JP2002538094A - Pharmaceutical composition for oral administration comprising benzamide and at least one absorption enhancer - Google Patents

Abstract

(57) [Summary] The present invention relates to a pharmaceutical composition comprising an active ingredient of a benzamide drug and an absorption enhancer having a P-glycoprotein inhibitory action.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a pharmaceutical composition for oral administration containing an active ingredient of a benzamide drug and at least one absorption enhancer.

[0002] Benzamides are compounds containing the following partial structure in their structural formula:

Embedded image These benzamides can be administered orally. However, Applicants have noted that oral administration of certain benzamides has been associated with incomplete absorption of about 30-
It could be observed to give 65% absorption. This "absorption" refers here to the fraction of the active ingredient which passes through the intestinal wall. This incomplete absorption may be the result of a variety of factors, mentioned below: low or very slow dissolution of the active ingredient; instability of the active ingredient throughout or just a part of the gastrointestinal tract system; Enzymatic degradation of the active ingredient in the mucous membrane; slow or incomplete absorption of the active ingredient due to slow and inactive transdiffusion of the intestinal wall or, in the case of active mechanisms, saturation of the transport system.

In recent years, it has been found that the phenomenon of intestinal absorption is the result of two contradictory factors over a given period of time, the permeability and the secretory flux as defined in the present invention as follows: Permeability is defined as the dose fraction of the active ingredient that has passed through the intestinal wall from the intestinal lumen to the space between and within cells. -Secretory flux is defined as the dose fraction of the active ingredient which has passed through the intestinal wall in the opposite direction. These two factors are complex phenomena depending on the physicochemical properties of the active ingredient and the transport system specific to the active ingredient.

[0004] The applicant has envisioned enhancing the absorption of benzamides by linking the benzamides with an absorption enhancer. The present invention comprises a pharmaceutical composition for oral administration comprising benzamide or a pharmacologically acceptable salt of this benzamide and at least one absorption enhancer. In general, the compositions according to the invention make it possible to reduce the dose of benzamides administered for a given effective dose. The composition also makes it possible to reduce the number of doses per day. Furthermore, due to the better absorption of the active ingredient, the compositions according to the invention allow for a given dose to reduce the individual variation in the circulating levels of the active ingredient.

[0005] Applicants have established that benzamides are substrates for the active efflux mechanism of P-glycoprotein. This active P-glycoprotein efflux mechanism may be responsible for the low intestinal absorption of certain active ingredients, as it contributes to high secretory flux. P-glycoprotein (Pgp), which is involved in membrane transport, is distributed, inter alia, in the intestinal lining (brushed epithelial cells). Its role is, inter alia, to prevent the infiltration of substrates into cells by their excretion into the intestinal tract. These substrates are thus subject to a secretory flux that prevents the passage of the substrates through the intestinal mucosa and thus affects their absorption.

[0006] A suitable absorption enhancer can be any substance capable of increasing permeability and / or inhibiting secretory flux, the behavior of which is likely to be increased permeability or secretory flux. The behavior may be limited to reduction or a mixture of both actions. In particular, a P-glycoprotein inhibitor can be used as an absorption enhancer in the present invention from the viewpoint of the role of the P-glycoprotein release mechanism in the absorption of benzamides through the intestinal wall.

[0007] Useful absorption enhancers for the compositions of the present invention include sucrose esters, especially sucrose stearate-palmitate, Sucroester® 15 (Sucroester®).
sucrose monopalmitate and sucrose monostearate such as ester (registered trademark) 15); alkyl esters of polyethylene sorbitan, especially polyoxyethylene sorbitan 20 monooleate (polysorbate 80) such as Tween (registered trademark) 80; Ethylene sorbitan 20 monolaurate (polysorbate 20)
And polyoxyethylene sorbitan 20 monostearate (polysorbate 60)
Cured or uncured polyethoxylated castor oil, especially polyethoxylated -40 cured castor oils such as Cremophor® RH40 (Cremophor® RH40), and polyethoxylated such as Cremophor® RH60 -60 hydrogenated castor oil; polyethoxylated castor oil, especially Cremophor® E
L-like polyethoxylated-35 castor oil; D-α-tocopheryl polyethylene glycol succinate (TPGS or vitamin E TPGS); poloxamers
rs), especially poloxamers 188 such as Lutrol® F68; nonoxynol; octoxynol, polyethoxylated glycerides, especially Gelseal® 44/14 (Gelucire® ) 44/1
4 (Gattefosse)) or Labrafil® (Gattfosse)
efosse)); terpenes, especially t-anethole, carvacrol, carvone, 1,
Examples include 8-cineole, eugenol, D-limonene, L-menthol, menthone, terpinene and thymol and other essential oil components, especially carveol, nerolidol and linalool.

