Polyacid/polyalkylene oxide gels and methods for their delivery and use

• US 20030152522A1
• Filed: 02/20/2003
• Published: 08/14/2003
• Est. Priority Date: 12/27/1999
• Status: Active Grant

• Current Assignee: Herbert E. Schwartz, Mark E. Miller, Stephanie M. Cortese, William G. Oppelt
• Original Assignee: Herbert E. Schwartz, Mark E. Miller, Stephanie M. Cortese, William G. Oppelt
• Inventors: Schwartz, Herbert E., Miller, Mark E., Oppelt, William G., Cortese, Stephanie M.
• Granted Patent: US 7,265,098 B2
• Time in Patent Office: Days
• US Class Current: 424/45
• CPC Class Codes: A61K 31/715 Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• CPC Class Codes: A61K 31/717 Celluloses
• CPC Class Codes: A61K 31/721 Dextrans
• CPC Class Codes: A61K 31/722 Chitin, chitosan
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• CPC Class Codes: A61K 31/728 Hyaluronic acid
• CPC Class Codes: A61K 31/74 Synthetic polymeric materials
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/122 Foams; Dry foams edible foams A61K9/0056
• 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 15/225 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 15/44 Medicaments
• CPC Class Codes: A61L 2300/00 Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
• CPC Class Codes: A61L 2300/418 Agents promoting blood coagulation, blood-clotting agents, embolising agents
• CPC Class Codes: A61L 2400/04 Materials for stopping bleeding
• CPC Class Codes: A61L 31/041 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: C08L 1/28 Alkyl 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 2666/04 : Macromolecular compounds according to groups C08L7/00 - C08L49/00, or C08L55/00 - C08L57/00; Derivatives thereof
• CPC Class Codes: C08L 2666/18 : Polyesters or polycarbonates according to C08L67/00 - C08L69/00; Derivatives thereof
• CPC Class Codes: C08L 2666/20 : Macromolecular compounds having nitrogen in the main chain according to C08L75/00 - C08L79/00; Derivatives thereof
• CPC Class Codes: C08L 2666/22 : Macromolecular compounds not provided for in C08L2666/16 - C08L2666/20
• 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 67/00 : Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain of polyester-amides C08L77/12; of polyester-imides C08L79/08; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 71/02 : Polyalkylene oxides
• CPC Class Codes: C08L 77/00 : Compositions of polyamides obtained by reactions forming a carboxylic amide link in the main chain of polyhydrazides C08L79/06; of polyamideimides or polyamide acids C08L79/08; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 85/00 : Compositions of macromolecular compounds obtained by reactions forming a linkage in the main chain of the macromolecule containing atoms other than silicon, sulfur, nitrogen, oxygen and carbon; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 85/02 : containing phosphorus

Abstract

The present invention relates to improved methods for delivering bioadhesive, bioresorbable, anti-adhesion compositions. Antiadhesion compositions can be 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 used as fluids, gels or foams. By providing a product bag, the compositions can be delivered as gels or as sprays. By dissolving propellant gases in the compositions, the materials can be delivered as foams, which have decreased density, and therefore can adhere to surfaces that previously have been difficult to coat with antiadhesion gels. Delivery systems can also provide mechanisms for expelling more product, and for directing the flow of materials leaving the delivery system. Bioresorbable, bioadhesive, antiadhesion, and/or hemostatic compositions are useful in surgery to prevent the formation and reformation of post-surgical adhesions. The biological and physical properties of such compositions 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 selecting the solids content of the composition. 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. A system for delivering an antiadhesion composition, comprising:

a canister containing said antiadhesion composition;

a valve adapted to permit flow of said antiadhesion composition therethrough; and

a pressure source.

2. The system of claim 1, further comprising a gas capsule.

3. The system of claim 1, further comprising a product bag for containing said antiadhesion composition.

4. The system of claim 1, further comprising a flow tube.

5. The system of claim 1, wherein said pressure source comprises an inert gas.

6. The system of claim 1, wherein said inert gas is selected from the group consisting of carbon dioxide, nitrogen, noble gases, hydrocarbons and fluorocarbons.

