Oral pharmaceutical formulation in the form of a plurality of microcapsules for prolonged release of active principle(s) with low solubility

Translation of description of equivalent WO 2004010983 A2

oral pharmaceutical formulation in the form of a plurality of microcapsules allowing extended principle of the release (s) active (s) slightly soluble (s)

The field of the invention is that the modified release of active principles (AP) Pharmaceutical low solubility.

In this presentation, the term "modified release" denotes without a release (or) principle (s) active (s) starting from the contact of the dosage form with the dissolution medium (in vivo or in vitro) or even a release (or) principle (s) active (s) beginning only after a predetermined period of, for example 0.5 to several hours. Thus the meaning of the invention, an extension of the release corresponds to a release time of 50% (or more) ingredient (s) active (s) that is typically several hours and can range from 0, from 25 to 20 hours, for example. The term "low solubility" refers to the active ingredients whose solubility in water is less than 10 g / 1 at 25 ° C.

More specifically, the invention relates to pharmaceutical sustained release formulations of active ingredients of low solubility, this formulation consisting of a plurality of microcapsules consist of a heart containing the active ingredient of low solubility and coated with a polymer layer which controls the release of the AP.

Of the various modified release systems, the dosage modified release systems consisting of a plurality of reservoir-type microcapsules of average diameter less than 1000 microns, are particularly advantageous. Indeed, in these systems, the principle of dose (s) active (s) to be administered is distributed among large number of microcapsules (typically 10,000 for a dose of 500 mg and a diameter of 400 microns) and such type of system, therefore, the following intrinsic advantages:

• The implementation of a mixture of microcapsules release profiles of different modified permits to produce release profiles having several waves of release or ensuring, by appropriate adjustment of the different fractions, a level of constant plasma concentration PA;

• the sensitivity to the variability in gastric emptying is reduced because the emptying, which takes place over a large number of particles, is statistically more reproducible; • setting the avoided contacting the fabrics with a high dose of AP, "dose dumping". Each microcapsule in fact contains only a very small dose in principle (s) active (s). Is thus avoided the risk of tissue damage by local over-concentration principle (s) active (s) aggressive; • It is possible to combine multiple dosage forms (immediate and / or delayed and / or prolonged) having one or more active ingredients in these "multimicrocapsular" systems;

• it does not induce degradation of PA; • The residence time of the microcapsules in the upper parts of the tract can be prolonged, which ensures an increase in the duration of passage (or) principle (s) active (s) to the absorption windows and thus maximizes the bioavailability (or) principle (s) active (s).

In case, however, the solubility of the AP is low, the production of a microparticulate modified-release form comes up against a major difficulty.

Diffusion of the active ingredient through the coating film surrounding each microcapsule is carried out under the influence of concentration gradient in dissolved AP between the inside and outside of the microcapsule. In other words, it is the osmotic pressure difference AP between the inside and outside of the microcapsule which is driving the release. The internal concentration of AP is the saturation concentration. The external concentration of AP is itself negligible in usual conditions (called "sink"). The release engine is therefore directly related to the saturation concentration of the AP, ie to its solubility.

For APs with low solubility, the saturation concentration of AP is low and the diffusion of the AP outward is a priori very slow, even for very thick coating films.

And anyway, for coating films of small thicknesses are encountered the following difficulties:

(A) The filing of a coating film of very small thickness is not uniform: gaps alongside areas of extra thickness, and the release of the AP is not extended.

(B) The industrial control process for depositing a very thin becomes very difficult and poorly reproducible.

Moreover, for thicker coating films, the release of the AP is extremely slow or nonexistent.

The difficulty in modifying the release of an AP with low solubility explains the small number of technical solutions that have been proposed to date. As regards pharmaceutical systems, solids, multimicrocapsular discloses those composed of a multiplicity of particles or microcapsules each carrying principle (s) active (s) coated with a film-coating layer based on ethyl cellulose, polyvinylpyrrolidone, magnesium stearate and castor oil, for example. Such dosage system is disclosed in the PCT application WO 96/11675. These microcapsules- reservoirs derive their multiplicity a benefit, which is a gastric emptying time more regular and reproducible. Furthermore, their size between 50 and 1000 microns and the characteristics of their coating enhances their transit time in the upper parts of the gastrointestinal tract and, consequently, to maintain the absorption principle (s ) active (s) during all or part of the residence time in the small intestine.