The invention is particularly suitable for the active ingredients, sulpiride and amisulpride, pharmaceutically acceptable salts thereof, their enantiomers and salts of these enantiomers. In addition to these benzamides, other benzamides such as lintopride, bromoprid, alizaprid, R-zacoprid, tiapride, sultopride, remoxiprid and veralipride can also be used in the present invention. Certain benzamides are useful as active ingredients as drugs for treating diseases of the central nervous system.

The present invention relates to amisulpride itself, ie, 4-amino-N-[(1-ethylpyrrolidine-
2-yl) methyl] -5- (ethylsulfonyl) -2-methoxybenzamide, its levorotatory enantiomer ((S) (−)-amisulpride) and the dextrorotatory enantiomer ((R) (+)
-Amisulpride), mixtures of these enantiomers, as well as the tartrate salt of amisulpride itself and its enantiomers, and also mixtures of these tartrate salts. A preferred tartrate salt is the D-(−)-tartrate salt of (S) (−)-amisulpride, in other words (S)-(−)-4-amino-N-[(1-ethylpyrrolidin-2-yl ) Methyl]-
5- (ethylsulfonyl) -2-methoxybenzamide [S- (R ^* , R ^* )]-2,3-dihydroxybutanediate. Amisulpride is a mental illness, more specifically paranoid and productive schizophrenia,
It is a neuroleptic drug used in the treatment of acute delirium psychosis and in the treatment of schizophrenia deficiency, depressive states with development and decline of residual psychosis. Amisulpride may also be used in people suffering from dysthymia, autism, muscle relaxant-induced late dyskinesia, Tourette's syndrome, manic-depressive disorder (MDP), manic or depressive symptoms, acute delirium, Beneficial in treating headaches and drug addiction.

In general, the compositions according to the invention increase the absorption of benzamides across the intestinal mucosa by at least 10%. The composition according to the invention can be used in any pharmaceutical formulation. Thus, the composition according to the invention may be in the form of a solution, suspension, emulsion, microemulsion, wafer capsule, gel capsule, sachet, tablet, effervescent tablet, multilayer tablet, etc. The object may be in immediate release or modified release form. For example, the composition according to the invention may be in the form of a gel capsule comprising a combination of an absorption enhancer and an active ingredient. Immediate release tablets according to the present invention tablet granules consisting of conventional excipients such as active ingredients, diluents, lubricants, disintegrants, binders and one or more absorption enhancers. Can be manufactured by Alternatively, these granules can be placed in a sachet or gel capsule.

[0011] Examples of the immediate-release preparation include a pharmaceutical preparation described in Patent Application WO 98/11881, the disclosure of which is reported as it is in the present invention. These are pharmaceutical compositions intended for oral administration, which are characterized in that, in addition to the active ingredient, they consist of a lipophilic phase. These pharmaceutical compositions are, inter alia, (1) solutions of lipids,
It can take the form of 2) emulsions or microemulsions, and (3) self-emulsifying mixtures. Absorption enhancers are incorporated, for example, into pharmaceutical compositions according to one of the following options. (1) In the case of a lipid solution or lipid suspension, the absorption enhancer is dissolved in the oil or lipid mixture. (2) In the case of an emulsion or microemulsion, the absorption promoter dissolves in the oil phase to form a part of the oil phase. They can be added to the oily components or surfactants of the composition. (3) In the case of a self-emulsifying mixture, the absorption promoter is dissolved in the self-emulsifying mixture.
They can be added to the oily components or the surfactants of the composition.

