LU85290A1 - NEW ORAL SULPIRIDE FORMS FOR SULPIRIDE - Google Patents

Description

. _ 1 _ * i The invention relates to new galenical forms of Sulpiride, which can be used orally, as well as to the process for their preparation.

Sulpiride, of structural formula K- (1-ethyl-pyrrolidinyl-2) œethyl-2-methoxy-suifamoy1-5 benzamide, is known as being an excellent inhibitory neuroleptic, having as main therapeutic indication 1 the treatment of acute and chronic psychoses, and its characteristics and properties are described in particular in French patents No. 1,472,025, 4,879 K and 5,916 M.

Active oral medications containing Sulpiride are currently in the form of tablets, capsules or drinkable solutions: * but, and the results set out below demonstrate this, these current forms! require a plurality of daily doses and sometimes have a reduced percentage of absorption by the body. We have therefore sought to modify the dosage form so as to! significantly improve patient acceptance by reducing par i the number of daily intakes.

The plasma half-life of the active principle Sulpiride being approximately 8 h 30, it appears a priori possible to produce a galenical form of the product; reducing the average daily intake to 2 capsules or tablets i per day, dosed in Sulpiride at 100 mg per capsule or tablet (with ur.e | taken in the morning and taken in the evening), otherwise to 1 capsule or 1 tablet per t I day, dosed at 200 mg of Sulpiride.

j For this, microgranules with long-term effect have been produced, according to! classical techniques described in particular in French patents No. 2,313,915 (Corneille) or No. 2,453,642 (Labaz). Conventionally, neutral grains have been used, the size of which was approximately 0.50 mm in diameter, and made up of 25 ° of starch and 75% of sucrose, onto which the Sulpiride has been sprayed using a turbine. an alcoholic solution of polyvinylpyrrolicone, then fibers j were applied. of conventional coatings, based on shellac, methacrylate or ethylcellulose type polymers, this way of obtaining kinetics for the release of the active principle Sulpiride in vitro cars from standard gastric and intestinal mediums, in accordance with the specifications below : “1st hour: release less than 40% - 4th hour: release less than 75% 'D - 6th hour: release more than 75% d 1 ^ Τι

The release at the first hour is carried out in an artificial gastric juice at pH 1.3, at the fourth hour and at the eighth hour respectively in artificial intestinal juices at pH 4.5 and pH 7. The operating conditions for studying the release of the active ingredient are known and described in the aforementioned patents.

Capsules and tablets dosed at 100 ng were then made with these microgranules and the absorption of Sulpiride was studied by determining the circulating plasma levels of Sulpiride by radio-innunology, then the results obtained were compared with those obtained from the form capsules currently on the market.

The results are recorded in table A below and show that with the two formulations of microgranules used (form I and form II), the loss in rate of active principle circulating is too great compared to that of the normal form. in capsules (form IV)., to enable an effective long-acting drug to be produced.

As an indication, for those skilled in the art, the forms I and II used had the following kinetics of in vitro release in artificial media:

form I form II

First hour release in pH medium: 1.3 20.0 Z 29.2%

Release at the fourth hour in a pH medium: 4.5 68.6% 58.4%

Release at the eighth hour in a pH medium: 7 90.8% 98.2%! "After studying a series of long-acting formulations which all gave results incompatible with obtaining a good well absorbed oral form, we had the idea of retaining the microgranule form (substantially spherical grains with a diameter of between 0.2 and 2 nnn) which must - in practice allow better absorption of the active principle than a conventional powder of the capsule or tablet, but having a kinetics of release in vitro much closer to these immediate forms, that is to say substantially releasing 90% of the active ingredient after one day in an artificial gastric medium of pH 1.3.

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Surprisingly, the results of the microgranules according to this kinetics in vitro have shown that, as a function of the comparative plasma levels, this form III consisting of microgranules put in capsules dosed at 100 mg makes it possible to obtain an absorption twice that obtained with the capsules. Sulpiride classics (form IV) while maintaining a slightly longer duration of action and considerably reducing the differences in absorption from one subject to another. This improvement in the absorption of Sulpiride both quantitatively and in terms of its regularity allows a reduction in the doses used and the number of daily doses.

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These results are expressed as Table A, as well as in Figure 1, showing the evolution of circulating plasma levels expressed in ng / ml of! Sulpiride, between 0 and 32 hours by comparison between form III and form IV.

Complementary experiments in which the external coatings of the microgranules according to the invention were varied have made it possible to determine that the preferential improved absorption form of Sulpiride had to respond substantially to the following analytical conditions of release in vitro:. 15 minutes: release between 35 and 50% in an artificial gastric medium of pH 1.3. 30 minutes: release between 60 and 75% in an artificial gastric medium of pH 1.3. 60 minutes: release between 80 and 95% in an artificial intestinal medium of pH A, 5! There is also an overall release greater than 90% in an artificial intestinal medium of pH 6.9

As an example of embodiment, the manufacturing formula for 2,500 capsules dosed at 100 μg of form III is indicated below, as well as its manufacturing process.

