GB2151920A - Oral compositions containing sulpiride - Google Patents

Description

1 GB 2 151920 A 1

SPECIFICATION

Oral compositions containing sulpiride The present invention concerns orally administrable pharmaceutical forms of Sulpiricle and their preparation.

Sulpiride, viz. N-(l-ethyl-2-pyrrolidinyl)methyl-2-methoxy-6sulphamoylbenzamide, is known as an excel lent neuroleptic disinhibitor, having as its main therapeutic indication the treatmnt of acute and chronic psychoses. Its characteristics and properties are described in particular in French Patents Nos. 1,472 025, 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-line of the active ingredient Sulpiride is about eight and a half hours. Ittherefore 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 on 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 20 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 polyvinylpyrroliclone, and then conventional coating fibres were applied, based on polymer of the shellac; methacrylate or ethylcellulose type, so as to produce pre-established standard kinetics for liberation of the Sulpiride in vitro 25 in gastric and intestinal media, in accordance with the following specifications:

1 st hour: liberation less than 40%.

4th hour: liberation less than 75%.

8th hour: liberation more than 75%.

Liberation at the first hour is effected in an artificial gastric juice having a pH of 1.3, and at the fourth and at 30 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 35 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 11), the loss in the amount of active ingredient 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 11 used had the following kinetics in respect of liberation in vitro in artificial media:

form 1 form 11 Liberation at the first hour in a medium of pH 1.3 20.0% 29.2% 45 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% 50 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 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 the differences in absorption form one subject to another. The above-indicated improvement in the absorption of Sulpiricle, 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 variation in the plasmatic proportions in circulation between 0 and 32 hours, expressed in ng/ml of Sulpiride, by comparison between 65 2 GB 2 151920 A 2 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 of the Sulpiride should substantially correspond to the following analytical conditions in respect 5 of liberation in vitro:

minutes: liberation between 35 and 50% in an artificial gastric medium of pH 1.3 minutes: liberation between 60 and 75% in an artificial gastric medium of pH 1.3 60minutes: 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.

The production formula for-2500 capsules with a dosage of 100 mg; of form 111, and the process for their 10 manufacture is set out below byway of example.

250 g of Sulpiride in a 20% ethanolic solution of polyvinyl pyrrol idone 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 methacrylic polymers marketed under the 15 registered trade mark Eudragit by Rohm and Haas in alcoholic solutions in proportions of 4 parts by weight of Eudragittype Lfor 1 part by weight of Eudragit type RL.

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 abouttwo days, and then the outside layer is completed 20 by projecting 40 g of a 13.5% ethanolic solution of Eudragit type RL. 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 Sulpiricle 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.

TABLE A

Kinetics Mean maximum Time corresponding Area under the curve observed (A U0 35 parameters concentration to mean Cmax (Cmax) in ngImI Mean (Tmax) O-Bhours 0-24 hours in hours in ngImI -1h in ngImI -1h Form 1 75 40 4 1.50 3.40 75 720 190 40 Form 11 80 -t 45 3.90 -t 1.40 3.65 80 780-t200 Form Ill 315:h 65 3.30 -t 1.30 1280 -t: 230 2970 -t 400 45 Form W 150-60 3.20 --t 1.30 715 -i: 320 1565 -t: 430

Claims (8)

1. Pharmaceutical oral compositions containing Sulpiride and in the form of microgranules formed by a 50 neutral grain of the type comprising a mixture of saccharose, starch, lactose, talc or stearic acid, to which the Sulpiride is applied, followed by an outer layer of microporous polymers of the ethylcellulose, shellac, methacrylate, cellulose acetophthalate or polyvinylpyrrolidone type, in which liberation in vitro of the Sulpiride in artificial gastric and intestinal media is substantially as follows:

after 15 minutes, 35 to 50% of 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; after more than 2 hours, more than 90% in a medium of pH 6.9.

2. Compositions as claimed in Claim 1 in which the polymer is one or more methacrylates.

3. Compositions as claimed in Claim 2 in which the methacrylate(s) islare of the type sold under the trade 60 mark Eudragit.

4. Compositions as claimed in Claim 3 in which the methacrylates comprise 3 to 4 parts by weight of methacrylates of the type Eudragit L and 0.5 to 2 parts by weight of methacrylates of the type Eudragit RL.

5. Compositions as claimed in any preceding claim in which the layer containing the Sulpiride applied to the neutral grain comprises from 0.5 to 5% by weight of polyvinyl pyrrolidone.

3 GB 2 151 920 A 3

6. Compositions as claimed in any preceding claim in which the layer containing the Sulpiride contains small proportions of talc.

7. A process for preparing compositions as claimed 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, applying a solution of the desired polymers to form the outer layer in quantity so as to adjust the Sulpiride in vitro liberation kinetics in accordance with the said characteristic values.

8. A process as claimed in Claim 7 in which the Sulpiride is applied in an alcoholic solution of polyvinyl pyrrolidone, an alcoholic solution of methacrylic polymers comprising about 4 parts by weight of lo Eudragit of type L and 1 part by weight of Eudragit of type RL is applied, drying is effected with talc and then 10 in a drying oven at 370C and the outer layer is completed by means of an alcoholic solution of Eudragit of type RL.

Printed in the UK for HMSO, D8818935, 6185, 7102. Published by The Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.