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

• US 9,895,369 B2
• Filed: 09/20/2016
• Issued: 02/20/2018
• 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:
  US15/270,493
• Publication Number:
  US 20170071938A1
• Time in Patent Office: 518 Days
• Field of Search: 514275
• 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 method of treating an ophthalmic disease or ameliorating a symptom of an ophthalmic disease in a patient in need thereof, the method comprising:

(i) implanting a device in a vitreous humor of an eye of the patient;

wherein the device comprises a reservoir chamber coupled to a porous structure;

wherein the reservoir chamber comprises a pharmaceutical formulation; and

(ii) wherein the device delivers the pharmaceutical formulation via the porous structure to the vitreous humor of the eye of the patient, thereby treating the ophthalmic disease or ameliorating the symptom of the ophthalmic disease;

wherein the pharmaceutical formulation comprises;

(i) a cyclodextrin, and (ii) about 30 mg/mL to about 60 mg/mL of an ophthalmic therapeutic agent;

wherein the ophthalmic therapeutic agent is;

(a) in solution in the formulation, and (b) has a solubility of less than 1 mg/mL in water.

2. The method of claim 1, wherein the ophthalmic disease is in a posterior segment of the eye of the patient.

3. The method of claim 1, further comprising filling the reservoir chamber with the pharmaceutical formulation after the device is inserted into the vitreous humor of the eye of the patient.

4. The method of claim 1, further comprising filling the reservoir chamber with the pharmaceutical formulation from about 30 days to about 6 months after the device is inserted into the vitreous humor of the eye of the patient.

5. The method of claim 1, wherein the pharmaceutical formulation comprises from about 30 mg/mL to about 40 mg/mL of the ophthalmic therapeutic agent.

6. The method of claim 1, wherein the pharmaceutical formulation comprises from about 40 mg/mL to about 60 mg/mL of the ophthalmic therapeutic agent.

7. The method of claim 1, wherein the weight ratio of the cyclodextrin to the ophthalmic therapeutic agent is from about 9:

1 to about 2;

1.

8. The method of claim 1, wherein the cyclodextrin is 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, or a combination of two or more thereof.

9. The method of claim 1, wherein the cyclodextrin is β

-cyclodextrin sulfobutyl ether, hydroxypropyl β

-cyclodextrin, or a combination thereof.

10. The method of claim 1, wherein the formulation comprises from about 585 mg/mL to about 660 mg/mL of the cyclodextrin.

11. The method of claim 1, wherein the formulation further comprises trehalose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, sodium hyaluronate, sodium alginate, polyethylene glycol, glycerin, propylene glycol, triacetin, N,N-dimethylacetamide, poly(vinyl pyrrolidone), pyrrolidone, or a combination of two or more thereof.

12. The method of claim 1, wherein the formulation further comprises from about 0.2% to about 1.0% of trehalose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, sodium hyaluronate, sodium alginate, polyethylene glycol, glycerin, propylene glycol, triacetin, N,N-dimethylacetamide, poly(vinyl pyrrolidone), pyrrolidone, or a combination of two or more thereof.

13. The method of claim 1, wherein the formulation further comprises poly(vinyl pyrrolidone).

14. The method of claim 1, where the formulation further comprises from about 0.8% to about 1.0% of the poly(vinyl pyrrolidone).

15. The method of claim 1, wherein the ophthalmic therapeutic agent is in the form of a pharmaceutically acceptable monovalent or divalent salt.

16. The method of claim 1, wherein the ophthalmic disease is retinopathy, macular degeneration, neovascularization, uveitis, retinal vein occlusion, ocular trauma, edema, ocular ischemia, Coat'"'"'s disease, or glaucoma.

17. The method of claim 1, wherein the ophthalmic disease is diabetic retinopathy, retinopathy of prematurity, sickle cell retinopathy, age-related macular degeneration, pathological choroidal neovascularization, pathological retinal neovascularization, surgery-induced neovascularization, surgery-induced edema, cystoid macular edema;

neovascular glaucoma, uveitis, retinal vein occlusion, ocular trauma, ocular ischemia, or Coat'"'"'s disease.