50 g of neutral grains are used, consisting of approximately 25% starch and 75% sucrose, of size substantially equal to 0.50 mm in diameter, to which 250 g of sulpiride incorporated in an alcoholic solution are applied in a turbine. (ethanol) of 20% polyvinylpyrrolidone.

After drying and sieving, outer layers were applied composed of methacrylic polymers marketed under the name Eudragit by j the company Rohm and Haas in alcoholic solutions s 4 parts by weight of Eudragit type L, for 1 part by Eudragit type RL weight.

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It is then dried with talc in small proportions, until microgranules are obtained which release substantially 100% in one hour according to the analytical conditions defined above.

Then dried in an oven at 37 ° C for about two days, then the outer layer is terminated by spraying 40g of an ethanclic solution, 13.5% Eudragit type RL. The titre observed is approximately 730 r.g of active principle per gram of microgranules.

The microgranules thus obtained meet the in vitro release standards defined above, as being representative of these galenical: new forms of the Sulpiride according to the invention.

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Their accelerated and natural stabilities have been shown to be excellent without the appearance of potentiated toxicity.

They can be used in capsules, tablets or suspension, in | neutral environments.

Of course, those skilled in the art can introduce variants, in particular in the respective proportions of the excipients and of the active principle, the composition of the neutral grains and in the nature of the polymers constituting the external layers, without thereby departing from the scope of the invention.

Claims (6)

1. New dosage forms of Sulpiride, usable orally; v comprising xricrogranules constituted by a neutral grain of the mixture i type of sucrose, starch, lactose, talc or stearic acid, on which the Sulpiride is applied, then an outer layer of microporous polymers of the ethylcellulose type, gum lacquer, methacrylates, cellulose acetophthalate or polyvinylpyrrolidone, characterized in that the in vitro release of Sulpiride in artificial gastric and intestinal environments:; . After 15 minutes is substantially between 35 and 50%, in a medium of pH 1.3; . After 30 minutes is substantially between 60 and 75% in a medium of pH 1.3. After 60 minutes is substantially between 80 and 95% in a medium of pH 4.5. More than 2 hours is significantly greater than 90%, in a medium of ρΉ 6.9 2. New dosage forms of Sulpiride, according to claim 1, characterized in that the outer layer of said œicrogranules is composed of one or more methacrylate of the Eucragit type (jR). 3. New dosage forms of Sulpiride, according to claim 1, characterized in that the outer layer of said microgranules is composed of mixtures of methacrylates comprising approximately 3 to 4 parts by weight of methacrylates of the Eudragit (r) l and 0.5 a type. 2 parts by weight of ^. Eudragit (JT) RL type methacrylates. 4. New dosage forms of Sulpiride, according to one of these claims 1 | i s 3, characterized in that the layer containing the Sulpiride applied on the neutral grain comprises from 0.5 to 5% by weight of polyvinylpyrrolidone. 5. New dosage forms of Sulpiride, according to one of claims 1 I to 4, characterized in that the layer containing the Sulpiride contains talc in small proportions. U k. _ ί 4 6. Process for the preparation of new galenic ferments eu Sulpiride, according to one of claims 1 S 5, characterized in that one projects in j turbine, by means of an alcoholic solution of polyvinylpyrrolidone,; approximately 70% by weight of Sulpiride on 20 1 by weight of neutral grains, that said microgranules are dried and sieved, then that an alcoholic solution of methacrylic polymers comprising approximately 4 is applied; parts by weight of Eudragit (jT) of type L and approximately 1 part by weight; of Rud type Eudragit (R), which is dried with talc, then in an oven at 37 ° C, for a sufficient period, before finishing the outer layer using an alcoholic solution of Eudragit of the RL type, so as to adjust the kinetics of in vitro release of the Sulpiride, according to the said = s ί characteristic values. \ K \ i - \ '\ / \ \> \ 1 v * ijj „* JA JS CD <~ N 0-1 OOOO ·, OC θ' OOO PD d I · - <CM -3 · -C <da) M * 'pC r — I + 1 + 1 + 1 + | ε eu -σ ο ο om \ eu cm co cm co MD> IC im im en m co CM * - <eu c CD eu rC o 0) rQ i C d rü O ou co-ι in ο ο o eu im oo in cm cd ci cm in H c +1 +1 QJ i — i +1 +1 cd +3 6 om! d - "s- md o m | O CO M «« IC hi cd I c in cm im O --f eu dic eu • H <• c Ö 1 <cd T3 C d eu d Ο ο ο o fo o Mi mMîcncn d, O Ps <U <co go C eu Bd wcx eu +1 +1 -fl +1 c O o BK ooo ο o ce- d σι in cm c £ f— Π) Λ Λ Λ tß? H <r en en en <S this cd B H eu; C "" * G) ri CC σ * OCX • H ü Ö0 i-1 £ O LO iTi O co <r vo vo • C ε S +1 +1 +1 -fl C eu eu ti in omo eu cd K im co> -e in d B cd en —io -hg ü X ü - Cd M- 'ε CD CO eu eu mcd I—! m> • u cr i — i i — i i — i i — i ^% Γ "Ϊ g c eu tu eu eu had cd ceu ε ε ε B Cd c c c c cd * ri ο ο ο o P-i G pu Fc ÎC i ·.