PHARMACEUTICAL COMPOSITIONS HAVING SPASMOLYTIC ACTIVITY

Abstract: The sulfate salt of idanpramine allows the preparation of pharmaceutical compositions endowed with favourable bioavailability properties.

Description: "PHARMACEUTICAL COMPOSITIONS HAVING SPASMOLYTIC ACTIVITY" The present invention relates to pharmaceutical compositions containing as the active ingredient (1-(2-piperidinoethyl)-4 ,4-bis-(4-methoxyphenyl)-2,5-imi- dazolidinedione (i.e. idanpramine) sulfate, and to the use thereof in human therapy. Idanpramine of formula I is a well-known therapeutical agent used as a spasmolytic agent [II Farmaco (Ed. Sci.) I960, 150:809; Arzn. Forsch. 1970, 20:277]. The hydrochloride salt, which is easy and economic to prepare, has been hitherto used for the preparation of suitable pharmaceutical formulation; however, the cha¬ racteristics of said salts are not perfectly suited for the envisaged pharmaceutical uses. Now it has been found that idanpramine sulfate al¬ lows to attain the following advantages, in comparison with the use of the free base or of the hydrochloride: 1) easier preparation of the pharmaceutical formula¬ tions; 2) better bioavailability of the active ingredient; 3) better hydrosolubility; 4) possibility of preparing sustained-release formu¬ lations having improved release characteristics of the active ingredient. A particularly preferred object of the invention is provided by capsules or tablets in which the active ingredient is slowly and gradually released during time. The active ingredient, idanpramine sulfate, as well as the pharmaceutical compositions of the invention, can be prepared by means of per se known methods. Thus, idanpramine sulfate can be obtained by trea¬ ting an aqueous or aqueous-alcoholic solution or suspen¬ sion of idanpramine base with sulfuric acid, recovering the salt by precipitation with a non-solvent, by lyophi- lization or similar techniques. The techniques and the excipients used for the pre¬ paration of- the pharmaceutical compositions are those described, for instance, in "Remington's Pharmaceutical Sciences Handbook", Hack Pub. Co., New York, USA. Besides the oral administration route, also the pa- renteral and rectal route may be envisaged: examples of formulations comprise capsule, sugar-coated pills, drops, solutions, syrups, vials, suppositories, rectal capsules, granulates, lozenges. The compositions of the invention will possibly contain other active ingredients having complementary, synergic or anyhow useful activities. Unitary dosages will usually contain 50 to 200 mg of idanpramine sulfate, and will be administered 1 to 3 times a day, depending on the conditions of the patient and the severity of the disease. The following non-limiting examples further illu¬ strate the invention. EXAMPLE 1 Rectal σapules Each rectal capsule contains: Active ingredient Idanpramine sulfate mg 180 Excicipients: Liquid paraffin mg 220 Solid paraffin mg 10 Gelatin mg 80 Glycerine mg 30 Ethyl p-hydroxybenzoate mg 0.33 Propyl " mg 0.2 Polyethylenglycol mg 5.6 Titanium dioxide mg 5.5 Glyceryl-mono-dioleate mg 4 Polyvinylacetate mg 0. , 2 EXAMPLE 2 Vials Each vial contains Active ingredient: Idanpramine sulfate mg 180 Excipients: Bidistilled water for injectable preparation q.s. EXAMPLE 3 Sugar-coated pills Each sugar-coated pill contains: Active ingredient: Idanpramine sulfate mg 60 Excipients: Dextrose mg 100 Talc mg 7 Maize starch mg 40 Gum arabic mg 3 Sodium stear te mg 10 Saccharose q.s. a mg 375 EXAMPLE 4 Drops Each 10 ml ampoule contains Active ingredient: Idanpramine sulfate mg 800 Exci ients: Sweeteners water q.s. a 10 ml Natural flavor q.s. EXAMPLE 5 "Retard" sugar-coated pills a) Composition for sugar-coated pill Active ingredient: Idanpramine sulfate mg 180 Excipients- Inert granules mg 76 PEG 4000 mg 7.71 Ethylcellulose mg 14.0 Stearic acid mg 1.40 Polymethacrylate mg 5.58 Talc mg 15.31 b) Preparation of inert granules A mixture comprising 75% saccharose and 25% maize starch was placed into a stainless steel rotary pan; while the rotary pan rotated, water was sprayed on the mixture, in an amount of 15% w/w based on the total mass, thus obtaining spherical granules of different sizes. The obtained granules were dried in thermostatic oven at 40°C, under forced ventilation. After drying, residual water must not be higher than 2%. Granules were sieved to separate those having the desired size from the ones having higher or lower diameter. c) Application of the medicament on the spherical granules , A predetermined amount of spherical nuclei was placed into a special rotary stainless steel pan rotating at moderate speed. The drug was distributed on the granules by means of a suited binding solution. The whole operation was carried out slowly so as to avoid as much as possible the formation of clots; when the predetermined amount of active principle has been applied, the granules were sieved through a 1340.u sieve and then dried at 35°C with forced ventilation. d) Application of the delaying membrane on the granules The granules obtained in c) were placed again in rotary pan. The delaying membrane was applied on them, slowly, keeping the pan at moderate speed and portion- wise, so as to obtain a uniform distribution of the coating on the granules surface; the product was dried with talc portions between each application. The application of the membrane was normally carried out in more than a phase, up to the obtainment of the desired i^ vitro release values. The granules were dried by insufflating air at 35 β C into the rotating pan, till the content of the residual solvents is within the predetermined limits. At the end of drying the granules, sieved so as to obtain a particle size ranging from 707 to 1340.U, are distributed in capsules size "1" by means of a suited incapsulating machine.

Claims: - - CLAIMS 1. Idanpramine sulfate as therapeutic agent. 2. Pharmaceutical compositions containing as an active principle idanpramine sulfate in admixture with acceptable excipients and optionally with other active principles. 3. Pharmaceutical compositions according to claim 2 for oral, parenteral or rectal administration. 4. Pharmaceutical compositions according to claim 3 in form of capsules, tablets, sugar-coated tablets, drops, suppositories, vials. 5. Pharmaceuticals compositions according to claim 2 in form of sustained release capsules. 6. Pharmaceutical compositions according to claim 5 wherein the active principle is coated with a membrane consisting of polymethaacrylate, ethylcellulose, polyethylenglycol.

Inventors: MAZZONI LUCIA, MAZZONI, LUCIA
Applicants: IBIS IST BIOCHIM SPERIMENT
Application year: 1988
Main classification: C07D233
IPC codes: A61K31, C07D233