Compositions of polyacids and polyethers and methods for their use in reducing adhesions

• US 6,869,938 B1
• Filed: 12/27/1999
• Issued: 03/22/2005
• Est. Priority Date: 06/17/1997
• Status: Expired due to Term

• Current Assignee: Fziomed, Inc.
• Original Assignee: Fziomed, Inc.
• Inventors: Blackmore, John M., Schwartz, Herbert E., Oppelt, William G., Cortese, Stephanie M.
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): OWENS JR, HOWARD V
• Application Number:
  US09/472,110
• Time in Patent Office: 1,912 Days
• Field of Search: 514/42, 514/57, 514/781, 514/912, 514/915, 536/3, 536/4, 536/51, 536/56, 536/112, 536/123.1
• US Class Current: 514/57
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: A61L 29/085 Macromolecular materials
• CPC Class Codes: A61L 31/041 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 31/042 Polysaccharides
• CPC Class Codes: A61L 31/145 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 33/062 Mixtures of macromolecular compounds
• CPC Class Codes: C08B 11/20 Post-etherification treatments of chemical or physical type, e.g. mixed etherification in two steps, including purification
• CPC Class Codes: C08B 15/00 Preparation of other cellulose derivatives or modified cellulose , e.g. complexes
• CPC Class Codes: C08B 37/00 Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof cellulose D21; microbiological processes C12P
• CPC Class Codes: C08L 1/26 Cellulose ethers
• CPC Class Codes: C08L 1/286 substituted with acid radicals, e.g. carboxymethyl cellulose [CMC] C08L1/282 takes precedence
• CPC Class Codes: C08L 2666/02 Organic macromolecular compounds, natural resins, waxes or and bituminous materials
• CPC Class Codes: C08L 2666/26 Natural polymers, natural resins or derivatives thereof according to C08L1/00 - C08L5/00, C08L89/00, C08L93/00, C08L97/00 or C08L99/00
• CPC Class Codes: C08L 5/00 Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
• CPC Class Codes: C08L 71/02 Polyalkylene oxides

Abstract

The present invention relates to improved methods for making and using bioadhesive, bioresorbable, anti-adhesion compositions made of intermacromolecular complexes of carboxyl-containing polysaccharides, polyethers, polyacids, polyalkylene oxides, multivalent cations and/or polycations. The polymers are associated with each other, and are then either dried into membranes or sponges, or are used as fluids or microspheres. Bioresorbable, bioadhesive, anti-adhesion compositions are useful in surgery to prevent the formation and reformation of post-surgical adhesions. The compositions are designed to breakdown in-vivo, and thus be removed from the body. Membranes are inserted during surgery either dry or optionally after conditioning in aqueous solutions. The anti-adhesion, bioadhesive, bioresorptive, antithrombogenic and physical properties of such membranes and gels can be varied as needed by carefully adjusting the pH and/or cation content of the polymer casting solutions, polyacid composition, the polyalkylene oxide composition, or by conditioning the membranes prior to surgical use. Multi-layered membranes can be made and used to provide further control over the physical and biological properties of antiadhesion membranes. Membranes and gels can be used concurrently. Antiadhesion compositions may also be used to lubricate tissues and/or medical instruments, and/or deliver drugs to the surgical site and release them locally.

Claims

1. An ionically crosslinked gel comprising:

a polyacid (PA);

a polyalkylene oxide (PO); and

a water soluble multivalent cation.

2. The gel of claim 1, wherein said polyacid is selected from the group consisting of a carboxypolysaccharide, polyacrylic acid, polyamino acid, polylactic acid, polyglycolic acid, polymethacrylic acid, polyterephthalic acid, polyhydroxybutyric acid, polyphosphoric acid, polystyrenesulfonic acid, and copolymers of said polyacids.

3. The gel of claim 1, wherein the polyacid is a carboxypolysaccharide selected from the group consisting of carboxymethyl cellulose (CMC), carboxyethyl cellulose, chitin carboxymethyl chitin, hyaluronic acid, alginate, propylene glycol alginate, pectin, carboxymethyl dextran, carboxymethyl chitosan, heparin, heparin sulfate, chondroitin sulfate and polyuronic acids including polymannuronic acid, polyglucuronic acid and polyguluronic acid.

4. The gel of claim 1, wherein the polyacid is carboxymethylcellulose.

5. The gel of claim 1, wherein the polyacid is carboxymethylcellulose having a molecular weight in the range of about 10 kd to about 10,000 kd and a degree of substitution in the range of greater than about 0 to about 3.

6. The gel of claim 1, wherein said polyalkylene oxide is selected from the group consisting of polypropylene oxide, polyethylene glycol, polyethylene oxide, and PEO/PPO block copolymers.

7. The gel of claim 1 wherein said polyalkylene oxide is polyethylene oxide or polyethylene glycol having a molecular weight in the range of about 200 d to about 8000 kd.

8. The gel of claim 1, wherein said polyalkylene oxide is polyethylene glycol having a molecular weight in the range of about 200 d to about 5 kd.