Embodiments of these compositions, particularly the lipophilic phase, are described in more detail below. In all cases (1), (2) or (3), the lipophilic phase may be solid or, preferably, liquid at room temperature. The lipophilic phase comprises (i) one or more fatty acids, (ii) animal oil, vegetable oil,
One or more oils or triglycerides, such as transesterified and / or polyethoxylated vegetable or synthetic oils, or (i.
ii) a mixture of two or more compounds as described in (i) and (ii) above, especially a mixture of fatty acids and oils.

The fatty acids (i) include those having 8 to 22 carbon atoms, in particular, capric acid,
Examples include caprylic acid, lauric acid, oleic acid, arachidonic acid, linolenic acid, linoleic acid or ricinoleic acid. As the vegetable oil (ii), olive oil, peanut oil, soybean oil, rapeseed oil, coconut oil,
Sesame oil, grape seed oil, corn oil, hazelnut oil or sunflower oil.

[0014] Triglycerides (ii) such as Captex® (Captex®) sold by Avitec or Miglyol® (Miglyol®) sold by Huls Triglycerides of capric and caprylic acids. Transesterified and / or polyethoxylated vegetable oils (ii) include polyethoxylated olive oil, polyethoxylated sunflower oil, polyethoxylated coconut oil or polyethoxylated castor oil. Animal oils include liver oil, especially cod liver oil or halibut liver oil. The preferred lipophilic phase, capric acid, caprylic acid, consisting of medium chain fatty acids or fatty acid esters of C ₈ -C _12, such as lauric acid or a combination thereof.

(1) Lipid Solutions When the pharmaceutical composition according to the invention is in the form of a solution of lipids (1), it is generally at least one fatty acid and / or at least one as mentioned above for the lipophilic phase. Lipophilic phase comprising the oil of the formula (1) as an essential component, and the active ingredient is dissolved in the lipophilic phase. Such lipid solutions are substantially free of a hydrophilic phase. Lipophilic phase of the lipid solution, for example, medium-chain fatty acids C ₈ -C ₁₂ or fatty acid esters such as capric acid, caprylic acid or lauric acid, or a combination of these, fatty acids was oleic acid You may.

(2) Emulsion or microemulsion In addition to the lipophilic phase, the emulsion or microemulsion contains a hydrophilic phase and at least one surfactant. The emulsion is water-in-oil (W / O) or, preferably, oil-in-water (O / W). The emulsion may be of the submicron emulsion type. Such emulsions are smaller than 1 μm, typically 0.3 μm
It has a discontinuous phase in the form of particles having an average particle size of 0.70.7 μm. Microemulsions defined as having a discontinuous phase, usually in the form of particles having an average particle size of 0.02 μm to 0.250 μm, are preferred. In the present invention, the discontinuous or dispersed phase consists of these particles or droplets.

The hydrophilic phase may contain or consist of one or more compounds selected from alcohols and water, such as glycerin, propylene glycol, polyethylene glycols having a molecular weight of 100 to 3000, and water. Good. The dispersed phase of the above emulsion is 5 to 30% by weight based on the total weight of the emulsion.
And may generally correspond to 10-20% by weight. The surfactant is chosen as a function of the nature of the emulsion. As one skilled in the art knows, the choice of surfactant to obtain a W / O or O / W emulsion or microemulsion depends, inter alia, on its HLB (hydrophilic-lipophilic balance).
Depends on. Surfactants suitable for any emulsion include sorbitan esters and polyoxyethylenated sorbitan esters, such as those sold under the brand names Tween® and Span®, especially polysorbates 80.

Lecithins of animal or plant origin, polyoxyethylenated castor oils such as those sold under the brand name Cremophor®, sucrose esters of fatty acids, aliphatic alkyl esters of polyethylene glycol, Fatty acid esters of polyethylene glycol, bile acids, monoglycerides, diglycerides or acetylated or polyethoxylated derivatives of these compounds, alone or in mixtures, may be used as surfactants. Monoglycerides, diglycerides or acetylated or polyethoxylated derivatives of these compounds include, among others, those containing one or two fatty chains each consisting of 8 to 24 carbon atoms, more specifically from Abitec and Eastman. Kapmal (registered trademark) (Ca
pmul®) and Mivaset® (Myvacet®), especially those sold under the brand names glyceryl monocaprylate, glyceryl monostearate, monoacetylated monoglycerides and diacetylated monoglycerides Respectively.

