Drug Delivery Systems and Applications

• US 20130071462A1
• Filed: 09/16/2011
• Published: 03/21/2013
• Est. Priority Date: 09/16/2011
• Status: Active Grant

• Current Assignee: Incept LLC
• Original Assignee: Incept LLC
• Inventors: Sawhney, Amarpreet S., Jarrett, Peter, El-Hayek, Rami
• Granted Patent: US 10,226,417 B2
• Time in Patent Office: Days
• US Class Current: 424/422
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• 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: A61K 9/5015 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61P 27/02 Ophthalmic agents

Abstract

Certain embodiments of the invention include medical materials and methods comprising a biodegradable hydrophilic hydrogel comprising dispersed lipophilic particles that comprise a therapeutic agent, wherein the lipophilic particles have a low water solubility in physiological saline at physiological temperature.

Claims

1. A medical material comprising

a biodegradable hydrophilic hydrogel comprising dispersed lipophilic particles that comprise a low water soluble lipophilic compound and further comprise a therapeutic agent that comprises a protein having a secondary and/or a tertiary structure, wherein the lipophilic particles are solid at 20°

C. and have a low water solubility in physiological saline at physiological temperature, with the protein being released from the microparticles and the medical material in a conformation that is substantially free of denaturation as measurable by enzyme-linked immunosorbent assay and isoelectric focusing.

2. The medical material of claim 1 wherein the low water soluble lipophilic compound has a molecular mass of no more than about 2000 Daltons.

3. The medical material of claim 1 wherein the particles have a melting point of between about 25°

C. and about 60°

C.

4. The medical material of claim 3 wherein the therapeutic agent comprises a drug with a log P of at least about 2.

5. The medical material of claim 4 wherein the low water soluble lipophilic compound has a log P of at least about 2.

6. The medical material of claim 3 wherein the lipophilic particles are a solid at physiological temperature.

7. The medical material of claim 1 wherein the hydrogel comprises covalently crosslinked hydrophilic polymers.

8. The medical material of claim 7 wherein the polymers comprise a member chosen from the group consisting of polyethylene oxide, polyvinyl pyrrolidinone, hyaluronic acid, and polyhydroxyethlymethacrylate.

9. The medical material of claim 1 wherein the hydrogel biodegrades by spontaneous hydrolysis of hydrolytically degradable linkages chosen from the group consisting of esters, carbonates, anhydrides and orthocarbonates.

10. The medical material of claim 1 wherein the hydrogel comprises ionically crosslinked polymers.

11. The medical material of claim 10 wherein the polymers comprise a member chosen from the group consisting of alginate, gellan, collagen, and polysaccharide.

12. The medical material of claim 1 wherein a cumulative amount of release of the agent reaches 90% of the agent at a time between about 1 month and about 6 months after placement of the hydrogel and particles in a saline solution.

13. The medical material of claim 1 wherein a cumulative amount of release of the agent reaches 90% of the agent at a time between about 5 days and about 1 month after placement of the hydrogel and particles in a saline solution.

14. The medical material of claim 1 wherein the lipophilic particles comprise at least one member chosen from the group consisting of lauric acid, capric acid, methyl stearate, and methyl palmitate.

15. A process of making a medical material comprising

coating a protein powder with a low water soluble lipophilic compound to make particles,

dispersing the particles in a medical hydrogel implant,

with the protein having a secondary and/or a tertiary structure and being released from the microparticles and the medical material in a conformation that is substantially free of denaturation as measurable by enzyme-linked immunosorbent assay and isoelectric focusing.

16. The process of claim 15 wherein the lipophilic compound comprises a fatty acid with a melting point between about 25°

C. and about 60°

C.

17. The process of claim 15 wherein the low water soluble lipophilic compound has a molecular mass of no more than about 2000 Daltons.

18. The process of claim 15 wherein the lipophilic compound is provided as a melt, and wherein coating a protein powder with a lipophilic compound to make particles comprises mixing the powder with the melt to coat the powder with the compound, cooling the mixture to a solid, and breaking up the solid to form the particles.

19. The process of claim 15 wherein the hydrogel is formed in a shape chosen from the group consisting of a rod and a disc.

20. The process of claim 15 further comprising dehydrating the hydrogel for storage.

21. The process of claim 15 wherein the hydrogel is formed in situ in a patient.

22. The process of claim 21 wherein the particles are mixed with a precursor that is reacted to form the hydrogel in situ.

