MEDICAL ORGANOGEL PROCESSES AND COMPOSITIONS

• US 20130156752A1
• Filed: 12/05/2012
• Published: 06/20/2013
• Est. Priority Date: 12/05/2011
• Status: Active Grant

• Current Assignee: Incept LLC
• Original Assignee: Incept LLC
• Inventors: Jarrett, Peter, El-Hayek, Rami, Sawhney, Amarpreet S.
• Granted Patent: US 9,205,150 B2
• Time in Patent Office: Days
• US Class Current: 424/130.1
• CPC Class Codes: A61K 38/38 Albumins
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• 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: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002

Abstract

Serial-solvent biomaterials are described. Embodiments include materials made in an organic solvent that are stripped of the solvent and used in a patient, where they imbibe water and form a hydrogel. These materials are useful for, among other things, delivering therapeutic agents, tissue augmentation, and radiological marking.

Claims

1. A process of making a medical material comprising forming an organogel around a powder of a water soluble biologic, with the powder being dispersed in the organogel.

2. The process of claim 1 wherein the water soluble biologic is a protein that has a molecular mass of at least about 10,000 Daltons and a sugar is associated with the protein.

3. The process of claim 1 wherein the powder is a first powder, with the process further comprising a second powder that comprises a second water soluble biologic agent, with the first powder and the second powder being dispersed through the organogel.

4. The process of claim 1 wherein the organogel is formed in an absence of aqueous solution.

5. The process of claim 1 further comprising removing solvents from the organogel to thereby form a xerogel.

6. The process of claim 5 wherein the solvents are removed by a process chosen from the group consisting of vacuum removal, lyophilization, and freezing followed by application of a vacuum.

7. The process of claim 5 wherein the xerogel is a hydrogel upon exposure to an aqueous solution.

8. The process of claim 7 wherein the water soluble biologics remain substantially in the powder, in a solid phase, when the hydrogel is formed, and slowly dissolve over a period of time when the hydrogel is exposed to physiological solution in vivo in a mammal.

9. The process of claim 7 wherein the biologic is a protein having a secondary and/or a tertiary structure, with the protein being released in a conformation that is substantially free of denaturation as measurable by, for example, enzyme-linked immunosorbent assay and isoelectric focusing.

10. The process of claim 1, wherein the organogel comprises covalently crosslinked hydrophilic polymers.

11. The process of claim 7, wherein the hydrogel is biodegradable by spontaneous hydrolysis of hydrolytically degradable linkages chosen from the group consisting of esters, carbonates, anhydrides and orthocarbonates.

12. The process of claim 1 wherein the organogel comprises block copolymers that foam the organogel and that, after the solvents are removed to form a xerogel, form a hydrogel upon exposure to an aqueous solution.

13. The process of claim 1 wherein the organogel comprises ionically crosslinked polymers.

14. The process of claim 1 wherein the organogel comprises a member chosen from the group consisting of alginate, gellan, collagen, and polysaccharide.

15. The process of claim 1 further comprising forming a plurality of particles out of:

the organogel, a xerogel made from the organogel, or a hydrogel made from the organogel.

16. The process of claim 1 comprising forming the organogel from a precursor in an organic solvent, with the precursor being chemically reacted to form covalent bonds to thereby form the organogel, wherein the organogel is covalently crosslinked.

17. The process of claim 16 wherein the precursor is reacted by free radical polymerization to form the organogel.

18. The process of claim 16 wherein the precursor is a first precursor comprising a first functional group and further comprising a second precursor comprising a second functional group, with the first functional group and the second functional group being reactive in the organic solvent to form the covalent bonds.

19. The process of claim 18 wherein the first functional group and the second functional group are each chosen from the group consisting of electrophile and nucleophile, and the reaction between the first functional group and second functional group is an electrophilic-nucleophilic reaction that forms the covalent bond.

20. The process of claim 19 wherein the electrophilic group comprises succimide, succinimide ester, n-hydroxysuccinimide, maleimide, succinate, nitrophenyl carbonate, aldehyde, vinylsulfone, azide, hydrazide, isocyanate, diisocyanate, tosyl, tresyl, or carbonyldiimidazole.

