Agitation process for preparing a carbetocin drug product
Inventors
Bryant, Christopher • Manning, Mark C. • Holcomb, Ryan E.
Assignees
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Publication Number
US-11844764-B2
Publication Date
2023-12-19
Expiration Date
Abstract
The present disclosure includes a method of making an improved carbetocin drug product. The disclosed method for making an improved carbetocin drug product comprises agitating a carbetocin preparation containing an aqueous solution of carbetocin and one or more excipients for a period of time to initiate the formation of aggregate-forming solids and filtering off the aggregates that form before further processing the remaining carbetocin into a final drug product. The present disclosure also relates to an improved carbetocin drug product, wherein the drug product is substantially free of aggregate-forming solids. The disclosed carbetocin drug product can be used for the treatment of a neurodevelopmental disorder, such as Präder-Willi syndrome. Additionally, the disclosed carbetocin drug product shows content uniformity of carbetocin over long periods of time before and after one or more freeze/thaw cycles, provides enhanced convenience and patient compliance, and/or are highly concentrated.
Core Innovation
The invention relates to a method for preparing a carbetocin drug product comprising carbetocin or a pharmaceutically acceptable salt thereof with increased resistance to aggregation. The method comprises dissolving carbetocin or a pharmaceutically acceptable salt thereof and one or more excipients chosen from a surface active agent, solubilizer, tonicity enhancer, an agent to adjust the pH, and combinations thereof to form an aqueous solution.
The aqueous solution is then agitated for a time period of hours to form aggregate-forming solids, and the formed aggregate-forming solids are removed to form a post-agitation solution. The post-agitation solution is then added to a container to form a final drug product.
The resulting carbetocin drug product has increased resistance to aggregation when tested with shaking stress compared to an aqueous solution of carbetocin that has not been treated according to the agitation and removal steps, and the final carbetocin drug product is substantially free of aggregate-forming solids.
Claims Coverage
The claim set centers on one independent inventive feature: a manufacturing sequence in which agitation forms aggregate-forming solids and the solids are removed before the final carbetocin drug product is formed, yielding increased resistance to aggregation under shaking stress. Dependent claims add formulation constraints and specific excipient selections.
Agitation and removal of aggregate-forming solids for aggregation resistance
A method for preparing a carbetocin drug product comprising carbetocin or a pharmaceutically acceptable salt thereof, dissolving carbetocin with one or more excipients chosen from a surface active agent, solubilizer, tonicity enhancer, an agent to adjust pH, agitating the aqueous solution for a time period of hours to form aggregate-forming solids, removing the formed aggregate-forming solids to form a post-agitation solution, and adding the post-agitation solution to a container to form a final drug product; wherein the carbetocin drug product has increased resistance to aggregation when tested with shaking stress compared to an aqueous solution of carbetocin that has not been treated according to the agitation and removal steps.
Substantially free of aggregate-forming solids final product
The method further provides a carbetocin drug product that is substantially free of aggregate-forming solids.
Visco-elastic cellulose-derivative surface-active polymer
An aqueous carbetocin solution includes a surface active agent that is a visco-elastic cellulose-derivative polymer selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), or carboxy methyl ethyl cellulose (CMEC).
Solubilizer selected from hydrotrope, amino acid, or cyclodextrin
The method is carried out using a solubilizer selected as a hydrotrope, amino acid, or cyclodextrin from the listed specific candidates including sodium benzoate, sodium salicylate, sodium benzene sulfonate, sodium benzene disulfonate, sodium cinnamate, sodium 3-hydroxy-2-naphthoate, sodium para-toluene sulfonate, sodium cumene sulfonate, nicotinamide, N,N-diethylnicotinamide, N,N-dimethyl benzamide, para-aminobenzoic acid hydrochloride, procaine hydrochloride, caffeine, sodium alkanoate, urea, N,N-dimethyl urea, arginine, methyl-R-cyclodextrin, randomly methylated-β-cyclodextrin (RM-β-CD), sulfobutylether-β-cyclodextrin (SBE-β-CD), epichlorohydrin-β-cyclodextrin, and carboxy methyl epichlorohydrin beta cyclodextrin.
Hydrotrope concentration range
The hydrotrope is present at a concentration ranging from about 50 mM to about 500 mM.
Carbetocin concentration range for the method
Carbetocin is present in a concentration ranging from about 10 mg/mL to about 40 mg/mL.
The inventive features consistently define an agitation-and-removal manufacturing sequence for carbetocin drug products, with dependent claim limitations directed to the final product state, specific surface active agents and solubilizers, and concentration ranges for hydrotrope and carbetocin.
Stated Advantages
Increased resistance to aggregation when tested with shaking stress compared to an aqueous solution of carbetocin that has not been treated according to the agitation and removal steps.
Final carbetocin drug product is substantially free of aggregate-forming solids.
Documented Applications
Intranasal use to treat Prader-Willi syndrome and related neurodevelopmental disorders.
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