Crystalline amifostine compositions and methods of the preparation and use of same
DCFirst Claim
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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°
C., but which provides a crystalline precipitate of amifostine upon cooling below 0°
C.;
(b) cooling said formulation to a temperature below 0°
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.
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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° 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.
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Citations
33 Claims
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1. A process for the preparation of a crystalline amifostine composition comprising the steps of:
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(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°
C., but which provides a crystalline precipitate of amifostine upon cooling below 0°
C.;(b) cooling said formulation to a temperature below 0°
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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, 26, 27, 28, 29, 31, 32, 33)
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21. A process for the preparation of a crystalline amifostine composition comprising the steps of:
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(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°
C. but which provides a crystalline precipitate of amifostine upon cooling below 0°
C.;(b) cooling said formulation to a temperature falling in the range of about -5°
C. to about -40°
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.
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30. A process for the preparation of a crystalline amifostine composition comprising the steps of:
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(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°
C. in about 160 minutes;(c) maintaining said formulation at about -35°
C. for about 240 minutes to form seeds of crystalline amifostine;(d) warming said formulation to about 0°
C. in about 25 minutes;(e) maintaining said formulation at about 0°
C. for about 600 minutes to anneal the seeds and precipitate crystalline amifostine;(f) cooling said formulation from about 0°
C. to about -15°
C. in about 15 minutes;(g) cooling said formulation from about -15°
C. to about -35°
C. in about 120 minutes;(h) maintaining said formulation at about -35°
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°
C. to about -20°
C. over about 54 hours;(k) maintaining said formulation at about -20°
C. for about 12 to about 24 additional hours to leave a crystalline amifostine composition having enhanced stability.
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Specification