Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof

1. A morphic form of fluticasone propionate (Form A) characterized by an X-ray powder diffraction pattern including peaks at about 7.8, 15.7, 20.8, 23.7, 24.5, and 32.5 degrees 2θ.

2. The morphic form of claim 1 characterized by an X-ray powder diffraction pattern further including peaks at about 9.9, 13.0, 14.6, 16.0, 16.9, 18.1, and 34.3 degrees 2θ.

3. The morphic form of claim 1 characterized by an X-ray powder diffraction pattern substantially similar to that set forth in FIG. 31A .

4. The morphic form of claim 1 , wherein the morphic form has a purity of greater than 99% by weight.

5. The morphic form of claim 1 further characterized by a tap density of no less than 0.35 g/cm 3 , no less than 0.40 g/cm 3 , no less than 0.45 g/cm 3 , no less than 0.50 g/cm 3 , or no less than 0.55 g/cm 3 .

6. The morphic form of claim 1 further characterized by a melting point of 299.5° C. with a melting range of 10° C.

7. The morphic form of claim 1 comprising fluticasone propionate nanoplates with an average size of about 100-1000 nm.

8. The morphic form of claim 7 , wherein the nanoplates each have an average size of about 100-800 nm.

9. The morphic form of claim 7 , wherein the nanoplates have the c-axis crystallographic direction substantially normal to the surfaces that define the thickness of the nanoplates.

10. The morphic form of claim 1 further characterized by a dissolution rate in water of about 1 μg/g/day in water al room temperature.

11. A pharmaceutical composition comprising the morphic form of claim 1 and a pharmaceutically acceptable carrier.

12. The composition of claim 11 , wherein the composition is a topical formulation comprising a suspension of between 0.0001%-10% of the fluticasone propionate.

13. A method of treating or alleviating a symptom of blepharitis, post-operative ocular inflammation, uveitis, dry eye, or eye allergy, the method comprising administering to a subject in need thereof an effective amount of the composition of claim 11 .

14. The method of claim 13 , wherein the method comprises administering topically to the lid margin, skin or ocular surface of a subject in need thereof an effective amount of the composition of claim 11 .

15. A method of treating or alleviating asthma or chronic obstructive pulmonary disease (COPD), the method comprising administering to a subject in need thereof an effective amount of the composition of claim 11 .

16. A method of manufacturing the morphic form of claim 1 , comprising:

providing a sterile phase I solution comprising fluticasone propionate and a solvent for fluticasone propionate;

providing a sterile phase II solution comprising at least one surface stabilizer and an antisolvent for fluticasone propionate, wherein the at least one surface stabilizer comprises a cellulosic surface stabilizer;

mixing the phase I solution and the phase II solution to obtain a phase III mixture, wherein sonication is applied when mixing the two solutions and the mixing is performed at a first temperature not greater than 20° C.; and

annealing the phase III mixture at a second temperature that is greater than the first temperature for a period of time (T 1 ) such as to produce a phase III suspension comprising the morphic form of claim 1 .

17. The method of claim 16 , wherein sonication is applied with an output power of about 10-75 watt.

18. The method of claim 16 , wherein the cellulosic surface stabilizer is methylcellulose having a viscosity of about 4 to 50 cP or methylcellulose with a molecular weight of not greater than 100 kDa, the first temperature is a temperature between 0° C. and 5° C., the second temperature is a temperature between 10° C. and 40° C., and T 1 is at least 8 hours.

19. The morphic form of claim 1 , wherein the unit cell structure of the morphic form is Monoclinic, P21, in which a is 7.7116 Å, b is 14.170 Å, c is 11.306 Å, β is 98.285 degrees, and volume is 1222.6 Å 3 .

20. The morphic form of claim 6 , wherein the morphic form is characterized by an X-ray powder diffraction pattern further including peaks at about 9.9, 13.0, 14.6, 16.0, 16.9, 18.1, and 34.3 degrees 2θ.

21. The morphic form of claim 20 , wherein the morphic form is further characterized by a tap density of no less than 0.35 g/cm 3 , no less than 0.40 g/cm 3 , no less than 0.45 g/cm 3 , no less than 0.50 g/cm 3 , or no less than 0.55 g/cm 3 .

22. The morphic form of claim 21 , wherein the morphic form is further characterized by a tap density of no less than 0.45 g/cm 3 .

23. The morphic form of claim 20 , wherein the morphic form comprises fluticasone propionate nanoplates with an average size of about 100-1000 nm.

24. The morphic form of claim 23 , wherein the nanoplates have the c-axis crystallographic direction substantially normal to the surfaces that define the thickness of the nanoplates.

25. The morphic form of claim 23 , wherein the nanoplates each have an average size of about 100-800 nm.

26. The morphic form of claim 20 , wherein the morphic form is further characterized by a dissolution rate in water of about 1 μg/g/day in water at room temperature.

27. The morphic form of claim 1 , wherein the morphic form is further characterized by a tap density of no less than 0.35 g/cm 3 , no less than 0.40 g/cm 3 , no less than 0.45 g/cm 3 , no less than 0.50 g/cm 3 , or no less than 0.55 g/cm 3 , and the morphic form has a dissolution rate in water of about 1 μg/g/day in water at room temperature.

28. The morphic form of claim 1 , wherein the morphic form has a purity of greater than 99% by weight and a dissolution rate in water of about 1 μg/g/day in water at room temperature.

29. The morphic form of claim 1 , wherein the morphic form has a purity of greater than 99% by weight and the morphic form comprises fluticasone propionate nanoplates with an average size of about 100-1000 nm, wherein the nanoplates have the c-axis crystallographic direction substantially normal to the surfaces that define the thickness of the nanoplates.