SUSTAINED DELIVERY OF EXENATIDE AND OTHER PEPTIDES

• US 20100021522A1
• Filed: 06/24/2009
• Published: 01/28/2010
• Est. Priority Date: 06/25/2008
• Status: Active Grant

• Current Assignee: ENDO Operations Limited (Endo, Inc.)
• Original Assignee: Endo Pharmaceuticals Solutions Incorporated (Endo International PLC)
• Inventors: Kuzma, Petr, Decker, Stefanie, Quandt, Harry
• Granted Patent: US 8,071,537 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• 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 47/40 Cyclodextrins; Derivatives thereof
• 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 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/08 for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin

Abstract

Described herein are implantable devices, formulations and methods of making implantable devices for the release of a polypeptide from an implantable device, and methods of use thereof.

Claims

1. An implantable device for the sustained release of a polypeptide, comprising:

a) a homogeneous copolymer matrix that, in a hydrated state, forms a hydrogel with an equilibrium water content value ranging from about 20% to about 85%, wherein the homogeneous copolymer matrix further comprises a release agent of a molecular weight of at least about 1000 Daltons; and

b) a solid formulation comprising a polypeptide, wherein the solid formulation is substantially encased within the homogeneous copolymer matrix.

2. The implantable device of claim 1, wherein the release agent comprises a non-ionic surfactant.

3. The implantable device of claim 1, wherein the release agent is selected from the group consisting of:

Brij 35, polyoxyetheylene(20)sorbitan trioleate, Tween 20, Tween 80, Vitamin E TPGS, and combinations thereof.

4. The implantable device of claim 1, wherein the implantable device has an outer surface area of about 350 mm² or greater when in a dry state.

5. The implantable device of claim 4, wherein the implantable device has an outer surface area ranging from about 350 mm² to about 600 mm² when in a dry state.

6. The implantable device of claim 1, wherein the implantable device has an outer surface area of about 500 mm² or greater when in a hydrated state.

7. The implantable device of claim 6, wherein the implantable device has an outer surface area ranging from about 500 mm² to about 800 mm² when in a hydrated state.

8. The implantable device of claim 1, wherein the polypeptide comprises a GLP-1 analogue.

9. The implantable device of claim 8, wherein the GLP-1 analogue is exenatide.

10. The implantable device of claim 1, wherein the homogeneous copolymer is formed using a formulations of Table 2.

11. The implantable device of claim 1, wherein the solid formulation comprises about 98% exenatide and about 2% stearic acid.

12. A method of delivering a polypeptide to a subject in a sustained release manner, the method comprising inserting an implantable device beneath the subject'"'"'s skin, wherein the implantable device comprises a homogeneous copolymer matrix comprising a release agent with a molecular weight of at least about 1000 Daltons, and a solid formulation comprising a polypeptide, wherein the solid formulation is substantially encased within the matrix.

13. The method of claim 12, wherein the implantable device is inserted in a dry state.

14. The method of claim 12, wherein the implantable device is inserted in a hydrated state.

15. The method of claim 12, wherein the implantable device provides a sustained release of the polypeptide over a period of at least about two months.

16. The method of claim 12, wherein the release agent comprises a non-ionic surfactant.

17. The method of claim 16, wherein the release agent is selected from the group consisting of:

Brij 35, polyoxyetheylene(20)sorbitan trioleate, Tween 20, Tween 80, Vitamin E TPGS, and combinations thereof.

18. The method of claim 12, wherein the implantable device has an outer surface area of about 350 mm² or greater when in a dry state.

19. The method of claim 18, wherein the implantable device has an outer surface area ranging from about 350 mm² to about 600 mm² when in a dry state.

20. The method of claim 12, wherein the implantable device has an outer surface area of about 500 mm² or greater when in a hydrated state.

21. The method of claim 20, wherein the implantable device has an outer surface area ranging from about 500 mm² to about 800 mm² when in a hydrated state.

22. The method of claim 12, wherein the polypeptide comprises a GLP-1 analogue.

23. The method of claim 22, wherein the GLP-1 analogue is exenatide.

24. The method of claim 12, wherein the homogeneous copolymer is formed using a formulations of Table 2.

25. The method of claim 24, wherein the solid formulation comprises about 98% exenatide and about 2% stearic acid.

26. The method of claim 12, wherein the subject is diabetic or in need of glycemic control.

27. A method of manufacturing an implantable device, wherein the implantable device can deliver a therapeutic polypeptide agent to a subject, and the release of the therapeutic polypeptide agent from the implantable device can be modulated by varying the components or the amounts of the components of the implantable device, the method comprising:

a) mixing one or more polymerizable monomeric substances;

b) adding one or more substances selected from the group consisting of;

an excipient, a wetting agent, a non-ionic surfactant, an organic solvent, an alcohol, a reducing agent, an oxidizing agent and an aqueous solvent; and

c) subjecting the mixture to conditions that cause the one or more polymerizable monomeric substances to polymerize in the presence of the one or more components,

thereby forming the implantable device.

28. The method of claim 27, wherein the one or more polymerizable monomeric substances comprises one or more compounds selected from the group consisting of:

2-hydroxyethyl methacrylate, ethyleneglycol dimethacrylate, and trimethylolpropane trimethacrylate.

29. The method of claim 27, wherein the mixture further comprises one or more components selected from the group consisting of:

benzoin methyl ether, Perkadox 16, and isopropyl alcohol.

30. The method of claim 27, wherein the rate of release of the therapeutic polypeptide can be modulated.

31. The method of claim 27, wherein the mixture is placed into a mold prior to being subjected to a polymerization step.

32. The method of claim 31, wherein the polymerization step is initiated by ultraviolet irradiation.

33. The method of claim 27, further comprising charging the implantable device with a desired amount of a therapeutic polypeptide agent.

34. The method of claim 33, wherein the therapeutic polypeptide agent comprises a GLP-1 analog.

35. The method of claim 34, wherein the GLP-1 analog comprises exenatide.

36. The method of claim 27, wherein the therapeutic polypeptide agent is combined with a wetting agent to form a solid formulation prior to being charged into the implantable device.

37. The method of claim 27, wherein the solid formulation comprises about 98% exenatide and about 2% stearic acid.

38. The method of claim 27, wherein the mixture comprises a mixture selected from the group consisting of:

a) about 78.72% HEMA, about 0.40% EGDMA, about 0.79% Vitamin E TDGS, about 0.24% BME, about 0.08% P-16, about 9.89% water and about 9.89% isopropyl alcohol;

b) about 78.72% HEMA, about 0.40% EGDMA, about 0.79% Vitamin E TDGS, about 0.24% BME, about 0.08% P-16 and about 19.78% water;

c) about 68.97% HEMA, about 0.35% EGDMA, about 0.69% Vitamin E TDGS, about 0.21% BME, about 0.07% P-16, about 14.85% water and about 14.85% isopropyl alcohol; and

d) about 68.97% HEMA, about 0.35% EGDMA, about 0.69% Vitamin E TDGS, about 0.21% BME, about 0.07% P-16 and about 29.71%.