Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof

• US 9,474,756 B2
• Filed: 08/06/2015
• Issued: 10/25/2016
• Est. Priority Date: 08/08/2014
• Status: Active Grant

• Current Assignee: Forsight Vision4, Inc. (Roche Holding AG)
• Original Assignee: Forsight Vision4, Inc. (Roche Holding AG)
• Inventors: Horvath, Judit, Astafieva, Irina, Erickson, Signe, Farinas, Kathleen Cogan
• Primary Examiner(s): Solola, Taofiq A
• Application Number:
  US14/819,682
• Publication Number:
  US 20160038488A1
• Time in Patent Office: 446 Days
• Field of Search: 514/275
• US Class Current: 1/1
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• 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 47/40 Cyclodextrins; Derivatives thereof
• CPC Class Codes: A61K 47/6951 using cyclodextrin cyclodextrins used as simple excipients A61K47/40
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• 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: A61M 5/14 Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 disclosure relates to stable formulations of receptor tyrosine kinase inhibitors (TKI), e.g., pazopanib; methods of preparation thereof; and use of the disclosed formulations in sustained delivery of the active agent to a target site. The disclosure further relates to methods of converting one polymorphic Form of a TKI to another polymorphic Form and/or an amorphous form.

Claims

1. A stable pharmaceutical formulation for controlled release of a therapeutic agent in the vitreous of an eye from a therapeutic delivery device having a reservoir chamber coupled to a porous structure, the formulation comprising about 40 mg/mL to about 70 mg/mL of a pharmaceutically acceptable monovalent or divalent salt of pazopanib in solution in the formulation, and a complexing agent comprising cyclodextrin;

poly(vinyl pyrrolidone) (PVP); and

/or Histidine HCl.

2. The formulation of claim 1, wherein the pharmaceutically acceptable monovalent or divalent salt is a halide salt of pazopanib.

3. The formulation of claim 2, wherein the pharmaceutically acceptable monovalent or the divalent salt is a chloride salt.

4. The formulation of claim 3, wherein the monovalent salt is stable in formulation up to a concentration of about 60 mg/mL.

5. The formulation of claim 3, wherein the divalent salt is stable in formulation up to a concentration of about 70 mg/mL.

6. The formulation of claim 1, wherein the cyclodextrin is selected from the group consisting of:

2-hydroxypropyl-β

-cyclodextrin, methyl-β

-cyclodextrin, randomly methylated-β

-cyclodextrin, ethylated-β

-cyclodextrin, triacetyl-β

-cyclodextrin, peracetylated-β

-cyclodextrin, carboxymethyl-β

-cyclodextrin, hydroxyethyl-β

-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β

-cyclodextrin, glucosyl-β

-cyclodextrin, maltosyl-β

-cyclodextrin, sulfobutyl ether-β

-cyclodextrin, branched-β

-cyclodextrin, hydroxypropyl-γ

-cyclodextrin, randomly methylated-γ

-cyclodextrin, trimethyl-γ

-cyclodextrin, and any combination(s) thereof.

16. The formulation of claim 1, wherein the pH of the formulation is 6-7.

7. A method of treating and/or ameliorating an ophthalmic disease or disorder of the posterior segment of the eye, comprising delivering to the vitreous, by controlled release, a stable pharmaceutical formulation contained in a reservoir chamber coupled to a porous structure of an intravitreal drug delivery device, the formulation comprising about 40 mg/L to about 70 mg/mL of a pharmaceutically acceptable monovalent or divalent salt of pazopanib in solution in the formulation and

a complexing agent comprising cyclodextrin;

poly(vinyl pyrrolidone) (PVP); and

/or Histidine HCl.

8. The method of claim 7, wherein the disease or disorder is chosen from diabetic retinopathy, age-related macular degeneration (AMD), pathologic choroidal neovascularization (CNV), pathologic retinal neovascularization, uveitis, retinal vein occlusion, ocular trauma, surgery induced edema, surgery induced neovascularization, cystoid macular edema, ocular ischemia, retinopathy of prematurity, Coat'"'"'s disease, sickle cell retinopathy, and neovascular glaucoma.

9. The method of claim 7, wherein the reservoir chamber is re-fillable and is re-filled with the formulation after the device is inserted into the eye.

10. The method of claim 9, wherein the reservoir chamber is re-filled with the formulation after the device has been in the eye for between 30-90 days, or up to 6 months.

11. The method of claim 7, wherein the cyclodextrin is selected from the group consisting of:

2-hydroxypropyl-β

-cyclodextrin, methyl-β

-cyclodextrin, randomly methylated-β

-cyclodextrin, ethylated-β

-cyclodextrin, triacetyl-β

-cyclodextrin, peracetylated-β

-cyclodextrin, carboxymethyl-β

-cyclodextrin, hydroxyethyl-β

-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β

-cyclodextrin, glucosyl-β

-cyclodextrin, maltosyl-β

-cyclodextrin, sulfobutyl ether-β

-cyclodextrin, branched-β

-cyclodextrin, hydroxypropyl-γ

-cyclodextrin, randomly methylated-γ

-cyclodextrin, trimethyl-γ

-cyclodextrin, and any combination(s) thereof.

12. The method of claim 7, wherein the monovalent salt is a halide.

13. The method of claim 12, wherein the halide is a chloride.

14. The method of claim 7, wherein the monovalent salt is stable in formulation up to a concentration of about 60 mg/mL.

15. The method of claim 7, wherein the divalent salt is stable in formulation up to a concentration of about 70 mg/mL.

17. The method of claim 7, wherein the pH of the formulation is 6-7.