The emulsion according to the invention may comprise from 0.01 to 5% by weight of surfactant, based on the dispersed phase. In the case of microemulsions, the proportion of water in the formulation is adjusted to ensure dissolution of the active ingredient. Preferably, in the microemulsion, the total weight of the absorption enhancer and surfactant is 2 to 15 times greater than the dispersed phase (whether water or oil). Additionally and preferably, the amount of absorption enhancer may be 0.5 to 10 times the weight of the surfactant.

(3) Self-emulsifying mixture For the purposes of the present invention, the expression “self-emulsifying mixture”, also known as pre-emulsion or pre-microemulsion, comprises at least one surfactant. By a mixture consisting of a lipophilic phase, this mixture forms an emulsion by merely mechanical stirring with the aqueous phase. The self-emulsifying mixture according to the invention is capable of forming an emulsion with the biological hydrophilic phase after oral administration. The surfactant constituting such a self-emulsifying mixture can be selected from the same surfactants used for the emulsion or microemulsion (2).

A preferred lipophilic phase consists of C ₈ -C ₁₂ medium chain fatty acids or fatty acid esters, such as capric acid, caprylylic acid or lauric acid, or combinations thereof. Preferably, the total weight of the absorption enhancer and surfactant in the self-emulsifying mixture is
0.5 to 6 times the dispersed phase (whether water or oil). Further, and preferably, the amount of absorption enhancer is 0.5 to 10 times the weight of the surfactant. These pharmaceutical compositions (1), (2) or (3) according to the invention may be used as diluents, preservatives, tonicity agents, antioxidants, thickeners, stabilizers, viscosity reducing agents such as ethanol. , Pharmaceutically acceptable additives such as gelling agents and pH buffers. The pharmaceutical composition of the present invention is prepared according to a conventional method for those skilled in the art. Thus, the "lipid solution" (1) can dissolve the active ingredient in the lipophilic phase with stirring. The above additives may be added as desired.

To prepare the “emulsion” (2), the lipophilic phase containing the absorption enhancer is added to the hydrophilic phase with stirring, to which the surfactant and, if desired, the hydrophilic additives have previously been added. Have been. The active ingredient is pre-added to one of the two phases depending on its hydrophilic or lipophilic affinity. The stirring is performed by Ultra-Turrax (registered trademark) (Ultra-T).
(urrax®) type device. To prepare a “submicron emulsion”, the emulsion thus obtained is applied to a very high pressure die, for example of the APV-Gaulin® type. Finer. To prepare the microemulsion, the oily phase, absorption enhancer and surfactant are mixed with water by simple stirring. The active ingredient is pre-introduced into the phase with a higher affinity.

The “self-emulsifying mixture” (3) can be prepared by adding the desired surfactant and the desired absorption enhancer to the lipophilic phase containing the active ingredient with stirring in a conventional manner. . These compositions (1), (2) or (3) may be divided liquids or undivided liquids, gels, soft capsules optionally with a measuring device such as a spoon,
It may be in the form of a pill or, preferably, a gel capsule. These gel capsules are made of gelatin or starch and are usually sealed by conventional methods. In these pharmaceutical compositions containing a lipid phase, the absorption enhancer is conveniently vitamin E TPGS or a mixture of TPGS and a monopalmitate of sucrose, such as Sucroester®15.

For example, such compositions comprise 1-30% by weight of active ingredient and 10-80% by weight of the above-mentioned absorption enhancers. Of these three types of compositions (1), (2) and (3), the self-emulsifying mixture is superior to the microemulsion for the basic active ingredient, and the microemulsion when the active ingredient is a salt. Is preferred. The combination of benzamides and absorption enhancers according to the invention is also suitable as a pharmaceutical form intended for controlled release.

The pharmaceutical preparations described in patent application WO 98/47506 can be mentioned, the teachings of which are included in the present invention as such. These formulations are suitable for benzamides or their enantiomers and their salts, as defined above. They are effervescent pharmaceutical compositions with controlled release. The inclusion of an absorption enhancer in a pharmaceutical composition of this type depends on the total amount of the components of the composition.
This is done by simply adding not more than 20% of the absorption enhancer. Alternatively, the absorption enhancer can be included in a separate phase from the pharmaceutical composition, such as an additional layer in the case of a tablet.

