Ophthalmologic irrigation solutions and method

• US 20040072809A1
• Filed: 07/30/2003
• Published: 04/15/2004
• Est. Priority Date: 07/30/2002
• Status: Abandoned Application

• Current Assignee: Omeros Corporation
• Original Assignee: Omeros Corporation
• Inventors: Demopulos, Gregory A., Palmer, Pamela Pierce, Herz, Jeffrey M.
• Application Number:
  US10/630,626
• Publication Number:
  US 20040072809A1
• Time in Patent Office: Days
• US Class Current: 514/171
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/4174 Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
• CPC Class Codes: A61K 31/4409 only substituted in position 4, e.g. isoniazid, iproniazid
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 23/02 Local anaesthetics
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/04 Artificial tears; Irrigation solutions
• CPC Class Codes: A61P 27/08 Mydriatics or cycloplegics
• CPC Class Codes: A61P 27/12 : for cataracts
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 29/02 : without antiinflammatory effect
• CPC Class Codes: A61P 39/06 : Free radical scavengers or antioxidants
• CPC Class Codes: A61P 41/00 : Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Solutions for perioperative intraocular application by continuous irrigation during ophthalmologic procedures are provided. These solutions include multiple agents that act to inhibit inflammation, inhibit pain, effect mydriasis (dilation of the pupil), and/or decrease intraocular pressure, wherein the multiple agents are selected to target multiple molecular targets to achieve multiple differing physiologic functions, and are included in dilute concentrations in a balanced salt solution carrier.

Claims

1. A method for perioperatively inhibiting inflammation, inhibiting pain, effecting mydriasis, and/or decreasing intraocular pressure during an ophthalmologic procedure, comprising continuously irrigating ocular tissues during an ophthalmologic procedure with a solution including at least first and second agents in a liquid irrigation carrier, the first and second agents being selected to act on a plurality of differing molecular targets, each agent being selected from the physiologic functional classes of anti-inflammatory agents, analgesic agents, mydriatic agents and agents for decreasing intraocular pressure (“

IOP reducing agents”

), the second agent providing at least one physiologic function different than a function or functions provided by the first agent.

2. The method of claim 1, wherein the solution comprises an anti-inflammatory agent selected from the group consisting of steroids, non-steroidal anti-inflammatory drugs (NSAIDS), anti-histamines, mast cell inhibitors, and inhibitors of inducible nitric oxide synthase (iNOS).

3. The method of claim 2, wherein:

the steroid, if selected, is selected from the group consisting of dexamethasone, fluorometholone and prednisolone;

the NSAID, if selected, is selected from the group consisting of flurbiprofen, suprofen, diclofenac, ketoprofen and ketorolac;

the anti-histamine, if selected, is selected from the group consisting of levocabastine, emedastine, olopatadine, ketotifen, and azelastine;

the mast cell inhibitor, if selected, is selected from the group consisting of cromolyn sodium, Iodoxamide, nedocromil, ketotifen and azelastine; and

the inhibitor of iNOS, if selected, is selected from the group consisting of N_G-monomethyl-L-arginine, 1400 W, diphenyleneiodium, S-methyl isothiourea, S-(aminoethyl) isothiourea, L-N⁶-(1-iminoethyl)lysine, 1,3-PBITU and 2-ethyl-2-thiopseudourea.

4. The method of claim 1, wherein the solution comprises an analgesic agent selected from the group consisting of local anesthetics and opioids.

5. The method of claim 4, wherein:

the local anesthetic, if selected, is selected from the group consisting of lidocaine, tetracaine, bupivacaine, and proparacaine; and

the opioid, if selected, is selected from the group consisting of morphine, fentanyl and hydromorphone.

6. The method of claim 1, wherein the solution comprises a mydriatic agent selected from the group consisting of alpha-I adrenergic receptor agonists and anticholinergic agents.

7. The method of claim 6, wherein:

the alpha-1 adrenergic receptor agonist, if selected, is selected from the group consisting of phenylephrine, epinephrine, and oxymetazoline; and

the anticholinergic agent, if selected, is selected from the group consisting of tropicamide, cyclopentolate, atropine and homatropine.

