Stable glassy state powder formulations

Abstract

A powdered, dispersible composition having stable dispersibility over time is provided. The composition exhibits a characteristic glass transition temperature (Tg) and a recommended storage temperature (Ts), wherein the difference between Tg and Ts is at least about 10° C. (i.e. Tg-Ts is greater than 10° C.). The composition comprises a mixture of a pharmaceutically-acceptable glassy matrix and at least one pharmacologically active material within the glassy matrix. It may be further mixed with a powdered, pharmaceutically-acceptable carrier. It is particularly valuable in unit dosage form having a moisture barrier, in combination with appropriate labelling instructions. A process for producing a powdered dispersible composition is also provided, wherein the process comprises removing the solvent from a solution comprising a solvent, a glass former and a pharmacologically active material under conditions sufficient to form a glassy matrix having the pharmacologically active material within the matrix.

Description

[0001] This application is a continuation-in-part of U.S. Ser. No. 08 / 733,225 filed Oct. 17, 1996, which in turn is a continuation-in-part of PCT Application No. PCT 96 / 05070, filed Apr. 12, 1996, which is a continuation-in-part of U.S. Ser. No. 08 / 423,515, filed Apr. 14, 1995, which applications are incorporated herein by reference in their entirety.[0002] 1. Field of the Invention[0003] This invention relates to powdered pharmaceutical compositions that exhibit improved stability of dispersibility over time for inhalation therapy, to processes for preparing such compositions, and to methods for treating certain disease states using such compositions. The invention is based on the discovery that the dispersibility of a powdered pharmaceutical composition can be maintained over time if the composition is prepared in a glassy state. While it has been known that the chemical stability of a pharmaceutical may be maintained in the glassy state, this is the first recognition that a glass...

AI Technical Summary

Benefits of technology

[0014] It is a further object of this invention to provide a process for manufacturing a pharmaceutical composition for pulmonary administration that has stable dispersibility over time.

[0016] A still further object of this invention is to provide a novel drug delivery system that is capable of maintaining a stable level of dispersibility over time.

Problems solved by technology

However, various disadvantages are evident with dry powder aerosol systems.

Furthermore, the powder particles may agglomerate and form hard cakes.

With propellant systems, valve clogging may occur if the powder agglomerates or the powder concentration is too high.

Additionally, powder may deposit on the valve seat and prevent the valve from closing properly.

This leads to leakage of the propellant.

This degradation of the solid state of the formulation over time makes it difficult to ensure delivery of a consistent and accurate dose of the drug active during the shelf life of the aerosol product.

This has made the development of delivery systems for oral inhalation delivery of labile peptides and proteins particularly difficult.

However, even in solid dosage forms, some proteins can be relatively unstable.

This poor stability can be a product of both the method of preparing solid dosage forms, where the active drug is a protein, and of the storage environment around the protein within the dosage form.

However, lyophilization and further processing can force a protein to undergo significant chemical and physical changes.

However, maintaining chemical and biological activity of the active protein is only half of the challenge where the delivery system comprises a dry powder aerosol dosage form.

While the prior art has at least in part addressed the problems of chemical and physical stability of active protein drugs, it has not adequately addressed the issue of solid state stability of an aerosol dry powder, i.e. dispersibility, for delivering proteins.

Nor has the prior art addressed the solid state stability of amorphous dry powder inhalable formulations for delivery of small molecule or peptide drugs.

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