Multiple speed process for preserving heat sensitive portions of a thermokinetically melt blended batch

Abstract

The present disclosure is directed to compositions and methods for making a pharmaceutical composition by thermokinetic compounding, wherein the compositions include one or more thermolabile components, for example one or more active pharmaceutical ingredients (API) with one or more pharmaceutically acceptable excipients. The methods comprise thermokinetic processing of the thermolabile components into a composite by blending certain thermolabile components in a thermokinetic mixer using multiple speeds during a single, rotationally continuous operation. The composite can be further processed into pharmaceutical compositions 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.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is related to and claims priority under U.S. Provisional Application Ser. No. 60 / 957,044, filed on Aug. 21, 2007, U.S. Provisional Application No. 61 / 050,922, filed on May 6, 2008, application Ser. No. 12 / 196,154, filed on Aug. 21, 2008, and International Patent Application 20 PCT / US2008 / 073913, entitled “Thermo-Kinetic Mixing for Pharmaceutical Applications,” filed on Aug. 21, 2008, and is a continuation of U.S. patent application Ser. No. 13 / 190,176 filed Jul. 25, 2011 entitled “Multiple Speed Process for Preserving Heat Sensitive Portions of a Thermokinetically Melt Blended Batch”, the entire contents of each of which are incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]Field of the Invention[0003]The present disclosure relates in general to the field of pharmaceutical manufacturing, and more particularly, to thermokinetic mixing of active pharmaceutical ingredients (APIs) to produce novel dosage forms...

AI Technical Summary

Benefits of technology

[0012]The present disclosure unexpectedly solves the issues associated with blending certain heat sensitive or thermolabile components in a thermokinetic mixer by using multiple speeds during a single, rotationally continuous operation on a batch containing thermolabile components. Identified herein is a novel thermokinetic mixer and mixing process that can blend heat sensitive or thermolabile components while minimizing any substantial thermal degradation. In particular, the disclosure is useful in processing mixtures that include thermolabile components whose exposure to a melt temperature or a cumulative heat input over a defined time period results in substantial degradation. The resulting pharmaceutical compositions have increased bioavailability and stability. In addition, the methods disclosed herein are easily scalable to commercial production of pharmaceutical compositions.

[0014]The present inventor investigated the melt blending of various mixtures including thermolabile components in a thermokinetic mixing chamber. The present inventor unexpectedly found that using multiple speeds during a single, rotationally continuous operation on certain batches containing thermolabile components solved the problem of exceeding a limit temperature or excessive heat input for the batch. The present inventor also surprisingly found that varying the shape, width and angle away from a shaft axis plane of a shaft extension or projection provided a method of controlling the shear delivered to a particle, which in turn provided control over shaft energy translated into heat energy available for softening or melting a polymer part of a particle in a thermokinetic mixing chamber.

[0020]Certain embodiments of the present disclosure are directed to thermokinetic mixers used to produce a pharmaceutical composition comprising one or more heat sensitive or thermolabile components. Various embodiments of the mixer may comprise one or more and any combination of the following: (1) a mixing chamber, for example a substantially cylindrical mixing chamber; (2) a shaft disposed through the center axis of the mixing chamber; (3) an electric motor connected to the shaft, for example which is effective to impart rotational motion to the shaft; (4) one or more projections or extensions from the shaft and perpendicular to the long axis of the shaft; (5) one more heat sensors, for example attached to a wall of the mixing chamber and operative to detect heat or temperature of at least a portion of the interior of the mixing chamber; (6) a variable frequency device, for example connected to the motor; (7) a door disposed in a wall of the mixing chamber, for example which is effective when opened during a process run to allow the contents of the mixing chamber to pass out of the mixing chamber; and (8) an electronic controller. In certain embodiments, a hygroscopic condition is maintained within the thermokinetic mixer. In other embodiments, the thermokinetic mixers are designed to maximize shear during batch processing.

Problems solved by technology

Current high-throughput molecular screening methods used by the pharmaceutical industry have resulted in a vast increase in the proportion of newly discovered molecular entities which are poorly water-soluble.

The therapeutic potential of many of these molecules is often not fully realized either because the molecule is abandoned during development due to poor pharmacokinetic profiles, or because of suboptimal product performance.

Also, in recent years the pharmaceutical industry has begun to rely more heavily on formulational methods for improving drug solubility owing to practical limitations of salt formation and chemical modifications of neutral or weakly acidic / basic drugs.

Although the application of thermokinetic compounding in the field of pharmaceutical manufacturing offers significant advantages over other methodologies known in the pharmaceutical arts, it is possible that issues can arise in continuously melt blending certain heat sensitive or thermolabile components with certain non-thermolabile components using a thermokinetic mixer.

In certain cases, this results in an exceedance of a limit temperature or heat input for an unacceptable duration.

The batch thus experiences unacceptable degradation of the thermolabile components, as the substantial amount of heat absorbed by the entire batch results in thermal degradation of thermolabile components instead of increasing overall batch temperature.

Substantially complete amorphosity is a measure well-known in the art of pharmaceutical preparation and processing; bioavailability may be significantly impaired in compositions lacking substantially complete amorphosity.

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