CONTROLLED RELEASE FORMULATIONS OF OCTREOTIDE

• US 20100317579A1
• Filed: 06/11/2010
• Published: 12/16/2010
• Est. Priority Date: 03/11/2005
• Status: Active Grant

• Current Assignee: ENDO USA Incorporated
• Original Assignee: Endo Pharmaceuticals Solutions Incorporated (Endo International PLC)
• Inventors: Decker, Stephanie, KUZMA, Petr
• Granted Patent: US 8,507,432 B2
• Time in Patent Office: Days
• US Class Current: 514/8.6
• CPC Class Codes: A61K 38/31 Somatostatins
• 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 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 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/06 of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
• CPC Class Codes: A61P 5/08 for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
• CPC Class Codes: A61P 5/12 for decreasing, blocking or antagonising the activity of the posterior pituitary hormones
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

A formulation of octreotide or pharmaceutically acceptable salts thereof, which provides controlled release of a therapeutically effective amount of octreotide for a period of at least about two months. Methods of treating acromegaly, decreasing growth hormone, decreasing IGF-1, and treating conditions associated with carcinoid tumors and VIPomas by administering a controlled release formulation of octreotide are provided herein.

Claims

1. A method of treating a patient suffering from a condition associated with overproduction of growth hormone or IGF-1 or suffering from one or more symptoms associated with such condition, said method comprising:

implanting subcutaneously into a patient in need thereof at least one implant comprising a hydrogel and a pharmaceutical formulation comprising octreotide;

wherein said pharmaceutical formulation is contained within said hydrogel, which hydrogel comprises a copolymer obtained from the copolymerization of a mixture comprising at least two hydrophilic, ethylenically unsaturated monomers;

wherein said pharmaceutical formulation contains between about 20 to about 150 milligrams of octreotide, in free form or salt form;

wherein said pharmaceutical formulation further comprises hydroxypropylcellulose; and

wherein said at least one implant releases a therapeutically effective amount of said octreotide to said patient over a period of at least about two months.

2. The method of claim 1, wherein said effective amount of said octreotide provides an in vivo average C_ss in said patient of about 0.1 ng/ml to about 9 ng/ml of octreotide.

3. The method of claim 1, wherein said pharmaceutical formulation contains from about 40 to about 90 milligrams of octreotide.

4. The method of claim 1, wherein said octreotide is octreotide acetate.

5. The method of claim 4, wherein said pharmaceutical formulation contains about 50 milligrams of said octreotide acetate.

6. The method of claim 4, wherein said pharmaceutical formulation contains about 80 milligrams of said octreotide acetate.

7. The method of claim 2, wherein said effective amount of said octreotide provides an in vivo average C_ss in said patient of about 1 ng/ml to about 2 ng/ml of octreotide.

8. The method of claim 1, wherein said at least one implant releases a therapeutically effective amount of octreotide over a period of about two months to about two years.

9. The method of claim 1, wherein said at least one implant releases a therapeutically effective amount of said octreotide over about six months.

10. The method of claim 1, wherein said at least two hydrophilic, ethylenically unsaturated monomers are 2-hydroxyethyl methacrylate and hydroxypropyl methacrylate.

11. The method of claim 1, wherein said copolymer comprises about 20% of 2-hydroxyethyl methacrylate and about 80% hydroxypropylmethacrylate.

12. The method of claim 1, wherein the pharmaceutical formulation contains about 0.5 to 20% w/w of the hydroxypropylcellulose

13. The method of claim 1, wherein said pharmaceutical formulation further comprises magnesium stearate.

14. The method of claim 13, wherein the pharmaceutical formulation contains about 0.5 to 5% w/w of the magnesium stearate.

15. The method of claim 1, wherein said at least one implant releases said octreotide at a rate of about 10 ug to about 1000 ug per day over a period of about six months.

16. The method of claim 1, wherein said at least one implant is two or more implants.

17. The method of claim 1, wherein said at least one implant releases said octreotide at a rate of about 30 μ

g to about 250 μ

g per day in vitro.

18. The method of claim 1, wherein the at least one implant is implanted in a dry state.

19. The method of claim 1, wherein the at least one implant is implanted in a hydrated state.

20. The method of claim 1, wherein said copolymer comprises about 40% of 2-hydroxyethyl methacrylate and about 60% hydroxypropylmethacrylate.

21. A method of treating a patient suffering from a condition associated with VIP-secreting tumors or suffering from one or more symptoms associated with such condition, said method comprising:

implanting subcutaneously into a patient in need thereof at least one implant comprising a hydrogel and a pharmaceutical formulation comprising octreotide;

wherein said pharmaceutical formulation is contained within said hydrogel, which hydrogel comprises a copolymer obtained from the copolymerization of a mixture comprising at least two hydrophilic, ethylenically unsaturated monomers;

wherein said pharmaceutical formulation contains between about 20 to about 150 milligrams of octreotide, in free form or salt form;

wherein said pharmaceutical formulation further comprises an effective amount of hydroxypropylcellulose; and

wherein said at least one implant releases a therapeutically effective amount of said octreotide to said patient over a period of at least about two months.

22. The method of claim 21, wherein said effective amount of said octreotide provides an in vivo average C_ss in said patient of about 0.1 ng/ml to about 9 ng/ml of octreotide.

23. The method of claim 21, wherein said pharmaceutical formulation contains from about 40 to about 90 milligrams of octreotide.