IE840817L - Novel galenic forms of sulpiride which can be used orally - Google Patents

Abstract

Orally administrable compositions containing sulpiride in microgranules formed by a neutral grain material and having an outer layer of a microporous polymer. The use of such compositions, which are made by projecting a solution of sulpiride onto the neutral grains and then applying the polymer, makes it possible to achieve absorption of sulpiride double that which is obtained with conventional capsules, while retaining a slightly greater period of action and considerably reducing the differences in absorption from one subject to another. The rate of liberation of sulpiride in artificial gastric and intestinal media is specified. [EP0147244A1]

Description

2 The present invention concerns orally administrate pharmaceutical forms of Sulpiride and their preparation.

Sulpiride, viz. N-(l-ethyl-2-pyrrolidinyI)methyl-2-methoxy-5-sulphamoylbenzamide, is known as an excellent neuroleptic disinhibitor, having as its main therapeutic indication the treatment of acute and chronic psychoses. Its characteristics and properties are described in particular in French Patents Nos. 1 472 023, 4879 M and 5916 M.

Available orally active medicaments containing Sulpiride include compressed tablets, capsules and drinkable aqueous solutions, but as set out below these forms require a plurality of daily doses and sometimes are incompletely absorbed by the organism. Consequently, attempts have been made to modify the form of composition to substantially enhance acceptance by patients while reducing the number of daily doses required.

The plasmatic half-life of the active ingredient Sulpiride is about eight and a half hours. It therefore seems possible to produce a form of the product enabling the average daily dose to be reduced to two capsules or tablets each containing 100 mg of Sulpiride, one being taken in the morning and. one in the evening, or even to one capsule or one tablet containing 200 mg of Sulpiride.

For that purpose, microgranules having a prolonged effect were produced, in accordance with the conventional processes described in particular in French Patents Nos. 2 313 915 and 2 453 642. Neutral grains about 0.50 mm in diameter and comprising 25% of starch and 75% of saccharose were used. The Sulpiride was directed onto them in a turbine process, by means of an alcoholic solution of polyvinylpyrrolidone, and then conventional coating fibres were applied, based on polymer of the shcllac, methacrylate or ethylcellulose type, so as to produce pre-established standard kinetics for liberation of the Sulpiride in vitro in gastric and intestinal media, in accordance with the following specifications: 1st liour : liberation less than 40%. 4 th hour : liberation less than 75%.

Sth hour : liberation more than 75%. 3 Liberation at the first hour is effected in an artificial gastric juice having a pH of 1.3, and at the fourth and at eighth hours in artificial intestinal juices having pHs of 4.5 and 7 respectively. The operating conditions for studying the liberation of the active ingredient are known and described in the above-mentioned patents.

Those microgranules were then used to produce capsules and compressed tablets giving a dosage of 100 mg; the absorption of the Sulpiride was studied by determining the plasmatic amounts of Sulpiride in circulation by means of radio-immunology; and the results obtained were compared with those obtained from the capsule form at present on the market.

The results are set out in Table A below and show that, with the two formulations of microgranules used (form I and form II), the loss in the amount of active ingredient circulating is too substantial with respect to that with the normal form of capsules (form IV) to make it possible to provide an effective prolonged-effect medicament.

Forms I and II used had the following kinietics in respect of liberation in vitro in artificial media: form I form II Liberation at the first hour in a medium of pH 1.3 20.0% 29.2% Liberation at the fourth hour in a medium of pH 4.5 68.6% 58.4% Liberation at the eighth hour in a medium of pH 7 90.8% 98.2% After studying a series of prolonged-effect formulations which all gave results incompatible with producing a good properly absorbed oral form, the idea was conceived of retaining the microgranule form (substantially spherical grains of a diameter of between 0.2 and 2 mm), which in practice should permit of better absorption of the active ingredient than a conventional powder of the capsule or the tablet, while having kinetics in respect of liberation in vitro much closer to those forms, that is to say, liberating substantially 90% of the active ingredient after one hour in an artificial gastric medium having a pH of 1.3.

Surprisingly, the results of the microgranules using those in vitro kinetics showed that, in dependence on the comparative plasmatic 4 proportions, the form III formed by microgranules put into capsule form with a dosage of 100 mg makes it possible to achieve a degree of absorption double that obtained with the conventional capsules of Sulpiride (form IV), while retaining a slightly greater period of action and substantially reducing 5 the differences in absorption from one subject to another. The above- indicated improvement in the absorption of Sulpiride, both in the quantitative respect and in respect of its regularity, permits of a reduction in the doses used and the number of daily doses to be taken. those results are set out in Table A, and also in Figure 1, showing the 10 variation in the plasmatic proportions in circulation between 0 and 32 hours, expressed in ng/ml of Sulpiride, by comparison between form III and form IV.

Complementary experiments, in the course of which the external coatings of the microogranules according to the invention are varied, made it possible to acertain that the preferential form with improved absorption 15 of the Sulpiride should substantially correspond to the following analytical conditions in respect of liberation in vitro; IS minutes : liberation between 33 and 50% in an artificial gastric medium of pH 1.3 30 minutes : liberation between 60 and 75% in an artificial 20 gastric medium of pH 1.3 60 minutes : liberation between 80 and 95% in an artificial intestinal medium of pH 4.5.

