Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-12-04
1998-04-21
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 31415
Patent
active
057418063
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/EP94/01652 filed May 24, 1994.
The present invention relates to a pharmaceutical composition containing, as active ingredient, methyl!-4H-carbazol-4-one, in particular a composition for rectal H-imidazol-1-yl)-methyl!-4H-carbazol- 4-one, which may be represented by the formula (I) ##STR1## and its physiologically acceptable salts and solvates are disclosed in GB2153821. The compound of formula (I) is described as a potent and selective antagonist of 5-hydroxytryptamine (5-HT) at "neuronal" 5-HT receptors of the type located on terminals of primary afferent nerves. Receptors of this type are now designated as 5-HT.sub.3 receptors and are also present in the central nervous system. 5-HT occurs widely in the neuronal pathways in the central nervous system and disturbance of these 5-HT containing pathways is known to alter behavioural syndromes such as mood, psychomotor activity, appetite and memory.
The compound is described as being of use in the treatment of a human or animal subject suffering from a condition caused by a disturbance of neuronal 5-HT function, for example in the treatment of a human subject suffering from migraine pain or a psychotic disorder such as schizophrenia. It is also stated that the compound may be useful in the treatment of conditions such as anxiety, obesity and mania.
Subsequently published patent applications disclose the use of the compound of formula (I) and other 5-HT.sub.3 antagonists for the treatment of a number of other conditions such as dementia, cognitive disorders and emesis.
Numerous clinical studies have demonstrated the effectiveness of the compound of formula (I) for the treatment of emesis, particularly the nausea and vomiting associated with cancer chemotherapy and radiotherapy and that occurring post-operatively. Hitherto, the drug has always been administered in the form of a salt, in particular in the form of its hydrochloride dihydrate salt, either by injection or orally.
Oral administration constitutes the generally preferred route for administration of pharmaceuticals since this route is particularly convenient and acceptable to patients. Unfortunately oral compositions may be associated with certain disadvantages, particularly in the treatment of conditions accompanied by nausea and/or vomiting. It is highly desirable, particularly in the treatment of acute conditions, that pharmaceutical compositions have a rapid and consistent onset of action combined with sustained activity and good bioavailability. Rapid absorption can be achieved by parenteral injection but this is unacceptable to some patients, particularly if the drug is to be administered without direct medical supervision i.e. self-administered.
Alternative routes for administration of the compound of formula (I) are proposed in GB 2153821 including rectal administration. GB 2153821 specifically discloses a number of pharmaceutical formulations containing azol-4-one hydrochloride dihydrate as active ingredient and a specific suppository formulation for rectal administration containing this active ingredient has been disclosed in, for example, EP-0278161.
The present invention provides a particularly advantageous pharmaceutical formulation, not hitherto specifically disclosed, which is suitable for rectal administration of the compound of formula (I).
There is thus provided according to the invention a pharmaceutical composition for rectal administration which comprises methyl-1H-imidazol-1-yl)-methyl!-4H-carbazol-4-one in the form of its free base or a pharmaceutically acceptable solvate thereof as active ingredient, together with one or more pharmaceutically acceptable carriers or excipients.
Unlike the prior art compositions, the compositions according to the invention contain the active ingredient in the form of its free base or a pharmaceutically acceptable solvate thereof. The applicants have found that the use of the free base rather than the hydrochloride salt of the compound of formula (I) is surprisingly advantageous when the active ingredient is administered rectal
REFERENCES:
patent: 4695578 (1987-09-01), Coates et al.
patent: 4983621 (1991-01-01), Bunce et al.
Boylan et al., "Handbook of Pharmaceutical Excipients", 1986, American Pharmaceutical Association & The Pharmaceutical Society of Great Britain, pp. 314-320.
Richard Isabelle
Thielemans Isabelle
Henley III Raymond
Laboratoire Glaxo Wellcome S.A.
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