9. The gel of claim 1, wherein said PA is in the range of about 10% to about 99% by weight of the total solids content.

10. The gel of claim 1, wherein the PA is in the range of about 50% by weight to about 99% by weight, of the total solids content.

11. The gel of claim 1, wherein the PA is in the range of about 90% by weight to about 99% by weight of the total solids content.

12. The gel of claim 1, wherein the PO is in the range of about 1% by weight to about 90% by weight, of the total solids content.

13. The gel of claim 1, wherein the PO is in the range of about 1% by weight to about 10% by weight, of the total solids content.

14. The gel of claim 1, wherein the PO is about 2.5% by weight, of the total solids content.

15. The gel of claim 1, wherein the total solids content of the gel is in the range of about 1% to about 10%.

16. The gel of claim 1, wherein said cation is a trivalent cation.

17. The gel of claim 1, wherein said cation is selected from the group consisting of Fe⁺³, Al⁺³, and Cr^+3.

18. The gel of claim 1, wherein said cation is a divalent cation.

19. The gel of claim 1, wherein said cation is a divalent cation selected from the group consisting of Ca⁺2, Zn⁺2, Mg⁺2 and Mn⁺2.

20. The gel of claim 1, wherein said cation is accompanied by an inorganic anion.

21. The gel of claim 1, wherein said cation is accompanied by an inorganic anion selected from the group consisting of Cl, PO₄²−

, HPO₃⁻

;

CO₃²−

;

HCO₃⁻

;

SO₄²− and

borates.

22. The gel of claim 1, wherein said cation is accompanied by an organic anion.

23. The gel of claim 1, wherein said cation is accompanied by an organic anion selected from the group consisting of citrate, oxalate and acetate.

24. The gel of claim 1, wherein the pH of the gel is in the range of about 2.0 to about 7.5.

25. The gel of claim 1, wherein the pH of the gel is in the range of about 2.5 to about 6.0.

26. The gel of claim 1, further comprising a drug.

27. The gel of claim 1, further comprising a drug selected from the group consisting of antithrombogenic drugs, anti-inflammatory drugs, hormones, chemotactic factors, analgesics, growth factors, cytokines, osteogenic factors and anesthetics.

28. The gel of claim 1, further comprising drug selected from the group consisting of heparin, tissue plasminogen activator, aspirin, ibuprofen, ketoprofen, proteins and peptides containing an RGD motif, and non-steroidal anti-inflammatory drugs.

29. The gel of claim 1 having a viscosity below about 500,000 centipoise.

30. The gel of claim 1, wherein the polyacid is about 90% by weight of the total solids content and the polyalkylene oxide is about 10% by weight of the total solids content.

31. The gel of claim 1, wherein the polyacid is about 97.5% by weight of the total solids content and the polyalkylene oxide is about 2.5% by weight of the total solids content.

32. The gel of claim 30, wherein said cation is Ca²⁺ and said gel further comprises Cl.

33. The gel of claim 31, wherein said cation is Ca²⁺ and said gel further comprises Cl⁻

.

34. The gel of claim 30, wherein the total solids content of said gel is about 4 gm/100 ml.

35. The gel of claim 31, wherein the total solids content of said gel is about 4 gm/100 Ml.

36. The gel of claim 30, wherein

said polyacid is carboxymethylcellulose having

an average molecular weight of about 700,000 Daltons;

and

a degree of substitution of between about 0.81 and about 0.83;

said polyalkylene oxide is polyethylene oxide having

an average molecular weight of about 4,000 kDaltons; and

said monoatomic cation is Ca²⁺ in a concentration of from about 0.2 gm/100 ml to about 0.5 mg/100 ml.

37. The gel of claim 31, wherein

said polyacid is carboxymethylcellulose having

an average molecular weight of about 700,000 Daltons;

and

a degree of substitution of between about 0.81 and about 0.83;

said polyalkylene oxide is polyethylene oxide having

an average molecular weight of about 4,000 kDaltons; and

said monoatomic cation is Ca²⁺ in a concentration of from about 0.2 gm/100 ml to about 0.5 mg/100 ml.

38. The gel of claim 36, wherein the total solids content of said gel is about 4 gm/100 ml.

39. The gel of claim 37, wherein the total solids content of said gel is about 4 mg/100 ml.

40. The gel of claim 1, wherein sufficient cations are present to provide said gel with a viscosity of about 200,000 centipoise to about 300,000 centipoise as measured at a rotation rate of ½

rpm.

41. The gel of claim 37, wherein sufficient calcium is present to provide said gel with a viscosity of about 200,000 centipoise to about 300,000 centipoise as measured at a rotation rate of ½

rpm.

42. An ionically cross-linked gel comprising:

a polyacid (PA);

a polyalkylene oxide (PO); and

a monoatomic water soluble multivalent cation selected from the group consisting of Ca⁺², Mg²⁺, Mn²⁺, Co²⁺, Al³⁺ and Fe³⁺.