Pharmaceutical composition formulated for pre-gastric absorption of monoamine oxidase B inhibitors

Abstract

The invention described herein provides a fast dispersing oral solid dosage form containing monoamine oxidase B inhibitor (MAO-B inhibitor) as the active ingredient, and method of treating disease therewith, such as Parkinson's disease. In one embodiment, the monoamine oxidase B inhibitor selegiline or its analogue can be the sole active ingredient in the composition administered. The dosage form composition is formulated to promote absorption through the buccal, sublingual, pharyngeal and / or esophageal mucous membrane tissue, such that at least 5% of the active ingredient is absorbed within one minute of placement in the oral cavity, as determined by a buccal absorption test. Monoamine oxidase B inhibitor compounds administered in accordance with the invention decrease the amount of undesirable metabolites associated with first pass effect of selegiline, for example, such as amphetamine and methamphetamine. The invention provides a number of other advantages over conventional orally administered tablet forms, including administration of monoamine oxidase B inhibitor compounds to patients that have difficulty swallowing.

Description

RELATED APPLICATION DATA [0001] This application is a continuation-in-part of U.S. patent application Ser. No. 10 / 610,613 filed Jul. 1, 2003, now pending, which is a continuation of U.S. patent application Ser. No. 08 / 894,764, filed Nov. 17, 1997, now abandoned, which is the U.S. national filing of International Patent Application No. PCT / GB96 / 00484 (WO 96 / 26720 published Sep. 6, 1996) with an international filing date of Jan. 3, 1996, which claims benefit of priority to Great Britain Patent Application No. 9504235.4 filed Feb. 3, 1995 and Great Britain Patent Application No. 9517063.5 filed Mar. 22, 1996.FIELD OF THE INVENTION [0002] The invention relates to a pharmaceutical composition for the treatment of diseases such as Parkinson's disease. In particular, the invention pertains to a fast disintegrating oral solid dosage form containing monoamine oxidase B inhibitor compounds as the active ingredient, and methods of treatment therewith. BACKGROUND OF THE INVENTION [0003] Selegil...

AI Technical Summary

Benefits of technology

[0013] The invention provides a pharmaceutical composition as a rapidly disintegrating solid oral dosage form comprising a carrier and monoamine oxidase B inhibitor compound as an active ingredient. It has been discovered that an oral solid pharmaceutical dosage form containing a monoamine oxidase B inhibitor, such as selegiline, can be prepared that permits effective pre-gastric oral administration and avoids the disadvantages associated with conventional swallowed tablet forms of the drug and permits its administration without other active ingredients and their associated risks.

[0014] The invention presents a number of significant improvements over conventional selegiline administration. The administration of monoamine oxidase B inhibiting compounds in fast dissolving oral solid dosage form improves ease and convenience of administration for practitioners and patients alike. This is especially the case in dysphagic patients with Parkinson's disease, wherein the invention avoids coordination of sipping water and swallowing the tablet because no water is needed to administer MAO-B inhibitors in the invention.

[0015] Further, no advanced preparation, measuring or mixing, etc. is needed. Thus, the inaccuracies of measuring out liquid doses are eliminated. As a solid dosage form, it can still be packaged, handled and manipulated by both caregiver and patient as easily as a conventional tablet.

Problems solved by technology

One problem associated with the administration of conventional tablet forms of selegiline is that the liver is known to be the principal site for conversion of active selegiline into metabolites, some of which are undesirable.

Consequently, this first pass of absorbed selegiline through the liver results in extensive metabolism of the drug, and a significant proportion of the absorbed dose of intact selegiline never reach systemic circulation or, therefore, the brain.

This phenomenon is generally known as the “first pass effect”, and results in a decrease in the bioavailability of selegiline administered in the conventional manner.

Another problem with conventional selegiline is its undesired metabolites.

Although it has been suggested that N-desmethylselegiline may contribute to the desired inhibition of monoamine oxidases (see, for example, Heinonen et al. in Chapter 10 of Szelenyi), methamphetamine and amphetamine exhibit no useful effect in Parkinson's disease.

Indeed, since methamphetamine and amphetamine are both stimulants of the central nervous system and of the heart, their presence produces undesirable side-effects such as insomnia and cardiac arrhythmias.

Clearly, this situation is far from satisfactory.

Yet another problem associated with conventional selegiline administration is that which is associated with its co-administration with levodopa.

Co-administration of selegiline with levodopa has even been associated with fatalities, and unadjusted (unreduced) amounts of levodopa can cause dyskenesias (defects in the ability to perform voluntary movement).

Yet another undesired side-effect of conventional selegiline administration is orthostatic hypotension and syncope is some patients, which has been linked to non-selective MAO inhibition.

Conventional selegiline can also cause undesirable and capricious side effects due to sudden changes in plasma concentration of selegiline itself and / or its known metabolites.

The presence or absence of food in the digestive tract may also contribute to the unpredictability.

Moreover, conventional tablets need to be administered with water, requiring another difficult swallowing act for such patients.

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