8. The method of claim 1, wherein the solution comprises an IOP reducing agent selected from the group consisting of beta adrenergic receptor antagonists, carbonic anhydrase inhibitors, alpha-2 adrenergic receptor agonists, and prostaglandin agonists.

9. The method of claim 8, wherein:

the beta adrenergic receptor antagonist, if selected, is selected from the group consisting of timolol, metipranolol and levobunolol;

the carbonic anhydrase inhibitor, if selected, is selected from the group consisting of brinzolamide and dorzolamide;

the alpha-2 adrenergic receptor agonist, if selected, is selected from the group consisting of apraclonidine, brimonidine and oxymetazoline; and

the prostaglandin agonist, if selected, is selected from the group consisting of latanoprost, travoprost and bimatoprost.

10. The method of claim 1, wherein each of the first and second agents in the solution is included at a concentration of no more than 100,000 nanomolar.

11. The method of claim 1, wherein each of the first and second agents in the solution is included at a concentration of no more than 10,000 nanomolar.

12. The method of claim 1, wherein the liquid irrigation carrier further comprises an adjuvant selected from electrolytes sufficient to provide a physiological balanced salt solution, a cellular energy source, a buffering agent, a free-radical scavenger and mixtures thereof.

13. The method of claim 12, wherein:

the electrolytes, if selected, comprise from 50 to 500 millimolar sodium ions, from 0.1 to 50 millimolar potassium ions, from 0.1 to 5 millimolar calcium ions, from 0.1 to 5 millimolar magnesium ions, from 50 to 500 millimolar chloride ions, and from 0.1 to 10 millimolar phosphate;

the buffer, if selected, comprises bicarbonate at a concentration of from 10 to 50 millimolar;

the cellular energy source if selected, is selected from dextrose and glucose and is present at a concentration of from 1 to 25 millimolar; and

the free-radical scavenger, if selected, comprises glutathione at a concentration of from 0.05 to 5 millimolar.

14. The method of claim 1, wherein the liquid irrigation carrier further comprises electrolytes sufficient to provide a physiological balanced salt solution, a cellular energy source, a buffering agent and a free-radical scavenger.

15. The method of claim 14, wherein:

the electrolytes comprise from 50 to 500 millimolar sodium ions, from 0.1 to 50 millimolar potassium ions, from 0.1 to 5 millimolar calcium ions, from 0.1 to 5 millimolar magnesium ions, from 50 to 500 millimolar chloride ions, and from 0.1 to 10 millimolar phosphate;

the buffer comprises bicarbonate at a concentration of from 10 to 50 millimolar;

the cellular energy source is selected from dextrose and glucose and is present at a concentration of from 1 to 25 millimolar; and

the free-radical scavenger comprises glutathione at a concentration of from 0.05 to 5 millimolar.

16. The method of claim 1, wherein the pH of the irrigation solution is between 5.5 and 8.0.

17. The method of claim 1, wherein the first and second agents comprise one or more anti-inflammatory agents in combination with one or more analgesic agents, and optionally may also include one or more IOP reducing agents and/or mydriatic agents.

18. The method of claim 1, wherein the first and second agents comprise one or more anti-inflammatory agents in combination with one or more IOP reducing agents, and optionally one or more analgesic and/or mydriatic agents.

19. The method of claim 1, wherein the first and second agents comprise one or more anti-inflammatory agents in combination with one or more mydriatic agents, and optionally one or more analgesic agents and/or IOP reducing agents.

20. The method of claim 1, wherein the first and second agents comprise one or more analgesic agents in combination with one or more IOP reducing agents, and optionally one or more anti-inflammatory agents and/or mydriatic agents.

21. The method of claim 1, wherein the first and second agents comprise one or more analgesic agents in combination with one or more mydriatic agents, and optionally one or more anti-inflammatory agents and/or IOP reducing agents.

22. The method of claim 1, wherein the first and second agents comprise one or more mydriatic agents in combination with one or more IOP reducing agents, and optionally one or more anti-inflammatory and/or analgesic agents.

