Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-12-02
2000-12-12
Rose, Shep K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514872, A61K 3154
Patent
active
061599654
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB96/00982 Apr. 24, 1996.
The present invention relates to anti-emetic pharmaceutical compositions and, in particular, to anti-emetic pharmaceutical compositions which contain methotrimeprazine.
Methotrimeprazine (Nozinan) was developed in the late 1950's as an anti-psychotic agent, particularly for the treatment of schizophrenia, its profile being similar to that of chlorpromazine. For use as an anti-psychotic agent it is recommended by mouth, initially at dosages of 25 to 50 mg daily, increased as necessary to dosages of up to 1 g daily.
More recently methotrimeprazine has been prescribed as an adjunctive treatment in terminal care, including the management of pain and associated distress, restlessness or vomiting. For terminal care use it is recommended at dosages of 12.5 to 50 mg every 4 to 8 hours orally, 12.5 to 25 mg every 6 to 8 hours by intramuscular injection or by intravenous injection, or 25 mg to 200 mg daily by continuous subcutaneous infusion using a syringe driver. The use of methotrimeprazine in terminal care is disclosed by D. J. Oliver in British Journal of Clinical Practice, September, 1985, Volume 39, Number 9. The most prominent side effect of the use of methotrimeprazine in terminal care is that of sedation with sedation occurring in over 50% of cases at the doses recommended for use.
The anti-emetic activity of methotrimeprazine has also been discussed by M. Higi et. al, J. Cancer Res. Clin. Oncol. 97, 81-86 (1980) In this article the anti-emetic effect of orally administered levomepromacine (methotrimeprazine) administered in two doses of 8 to 15 mg 12 hours and 1 hour before the administration of the cytotoxic agents, i.e. at a total dosage of from 16 to 30 mg, is discussed. The most common side effect of this treatment is stated to be somnolence.
A considerable amount of published data also exists on the analgesic properties of methotrimeprazine when used in various settings e.g. pre- and post-operatively, post-myocardial infarction, during labour, in chronic pain syndromes and in patients with cancer. A major limitation to its use as an analgesic is, however, the high incidence of sedation which occurs with single intravenous or intramuscular injections of .gtoreq.7.5 mg.
We have now surprisingly discovered that methotrimeprazine is effective as an anti-emetic, for example in the treatment of the nausea and/or vomiting which is frequently experienced by terminal cancer patients, at very low doses which have previously not been prescribed for the acknowledged indications of the drug. At the low doses at which we have found that methotrimeprazine is effective for the treatment of nausea and/or vomiting the acknowledged side effect of sedation at higher doses is not encountered.
Accordingly, in one aspect the present invention provides a non-sedating anti-emetic composition in oral unit dosage form comprising from 1 to 5 mg of methotrimeprazine per unit dosage.
In a second aspect the present invention provides a non-sedating anti-emetic composition in unit dosage form for parenteral administration comprising from 1 to 5 mg of methotrimeprazine in each unit dosage for parenteral administration.
The non-sedating compositions of the present invention in oral dosage form comprise from 1 to 5 mg per unit dosage, preferably from 2 to 4 mg per unit dosage, of methotrimeprazine.
The frequency of the dosing regime will depend upon the severity of the nausea and/or vomiting being treated and upon the response to treatment. Typically, however, the oral dosage form will be up to 10 mg per day in appropriate divided doses, more preferably up to 8 mg per day in divided doses. A typical dosage regime would be from 2 to 4 mg twice a day.
The oral unit dosage form of the compositions will generally be in the form of tablets or capsules; or in the form of powders, granules or spheroids packed into sachets; or in the form of solutions or suspensions when the liquid formulations will generally be formulated to provide the unit dosage in 5 to 20 ml.
The oral unit dosage
REFERENCES:
M. Higi et al., "Verbesserte antiemetische . . . Erbrechen"in Disch. Med. Wochenschr., vol. 105, No. 22, 1980, pp. 794-795.
M. Higi et al., "Pronounced Antiemetic . . . Chemotherapy"in J. Cancer Res. Clin. Oncol., 97, No. 1, 1980, pp. 81-86.
V. Vetter et al., "Prophylaxe von Nausea . . . Chemotherapie" in Monatsschrift Kinderheilkunde, vol. 143, No. 12, Dec. 1995, pp. 1242-1246.
Dictionaire Vidal, Paris, 63 Ed., 1987, p. 1090, "Nozinan".
Koperberg, "Farmacotherapeutisch Kompas," Amstelveen, NL, 1984, p. 46, "Minozinan."
B. Paradis, "Analgesic and Anaesthetic Properties of Levomepromazine (Nozinan.RTM.) (R.P. 7044)" in Canadian anaesthetic Soc. J., 9, 1962, pp. 153-160.
M. Minuck, "Postoperative Analgesia . . . Agents" in Canadian Anaesthetic Soc. J., 19, 1972, pp. 18-22.
J. Bellens, "Analgesic Treatment with Levomepromazine (Nozinan.RTM.) . . . " in Videnskab OG Praksis, No. 21, May 18, 1981, pp. 1315-1316.
O. Davidsen et al., "Analgesic Treatment . . . Infarction" in Acta Med Scand, 205, 1979, pp. 191-194.
P. Callaghan et al., "Methotrimeprazine for Obstetric Analgesia" in Am. J. Obs. & Gynaecol., 95:636, 1966, pp. 82-85.
E. Montilla et al., "Analgesic Effect . . . Clinical Comparison" in Archives of Internal Medicine, 111:725, 1963, pp. 23-25.
S. Bloomfield et al., "Comparative . . . Pain" in Canadian Med. Ass. J., 40:1156, 1964, pp. 12-16.
W. Beaver et al., "A Comparison . . . Cancer" in Clinical Pharmacology, 7:436, 1966, pp. 3-11.
D. Oliver, "The Use of Methotrimeprazine in Terminal Care" in British J. Clin. Practice, 39:339, 1985.
M. Baines, "Terminal Illness" in Textbook of Medical Treatment, Edinburgh, 15th Ed., 1987:1-16.
C. Saunders, "Terminal Care" in Oxford Textbook of Medicine, Oxford U. Press, 28.1-28.13, 1983.
G. Jordan, "Management of Postoperative Pain with Parenteral Methotrimeprazine" (source and date unknown).
Barkby Grahame David
Hallwood Philip Malcolm
Jagoe Donna A.
Link Pharmaceuticals Limited
Rose Shep K.
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