Method for preparing organic solvent-free lyophilized cyclophosphamide
Inventors
Kang, Won Ho • Jung, Won Tae • Kang, Jung Hoon • CHOI, Youn Woong
Assignees
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Publication Number
US-11707434-B2
Publication Date
2023-07-25
Expiration Date
Abstract
The present invention relates to a method for preparing a lyophilized cyclophosphamide composition, wherein 99% or more of the finally prepared lyophilized cyclophosphamide composition is reconstituted within 15 seconds when water for pharmaceutical use is injected thereinto at a ratio of 50 mL per 1 g of anhydrous cyclophosphamide, comprising a step of dissolving D-mannitol or lactose, as a lyoprotectant, and cyclophosphamide in a water solvent in a selected reaction vessel; and a lyophilized cyclophosphamide composition for injection prepared thereof.
Core Innovation
The invention relates to a method for preparing a lyophilized cyclophosphamide composition in which 99% or more of the finally prepared lyophilized cyclophosphamide composition is reconstituted within 15 seconds when water for pharmaceutical use is injected at a ratio of 50 mL per 1 g of anhydrous cyclophosphamide. The method comprises dissolving D-mannitol or lactose, as a lyoprotectant, and cyclophosphamide in a water solvent in a reaction vessel at 40 °C to 70 °C.
The solution obtained in the preceding step is filled into a vial prepared by sterilization, or is sterilized by filtration using a membrane having a size of 0.2 µm or less and dispensed into a container for injection. The cyclophosphamide solution is lyophilized to form a lyophilized cake and sealed.
Related product and packaging aspects specify that the lyophilized composition is packaged in an injection container with a predetermined injection volume such that 50 mL to 500 mL of water for pharmaceutical use is added per 1,000 mg of anhydrous cyclophosphamide. The lyophilized product is also described in terms of cake porosity in the range of 40% to 90%.
Claims Coverage
The independent claims are clm-00001, clm-00010, and clm-00015. Across these independent claims, the central inventive features include rapid 15-second reconstitution tied to a specified water-to-cyclophosphamide ratio, formulation using D-mannitol or lactose as a lyoprotectant with defined dissolution conditions, and lyophilization into a sealed injection-cake product with sterilization and, in one claim, membrane filtration.
Rapid reconstitution performance tied to water ratio
A method for preparing a lyophilized cyclophosphamide composition wherein 99% or more of the finally prepared lyophilized cyclophosphamide composition is reconstituted within 15 seconds when water for pharmaceutical use is injected thereinto at a ratio of 50 mL per 1 g of anhydrous cyclophosphamide.
Lyoprotectant dissolution of cyclophosphamide in water solvent at 40 °C to 70 °C
Dissolving D-mannitol or lactose, as a lyoprotectant, and cyclophosphamide in a water solvent in a reaction vessel at 40 °C to 70 °C.
Sterilization by filling into sterilized vial or filtration with 0.2 µm or less
Filling the solution obtained in the previous step into a vial prepared by sterilization, or sterilizing the solution obtained in the previous step by filtration with a membrane having a size of 0.2 µm or less and dispensing the solution into a container for injection.
Lyophilization to form lyophilized cake and sealing
Lyophilizing the cyclophosphamide solution filled into the vial, or lyophilizing the solution dispensed into the container to form a lyophilized cake, followed by sealing.
Defined cyclophosphamide and lyoprotectant amounts for dissolution
Dissolving 0.01 g to 0.1 g of cyclophosphamide per 1 mL of a water solvent based on weight of the anhydrous cyclophosphamide, and 5 to 250 parts by weight of D-mannitol or lactose based on 100 parts by weight of the anhydrous cyclophosphamide in the water for pharmaceutical use.
Quantified post-lyophilization water addition range to prepare injection
Adding 20 mL to 500 ml of water for pharmaceutical use to the lyophilized cyclophosphamide composition per 1 g of anhydrous cyclophosphamide.
The independent claims collectively define rapid reconstitution (99% or more within 15 seconds) after injection of pharmaceutical-use water at a specified ratio, supported by dissolving cyclophosphamide with D-mannitol or lactose in a water solvent at 40 °C to 70 °C, followed by sterilization by sterilized vial filling and/or 0.2 µm filtration, lyophilization into a cake, and sealing, with additional quantification of dissolution amounts and water addition ranges for injection preparation.
Stated Advantages
Avoids residual organic solvent side effects.
Improves stability/solubility.
Reduces insoluble particles.
Improves dissolution convenience, including field use.
Documented Applications
A cyclophosphamide injection prepared from a lyophilized cyclophosphamide composition by adding 20 mL to 500 mL of water for pharmaceutical use per 1 g of anhydrous cyclophosphamide.
Use as an injection container product where water for pharmaceutical use is added according to a predetermined injection volume range.
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