7. The system of claim 1, wherein said pressure source provides a pressure in the range of about 21 psig and about 313 psig.

8. The system of claim 1, wherein said antiadhesion composition is delivered as a foam.

9. The system of claim 3, wherein said antiadhesion composition is delivered as a gel or a spray.

10. The system of claim 1, wherein said antiadhesion composition comprises:

a polyacid (PA); and

a polyalkylene oxide (PO).

11. The system of claim 10, wherein said antiadhesion composition further comprises

a multivalent cation.

12. The system of claim 10, 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.

13. The system of claim 10, 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.

14. The system of claim 10, wherein the polyacid is carboxymethylcellulose.

15. The system of claim 10, 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.

16. The system of claim 10, wherein said polyalkylene oxide is selected from the group consisting of polypropylene oxide, polyethylene glycol, polyethylene oxide, and PEO/PPO block copolymers.

17. The system of claim 10, 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.

18. The system of claim 10, wherein said polyalkylene oxide is polyethylene glycol having a molecular weight in the range of about 200 d to about 5 kd.

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

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

21. The system of claim 10, wherein the PO is in the range of about 1% by weight to about 90% by weight, of the total solids content.

22. The system of claim 10, wherein the total solids content of the gel is up to about 10%.

23. The system of claim 11, wherein said cation is a divalent or a trivalent cation.

24. The system of claim 10, wherein the pH of the antiadhesion composition is in the range of about 2.0 to about 7.5.

25. The system of claim 1, further comprising a drug.

26. The system of claim 1, wherein said antiadhesion composition further comprises a drug selected from the group consisting of antithrombogenic drugs, clotting agents, anti-inflammatory drugs, hormones, chemotactic factors, analgesics, growth factors, cytokines, osteogenic factors and anesthetics.

27. The system of claim 1, wherein said antiadhesion composition has a viscosity below about 2,000,000 centipoise.

28. A method for decreasing post-surgical adhesions, comprising the step of placing, using the delivery system of claim 1, an antiadhesion composition in contact with a tissue that in the absence of said gel would form an adhesion with an adjacent tissue.

29. The method of claim 28, wherein said surgical procedure is selected from the group consisting of abdominal, ophthalmic, orthopedic, gastrointestinal, thoracic, cranial, cardiovascular, gynecological, urological, plastic, musculoskeletal, spinal, nerve, tendon, otorhinolaryngological and pelvic.

30. The method of claim 28, wherein said surgical procedure is selected from the group consisting of appendectomy, cholecystectomy, hernial repair, lysis of peritoneal adhesions, kidney surgery, bladder surgery, urethral surgery, prostate surgery, salingostomy, salpingolysis, ovariolysis, removal of endometriosis, surgery to treat ectopic pregnancy, myomectomy of uterus, myomectomy of fundus, hysterectomy, laminectomy, discectomy, tendon surgery, spinal fusion, joint replacement, joint repair, strabismus surgery, glaucoma filtering surgery, lacrimal drainage surgery, sinus surgery, ear surgery, bypass anastomosis, heart valve replacement, thoracotomy, synovectomy, chondroplasty, removal of loose bodies and resection of scar tissue.

31. A method for treating symptoms of joint inflammation, comprising the step of delivering an antiadhesion composition, using the delivery system of claim 1, to said site of joint inflammation

32. The method of claim 31, wherein said step of delivering is carried out using an arthroscope.

33. A method for decreasing post-traumatic adhesions, comprising the step of delivering an antiadhesion composition, using a delivery system of claim 1, to a site of trauma the composition of claim 1.

34. A method of preventing adhesion reformation, comprising the steps of:

(a) resecting said adhesion to separate the previously adherent tissues; and

(b) delivering an antiadhesion composition, using the delivery system of claim 1, between the previously adherent tissues.

35. A method for decreasing surgical trauma caused by a surgical instrument, comprising coating said surgical instrument with an antiadhesion composition, using the system of claim 1, prior to using said surgical instrument.

36. A method for decreasing friction between adjacent tissues, comprising delivering an antiadhesion composition, using the delivery system of claim 1, between said adjacent tissues.

