Drug delivery system for controlled ocular therapy

• US 4,281,654 A
• Filed: 04/07/1980
• Issued: 08/04/1981
• Est. Priority Date: 04/07/1980
• Status: Expired due to Term

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Shell, John W., Gale, Robert M.
• Primary Examiner(s): ROSENBAUM, C FRED
• Application Number:
  US06/138,150
• Time in Patent Office: 484 Days
• Field of Search: 128/260, 128/268, 128/127, 128/130, 424/19, 424/22
• US Class Current: 424/427
• CPC Class Codes: A61F 9/0017 implantable in, or in contact with, the eye, e.g. ocular inserts
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants

Abstract

A drug delivery system is disclosed useful for controlled ocular therapy. The system is manufactured as an ocular insert, and it comprises a beta-adrenergic blocking osmotic solute and a parasympathomimetic osmotic solute dispersed in a polymer with the solutes surrounded by the polymer. The system, when placed in the eye, delivers both drugs at a controlled rate over time. A method also is disclosed for the management of intraocular pressure using the ocular system.

Claims

1. An ocular therapeutic system for dispensing medications to an eye, said system sized, shaped and adapted for easy insertion and comfortable retention in the eye and comprising depots of 1 to 40 weight percent of a therapeutically acceptable beta-adrenergic solute that lowers intraocular pressure by decreasing aqueous humor formation, and 1 to 40 weight percent of a therapeutically acceptable parasympathomimetic solute that lowers intraocular pressure by increasing the outflow of aqueous humor, said depots dispersed in and surrounded substantially individually by a polymer that is essentially impermeable to the passage of the solutes and is permeable to the passage of an exterior fluid.

2. An ocular therapeutic system useful for the management of ocular pressure, said system shaped, sized and structured for easy insertion and prolonged comfortable retention in the eye and comprising depots of medication consisting essentially of from 1 to 40 weight percent of a beta-adrenergic blocking therapeutically acceptable salt particles of 0.1 to 100 micron size and 1 to 40 weight percent of a parasympathomimetic therapeutically acceptable salt particles of 0.1 to 100 micron size, said depots dispersed in and surrounded substantially by an inert therapeutically acceptable polymer that is impermeable to the passage of the therapeutically acceptable salts and permeable to the passage of eye fluid.

3. The ocular therapeutic system useful for the management of ocular pressure according to claim 2 wherein the therapeutically acceptable salts are selected from the group consisting of inorganic salts, organic salts and quaternary addition salts.

4. The ocular therapeutic system useful for the management of ocular pressure according to claim 2 wherein the therapeutically acceptable salt is a member selected from the group consisting essentially of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, sulfamate, phosphate, maleate acetate, bitartrate, citrate, oxalate, succinate, benzoate, tartrate, fumarate, malate, pamoate, and mandelate.

5. The ocular therapeutic system useful for the management of ocular pressure according to claim 2 wherein the system is manufactured as an insert for easy insertion and prolonged retention in a human eye for dispensing medications to the eye in a therapeutically effective amount for managing ocular pressure, and the depots comprise 5 to 60 percent by weight of the insert.

6. The ocular therapeutic system useful for the management of ocular pressure according to claim 2 wherein the beta-adrenergic blocking drug is a member selected from the group consisting of acebutolol, alprenolol, atenolol, bevantol, bucumolol, bupranolol, bufuralol, bunitrolol, butidrine, butoxamine, carteolol, exaprolol, indenolol, labeltalol, metoprolol, mepindol, moprolol, nadolol, nifenalol, oxprenolol, prolol, mepindolol, moprolol, pamatolol, penbutolol, pargolol, pindolol, procinolol, practolol, satalol, tazolol, timolol, tiprenolol, tolamolol, and toliprolol.

7. The ocular therapeutic system useful for the management of ocular pressure according to claim 2 wherein the parasympathominetic drug is pilocarpine.

8. The ocular therapeutic system useful for the management of ocular pressure according to claim 2 wherein the therapeutically polymer is a member selected from the group consisting essentially of ethylene-vinyl acetate copolymer, ethylene-vinyl hexanoate copolymer, ethylene-vinyl propronate copolymer, ethylene-vinyl butyrate copolymer, ethylene-vinyl pentanoate copolymer, ethylene-vinyl trimethyl acetate copolymer, ethylene-vinyl diethyl acetate copolymer, ethylene-vinyl 3-methyl butanoate copolymer, ethylene-vinyl 3-3-dimethyl butanoate copolymer, and ethylene-vinyl benzoate copolymer.

