Thermo-kinetic mixing for pharmaceutical applications
Inventors
Brough, Chris • McGinity, James W. • Miller, Dave A. • DiNunzio, James C. • Williams, III, Robert O.
Assignees
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Publication Number
US-11439650-B2
Publication Date
2022-09-13
Expiration Date
Abstract
Compositions and methods for making a pharmaceutical dosage form include making a pharmaceutical composition that includes one or more active pharmaceutical ingredients (API) with one or more pharmaceutically acceptable excipients by thermokinetic compounding into a composite. Compositions and methods of preprocessing a composite comprising one or more APIs with one or more excipients include thermokinetic compounding, comprising thermokinetic processing the APIs with the excipients into a composite, wherein the composite can be further processed by conventional methods known in the art, such as hot melt extrusion, melt granulation, compression molding, tablet compression, capsule filling, film-coating, or injection molding.
Core Innovation
The pharmaceutical composition includes at least one active pharmaceutical ingredient (API) with at least one pharmaceutically acceptable excipient that is thermokinetically processed into a composite. The at least one API comprises a thermally labile or poorly water-soluble API, and the composite is formed by thermokinetic processing at an average temperature that is at or below a glass transition temperature or a melting point of the at least one API.
The described thermokinetic processing produces the composite while maintaining an average temperature at or below thermal transition limits associated with the API. In this way, thermokinetic processing is used to create composite forms that include amorphous composite variants, including single-phase amorphous composite.
The thermokinetically processed composites are further processed using hot melt extrusion, melt granulation, compression molding, tablet compression, capsule filling, film-coating, or injection molding. The resulting compositions are characterized by improved solid dispersion/composite properties in relation to amorphous behavior, with emphasis on drug potency retention and reduced API degradation products.
Claims Coverage
The document contains one independent claim directed to a pharmaceutical composition made by thermokinetically processing an API and a pharmaceutically acceptable excipient into a composite at an average temperature at or below an API glass transition temperature or melting point. The independent claim is further refined by dependent claims that add quantitative constraints on degradation products and drug potency, specify excipient polymer identity, constrain composite phase/morphology, and limit further solid-form processing operations.
Thermokinetically processed composite at or below API transition temperature
A pharmaceutical composition comprising at least one API and at least one pharmaceutically acceptable excipient thermokinetically processed into a composite, where the at least one API comprises a thermally labile or poorly water-soluble API, and wherein the composite is processed at an average temperature that is at or below a glass transition temperature or a melting point of the at least one API.
Excipient polymer selected from enumerated polymers
The pharmaceutically acceptable excipient comprises a polymer selected from the group consisting of methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, cellulose acetate trimellate, hydroxypropyl methylcellulose phthalate, cellulose acetate butyrate, polyvinylpyrrolidones, polyacrylates, polymethacrylates, polyvinyl alcohols, polyethylene glycols, polyvinyl acetate polyvinylpyrrolidone copolymers, polyethylene oxides, dimethylaminoethyl methacrylate-methacrylic acid ester copolymers, ethylacrylate-methylmethacrylate copolymers, poly(methyacrylate ethylacrylate) copolymers, poly(methacrylate methylmethacrylate) copolymers, starches, pectins, polysaccharides, gum arabic, guar gum, and xanthan gum.
Single-phase amorphous composite
The composite is a single phase, amorphous composite.
Further processing by specified solid-form operations
The composite is further processed by hot melt extrusion, melt granulation, compression molding, tablet compression, capsule filling, film-coating, or injection molding.
API degradation products below threshold
The pharmaceutical composition comprises less than about 1.0% degradation products of the at least one API.
Post-processing drug potency retention requirement
After processing, the at least one API has at least about 94% drug potency as compared to the at least one API before processing.
Across the independent claim and dependent refinements, the core inventive concept is thermokinetic processing into a composite at an average temperature at or below an API glass transition temperature or melting point for thermally labile or poorly water-soluble APIs, with further limitations including single-phase amorphous composites, specific polymer excipient selections, specified downstream solid-form processing operations, reduced API degradation products, and high retained drug potency.
Stated Advantages
Reduced API degradation products.
Improved amorphous composite/solid dispersion properties (e.g., supersaturation and dissolution) as described in the document.
Higher drug potency with less degradation products as described in the document.
Increased glass transition temperature/stability as described in the document.
Documented Applications
Producing dosage forms via conventional downstream operations, including hot melt extrusion, melt granulation, compression molding, tablet compression, capsule filling, film coating, and injection molding, using thermokinetically processed composites.
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