Method and composition for pharmaceutical product

Abstract

This invention is directed to a composition comprising dry granulated tenofovir DF and emtricitabine, and a method for making same. Dry granulation was unexpectedly found to be important in preparing a tenofovir DF containing composition suitable for inclusion in a combination dosage form containing emtricitabine, efavirenz and tenofovir DF.

Description

BACKGROUND OF THE INVENTION [0001] This application relates to products for the treatment of viral infections, in particular HIV infections, using the known antiviral compounds efavirenz (tradename Sustiva, also known as EFV), emtricitabine (tradename Emtriva, also known as FTC) and tenofovir DF (disoproxil fumarate, also known as TDF) (tradename Viread, sold in combination with emtricitabine under the tradename Truvada). [0002] The Truvada product is produced by wet granulation of emtricitabine and tenofovir DF (WO 04 / 64845), which under the circumstances produces a chemically stable dosage form. This product does not contain efavirenz. [0003] HIV therapy using efavirenz as well as emtricitabine and tenofovir DF has been considered desirable. (hereafter “triple combination”; see WO 04 / 64845). Manufacturing a commercially viable triple combination product, however, would require that the final product meet stringent FDA requirements for bioequivalence to the commercial products, Vir...

AI Technical Summary

Benefits of technology

[0010] In accordance with this invention, a stable preparation of emtricitabine / tenofovir DF is provided by dry granulating a composition comprising a pharmaceutically acceptable excipient, tenofovir DF and emtricitabine. The omission of destabilizing amounts of water from the granulation process eliminates the disadvantageous formation of an emtricitabine / tenofovir DF eutectic mixture and enhances the stability of the resulting pharmaceutical product. The practice of the method of this invention produces a composition comprising dry granulated emtricitabine and tenofovir DF.

Problems solved by technology

Initial efforts to simply combine the three drugs (active pharmaceutical intermediates, or APIs) into a unitary, essentially homogeneous composition manufactured by wet granulation failed to produce a chemically stable tablet.

The tenofovir DF in this combination tablet was highly unstable and rapidly degraded in stability studies.

The efavirenz formulation was unexpectedly incompatible with tenofovir DF, a result now attributed to the surfactant (sodium lauryl sulfate) found in the efavirenz portion of the formulation.

This resulted in a tablet that failed to achieve bioequivalence with respect to efavirenz in human clinical trials.

Unexpectedly, this approach also failed to produce the desired bioequivalence in between the commercial product, Sustiva (efavirenz), and clinical trial material (i.e., proposed commercial triple combination product).

An additional obstacle to the triple combination dosage form was presented, and it is this problem that the present application is directed to solving.

As noted above, simply combining the excipients present in the known commercial products, Truvada and Sustiva tablets, was undesirable because the resulting tablet would contain the entire excipient load of the known tablets and thus would be large for a single tablet and present a dosage form that was difficult to swallow and therefore inconvenient for patient use.

However, simply reducing the proportion of excipient to API and wet granulating in accord with the known process was not effective in producing a stable composition.

Wet granulation of a preparation in which the proportion of excipient had been reduced to manageable amounts for a triple combination tablet unexpectedly resulted in a chemically unstable preparation.

These dissolved APIs, when dried during granulation, form a glassy or amorphous product, which is chemically unstable in comparison to the crystalline API.

In the prior process enough excipient is present to ameliorate the effect of the excess water is, but this was not feasible when the ratio of excipient to API is reduced to a level required for a manageable triple combination oral dosage form.

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