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Details for Patent: 5,413,995

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Details for Patent: 5,413,995

Title: Lyophilized cyclophosphamide
Abstract:A lyophilized pharmaceutical solid composition containing cyclophosphamide for reconstitution with water to provide a solution for oral or parenteral administration. This lyophilized cyclophosphamide solid composition demonstrates improved stability, solubility characteristics and enhanced appearance compared with currently available dry powder pre-mix compositions of cyclophosphamide. The lyophilized solid composition contains about 20 parts by weight of cyclophosphamide, about 11/4-2 parts by weight of water and from about 10-85 parts by weight of excipient which is comprised mainly of mannitol. Processes for making the composition are disclosed.
Inventor(s): Alexander; Robert L. (Evansville, IN), Bequette; Robert J. (Evansville, IN), Kensler; Terry T. (Evansville, IN), Scott; Joseph A. (Evansville, IN)
Assignee: Mead Johnson & Company (Evansville, IN)
Filing Date:Mar 08, 1985
Application Number:06/709,744
Claims:1. A process for producing a lyophilized cyclophosphamide pharmaceutical solid composition with improved stability, superior solubility, and enhanced appearance which comprises

(a) dissolving about two parts by weight of cyclophosphamide monohydrate and from about 1-8 parts by weight of excipient comprising mannitol in sufficient water to give about a 1.67 to 4% (W/V) concentrated cyclophosphamide solution;

(b) filling a container with said solution to a desired cyclophosphamide content;

(c) lyophilizing said solution of desired cyclophosphamide content in said container to a dryness of about 2% or less; and

(d) humidifying the lyophilizate by means of exposure to water vapor at about room temperature and a pressure of from about 100 millitorr to atmospheric pressure for an effective time of at least 2 hours until about 1 equivalent of water per equivalent of anhydrous cyclophosphamide is taken up.

2. The process of claim 1 wherein lyophilization step (c) comprises rapidly freezing said solution of desired cyclophosphamide content and then employing a chamber pressure of about 50-500 millitorr, a shelf temperature of about 20.degree.-25.degree., and a condenser temperature of about -60.degree. for about 18-36 hours in order to reduce the moisture in the container to about 2% or less.

3. The process of claim 1 wherein the rehydration step (d) comprises exposing the lyophilizate to air with a controlled humidity of about 60-80% at atmospheric pressure and room temperature for about 1-2 days.

4. The process of claim 1 wherein the rehydration step (d) comprises relieving the vacuum of the lyophilization chamber with a gas which can be air or nitrogen containing about 80% relative humidity at room temperature and holding the lyophilizate in contact with this moist atmosphere for about 18-24 hours until about one equivalent of water per equivalent of anhydrous cyclophosphamide is taken up.

5. The process of claim 1 wherein the rehydration step (d) is accomplished by exposing the lyophilizate to water vapor at a pressure of about 100 millitorr to 25 torr and about 25.degree. for about 2-6 hours until about 1 equivalent of water per equivalent of anhydrous cyclophosphamide is taken up.

6. The process of claim 1 wherein the rehydration step (d) is accomplished by exposing the lyophilizate to water vapor at a pressure of about 100 millitorr to 25 torr and about 25.degree. for about 2-6 hours until about 1 equivalent of water per equivalent of anhydrous cyclophosphamide is taken up.

7. A process for producing lyophilized cyclophosphamide pharmaceutical solid composition with improved stability, superior solubility, and enhanced appearance which comprises

(a) dissolving about 2 parts by weight of cyclophosphamide monohydrate and from about 1-8 parts by weight of excipient comprising mannitol in sufficient water to give about a 1.67 to 4% (W/V) concentrated cyclophosphamide solution;

(b) filling a container with said solution to a desired cyclophosphamide content;

(c) lyophilizing said solution at a chamber pressure of about 500 millitorr and an initial shelf temperature of about 10.degree. and an initial lyophilization condenser temperature of about -60.degree. for about 10-12 hours;

(d) continuing the lyophilization of said solution at a chamber pressure of about 500 millitorr but with a shelf temperature of about -10.degree. and a condenser temperature of about -30.degree. for a total lyophilization time of 36-48 hours at which point the amount of water remaining is approximately equimolar with the cyclophosphamide on an anhydrous basis.

8. A process for producing a lyophilized cyclophosphamide pharmaceutical solid composition with improved stability, superior solubility, and enhanced appearance which comprises

(a) dissolving from about 2 parts by weight of cyclophosphamide monohydrate and from about 1-8 parts by weight of excipient comprising mannitol in sufficient sterile water to give about a 1.67 to 4% (W/V) concentrated cyclophosphamide solution;

(b) filtering the cyclophosphamide solution and then filling a container under sterile conditions, with the filtered cyclophosphamide solution to a desired cyclophosphamide content;

(c) lyophilizing the solution of desired cyclophosphamide content in the container to a dryness of about 2% or less moisture by rapidly freezing the solution in its container and then subjecting the frozen cyclophosphamide solution to lyophilization conditions comprising a chamber pressure of about 50-500 millitorr, a condenser temperature of about -60.degree., and a shelf temperature of about 0.degree.-25.degree., for about 14-36 hours;

(d) humidifying the lyophilizate by exposing it to water vapor at a pressure of about 100 millitorr to 25 torr at about 25.degree. for about 2-6 hours until about 1 equivalent of water per equivalent of anhydrous cyclophosphamide is taken up; and

(e) aseptically sealing the container which contains the lyophilized cyclophosphamide pharmaceutical solid composition.

9. A process for producing a lyophilized cyclophosphamide pharmaceutical solid composition with improved stability, superior solubility, and enhanced appearance which comprises

(a) dissolving from about 2 parts by weight of cyclophosphamide monohydrate and from about 1-8 parts by weight of excipient comprising mannitol in sufficient sterile water to give about a 1.67 to 4% (W/V) concentrated cyclophosphamide solution;

(b) filtering the cyclophosphamide solution and then filling a container under sterile conditions, with the filtered cyclophosphamide solution to a desired cyclophosphamide content;

(c) initially lyophilizing the solution of desired cyclophosphamide content in the container by rapidly freezing the solution in its container and then subjecting the frozen cyclophosphamide solution to lyophilization conditions comprising a chamber pressure of about 500 millitorr, an initial shelf temperature of about 10.degree., and an initial lyophilization condenser temperature of about -60.degree. for about 10-12 hours;

(d) continuing the lyophilization of the frozen solution at a chamber pressure of about 500 millitorr but with a shelf temperature of about -10.degree. and a condenser temperature of about -30.degree. for a total lyophilization time of 36-48 hours at which point the amount of water remaining is approximately equimolar with the cyclophosphamide on an anhydride basis; and

(e) aseptically sealing the container which contains the lyophilized cyclophosphamide pharmaceutical solid composition.

10. In a process for freeze-drying a dosage amount of cyclophosphamide hydrate from an aqueous solution the improvement comprising carrying out said process in two stages, the first stage comprising freeze-drying a solution of cyclophosphamide hydrate in combination with from about 0.5 times to about 2 times its weight of an excipient in which mannitol is present as the major excipient by weight, until the moisture content of freeze-dried material is less than 2% by weight of the freeze-dried material, and the second stage comprising rehydrating the freeze-dried material by contacting it with water vapor until the relative humidity to which the material is exposed is about 60-80% and maintaining the relative humidity at this level so that the moisture content of the product is in the range from about 2% to about 7% based on the total net weight of product, and the integrity of said cyclophosphamide hydrate is maintained.
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