UTILIZATION OF BROMURE D'OTILONIUM (DCI) FOR TOPIC APPLICATION IN THE GASTROINTESTINAL TRACT AND RELATIVE PHARMACEUTICAL FORMULATION APPROPRIATE FOR SUCH USE

Abstract: Use of bromure d'otilonium, that is otilonii bromidum, for local application in the gastrointestinal tract of the digestive system and relative pharmaceutical formulation appropriate for such use, to obtain the arrest of the motility in order to allow endoscopic manoeuvres for diagnostic and therapeutic purposes.

Description: The present invention relates to a new pharmaceutical composition having as active principle otilonium bromide, which has the following formula: Otilonium bromide is a myolytic active substance which has been used for some time in clinical practice, by oral administration, for the therapy of spastic-dyskinetic forms of the digestive or alimentary canal both on a functional and organic basis. In "Chir. Gastroent.", Vol.15, No.2, 1981, pages 288-294, there is described the use of otilonium bromide in premedication for endoscopic purposes. There otilonium bromide is administered orally about one hour prior to endoscopy of the upper gastrointestinal tract. Use of otilonium bromide for colon preparation for endoscopy is described also in "Gastroenterol. y Hepatol.", Vol.7, 1984, pages 362-368. Also in this case otilonium bromide is administered by the oral route twice at time interval prior to endoscopy. The first administration took place 14 hours before endoscopy. This known administration route has several drawbacks due, in particular, to the fact that administration must take place several hours before endoscopy is carried out. This is necessary in order to allow the otilonium bromide to reach the area where endoscopy must be carried out. Moreover, since the time required varies dramatically from subject to subject, it is quite difficult to get just the right moment to perform the endoscopy, i.e. the very moment in which the otilonium bromide becomes active in the required area. The invention provides a new pharmaceutical form of this active principle which is suitable to effect a local application (instillation or nebulization) in the gastrointestinal tract, i.e. a topical direct administration, rather then an oral administration. By causing an immediate stop of the motility of the gastrointestinal tract at the sprinkling point, said administration route will allow endoscopic manoeuvres both for diagnostic and therapeutic purposes (bioptic sampling, removal of polypoid formations, and others), just after the application of otilonium bromide. According to the invention, the pharmaceutical composition comprises otilonium bromide as an active principle and an antifoaming excipient as well as an emulsifying excipient. This formulation prevents formation of foam during instillation or nebulization of the compound in the gastrointestinal tract. This allows a clear endoscopic vision of the bowel just after administration of the otilonium bromide. The invention also refers to a kit comprising a bottle containing a pharmaceutical composition consisting of otilonium bromide as active principle and at least an antifoaming and at least an emulsifying excipient. The kit of the invention further comprises a vial of sterile water used as solvent, which is added to the content of the bottle prior to use. The solution can be used with a suitable device for instillation or nebulization inside the gastrointestinal tract. The active principle is stored in a dry state because otilonium bromide is not stable for long time in water solution. Basic excipients of the above pharmaceutical form can be: one or more antifoaming compounds such as linear chain primary amine salts compounds (for example tetradecylamine acetate), sulfonated oils, alkyl-phenyl-glycolethers, primary alcohols with more than five carbon atoms, polyethyleneglycols, methylic or phenylic derivatives of polysiloxane and mixtures of same; and one or more emulsifying compounds such as sugar esters (for example sucrose stearate, palmitate and others), sorbitanesters of fatty acids (such as sorbitan-monostearate - monopalmitate - monooleate and others), polyoxyethylenesorbitanesters of fatty acids (such as polyoxyethylenesorbitan-monopalmitate, -monostearate, -monooleate, and others), polyoxyethylenic esters of fatty acids (such as polyoxyetilene-stearate, -laurate, -palmitate and others), polyoxyethylenic ethers of superior alcohols (such as polyoxyethylene-laurylether, -stearylether, -cetylether, -oleylether and others), fatty acid esters (such as glycerylstearate, glycerylpalmitate, glyceryloleate, cetylpalmitate, ethyleneglycolstearate, polyethyleneglycolstearate, propyleneglycolstearate, and others). Said formulation prevents the formation of foaming on instillation, and this advantageously assists endoscopic operations. The preparation of the powder mixture contained in the bottle is carried out by solubilizing the excipients in an appropriate inert solvent, such as methylene chloride, chloroform, acetone, etc., in such a manner as to reach a concentration between 15% and 30%. Subsequently, said solution is made to be absorbed in a