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STABLE FAST DISSOLVING ORAL DOSAGE FORM CONTAINING REVERSIBLE INHIBITOR OF THE ENZYME ACETYLCHOLINESTERASE

IP.com Disclosure Number: IPCOM000185216D
Publication Date: 2009-Jul-16
Document File: 4 page(s) / 86K

Publishing Venue

The IP.com Prior Art Database

Abstract

STABLE FAST DISSOLVING ORAL DOSAGE FORM CONTAINING REVERSIBLE INHIBITOR OF THE ENZYME ACETYLCHOLINESTERASE

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STABLE FAST DISSOLVING ORAL DOSAGE FORM CONTAINING REVERSIBLE INHIBITOR OF THE ENZYME ACETYLCHOLINESTERASE

Orally disintegrating dosage forms are becoming an increasingly important in the area of better patient compliance comparative to the conventional solid dosage pharmaceutical forms such as capsules and tablets for oral administration, which are the most commonly used.

One of the main goals of the development was to prepare orally disintegrating tablets (ODT) without the need that the active ingredient come in contact with solvent or is subjected to the higher temperatures, and that the composition can be prepared in a simple way, resulting in ODT which disintegrates fast without leaving the unpleasant feeling of coarse dispersion in the mouth and which show a low friability rendering them suitable for a normal packaging and storing procedures.

(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride (DH) (Figure 1) is a reversible inhibitor of the enzyme acetylcholinesterase used to treat dementia (a brain disorder that affects the ability to remember, think clearly, communicate, and perform daily activities and may cause changes in mood and personality) associated with Alzheimer's disease (a brain disease that slowly destroys the memory and the ability to think, learn, communicate and handle daily activities) (1).

Figure 1. Structural formula of DH.

DH, used in our formulation, was prepared from its base (DB).  The aim of our development work was to define the characteristics of DH, primarily the formulation characteristics, e.g. the choice of the excipients and pharmaceutical-technological procedure of preparation of the ODT.

The DH is present in the in compositions in its crystalline or amorphous form. Preferably DH is present in one of various polymorphic forms, in particular as any of polymorph I to IV. These polymorphic forms of DH as well as the preparation thereof are disclosed for example in WO 97/46527.

A particularly preferred process was found comprising the following steps: preparing granulate, mixing the granulate with the active ingredient (DH) and excipients and compressing the obtained mixture to the desired form.

Preparation of granulate: Mannitol, microcystalline cellulose, low substituted hydroxypropylcellulose and/or crospovidone, optionally flavour (e.g. flavour banana) and sweetener (e.g. aspartame) were mixed in high-shear mixer and granulated with purified water. The composition of the granules was as follows:

1.        Granulate

 

1.1 Mannitol

40-60 wt.%

1.2 Microcrystalline cellulose

4-10 wt.%

1.3 Low-substituted hydroxypropylcellulose and/or crospovidone

10-20 wt.%

1.4 Flavour

1-2 wt.%

1.5 Sweetener

0.5-1.5 wt.%

Alternative preparation of granulate: DH, mannitol, Eudragit E PO and aspartame were mixed in high-shear mixer and granulated wit...