23. The solution of claim 1, wherein the solution comprises an NSAID, timolol and phenylephrine.

24. The solution of claim 1, wherein the solution comprises an NSAID, timolol and tropicamide.

25. The solution of claim 1, wherein the solution comprises oxymetazoline and an NSAID.

26. The solution of claim 1, wherein the solution comprises a steroid, an NSAID, timolol and phenylephrine.

27. The solution of claim 1, wherein the solution comprises timolol, an NSAID, tropicamide and a local anesthetic.

28. A method for perioperatively inhibiting inflammation, inhibiting pain, effecting mydriasis, and/or decreasing intraocular pressure during an ophthalmologic procedure;

comprising irrigating ocular tissues during an ophthalmologic procedure with a solution including at least first and second agents in a liquid irrigation carrier, the first and second agents being selected to act on a plurality of differing molecular targets, each agent being selected from the physiologic functional classes of anti-inflammatory agents, analgesic agents, mydriatic agents and agents for decreasing intraocular pressure (“

IOP reducing agents”

), the second agent providing at least one physiologic function different than a function or functions provided by the first agent, each agent being included at a concentration of no more than 100,000 nanomolar.

29. A perioperative irrigation solution for use during ophthalmologic procedures to inhibit inflammation, inhibit pain, effect mydriasis, and/or decrease intraocular pressure during the procedure, including at least first and second agents in a liquid irrigation carrier, the first and second agents being selected to act on a plurality of differing molecular targets, each agent being selected from the physiologic functional classes of anti-inflammatory agents, analgesic agents, mydriatic agents and agents for decreasing intraocular pressure (“

IOP reducing agents”

), the second agent providing at least one physiologic function different than a function or functions provided by the first agent, each agent being included at a concentration of no more than 100,000 nanomolar.

30. The solution of claim 29, wherein the solution comprises an anti-inflammatory agent selected from the group consisting of steroids, non-steroidal anti-inflammatory drugs (NSAIDS), anti-histamines, mast cell inhibitors, and inhibitors of inducible nitric oxide synthase (iNOS).

31. The solution of claim 30, wherein:

the steroid, if selected, is selected from the group consisting of dexamethasone, fluorometholone and prednisolone;

the NSAID, if selected, is selected from the group consisting of flurbiprofen, suprofen, diclofenac, ketoprofen and ketorolac;

the anti-histamine, if selected, is selected from the group consisting of levocabastine, emedastine, olopatadine, ketotifen, and azelastine;

the mast cell inhibitor, if selected, is selected from the group consisting of cromolyn sodium, Iodoxamide, nedocromil, ketotifen and azelastine; and

the inhibitor of iNOS, if selected, is selected from the group consisting of N^G-monomethyl-L-arginine, 1400 W, diphenyleneiodium, S-methyl isothiourea, S-(aminoethyl) isothiourea, L-N⁶-(1-iminoethyl)lysine, 1,3-PBITU and 2-ethyl-2-thiopseudourea.

32. The solution of claim 29, wherein the solution comprises an analgesic agent selected from the group consisting of local anesthetics and opioids.

33. The solution of claim 32, wherein:

the local anesthetic, if selected, is selected from the group consisting of lidocaine, tetracaine, bupivacaine, and proparacaine; and

the opioid, if selected, is selected from the group consisting of morphine, fentanyl and hydromorphone.

34. The solution of claim 29, wherein the solution comprises a mydriatic agent selected from the group consisting of alpha-1 adrenergic receptor agonists and anticholinergic agents.

35. The solution of claim 34, wherein:

the alpha-1 adrenergic receptor agonist, if selected, is selected from the group consisting of phenylephrine, epinephrine, and oxymetazoline; and

the anticholinergic agent, if selected, is selected from the group consisting of tropicamide, cyclopentolate, atropine and homatropine.

36. The solution of claim 29, wherein the solution comprises an IOP reducing agent selected from the group consisting of beta adrenergic receptor antagonists, carbonic anhydrase inhibitors, alpha-2 adrenergic receptor agonists, and prostaglandin agonists.