homogeneous way on the active principle utilizing a suitable apparatus. The mixture thus obtained is desiccated in an appropriate manner until the total elimination of the solvent. Alternatively, the preparation of the above mixture can be carried out by allowing the various excipients, previously mixed and melted, to be absorbed on the active principle by using an appropriate apparatus. The following formulations are given as unrestrictive examples: Clinical experiments using the pharmaceutical form of the composition of the above specific example comprised the nebulization or the instillation inside the bowels (colon or stomach) or the instillation in the esophagus, before clinical examination, in subjects presenting such functional dyskinetic affections of the esophagus and of the gastroenteric system as to require an endoscopic examination for diagnostic purposes. Said endoscopic examination turned out particularly easy due to the immediate arrest of the motility of the bowel under observation, and the effectiveness of the formulation has always been satisfactory, due both to the possibility of an extempore preparation of the solution and to the presence of the antifoaming and emulsifying excipients.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A pharmaceutical composition for topical use in the gastrointestinal tract, containing otilonium bromide as an active principle, characterized in that it further comprises at least an antifoaming excipient and at least an emulsifying excipient. Pharmaceutical composition according to claim 1, characterized in that the antifoaming excipient is a methylic or phenylic derivative of polysiloxane. Pharmaceutical composition according to claim 1 or 2, characterized in that the emulsifying excipient is chosen among one or more of the following: a sugar ester, a sorbitanester of fatty acids, a polyoxyethylenesorbitan ester of fatty acids, a polyoxyethylenic ester of fatty acids, a polyoxyethylenic ether of superior alcohols, a fatty acid ester. Pharmaceutical composition according to any preceding claim, having the following formulation: otilonium bromide mg 10 - 300 dimethylpolysiloxane mg 0,3 - 10 glycerylmonostearate mg 0,01 - 0,5 sorbitanmonopalmitate mg 0,08 - 2,5 sucrose monopalmitate mg 0,01 - 0,5 water ml 12 - 18 Pharmaceutical composition according to claim 4, having the following formulation: otilonium bromide mg 150 dimethylpolysiloxane mg 5 glycerylmonostearate mg 0,25 sorbitanmonopalmitate mg 1,25 sucrose monopalmitate mg 0,25 water ml 15 A pharmaceutical kit comprising a bottle containing a pharmaceutical composition according to claim 1, and a solvent vial containing sterile water, the sterile water being added to the pharmaceutical composition prior to the topical administration. A method for the preparation of a pharmaceutical composition according to claim 1, characterized in that the excipients are brought in solution in a solvent, the solution is absorbed on the otilonium bromide, and the solvents are removed by drying. A method for the preparation of a pharmaceutical composition according to claim 1, characterized in that the excipients are mixed and melted, and the melted excipients are absorbed on the otilonium bromide in a suitable apparatus. Claims for the following Contracting States : ES, GR Method for the preparation of a pharmaceutical composition comprising otilonium bromide as an active principle, characterized that to said otilonium bromide there is added at least one antifoaming excipient and at least one emulsifying excipient. Method according to claim 1, characterized in that the antifoaming excipient is a methylic or phenylic derivative of polysiloxane. Method according to claim 1 or 2, characterized in that the emulsifying excipient is chosen among one or more of the following: a sugar ester, a sorbitanester of fatty acids, a polyoxyethylenesorbitan ester of fatty acids, a polyoxyethylenic ester of fatty acids, a polyoxyethylenic ether of superior alcohols, a fatty acid ester. Method according to any preceding claim, characterized in that the following formulation is used: otilonium bromide mg 10 - 300 dimethylpolysiloxane mg 0,3 - 10 glycerylmonostearate mg 0,01 - 0,5 sorbitanmonopalmitate mg 0,08 - 2,5 sucrose monopalmitate mg 0,01 - 0,5 water ml 12 - 18 Method according to claim 4, characterized in that the following formulation is used: otilonium bromide mg 150 dimethylpolysiloxane mg 5 glycerylmonostearate mg 0,25 sorbitanmonopalmitate mg 1,25 sucrose monopalmitate mg 0,25 water ml 15 Method according to claim 1, characterized in that the excipients are brought in solution in a solvent, the solution is absorbed on the otilonium bromide, and the solvents are removed by drying. Method according to claim 1, characterized in that the excipients are mixed and melted, and the melted excipients are absorbed on the otilonium bromide in a suitable apparatus.

Inventors: BUCCI, PAOLO, CASINI, ALESSANDRO, PARTI, SANDRO
Applicants: A. MENARINI INDUSTRIE FARMACEUTICHE RIUNITE S.R.L.
Application year: 1987
Main classification: A61K31
IPC codes: A61K47, A61K31, A61B1, A61K9, A61M19, A61P25, A61P1