Thermo-irreversible gel corneal contact lens formed in situ

• US 5,376,693 A
• Filed: 10/26/1990
• Issued: 12/27/1994
• Est. Priority Date: 08/07/1990
• Status: Expired due to Fees

• Current Assignee: MDV Technologies, Inc. (Alliance Pharmaceutical Corporation)
• Original Assignee: Mediventures, Inc.
• Inventors: Viegas, Tacey X., Reeve, Lorraine E., Henry, Raymond L.
• Primary Examiner(s): Michl, Paul R.
• Assistant Examiner(s): MERRIAM, ANDREW EDWIN
• Application Number:
  US07/604,701
• Time in Patent Office: 1,523 Days
• Field of Search: 523/106, 525/937, 524/916, 424/427, 424/78.04, 424/486, 424/488, 514/944, 514/781, 514/779, 514/777, 514/772.1, 623/5, 350/160 H
• US Class Current: 523/106
• CPC Class Codes: A61F 9/00819 with photoablatable masks
• 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 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• 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 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: Y10S 524/916 Hydrogel compositions
• CPC Class Codes: Y10S 525/937 Utility as body contact e.g. implant, contact lens or I.U.D.

Abstract

Balanced pH, thermo-irreversible gels comprising a polyoxyalkylene compound and an ionic polysaccharide are ideal materials for the formation of a protective contact lens over the cornea of the eye of a mammal.

Claims

1. A process for forming a protective corneal contact lens in situ comprising administering to a cornea of an eye of a mammal an aqueous composition, wherein said aqueous composition is an aqueous gel having a desired osmolality and pH and comprising

(1) an ionic polysaccharide,

(2) a surfactant,

(3) a polyoxyalkylene polyether having an average molecular weight of about 10,000 to about 100,000, wherein said polyoxyalkylene polyether is selected from the group consisting of

(A) polyoxyalkylene polyethers prepared by reacting ethylene oxide and at least one lower alkylene oxide having 3 to 4 carbon atoms with at least one active hydrogen-containing compound having from 3 to 10 carbon atoms and from 3 to 6 active hydrogens to prepare a heteric or block copolymer intermediate and further reacting said copolymer intermediate with at least one alpha-olefin oxide having an average carbon chain length of about 20 to about 45 aliphatic carbon atoms and wherein said alpha-olefin oxide is present in the amount of about 0.3 to 10 percent by weight based upon the total weight of said polyether and

(B) polyoxylkylene polyethers prepared by reacting ethylene oxide with at least one active hydrogen-containing compound having from 2 to 10 carbon atoms and from 2 to 6 active hydrogens to prepare a homopolymer intermediate and further reacting said homopolymer intermediate with at least one alpha-olefin oxide having an average carbon chain length of about 20 to 45 aliphatic carbon atoms and wherein said alpha-olefin oxide is present in the amount of about 0.3 to 10 percent by weight based on the total weight of said polyether, and

(4) a latent form of a counter-ion capable of thermo-irreversibly cross-linking the ionic polysaccharide.

2. The process of claim 1, further comprising rendering said aqueous composition thermally irreversible, subsequent to cornea contact, by contacting said aqueous composition with a divalent or trivalent metal counter-ion capable of thermo-irreversibly cross-linking the ionic polysaccharide.

3. A process as defined in claim 1, wherein said aqueous composition further contains an effective amount of a medicament or drug.

4. The process of claim 2, wherein said polyether is prepared using a heteric copolymer intermediate and wherein the pH is maintained at 7.4±

0.2.

5. The process of claim 4, wherein, said polyether is prepared using an alpha-olefin oxide having an average carbon chain length of about 20 to 30 carbon atoms, present in the amount of about 0.3 to 10 percent of the total weight of said polyether.

6. The process of claim 5, wherein said polyether contains a proportion of ethylene oxide residue to the residue of said lower alkylene oxide of about 70 to about 90 percent by weight of ethylene oxide residue to about 30 to about 10 percent by weight of said lower alkylene oxide residue.

7. The process of claim 6, wherein said polyether is prepared using propylene oxide as the lower alkylene oxide.

8. The process of claim 2, wherein said polyether is prepared using a block copolymer intermediate.

9. The process of claim 8, wherein said polyether is prepared using an alpha-olefin oxide having an average carbon chain length of about 20 to 30 carbon atoms, which is present in the amount of about 0.3 to 10 percent of the total weight of said polyether.