9. An ocular insert consisting essentially of (a) discrete depots comprising a beta-adrenergic blocking osmotically effective solute and a parasympathomimetic osmotically effective solute, which solutes have a size of 0.1 to 100 microns and exhibit an osmotic pressure gradient across the wall of the depot against an external fluid present in the environment of use;

(b) a film of an ethylene-vinyl ester copolymer forming the insert, imparting size and shape to the insert for easy insertion and prolonged retention in the environment of use, said film substantially impermeable to the passage of the solutes, permeable to the passage of the external fluid and substantially surrounding individually and serving as the wall of the depots; and

(c) wherein, when the insert is positioned in the environment of use, fluid from the environment is imbibed through the wall into the depots to continuously dissolve the solutes and generate a hydrostatic pressure in the depots which pressure is applied against the wall of the depots thereby forming apertures and releasing the formulation from the depots at the surface and from within the insert by the inward progressive aperture formation in depots at a controlled rate over release over a prolonged period of time.

10. A method for treating glaucoma in a warm-blooded animal, which consists essentially in lowering the intraocular pressure associated with glaucoma by administering to the eye of the animal a drug formulation, the method consisting essentially in the steps of:

(a) positioning in the eye an ocular insert, said insert consisting essentially of;

(1) depots of a drug formulation consisting of a beta-adrenergic blocking osmotic solute that can lower intraocular pressure, and a parasympathomimetic osmotic solute that can lower intraocular pressure, which solutes exhibit osmotic pressure gradients across the wall of the depots against an external fluid, said depots dispersed in;

(2) a film sized and shaped as an insert for easy positioning and retention in the eye of the animal, said film a polymeric material that surrounds individually and forms the wall of the discrete depots, is non-toxic nonerodible, impermeable to the passage of solutes and permeable to the passage of fluid;

(b) imbibing fluid from the eye into the depots to dissolve the solutes and fill the depots with solution, thereby exerting pressure against the wall of the depots and forming apertures that release drug formulation from the depots at the surface and from the interior of the insert through formulation dispensing paths made by the inward progressive aperture formation in related depots;

thereby,

(c) administering the beta-adrenergic drug and the parasympathomimetic drug to the eye at a controlled rate for treating glaucoma over a prolonged period of time.

11. The method for treating glaucoma in a warm-blooded animal according to claim 10, wherein the glaucoma is wide-angleglaucoma, the polymeric material is ethylene-vinyl acetate copolymer and the animal is a human.

12. The method for treating glaucoma in a warm-blooded animal according to claim 10, wherein the glaucoma is secondary glaucoma, the polymeric material is ethylene-vinyl acetate copolymer, and the animal is a human.

13. The method for treating glaucoma in a warm-blooded animal according to claim 10, wherein the insert administers simultaneously from 0.5 to 125 micrograms per hour of timolol and from 1 to 100 micrograms per hour of pilocarpine.

14. The method for treating glaucoma in a warm-blooded animal according to claim 10, wherein the insert administers simultaneously from 0.5 to 125 micrograms of metoprolol and from 1 to 100 micrograms per hour of pilocarpine for treating the glaucoma.

15. A composition of matter useful for manufacturing a drug delivery device, said composition comprising from 1 to 40 weight percent of a beta-adrenergic blocking solute and from 1 to 40 weight percent of a parasympathomimetic solute with the remaining weight percent ethylene-vinyl ester copolymer.

16. The composition of matter useful for manufacturing a drug delivery device according to claim 15 wherein said copolymer is ethylene-vinyl acetate copolymer.

17. The composition of matter useful for manufacturing a drug delivery device according to claim 15 wherein said parasympathomimetic solute is pilocarpine therapeutically acceptable acid addition salt.

18. The composition of matter useful for manufacturing a drug delivery device according to claim 15 wherein said parasympathomimetic solute is a member selected from the group consisting essentially of pilocarpine hydrochloride, pilocarpine nitrate, and pilocarpine sulfate.

19. The composition of matter useful for manufacturing a drug delivery device according to claim 15 wherein the beta-adrenergic blocking solute is the therapeutically acceptable salt.

20. The composition of matter useful for manufacturing a drug delivery device according to claim 15 wherein the beta-adrenergic blocking solute is a member selected from the group consisting essentially of metoprolol therapeutically acceptable acid addition salt, oxprenolol therapeutically acceptable acid addition salt, and timolol therapeutically acceptable acid addition salt.

21. The composition of matter useful for manufacturing a drug delivery device according to claim 15 wherein the beta-adrenergic blocking solute is a member selected from the group consisting of metoprolol fumarate, metoprolol tartrate, and metoprolol bitartrate.

22. The composition of matter useful for manufacturing a drug delivery device according to claim 15 wherein the beta-adrenergic blocking solute is metoprolol fumarate and the parasympathomimetic solute is pilocarpine nitrate.

23. The composition of matter useful for manufacturing a drug delivery device according to claim 15 wherein the beta-adrenergic blocking solute is timolol maleate.