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Claims for Patent: 8,367,701

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Claims for Patent: 8,367,701

Title:Crystalline pharmaceutical and methods of preparation and use thereof
Abstract: Novel crystalline polymorphic forms, Forms A, B, C, D, and E of a compound of Formula I, which has been found to be a potent inhibitor of LFA-1, are disclosed. Methods of preparation and uses thereof in the treatment of LFA-1 mediated diseases are also disclosed in this invention. ##STR00001##
Inventor(s): Burnier; John (Pacifica, CA), Gadek; Thomas (Oakland, CA), Naud; Frederic (Binningen, CH)
Assignee: SARcode Bioscience Inc. (Brisbane, CA)
Application Number:13/289,172
Patent Claims: 1. A composition comprising a compound of Formula I: ##STR00028## comprising a purity of greater than about 90%, and/or a pharmaceutically acceptable salt thereof.

2. The composition of claim 1, wherein the purity is greater than about 98%.

3. The composition of claim 1, wherein the compound comprises at least about 95% of an S-enantiomer.

4. The composition of claim 1, wherein the compound is not the calcium salt of the free acid.

5. The composition of claim 1, wherein the compound is a crystalline form (Form A) comprising an X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2.theta. of about 18.2, 21.4, and 22.7 degrees.

6. The composition of claim 5, wherein the form undergoes a predominant endotherm at about 145.degree. C.

7. The composition of claim 5, wherein the form is produced by isolating the form from a suspension of the compound in an organic solvent which is acetonitrile, methyl ethyl ketone, or water.

8. The composition of claim 1, wherein the compound is a crystalline form (Form B) comprising an X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2.theta. of about 12.1, 17.1, and 18.5 degrees.

9. The composition of claim 1, wherein the compound is a crystalline form (Form C) comprising an X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2.theta. of about 4.8, 17.8, and 21.5 degrees.

10. The composition of claim 1, wherein the compound is a crystalline form (Form D) comprising an X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2.theta. of about 17.6, 21.7, and 24.8 degrees.

11. The composition of claim 1, wherein the compound is a crystalline form (Form E) comprising an X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2.theta. of about 5.12, 8.26, and 17.8 degrees.

12. The composition of claim 1, wherein the compound is an amorphous form.

13. The composition of claim 1, wherein the compound comprises less than 0.5% of any one byproduct of chemical synthesis of the compound.

14. The composition of claim 1, wherein the compound comprises less than a total of 1.5% of all byproducts of the chemical synthesis.

15. A method of producing the form of the compound of claim 5: ##STR00029## comprising the steps of: a) suspending the compound of Formula I in a solvent; b) filtering the suspension to isolate a crystalline product; and c) washing the crystalline product with water thereby obtaining the form of the compound of claim 5.

16. The method of claim 15 wherein the solvent is acetonitrile or methyl ethyl ketone.

17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1.

18. The pharmaceutical composition of claim 17, wherein said compound has been converted to a salt.

19. The pharmaceutical composition of claim 17, wherein said compound comprises the amorphous form or any of crystalline Forms A, B, C, D, or E, or a combination thereof, of said compound.

20. The pharmaceutical composition of claim 17, wherein said carrier further comprises one or more pharmaceutically acceptable excipients.

21. The pharmaceutical composition of claim 17, further comprising at least one additional therapeutic agent.

22. The pharmaceutical composition of claim 21, wherein the additional therapeutic agent is an antioxidant, antiinflammatory agent, antimicrobial agent, antiangiogenic agent, anti-apoptotic agent, vascular endothelial growth factor inhibitor, antiviral agent, calcineurin inhibitor, corticosteroid, antihistamine, mast cell stabilizing agent, or immunomodulator.

23. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is a gel comprising about 1% W/V of said compound; and further wherein said pharmaceutically acceptable carrier comprises up to about 15% W/V Dimethyl Isosorbide; up to about 25% W/V Transcutol; up to about 12% W/V Hexylene glycol, up to about 0.15% W/V Methylparaben; up to about 0.05% W/V Propylparaben; up to about 1% W/V Hydroxyethyl Cellulose; and water.

24. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is an ointment comprising about 1% W/V of said compound; and further wherein said pharmaceutically acceptable carrier comprises up to about 10% W/V Dimethyl Isosorbide; up to about 0.02% W/VButylated Hydroxytoluene; up to about 2% W/V Span 80; up to about 10% W/VWhite Wax; and White Petrolatum.

25. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is a water based lotion comprising about 1% W/V of said compound; and further wherein said pharmaceutically acceptable carrier comprises up to about 15% W/V Dimethyl Isosorbide; up to about 25% W/V Transcutol; up to about 12% W/V Hexylene glycol; up to about 5% W/V Propylene Glycol; and pH 6.0 25% Trolamine, wherein the lotion is buffered to a pH of about pH 4.0 to about pH 7.5.

26. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is an aqueous solution buffered to a pH of about 6.0 to about 8.0 with Sodium Phosphate, Monobasic, and further wherein said pharmaceutically acceptable carrier comprises about 1% W/V of the compound of claim 1, up to about 0.1% W/V EDTA, and, optionally, up to about 0.4% w/w Methylparaben, and optionally, up to about 0.02% w/w Propylparaben.

27. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is a biocompatible solid or gel.

28. The pharmaceutical composition of claim 27 wherein the biocompatible solid is biodegradable.

29. The pharmaceutical composition of claim 17, wherein the composition is suitable for administration via instillation, via aerosol, via inhalation, orally, topically, transdermally, via insert, or via injection.

30. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is formulated to deliver a therapeutically effective amount of the compound of Formula I locally.

31. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is formulated to deliver less than a therapeutically effective amount of the compound of Formula I systemically.

32. A method of treating disease in a subject, comprising the steps of administering an effective amount of the pharmaceutical composition of claim 17 to the subject in need thereof, wherein said disease is an inflammation-mediated disease.

33. The method of claim 32, wherein the disease is an inflammatory eye disorder which is intraocular, periocular and ocular surface inflammation, Keratoconjunctivitis, keratoconjunctivitis sicca (KCS, aka Dry Eye), KCS in patients with Sjogren's syndrome, allergic conjunctivitis, uveitis, inflammation of the eye, the cornea and periocular tissue from contact lens wear, inflammation of the eye following surgery including LASIK, intraocular inflammation including inflammation of the retina and the anterior and posterior segments of the eye, uveitis, retinitis, edema and retinopathies including diabetic macular edema and diabetic retinopathy, corneal inflammation including rejection of corneal transplants Graves' disease (Basedow disease), or Graves ophthalmopathy.

34. The method of claim 32, wherein the disease is an allergic disease which is allergic conjunctivitis, allergic rhinitis, allergic asthma, or allergic contact dermatitis.

35. The method of claim 32, wherein the disease is psoriasis, irritant contact dermatitis, eczematous dermatitises, seborrhoeic dermatitis, cutaneous manifestations of immunologically-mediated disorders, alopecia, alopecia areata, or scar formation.

36. The pharmaceutical composition of claim 27, comprising a compound of Formula I: ##STR00030## which comprises a purity greater than about 90% and a pharmaceutically acceptable biocompatible matrix wherein the compound comprises a solid form within the biocompatible matrix.

37. The pharmaceutical composition of claim 36, wherein the solid form is the amorphous form or any of crystalline Forms A, B, C, D, or E, or a combination thereof, of said compound.

38. The pharmaceutical composition of claim 36, wherein the biocompatible matrix is a polyacrylate, methacyrlate, polyolefin, polyamide, fluoropolymer, cellulose derivative, polyvinyl alcohol, polyvinylpyrrolidone, coated zeolite, or PLGA microsphere or nanosphere.

39. The pharmaceutical composition of claim 36, wherein the biocompatible matrix is biodegradable.

40. The pharmaceutical composition of claim 36, wherein a release of the compound from the biocompatible matrix comprises a slow release profile or a sustained release profile.

41. A compound of the formula: ##STR00031## or its pharmaceutically acceptable salts.
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