But the multimicrocapsular pharmaceutical system according to WO-96/11675 can be improved regarding the PA poorly soluble orally administrable because it does not offer a solution to the spread of such poorly soluble PA through a film of coating a sufficiently large thickness, e.g., several microns.

Regarding the prior art on microcapsules with modified release of active principle sparingly soluble, it should first of all mention the PCT patent application WO 99/49846 describes a pharmaceutical preparation composed of submicron particles (0, 05-10 microns) combining an active ingredient poorly soluble with a phospholipid compound, a compound modifying the surface charges and a polymer block. This preparation aims to improve the bioavailability and stability of the active ingredient and has applications in injectable forms or to be administered by ocular or nasal route. A sustained release form is only obtained in the case of intramuscular injection. PCT patent application WO-00/18374 discloses an invention of the same nature as the previous one: the active ingredient in the form of submicronic particles (<1000 n) is stabilized by a compound associated with the particle surface and mixed with a polymer. This mixture can then be formed into granules or pellets and optionally compressed. The active ingredient is quickly dissolved and this is increasing the bioavailability obtained through allowing downsizing of having an effective plasma concentration over an extended period.

GB-patent application 2 202 143 describes spheroids of diameter greater than 0.5 mm and preferably greater than 0.8 mm, containing the poorly soluble active agent dispersed in 70 to 99.5% microcrystalline cellulose. This matrix form requires no coating controlling the release of active ingredient.

JP-8073345 patent application discloses a controlled release system consisting of a film granulate. The granule contains a poorly soluble active ingredient neutral pH and inorganic acids. This system offers a suitable solution only in case of poorly soluble basic active principles.

Finally, European Patent EP-B-0249587 relates to a solid preparation for the slow release of an active substance, slightly soluble (<0.1 wt%). This controlled release formulation may be in the form of capsules comprising capsules consisting of coated granules. Granules comprise the active principle with low solubility and a solubilizing constituted by the commercial product Cremophor RH 40 (polyethoxylated hydrogenated castor oil: 40 ethylene oxide units) and other additives such as polyvinylpyrrolidone, cellulose, starch and lactose. These granule size between 700 and 1120 microns are coated with an ethylcellulose coating layer for controlling the release. The ingredients of the granules that are polyvinylpyrrolidone, cellulose, corn starch and lactose, seem to be the elements of the own hydrophilic gel system in the dosage form according to EP-B-0 249 587. These capsules therefore comprise a single component (ethyl cellulose) in their coating layer, which limits its capacity for modifying the release of the active ingredient. In particular, it is doubtful that a coating layer composed solely of ethyl cellulose (known to form impermeable films), allows the release of an AP with low solubility in a controlled manner and industrially reproducible over a period of several hours , for example.

None of these patent applications describes reservoir type of microparticles or microcapsules for which sustained release of the active ingredient poorly soluble is controlled by diffusion through a membrane having a thickness sufficient to ensure a controlled and industrially reproducible permeability. They do not teach either how to achieve such a system.

Before this emptiness of the prior art, one of the essential objectives of the present invention to provide a modified release form of poorly soluble PA (s) consists of a plurality of microcapsules, each formed by a heart containing the AP and coated with a coating film.

Another object of the present invention is to provide a plurality of AP microcapsules of reservoir type of low solubility, for oral administration of this (or these) last (s), the coating film of these microcapsules having a thickness sufficient to ensure a controlled and industrially reproducible permeability. Another essential object of the present invention is to provide a plurality of sparingly soluble AP microcapsules (s) of less than 1000 microns in size.

Another object of the present invention to provide an oral dosage form and consists of a large number (for example of the order of several thousands) of microcapsules, this multiplicity statistically ensuring good reproducibility of the PA transit kinetics throughout the gastrointestinal tract, so that it results in a better control of the bioavailability and therefore better efficiency.

Another essential object of the present invention is to provide a plurality of microcapsules of AP with low solubility (s) for the oral administration of this (these) last (s) in a sustained release profile and / or optionally delayed so that the half-release t ₂ is between 0.25 and 20 hours.

Another essential object of the present invention is to provide an oral modified release in which it (or them) PA is (are) as a plurality of particles individually coated to form microcapsules and in which it is possible to mix more multimicrocapsular active ingredients in form, released under different respective release times.