10. The process of claim 9, wherein said polyether is prepared using a proportion of ethylene oxide residue to the residue of said lower alkylene oxide of from about 70 to about 90 percent by weight of ethylene oxide residue to about 30 to about 10 percent by weight of said lower alkylene oxide residue.

11. The process of claim 10, wherein said polyether is prepared using propylene oxide as the alkylene oxide.

12. The process of claim 2, wherein said polyether is polyether (B).

13. The process of claim 12, wherein said polyether is prepared using an alpha-olefin oxide having an average carbon chain length of about 20 to 30 carbon atoms, present in the amount of about 0.3 to 10 percent of the total weight of said polyether, said ionic polysaccharide is chitosan, said counter-ion is present as an ionic compound in a microencapsulated component or present as an anion in an ion exchange resin, and said ionic compound is selected from the group consisting of the metal phosphates, metaphosphates, pyrophosphates, tripolyphosphates, and mixtures thereof.

14. The process of claim 12, wherein said polyether is prepared using an alpha-olefin oxide having an average carbon chain length of about 20 to 30 carbon atoms, present in the amount of about 0.3 to 10 percent of the total weight of said polyether, said counter-ion is selected from the group consisting of calcium, strontium, aluminum, and mixtures thereof, said ionic polysaccharide is selected from the group consisting of an ammonium alginate, an alkali metal alginate, and mixtures thereof, and said counter-ion is present in an ionic compound as a microencapsulated component or present as a cation in an ion exchange resin.

15. A protective corneal contact lens formed in situ from an aqueous gel having a desired osmolality and pH and comprising

(1) an ionic polysaccharide,

(2) a surfactant,

(3) a polyoxyalkylene polyether having an average molecular weight of about 10,000 to 100,000 which is selected from the group consisting of

(A) polyoxyalkylene polyethers prepared by reacting ethylene oxide and at least one lower alkylene oxide having 3 to 4 carbon atoms with at least one active hydrogen-containing compound having from 3 to 10 carbon atoms and from 3 to 6 active hydrogens to prepare a heteric or block copolymer intermediate and further reacting said copolymer intermediate with at least one alpha-olefin oxide having an average carbon chain length of about 20 to about 45 aliphatic carbon atoms, and wherein said alpha-olefin oxide is present in the amount of about 0.3 to 10 percent by weight based upon the total weight of said polyether and

(B) polyoxyalkylene polyethers prepared by reacting ethylene oxide with at least one active hydrogen-containing compound having from 2 to 10 carbon atoms and from 2 to 6 active hydrogens to prepare a homopolymer intermediate and further reacting said homopolymer intermediate with at least one alpha-olefin oxide having an average carbon chain length of about 20 to 45 aliphatic carbon atoms, and wherein said alpha-olefin oxide is present in the amount of about 0.3 to 10 percent by weight based on the total weight of said polyether, and

(4) a latent form of a counter-ion capable of thermo-irreversibly cross-linking the ionic polysaccharide.

16. The contact lens of claim 15, wherein said contact lens is rendered thermally irreversible, subsequent to corneal contact, with a divalent or trivalent metal counter-ion capable of cross-linking the ionic polysaccharide.

17. The contact lens of claim 16, wherein said polyether is prepared using a heteric copolymer intermediate and wherein the pH is maintained at 7.4±

0.2.

18. The contact lens of claim 17, wherein said polyether is prepared using an alpha-olefin oxide having an average carbon chain length of about 20 to 30 carbon atoms, present in the amount of about 0.3 to 10 percent of the total weight of said polyether.

19. The contact lens of claim 18, wherein the polyether is prepared using a proportion of ethylene oxide residue to the residue of said lower alkylene oxide of about 70 to about 90 percent by weight of ethylene oxide residue to about 30 to about 10 percent by weight of said lower alkylene oxide residue.

20. The contact lens of claim 19, wherein said polyether is prepared using propylene oxide as the lower alkylene oxide.

21. The contact lens of claim 16, wherein said polyether is prepared using a block copolymer intermediate.

22. The contact lens of claim 21, wherein said polyether is prepared using an alpha-olefin oxide having an average carbon chain length of about 20 to 30 carbon atoms and is present in the amount of about 0.3 to 10 percent of the total weight of said polyether.

