Drug-delivering composite structures

• US 20070134305A1
• Filed: 12/07/2006
• Published: 06/14/2007
• Est. Priority Date: 12/07/2005
• Status: Active Grant

• Current Assignee: Meital Zilberman
• Original Assignee: Ramot at Tel Aviv University Limited (Tel Aviv University)
• Inventors: Zilberman, Meital
• Granted Patent: US 9,446,226 B2
• Time in Patent Office: Days
• US Class Current: 424/443
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 38/44 Oxidoreductases (1)
• 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: A61K 9/0092 Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61K 9/70 Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug hollow drug-filled fibres A61K9/0092
• CPC Class Codes: A61M 31/002 Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time artificial gland structures or devices A61F2/022; intra-uterine contraceptive devices A61F6/14; tampons for introducing into the vagina A61F13/20, A61L15/00; suppositories or bougies for intra-vaginal or intra-uterine application A61K9/02; physical forms of medicinal preparations for sustained or differential drug release A61K9/20, A61K9/50
• CPC Class Codes: C12Y 111/01007 Peroxidase (1.11.1.7), i.e. horseradish-peroxidase
• CPC Class Codes: D06M 16/00 Biochemical treatment of fibres, threads, yarns, fabrics, or fibrous goods made from such materials, e.g. enzymatic
• CPC Class Codes: Y10T 442/2525 Coating or impregnation functions biologically [e.g., insect repellent, antiseptic, insecticide, bactericide, etc.]

Abstract

Composite structures composed of a fibril core and a polymeric coat and designed capable of encapsulating both hydrophobic and hydrophilic bioactive agents while retaining the activity of these agents are disclosed. Further disclosed are processes of preparing such composite structures, and medical devices and disposable articles made therefrom.

Claims

1. A composite structure comprising a fibril core and a polymeric coat coating at least a part of said fibril core, the structure being designed such that said coat is capable of encapsulating at least one bioactive agent while retaining an activity of said bioactive agent and/or capable of releasing a bioactive agent encapsulated in said coat in a pre-determined release rate.

2. The composite structure of claim 1, wherein said polymeric coat is a porous coat.

3. The composite structure of claim 2, wherein said polymeric coat is characterized by an average pore diameter that ranges from about 1 nm to about 1 mm.

4. The composite structure of claim 2, wherein said polymeric coat is characterized by a pore density that ranges from about 70% of void volume per coat volume to about 95% of void volume per coat volume.

5. The composite structure of claim 2, wherein a thickness of said polymeric coat ranges from about 1 μ

m to about 2000 μ

m.

6. The composite structure of claim 1, wherein said fibril core is characterized by a tensile strength of at least 100 MPa.

7. The composite structure of claim 1, wherein a diameter of said fibril core ranges from about 1 μ

m to about 1 cm.

8. The composite structure of claim 1, wherein said polymeric coat is biodegradable.

9. The composite structure of claim 1, wherein said coat comprises at least one bioactive agent encapsulated therein and/or applied thereon.

10. The composite structure of claim 1, wherein said core comprises at least one bioactive agent encapsulated therein.

25. A fibrous composition-of-matter comprising the composite structure of claim 1.

42. A medical device comprising the composite structure of claim 1.

43. A medical device comprising the fibrous composition-of-matter of claim 25.

46. An article-of-manufacture comprising the composite structure of claim 1.

11. A composite structure comprising a fibril core and a polymeric coat coating at least a part of said fibril core, said coat comprises at least one bioactive agent encapsulated therein in and/or applied thereon.

12. The composite structure of claim 11, wherein an activity of said at least one bioactive agent is at least partially retained.

13. The composite structure of claim 11, wherein said coat is capable of releasing said bioactive agent in a pre-determined release rate.

14. The composite structure of claim 12, wherein said at least one bioactive agent is selected from the group consisting of a hydrophobic bioactive agent and a hydrophilic bioactive agent.

15. The composite structure of claim 12, wherein said at least one bioactive agent is selected from a group consisting of a macro-biomolecule and a small organic molecule.

16. The composite structure of claim 11, wherein said polymeric coat is a porous coat.

17. The composite structure of claim 16, wherein said polymeric coat is characterized by an average pore diameter that ranges from about 1 nm to about 1 mm.

18. The composite structure of claim 16, wherein said polymeric coat is characterized by a pore density that ranges from about 50% of void volume per coat volume to about 95% of void volume per coat volume.

19. The composite structure of claim 11, wherein a thickness of said polymeric coat ranges from about 1 μ

m to about 2000 μ

m.

20. The composite structure of claim 11, wherein said coat is biodegradable.

21. The composite structure of claim 11, wherein said fibril core is characterized by a tensile strength of at least 100 MPa.

22. The composite structure of claim 11, wherein a diameter of said fibril core ranges from about 1 μ

m to about 1 cm.

