Crystalline forms of therapeutic compounds and uses thereof

• US 10,160,765 B2
• Filed: 09/22/2017
• Issued: 12/25/2018
• Est. Priority Date: 11/01/2013
• Status: Active Grant

• Current Assignee: Kala Bio, Inc.
• Original Assignee: Kala Pharmaceuticals, Inc.
• Inventors: Enlow, Elizabeth, Nguyen, Minh Ngoc, Ong, Winston Z.
• Primary Examiner(s): Ward, Paul V
• Application Number:
  US15/712,645
• Publication Number:
  US 20180009824A1
• Time in Patent Office: 459 Days
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• 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 9/0034 Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/5021 Organic macromolecular compounds
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 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: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 491/107 with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Abstract

Described herein are certain crystalline forms of Compound 3, as well as pharmaceutical compositions employing the crystalline forms. Also provided are particles (e.g., nanoparticles) comprising such crystalline forms or pharmaceutical compositions. In certain examples, the particles are mucus penetrating particles (MPPs). The present invention further relates to methods of treating or preventing diseases using crystalline forms or pharmaceutical compositions.

Claims

1. A method of inhibiting aberrant vascular endothelial growth factor (VEGF) signaling comprising administering to a subject in need thereof a therapeutically effective amount of crystalline form A of 7-(3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolin-7-yloxy)propyl)-2-oxa-7-azaspiro[3.5]nonane having an X-ray powder diffraction (XRPD) pattern with peaks at about 6.11, 9.63, 16.41, 18.60, 20.36 and 23.01±

0.3 degrees two theta, or 14.45, 9.17, 5.40, 4.77, 4.36 and 3.86±

0.3 Å

in d-spacing.

2. The method of claim 1, wherein crystalline Form A further has XRPD peaks at about 11.46, 12.26, 18.16, 19.51, 21.12 and 25.71±

0.3 degrees two theta or 7.71, 7.22, 4.88, 4.55, 4.20 and 3.46±

0.3 Å

in d-spacing.

3. The method of claim 1, wherein crystalline Form A has the XRPD pattern as shown in FIG. 1.

4. The method of claim 1, wherein the crystalline form is administered topically, by injection, to the eye, orally, or by inhalation.

5. The method of claim 1, wherein the inhibition of aberrant VEGF signaling treats an ocular disease.

6. The method of claim 5, wherein the ocular disease is retinopathy, age-related macular degeneration, corneal neovascularization, diabetic macular edema, or retinal vein occlusion.

7. The method of claim 1, wherein the aberrant signaling of VEGF is associated with cancer.

14. The method of claim 1, wherein the inhibition of VEGF signaling comprises inhibiting abnormal angiogenesis.

8. A method of inhibiting aberrant vascular endothelial growth factor (VEGF) signaling comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising:

a plurality of coated particles, comprising;

a core particle comprising crystalline form A of 7-(3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolin-7-yloxy)propyl)-2-oxa-7-azaspiro[3.5]nonane having an XRPD pattern with peaks at about 6.11, 9.63, 16.41, 18.60, 20.36 and 23.01±

0.3 degrees two theta, or 14.45, 9.17, 5.40, 4.77, 4.36 and 3.86±

0.3 Å

in d-spacing, wherein the crystalline form constitutes at least about 80 wt % of the core particle; and

a coating comprising one or more surface-altering agents surrounding the core particle.

9. The method of claim 8, wherein the one or more surface-altering agents comprises a triblock copolymer comprising a hydrophilic block-hydrophobic block-hydrophilic block configuration, wherein the hydrophobic block has a molecular weight of at least about 2 kDa, and the hydrophilic blocks constitute at least about 15 wt % of the triblock copolymer.

10. The method of claim 8, wherein the crystalline form is administered topically, by injection, to the eye, orally, or by inhalation.

11. The method of claim 8, wherein the inhibition of aberrant VEGF signaling treats an ocular disease.

12. The method of claim 11, wherein the ocular disease is retinopathy, age-related macular degeneration, corneal neovascularization, diabetic macular edema, or retinal vein occlusion.

13. The method of claim 8, wherein the aberrant signaling of VEGF is associated with cancer.

15. The method of claim 8, wherein the inhibition of VEGF signaling comprises inhibiting abnormal angiogenesis.