37. The solution of claim 36, wherein:

the beta adrenergic receptor antagonist, if selected, is selected from the group consisting of timolol, metipranolol and levobunolol;

the carbonic anhydrase inhibitor, if selected, is selected from the group consisting of brinzolamide and dorzolamide;

the alpha-2 adrenergic receptor agonist, if selected, is selected from the group consisting of apraclonidine, brimonidine and oxymetazoline; and

the prostaglandin agonist, if selected, is selected from the group consisting of latanoprost, travoprost and bimatoprost.

38. The solution of claim 29, wherein each of the first and second agents in the solution is included at a concentration of no more than 10,000 nanomolar.

39. The solution of claim 29, wherein the liquid irrigation carrier further comprises an adjuvant selected from electrolytes sufficient to provide a physiological balanced salt solution, a cellular energy source, a buffering agent, a free-radical scavenger and mixtures thereof.

40. The solution of claim 39, wherein:

the electrolytes, if selected, comprise from 50 to 500 millimolar sodium ions, from 0.1 to 50 millimolar potassium ions, from 0.1 to 5 millimolar calcium ions, from 0.1 to 5 millimolar magnesium ions, from 50 to 500 millimolar chloride ions, and from 0.1 to 10 millimolar phosphate;

the buffer, if selected, comprises bicarbonate at a concentration of from 10 to 50 millimolar;

the cellular energy source, if selected, is selected from dextrose and glucose and is present at a concentration of from 1 to 25 millimolar; and

the free-radical scavenger, if selected, comprises glutathione at a concentration of from 0.05 to 5 millimolar.

41. The solution of claim 29, wherein the liquid irrigation carrier further comprises electrolytes sufficient to provide a physiological balanced salt solution, a cellular energy source, a buffering agent and a free-radical scavenger.

42. The solution of claim 41, wherein:

the electrolytes comprise from 50 to 500 millimolar sodium ions, from 0.1 to 50 millimolar potassium ions, from 0.1 to 5 millimolar calcium ions, from 0.1 to 5 millimolar magnesium ions, from 50 to 500 millimolar chloride ions, and from 0.1 to 10 millimolar phosphate;

the buffer comprises bicarbonate at a concentration of from 10 to 50 millimolar;

the cellular energy source is selected from dextrose and glucose and is present at a concentration of from 1 to 25 millimolar; and

the free-radical scavenger comprises glutathione at a concentration of from 0.05 to 5 millimolar.

43. The solution of claim 29, wherein the pH of the irrigation solution is between 5.5 and 8.0.

44. The solution of claim 29, wherein the first and second agents comprise one or more anti-inflammatory agents in combination with one or more analgesic agents, and optionally may also include one or more IOP reducing agents and/or mydriatic agents.

45. The solution of claim 29, wherein the first and second agents comprise one or more anti-inflammatory agents in combination with one or more IOP reducing agents, and optionally one or more analgesic and/or mydriatic agents.

46. The solution of claim 29, wherein the first and second agents comprise one or more anti-inflammatory agents in combination with one or more mydriatic agents, and optionally one or more analgesic agents and/or IOP reducing agents.

47. The solution of claim 29, wherein the first and second agents comprise one or more analgesic agents in combination with one or more IOP reducing agents, and optionally one or more anti-inflammatory agents and/or mydriatic agents.

48. The solution of claim 29, wherein the first and second agents comprise one or more analgesic agents in combination with one or more mydriatic agents, and optionally one or more anti-inflammatory agents and/or IOP reducing agents.

49. The solution of claim 29, wherein the first and second agents comprise one or more mydriatic agents in combination with one or more IOP reducing agents, and optionally one or more anti-inflammatory and/or analgesic agents.

50. The solution of claim 29, wherein the solution comprises an NSAID, timolol and phenylephrine.

51. The solution of claim 29, wherein the solution comprises an NSAID, timolol and tropicamide.

52. The solution of claim 29, wherein the solution comprises oxymetazoline and an NSAID.

53. The solution of claim 29, wherein the solution comprises a steroid, an NSAID, timolol and phenylephrine.

54. The solution of claim 29, wherein the solution comprises timolol, an NSAID, tropicamide and a local anesthetic.