23. The process of claim 22 wherein the precursor is reacted by a technique chosen from the group consisting of free radical polymerization and thermally sensitive gelation in response to a body temperature of the patient.

24. The process of claim 22 wherein the precursor is a first precursor comprising nucleophilic groups, and further comprising reacting the first precursor with the second precursor comprising electrophilic groups, with the electrophilic groups and nucleophilic groups reacting with each other to form covalent bonds to thereby form the hydrogel.

25. The process of claim 15 wherein coating a protein powder with a lipophilic compound to make particles comprises

mixing the protein powder with a lipophilic compound to form a mixture of the powder and the compound,

dispersing the mixture into a solution to form droplets of the mixture, and

cooling the droplets to a solid phase and thereby form the particles.

26. The process of claim 25 wherein cooling the droplets comprises providing the solution as a non-solvent for the lipophilic compound at a temperature below the melting point of the lipophilic compound.

27. The process of claim 15 wherein coating a peptide powder with a lipophilic compound to make particles comprises

mixing the powder and a solution of the lipophilic compound to make a suspension that comprises droplets of the powder and the lipophilic compound,

and cooling the droplets to thereby form the particles.

28. The process of claim 15 further comprising providing the hydrogel as a plurality of hydrogel particles.

29. The process of claim 15 wherein the particles are dehydrated for storage and, at the time of use, mixed with a carrier to form a slurry that is injectable into a patient.

30. The process of claim 15 wherein the particles have a melting point between about 25°

C. and about 60°

C.

31. The process of claim 15 wherein the particles are solid at physiological temperatures in vivo and have a melting point of less than about 60°

C.

32. The process of claim 15 wherein the particles are made, and the hydrogel is created, without exposure of the peptide to a solvent.

33. The process of claim 15 wherein the peptide in the particle is substantially free of denaturation as measurable by comparison of the protein in the particle to the protein before mixing with the hydrophobic coating, with the comparison being made by enzyme-linked immunosorbent assay and isoelectric focusing.

34. The process of claim 15 wherein, after placement in an excess of physiological solution at physiological temperature, a cumulative amount of release of the agent reaches 90% of the agent at a time between about 1 and about 6 months after placement of the hydrogel and particles in a saline solution.

35. The process of claim 15 wherein, after placement in an excess of physiological solution at physiological temperature, a cumulative amount of release of the agent reaches 90% of the agent at a time between about 5 days and about 1 month after placement of the hydrogel and particles in a saline solution.

36. A method of delivering a therapeutic agent to a patient comprising placing a hydrogel in a patient that comprises a collection of particles that comprise a low water soluble lipophilic compound and a therapeutic agent, with the agent being released into the patient.

37. The method of claim 36 wherein the hydrogel is molded into a unitary implant that is subsequently implanted in the patient.

38. The method of claim 36 wherein the implant is implanted in a substantially dehydrated state.

39. The method of claim 36 wherein the hydrogel is an injectable suspension or slurry that is injected into the patient.

40. The method of claim 36 wherein the hydrogel is placed into the patient at or near an eye at a location chosen from the group consisting of intravitreal, cornea, retinal, subconjunctival, scleral, and punctal.

41. The method of claim 36 wherein the hydrogel is placed through a 25 gauge or finer needle into the target tissue.

42. The method of claim 36 wherein the hydrogel is placed in a tissue, in an organ, subcutaneously, or intramuscularly.

43. A kit comprising an applicator, a hydrogel precursor, and lipophilic particles that comprise a low water soluble lipophilic compound and a therapeutic agent, wherein the lipophilic particles are solid at 20°

C. and have a low water solubility in physiological saline at physiological temperature, with the applicator being adapted to deliver a mixture of the particles and the precursor into an eye.

44. The kit of claim 43 wherein the particles have a melting point of between about 25°

C. and about 60°

C.

45. The kit of claim 43 wherein the therapeutic agent comprises a protein, with the protein having a secondary and/or tertiary structure and being released from the microparticles and the medical material in a conformation that is substantially free of denaturation as measurable by enzyme-linked immunosorbent assay and isoelectric focusing.

46. The kit of claim 43 wherein the lipophilic particles comprise at least one member chosen from the group consisting of lauric acid, capric acid, methyl stearate, and methyl palmitate.

47. The kit of claim 43 wherein the low water soluble lipophilic compound has a molecular mass of no more than about 2000 Daltons.

48. The kit of claim 43 wherein the therapeutic agent comprises a drug with a log P of more than about 2.

49. The kit of claim 43 wherein the low water soluble lipophilic compound has a log P of at least about 2.