Ablatable mask of polyoxyalkylene polymer and ionic polysaccharide gel for laser reprofiling of the cornea

• US 5,277,911 A
• Filed: 10/26/1990
• Issued: 01/11/1994
• 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): WEBMAN, EDWARD J
• Application Number:
  US07/604,705
• Time in Patent Office: 1,173 Days
• Field of Search: 424/427, 424/486, 424/488, 514/772.1, 514/777, 514/779, 514/781, 514/944, 252/315.2, 252/315.3, 523/121, 523/137, 523/179, 525/405, 525/916, 606/5, 524/916, 340/796
• US Class Current: 424/427
• 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 525/916 Polymer from ethylenic monomers only, having cationic group

Abstract

Balanced pH, thermo-irreversible polyoxyalkylene polymer and ionic polysaccharide gels are ideal materials for use as an ablatable mask or coating over the cornea of the eye of a mammal during excimer laser keratectomy. The depth and smoothness of the ablated corneal surface can be controlled by molding the desired surface curvature into the mask surface using a contact lens as a mold which is pressed onto the gel surface coating the cornea.

Claims

1. An ablatable corneal mask for use in excimer laser keratectomy for correction of myopia and hyperopia, said mask comprising a thermally irreversible, osmotically balanced aqueous gel, having a buffered pH, wherein said aqueous gel is the reaction product of a thermally reversible aqueous gel and a multivalent counter-ion, wherein said thermally reversible aqueous gel is a liquid at room temperature or below and a gel at mammalian body temperature, said thermally reversible aqueous gel containing

(1) about 0.2% to about 2.5% by weight of an ionic polysaccharide;

(2) about 10% to about 50% by weight of 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 polyoxyalkylene 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 pharmaceutically acceptable buffer sufficient to maintain the pH of said thermally reversible aqueous gel at a desired level;

wherein the muiltivalent counter-ion is capable of thermo-irreversibly gelling the ionic polysaccharide in the thermally reversible aqueous gel.

2. The mask of claim 1, wherein Y in said polyoxyalkylene block copolymer is derived from a water soluble organic compound having 1 to about 6 carbon atoms wherein the pH of said thermally reversible aqueous gel is maintained at 7.4±

0.2, and the multivalent counter-ion is a divalent of trivalent counter-ion.

3. The mask of claim 2, 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.

4. The mask of claim 3, 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.

5. The mask of claim 4, wherein the intermediate of Formula II is prepared by initiation with propylene glycol and has a molecular weight of at least about 1500.

6. The mask of claim 3, wherein said polyoxyalkylene block copolymer has the formula

7. The mask of claim 6, 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 thermally reversible aqueous gel and wherein the counter-ion is present in said thermally reversible aqueous gel in latent form.

8. The mask of claim 7, wherein said polyoxyalkylene block copolymer is present in the amount of about 15% to about 30% by weight in said thermally reversible 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.

9. The mask of claim 7, wherein said polyoxyalkylene block copolymer is present in the amount of about 15% to 30% by weight of said aqueous thermally reversible gel, the 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 wherein 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.

10. A process for excimer laser keratectomy for correction of myopia and hyperopia comprising:

forming a thermo-reversible aqueous gel corneal mask in situ on a cornea of an eye of a mammal, said mask comprising an aqueous composition having a buffered pH and characterized as a liquid at room temperature or below and a thermo-reversible, osmotically balanced aqueous gel at mammalian body temperature,

rendering said mask thermo-irreversible by contacting said mask with a divalent or trivalent counter-ion,

wherein said aqueous composition comprises;

(1) about 0.2% to about 2.5% by weight of an ionic polysaccharide;

(2) about 10% to about 50% by weight of 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, 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 pharmaceutically acceptable buffer sufficient to maintain the pH of said aqueous composition at a desired level;

wherein the divalent or trivalent counter-ion is capable of thermo-irreversibly gelling said aqueous composition.

11. The process of claim 10, 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 polyoxyalkylene block copolymer and wherein the pH is maintained at about 7.4±

0.2.

12. The process of claim 11, 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.

13. The process of claim 12, wherein said Y is a compound selected from the group consisting of propylene glycol, glycerin, pentaerythritol, trimethylolpropane, ethylenediamine, and mixtures thereof.

14. The process of claim 13, 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.

15. The process of claim 13, 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

16. The process of claim 13, wherein said excimer laser is an argon fluoride laser which delivers light at about 193 nm and wherein said polyoxyalkylene block copolymer has the formula

17. The process of claim 16, wherein said copolymer is ##STR6##

18. The process of claim 16, wherein said ionic polysaccharide is chitosan and said counter-ion is present as an ionic compound in a microencapsulated component or present as an anion in an ion exchange resin, wherein said ionic compound is selected from the group consisting of the metal phosphates, metaphosphates, pyrophosphates, tripolyphosphates, and mixtures thereof.

