Non-polymeric sustained release delivery system

• US 5,888,533 A
• Filed: 11/21/1997
• Issued: 03/30/1999
• Est. Priority Date: 10/27/1995
• Status: Expired due to Term

• Current Assignee: Atrix Laboratories, Inc. (TOLMAR Holding, Inc.)
• Original Assignee: Atrix Laboratories, Inc. (TOLMAR Holding, Inc.)
• Inventors: Dunn, Richard L.
• Primary Examiner(s): Azpuru, Carlos A.
• Application Number:
  US08/975,765
• Time in Patent Office: 494 Days
• Field of Search: 424/423, 424/426
• US Class Current: 424/423
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• 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 9/0024 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: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to a method and composition for forming an implant in-situ within a body using non-polymeric materials, and the use of such implants as medical devices and drug delivery systems. The composition can be applied to an animal to treat periodontal disease or other tissue defect, enhance compatibility and performance of an implantable article, and deliver a biologically active agent.

Claims

1. A flowable composition for forming a solid biodegradable implant in situ within a body, comprising:

(a) a non-polymeric, water-insoluble material that is biodegradable; and

(b) a biocompatible, organic solvent that at least partially solubilizes the non-polymeric, water-insoluble material and is miscible to dispersible in water or body fluids, and capable of dissipating, diffusing or leaching from the composition into body fluid upon placement within a body, whereupon the non-polymeric material coagulates or precipitates to form the solid implant.

2. The composition of claim 1, wherein the non-polymeric material is selected from the group consisting of sterols, cholesteryl esters, C₁₂ -C₂₄ fatty acids, C₁₈ -C₃₆ monoglycerides, C₁₈ -C₃₆ diglycerides, C₁₈ -C₃₆ triglycerides, sucrose fatty acid esters, sorbitan fatty acid esters, C₁₆ -C₁₈ fatty alcohols, esters of fatty alcohols with fatty acids, anhydrides of fatty acids, phospholipids, lysoderivatives of phospholipids, sphingomyelins, derivatives of sphingosine, sphingomyelins, ceramindes, glycosphingolipids, lanolin, lanolin alcohols, and mixtures thereof.

3. The composition according to claim 2, wherein the non-polymeric material is a sterol selected from the group consisting of cholesterol, stigmasterol, β

-sitosterol, estradiol, and mixtures thereof.

4. The composition of claim 2, wherein the non-polymeric material is a C₁₂ -C₂₄ fatty acid selected from the group consisting of lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, and mixtures thereof.

5. The composition according to claim 2, wherein the non-polymeric material is a C₁₈ -C₃₆ mono-, di- and triacylglyceride selected from the group consisting of glyceryl monostearate, glyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate, glyceryl monodocosanoate, glyceryl monomyristate, glyceryl monodicenoate, glyceryl dipalmitate, glyceryl didocosanoate, glyceryl dimyristate, glyceryl didecenoate, glyceryl tridocosanoate, glyceryl trimyristate, glyceryl tridecenoate, glycerol tristearate, and mixtures thereof.

6. The composition according to claim 2, wherein the non-polymeric material is a C₁₆ -C₁₈ fatty alcohol selected from the group consisting of cetyl alcohol, myristyl alcohol, stearyl alcohol, cetostearyl alcohol, and mixtures thereof.

7. The composition according to claim 2, wherein the non-polymeric material is a phospholipid or lysoderivative thereof selected from the group consisting of phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, and mixtures thereof.

8. The composition according to claim 2, wherein the non-polymeric material is selected from the group consisting of stearyl sphingomyelin, palmitoyl sphingomyelin, tricosanyl sphingomyelin, stearyl ceramide, palmitoyl ceramide, and mixtures thereof.

9. The composition according to claim 1, wherein the non-polymeric material is selected from the group consisting of cholesterol, glyceryl monostearate, glyceryl tristearate, stearic acid, stearic anhydride, glyceryl monooleate, glyceryl monolinoleate, and mixtures thereof.

10. The composition according to claim 1, wherein the solvent is selected from the group consisting of N-methyl-2-pyrrolidone, 2-pyrrolidone, propylene carbonate, dimethyl carbonate, ethanol, acetic acid, ethyl acetate, ethyl lactate, methyl acetate, acetone, methyl ethyl ketone, isopropylidene glycol, glycerol formal, glycofurol, dimethylformamide, dimethyl sulfoxide, dimethylsulfone, tetrahydrofuran, caprolactam, N,N-dimethyl-m-toluamide, 1-dodecylazacycloheptan-2-one, and mixtures thereof.

