MXPA97003249A - Oral compositions of extended release of cisapr - Google Patents

Abstract

The present invention relates to: extended release formulations consisting of (L) -tartrate of cisapride, in particular an oral formulation, the use thereof as a medicine, especially in the treatment of gastrointestinal disorders

Description

QRFTLE COMPOSITIONS OF EXTENDED RELEASE OF CISQPRTDQ GIE? QRIR PE THE INVENTION The present invention relates to extended release formulations containing (L) -taptane time, in particular? > for oral administration, to the use of them as medicine, especially in the treatment of disorders «jast oi test ina e. European Patent No. 0,076,530 describes the gastropropatic agent cisapride and the classical compositions thereof. The cisappda has the following structural formula The systematic chemical name of cisappda is cis-4-arn? No-5-chloro-N-Cl-C3- (4-fluorofenox?) Prop? L] -3-methox? -4-p? Pend? N? l] -2-rnetox? benzar? da. Cisappda is a racemic mixture of 2 enantiomers. Cisapride has excellent stimulating properties of the gastrointestinal trait and is said to be devoid of antidopammerg activity. It has already been widely reported about its usefulness in a variety of gastrointestinal disorders. The useful extended release formulations of cisapri a for oral administration should release an active ingredient, i.e. cisappda, for a prolonged period of 15 to 24 hours, ie throughout the gastrointestinal tract with its variant pH values. However, the solubility of cisapr gives much depends on the surrounding μH. The solubility of cisapride is maximal in a strongly acidic medium with a pH of 1 to 2, as, for example, in gastric juice. The solubility decreases rapidly when the pH of the medium increases (physiological), for example in the intestines. An effective sustained release formulation of cisappda must therefore work not only in highly acidic media but also in less acidic or neutral media. In addition, an extended release formulation must release the active ingredient as fast as the formulation is administered and must release the active ingredient in a constant manner, preferably following the order 0 kinetics at first order. This profile is desired because it provides relief to the patient and quickly after administration and overdosing is avoided when the formulation is administered for a consecutive time. A solution to this problem was found in the use of (+) - c? S-4-am? No ~ 5-chloro-N-Hl- [3- (4-fluorophenoxy?) Prop? LH-3-rnetox? -4 - ??? er? D? N? L3-2 ~ metox enzam? aCR (R - *, R *)] - ?, 3-dihydroxybutanedioate (1: 1) - referred to herein as "(L) -tart time d cisapride" - in a matrix formulation as described below (L) ) cisappda tartrate is the racemic cisapride salt with (+) - L-tartaric acid and is exemplified in European Patent No. 0,076,530 as the compound number 241. A further aspect of this invention is the fact that the process Production for the present extended release formulations is very simple as shown in the examples according to the present invention. This is in contrast to the production methods known in the art for preparing extended release formulations. In comparison with other salts of cisapride the salt form with acid GR (R *, R *) 1-2,3-dihydroxybutanedioic acid, ie (+) - L-tartaric acid (the natural form of tartaric acid) exhibits a solubility in remarkably good water. Cisapride being a racemic mixture and L-tartaric acid being a single enantiomer, the resulting form of salt is in principle a mixture of two diastereomeric salts: (L) -tartrate of (+) - cisapride and (L) -tartrate of (-) -ci aprida. Unexpectedly, it was shown that cisapride salt (L) -tartrate is a mixture of diasterorneros C (3R4S) 2R3R) 3 and C (3S4R) (2R3R)], which crystallize as a double salt in a 1: 1 ratio. (This was confirmed by X-rays). The (3R4R) and (3S4R) refer to the respective enantiomer of cisapride and the (2R3R) refers to the optically pure L-ar. Unexpectedly, formulations containing cisapride (L) -tartrate were found to release cisapride in a racemic form, with equal amounts of (+) - cisapride and (-) - cisapride or in other words the forms of the diurnal salts in the tartrate of (+) - cisapride and (L) - tartrate of (-) - cisapride have unexpectedly equal dissolution relations. Furthermore, it was also found that during the preparation of cisapride (L) -tartrate no enrichment of one of the two forms of diastere dical salts could be detected. The compositions according to the present invention contain pharmaceutically acceptable carriers and excipients, such as fillers, e.g. lactose, sucrose, mannitol, corn starch, preferably lactose; lubricants, v.gr. stearic acid, magnesium stearate, talc or silicon or mixtures thereof; preferably a mixture of magnesium stearate, talc and colloidal silicon oxide (fierosil R). Other pharmaceutically acceptable additives such as colorants and flavors and the like may also be present. The "delayed" effect or "extended release" effect is due to the fact that cieapride (L) -tartrate is fixed in a mixture of two viscous polymers. Therefore, the formulation consists of a mixture of a highly viscous hydrophilic polymer and a viscous hydrophilic polymer, which releases the active ingredient gradually from the formulation. For the present active ingredient, the (L) ~ cisapride tartrate, this can conveniently be achieved by using a mixture of hydroxypropyl ethyl cellulose and another viscous cellulose derivative such as hydroxyprothylcellulose, ethylcellulose, hydroxycellulose, hydroxyethyltruculcellulose, Rilethylcellulose, preferably hydroxypropylcellulose. These two hydrophilic polymers expand when in contact with water, thus creating a porous mx from which cisapride can be gradually released. Said polymers themselves also dissolve slowly in the aqueous medium. Consequently, the surface of the formulation is also constantly dissolving and thus the aqueous medium can reach the most intimate mixture of polymers which in turn begins to expand and release the active ingredient thus providing a continuous release of the active ingredient followed by a kinetic of order 0 and first order. The hydroxypropyltriethiicellulose used in the aforementioned mixture preferably has a viscosity of about 15,000 Pa, e.g. Hypro elose 2208. The hydroxypropyltrilethylcellulose used in the aforementioned mixture should preferably have a viscosity ranging from 150 to 700 rnPa, preferably from 200 to 600 rnPa, e.g. Klucel EFR. The relative amount of said mixture of viscous hydrophilic cellulose polymers in a formulation preferably ranges from 15% to 35% of the total weight of the composition. The relative amount of mixture of viscous hydrophilic cellulose polymers correlates with the period during which the active ingredient is released. The minimum limit, ie 15%, gives a reasonably extended release period of approximately 900 minutes. The maximum limit, that is to say 35%, leads to longer periods of release releasing still more all the active ingredient present in the formulation. With relative amounts greater than 35% it is expected that there is an incomplete release of the active ingredient. The ratio of the weight of the hydroxypropyl ethyl cellulose to the weight of the other cellulose polymer ranges from 0.33 to 3. In particular, the weight ratio of the hydroxypropyl etiicellulose to the weight of the hydroxypropyl cellulose ranges from 0.33 to 3. The preferred ratio is 1, ie equal amounts of hydroxypropyl-rnetiicellulose and hydroxypropylcellulose are present. The preferred oral formulation of the present invention is a tablet. Said tablets may have different kinds of forms, e.g. oblong or completely circular. The shape of the tablet influences the period of release, due to the fact that different forms have a different ratio of surface to volume. A person skilled in the art will appreciate that the volume of the tablet is a function of other parameters such as the actual composition, the form, the desired period of release and the desired dose. The exemplified compositions are given for completely circular tablets with a diameter of approximately 11.5 mm and a height of 5.2 nm. These tablets may have lines or break marks and may carry a symbol or other signals. Such tablets may optionally be coated with coating compositions known in the art. Coated tablets are the preferred formulation in this invention. The ingredients and relationships above apply to the core of the formulation in general, to the core of the tablet in particular. The compositions of these "formulation cores" will be referred to below as core compositions. Suitable coating formulations consist of a film-forming polymer such as, for example, hydroxypropylmethylcellulose, e.g. the hypromellose 2910 (5 rnPa.s); a plasticizer such as, for example, a glycol, e.g. propylene glycol; an opacifier, such as titanium dioxide; a film softener, such as talcum powder. Water is added as solvent.

