OCTREOTIDE IMPLANT HAVING A RELEASE AGENT

• US 20100022450A1
• Filed: 06/24/2009
• Published: 01/28/2010
• Est. Priority Date: 06/25/2008
• Status: Active Grant

• Current Assignee: Endo Pharmaceuticals Solutions Incorporated (Endo International PLC)
• Original Assignee: Endo Pharmaceuticals Solutions Incorporated (Endo International PLC)
• Inventors: KUZMA, Petr, Decker, Stefanie, Quandt, Harry
• Granted Patent: US 7,960,335 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 38/31 Somatostatins
• 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: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/08 : for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Abstract

Methods, formulations and kits are described that allow for the controlled release of octreotide, e.g., octreotide acetate, in a subject.

Claims

1. A formulation for the controlled release of octreotide after implantation into a subject comprising a preparation substantially encased in a hydrophilic polymer selected from polyurethane based polymers and methacrylate based polymers, wherein the preparation comprises octreotide, wherein the formulation is effective to permit release of octreotide at a rate of about 30 μ

g to about 800 μ

g per day over about six months in vivo, and wherein the hydrophilic polymer but not the preparation further comprises a release agent with a molecular weight of at least about 1000 Daltons.

2. The formulation of claim 1, wherein the release agent is a non-ionic surfactant.

3. The formulation of claim 2, wherein the non-ionic surfactant comprises a polyethylene glycol hydrophilic tail and a lipophilic head.

4. The formulation of claim 1, wherein the release agent is selected from the group consisting of:

Brij 35, polyoxyethylene(20)sorbitan trioleate, Tween 20, Tween 80, Vitamin E TPGS, and a mixture of any two or more thereof.

5. The formulation of claim 1, wherein the release agent has a molecular weight of at least about 1200 Daltons.

6. The formulation of claim 1, wherein the hydrophilic polymer has an exterior surface area of about 350 mm² or greater.

7. The formulation of claim 6, wherein the hydrophilic polymer has an exterior surface area ranging from about 350 mm² to about 1500 mm².

8. The formulation of claim 1, wherein the formulation permits release of octreotide at an average rate ranging from about 75 μ

g per day to about 300 μ

g per day in vivo.

10. The formulation of claim 1, wherein the hydrophilic polymer comprises a mixture of 2-hydroxyethyl methacrylate and hydroxypropyl methacrylate.

11. The formulation of claim 8, wherein the formulation provides an in vivo average C_ss of about 0.1 ng/mL to about 9 ng/mL of octreotide in the subject.

12. The formulation of claim 11, wherein the formulation provides an in vivo average C_ss of about 1 ng/mL to about 4 ng/mL of octreotide in the subject.

13. The formulation of claim 1, wherein the preparation comprises about 40 mg to about 120 mg of octreotide.

14. The formulation of claim 13, wherein preparation comprises about 50 mg of octreotide acetate.

15. The formulation of claim 13, wherein the preparation comprises about 85 mg of octreotide acetate.

16. The formulation of claim 10, wherein the hydrophilic polymer comprises a mixture of about 20% of 2-hydroxyethyl methacrylate and about 80% hydroxypropylmethacrylate.

17. The formulation of claim 10, wherein the hydrophilic polymer comprises a mixture of about 40% of 2-hydroxyethyl methacrylate and about 60% hydroxypropylmethacrylate.

18. The formulation of claim 1, wherein the preparation further comprises an excipient selected from the group consisting of:

magnesium stearate, stearic acid, vegetable stearin, talc and silica.

19. The formulation of claim 1, wherein the preparation further comprises a compound selected from the group consisting of:

hydroxypropylcellulose, hydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, modified starch and crosslinked polyvinyl pyrrolidone.

9. The formulation of claim 9, wherein the octreotide is octreotide acetate.

20. A method of decreasing GH levels or IGF-1 levels in a subject and/or treating an octreotide-sensitive disease, disorder or symptom, the method comprising subcutaneously implanting at least one dry implantable device comprising a preparation encased in a hydrophilic polymer, wherein the preparation comprises octreotide, and wherein the hydrophilic polymer but not the preparation further comprises a release agent having a molecular weight of at least 1000.

25. The method of claim 24, wherein the preparation comprises about 40 mg to about 120 mg of octreotide acetate.

26. The method of claim 24, wherein two implantable devices are implanted subcutaneously.

27. The method of claim 24, wherein the implantable device remains implanted in a patient for a continuous time period ranging from about six months to about two years.

28. The method of claim 27, wherein the implantable device remains implanted in the patient for a continuous time period ranging from about six months to about one year.

29. The method of claim 24, wherein the implantable device is sterilized by irradiation.

30. The method of claim, wherein the octreotide-sensitive disease, disorder or symptom is selected from the group consisting of:

acromegaly or symptoms associated with acromegaly, a symptom associated with a carcinoid tumor, VIPoma or neuroendocrine tumor, carcinoid syndrome, proliferative diabetic retinopathy, rosacea, pancreatitis, gastrointestinal bleeding, pancreatic and intestinal fistulas, Graves-Basedow opthalmopathy, glaucoma, and/or corneal disease associated with vasularization treating acromegaly or symptoms associated with acromegaly.

31. The method of claim 31, wherein a symptom associated with a carcinoid tumor, VIPoma or neuroendocrine tumor is selected from the group consisting of severe diarrhea, watery diarrhea or flushing episodes.

32. A kit comprising:

a) a formulation for the controlled release of octreotide after implantation into a subject comprising a preparation substantially encased in a hydrophilic polymer selected from polyurethane based polymers and methacrylate based polymers, wherein the preparation comprises octreotide, wherein the formulation is effective to permit release of octreotide at a rate of about 30 μ

g to about 800 μ

g per day over about six months in vivo, and wherein the hydrophilic polymer but not the preparation further comprises a release agent with a molecular weight of at least about 1000 Daltons.