Claims for Patent: 5,413,995

Summary 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)
Application Number:	06/709,744
Patent 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.

Details for Patent 5,413,995

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	ZOSTAVAX	zoster vaccine live	For Injection	125123	05/25/2006		2012-05-09