according to any one of claims lto 11, when introduced into a joint of an animal or a human.

13. A composition according to any one of claims 1 to 11 when used to reduce the coefficient of kinetic friction imparted to the boundary surfaces of a joint of an animal or human upon articulation to a value of between 0.003 to 0.05.

14. A composition according to cla±m 13, wherein the reduced coefficient of kinetic friction occurs at loading values -2 on said surfaces up to 20 kg.cm A composition according to any one of claims 1 to 11, when used as a physiological release agent.

16. A method for improving lubrication of surfaces in the o: joints of animals or humans comprising the steps of: administering to an affected joint a water based lubricant and/or release composition comprising at o least one surface active phospholipid selected from sphingolipids or phosphoglycerides, and hyaluronic acid or a water soluble salt thereof, and the composition optionally further comprising pharmaceutically acceptable excipients and/or additives and optionally, 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

17. A method according to claim 16, wherein the composition is administered by injection.

18. A method according to claim 16 or 17, for the treatment of arthritic joints.

19. A method according to claim 18 for the treatment of joints affected by osteoarthitis or rheumatic disease. Jt 0098e/VMJ T ir 1 10 A method according to claim 16 or 17, for use as a lubricant between tissue surfaces in an animal, including a human, in contact with each other. DATED this 11th day of December 1991. MACNAUGHT PTY LIMITED By Its Patent Attorneys ARTHUR S. CAVE CO. 0098e/vMJ ./2 7 INTERNATIONAL SEARCH REPOR f 6g004ON*4 ^a14O.9 oil PCT/AU 88/00322 1. CLAS3IVIC A MIN Of SUSJICT MATT APIN SO.0* ZgCOO-00a,,e. gimegV 8200P. .:q0, Aggefegaf to 60mo04664 Paw" ese Cets" g..o PC* of 600 Ot.essAseedwasow #se PC Int. Cl. 4 A61K 31/725, 31/685, 31/66 M. POILDUS EARCHIC IPC A61K 31/725 a S54 0"M olm.50 begiw.4. 0 f nON5.4.60.4 AU IPC as above; Australian Classification 87.16. 1K. DOCUMENTS COWSU0KID STO 89 AIL9VANT's A AU,B, 35807/84 (574405) (MILES LABORATORIES) (1-20) May 1985 (30.05.85) A IS,A, 4141973 (BALAZS) 27 February 1979 (27.02.79) (1-20) A Patent Abstracts of Japan, C 167, page 36, (1-20) JP,A, 58-37001 (MIDORI JUJI 4 March 1983 (04.03.83) A WO,A, 86/05984 (PHARMACIA AB) 23 October 1986 (1-20) (23.10.86) A EP,A, 161887 (SOLKAGAKU KOGYO) 21 November 1985 (1-20) (21.11.85) P,A EP,A, 265116 (FIDIA SpA) 27 April 1988 (27.04.88) (1-20) soma 060096mm as4 e eswwt In bdos a"s060 5 'A'086mkO *6*0 OWVOOOO WO 1110 R "WN so w ON*. 6080 4. .60 soweeO6W *A ousom e.5eg s gomos gm. so 0 eO U 6-04.50. no geso 64.gow0"Ita9 "1 goumi s Go sisemn -5 as, mmm ~gg.osgw00.S4.O~.4 -r.Sm. *l"4 6000.44. S"omt sesoon" o6we"f 41g00eow ame" 4109044.6 00141* Of Oman" too"" 14 9 gamma nor w -0 olouw oftasem... a. .6066an 44O00 megasassoguMIso 6""aWse .*sow""4 ofas 0W tooaaeo: SO W 64 5500Wts som 41811110 0e~moo.. o.o1 o6 amtt e seeme fU s"Wms o meft~ M" "0"s d0delwak"".46mgmtmsowo 009605 00% wfer U oow s %0 f0101 4V m 00 bn0 506 S6.66Oi~ ee "R eone"" ""mSWIM" ov. CIRMvwCAmWN 0D0ole 6.4Ceese 0 oes mod oe*0000 W" Do ofg"".4 WG wsemwu.0&f.e" ^"Oft 14 November 1988 (14.11.88) 'In NOVMB. gq (1-1156 omOO0 Seassg6t~ ~ns.Aeno@~rBDGAE' Australian Patent Office J. BDGAE Geem PCTIOSAflt #oes0.0*66 40%W 04W6 Th members rel internation for these p Patent Dowu Cited in Se, Report AU' 3580"7/8, WO 860 5981 16188; Ec 265110 23S83/1 1 ANNEX TO THE INTERNATIONAL SEARCH REPORT ON i__ INTERNATIONAL APPLICATION NO. PCT/AU 88/00322 This Annex lists the known publication level patent family members relating to the patent documents cited in the above-mentioned international search report. The Australian Patent Office is in no way liable for these particulars which are merely given for the purpose of information. Patent Document. Cited in Search Patent Family Members Report AU 35807/84 EP 143393 FI 844598 IL 73606 JP 60135043 NO 844462 WO 8605984 EP 217914 SE 8501723 EP 161887 JP 60233101 US 4716224 JP 60153841 JP 60157774 JP 61210034 EP 167363 JP 61164558 JP 61168362 JP 61172808 JP 61012701 EP 265116 AU 79600/87 DK 5360/87 FI 874504 HU 45734 JP 63105003 WO 874251 PT 85908 ZA 8707559 END OF ANNEX a rii: I 23583/1