23. The contact lens of claim 22, wherein the polyether is prepared using a proportion of ethylene oxide residue to the residue of said lower alkylene oxide of about 70 to about 90 percent by weight of ethylene oxide residue to about 30 to about 10 percent by weight of said lower alkylene oxide residue.

24. A contact lens as defined in claim 15, wherein said aqueous gel further contains an effective about of a medicament or drug.

25. The contact lens of claim 23, wherein said polyether is prepared using propylene oxide as the lower alkylene oxide.

26. The contact lens of claim 16, wherein said polyether is polyether (B) of claim 20.

40. The contact lens of claim 26, wherein said polyether is prepared using an alpha-olefin oxide having an average carbon chain length of about 20 to 30 carbon atoms, present in the amount of about 0.3 to 10 percent of the total weight of said polyether, said counter-ion is selected from the group consisting of calcium, strontium, aluminum, and mixtures thereof, said ionic polysaccharide is selected from the group consisting of an ammonium alginate, an alkali metal alginate, and mixtures thereof, and said counter-ion is present in an ionic compound as a microencapsulated component or an ion exchange resin.

41. The contact lens of claim 26, wherein said polyether is prepared using an alpha-olefin oxide having an average carbon chain length of about 20 to 30 carbon atoms, present in the amount of about 0.3 to 10 percent of the total weight of said polyether, said ionic polysaccharide is chitosan, said counter-ion is present as an ionic compound in a microencapsulated component or present as an anion in an ion exchange resin, and said ionic compound is selected from the group consisting of the metal phosphates, metaphosphates, pyrophosphates, tripolyphosphates, and mixtures thereof.

27. A protective corneal contact lens, said contact lens being formed from an aqueous gel having a desired osmolality and pH, which is a liquid at room temperature or below and a thermo-reversible gel at mammalian body temperature, said aqueous gel containing

(1) an ionic polysaccharide;

(2) a polyoxyalkylene block copolymer of formula

space="preserve" listing-type="equation">Y[(A).sub.n --E--H].sub.x (I)

wherein A is a polyoxyalkylene moiety having an oxygen/carbon atom ratio of less than 0.5, x is at least 2, Y is derived from water or an organic compound containing x reactive hydrogen atoms, E is a polyoxyethylene moiety constituting at least 60% by weight of the ppolyoxyalkylene block copolymer, n has a value such that the average molecular weight of A is at least about 500, as determined by the hydroxyl number of an intermediate of formula

space="preserve" listing-type="equation">Y[(A).sub.n --H].sub.x (II)

and the total average molecular weight of the polyoxyalkylene block copolymer is at least about 5000; and

(3) a latent form of a counter-ion capable of thermo-irreversibly gelling the ionic polysaccharide.

28. The contact lens of claim 27, wherein said contact lens is rendered thermally irreversible, subsequent to corneal contact, with a divalent or trivalent metal counter-ion capable of thermo-irreversibly gelling the ionic polysaccharide.

29. The contact lens of claim 27, wherein said aqueous gel further contains an effective amount of a medicament or drug.

30. The contact lens of claim 28, wherein Y in said polyoxyalkylene block copolymer is derived from a water soluble organic compound having 1 to about 6 carbon atoms and wherein the pH is maintained at 7.4±

0.2.

31. The lens of claim 30, wherein said polyoxyalkylene moiety is derived from an alkylene oxide selected from the group consisting of butylene oxide, propylene oxide, and mixtures thereof and Y is derived from an organic compound selected from the group consisting of propylene glycol, glycerin, pentaerythritol, trimethylolpropane, ethylenediamine and mixtures thereof.

32. The lens of claim 31, wherein said copolymer is a polyoxyethylene-polyoxypropylene block copolymer wherein said polyoxyethylene moiety constitutes at least about 70% by weight of the copolymer, the average molecular weight of A is at least about 1200, and the total molecular weight of the copolymer is at least about 10,000.

33. The lens of claim 32, wherein the intermediate of Formula II is prepared by initiation with propylene glycol and has a molecular weight of at least about 1500.

