Submicron emulsions as ocular drug delivery vehicles

• US 5,496,811 A
• Filed: 01/05/1993
• Issued: 03/05/1996
• Est. Priority Date: 08/28/1992
• Status: Expired due to Fees

• Current Assignee: Pharmos Corporation
• Original Assignee: Pharmos Corporation
• Inventors: Bar-Ilan, Amir, Vered, Micha, Friedman, Doron, Aviv, Haim
• Primary Examiner(s): FAY, ZOHREH A
• Application Number:
  US08/000,854
• Time in Patent Office: 1,155 Days
• Field of Search: 514/76, 514/75, 514/78, 514/912, 514/546, 514/547, 514/560
• US Class Current: 514/78
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence

Abstract

An ocular drug delivery vehicle of an oil-in-water submicron emulsion comprising about 0.5 to 50% of a first component of an oil, about 0.1 to 10% of a second component of an emulsifier, about 0.05 to 5% of a non-ionic surfactant and an aqueous component, with the mean droplet size being in the submicron range, i.e., below about 0.5 μm and preferably between about 0.1 and 0.3 μm. Also, topical pharmaceutical compositions containing a drug such as an anti-glaucoma drug, beta adrenergic blocker or other autonomic system drug, a local anesthetic, a steroid, a non-steroidal anti-inflammatory drug, an antibiotic drug, an antifungal drug, an antiviral drug or combinations thereof and the vehicle described above. Methods of administering such vehicles or compositions to the eye of a patient while reducing irritation thereof and providing increased bioavailability of the drug.

Claims

1. An ocular drug delivery vehicle of an oil-in-water submicron emulsion consisting essentially of about 0.5 to 50% of a first component of an oil, about 0.1 to 10% of a second component of an emulsifier, comprising a phospholipid, about 0.05 to 5% of a non-ionic surfactant and an aqueous component, said submicron emulsion having a mean droplet size in the range of 0.05 to 0.5 μ

m, and a weight ratio of surfactant to oil of about 1;

1 or less.

2. The vehicle of claim 1 wherein the mean droplet size is between about 0.1 and 0.3 μ

m.

3. The vehicle of claim 1 wherein the first component is a medium chain triglyceride oil, a vegetable oil, a mineral oil or mixtures thereof.

4. The vehicle of claim 3 wherein the first component is present in an amount of about 1 to 20%.

5. The vehicle of claim 3 wherein the first component is present in an amount of about 30 to 50% to form a viscous composition.

6. The vehicle of claim 1 wherein the phospholipid is lecithin, phosphatidylcholine, phosphatidylethanolamine or mixtures thereof.

7. The vehicle of claim 1 wherein the emulsifier is present in an amount of about 0.2 to 5%.

8. The vehicle of claim 1 wherein the surfactant is a non-ionic alkylene oxide condensate of an organic compound which contains one or more hydroxyl groups.

9. The vehicle of claim 8 wherein the surfactant is an ethoxylated alcohol or ester compound.

10. The vehicle of claim 9 wherein the non-ionic surfactant is present in an amount of about 0.2 to 5%.

11. The vehicle of claim 1 wherein the first component is present in an amount of about 1 to 20%, and the second component and the ionic surfactant are each present in an amount of about 0.2 to 1% so that the weight ratio of surfactant to oil is about 1:

1 to about 1;

100.

23. A method for reducing eye irritation induced by the administration of a drug, which comprises administering said drug to the eye together with the ocular drug delivery vehicle of claim 1.

24. The method of claim 23 which further comprises selecting the emulsion to have droplets of a mean diameter of between about 0.1 and 0.3 μ

m.

25. A method for reducing eye irritation which comprises administering to an irritated eye an effective amount of the ocular drug delivery vehicle of claim 1.

26. The method of claim 25 which further comprises selecting the emulsion to have droplets of a mean diameter of between about 0.1 and 0.3 μ

m.

29. A method for administering increased amount of a drug to the eye without causing irritation thereof, which comprises administering said increased amount of said drug to the eye with the ocular drug delivery vehicle of claim 1.

30. The method of claim 29 which further comprises selecting the emulsion to have droplets of a mean diameter of between about 0.1 and 0.3 μ

m.

35. A method for providing increased bioavailability of an ophthalmic drug which comprises administering said drug to the eye with the ocular drug delivery vehicle of claim 1.

36. The method of claim 35 which further comprises selecting the emulsion to have droplets of a mean diameter of between about 0.1 and 0.3 μ

m.

12. A topical ophthalmic composition comprising an effective amount of an ophthalmic drug and an ocular drug delivery vehicle consisting essentially of about 0.5 to 50% of a first component of an oil, about 0.1 to 10% of a second component of an emulsifier, comprising a phospholipid, about 0.05 to 5% of a non-ionic surfactant and an aqueous component, said submicron emulsion having a mean droplet size in the range of 0.05 to 0.5 μ

m, and a weight ratio of surfactant to oil of about 1;

1 or less.

13. The composition of claim 12 wherein the drug is an anti-glaucoma drug, beta adrenergic blocker or other autonomic system drug, a local anesthetic, asteroid, a non-steroidal anti-inflammatory drug, an antibiotic drug, an antifungal drug, an antiviral drug or combinations thereof.

14. The composition of claim 12 wherein the drug is hydrophilic or amphiphilic.

15. The composition of claim 13 wherein the drug is pilocarpine or timolol.

16. The composition of claim 12 wherein the drug is hydrophobic.

17. The composition of claim 16 wherein the drug is indomethacin, betaxolol or adaprolol.

18. The composition of claim 12 wherein the drug is present in an amount of about 0.05 to 5% by weight.

19. The composition of claim 12 further comprising a preservative, an antioxidant or an osmotic agent.

20. The composition of claim 12 further comprising an effective amount of an additional drug.

21. The composition of claim 20 wherein the additional drug is a β

-adrenergic blocker, a cannabinoid, a cholinesterase inhibitor, a sympathomimetic or a carbonic anhydrase inhibitor.

22. The composition of claim 15 wherein the ophthalmic drug includes an effective amount of the combination of a first ophthalmic drug and a second drug which decreases intraocular pressure when administered to the eye of a patient.

27. A method for administering a topical ophthalmic composition of a drug having a therapeutic effect on the eye, which comprises formulating the topical ophthalmic composition of claim 12 and administering an effective amount of such composition to the eye of a patient.

28. The method of claim 27 which further comprises selecting the emulsion to have droplets of a mean diameter of between about 0.1 and 0.3 μ

m.

31. A method for administering increased amount of a drug to the eye without causing irritation thereof, which comprises administering said increased amount of said drug to the eye in the composition of claim 12.

32. The method of claim 31 which further comprises selecting the emulsion to have droplets of a mean diameter of between about 0.1 and 0.3 μ

m.

33. A method for providing increased bioavailability of an ophthalmic drug which comprises administering said drug to the eye in the composition of claim 12.

34. The method of claim 33 which further comprises selecting the emulsion to have droplets of a mean diameter of between about 0.1 and 0.3 μ

m.

37. The method of claim 28 wherein the drug is pilocarpine or timolol.