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Claims for Patent: 5,424,471

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Claims for Patent: 5,424,471

Title: Crystalline amifostine compositions and methods of the preparation and use of same
Abstract:The present invention relates to a sterile, stable vacuum dried crystalline amifostine composition and, optionally, pharmaceutically acceptable excipient(s). Typically, the crystalline compositions of the present invention exhibit enhanced stability at temperatures ranging from about 4.degree. C. to about ambient temperature for a period of at least 2 years relative to existing solid vacuum dried amorphous amifostine preparations. The reconstituted compositions of the present invention are suitable for administration to humans as a radio- or chemoprotecting agent.
Inventor(s): Kennedy; Paul E. (Phoenixville, PA), Rajewski; Roger A. (Lawrence, KS), Baldoni; John M. (Glenmore, PA)
Assignee: U.S. Bioscience, Inc. (West Conshohocken, PA)
Application Number:08/099,298
Patent Claims: 1. A process for the preparation of a crystalline amifostine composition comprising the steps of:

(a) preparing a formulation comprising amifostine, alcohol and water in which the relative amounts of amifostine, alcohol and water are such that a particulate-free solution is obtained at temperatures ranging from about room temperature to about 10.degree. C., but which provides a crystalline precipitate of amifostine upon cooling below 0.degree. C.;

(b) cooling said formulation to a temperature below 0.degree. C. for a period of time sufficient to effect the precipitation of the crystalline amifostine; and

(c) vacuum drying the resulting mixture to leave a solid crystalline amifostine preparation having enhanced stability.

2. The process of claim 1 which further comprises introducing a sterile inert gas over said preparation after completion of the vacuum drying of step (c).

3. The process of claim 2 in which said inert gas is selected from the group consisting of argon, nitrogen and helium.

4. The process of claim 1 in which the temperature of step (b) is about a eutectic point of said formulation.

5. The process of claim 4 which further comprises, after step (b), raising the temperature of the resulting mixture to an annealing temperature that lies about 1.degree. to about 20.degree. C. above said eutectic temperature, followed by cooling the temperature of said mixture from said annealing temperature back to said eutectic temperature or below prior to performing step (c).

6. The process of claim 4 in which said eutectic temperature falls in the range of about 0.degree. C. to about -80.degree. C.

7. The process of claim 5 in which said annealing temperature falls in the range of about -30.degree. C. to about 10.degree. C. and said eutectic temperature falls in the range of about 0.degree. C. to about -80.degree. C.

8. The process of claim 1 in which said formulation comprises about 50 to about 400 mg amifostine per ml of formulation, about 1-35% (v/v) alcohol, and about 65-99% (v/v) water.

9. The process of claim 1 in which said formulation comprises about 125 to about 250 mg amifostine per ml of formulation, about 5-20% (v/v) alcohol, and about 80-95% (v/v) water.

10. The process of claim 1 in which said formulation comprises about 100 mg amifostine per ml of formulation, about 10% (v/v) alcohol, and about 90% (v/v) water.

11. The process of claim 1 in which said temperature of step (b) falls in the range of about -5.degree. C. to about -40.degree. C.

12. The process of claim 1 in which said temperature of step (b) is about -20.degree. C.

13. The process of claim 1, which further comprises a sterilization step.

14. The process of claim 13 in which said sterilization step comprises sterile filtering said formulation of step (a) prior to cooling.

15. The process of claim 1, 4, 5 or 14 in which said crystalline amifostine is a hydrate of amifostine.

16. The process of claim 1, 4, 5 or 14 in which said crystalline amifostine is an amifostine trihydrate.

17. The process of claim 1, 4, 5 or 14 in which said crystalline amifostine contains from about 1 mole to about 3 moles of water of crystallization.

18. The process of claim 1, 4, 5 or 14 in which said formulation further comprises a pharmaceutically acceptable excipient.

19. The process of claim 18 in which said excipient is selected from the group consisting of sodium chloride, glycine, dextrose, sucrose and mannitol.

