Formulations and methods for lyophilization and lyophilates provided thereby
Inventors
Assignees
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Publication Number
US-10426729-B2
Publication Date
2019-10-01
Expiration Date
Abstract
The present invention provides compositions, methods for lyophilizing compounds and making pharmaceutical compositions, and kits providing solutions and lyophilized formulations of compounds. The compositions, methods, and kits are particularly useful in pharmaceutical applications involving therapeutic agents that have low solubility at low pH and medium pH values. Certain embodiments provide methods for lyophilizing compounds in liquid solutions, which include the steps of: a) preparing aqueous solutions of a compound of interest in the absence of buffer; b) adjusting the pH to high values of pH in order to increase the solubility of the compound of interest; and c) freeze-drying the solution to provide a lyophilized solid composition. Aqueous solutions including buffer are also disclosed. Lyophilized formulations, including micronized and non-micronized powders, are provided.
Core Innovation
The document describes lyophilization-based formulation strategies for poorly soluble weak-acid drugs, with particular focus on glibenclamide. It addresses how to create a stable lyophilized solid that is reconstituted to form an aqueous solution suitable for intravenous use.
A key aspect is preparing a substantially buffer-free high-pH formulation prior to freeze-drying, and selecting a pH level greater than 7.4, including values such as greater than 8 and sometimes about 9-11+. The approach links the high pH preparation to improved solubility behavior and enables reconstitution after lyophilization.
The lyophilized compositions include glibenclamide or a pharmaceutically acceptable salt, at least one substantially pharmaceutically inert compound, and one or more alkali bases. Stability is reported for lyophilized glibenclamide as stable for at least about 3 months at 25°C and 60% relative humidity, supporting the formation of reconstitutable solutions after reconstitution in deionized water.
Claims Coverage
Two independent claims are provided. The claim set centers on formulating a lyophilized composition containing glibenclamide with inert components and alkali bases so that, after reconstitution to a defined concentration in deionized water, the solution pH is greater than 8 and the lyophilized composition remains stable for at least 3 months at 25°C and 60% relative humidity.
Reconstituted lyophilized glibenclamide with inert compounds and alkali bases (treatment of stroke-related conditions)
A method of treating a patient suffering from stroke, hemorrhage, neuronal cell swelling, traumatic brain injury, spinal cord injury, organ ischemia, myocardial infarction, or sepsis by administering a reconstituted pharmaceutical formulation comprising a lyophilized composition comprising glibenclamide or a pharmaceutically acceptable salt, at least one substantially pharmaceutically inert compound selected from glucose, fructose, mannose, galactose, mannitol, sorbitol, lactose, trehalose, sucrose, sodium chloride and potassium chloride, and one or more alkali bases; wherein the lyophilized composition contains alkali bases in an amount sufficient so that reconstitution in deionized water at about 0.2 mg/mL to about 1.0 mg/mL yields a pH greater than 8, and wherein the lyophilized composition is stable for at least 3 months at 25°C and 60% relative humidity.
Lyophilized glibenclamide kit with sterile deionized water, inert compounds, and alkali bases
A kit comprising a vial of sterile deionized water and a vial of a lyophilized composition comprising glibenclamide or a pharmaceutically acceptable salt, at least one substantially pharmaceutically inert compound selected from glucose, fructose, mannose, galactose, mannitol, sorbitol, lactose, trehalose, sucrose, sodium chloride and potassium chloride, and one or more alkali bases; wherein reconstitution in the sterile deionized water at about 0.2 mg/mL to about 1.0 mg/mL yields a pH greater than 8, and wherein the lyophilized composition is stable for at least 3 months at 25°C and 60% relative humidity.
Across the independent claims, the inventive focus is on a lyophilized composition containing glibenclamide plus specified substantially pharmaceutically inert compounds and one or more alkali bases such that reconstitution in deionized or sterile deionized water at about 0.2-1.0 mg/mL produces a solution with pH greater than 8, while the lyophilized composition remains stable for at least 3 months at 25°C and 60% relative humidity. One claim uses the reconstituted formulation for treating specified medical conditions, and one claim provides a corresponding vial-based kit with sterile deionized water.
Stated Advantages
Provides lyophilized compositions that remain stable for at least 3 months at 25°C and 60% relative humidity.
Enables reconstitution in deionized water to form a solution having pH greater than 8.
Documented Applications
Treating patients suffering from stroke, hemorrhage, neuronal cell swelling, traumatic brain injury, spinal cord injury, organ ischemia, myocardial infarction, or sepsis by administering a reconstituted pharmaceutical formulation.
Use as a kit comprising sterile deionized water and a vial of the lyophilized composition for reconstitution to form a reconstituted pharmaceutical composition.
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