Formulations and methods for lyophilization and lyophilates provided thereby
Inventors
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10117834-B2
Publication Date
2018-11-06
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 invention relates to lyophilized pharmaceutical compositions and corresponding kits for poorly soluble weak-acid drugs, specifically glibenclamide (glyburide) and pharmaceutically acceptable salts thereof. The compositions include glibenclamide or a pharmaceutically acceptable salt thereof, 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. When the lyophilized pharmaceutical composition is reconstituted in deionized water at a concentration of about 0.2 mg/mL to about 1.0 mg/mL, the resulting pH is greater than 8.
The disclosed compositions are characterized by stability and by a controlled pH profile through reconstitution and dilution. The lyophilized pharmaceutical composition is stable for at least 3 months at 25° C. and 60% relative humidity. The formulation approach emphasizes substantially pharmaceutically inert excipients and uses alkali bases in an amount sufficient to achieve the specified pH after reconstitution.
The invention further includes a method for preparing a pharmaceutically acceptable injection solution having increased solubility of glibenclamide or a pharmaceutically acceptable salt thereof by lyophilizing glibenclamide in a liquid solution. The method includes preparing an aqueous solution comprising glibenclamide or a pharmaceutically acceptable salt thereof and a substantially pharmaceutically inert compound, adjusting the pH of the aqueous solution to a value greater than pH 10 to increase solubility, and freeze-drying to provide a lyophilized solid composition, wherein organic solvents are not used in the method.
After reconstitution, the pH is reduced to less than 10 and then diluted to a target concentration of about 1.0 mg/mL with a pH of about 6 to about 8. The disclosed approach provides lyophilized solids in either micronized or non-micronized form and includes example packaging concepts involving a vial with diluent and a pH adjuster.
Claims Coverage
The partial content includes two independent claims. Together, they cover a lyophilized pharmaceutical composition for glibenclamide with inert excipients and alkali bases to achieve a specified pH after reconstitution and stability at defined storage conditions, and a method for preparing a pharmaceutically acceptable injection solution by pH-adjusted aqueous lyophilization without organic solvents, followed by reconstitution and dilution to target concentration and pH.
Lyophilized composition with inert excipients and alkali base-controlled reconstitution pH
A lyophilized pharmaceutical composition comprising glibenclamide or a pharmaceutically acceptable salt thereof, 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 one or more alkali bases are present in an amount sufficient such that when reconstituted in deionized water at a concentration of about 0.2 mg/mL to about 1.0 mg/mL, its pH is greater than 8.
Stability for at least 3 months at defined storage conditions
The lyophilized pharmaceutical composition is stable for at least 3 months at 25° C. and 60% relative humidity.
pH-adjusted aqueous lyophilization without organic solvents for increased solubility injection
A method for preparing a pharmaceutically acceptable injection solution having increased solubility of glibenclamide or a pharmaceutically acceptable salt thereof by lyophilizing glibenclamide in a liquid solution, comprising preparing an aqueous solution comprising glibenclamide or a pharmaceutically acceptable salt thereof and a substantially pharmaceutically inert compound; adjusting the pH of the aqueous solution to a value greater than pH 10 to increase the solubility of glibenclamide; freeze-drying the solution to provide a lyophilized solid composition; reconstituting the lyophilized solid composition in an aqueous solution to form a reconstituted glibenclamide solution having a pH less than 10; and diluting the reconstituted glibenclamide solution with an aqueous solution to form a diluted glibenclamide solution having glibenclamide or a pharmaceutically acceptable salt thereof at a concentration of about 1.0 mg/mL and a pH of about 6 to about 8, wherein organic solvents are not used in said method.
Across the two independent claims, the core inventive coverage centers on lyophilized glibenclamide formulations that use substantially pharmaceutically inert excipients plus alkali bases to control pH upon reconstitution and maintain stability, and on a preparation method that increases solubility via aqueous high-pH lyophilization followed by reconstitution and dilution to a near-neutral pH and specified concentration, with the method excluding organic solvents.
Stated Advantages
Increased solubility of glibenclamide in a pharmaceutically acceptable injection solution prepared by lyophilizing glibenclamide in a liquid solution.
Stability of the lyophilized pharmaceutical composition for at least 3 months at 25° C. and 60% relative humidity.
Documented Applications
Pharmaceutically acceptable injection solution preparation with increased solubility of glibenclamide or a pharmaceutically acceptable salt thereof using lyophilizing, reconstitution, and dilution to target pH and concentration.
Lyophilized pharmaceutical composition use for glibenclamide or pharmaceutically acceptable salt formulated with substantially pharmaceutically inert compounds and alkali bases, with stability under defined storage conditions.
Interested in licensing this patent?