21. The process of claim 20 wherein the nucleophile group comprises a primary amine or a primary thiol.

22. The process of claim 16 wherein the first precursor and the second precursor are water soluble.

23. The process of claim 16 wherein at least one of the first precursor and the second precursor comprises a synthetic polymer.

24. The process of claim 23 wherein the first precursor comprises a polymer chosen from the group consisting of polyethylene glycol, polyacrylic acid, polyvinylpyrrolidone, and block copolymers thereof.

25. The process of claim 1 wherein the therapeutic agent comprises a fluoroquinolone, moxifloxacin, travoprost, dexamethasone, an antibiotic, or a vestibulotoxin.

26. The process of claim 1 wherein the organogel is physically crosslinked by foimation of domains, the process further comprising forming the organogel from a precursor in an organic solvent, with the precursor being a block copolymer that comprises a first block and a second block.

27. The process of claim 26 comprising heating a mixture of the precursor and the organic solvent and allowing the solution to cool, thereby precipitating at least the first block of the copolymeric precursor, with said domains comprising at least the first block.

28. The process of claim 26 comprising:

mixing the precursor in a first organic solvent that dissolves the copolymeric precursor, with all of the blocks of the copolymeric precursor being soluble in the first organic solvent, and

adding a second organic solvent that is miscible with the first organic solvent, with the first block of the copolymeric precursor being insoluble in the second organic solvent, with the second solvent being effective to form the domains, with the domains comprising the first block of the copolymer.

29. The process of claim 26 wherein the copolymeric precursor comprises a block chosen from the group consisting of polyethylene glycol.

30. The process of claim 1 wherein the organogel is free of hydrophobic materials.

31. The process of claim 1 comprising preparing the powder of the biologic according to a method that avoids denaturation of the biologic, and, once the powder has been prepared, preventing exposure of the powder to water until the medical material is used with a patient.

32. A biomaterial for controlled release of a therapeutic water soluble biologic comprising a pharmaceutically acceptable xerogel that comprises solid particles of the biologic dispersed therein with the xerogel being a hydrogel when exposed to water.

33. The biomaterial of claim 32 wherein the xerogel comprises covalently crosslinked hydrophilic polymers.

34. The biomaterial of claim 32 wherein the water soluble biologic is a protein having a secondary and/or tertiary structure.

35. The biomaterial of claim 32 wherein the water soluble biologic remains substantially in the solid phase, when the hydrogel is formed, and slowly dissolve over a period of time when the hydrogel is exposed to physiological solution in vivo in a mammal.

36. The biomaterial of claim 32 wherein the organogel comprises covalently crosslinked hydrophilic polymers.

37. The biomaterial of claim 32 wherein the xerogel, after hydration in water, is biodegradable by spontaneous hydrolysis of hydrolytically degradable linkages chosen from the group consisting of esters, carbonates, anhydrides and orthocarbonates.

38. The biomaterial of claim 32 wherein the xerogel is a chemical reaction product of a first precursor comprising a first functional group and a second precursor comprising a second functional group, with the first functional group and the second functional group reacted to form covalent bonds.

39. A method of controlled drug delivery comprising placing the biomaterial of claim 32 in contact with a tissue of a patient.

40. The method of claim 39, with the tissue comprising an intraperitoneal space, a muscle, a dermis, an epidermis, a natural lumen or void, an abdominal cavity, a prostate, a rectum, a location between a prostate and a rectum, a breast, a tissue between a radiation target and healthy tissue, and a vasculature.

41. A kit comprising the biomaterial of claim 32.

42. The kit of claim 41, wherein the biomaterial is a collection of xerogel particles that form hydrogel particles upon exposure to water.

43. A process of making a medical material comprising

forming an organogel,

making a xerogel from the organogel,

and providing the xerogel as a collection of particles, wherein the xerogel is a hydrogel upon exposure to an aqueous solution.

44. The process of claim 43 comprising making a plurality of the collections of particles, with the collections having different rates of degradation in vivo, and mixing collections to make a biomaterial having a degradation performance as desired.