Some suitable core compositions are: (L) -cisapride tartrate: from 2 to 15% by weight filler: from 50 to 70% by weight hydrophilic polymer mixture: from 15 to 35% by weight lubricants: from 0.5 to 10% in weigh Some interesting core compositions are: (L) -cisapri tartrate a: 5 to 15% by weight filler: 50 to 70% by weight hydrophilic polymer blend: 15 to 35% by weight lubricants: from 0.5 to 10 % in weigh Some more interesting core compositions are: (L) -cisapride tartrate: from 8 to 12% by weight filler: from 55 to 65% by weight hydrophilic polymer mixture: from 20 to 25% by weight lubricants: from 2.5 to 8% by weight Some compositions the nucleus in particular are: (L) -cisapride tartrate: approx. 9% by weight filler: approx. 61% by weight hydrophilic polymer mixture: approx. 23.5% by weight lubricants: approx. 6.5% by weight Some preferred core compositions are: (L) -cisapride tartrate: approx. 9% by weight lactose: approx. 61% by weight hydroxypropylmethylcellulose: from 5.5 to 18% by weight (*) hydroxypropylcellulose: from 5.5 to 18% by weight (• *) lubricants: approx. 6.5% by weight (* •) being the total amount of the cellulose derivatives in weight percentage of approximately 23.5%.

In view of the stimulatory properties of gaintestinal notification of cisapride, the present invention provides for the use of the present formulation as a medicine, in particular in the treatment of gaintestinal disorders.

EXPERIMENTAL P RTE EXAMPLE 1 To a stirred solution of c ts.-4-amino-5-chloro-l-C3- (4-fluorophenoxy) propyl] -3-methoxy-4-p-peridonyl] -2 ~ rnetoxibenzarnide (4 g) in ethanol (18 rnl) was added CR (R *, R *) 1-2,3-dihydroxyatanedioic acid (1.4 g) in ethanol (20 rnl) and the product will crystallize. It was separated by filtering and dried, yielding 4.8 g (89%) of (+) - c? S-4-am? No-5-chloro-£? -ll- [3- (4-fluorophenoxy?) Prop? ] -3-rnetox? -4-p? Perid? L] -2-methox? Benzane [R (R *, R *)] - 2,3-dihydroxybutanedioate (1: 1), ie ( L) cisapride tartrate. The melting point is 197.1 ° C and CaH »is 6.7 (c = 0.1% methanol).

