Sabeluzole oral suspensions

Details Sabeluzole oral suspensions Sabeluzole oral suspensions

1997-03-27

1997-12-23

Henley, III, Raymond

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

A61K 31445

Patent

active

057008140

DESCRIPTION:

BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the national stage of application No. PCT/EP 95/03966, filed on Oct. 6, 1995, which application claims priority from EP 94.202.986.9, filed on Oct. 14, 1994.
The invention relates to physicochemically stable sabeluzole formulations having a satisfactory taste and aftertaste.
In U.S. Pat No. 4,861,785 then are described compounds having antihypoxic and antianoxic properties useful in indications such as shock, cardiac arrest and severe blood loss. Among these compounds features ineethanol, which is generically known as sabeluzole. Subsequent investigations have shown the potential of sabeluzole in the treatment of patents suffering from chronic neuro-degenerative diseases such as dementia of the Alzheimer type (DAT) or Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dementia associated with Parkinson's disease and other central nervous system diseases which are characterized by progressive dementia.
Administration of an oral dosage form is the preferred route of administration for many pharmaceuticals because it provides for easy, low-cost administration. However, patient compliance can be a problem when the patient is requested to swallow a solid formulation such as a tablet or a capsule. Therefore, the development of a liquid oral formulation is often desirable.
The development of a liquid oral formulation of sabeluzole is hampered by the unpleasant bitter taste of the compound. The bitter flavour of sabeluzole is inevitably tasted during drinking or immediately after swallowing a solution comprising the compound. A clear improvement in taste is observed using a suspension of sabeluzole instead of a solution of the compound. In particular the bitter aftertaste is significantly reduced. The development of a useful suspension of sabeluzole, however, is hampered by chemical stability problems of the compound. In particular, aqueous suspensions of sabeluzole at pH 7 suffer from degradation of sabeluzole and have an unacceptable shelf-life. A stable sabeluzole suspension was prepared by maintaining the pH in a strict range from about 8 to 10. These suspensions were further specifically adapted so as to allow them to be diluted with cold beverages such as fruit juice and also hot beverages such as tea, cocoa and coffee. These features are considered essential properties in a medicament which has to be administered to patients whose compliance with therapy is a major concern.
The present invention is concerned with stable aqueous sabeluzole suspensions having a pH in the range from 8 to 10. In particular, the invention relates to aqueous suspensions for oral administration comprising sabeluzole and a pharmaceutically acceptable carrier, having a pH in the range from 8 to 10.
The term "stable" as used herein relates to compositions wherein the decrease in the sabeluzole content is less than 10%, preferably less than 5% and most preferably less than 2%, after storage at room temperature for up to 3 months.
The term sabeluzole as used hereinabove also comprises the solvates which sabeluzole is able to form and said solvates are meant to be included within the scope of the present invention. Examples of such solvates are, e.g. the hydrates, alcoholates and the like.
Sabeluzole has an asymmetric carbon atom and the absolute configuration of this asymmetric centre may be indicated by the stereochemical descriptors R and S. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, in particular the racemate.
Two polymorphs of sabeluzole base are known. The higher melting polymorph I (mp. 101.7.degree. C., maximum 105.3.degree. C., heat of fusion=99.6 J/g) can be distinguished easily by its DSC characteristics from the lower melting polymorph II (mp. 88.9.degree. C., maximum 91.6.degree. C., heat of fusion 84.2 J/g). X-ray diffraction analysis has confirmed the existence of the two polymorphs. Polymorph II is metastable and dissolves considerably more rapidly th

REFERENCES:
patent: 4861785 (1989-08-01), Stokbroekx et al.
patent: 5434168 (1995-07-01), Stokbroekx et al.

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