Hydrogel polymeric compositions and methods

• US 10,251,954 B2
• Filed: 06/20/2016
• Issued: 04/09/2019
• Est. Priority Date: 07/09/2007
• Status: Active Grant

• Current Assignee: Incept LLC
• Original Assignee: Incept LLC
• Inventors: Sawhney, Amarpreet S., Ransone, II, William H.
• Primary Examiner(s): Shomer, Isaac
• Application Number:
  US15/186,994
• Publication Number:
  US 20160296623A1
• Time in Patent Office: 1,023 Days
• Field of Search: None
• 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 ophthalmic disease affecting an eye of a patient comprising forming a covalently-crosslinked hydrogel for controlled release of a therapeutic agent.

Claims

1. A synthetic, biocompatible polymeric hydrogel for delivering a therapeutic agent to an eye comprising:

a first water soluble synthetic precursor covalently crosslinked to a second water soluble synthetic precursor to form the biocompatible hydrogel,

a hydrophobic steroid small molecule drug in a particulate form free of encapsulating materials, with the steroid being in direct contact with the hydrogel and being releasable from the hydrogel to provide therapy during a period of time in a range from 10 days to 50 days,

wherein any precursors that contribute to form the hydrogel are free of hydrophobic polymeric blocks and provide a molecular weight of 500-10,000 Daltons between crosslinks based on a 1;

1 stoichiometric reaction between the first precursor and the second precursor,

wherein the hydrogel is internally covalently crosslinked and is low-swelling, as measurable by the hydrogel having a weight increasing no more than about 50% upon exposure to a physiological solution for twenty-four hours relative to a weight of the hydrogel at the time of formation, and wherein the hydrogel is water-degradable, as measurable by the hydrogel being dissolvable in vitro in an excess of water by degradation of the water-degradable group.

2. The hydrogel of claim 1 wherein the first precursor comprises polyethylene glycol repeats.

3. The hydrogel of claim 1 wherein the first precursor comprises electrophilic functional groups before the crosslinking and the second precursor comprises nucleophilic functional groups before the crosslinking, wherein the first nucleophilic functional groups react with the electrophilic functional groups to covalently crosslink the precursors.

4. The hydrogel of claim 3 wherein the second precursor is dilysine, trilysine, or tetralysine.

5. The hydrogel of claim 1 wherein the first precursor comprises an acrylate-capped polyethylene glycol.

6. The hydrogel of claim 1 wherein the water-degradable group is an ester.

7. The hydrogel of claim 1 wherein the steroid is chosen from the group consisting of triamcinolone, fluorometholone, prednisolone, and loteprednol and their salts or derivatives.

8. The hydrogel of claim 1 wherein the steroid comprises dexamethasone.

9. The hydrogel of claim 1 wherein the steroid is indicated for use in a treatment of ocular inflammation or allergic conjunctivitis.

10. The hydrogel of claim 1 wherein the steroid is indicated for use in a treatment of cystoid macular edema, diabetic macular edema (DME), or diabetic retinopathy.

11. The hydrogel of claim 1 wherein the first precursor comprises poly(ethylene) glycol repeats and the steroid comprises dexamethasone.

23. The hydrogel of claim 1 wherein the first water soluble synthetic precursor comprises an 8-armed polyethylene glycol having a molecular weight of 15,000.

24. The hydrogel of claim 1 wherein the first water soluble synthetic precursor comprises a polyethylene glycol of 4-16 arms, with the arms having a molecular weight of 1,000-5,000.

12. A synthetic, biocompatible polymeric device for delivering a drug to an eye, the device consisting essentially of

a hydrogel and a drug dispersed in the hydrogel,

the hydrogel comprising a first water soluble synthetic precursor covalently crosslinked to a second water soluble synthetic precursor to form the biocompatible hydrogel,

the drug comprising a hydrophobic steroid small molecule drug in a particulate form free of encapsulating materials, with the steroid being in direct contact with the hydrogel and being releasable from the hydrogel to provide therapy during a period of time in a range from 10 days to 50 days,

wherein any precursors that contribute to form the hydrogel are free of hydrophobic polymeric blocks and provide a molecular weight of 500-10,000 Daltons between crosslinks,

wherein the hydrogel is internally covalently crosslinked and is low-swelling, as measurable by the hydrogel having a weight increasing no more than about 50% upon exposure to a physiological solution for twenty-four hours relative to a weight of the hydrogel at the time of formation, and wherein the hydrogel is water-degradable, as measurable by the hydrogel being dissolvable in vitro in an excess of water by degradation of the water-degradable group.

13. The hydrogel of claim 12 wherein the first precursor comprises polyethylene glycol repeats.

14. The hydrogel of claim 12 wherein the first precursor comprises electrophilic functional groups before the crosslinking and the second precursor comprises nucleophilic functional groups before the crosslinking, wherein the first nucleophilic functional groups react with the electrophilic functional groups to covalently crosslink the precursors.

15. The hydrogel of claim 14 wherein the second precursor is dilysine, trilysine, or tetralysine.

16. The hydrogel of claim 12 wherein the first precursor comprises an acrylate-capped polyethylene glycol.

17. The hydrogel of claim 12 wherein the water-degradable group is an ester.

18. The hydrogel of claim 12 wherein the steroid is chosen from the group consisting of triamcinolone, fluorometholone, prednisolone, and loteprednol and their salts or derivatives.

19. The hydrogel of claim 12 wherein the steroid comprises dexamethasone.

20. The hydrogel of claim 12 wherein the steroid is indicated for use in a treatment of ocular inflammation or allergic conjunctivitis.

21. The hydrogel of claim 12 wherein the steroid is indicated for use in a treatment of cystoid macular edema, diabetic macular edema (DME), or diabetic retinopathy.

22. The hydrogel of claim 12 wherein the first precursor comprises poly(ethylene) glycol repeats and the steroid comprises dexamethasone.