34. The contact lens of claim 33, wherein said polyoxyalkylene block copolymer has the formula

35. The lens of claim 34, wherein said polyoxyalkylene block copolymer is ##STR4## present in the amount of about 10 to about 40% by weight of the total weight of said aqueous gel.

36. The contact lens of claim 34, wherein said polyoxyalkylene block copolymer is present in the amount of about 15% to about 30% by weight in said aqueous gel, said counter-ion is selected from the group consisting of calcium, strontium, aluminum, and mixtures thereof, and said ionic polysaccharide is selected from the group consisting of an ammonium alginate, an alkali metal alginate, and mixtures thereof.

37. The contact lens of claim 34, wherein said polyoxyalkylene block copolymer is present in the amount of about 15 to 30% by weight of said aqueous gel, the optional latent form of said counter-ion is present as an ionic compound in a microencapsulated component or present as an anion in an ion exchange resin and said ionic compound is selected from the group consisting of the metal phosphates, metaphosphates, pyrophosphates, tripolyphosphates, and mixtures thereof, and said ionic polysaccharide is chitosan.

38. A process for forming a protective corneal contact lens situ comprising administering to an eye of a mammal an aqueous composition having a desired osmolality and pH, which is a liquid at room temperature or below and a thermo-reversible aqueous gel at mammalian body temperature, wherein said aqueous composition comprises:

(1) an ionic polysaccharide;

(2) a polyoxyalkylene block copolymer of formula

space="preserve" listing-type="equation">Y[(A).sub.n --E--H].sub.x (I)

where A is a polyoxyalkylene moiety having an oxygen/carbon atom ratio of less than 0.5, x is at least 2, Y is derived from water or an organic compound containing x reactive hydrogen atoms, E is a polyoxyethylene moiety, n has a value such that the average molecular weight of A is at least about 500, as determined by the hydroxyl number of an intermediate of formula

space="preserve" listing-type="equation">Y[(A).sub.n --H].sub.x (II)

and wherein the total average molecular weight of the polyoxyalkylene block copolymer is at least about 5000; and

(3) a latent form of a counter-ion capable of thermo-irreversibly gelling said aqueous composition.

39. The process of claim 38, further comprising rendering said contact lens thermo-irreversible, subsequent to eye contact, by contacting said contact lens with a divalent or trivalent counter-ion capable of theremo-irreversibly gelling said aqueous composition.

42. The process of claim 38, wherein Y in said formulas I and II is a water soluble organic compound having 1-6 carbon atoms, and said copolymer is selected from the group consisting of a polyoxyethylene-polyoxybutylene block copolymer, a polyoxyethylene-polyoxypropylene block copolymer and mixtures thereof, and wherein the polyoxyethylene moiety constitutes at least 70% by weight of the polymer and wherein the pH is maintained at about 7.4±

0.2.

43. The process of claim 42, wherein said copolymer is selected from block copolymers which form aqueous gels at a concentration of about 10-40% by weight of the total weight of said composition.

44. The process of claim 43, wherein said Y is a compound selected from the group consisting of propylene glycol, glycerin, pentaerythritol, trimethylolpropane, ethylenediamine, and mixtures thereof.

45. The process of claim 44, wherein Y is derived from propylene glycol, A is the residue of propylene oxide, and the intermediate of Formula II has an average molecular weight of at least about 900.

46. The process of claim 44, wherein Y is derived from butylene glycol, A is the residue of butylene oxide, and the intermediate of Formula II has an average molecular weight of at least about 500.

47. The process of claim 44, wherein said polyoxyalkylene block copolymer has the formula

48. The process of claim 47, wherein said copolymer is ##STR6##

49. The process of claim 47, wherein said ionic polysaccharide is chitosan, said counter-ion is present as an ionic compound in a microencapsulated component or present as an anion in an ion exchange resin, and said ionic compound is selected from the group consisting of the metal phosphates, metaphosphates, pryophosphates, tripolyphosphates, and mixtures thereof.

50. The process of claim 49, wherein said counter-ion is selected from the group consisting of calcium, strontium, aluminum and mixtures thereof, said ionic polysaccharide is selected from the group consisting of an ammonium alginate, an alkali metal alginate, and mixtures thereof, and said counter-ion is present in an ionic compound as a microencapsulated component or present as a cation in an ion exchange resin.

51. The process of claim 38, wherein said aqueous composition further contains an effective amount of a medicament or drug.