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-10668085-B2
Publication Date
2020-06-02
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
Thermokinetic compounding thermokinetically processes one or more active pharmaceutical ingredients (APIs) having an immiscible crystalline or intermediate morphology with one or more pharmaceutically acceptable excipients into a composite. At least one API in the composite is amorphous, and the composite has less than about 1.0% degradation products of the at least one API.
For thermally labile or poorly water-soluble APIs, the thermokinetic processing forms a composite that is a single phase, miscible composite. The composite is characterized by retained API integrity, including low degradation products and performance-related outcomes associated with the thermokinetic processing of APIs with pharmaceutically acceptable excipients.
The described thermokinetic compounding is distinguished from approaches such as hot-melt extrusion by enabling compounding thermally incompatible materials under brief processing times and low temperatures, with high shear and no-melt-flow processing. The document describes conversion to amorphous material, phase and mixing characterized by single versus multiple glass transition temperatures, and improved dissolution-related behavior, including supersaturation and precipitation-rate outcomes.
Claims Coverage
The partial set includes three independent claims, each directed to a pharmaceutical composition in which APIs are thermokinetically processed, or molten mixed without viscous flow, with pharmaceutically acceptable excipients into a composite, with explicit constraints on degradation products and, in dependent claims, on drug potency, excipient polymer selections, and exclusion of a processing agent. The independent claims collectively cover three inventive features.
Thermokinetically processed composite with amorphous api and low degradation products
A pharmaceutical composition comprising one or more active pharmaceutical ingredients (APIs) having an immiscible crystalline or intermediate morphology with one or more pharmaceutically acceptable excipients thermokinetically processed into a composite, wherein at least one of the APIs in the composite is amorphous, and the composition has less than about 1.0% degradation products of said at least one API.
Single-phase miscible composite from thermokinetically processed thermally labile or poorly water-soluble api
A pharmaceutical composition comprising one or more active pharmaceutical ingredients (APIs) with one or more pharmaceutically acceptable excipients thermokinetically processed into a composite, wherein at least one of the APIs is thermally labile or poorly water-soluble, in which the composite is a single phase, miscible composite.
Molten mixing without viscous flow composite with low degradation products of thermally labile apis
A pharmaceutical composition comprising one or more active pharmaceutical ingredients (APIs) with one or more pharmaceutically acceptable excipients processed by molten mixing without viscous flow into a composite, wherein at least one of the APIs is thermally labile, wherein the composite has less than about 1.0% degradation products of each thermally labile API.
Across the independent claims, the main inventive aspects are the formation of a composite pharmaceutical composition by thermokinetic processing, or molten mixing without viscous flow, of APIs with pharmaceutically acceptable excipients, with explicit structural and quality limitations: amorphous API arising from immiscible crystalline or intermediate morphology, single-phase miscible composite for thermally labile or poorly water-soluble APIs, and less than about 1.0% degradation products for thermally labile APIs.
Stated Advantages
Enables reduced API degradation and low degradation-product levels, including less than about 1.0% degradation products of specified APIs.
Provides preservation or retention of drug potency, including reported potency retention relative to unprocessed API.
Improves solid-state properties, including higher glass transition temperature and changes in amorphous or phase behavior.
Improves dissolution-related performance, including enhanced dissolution, supersaturation, and reduced precipitation rates, including in compositions without plasticizers.
Allows processing of thermally incompatible materials using brief processing times and low temperatures with high shear and no-melt-flow processing.
Documented Applications
Use in preparing pharmaceutical compositions or dosage forms from APIs and pharmaceutically acceptable excipients via thermokinetic compounding, including conversion into amorphous or compositional composites.
Use for thermally labile APIs and poorly water-soluble APIs, including forming single-phase miscible composites and achieving low degradation products.
Use illustrated with example APIs such as ketoconazole, acetaminophen, indomethacin, itraconazole, griseofulvin, and hydrocortisone, and excipients or polymers including EUDRAGIT® L100-55, Methocel™ E50, Kollidon® 30, HPMC E5, Carbomer 974P, and PVP K30.
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