Moreover, an overall liberation rate of higher than 90% is noted in an artificial intestinal medium of pH 6.9. 25 In accordance with the present invention, there are provided pharmaceutical compositions for oral administration containing Sulpiride and in the form of microgranules having a diameter of from 0.2 to 2 mm, constituted by a neutral core comprising a mixture of saccharose and starch, a layer of Sulpiride and polyvinylpyrrolidone, and an outer layer comprising 30 a copolymer A of methacrylic acid and methyl methacrylate with a copolymer B of ethyl acrylate, methyl methacrylate and N,N,N-trimethyI 2-[(2-methyl-l-oxo-2-propenyl) oxy] ethanaminium chloride, coated with a layer of the said copolymer B, in which the liberation in vitro of the Sulpiride in artificial gastric and intestinal media is substantially as set 35 forth immediately above. Copolymers A and B are preferably those sold under the trade marks Eudragit L - 100 and Eudragit RL - 100, respectively.

The production formula for 2300 capsules with a dosage of 100 mg, of form III, and the process for* their manufacture is set out below by way of example. 230 g of Sulpiride in a 20% ethanolic solution of polyvinylpyrrolidone is applied by a turbine process to 50 g of neutral grains substantially 0.50 mm in diameter and comprising about 25% of starch and 75% of saccharose.

After drying and sieving, outside layers are applied, comprising the said copolymers A and B, preferably those marketed under the registered trade mark Eudragit by Rohm and Haas in alcoholic solutions in proportions of 4 parts by weight of Copolymer A (preferably Eudragit L - 100) for 1 part by weight of Copolymer B (preferably Eudragit RL - 100).

Drying is then effected with small proportions of talc until microgranules are produced, which liberate substantially 100% Sulpiride in an hour in accordance with the analytical conditions defined above.

Drying is then effected in a drying oven at 37°C for about two days, and then the outside layer is completed by projecting 40 g of a 13.5% ethanolic solution of Copolymer B (preferably Eudragit RL - 100). The titre found is about 730 mg of active ingredient per gram of microgranules.

The microgranules produced in that way comply with the standards in respect of in vitro liberation as set out above, as representative of the novel forms of Sulpiride in accordance with the invention.

Their accelerated and natural stabilities are found to be excellent, without the appearance of potential toxicity.

They may be used in the form of capsules, compressed tablets or suspensions in neutral media.

It will be appreciated that variations may be introduced, in particular with regard to the proportions of the excipients and the active ingredient, the composition of the neutral grains, and the nature of the polymers forming the outer layers.

In the foregoing description, parts and percentages are by weight unless otherwise stated.

Kinotics parameters Mean maximum concentration (Qnax) in ng/ml Form i Form II Form III Form IV 75 - 40 80-45 315 - 65 150 - 60 TABLE A Time corresponding Area under the curve observed (AUC) SJmSi* °-24to,3fc in hours in ng/ml in ng/ml 4 ± 1.50 340 - 75 3.90 - 1.40 365 - 80 3.30 - 1.30 1280 -230 3.20 - 1.30 715 *320 720 ♦ 190 780 + 200 2970 + 400 1565 430 7

Claims (9)

1. A pharmaceutical composition for oral administration containing Sulpiride and in the form of microgranules having a diameter of from 0.2 to 2 mm, constituted by a neutral core comprising a mixture of saccharose and 5 starch, a layer of Sulpiride and polyvinylpyrrolidone, and an outer layer comprising a copolymer A of methacrylic acid and methyl methacrylate with a copolymer B of ethyl acrylate, methyl methacrylate and N,N,N-trimethyl 2- [(2-methyI-1 -oxo-2-propenyI) oxy] ethanaminium chloride, coated with a layer of the said copolymer B, in which the liberation in vitro 10 of the Sulpiride in artificial gastric and intestinal media is substantially as follows: after 15 minutes, 35 to 50% in a medium of a pH 1.3; after 30 minutes, 60 to 75% in a medium of pH 1.3; after 60 minutes, 80 to 95% in a medium of pH 4.5; 15 after more than 2 hours, more than 90% in a medium of pH 6.9.

2. A composition as claimed in Claim 1, in which the mixture of methacrylate polymers comprises 3 to 4 parts by weight of methacrylates of the said Copolymer A and 0.5 to 2 parts by weight of methacrylates of the said Copolymer B. 20

3. A composition as claimed in Claim 1 or 2, in which the layer containing the Sulpiride applied to the neutral grain comprises from 0.5 to 5% by weight of polyvinylpyrrolidone.

4. A composition as claimed in a preceding claim, in which the layer containing the Sulpiride contains small proportions of talc. 25

5. A process for preparing a ccrrpositian as clainod in any preceding claim, comprising projecting in a turbine process about 70 parts by weight of Sulpiride in solution onto 20 parts by weight of neutral grains, drying and sifting the microgranules, ^nd applying a solution of the desired polymers to form the outer layer in quantity so as to adjust the Sulpiride in vitro 30 liberation kinetics in accordance with the said characteristic values. 8

6. A process as claimed in Claim 5, in which the Sulpiride is applied in an alcoholic solution of polyvinylpyrrolidone, an alcoholic solution of methacrylic polymers comprising about 4 parts by weight of the said Copolymer A and I part by weight of the said Copolymer B is applied, drying is effected with talc and then in a drying oven at 37°C and the outer layer is completed by means of an alcoholic solution of the said Copolymer B.

7. A pharmaceutical composition according to claim 1, substantially as hereinbefore described.

8. A process according to claim 5 for preparing a composition, substantially as hereinbefore described.

9. . A composition whenever-prepared by a process claimed in any one of claims 5, 6 or 8. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.