Ophthalmic preparations

• US 20080299206A1
• Filed: 01/16/2008
• Published: 12/04/2008
• Est. Priority Date: 03/07/2006
• Status: Active Grant

• Current Assignee: SGN Nanopharma Incorporated
• Original Assignee: Novavax Inc.
• Inventors: Lee, Robert, Shenoy, Dinesh
• Granted Patent: US 10,137,083 B2
• Time in Patent Office: Days
• US Class Current: 424/489
• CPC Class Codes: A61K 38/13 Cyclosporins
• 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 47/186 Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• 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
• CPC Class Codes: A61P 27/02 Ophthalmic agents

Abstract

The present invention provides ophthalmic formulations containing cyclosporine, methods for preparing the formulation, and methods for using the formulation.

Claims

1. An ophthalmic formulation comprising:

(a) cyclosporine or a derivative thereof,

(b) at least one solvent,

(c) at least one oil,

(d) at least one surfactant,

(e) at least one preservative, and

(f) water or buffer.

2. The opthalmic formulation of claim 1, wherein the cyclosporine is cyclosporine A.

3. The ophthalmic formulation of claim 1, wherein cyclosporine or a derivative thereof is in a solid particulate state and in a soluble state.

4. The ophthalmic formulation of claim 3, wherein the formulation is a mixture of particles of cyclosporine or a derivative thereof suspended in emulsion droplets and sterically stabilized particulate cyclosporine or a derivative thereof in the water or buffer.

5. The ophthalmic formulation of claim 1, wherein the formulation comprises globules of oil comprising dissolved cyclosporine or a derivative thereof, wherein the globules have a diameter of less than about 10 microns.

6. The ophthalmic formulation of claim 5, wherein the globules have a diameter selected from the group consisting of less than about 9 microns, less than about 8 microns, less than about 7 microns, less than about 6 microns, less than about 5 microns, less than about 4 microns, less than about 3 microns, less than about 2 microns, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 290 nm, less than about 280 nm, less than about 270 nm, less than about 260 nm, less than about 250 nm, less than about 240 nm, less than about 230 nm, less than about 220 nm, less than about 210 nm, less than about 200 nm, less than about 190 nm, less than about 180 nm, less than about 170 nm, less than about 160 nm, less than about 150 nm, less than about 140 nm, less than about 130 nm, less than about 120 nm, less than about 110 nm, less than about 100 nm, less than about 90 nm, less than about 80 nm, less than about 70 nm, less than about 60 nm, less than about 50 nm, less than about 40 nm, less than about 30 nm, less than about 20 nm, or less than about 10 nm.

7. The formulation of claim 1, wherein the oil is selected from the group consisting of sweet almond oil, apricot seed, oil, borage oil, canola oil, coconut oil, corn oil, cotton seed oil, fish oil, jojoba bean oil, lard oil, boiled linseed oil, Macadamia nut oil, medium chain triglycerides (Crodamol GTCC), mineral oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, squalene, sunflower seed oil, tricaprylin (1,2,3-trioctanoyl glycerol), and wheat germ oil.

8. The formulation of claim 1, wherein the solvent is selected from the group consisting of isopropyl myristate, triacetin, N-methylpyrrolidinone, aliphatic and aromatic alcohols, ethanol, dimethyl sulfoxide, dimethyl acetamide, ethoxydiglycol, polyethylene glycols, and propylene glycol.

9. The formulation of claim 1, wherein the surfactant is selected from the group consisting of sorbitan esters, glycerol esters, polyethylene glycol esters, block polymers, acrylic polymers, ethoxylated fatty esters, ethoxylated alcohols, ethoxylated fatty acids, monoglycerides, silicon based surfactants, and polysorbates.

10. The formulation of claim 9, wherein the surfactant is Polysorbate 80.

11. The formulation of claim 9, wherein the sorbitan ester surfactant is Span or Arlacel, wherein the glycerol ester is glycerin monostearate, wherein the polyethylene glycol ester is polyethylene glycol stearate, wherein the block polymer is a Pluronic, wherein the acrylic polymer is Pemulen, wherein the ethoxylated fatty ester is Cremophor RH-40, wherein the ethoxylated alcohol is Brij, and wherein the ethoxylated fatty acid is Tween 20.

12. The formulation of claim 1, wherein formulation is cationic.

13. The formulation of claim 1, wherein the preservative is cationic.

14. The formulation of claim 1, wherein the preservative is a quaternary ammonium compound.

15. The formulation of claim 1, wherein the preservative is selected from the group consisting of cetyltrimethylammonium bromide, cetylpyridinium chloride, benzethonium chloride, and benzalkonium chloride.

16. The formulation of claim 1, wherein the preservative is benzalkonium chloride.

17. The formulation of claim 1, further comprising a viscosity modifier.

18. The formulation of claim 17, wherein the viscosity modifier is selected from the group consisting of a cellulose derivative, a polysaccharide and a synthetic polymer.

