Adhesive hydrogels for ophthalmic drug delivery

• US 9,125,807 B2
• Filed: 07/09/2007
• Issued: 09/08/2015
• Est. Priority Date: 07/09/2007
• Status: Active Grant

• Current Assignee: Incept LLC
• Original Assignee: Incept LLC
• Inventors: Sawhney, Amarpreet S., Ransone, William H. II
• Primary Examiner(s): Shomer, Isaac
• Application Number:
  US11/825,848
• Publication Number:
  US 20090017097A1
• Time in Patent Office: 2,983 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/4422 1,4-Dihydropyridines, e.g. nifedipine, nicardipine
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4458 only substituted in position 2, e.g. methylphenidate
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• 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 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics

Abstract

Some aspects of this disclosure relate to a method of treating an opthalmic disease affecting an eye of a patient comprising forming a covalently-crosslinked hydrogel in situ at a peri-ocular, intra-ocular, or intra-vitreal site for controlled release of a therapeutic agent.

Claims

1. A method of treating an opthalmic disease affecting an eye of a patient comprising forming, a biodegradable covalently-crosslinked hydrogel in situ at a topical site, the hydrogel comprising a therapeutic agent that is released to treat the ophthalmic disease over a period of time that is at least about two days, wherein the hydrogel is adherent only to the site and the hydrogel is low-swelling, as measurable by the hydrogel having a weight increasing no more than about 40 % upon exposure to a physiological solution for twenty-four hours relative to a weight of the hydrogel at the time of formation and is water-degradation, as measurable by the hydrogel being dissolvable in vitro in an excess of water by degradation of water-degradable groups.

2. The method of claim 1 wherein the topical site is the conjunctiva.

3. The method of claim 1 wherein the hydrogel is formed by combining a first synthetic precursor comprising nucleophilic groups with a second synthetic precursor comprising electrophilic groups to form covalent crosslinks by reaction of the nucleophilic groups with the electrophilic groups to form the biocompatible hydrogel.

4. The method of claim 3 further comprising injecting an aqueous mixture of the precursors to the site.

5. The method of claim 1 further comprising applying an aqueous mixture of the precursors to the site, with the mixture having a viscosity of less than about 1000 centipoise.

6. The method of claim 3 wherein the first synthetic precursor comprises a hydrophilic portion and a hydrophobic portion.

7. The method of claim 1 wherein the hydrogel further comprises a plurality of particles that release the therapeutic agent.

8. The method of claim 1 wherein the hydrogel is formed by combining a first synthetic precursor comprising nucleophilic groups with a second synthetic precursor comprising electrophilic groups to firm covalent crosslinks by reaction of the nucleophilic groups with the electrophilic groups to form the biocompatible hydrogel or wherein the hydrogel is formed by free radical polymerization of functional groups on the precursors.

9. The method of claim 1 wherein the hydrogel is formed by combining a first synthetic precursor with a second synthetic precursor, wherein the first synthetic precursor comprises a hydrophilic portion and a hydrophobic portion.

10. The method of claim 1 wherein the disease is dry eye and the therapeutic agent comprises cyclosporine.

11. The method of claim 1 wherein the disease is wet macular degeneration and the therapeutic agent comprises an inhibitor of vascular growth.

12. The method of claim 1 wherein the therapeutic agent comprises a non-steroidal anti-inflammatory drug.

13. The method of claim 1 wherein the therapeutic agent is present in a separate phase when the precursor(s) are reacted to produce the hydrogel.

14. The method of claim 1 further comprising a visualization agent so that a user applying the hydrogel can observe the hydrogel.

15. The method of claim 1 wherein the therapeutic agent is released over a period of time that includes 120 days.

16. The method of claim 1 wherein the therapeutic agent is released over a period of time within a range from about two days to about two years.

17. The method of claim 1 wherein the hydrogel weight increases no more than 10%.

18. The method of claim 1 wherein the hydrogel is formed by combining a first synthetic precursor comprising at least three nucleophilic groups with a second synthetic precursor comprising at least six electrophilic groups to form covalent crosslinks by reaction of the nucleophilic groups with the electrophilic groups to form the biocompatible hydrogel.

19. The method of claim 18 wherein the gelation time of the hydrogel is between 15 seconds and 60 seconds.

20. The method of claim 18 wherein the second synthetic precursor, before reaction, comprises an 8-armed polyethylene glycol with each arm terminating in the electrophilic group.

21. The method of claim 18 wherein the hydrogel is formed at a pH of no more than 8.

22. The method of claim 1 wherein the hydrogel is formed at a pH of no more than 8.

23. The method of claim 2 wherein the topical site is the superior fornix.

24. The method of claim 2 wherein the topical site is the inferior fornix.

25. The method of claim 1 wherein the disease comprises conjunctivitis.

26. The method of claim 1 wherein the disease comprises blepharitis.

27. The method of claim 1 wherein the disease is keratitis.

28. The method of claim 1 wherein the disease is keratoconjuctivitis sicca.

29. The method of claim 1 wherein the disease is macular degeneration.

30. The method of claim 1 wherein the disease is glaucoma.