37. The delivery system of claim 1, wherein said antiadhesion composition further comprises a plasticizer.

38. The delivery system of claim 37, wherein the plasticizer is selected from the group consisting of glycerol, ethanolamines, ethylene glycol, 1,2,6-hexanetriol, monoacetin, diacetin, triacetin, 1,5-pentanediol, PEG, propylene glycol, and trimethylol propane.

39. The delivery system of claim 37, wherein the concentration of said plasticizer is in the range of greater than about 0% to about 30% by weight.

40. A gas capsule for use with the delivery system of claim 1, comprising:

walls defining a gas chamber;

an end comprising a resilient valve flap; and

a lip.

41. The gas capsule of claim 40, wherein said lip is resilient.

42. The gas capsule of claim 40 adapted to contain a pressure differential between the inside of said capsule and the surrounding environment, of about 100 psig.

43. The system of claim 10, wherein said antiadhesion composition has at least one additional property selected from the group consisting of antithrombogenicity, bioadhesiveness, bioresorbability and hemostatic.

44. The system of claim 3, further comprising at least one gas capsule in said product bag.

60. The system of claim 1, wherein said antiadhesion composition comprises:

a polyacid (PA);

a polyalkylene oxide (PO); and

a multivalent cation.

45. An antiadhesion foam comprising:

an antiadhesion composition comprising a PA and a PO; and

a foaming gas.

46. The antiadhesion foam of claim 45, wherein the foaming gas is CO₂.

47. The antiadhesion foam of claim 45, wherein the foaming gas is N₂.

48. The antiadhesion foam of claim 45, wherein the PA is CMC and the PO is PEO.

49. The antiadhesion foam of claim 45, wherein the density of said foam is in the range of about 0.001 to about 1 times the density of the un-foamed antiadhesion composition.

50. The antiadhesion foam of claim 45, wherein said foam has a cell size of between about 0.001″

to about 1.0″

.

51. The antiadhesion foam of claim 45, further comprising a drug.

52. The antiadhesion foam of claim 45, further comprising a hemostatic agent.

53. The antiadhesion foam of claim 45, further comprising a multivalent cation.

54. The antiadhesion foam of claim 53, wherein said multivalent cation is selected from the group consisting of calcium, aluminum, and iron.

55. The antiadhesion foam of claim 53 having a pH of below about 7.5.

56. The antiadhesion foam of claim 53 having a pH below about 6.0

57. The antiadhesion foam of claim 53 having a pH below about 5.0.

58. The antiadhesion foam of claim 53 having a pH below about 4.0.

59. The antiadhesion foam of claim 53 having a pH below about 3.0.

69. The antiadhesion foam of claim 53, wherein said multivalent cation is selected from the group consisting of Ca²⁺, Mg²⁺, Zn³⁺, Mn²⁺, Fe³⁺, Cr³⁺ and Al³⁺

61. A system for delivering a composition, comprising:

a canister containing said composition;

a gas capsule;

a valve adapted to permit flow of said composition therethrough; and

a pressure source.

62. The system of claim 61, further comprising a product bag for containing said composition.

63. The system of claim 61, further comprising a flow tube.

64. The system of claim 61, wherein said pressure source comprises an inert gas.

65. The system of claim 61, wherein said inert gas is selected from the group consisting of carbon dioxide, nitrogen, noble gases, hydrocarbons and fluorocarbons.

66. The system of claim 61, wherein said composition is an antiadhesion comprising:

a polyacid (PA); and

a polyalkylene oxide (PO).

67. The system of claim 66, further comprising a multivalent cation.

68. The system of claim 66, wherein said multivalent cation is selected from the group consisting of Ca²⁺, Mg²⁺, Zn³⁺, Mn²⁺, Fe³⁺, Cr³⁺ and Al³⁺.

70. The system of claim 66, further comprising a hemostatic agent.

71. The system of claim 70, wherein said hemostatic agent is selected from the group consisting of thrombin, fibrillar collagen, norepinephrine, epinephrine, phenylpropanolamine, dopamine, metaraminol, methoxamine, ephedrine, and propylhexedrine.