11. The composition according to claim 1, wherein the solvent is selected from the group consisting of N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl lactate, propylene carbonate, glycofurol, glycerol formal, isopropylidene glycol, and mixtures thereof.

12. The composition according to claim 1, wherein the solvent comprises a mixture of a first solvent capable of dissolving the non-polymeric material, and a second solvent incapable or less capable than the first solvent of dissolving the non-polymeric material;

the first and second solvents included in said mixture at a ratio to at least partially dissolve the non-polymeric material therein;

wherein upon placement of the composition within the body, the first solvent dissipates, disperses, or leaches into body fluid thereby resulting in an increase in the ratio of the second solvent to the first solvent whereupon the non-polymeric material precipitates or coagulates to form a solid matrix.

13. The composition according to claim 12, wherein the first solvent is selected from the group consisting of N-methyl-2-pyrrolidone, 2-pyrrolidone, acetone, ethyl acetate, methyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, glycerol formal, glycofurol, isopropylidene glycol, tetrahydrofuran, caprolactam, and mixtures thereof.

14. The composition according to claim 12, wherein the second solvent is selected from the group consisting of water, ethanol, propylene glycol, and polyethylene glycol.

15. The composition according to claim 1, further comprising a biologically-active agent.

16. The composition according to claim 15, wherein the biologically-active agent is selected from the group consisting of an antibacterial agent, antimicrobial agent, antifungal agent, antiviral agent, and mixtures thereof.

17. The composition according to claim 15, wherein the biologically-active agent is selected from the group consisting of an anti-inflammatory agent, antiparasitic agent, analgesic agent, anaesthetic agent, immunogen, growth factor, anti-neoplastic agent, hormone, antihistamine, osteoinductive agent, cardiovascular agent, anti-ulcer agent, bronchodilating agent, vasodilating agent, central nervous system agent, antipsychotic agent, and mixtures thereof.

18. The composition according to claim 15, wherein the biologically-active agent is a growth factor selected from the group consisting of platelet-derived growth factor, insulin-derived growth factor, transforming growth factor-α

, transforming growth factor-β

, epidermal growth factor, fibroblast growth factor, interleukin-1, and mixtures thereof.

19. The composition according to claim 15, wherein the biologically-active agent is tetracycline or doxycycline.

20. The composition according to claim 15, further comprising a controlled release component that comprises the active agent.

21. The composition according to claim 1, further comprising a pore-forming agent selected from the group consisting of a sugar, a salt, a water-soluble polymer, and a water-insoluble substance that rapidly degrades to a water-soluble substance.

22. The composition according to claim 1, further comprising a release rate modification agent for controlling the rate of release of a biologically-active agent in vivo from the implant matrix.

23. The composition according to claim 22, wherein the release rate modification agent is an epoxidized vegetable oil.

24. The composition according to claim 22, wherein the release rate modification agent is an organic solvent different from the organic solvent of claim 1 (b), being selected from the group consisting of dimethyl adipate, propylene glycol, polyethylene glycol, ethyl heptanoate, glycerol triacetate, dimethyl phthalate, and mixtures thereof.

25. The composition according to claim 1, having a consistency ranging from watery to viscous to spreadable.

30. The composition according to claim 1, wherein the solvent is at least about 5% soluble in water.

26. A non-polymeric system suitable as a controlled release implant, comprising:

a solid, microporous matrix formed by contact between an aqueous medium and a flowable composition of a water-insoluble, biodegradable, non-polymeric material and a biocompatible, organic solvent that at least partially solubilizes the non-polymeric material, and is miscible to dispersible in water or body fluids, and capable of dissipating, diffusing or leaching from the composition into body fluid upon placement within a body, whereupon the non-polymeric material coagulates or precipitates to from the solid implant.

27. The non-polymeric system according to claim 26, wherein the matrix comprises a core and a skin, the core having pores between about 1-500 microns in diameter, and the skin having pores of less than about 50 microns in diameter.

28. The non-polymeric system according to claim 26, wherein the matrix has a porosity effective to provide a barrier for guided tissue regeneration.

29. The non-polymeric system according to claim 26, wherein the composition further comprises a biologically-active agent, pore-forming agent, release rate modifying agent, or a combination thereof.