Topical drug delivery systems for ophthalmic use

• US 9,017,725 B2
• Filed: 05/05/2010
• Issued: 04/28/2015
• Est. Priority Date: 06/09/2009
• Status: Active Grant

• Current Assignee: Aurinia Pharmaceuticals Inc.
• Original Assignee: Aurinia Pharmaceuticals Inc.
• Inventors: Mitra, Ashim K., Velagaleti, Poonam R., Grau, Ulrich M.
• Primary Examiner(s): Huang, Gigi
• Application Number:
  US12/774,600
• Publication Number:
  US 20100310642A1
• Time in Patent Office: 1,819 Days
• Field of Search: 424/489
• US Class Current: 424/489
• CPC Class Codes: A61K 31/14 Quaternary ammonium compounds, e.g. edrophonium, choline betaines A61K31/205
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• 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 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/107 Emulsions ; Emulsion preconcentrates; Micelles composition of emulsions A61K47/00
• 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

Topical drug delivery systems for ophthalmic use including mixed nanomicellar formulations of water-insoluble drugs and methods of treating diseases affecting the posterior ocular segments are disclosed. In an embodiment, an aqueous ophthalmic solution includes nanomicelles in a physiologically acceptable buffer, having a pH of 5.0 to 8.0, wherein a corticosteroid at a concentration from about 0.01% w/v to about 1.00% w/v is solubilized through entrapment in a mixed micellar hydrophobic core with a corona composed of hydrophilic chains extending from the hydrophobic core, wherein the nanomicelles comprise vitamin E TPGS at a concentration ranging from about 3.0% w/v to about 5.0% w/v stabilized with octoxynol-40 at a concentration ranging from about 1.0% w/v to about 3.0% w/v.

Claims

1. An aqueous ophthalmic solution comprising nanomicelles in a physiologically acceptable buffer, having a pH of 5.0 to 8.0, wherein the nanomicelles consist essentially of dexamethasone, vitamin E TPGS and octoxynol-40, wherein the dexamethasone at a concentration ranging from about 0.01% w/v to about 1.00% w/v is solubilized through entrapment in a mixed micellar hydrophobic core with a corona composed of hydrophilic chains extending from the hydrophobic core, wherein the vitamin E TPGS at a concentration ranging from about 2.0% w/v to about 5.0% w/v is stabilized with the octoxynol-40 at a concentration ranging from about 1.0% w/v to about 3.0% w/v, wherein the aqueous ophthalmic solution is stable after about 40 days at about 4°

C.

2. The aqueous ophthalmic solution of claim 1 wherein the concentration of the dexamethasone is from about 0.05% w/v to about 0.25% w/v.

3. The aqueous ophthalmic solution of claim 1 wherein the pH is in a range from about 6.6 to about 7.0.

4. The aqueous ophthalmic solution of claim 1 wherein the concentration of the vitamin E TPGS is from about 4.0% w/v to about 5.0% w/v.

5. The aqueous ophthalmic solution of claim 1 wherein the concentration of the octoxynol-40 is from about 1.5% w/v to about 2.5% w/v.

6. An eye drop formulation comprising nanomicelles in a physiologically acceptable buffer, wherein the nanomicelles consist essentially of:

dexamethasone at a concentration ranging from about 0.01% w/v to about 1.00% w/v;

vitamin E TPGS at a concentration ranging from about 2.0% w/v to about 5.0% w/v; and

octoxynol-40 at a concentration ranging from about 1.0% w/v to about 3.0% w/v,

wherein the dexamethasone is solubilized through entrapment in a mixed micellar hydrophobic core of the vitamin E TPGS and the octoxynol-40, wherein the aqueous ophthalmic solution is stable after about 40 days at about 4°

C.

7. The eye drop formulation of claim 6 wherein the concentration of the dexamethasone is from about 0.05% w/v to about 0.25% w/v.

8. The eye drop formulation of claim 6 wherein the concentration of the vitamin E TPGS is from about 4.0% w/v to about 5.0% w/v.

9. The eye drop formulation of claim 6 wherein the concentration of the octoxynol-40 is from about 1.5% w/v to about 2.5% w/v.

10. The eye drop formulation of claim 6 wherein the dexamethasone is present in the formulation at a concentration of about 0.1 wt % w/v, the vitamin E TPGS is present in the formulation at a concentration of about 4.5% w/v, and the octoxynol-40 is present in the formulation at a concentration of about 2.0% w/v.

11. A kit comprising:

a unit dose of an aqueous ophthalmic solution comprising nanomicelles in a physiologically acceptable buffer, having a pH of 5.0 to 8.0, wherein the nanomicelles consist essentially of dexamethasone, vitamin E TPGS and octoxynol-40, wherein the dexamethasone at a concentration ranging from about 0.01% w/v to about 1.00% w/v is solubilized through entrapment in a mixed micellar hydrophobic core with a corona composed of hydrophilic chains extending from the hydrophobic core, wherein the vitamin E TPGS at a concentration ranging from about 2.0% w/v to about 5.0% w/v is stabilized with the octoxynol-40 at a concentration ranging from about 1.0% w/v to about 3.0% w/v, wherein the unit dose in contained within a vial prepared from a pharmaceutically acceptable packaging material, wherein the aqueous ophthalmic solution is stable after about 40 days at about 4°

C.

12. The kit of claim 11 wherein the unit dose is about 50 μ

L.

13. The kit of claim 11 wherein the dexamethasone is present in the formulation at a concentration of about 0.1 wt % w/v, the vitamin E TPGS is present in the formulation at a concentration of about 4.5% w/v, and the octoxynol-40 is present in the formulation at a concentration of about 2.0% w/v.

14. The kit of claim 11 wherein the pharmaceutically acceptable packaging material is low density polyethylene or high density polyethylene.

15. A method of treating a back-of-the-eye ocular condition with dexamethasone in a patient in need thereof comprising:

administering to an eye of a patient an effective amount of an aqueous ophthalmic solution comprising nanomicelles in a physiologically acceptable buffer, having a pH of 5.0 to 8.0, wherein the nanomicelles consist essentially of dexamethasone, vitamin E TPGS and octoxynol-40, wherein the dexamethasone at a concentration ranging from about 0.01% w/v to about 1.00% w/v is solubilized through entrapment in a mixed micellar hydrophobic core with a corona composed of hydrophilic chains extending from the hydrophobic core, wherein the vitamin E TPGS at a concentration ranging from about 2.0% w/v to about 5.0% w/v is stabilized with the octoxynol-40 at a concentration ranging from about 1.0% w/v to about 3.0% w/v, wherein the aqueous ophthalmic solution is stable after about 40 days at about 4°

C.

16. The method of claim 15 wherein the dexamethasone is present in the solution at a concentration of about 0.1 wt % w/v, the vitamin E TPGS is present in the solution at a concentration of about 4.5% w/v, and the octoxynol-40 is present in the solution at a concentration of about 2.0% w/v.