[0026] Sustained-release compositions suitable for the practice of the present invention include two different types of spheroids (i) and (ii), namely (i) consisting of the active ingredient and an absorption enhancer ( gel capsules composed of ii). (I) and (ii) are coated to control the dispersion. This coating is specifically made of polymers such as ethyl cellulose, Rohm Pharm
Formed with polymers such as methyl methacrylate copolymers such as Eudragit® RS (Eudragit® RS), Eudragit® RL, Eudragit® NE sold by the company a be able to. Conveniently the coating in each type of spheroid is chosen such that the rate of release of the active ingredient and release of the absorption enhancer is close. Coating can be performed according to methods known to those skilled in the art, for example, using an air fluidized bed apparatus (such as Glatt GPCG3) or a turbo mixer (such as Accelacota).

Similarly, bilayer sustained release tablets are applicable for the use of the composition according to the invention. In this two-layer tablet, the first layer comprises the active ingredient and a controlled release excipient, and the second layer comprises a controlled release enhancer which may be the same as or different from the absorption enhancer and the excipient of the first layer. Consists of a formulation. The controlled release excipient can be a hydrophilic polymer or lipid excipient. These hydrophilic polymers include methylhydroxyethylcellulose, carboxymethylcellulose and its salts such as carboxymethylcellulose sodium or carboxymethylcellulose calcium, and preferably hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxypropylcellulose and hydroxypropylmethylcellulose. Cellulose derivatives such as a mixture of alginates, xanthan gum,
Natural polysaccharides, such as guar gum, gum arabic or carob gum; and polyvinylpyrrolidone, polyacrylates, especially Carbopol®
Polymers derived from acrylic and methacrylic acids and their salts, such as those marketed under the brand name, or hydrophilic synthetic polymers, such as amino acid polymers such as polylysine. These lipid excipients include hydrogenated castor oil, beeswax, carnauba wax, glyceryl trimiristate, glyceryl trilaurate, glyceryl tristearate, cetyl palmitate and glyceryl behenate. It is advantageous to choose a formulation in which the release rate of the active ingredient and the release rate of the absorption enhancer tend to be similar.

The composition according to the invention comprises 5-90% by weight of active ingredient and 5-80% by weight, preferably 10-50% by weight, of absorption enhancer. When the active ingredient is amisulpride, the amount of amisulpride body is 20 to 400 mg, preferably 100 to 400 mg. For example, for (S) (−)-amisulpride, the amount of (S) (−)-amisulpride body is 10 to 400 mg, preferably 50 to 300 mg. In the case of sulpiride, the amount of sulpiride is 50 to 500 mg, preferably 100 to 500 mg
It is. The effect of various absorption enhancers on the absorption of (D) (-)-tartrate of amisulpride and (S) (-)-amisulpride was tested on the following experimental models:

Experimental Model The absorption of (D) (−)-tartrate of amisulpride and (S) (−)-amisulpride was studied by transmembrane passage of these compounds in model Caco2-TC7. This system is obtained from human colon cells [Characterization of newly isolated Caco2 c
lone (TC-7), as a model of transport processes and biotransformation of
drugs. I. Caro et al., International Journal of Pharmaceutics, 116 (1995), 1
47-157]. Absorption is the result of flow from the large intestine into the blood circulation, and / or in some opposite direction. The effect of the absorption enhancer, using the model Caco2-TC7, represents the normal flow for absorption, increased apical-to-basal transmembrane translocation, and basal-to-apical flow evidence for secretory flow. Measured by reduction.

Results [0030] The absorption enhancers listed in Tables 1 and 2 and tested at a concentration of 0.16 mg / ml include amisulpride and the (D) (-)-tartrate salt of (S) (-)-amisulpride. A factor of 3 increases the permeability from apical to basal, and a factor of 3-4 reduces secretion fluid flow. The decrease in secretion fluid flow is to a lesser extent for Suculoester®15. The results are similar whether the concentration of the accelerator is 10 times lower or higher.

Table 1 Effect of absorption enhancer (0.16 mg / ml) on in vitro transport of amisulpride (20 μM). Permeability is compared to control and expressed as a percentage.

[Table 1]

Table 2 Effect of absorption enhancer (0.16 mg / ml) on in vitro transport of (D) (−)-tartrate (20 μM) of (S) (−)-amisulpride The results are compared to controls , Expressed as a percentage.