Having set themselves all the above objectives, among others, the inventors had the merit of developing a multimicrocapsular pharmaceutical system with prolonged release of APs with low solubility:

- That allows to adjust the half-release time of the AP between 0.25 and 20 pm

- That is reproducible and easy to implement industrially with a mass ratio of the coating film to the mass of the particle, greater than 3% w / w dry, preferably greater than 5% w / w dry and even more preferably between 3 and 40% w / w dry.

To do this, the inventors had the merit to discover after many tests of particular structure of microcapsules that can meet the aims stated above, among others.

Thus, the invention relates to microcapsules for the modified release of at least one AP with low solubility, to be administered orally and of the type:

• each consisting of a heart with at least one active ingredient and a coating film applied on the heart and controlling the prolonged release (or) AP,

• the mean diameter is less than 1000 microns, preferably between 800 and 50 microns and more preferably still between 600 and

100 microns

• in which the coating film of each microcapsule contains the following components: - '~ -I • at least one film-forming polymer (PI) insoluble in the fluids of the gastrointestinal tract - "-II-- at least one water-soluble polymer (P2) -" -III- at least one plasticizer (PL) - "-IV- and optionally at least one surfactant (SA) lubricant; characterized in that:

> Their coating film represents at least 3% w / dry w, preferably at least 5% w / w dry their total mass, their heart contains at least one AP and at least one solubilizing agent having the particularity, therefore it is placed in aqueous solution at a concentration of

20% w / w at 37 ° C, increase of more than 50% the solubility of the AP.

It is interesting to note that the original structure of microcapsules with a heart comprising a solubilizing agent and a coating based on P1 / P2 / PL / (TA), is designed to significantly improve the solubility of the AP in aqueous solution. To achieve this, the microcapsules according to the invention are indeed made so that they facilitate the wetting of the surface of the crystals of the AP by water.

The solubility of active ingredient is measured, for example by introducing the PA in an aqueous solution containing solubilizing agent. The solution was stirred at 37 ° C for

6 hours and then filtered through a filter of 0.2 .mu.m pore diameter. The content of solubilized AP is evaluated by HPLC or other suitable analytical technique.

Preferably, the components PI, P2 and PL of the coating film satisfy the following characteristics:

• mass fraction by dry weight of PI relative to the total mass of the coating of between 40 and 90% and preferably between 50 and 80%;

"Mass fraction by dry weight P2 / P1 + P2 of between 15 and 60% and preferably between 15 and 55%";

• mass fraction by dry weight PL / PI + PL of between 1 and 30% and preferably between 5 and 25%.

According to an advantageous variant, the coating film comprises component TA in a proportion of 2 to 20% and preferably between 4 and 15% of the total mass of the dry coating.

Preferably, the coating film is 3 to 40% w / w dry total mass of the microcapsules. In accordance with preferred methods for carrying out the invention, the heart containing the AP and the solubilizing agent may have either of the following structures:

A structure

The heart consists of a microbead approved for chronic oral administration, consisting for example and without limitation, derivatives of cellulose and / or hydrophilic compounds such as sucrose and / or dextrose, etc.

This neutral heart is covered by a layer comprising a mixture of AP and at least one solubilizing agent as defined below.

Structure B The heart is composed of a single crystal of PA coated with a layer containing the solubilizer defined below.

structure C

The heart is a granule composed of the mixture of PA, of one or more granulation excipients known to those skilled in the art and one or more solubilizing agents defined below.

Besides the fact that they solve the technical problem underlying the invention, one of the many advantageous features such solubilizing agents is that they belong to the family of pharmaceutical excipients approved for chronic oral administration, by most authorities on the subject in the world.

Additionally, these solubilizers are selected such that they do not induce degradation of the AP.

Advantageously, the (or) agent (s) solubilizing (s) present (s) in the heart with the AP confer (s) to the heart in which (s) is (are) included properties such as behavior heart bare (uncoated) in a given dissolving test TD defined in the below examples, is as follows: release of 80%> of the AP in less than two hours, preferably in less than one hour.

