Low-dose doxepin formulations and methods of making and using the same

Abstract

The invention disclosed herein generally relates to low-dose oral doxepin pharmaceutical formulations and the use of these formulations to promote sleep.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application No. 60 / 911,806 filed on Apr. 13, 2007, both entitled LOW-DOSE DOXEPIN FORMULATIONS AND METHODS OF MAKING AND USING THE SAME; the disclosure of which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]Embodiments of the invention disclosed herein relate to low-dose oral doxepin pharmaceutical formulations, methods of making the formulations, and the use of these formulations to promote sleep.BACKGROUND OF THE INVENTION[0003]Low doses of doxepin can be used to treat sleep disorders, such as insomnia. Sleep is essential for health and quality of life. Insomnia is a growing health problem in the United States. It is believed that more than 10-15 million people suffer from chronic insomnia and up to an additional 70 million people suffer from some form of insomnia each year. Insomnia is a condition characterized by difficulty falling asleep (sleep ons...

AI Technical Summary

Benefits of technology

[0008]In the development of pharmaceutical dosage forms, it can be desirable to achieve any of several different objectives. For example, preferably the dosage form can be uniform with respect to drug substance content, fast dissolving, stable, easy to swallow, palatable, and otherwise acceptable to patients in order to maximize patient compliance. In certain contexts, early and / or accelerated onset of drug action also can be advantageous. For example, in the context of sleep, early onset of drug action can be important due to the discreet window of time in which a patient needs to sleep. Also in the context of sleep, the dosage form preferably maintains sleep for a full 7 or 8 hour sleep cycle without significant next-day sedation.

[0012]In particular, embodiments disclosed herein relate to pharmaceutical dosage forms comprising low doses of doxepin hydrochloride, methods of manufacturing low-dose doxepin dosage forms, and methods of using the formulations and dosage forms. Preferably, the low doses of doxepin hydrochloride can be provided as rapidly dissolving dosage forms, as described herein, which can be advantageously used for treatment of insomnia. In some aspects, the formulations have one or more of: improved friability, compression, dissolution, uniformity, dissolvability, palatability, and the like. Also, in some aspects, the formulations can permit at least one or more of: rapid onset, greater and / or more rapid plasma levels, and the like.

[0013]Additional embodiments disclosed herein relate to new and economic methods of manufacture for low-dose dosage forms of doxepin, including, for example, on a large scale. In a preferred embodiment, the methods of manufacture can achieve uniformity of drug substance content and overcome segregation issues that can plague low dose formulations, and can do so in an economical and efficient manner. Some embodiments of the invention relate to low dose doxepin formulations that are amenable to direct compression and that produce a high yield of low dose doxepin dosage forms having acceptable content uniformity, hardness, and friability.

[0046]Some embodiments relate to methods for processing or producing low dose doxepin dosage forms, for example, from about 0.5 mg to about 9 mg doxepin, while obtaining high content uniformity. The methods can include minimizing segregation of low dose doxepin, which segregation can cause a lack of uniformity of dosage forms, by minimizing fluidization of low dose doxepin blended with a filler, including any of the fillers listed herein. In some embodiments, the minimizing of fluidization can be accomplished by minimizing airflow through a blend of low dose doxepin and one more fillers. Examples of minimizing airflow can include providing vents, valves or other devices that permit the release of air from containment devices that transport or hold the low dose doxepin blend. Also, fluidization can be minimized by reducing the amount of airspace in a dosage form press, such that there is less opportunity for contact of the blend with air. Also, the low dose formulations can be produced using a wet granulation method in order to avoid fluidization. Furthermore, carriers or fillers that bind with greater strength to the doxepin can be utilized. Such carriers / fillers can be easily incorporated by one of skill in the art.

[0047]Also, content uniformity can be maintained or enhanced by minimizing agglomeration or re-agglomeration of doxepin in the low dose doxepin formulations. Examples of minimizing agglomeration are described herein. Such methods can include, for example, diluting or layering the low dose doxepin with one or more fillers (including those listed or described herein). The methods can also include the use of a cone mill, a co mill or the like, including devices that minimize the separation of the doxepin from filler blends and dilution blends / mixes.

Problems solved by technology

However, efficient mixing and acceptable content uniformity are difficult to achieve for low dose dosage forms.

Mixed particle sized powders can segregate due to operational vibrations, resulting in final dosage forms with poor drug or active pharmaceutical ingredient (API) content uniformity.

Granulation processes may be energy intensive unit operations requiring complicated and expensive equipment as well as technical skill.

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