20. A method of treating a subject in need comprising administering the formulation of claim 1 or claim 19 to the eye of a subject.

21. The method according to claim 20, wherein the subject suffers from a condition selected from the group consisting of an aqueous deficient dry-eye state, phacoanaphylaxis endophthalmitis, and uveitis.

19. An ophthalmic formulation comprising:

(a) cyclosporine A,

(b) ethanol,

(c) medium chain triglycerides,

(d) Polysorbate 80,

(e) benzalkonium chloride, and

(f) phosphate buffer.

22. A method for preparing particles of cyclosporine or a derivative thereof, comprising:

(a) forming an emulsion base by suspending cyclosporine or a derivative thereof in a mixture of oil, solvent, surfactant, preservative, and water or buffer to form an emulsion base, and

(b) homogenizing the emulsion base to form particles of cyclosporine or a derivative thereof, droplets comprising solubilized cyclosporine or a derivative thereof, or a combination thereof.

23. The method of claim 22, wherein the homogenizing step is performed via a high-pressure system at 1,000 to 40,000 psi.

24. The method of claim 22, wherein the cyclosporine or a derivative thereof, droplets have an average or mean particle size selected from the group consisting of less than about 10 microns, less than about 9 microns, less than about 8 microns, less than about 7 microns, less than about 6 microns, less than about 5 microns, less than about 4 microns, less than about 3 microns, less than about 2 microns, and about 1 micron or greater.

25. The method of claim 22, wherein the cyclosporine or derivative thereof, droplets have a mean particle size selected from the group consisting of less than about 1 micron, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 290 nm, less than about 280 nm, less than about 270 nm, less than about 260 nm, less than about 250 nm, less than about 240 nm, less than about 230 nm, less than about 220 nm, less than about 210 nm, less than about 200 nm, less than about 190 nm, less than about 180 nm, less than about 170 nm, less than about 160 nm, less than about 150 nm, less than about 140 nm, less than about 130 nm, less than about 120 nm, less than about 110 nm, less than about 100 nm, less than about 90 nm, less than about 80 nm, less than about 70 nm, less than about 60 nm, less than about 50 nm, less than about 40 nm, less than about 30 nm, less than about 20 nm, or less than about 10 nm.

26. The method of claim 22, wherein the emulsion base of step (a) further comprises a viscosity modifier.

27. The method of claim 26, wherein the viscosity modifier is selected from the group consisting of a cellulose derivative, a polysaccharide and a synthetic polymer.

28. A method for preparing particles of cyclosporine or a derivative thereof, comprising:

(a) dissolving cyclosporine or a derivative thereof in a mixture of (i) at least one oil, (ii) at least one solvent, and (iii) at least one surfactant to form an emulsion pre-mix,

(b) adding at least one preservative, and water or buffer to the emulsion pre-mix, and

(c) homogenizing or vigorously stirring the mixture of step (b), whereby cyclosporine A or a derivative thereof is precipitated into particles.

29. The method of claim 28, wherein the homogenizing step is performed via a high-pressure system at 1,000 to 40,000 psi.

30. The method of claim 28, wherein the cyclosporine or a derivative thereof, droplets have an average or mean particle size selected from the group consisting of less than about 10 microns, less than about 9 microns, less than about 8 microns, less than about 7 microns, less than about 6 microns, less than about 5 microns, less than about 4 microns, less than about 3 microns, less than about 2 microns, and about 1 micron or greater.

31. The method of claim 28, wherein the cyclosporine A or derivative thereof, droplets have a mean particle size selected from the group consisting of less than about 1 micron, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 290 nm, less than about 280 nm, less than about 270 nm, less than about 260 nm, less than about 250 nm, less than about 240 nm, less than about 230 nm, less than about 220 nm, less than about 210 nm, less than about 200 nm, less than about 190 nm, less than about 180 nm, less than about 170 nm, less than about 160 nm, less than about 150 mm, less than about 140 nm, less than about 130 nm, less than about 120 nm, less than about 110 nm, less than about 100 nm, less than about 90 nm, less than about 80 nm, less than about 70 nm, less than about 60 nm, less than about 50 nm, less than about 40 nm, less than about 30 nm, less than about 20 nm, or less than about 10 nm.

32. The method of claim 28, wherein the mixture of step (a) or the mixture of step (b) further comprises a viscosity modifier.

33. The method of claim 32, wherein the viscosity modifier is selected from the group consisting of a cellulose derivative, a polysaccharide and a synthetic polymer.

34. A method for preparing particles of cyclosporine or a derivative thereof, comprising:

(a) dissolving cyclosporine or a derivative thereof in ethanol to form a solution,

(b) adding Polysorbate 80 and medium chain triglyceride to the solution of step (a),

(c) adding benzalkonium chloride dissolved in water to the solution of (b), and

(d) subjecting the solution of (c) to high-pressure homogenization to produce particles of cyclosporine or a derivative thereof.