23. The composite structure of claim 11, wherein said coat further comprises at least one additional agent.

24. The composite structure of claim 11, wherein said core comprises at least one bioactive agent encapsulated therein.

26. A fibrous composition-of-matter comprising the composite structure of claim 11.

44. A medical device comprising the composite structure of claim 11.

45. A medical device comprising the fibrous composition-of-matter of claim 26.

47. An article-of-manufacture comprising the composite structure of claim 11.

27. A process of preparing a composite structure which comprises a fibril core and a polymeric coat coating at least a part of the fibril core, the process comprising:

contacting a fiber and an emulsion of an aqueous solution and an organic solution, said organic solution containing at least one second polymer, to thereby obtain said fiber having a layer of said emulsion applied on at least a part thereof; and

freeze-drying said fiber having said layer applied thereon, thereby obtaining the composite structure.

28. The process of claim 27, wherein said fiber is a polymeric fiber made from at least one first polymer.

29. The process of claim 28, further comprising, prior to said contacting:

spinning said at least one first polymer, to thereby obtain a crude fiber; and

drawing said crude fiber, to thereby obtain said fiber.

30. The process of claim 27, wherein said emulsion is prepared by:

dissolving said at least one second polymer in an organic solvent to thereby obtain said organic solution;

contacting said organic solution and said aqueous solution to thereby obtain a mixture; and

emulsifying said mixture to thereby obtain said emulsion.

31. A process of preparing a composite structure which comprises a fibril core and a polymeric coat coating at least a part of the fibril core, wherein the coat comprises at least one bioactive agent encapsulated therein and/or applied thereon, the process comprising:

contacting a fiber and an emulsion containing an aqueous solution and an organic solution, said organic solution containing at least one second polymer and said emulsion further containing said at least one bioactive agent either within said aqueous solution or within said organic solution, to thereby obtain said fiber having a layer of said emulsion applied on at least a part thereof; and

freeze-drying said fiber having said layer applied thereon, thereby obtaining the composite structure.

32. The process of claim 31, further comprising, prior to said contacting:

spinning said at least one first polymer, to thereby obtain a crude fiber; and

drawing said crude fiber, to thereby obtain said fiber.

33. The process of claim 31, wherein said emulsion is prepared by:

dissolving said at least one second polymer in an organic solvent to thereby obtain said organic solution;

contacting said organic solution and said aqueous solution to thereby obtain a mixture; and

emulsifying said mixture to thereby obtain said emulsion.

34. The process of claim 33, wherein a concentration of said second polymer in said organic solvent ranges from about 1 weight to volume percentages to about 50 weight to volume percentages.

35. The process of claim 33, wherein a ratio of said aqueous solution and said organic solution in said mixture ranges from about 1 parts of said organic solution to 1 part said aqueous solution to about 20 parts of said organic solution to 1 part said aqueous solution.

36. The process of claim 33, wherein said aqueous solution contains said bioactive agent.

37. The process of claim 36, wherein a ratio of said aqueous solution and said organic solution in said mixture ranges from about 3 part of said organic solution to 1 part said aqueous solution to about 20 parts of said organic solution to 1 part said aqueous solution.

38. The process of claim 36, wherein a concentration of said bioactive agent in said aqueous solution ranges from about 1 weight percentage to about 20 weight percentages.

39. The process of claim 33, wherein said organic solution contains said bioactive agent.

40. The process of claim 39, wherein a ratio of said aqueous solution and said organic solution in said mixture ranges from about 1 part of said organic solution to 1 part said aqueous solution to about 8 parts of said organic solution to 1 part said aqueous solution.

41. The process of claim 39, wherein a concentration of said bioactive agent in said organic solution ranges from about 0.1 weight percentage to about 10 weight percentages.

48. A method of predicting release rate of a bioactive agent from a composite structure having a fibril core at least partially coated by a biodegradable polymeric coat, the biodegradable polymeric coat being initially incorporated with an initial concentration of the bioactive agent, the method comprising:

solving a diffusion equation so as to obtain the concentration distribution of the bioactive agent in the biodegradable polymeric coat as a function of time;

integrating said concentration distribution over a volume of said biodegradable polymeric coat so as to obtain an integrated bioactive agent mass as a function of time; and

using said integrated bioactive agent mass for predicting the release rate of the bioactive agent.

49. The method of claim 48, wherein said diffusion equation comprises a time-dependent diffusion coefficient.

50. The method of claim 49, wherein said time-dependent diffusion coefficient comprises a constant term which is proportional to a porosity characterizing the polymeric coat.

51. The method of claim 50, wherein said constant term is proportional to the ratio of said porosity to a tortuosity characterizing the polymeric coat.

52. The method of claim 49, wherein said time-dependent diffusion coefficient comprises a degradation profile characterizing the polymeric coat.