Liquid ophthalmic sustained release delivery system

• US 5,422,116 A
• Filed: 02/18/1994
• Issued: 06/06/1995
• Est. Priority Date: 02/18/1994
• Status: Expired due to Term

• Current Assignee: Novartis Corporation (Novartis Ag)
• Original Assignee: Ciba-Geigy Corporation (Novartis Ag)
• Inventors: Yen, Shau-Fong, Reed, Kenneth W.
• Primary Examiner(s): Nutter, Nathan M.
• Application Number:
  US08/198,924
• Time in Patent Office: 473 Days
• Field of Search: 424/427, 424/428, 424/484, 424/485, 424/488, 514/777, 514/912, 514/913, 514/914, 514/915, 514/950, 514/954, 514/955, 514/964
• US Class Current: 424/427
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61P 27/02 Ophthalmic agents

Abstract

Disclosed is a sustained release liquid aqueous ophthalmic delivery system and a method of providing a slow and sustained release of ophthalmic treating agents to the eye of a mammal which comprises administering to the eye of a said mammal an effective amount of a homogeneous liquid aqueous ophthalmic pharmaceutical composition, of pH between about 3.0 and about 6.2, which is adminstrable in drop form and which comprises an ophthalmically effective concentration of a said ophthalmic treating agent and about 0.05% to about 10% by weight of the polymer chitosan; said polymer consisting essentially of

(A) monomeric β(1→4)-D-glucosamine linked units and of

(B) monomeric β(1→4)-D-glucosamine linked units which are scattered

randomly in the molecule of the polymer, the numerical proportions of A and B being from about 60 to about 99% of A and about 1 to about 40% of B, the viscosity rating being from about 3 to about 3000 cps; in which method, upon contact with the higher pH of the ocular fluid, said liquid formulation is converted to a stiff gel from which the ophthalmic treating agent is slowly released over a prolonged period of time.

Claims

1. A method of providing a slow and sustained release of an ophthalmic treating agent to the eye of a mammal which comprises administering to the eye of a said mammal an effective amount of a homogeneous liquid aqueous ophthalmic pharmaceutical composition, of pH between about 3.0 and about 6.2, which is administrable in drop form and which comprises an ophthalmically effective concentration of a said ophthalmic treating agent and about 0.05% to about 10% by weight of the polymer chitosan as the release rate controlling agent;

said polymer consisting essentially of

(A) monomeric β

(1→

4)-D-glucosamine linked units and of

(B) monomeric β

(1→

4)-N-acetyl-D-glucosamine linked units which are scattered randomly in the

molecule of the polymer, the numerical proportions of A and B being from about 60 to about 99% of A and about 1 to about 40% of B, and the viscosity rating of the polymer being from about 3 to about 3000 cps;

in which method, upon contact with the higher pH of the ocular fluid, said liquid formulation is converted to a stiff gel from which the ophthalmic treating agent is slowly released over a prolonged period of time.

2. A method according to claim 1 in which the ophthalmic treating agent is an ocular non-steroidal antiinflammatory drug, an ocular steroidal antiinflammatory agent, an ocular antibacterial agent, an ocular antifungal agent, an ocular antiviral agent, an anti-glaucoma agent, a miotic agent, an ocular decongestant, an antihistamine, a prostaglandin, a transdermal growth factor, an ocular nutrient or a demulcent.

3. A method according to claim 2 in which the non-steroidal antiinflammatory agent is diclofenac, flurbiprofen, suprofen, piroxicam or ketorolac, or an ophthalmologically acceptable salt thereof.

4. A method according to claim 2 in which the steroidal antiinflammatory agent is prednisolone acetate, prednisolone, fluorometholone, fluorometholone acetate, hydrocortisone, hydrocortisone acetate or dexamethasone.

5. A method according to claim 2 in which the antibacterial agent is chloramphenicol, ciprofloxacin, gentamycin, norfloxacin, sulfacetamide, tetracycline, tobramycin, vancomycin, ticarcillin, polymyxin B, penicillin G, neomycin, moxalactam, methicillin, kinamycin, gentamycin, erythromycin, colistimethate, clindamycin, cefazolin, carbenicillin, bacitracin, ampicillin or amikacin, or an ophthalmologically acceptable salt thereof.

