This invention relates to prevention and treatment of diarrhoea, and pharmaceutical compositions therefor.

EP-A- 189002 (Sandoz-Patent-Gmbh) relates to the use of certain compounds for the treatment of serotonin induced gastrointestinal disturbances incuding diarrhoea e.g. secretory diarrhoea, bacterial induced diarrhoea, choleic diarrhoea, traveller's diarrhoea and psychogenic diarrhoea. Tropisetron [(3α-tropanyl)-lH-indole-3-carboxylic acid ester] and benzo[b]thiophen-3-yl carboxylic acid endo-9- methyl-aza-bicyclo[3,3,l]non-3-yl ester were reported to inhibit cholera toxin-induced secretory diarrhoea in mice at a dose of 100 to 500 μg/kg.

Example 6 of EP-A-2004 4 (Beecham Group p.l.c.) describes the preparation of the compound, granisetron (or BRL 43694 monohydrochloride) which is available in the United Kingdom as KYTRIL* a medicament for the treatment of cytotoxic agent induced nausea and vomiting in cancer patients.

Sjoqvist et al (Acta Physiol Scand 1992, 145, 229-237 describes the effects of several 5-hydroxytryptamine (5-HT) receptor antagonists, including ondansetron and granisetron, in diminishing cholera toxin induced diarrhoea in rats. Granisetron was administered at doses of 40 and 400 μg kg i.v.and the cholera-toxin-induced fluid secretion was roughly halved in both cases. Proc. West. Pharmacol. Soc. 35: 221-226(1992) relates to the effect of 5-hydroxytryptamine agonists and antagonists on cholera toxin induced intestinal fluid accumulation in conscious rats.

We have now found that granisetron is of potential use in the prevention and treatment of diarrhoea in man at the dose levels used in antiemetic treatment. Diarrhoea is often associated with HIV positive and ALDS conditions and other immunodeficiency diseases especially those involving gastrointestinal mucosal integrity and/or local mucosal inflammatory conditions, carcinoid syndrome and other gastro-intestinal tumours and also treatment regimens for cancer. Diarrhoea is also associated with cholera.

1 registered trade mark of SmithKline Beecham p.l.c.

Accordingly, the present invention provides the use of granisetron in the manufacture of a medicament for the treatment or prophylaxis of diarrhoea.

The present invention also provides a method of treatment of or prophylaxis of diarrhoea in mammals, including man, by administration of granisetron to the mammal in need thereof.

The administration of granisetron may be by way of known methods, such as oral, or parenteral administration.

An amount effective to treat the disorder hereinbefore described depends on the usual factors such as the nature and severity thereof and the weight of the mammal. However, a unit dose will normally contain 0.5 to 10 mg, for example 1 to 3 mg of granisetron.

For oral or parenteral administration, it is greatly preferred that granisetron is administered in the form of a unit-dose composition, such as a unit dose oral or parenteral composition. Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories.

Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletung agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art.

Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycoUate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.

These solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the _^ active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, 5 methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl c-hydroxybenzoate or 10 sorbic acid, and if desired conventional flavouring or colouring agents.

Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.

For parenteral administration, fluid unit dose forms are prepared containing granisetron and a sterile vehicle. The compound, depending on the vehicle and the 15 concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compouαd in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water 20 removed under vacuum.

Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution 2.5 of the compound of the invention.

As is common practice, the compositions will usually be accompanied by written or printed directions for use in the treatment concerned.

The present invention further provides a pharmaceutical composition for use in the treatment and/or prophylaxis of diarrhoea, which comprises granisetron and a 30 pharmaceutically acceptable carrier. Such compositions may be prepared in the manner as hereinbefore described.

Human Studies

A modified triple-lumen intestinal perfusion technique is used in which very small amounts of pure cholera toxin (15-20μg) are introduced into an isolated segment of human proximal small intestine. This results in the production of a subclinical secretory state in which the rate of water and electrolyte secretion is identical to that in human cholera. This model thus, presents a unique situation for studying the mechanism of cholera-toxin CT-induced secretion in man, and enables the study of potentially useful antisecretory compounds. 5-HT is released into the intestinal lumen in this model and secretion can be reversed with glucose-electrolyte solutions, which are currently the standard therapy for replacing water and electrolytes in acute diarrhoeal states. The effect of granisetron on basal and CT-induced secretory states is studied using triple-lumen perfusion to measure changes in water and electrolyte transport.

Method: The triple-lumen assembly is passed through the mouth into the proximal small intestine where a segment of jejunum is isolated between two occluding balloons. 15-20μg of highly purified CT is then introduced into the occluded segment and allowed to remain there for 2h. Granisetron is administered at the same time that the CT is introduced into the intestinal segment. At the end of the 2h period, the segment is drained, gently lavaged to remove "unbound" CT and the balloons then deflated. Perfusion of the segment with an isotonic plasma elecrolyte solution is then commenced and the effect of granisetron or placebo is assessed on water and electrolyte transport.

The results of a study in humans is described by Turvill et al, Gastroenterology, 1996, 110 (4 Suppl) A368