[Table 2]

The embodiments described below of the present invention do not limit the scope thereof.

Formulation Examples Example 1: (S) (−)-Amisulpride (D) (−)-Tartrate Granules

[Table 3]

The last two components and all but one half of the sodium carboxymethylcellulose are mixed and water is added to make granules. The mixture obtained is dried at 55 ° C. and sized (0.8 mm sieve). Add the remaining sodium carboxymethylcellulose and mix. The mixture is lubricated by adding magnesium stearate and colloidal silica and mixing in a Turbula® mixer. The granules are dispensed into a quick release sachet. The same granules for immediate release, dosage
70 mg of (D) (−)-tartrate of (S) (−)-amisulpride (i.e. 50 mg of (S) (
-)-Amisulpride body) and dispensed into gel capsules. 70 mg of (S) (−) −
Controlled release tablets containing the (D) (-)-tartrate salt of amisulpride can also be prepared by tableting on a rotary machine of format 8R8.

Example 2: Effervescent Tablet with Controlled Release of (S) (−)-Amisulpride (D) (−)-Tartrate

[Table 4]

The active ingredient, tartaric acid, hydroxypropyl methylcellulose, lactose and sucrose esters are mixed to form granules. After drying the granules in an oven at 55 ° C, 0.8
Sizing with a sieve of mm. Sodium bicarbonate is added to the granules and the whole is mixed in a Turbula® mixer for 10 minutes. Add colloidal silica and magnesium stearate to smooth the granules. Mixing is Turbula (registered trademark)
Perform for 10 minutes in the mixer. The mixture is compressed into format 11R11.

Example 3 Water-in-oil Microemulsion Containing (S) (−)-Amisulpride (D) (−)-Tartrate

[Table 5]

A mixture of absorption enhancer / surfactant / oil is prepared by magnetic stirring. (S) (
(D) (-)-tartrate salt of-)-amisulpride is dissolved in the water used in the composition,
The aqueous solution is added to the above mixture with stirring. The resulting mixture is in the form of a paste. 0.64 g of this mixture is added to 250 ml of 0.01 M hydrochloric acid at 37 ° C. and stirred at 50 rpm. The size of the droplets is measured using a Zetasizer® laser machine (Zetasizer® laser machine (Malvern Instruments)): the size of the droplets is equal to 19 nm. The dissolution profile of the resulting formulation in 1000 ml of 0.01 M hydrochloric acid is measured using a rotary wing device as described in the European Pharmacopoeia. Its rotation speed is 50 rpm and the temperature is 37 ° C. The amount of dissolved (S) (−)-amisulpride (D) (−)-tartrate is determined by measuring the optical density of the solution at 254 nm. Dissolution is fast (Figure 1).

Example 4: Pre-microemulsion containing amisulpride

[Table 6]

A mixture of absorption enhancer / surfactant / oil is prepared by magnetic stirring. Amisulpride is added to the mixture by magnetic stirring so that the active ingredient is in suspension. 1.2 g of the obtained mixture is added to 1000 ml of 0.01 M hydrochloric acid at 37 ° C., and the mixture is stirred at 50 rpm. The size of the droplets is measured using a Zetasizer® laser device (Malvern Instruments): the size of the droplets is equal to 36 nm. The dissolution profile of the formulation was measured at 50 rpm using a rotary wing device as described in the European Pharmacopoeia. The solvent is 0.01 M hydrochloric acid and a phosphate buffer at a concentration of 0.015 M, pH 7.5. In each case, use a volume of 1000 ml of hydrochloric acid. The amount of dissolved amisulpride is determined by measuring the optical density of the solution at 254 nm. Dissolution is fast at both pHs (Figure 2).

Example 5 Water-in-oil Microemulsion Containing (S) (−)-Amisulpride (D) (−)-Tartrate

[Table 7]

A mixture of absorption enhancer / surfactant / oil is prepared by magnetic stirring. (S) (
(D) (-)-tartrate salt of-)-amisulpride is dissolved in the water used in the composition,
The aqueous solution is added to the above mixture by magnetic stirring. Obtain a clear liquid. 1.14 g of the obtained liquid is added to 250 ml of 0.01 M hydrochloric acid at 37 ° C., and the mixture is stirred at 50 rpm. Droplet size was measured using a Nanosizer laser device (Malvern Instruments): Droplet size equals 75 nm. Using 1.14 g of the obtained preparation, a dissolution profile in hydrochloric acid is measured. The method used is the same as the method in Example 5, except for the corrections made on the excipients, as described in the United States Pharmacopeia. Dissolution is extremely fast (Figure 3).

