SALT OF DICLOFENAC WITH A CYCLIC ORGANIC BASE AND PHARMACEUTICAL COMPOSITIONS WHICH CONTAIN IT

Abstract: The salt of diclofenac with a cyclic organic base is prepared by dissol­ ving diclofenac in a suitable organic solvent, adding said cyclic organic base, reacting the two components together, removing the solvent and cry­ stallising the product obtained. Said salt is water soluble to an extent from 20% w/v to an extent excee­ ding 50% w/v, and is used to prepare pharmaceutical compositions prefera­ bly in granular form for use by dissolving in water for oral administration.

Description: This invention relates to the salt of diclofenac with a cyclic organic base and to pharmaceutical compositions which contain it. More particularly, the invention relates to the salt of diclofenac with a cyclic organic base in the various pharmaceutical forms, and preferably in granular form for use in extemporaneous solutions for oral administration. Diclofenac (2-[2,6-dichlorophenyl)-amino] benzeneacetic acid) is an anti-inflammatory medicament which has been known for a considerable time and which together with numerous other compounds falls under the general formula of USA patent 3,558,690. One of the characteristics of these compounds is that they cyclize in an acid environment to give the corresponding indolinones. In order to obtain stabilisation of the open form, they are salified with non-toxic organic or inorganic bases as described for example in the aforesaid patent. However, in this patent no information is given regarding the solubility of said salts in water, and notwithstanding the fact that several years have passed since the teachings of the said patent were made available, no aqueous pharmaceutical composition of diclofenac has been marketed. We have now found that it is possible to obtain a highly watersoluble diclofenac salt by salifying diclofenac with a cyclic organic base having the general formula (I) in which n is 2 or 3. This is very surprising in the light of the fact that USA patent 3,558,690 comprises salts of diclofenac with bases such as 2-amino-ethanol and pyrrolidine which are very close to the bases of the formula (I) from a structural viewpoint, whereas these salts are practically insoluble in water. In contrast to the tablet form currently used for oral administration one particular unforseable advantage of the salt of diclofenac with a base of formula (I) is that when prepared in granular form and stored in water-impermeable sachets, it enables extemporaneous aqueous solutions to be prepared which while totally maintaining their activity level do not give rise to gastrolesion. The enormous advantage of such a behaviour which obviates any risk to the patient ingesting the medicament is an obvious considerable merit in terms of its pharmaceutical application. The salt of diclofenac with a base of formula (I) therefore constitutes a subject of the present invention, a further subject of the invention being pharmaceutical compositions containing a therapeutically useful dosage of said salt. The process for preparing this salt is extremely simple from an industrial viewpoint, it being characterised by dissolving diclofenac in a suitable organic solvent, adding a base of formula (I), reacting said compounds together at ambient temperature, removing the solvent and crystallising the product obtained. Suitable organic solvents for dissolving diclofenac are acetone, ethanol and chloroform. The base is used in equimolar quantity or in slight excess with respect to the diclofenac. The reaction is conducted at ambient temperature under agitation for a time of between 0,5 and 3 hours. The solvent is removed by distillation under vacuum at a temperature of between 35 and 45°C. The salt is crystallised by treating the distillation residue with hexane or petroleum ether under energetic agitation. The unrefined salt obtained is redissolved in acetone and recrystallised from hexane or petroleum ether. The solubility characteristics of the salt of diclofenac with hydroxyethylpyrrolidine (ID) compared with the salts of diclofenac with sodium (SD), with pyrrolidine (PD) and with 2-aminoethanol (AD) are given in the following table. The salt of diclofenac with a base of formula (I) also has high shelf life. The pharmaceutical compositions according to the present invention conttain a therapeutically active quantity of the salt of diclofenac with a base of formula (I) together with pharmaceutically acceptable liquid or solid excipients of organic or inorganic type, and can be administered orally. Preferably, said compositions contain an active ingredient quantity corresponding to 10-200 mg of diclofenac per unit dosage. Examples of preferred pharmaceutical forms are granular forms packaged in sachets of water-impermeable material, and are dissolved in a little water to form solutions for oral administration. In addition to the excipients, said compositions can contain preservatives, stabilisers, wetting agents, emulsifiers, osmotic presssure regulating salts, buffers, dystuffs, sweeteners and flavourings. They are prepared by known methods and can contain other therapeutic agents. The following examples are described by way of non-limiting illustration of the present invention. EXAMPLE 1 Preparation of the salt of diclofenac with hydroxyethylpyrrolidine 14.75 g (49.8 mmoles) of 2-[(2,6-dichlorophenyl)-amino] benzeneacetic acid (diclofenac) were dissolved in acetone (50 ml), and 5.75 g (49.9 mmoles) of freshly distilled hydroxyethylpyrrolidine were added to the solution obtained. After keeping the solution under agitation for one hour at ambient temperature, the solvent was removed under vacuum at 40°C. The oily residue was treated with hexane (100 ml) and the obtained mixture kept under energetic agitation until the oil was trasformed into a crystalline solid, which was separated by filtration and dried. 17 g of product were obtained having an M.P. of 57-58°C (yield 83% of theoretical). The unrefined product obtained in this manner was dissolved in acetone (50 ml), decolorised with animal charcoal and filtered. The solution was evaporated under vacuum, and the residue treated with hexane as described heretofore. The salt of diclofenac with hydroxyethilpyrrolidine was obtained in its pure state, with an M.P. of 97.5-100°C. EXAMPLE 2 Preparation of a granulate containing the salt of diclofenac with hydroxyethylpyrrolidine A granulate was prepared having the following composition: 70 g of the salt of diclofenac with hydroxyethylpyrrolidine, 1.798 Kg of sorbitol and 50 g of aspartame were mixed together in a steel cube mixer for 20 minutes. 150 g of polyethyleneglycol 6000, 1 g of E 124 and 1 g of E 110 HC were dissolved in 250 ml of boiling water under agitation The solid mixture and solution prepared in this manner were mixed together in a fluidised bed granulator using 100 ml of mixing water. The granulate obtained in this manner was sieved through an oscillating screen with a mesh size of 1 mm. 130 g of flavouring was sieved separately with the same screen, and was mixed with the said granulate in a cube mixer for 20 minutes. The granulate obtained in this manner was dispensed into sachets of water-impermeable material, dispensing 2,2 g of granulate into each sachet. At the moment of use, the contents of each sachet were easily dissolved in a little water to form a drinkable solution which in terms of acid contains 50 mg of diclofenac.