20. The process of claim 18 in which said excipient is mannitol.

21. A process for the preparation of a crystalline amifostine composition comprising the steps of:

(a) preparing a formulation comprising about 50 to about 300 mg amifostine per ml of said formulation, about 3 to about 30% (v/v) ethanol, about 70-97% (v/v) water, and, optionally, about 5 to about 300 mg of a pharmaceutically acceptable excipient per ml of said formulation such that a particulate-free solution is obtained at temperatures ranging from about room temperature to about 10.degree. C. but which provides a crystalline precipitate of amifostine upon cooling below 0.degree. C.;

(b) cooling said formulation to a temperature falling in the range of about -5.degree. C. to about -40.degree. C. for a period of time sufficient to effect the precipitation of the crystalline amifostine; and

(c) vacuum drying the resulting mixture to leave a solid crystalline amifostine preparation having enhanced stability.

22. The process of claim 1, 4, 5 or 21 in which the step(s) taken after step (a) and before step (c) are carried out over a period of about 0.5 to about 72 hours.

23. The process of claim 1, 4, 5 or 21 in which the step(s) taken after step (a) and before step (c) are carried out over a period of about 2 to about 24 hours.

24. The process of claim 1, 4, 5 or 21 in which step (c) is carried out over a period of about 1 to about 72 hours.

25. The process of claim 1, 4, 5 or 21 in which step (c) is carried out over a period of about 10 to about 20 hours.

26. The process of claim 1, 4, 5 or 21 in which step (c) is carried out at a vacuum of about 10 to about 1000 mTorr.

27. The process of claim 1, 4, 5 or 21 in which step (c) is carried out at a vacuum of about 150 mTorr.

28. The process of claim 1 wherein the alcohol is a C.sub.1 -C.sub.5 alkyl alcohol.

29. The process of claim 1 wherein the alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol and 2-pentanol.

30. A process for the preparation of a crystalline amifostine composition comprising the steps of:

(a) preparing a formulation comprising about 100 mg amifostine per mL of said formulation, about 100 mg of a pharmaceutically acceptable excipient per mL of said formulation, and about 12.5% (v/v) ethanol in water solution such that a particulate free solution is obtained at about room temperature;

(b) cooling said formulation from room temperature to about -35.degree. C. in about 160 minutes;

(c) maintaining said formulation at about -35.degree. C. for about 240 minutes to form seeds of crystalline amifostine;

(d) warming said formulation to about 0.degree. C. in about 25 minutes;

(e) maintaining said formulation at about 0.degree. C. for about 600 minutes to anneal the seeds and precipitate crystalline amifostine;

(f) cooling said formulation from about 0.degree. C. to about -15.degree. C. in about 15 minutes;

(g) cooling said formulation from about -15.degree. C. to about -35.degree. C. in about 120 minutes;

(h) maintaining said formulation at about -35.degree. C. for about 180 minutes;

(i) evacuating the air around said formulation to a pressure less than about 150 microns;

(j) warming said formulation from about -35.degree. C. to about -20.degree. C. over about 54 hours;

(k) maintaining said formulation at about -20.degree. C. for about 12 to about 24 additional hours to leave a crystalline amifostine composition having enhanced stability.

31. Crystalline amifostine which is prepared according to the process of any of claims 1, 2, 4, 5, 7, 8, 9, 10, 21 or 30 and which is thermally-stable, sterile, and suitable for reconstitution with a pharmaceutically acceptable vehicle into an injectable particulate-free drug product for parenteral administration to a human patient.

32. Crystalline amifostine which is prepared according to the process of claim 13 and which is thermally-stable, sterile, and suitable for reconstitution with a pharmaceutically acceptable vehicle into an injectable particulate-free drug product for parenteral administration to a human patient.

33. Crystalline amifostine which is prepared according to the process of claim 18 and which is thermally-stable, sterile, and suitable for reconstitution with a pharmaceutically acceptable vehicle into an injectable particulate-free drug product for parenteral administration to a human patient.
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