Controlled release CGRP delivery composition for cardiovascular and renal indications

• US 7,976,847 B2
• Filed: 01/13/2005
• Issued: 07/12/2011
• Est. Priority Date: 01/13/2004
• Status: Expired due to Fees

• Current Assignee: VasoGenix Pharmaceuticals, Inc.
• Original Assignee: VasoGenix Pharmaceuticals, Inc.
• Inventors: Southard, George L., Southard, Jeffrey L.
• Primary Examiner(s): Li; Ruixiang
• Application Number:
  US10/586,209
• Publication Number:
  US 20080069865A1
• Time in Patent Office: 2,371 Days
• Field of Search: None
• US Class Current: 424/198.1
• CPC Class Codes: A61K 38/225 Calcitonin gene related peptide
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative 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 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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

Abstract

The present invention provides methods of treating heart failure and improving renal function, and/or preventing the advancement of heart failure into advanced stages, and methods of counteracting ischemia due to a myocardial infarction by providing improved methods of administering a therapeutically effective amount CGRP as a controlled release formulation. The therapies can be administered on an outpatient or inpatient basis and can further be used as maintenance therapies.

Claims

1. A method of treating heart failure in a patient, comprising delivering to said patient CGRP in an amount effective to provide symptomatic relief, or delay progression of the disease state of heart failure in said patient, wherein said CGRP is delivered to said patient as a controlled release composition,

wherein said controlled release composition comprises a flowable thermoplastic polymer composition comprising a biocompatible polymer, a biocompatible solvent and CGRP and said composition is delivered to a bodily tissue or fluid in said patient, wherein the amounts of the polymer and the solvent are effective to form a biodegradable polymer matrix containing CGRP in situ when said composition contacts said bodily fluid tissue or fluid,

wherein the polymer matrix comprises between about 5% and 15% CGRP by weight and said CGRP is released from said polymer matrix at a rate that will maintain circulating plasma levels of CGRP between 11±

5 pg/ml and 186±

127 pg/ml over a period of 7 to 180 days.

2. The method of claim 1, wherein said CGRP is in the form of a conjugate comprising CGRP coupled to a polymer.

3. The method of claim 2, wherein said polymer is a poly(alkylene glycol) or a polysaccharide.

4. The method of claim 1, wherein the composition further comprises a controlled release additive.

5. The method of claim 1, wherein said composition comprises between about 0.56 and 290 mg CGRP and between about 0.01 and 5.8 mL of said composition is administered to said patient.

6. The method of claim 1, wherein said composition comprises about 0.56 and 290 mg CGRP and between about 0.004 and 1.93 mL of said composition is administered to said patient.

7. The method of claim 1, wherein said biocompatible polymer is selected from the group consisting of polylactides, polyglycolides, polyanhydrides, polyorthoesters, polycaprolactones, polyamides, polyurethanes, polyesteramides, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyacrylates, polyalkylene succinates, poly(malic acid), poly(amino acids) and copolymers, terpolymers, cellulose diacetate, ethylene vinyl alcohol, and copolymers and combinations thereof.

8. The method of claim 1, wherein the polymer matrix releases CGRP by diffusion, erosion, or a combination of diffusion or erosion as the polymer matrix biodegrades in said patient.

9. The method of claim 1, wherein said CGRP is delivered via a puncture needle or catheter.

10. The method of claim 1, further comprising administering one or more drugs selected from the group consisting of anti-proliferative agents, anti-clotting agents, vasodilators, diuretics, beta-blockers, calcium ion channel blockers, blood thinners, cardiotonics, ACE inhibitors, anti-inflammatories, and antioxidants.

11. The method of claim 10, wherein said drug is added to said polymer composition prior to administration such that said solid polymer matrix further contains said drug.

12. The method of claim 10, wherein said drug is administered as a separate formulation before, simultaneously, or subsequently to administration of said polymer composition.

13. The method of claim 1, wherein the length of said treatment is sufficient to relieve or attenuate one or more symptoms of heart failure.

14. The method of claim 1, wherein said treatment is sufficient to improve the quality of life of said patient.

15. The method of claim 1, wherein said patient is a pediatric patient.

16. The method of claim 1, wherein said controlled release composition comprises biodegradable microspheres incorporating CGRP.

17. The method of claim 16, wherein said microspheres comprise poly(lactic-co-glycolic acid), poly(lactic acid), poly(caprolactone), polycarbonates, polyamides, polyanhydrides, polyamino acids, polyortho esters, polyacetals, polycyanoacrylates degradable polyurethanes, polyacrylates, ethylene-vinyl acetate copolymers, acyl substituted cellulose acetates, and derivatives and copolymers thereof.

18. The method of claim 16, wherein said CGRP is in the form of a conjugate comprising CGRP coupled to a polymer.

19. The method of claim 16, wherein said microspheres are embedded in a gel matrix.

20. The method of claim 19, wherein said CGRP is in the form of a conjugate comprising CGRP coupled to a polymer.

21. The method of claim 19, wherein said polymer is a poly(alkylene glycol) or a polysaccharide.

22. The method of claim 1, wherein said controlled release composition comprises CGRP conjugated to a polymer.

24. The method of claim 1, comprising:

(a) administering CGRP to said patient by a method selected from parenteral, oral, sublingual, intranasal, intracoronary, intra-arterial, intravenous, transmucosal, or intradermal delivery for a time and at a dose effective to provide symptomatic relief, or delay progression of the disease state of heart failure in said patient.

25. The method of claim 24, wherein said controlled release formulation comprises biodegradable microspheres incorporating CGRP.

26. The method of claim 24, wherein said controlled release formulation comprises CGRP coupled to a polymer.

23. A method of treating heart failure in a patient, comprising administering a flowable composition comprising a biocompatible polymer, a biocompatible solvent and CGRP to a bodily tissue or fluid in said patient, wherein the amounts of the polymer and the solvent are effective to form said polymer matrix comprising CGRP in situ when the formulation contacts said bodily fluid tissue or fluid wherein polymer matrix comprises between about 5% and 15% CGRP by weight and said CGRP is released from said polymer matrix at a rate between about 0.0008 and 0.016 μ

g/min/kg body weight over a period of 7 to 180 days.