Example 6: Self-emulsifying mixture into an oil-in-water microemulsion in the form of a gel capsule containing (S) (−)-amisulpride body

[Table 8]

A mixture of excipients is prepared by magnetic stirring while maintaining at 50 ° C. on a water bath.
The active ingredient is added and the mixture is filled into gel capsules. The gel capsule is added to 500 ml of 0.01 M hydrochloric acid at 37 ° C. and stirred at 50 rpm. Droplet size was measured using a Nanosizer laser device (Malvern Instruments): Droplet size equals 23 nm. The dissolution performed under the above conditions is fast: 63% of the active ingredient dissolves in 10 minutes.

Example 7: In the form of a gel capsule containing (S) (−)-amisulpride body,
Self-emulsifying mixture that becomes an oil-in-water microemulsion

[Table 9] The mixture was prepared in the same manner as in the previous example, and
15 is added immediately before the active ingredient. A suspension is obtained and filled into gel capsules. Dissolution is carried out as in the previous example, with 60% of the active ingredient dissolving in 10 minutes and the droplet size is equal to 15 nm.

Example 8: Self-emulsifying mixture into an oil-in-water microemulsion in the form of a gel capsule containing (S) (−)-amisulpride body

[Table 10] This example can be compared to Example 4 performed with R, S-Amisulpride, where under the same dissolution conditions at pH 2, 65% of the active ingredient dissolves in 10 minutes.

Example 9: Semi-solid suspension containing (S) (−)-Amisulpride (D) -tartrate in the form of a gel capsule and becoming a solution:

[Table 11] The active ingredient is added to the liquid absorption enhancer at 50 ° C. with stirring. The mixture is filled into gel capsules. Dissolution is fast and complete.

[Brief description of the drawings]

1 shows the dissolution profile at pH 2 of a gel capsule containing 140 mg of (S) (−)-amisulpride of (D) (−)-tartrate of Example 3. FIG.

FIG. 2: pH 2 and pH 7.5 of gel capsules containing 200 mg of amisulpride from Example 4.
3 shows the dissolution profile.

FIG. 3 shows the dissolution profile at pH 2 of gel capsules containing 140 mg of (D) (−)-tartrate of (S) (−)-amisulpride of Example 5.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/166 A61K 31/166 31/40 31/40 31/4164 31/4164 31/4192 31/4192 47 / 10 47/10 47/34 47/34 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL , PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA , CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD , SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Dufour, Alain France, F-92100 Boulogne-Billancourt, Rue Morien, 4 (72) Inventor Gilet, Gerard France, F-75013 Paris, Ryu-yu-Jane Udine, 49 (72) Inventor Jome, Cecil France, F-13080 Rhuine, Cartier-Tullin, Lut de Gardanne, 4090 (72) Inventor Ruwi, Garrett, F-91410 Dourdan, Avenue Paris, 39 F term (reference) 4C076 AA17 AA31 AA39 AA40 AA48 AA54 AA56 BB01 CC01 DD09 DD25 DD29 DD34 DD37 DD39 DD40 DD41 DD43 DD46 DD63 DD67 DD68 DD70 EE23 EE31 EE32 EE53 FF04 FF06 FF16 4C086 AA01 AA02 BC07 BC38 BC61 MA02 MA05 MA22 MA35 MA37 MA52 NA11 ZA12 ZA18 4C206 AA01 AA02 GA07 GA17 JA09 MA02 MA05 MA42 MA55 MA57 MA72 NA11 ZA12

Claims (21)

