Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus esters
Reexamination Certificate
2002-02-08
2003-09-02
Davis, Brian (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus esters
C514S090000, C514S110000
Reexamination Certificate
active
06613927
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The invention pertains to lyophilized ifosfamide, solutions thereof, and methods of preparing and using lyophilized ifosfamide.
BACKGROUND OF THE INVENTION
Ifosfamide is a chemotherapeutic agent of the formula:
and is described in U.S. Pat. No. 3,732,340. Ifosfamide is sometimes referred to as N,3-bis(2-chloroethyl) tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine-2-oxide, and 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide. Ifosfamide has the molecular formula C
7
H
15
Cl
2
N
2
O
2
P, and has a molecular weight of 261.1. Ifosfamide is manufactured as a white crystalline powder, which has a melting point of about 48-51° C. and which is highly hygroscopic. Ifosfamide begins to sinter at temperatures below its melting point and, therefore, must be stored at relatively low temperatures (room temperature or below). In addition, contact with moisture in the air should be avoided whenever possible. Ifosfamide dissolves in water to the extent of at least about 10 wt %, but has limited stability in an aqueous solution (reported in some references as about 3-4 hours at 20-22° C., or 36 hours at 4-6° C.).
Ifosfamide is approved in the U.S. for third-line chemotherapy of germ cell testicular cancer and is ordinarily used in combination with a prophylactic agent for hemorrhagic cystitis, such as mesna. Ifosfamide is presently marketed in the U.S. under the name IFEX®, which is supplied as a crystalline powder and is stored in 1 g and 3 g single dose vials. For therapeutic applications, the powder is dissolved in a sterile aqueous vehicle such as Sterile Water for Injection, USP; or a sterile aqueous vehicle that contains a bacteriostat, e.g., Sterile Bacteriostatic Water for Injection, USP (preserved with benzyl alcohol or parabens), and is administered by injection. Typically, the 1 g and 3 g dosage forms are constituted in 20 mL and 60 mL of the aqueous vehicle, respectively, to achieve a final concentration of 50 mg/mL. Solutions of ifosfamide may be diluted further to achieve concentrations of 0.6-20 mg/mL in injectable fluids such as 5% Dextrose Injection, USP; 0.9% Sodium Chloride Injection, USP; Lactated Ringer's Injection, USP; or Sterile Water for Injection, USP.
Ifosfamide is normally administered intravenously at a dosage of about 1.2 g/m
2
per day for five consecutive days. Treatment is repeated every 3 weeks or after recovery from hematologic toxicity. The duration of the infusion is generally about 30 minutes, but may be 1 to 2 hours. Ifosfamide solutions should be refrigerated and be used within 24 hours. See, e.g.,
Physicians' Desk Reference
, 56
th
Ed., Medical Economics Co., Inc., Montvale, N.J., pp. 1123-1124 (2002).
The manufacture of ifosfamide sterile powder involves a powder fill operation that presents a number of practical problems. During the production of the sterile powder, the powder is processed in a way that causes variations in the flow properties. The variation in flow properties greatly impairs the accuracy of dosage during the filling process. The sterile powder fill operation further employs specialized equipment. The powder fill operation is costly and may be further complicated by the risk of microbial contamination during the operation. Moreover, the powder fill process creates risks of accidental exposure to the powder by personnel that are involved in the production process. The processing and storage of ifosfamide powder is still further complicated by its hygroscopic properties, sensitivity to heat, and relatively low melting point. If the powder is stored for a long period of time, the product sinters and its dissolution time increases significantly.
Various approaches for manufacturing lyophilized forms of ifosfamide have been proposed. For example, U.S. Pat. Nos. 5,750,131 and 5,972,912 describe the lyophilization of one or more amino acids in combination with ifosfamide. U.S. Pat. No. 5,204,335 describes the lyophilization of hexitols in combination with ifosfamide, and U.S. Pat. No. 4,959,215 describes the lyophilization of hexitols in combination with ifosfamide/mesna mixtures. In addition, U.S. Pat. No. 5,227,373 describes the lyophilization of urea in combination with ifosfamide.
While the lyophilization processes described above overcome some of the problems associated with the crystalline powder, such processes are disadvantageous in that they utilize auxiliary materials such as amino acids, hexitols and urea, are not present in the product that is approved for human chemotherapy. Thus, there remains a need for a stable, sterile form of lyophilized ifosfamide that contains no auxiliary materials, and methods of producing such a product. The invention provides such a product and production processes. These and other advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a stable, sterile, pharmaceutical product that consists essentially of lyophilized ifosfamide. The lyophilized ifosfamide of the present invention is preferably contained in within a container that is aseptically sealed. Preferably, the container contains a therapeutically effective amount of the ifosfamide of the present invention and is of sufficient volume to contain the volume of solution that is recommended for constitution. The present invention further provides a solution prepared by dissolving the lyophilized ifosfamide of the present invention in an aqueous vehicle, such as a sterile aqueous solvent that is suitable for injection.
The present invention further provides a method of producing lyophilized ifosfamide, which method includes freezing a sterile aqueous solution of ifosfamide to produce a frozen mixture;
subjecting the frozen mixture to a primary drying stage, which includes applying a vacuum to reduce the pressure by an amount or to a level that is effective to remove the aqueous solvent from the frozen mixture, and, while applying the vacuum, raising the temperature to a primary drying temperature, to produce a first intermediate; and
subjecting the first intermediate to a secondary drying stage, which includes applying a vacuum to reduce the pressure by an amount or to a level that is effective to remove the aqueous solvent from the first intermediate, and, while applying the vacuum, raising the temperature to a secondary drying temperature, to produce the pharmaceutical product.
The method of the present invention can be applied toward the production of stable, sterile, essentially pure dosage forms of ifosfamide (e.g., a sterile single-dose ifosfamide product), which method includes:
filling one or more containers, each container defining an opening, with a sterile solution consisting essentially of a therapeutically effective amount of ifosfamide and an aqueous solvent;
subjecting the sterile solution in the one or more containers to the present method of producing lyophilized ifosfamide; and
sealing the opening of the one or more containers, to produce the pharmaceutical product.
The dosage form prepared in accordance with the present invention preferably contains a dosage that is within about 5% of the label claim. The lyophilized ifosfamide of the present invention can be administered to a patient using standard therapeutic methods for delivering ifosfamide (e.g., by injection).
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a stable, sterile, pharmaceutical product that consists essentially of lyophilized ifosfamide. The lyophilized ifosfanlide of the present invention is a white to off-white solid of high purity and has a low moisture content. The lyophilized ifosfamide of the present invention is preferably greater than 98% pure (i.e., contains less than 2% total impurities based on the total weight of ifosfamide), and is more preferably greater than 99% pure (i.e., contains less than about 1% impurities). Preferably, the lyophilized ifosfamide of the present invention has a m
American Pharmaceutical Partners, Inc.
Davis Brian
Leydig , Voit & Mayer, Ltd.
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