19. The process of claim 16, wherein said counter-ion is selected from the group consisting of calcium, strontium, aluminum, and mixtures thereof, said ionic polysaccharides 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.

20. A process for excimer laser keratectomy to correct myopia and hyperopia comprising:

forming a thermally reversible, osmotically balanced aqueous gel composition in situ on a cornea of an eye of a mammal, and

rendering said composition thermally irreversible by contacting said composition with a divalent or trivalent metal counter-ion,

said composition having a buffered pH and comprising

(1) about 0.2% to about 2.5% by weight of an ionic polysaccharide,

(2) about 0.1% to about 10% by weight of a combination of a surfactant and 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) 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,

wherein the divalent or trivalent counter-ion is capable of cross-linking the ionic polysaccharide.

21. The process of claim 20, wherein said polyether is prepared using a heteric copolymer intermediate and wherein the pH is maintained at 7.4±

0.2.

22. The process 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, present in the amount of about 0.3 to 10 percent of the total weight of said polyether.

23. The process of claim 22, 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.

24. The process of claim 23, wherein said polyether is prepared using propylene oxide as the lower alkylene oxide.

25. The process of claim 20, wherein said polyether is prepared using a block copolymer intermediate.

26. The process of claim 25, 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.

27. The process of claim 26, 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.

28. The process of claim 27, wherein said polyether is prepared using propylene oxide as the alkylene oxide and wherein said excimer laser is an argon fluoride laser which delivers light at 193 nm.

29. The process of claim 20, wherein said polyether is polyether (B).

30. The process of claim 29, 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, and said counter-ion is present as an ionic compound in a microencapsulated component or present as an anion in an ion exchange resin, wherein said ionic compound is selected from the group consisting of the metal phosphates, metaphosphates, pyrophosphates, tripolyphosphates, and mixtures thereof.

31. The process of claim 29, 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.

41. The mask of claim 32, wherein said polyether is polyether (B) of claim 30.

42. The composition of claim 41, 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.

43. The mask of claim 41, 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, and said counter-ion is present as an ionic compound in a microencapsulated component or present as an ionic in an ion exchange resin, wherein said ionic compound is selected from the group consisting of metal phosphates, metaphosphates, pyrophosphates, tripolyphosphates, and mixtures thereof.

32. A thermally irreversible, osmotically balanced gel ablatable corneal mask for use in excimer laser keratectomy for correction of myopia and hyperopia, said mask being rendered thermally irreversible, subsequent to corneal contact, with a divalent or trivalent metal counter-ion, said mask being formed from an aqueous composition having a buffered pH and comprising

(1) about 0.2% to about 2.5% by weight of an ionic polysaccharide, and

(2) about 0.1% to about 10% by weight of a combination of a surfactant and a polyoxyalkylene polyether having a molecular weight of about 10,000 to about 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,

wherein the divalent or trivalent counter-ion is capable of cross-linking the ionic polysaccharide.

33. The mask of claim 32, wherein said polyether is prepared using a heteric copolymer intermediate and wherein the pH is maintained at 7.4±

0.2.

34. The mask of claim 33, 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.

35. The mask of claim 34, 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.

36. The mask of claim 35, wherein said polyether is prepared using propylene oxide as the lower alkylene oxide.

37. The mask of claim 32, wherein said polyether is prepared using a block copolymer intermediate.

38. The mask of claim 37, 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.

39. The mask of claim 38, 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.

40. The mask of claim 39, wherein said polyether is prepared using propylene oxide as the lower alkylene oxide.

44. An ablatable corneal mask for use in excimer laser keratectomy for correction of myopia and hyperopia, said mask comprising a thermally irreversible, osmotically balanced, aqueous gel, having a buffered pH, which is the reaction product of a thermally reversible aqueous gel which is a liquid at room temperature or below and a divalent or trivalent counter-ion, said thermally reversible aqueous gel comprising

(1) about 0.2% to about 2.5% by weight of an ionic polysaccharide and

(2) about 10% to about 50% by weight of a polyoxyalkylene block copolymer of formula

45. A process for excimer laser keratectomy for correction of myopia and hyperopia comprising:

forming a thermo-reversible, osmotically balanced, aqueous gel corneal mask in situ on a cornea of an eye of a mammal, said corneal mask having a buffered pH, and characterized as liquid at room temperature or below and a thermo-reversible gel at mammalian body temperature, and

rendering said corneal mask thermo-irreversible by contacting said thermo-reversible corneal mask with a divalent or trivalent metal counter-ion, wherein said thermo-reversible corneal mask is formed using a composition comprising

(1) about 0.2% to about 2.5% by weight of an ionic polysaccharide and

(2) about 10% to about 50% by weight of 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, n has 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;

wherein the divalent or trivalent metal counter-ion is capable of thermo-irreversibly gelling said composition.