[Claims] 1. A pharmaceutical composition for oral administration, comprising a benzamide-based active ingredient and at least one absorption enhancer. 2. The method according to claim 1, wherein the active ingredient is amisulpride, sulpiride, lintopride, bromoprid, azaprid, R-zacoprid, thiapride, sultprid, remoxiprid, veralipride, their enantiomers, and pharmaceutically acceptable salts of the above compounds and pharmaceutically acceptable salts. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is selected from salts of the above enantiomers. 3. The pharmaceutical composition according to claim 2, wherein the active ingredient is amisulpride. 4. The pharmaceutical composition according to claim 2, wherein the active ingredient is (S) (-)-amisulpride. 5. The active ingredient is (D)-(-)-of (S) (-)-amisulpride.
3. The pharmaceutical composition according to claim 2, which is a tartrate. 6. An absorption enhancer comprising: sucrose esters, alkyl esters of polyoxyethylene sorbitan, hardened or unhardened polyethoxylated castor oil, succinic acid-D-α-tocopheryl polyethylene glycol succinate (TPGS),
The pharmaceutical composition according to any one of claims 1 to 5, wherein the composition is selected from poloxamers, nonoxynol, octoxynol, polyethoxylated glycerides, terpenes, carveol, nerolidol and linalool. 7. An absorption enhancer comprising polyoxyethylene sorbitan 20 monooleate (polysorbate 80), polyoxyethylene sorbitan 20 monolaurate (polysorbate 20), polyoxyethylene sorbitan 20 monostearate (polysorbate 60), and polyethoxylation. -40 hydrogenated castor oil, polyethoxylated-35 castor oil, characterized by being selected from t-anethole, carvacrol, carvone, 1,8-cineole, eugenol, d-limonene, L-menthol, menthone, terpinene and thymol 7. The pharmaceutical composition according to claim 6. 8. The composition of claim 1, wherein said composition is in the form of a solution, suspension, emulsion, microemulsion, wafer capsule, gel capsule, sachet, tablet, effervescent tablet or multi-layer tablet. The pharmaceutical composition according to any one of claims 1 to 7, wherein the composition is in a form in which sex is regulated. 9. The pharmaceutical composition according to claim 1, wherein the composition is in the form of a gel capsule comprising a combination of an absorption enhancer and an active ingredient. 10. The pharmaceutical composition according to claim 1, wherein the composition comprises a lipophilic phase. 11. A lipophilic phase comprising one or more of (i) one or more fatty acids, (ii) an animal oil, a vegetable oil, a transesterified and / or polyethoxylated vegetable oil or a synthetic oil. 11. A medicament according to claim 10, which consists of or more oils or triglycerides, or (iii) a mixture comprising two or more compounds according to (i) and (ii) above. Composition. 12. The pharmaceutical composition according to claim 10, wherein the composition is in the form of a solution or suspension of lipid. 13. The pharmaceutical composition according to claim 12, wherein the lipophilic phase is composed of C ₈ -C ₁₂ medium-chain fatty acids or fatty acid esters. 14. The pharmaceutical composition according to claim 10, wherein the composition is in the form of an emulsion or a microemulsion. 15. The pharmaceutical composition according to claim 14, wherein the hydrophilic phase comprises and / or may contain one or more compounds selected from alcohols and water. . 16. The surfactant may include sorbitan esters, polyethoxylated sorbitan esters, lecithins derived from animals or plants, polyoxyethylated castor oils, sucrose esters of fatty acids, and fatty alcohol esters of polyethylene glycol. 16. Fatty acid esters of polyethylene glycol, bile acids, monoglycerides, diglycerides or acetylated or polyethoxylated derivatives of these compounds, used alone or in a mixture. Pharmaceutical composition. 17. The composition according to claim 10, wherein the composition is a self-emulsifying mixture.
A pharmaceutical composition according to claim 1. 18. The pharmaceutical composition according to claim 17, wherein the surfactant is selected from the surfactant according to claim 16. 19. The pharmaceutical composition according to any one of claims 1 to 8, wherein the composition is in the form of an effervescent tablet with modified release. 20. A composition according to claim 2, wherein one of the compositions contains an active ingredient and the other contains an absorption enhancer.
9. The pharmaceutical composition according to claim 1, which is in the form of a gel capsule composed of spheroids of the type. 21. The composition is in the form of a sustained release two-layer tablet, wherein the first layer comprises the active ingredient and an excipient for controlling release, the second layer comprises an absorption enhancer and the excipient of the first layer. The pharmaceutical composition according to any one of claims 1 to 8, comprising a release excipient which may be the same as or different from the excipient.