6. A method according to claim 2 in which the antifungal agent is amphotericin B, flucytosine, natamycin or myconazole.

7. A method according to claim 2 in which the antiviral agent is idoxuridine, trifluridine, vidarabine, acyclovir or ganciclovir.

8. A method according to claim 2 in which the miotic agent is carbachol, pilocarpine, physostigmine, demecarium, echothiophate or isoflurophate, or an ophthalmologically acceptable salt thereof.

9. A method according to claim 2 in which the antiglaucoma agent is dipivefrin, epinephrine, hydralazine, pilocarpine, carbachol, betaxolol, carteolol, lerobunolol, metipranolol, timolol, isosorbide, azetazolamide or methazolamide, or an ophthalmologically acceptable salt thereof.

10. A method according to claim 2 in which the ocular decongestant is naphazoline, phenylephrine or tetrahydrozoline, or an ophthalmologically acceptable salt thereof.

11. A method according to claim 2 in which the ocular nutrient is a form of Vitamin A comprising Vitamin A acid, Vitamin A alcohol, Vitamin A acetate or Vitamin A palmitate.

12. A method according to claim 1 in which the formulation has a pH between about 4.0 to about 6.0.

13. A method according to claim 1 in which the concentration of ophthalmic treating agent is from about 0.001% to about 10% by weight.

14. A method according to claim 1 in which the ophthalmic pharmaceutical composition comprises an osmotic agent and a preservative.

15. A method according to claim 14 in which the ophthalmic pharmaceutical composition also comprises a surfactant or wetting agent.

16. A sustained release liquid aqueous ophthalmic delivery system for an ophthalmic treating agent of a pH between about 3.0 to about 6.2, which comprises about 0.05% to about 10% by weight of the polymer chitosan as the release rate controlling agent, said polymer consisting essentially of

(A) monomeric β

(1→

4)-D-glucosamine linked units and

(B) monomeric β

(1→

4)-N-acetyl-D-glucosamine linked units which are scattered randomly in the molecule of the polymer, the numerical proportions of A and B being from about 60 to about 99% of A and about 1 to about 40% of B, and the viscosity rating of the polymer being from about 3 to about 3000 cps;

said delivery system which is administrable in drop form being converted to a stiff gel on contact with the higher pH of the ocular fluid so as to provide a slow release into the eye for a prolonged period of time of the ophthalmic treating agent incorporated therein.

17. An ophthalmic delivery system of claim 16 in which said ophthalmic treating agent is present at a concentration of from about 0.001 to about 10% by weight.

18. An ophthalmic delivery system according to claim 17 which has an osmolality of about 240-340 mosmol/Kg and may further comprise an osmotic agent and a preservative.

19. An ophthalmic delivery system of claim 18 of pH between about 4.0 and about 6.0.

20. An ophthalmic delivery system according to claim 16 in which the ophthalmic treating agent is an ocular non-steroidal antiinflammatory drug, an ocular steroidal antiinflammatory agent, an ocular antibacterial agent, an ocular antifungal agent, an ocular antiviral agent, an anti-glaucoma agent, a miotic agent, an ocular decongestant, an antihistamine, a prostaglandin, a transdermal growth factor, an ocular nutrient or a demulcent

21. A liquid aqueous ophthalmic pharmaceutical composition of pH between about 3.0 and about 6.2, which is administrable in drop form, and which comprises about 0.05% to about 10% by weight of the polymer chitosan as the release rate controlling agent and an ophthalmic treating agent at an effective concentration;

said polymer consisting essentially of

(A) monomeric β

(1→

4)-D-glucosamine linked units and of

(B) monomeric β

(1→

4)-N-acetyl-D-glycosamine linked units which are scattered randomly in the molecule of the polymer, the numerical proportions of A and B being from about 60 to 99% of A and about 1 to about 40% of B, and the viscosity rating of the polymer being from about 3 to about 3000 cps;

said pharmaceutical composition upon contact with the higher pH of the ocular fluid being converted to a stiff gel so as to provide a slow release of the ophthalmic treating agent into the eye for a prolonged period of time.