EXAMPLE 2 Ingredients for the preparation of 1000 tablets (570 g) of formulation 1: Ingredient Quantity% by weight of the tablet (L) -cisapride tartrate 52.92g 9.3% Lactose 346.08g 60.7% Hydroxip opilmet.ilcelulosa 2208 66g 11.6% Klucel. EFR 67.95g 11.9% Water (*) 60g Isopropanol (*) 140g Agnecio layer 2.85g 0.5% Aerosil R 5.7g 1.0% Talc 28.5g 5.0% (• *) These ingredients are contained in the final composition of the tablet.

Preparation: The above-mentioned amounts of (C-taprrate, lactose, hydroxypropyl etiicellulose, Klucel EFR tartrate were screened on a stainless steel mesh screen (0.95 mm mesh) and mixed in a planetary powder mixer for 5 minutes. The mixture was soaked with isopropanol and water, the soaked mixture was again tanned on a screen with mesh (mesh: 1.8 m), the mixture was dried overnight at a temperature of 45 ° C. The granulated or dried material was sieved over the a screen with mesh (mesh: 0.95 mm) The dried and sieved granulated material was mixed with magnesium stearate, Aerosil R and talc sieved in a planetary powder mixer for 5 minutes.

Preparation of the tablets: Using the above-described mixture, 1000 tablets are compressed.

EXAMPLE 3 Ingredients for the preparation of 1000 tablets (tablets of 570 mg) with the formulation 2. Ingredient Weight of the tablet (L) cisapride tartrate 52.92g 9.3% Lactose 346.08g 60.7% Hipro elosa 2208 40g 7.0% Klucel EFR 93.95 g 16.5% Water (*) 45g Isopropanol (*) L05g Magnesium stearate 2.85g 0.5% Aerosil R 5.7g 1.0% Talc 28.5g 5.0% (*) these ingredients are not contained in the final composition of the tablet.

The preparation is completely analogous to the preparation described for formulation l. EXAMPLE 4 Ingredients for the preparation of 1000 tablets of the formulation: (L) cisapride tartrate 52.92 rng lactose lionhydrate 346.08 mg Hipro elosa 2208 15000mPa.s 66 rng Hydroxypropylcellulose 67.95 rng Water (*) Isopropanol (* •) Magnesium stratum 2.85 rng Aerosil R 5.7 rng Talco 28.5 rng Coating composition: Hypromellose 2910 5mPa.s 12 g Propylene glycol 3 rng Titanium dioxide 3 rng Talc 2 mg Water (*) 120 g preparation: The (L) -tartrate of cisapride, lactose, hypromellose and Klucel R are mixed in a high-shear mixing granulator and soaked with a mixture of isopropanol and water. The granulate thus formed is dried by heating in vacuo. After calibrating the dried granulated material, Aerosil, talc and magnesium layer are added and mixed until a homogenous mixture is obtained. Compressed biconvex tablets with a diameter of 11.5 m weighing approximately 570 rng. The tablets are coated in a suitable coating vessel with a coating suspension consisting of hyprornelosa (5 Pa.s), propylene glycol, titanium dioxide, talc and water.

Claims (10)

NQVEDflP PE Lfl INVENTION REVIVALS

1. - An extended release formulation comprising (L) -tartrate of cisapride suitable for oral administration.

2. An extended release formulation according to claim 1, which comprises a mixture of hydroxypropyltrilethylcellulose and another viscous cellulose polymer.

3. An extended release formulation according to claim 2, which comprises a mixture of hydroxypropyltriethiicellulose and hydroxypropylcellulose.

4. An extended release formulation according to claim 2, further characterized in that the core of the formulation comprises 15% to 35% of the mixture of hydroxypropyl ethylcellulose and another viscous cellulose polymer.

5. An extended release formulation according to claim 4, further characterized in that the ratio of the weight of the hydroxypropyl cellulose to the weight of the hydroxypropyl cellulose ranges from about 0.33 to about 3.

6. An extended release formulation in accordance with Claim 5, further characterized in that the ratio of the weight of the hydroxypropylmethylcellulose to the weight of the hydroxypropylcellulose is approximately l.

7. An extended release formulation according to any of claims 1 to 4, comprising: about 9% by weight of cisapride (L) -tartrate, about 31 61% by weight of lactose, of 5.5 % to 18% of hydroxypropylmethyl cellulose, from 5.5% to 18% of hydroxypropyl cellulose, about 6.5% by weight of lubricants, the total percentage by weight of the cellulose derivatives being about 23.5%.

8. A crystalline form of cisapride (L) -tartrate, characterized in that the diastereors C (3R4S) (2R3R) 1 and C3S4R) (2R3R)] crystallize as a double salt in a 1: 1 ratio.

9. Process for preparing an extended release formulation according to any of claims 1 to 7, further characterized in that the active ingredient is intimately mixed with the other pharmaceutically acceptable ingredients.

10. Use of a composition according to any of claims 1 to 7, for use as medicine, especially for treating gastrointestinal disorders.