Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-10-11
1998-06-09
MacMillan, Keith D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514270, 514289, 514315, 514318, A61K 3140
Patent
active
057634769
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP95/00765, filed Mar. 1, 1995.
The invention relates to a sublingual or buccal pharmaceutical composition, and more specifically to a sublingual or buccal composition for the treatment of various mental disorders.
The compound 5-c!pyrrole and the preparation thereof are disclosed in U.S. Pat. No. 4,145,434. The compound is described as having CNS-depressant activity and antihistamine and antiserotonin activities.
The pharmacological profile of 5-c!pyrrole, its kinetics and metabolism, as well as the first safety and efficacy studies in human volunteers and in schizophrenic patients were reviewed by De Boer et al. (Drugs of the Future 1993, 18(12), 1117-1123). It has been established that Org 5222 yrrole maleate (1:1)! is a very potent dopamine and serotonin antagonist with potential antipsychotic activity.
Phase I clinical studies on the effects of perorally administered 5-c!pyrrole however, revealed that serious cardiotoxic effects, e.g. postural hypotension and/or impairment of baroreceptor functioning, occurred.
Surprisingly, it has now been found that on sublingual or buccal administration, 5-c!pyrrole has substantially less cardiovascular side effects.
The invention therefore relates to a sublingual or buccal pharmaceutical composition comprising ,5-c!pyrrole or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable auxiliaries suitable for use in sublingual or buccal compositions.
The compositions of the invention are useful in treating mammals, including humans, suffering from diseases which are susceptible to treatment by 5-c!pyrrole. Such diseases include mental disorders, such as tension, excitation, anxiety, psychosis, and schizophrenia. The compositions may also be used for antihistamine and for antiserotonin related diseases.
In its simplest form the pharmaceutical composition of the invention consists of an aqueous solution, for instance comprising 0.9% (w/v) of sodium chloride and the active compound rrole, or a pharmaceutically acceptable salt thereof. The maleate salt (Org 5222) is a preferred salt. The active compound is rapidly absorbed from these aqueous pharmaceutical compositions, when kept under the tongue or in the mouth of a patient.
Preferred pharmaceutical compositions are solid pharmaceutical compositions which rapidly disintegrate in the mouth of a subject, upon insertion into the buccal pouch or upon placement under the tongue. Rapid disintegration means that the pharmaceutical composition is disintegrated within 30 seconds in water at 37.degree. C., and preferably within 10 seconds, as measured according to the procedure described in Remington's Pharmaceutical Sciences, 18th Edition (Ed. A. R. Genaro), 1990, pp 1640-1641; see also US Pharmacopeia, Chapter <701>.
In a preferred embodiment the pharmaceutical compositions of the invention are tablets or lozenges which comprise a rapidly disintegrating composition of a pharmaceutically acceptable water-soluble or water-dispersable carrier material. Tablets and lozenges comprising a rapidly disintegrating composition of a pharmaceutically acceptable water-soluble or water-dispersable carrier material are known in the art, for example as disclosed in U.S. Pat. No. 4,371,516. Such tablets may be prepared by freeze-drying of an aqueous solution comprising rrole, a water-soluble or water-dispersable carrier material and, optionally, pharmaceutically acceptable excipients. Such excipients are known in the art, see for instance Remington's Pharmaceutical Sciences, 18th Edition (Ed. A. R. Genaro), 1990, pp 1635-1638, and are commonly used in pharmaceutical compositions, for instance surfactants, colouring agents, flavouring agents, preservatives and the like.
The water-soluble or water-dispersable carrier material is preferably water-soluble. Suitable water-soluble carrier materials are (poly)saccharides like hydrolysed dextran, dextrin, mannitol, and alginates, or mixtures thereof, or mixtures thereof with other carrier materials like polyvinylalcohol, polyvinylpyrrolidine and
REFERENCES:
Handbook of Pharmaceutical Excipients, ISBN (US): 0-917330-56-0, Published 1986, pp. 119-120.
Delbressine Leonardus Petrus Carla
Wieringa Johannes Hubertus
Akzo Noble N.V.
Gormley Mary E.
Klesner Sharon N.
MacMillan Keith D.
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