Claims: The salt of diclofenac (2-[2,6-dichlorophenyl)-amino]-benzeneacetic acid) with a cyclic organic base having the general formula (I) in which n is 2 or 3. Pharmaceutical compositions useful as antiinflammatory, characterised by essentially containing a therapeutically active quantities of the salt of diclofenac with a cyclic organic base according to claim 1, together with pharmaceutically acceptables excipients. Compositions as claimed in claim 2, characterised by containing a quantity of the salt of diclofenac with said cyclic organic base corresponding to 10-200 mg of diclofenac per unit dosage. Compositions as claimed in claim 2, characterised by being prepared in granular form and packaged into water-impermeable sachets, suitable to be converted easily into an aqueous solution for oral administration. Process for preparing the salt of "diclofenac" (2-[2,6-dichlorophenyl)--amino]-benzene acetic acid) with a cyclic organic base according to claim 1, characterised by dissolving the diclofenac in a suitable organic solvent, adding said cyclic organic base at ambient temperature, removing the reaction solvent and then crystallising the product obtained. Process according to claim 5 characterised in that the reaction solvent is acetone. Process according to claim 5 characterised in that the crystallization occurs in presence of hexane. Claims for the following Contracting States: GR, ES Process for preparing the salt of diclofenac (2-[2,6-dichlorophenyl)-amino]-benzeneacetic acid) with a cyclic organic base having the general formula (I) in which n is 2 or 3 characterised by dissolving the diclofenac in a suitable organic solvent, adding said cyclic organic base at ambient temperature, removing the reaction solvent and then crystallising the product obtained. Process according to claim 1, characterised in that the reaction solvent is acetone. Process according to claim 1, characterised in that the crystallization occurs in presence of hexane.

Inventors: DI SCHIENA, MICHELE, ZIGGIOTTI, ANTONIO
Applicants: ALTERGON S.A.
Application year: 1987
Main classification: C07C229
IPC codes: A61K31, C07D295, A61P29, C07C229, C07C227, C07C67