These solubilizing agents are preferably chosen without limitation from the following families: (a) hydrophilic polymers, preferably:

- Polyvinylpyrrolidone,

- Polyvinyl alcohol, - hydrophilic derivatives of cellulose, preferably hydroxypropylcellulose and / or carboxymethylcellulose,

- Maltodextrins,

- Polyethylene glycol (PEG); (B) surfactants, preferably:

- Polyoxyethylene-polyoxypropylene copolymers,

- Polyoxyethylene hydrogenated castor oil,

- SodiumDodécylSulfate, - esters of sucrose and of sorbitan,

- Phospholipids,

- Polyethylene glycol (PEG) -stearate,

- Disodiumpamoate,

- Polyoxyethylenated oils, - polysorbates;

(C) or else from sequestering agents, preferably cyclodextrins;

(D) and mixtures thereof.

According to a preferred feature of the invention, the mass fraction [solubilizing agent] x 100 / [solubilizing agent + AP] is greater than or equal to 5% and preferably between 10 and 98%.

Preferably, PI is selected from the group of following products:

• water-insoluble derivatives of cellulose, preferably ethylcellulose and / or cellulose acetate,

• acrylic derivatives,

• polyvinyl acetates,

• and mixtures thereof.

Preferably, P2 is selected from the group of following products:

• water-soluble derivatives of cellulose,

• polyacrylamides,

• poly-N-vinylamides,

• poly-N-vinyl lactams, "polyvinyl alcohol (PVA),

• polyoxyethylenes (POE)

• polyvinylpyrrolidones (PVP) (the latter being preferred)

• and mixtures thereof.

Preferably, PL is selected from the group of following products:

• glycerol and its esters, preferably from the following subgroup: acetylated glycerides, glycér olmono-stearate, glyceryl triacetate, glyceryl tributyrate, phthalates, preferably from the following subgroup: dibutyl phthalate, diethyl phthalate, dimethyl, dioctylphthalate, citrates, preferably from the following subgroup: acetyl, acetyltriethylcitrate, tributyl, triethyl citrate, sebacates, preferably from the subgroup following: diethyl sebacate, dibutyl sebacate, adipates, azelates, benzoates, plant oils, fumarates, malates, preferably diethyl, oxalates, preferably diethyl succinates; preferably dibutyl succinate, butyrates, esters of cetyl alcohol, salicylic acid, triacetin, malonates, preferably diethyl malonate, cutin, castor oil (that is one particularly preferred), and mixtures thereof.

e preferably TA is selected from the group of following products:

• anionic surfactants, preferably from the subgroup of alkali or alkaline earth salts of fatty acids, stearic and / or oleic acid being preferred,

• and / or nonionic surfactants, preferably from the following subgroup: o polyoxyethylenated oils, preferably polyoxyethylenated hydrogenated castor oil, o polyoxyethylene-polyoxypropylene copolymers, o polyoxyethylenated sorbitan esters, o derivatives polyoxyethylenated castor oil, o stearates, preferably calcium, magnesium, aluminum or zinc, o stéarylfumarates, preferably sodium, o glyceryl behenate, o and mixtures thereof. The preparation according to the invention allows a multimicrocapsular form with modified release of APs with low solubility, the half time of release of the AP can be adjusted between 0.25 and 20 hours in a reproducible manner through the use of a film coating that can be called diffusion coating film, thick enough.

In addition, for sparingly soluble AP whose absorption window is limited, such a plurality of microcapsules (typically 10,000 for a dose of 500 mg and an average diameter of 400 microns) has the following intrinsic advantages:

• The implementation of a mixture of microcapsules of controlled release profiles and different controlled, allows to produce release profiles having several waves of release or ensuring, by appropriate adjustment of the different fractions, a constant level of plasma concentration of AP . "The variability of gastric emptying is reduced because the emptying, which takes place over a large number of particles, is statistically more reproducible.

• contacting tissue is avoided with a high dose of AP "dose dumping". Each microcapsule in fact contains only a very small dose of AP. Is thus avoided the risk of tissue damage by local over-concentration of aggressive AP.

• Stay microcapsules time in the upper parts of the tract can be prolonged, which ensures an increase in the PA transition period before the absorption windows and thus maximizes the bioavailability of the AP.

Poorly soluble PA used for the preparation of microcapsules with modified release, preferably controlled according to the invention can be selected from at least one of the major varieties of active substances: antidiabetic agents, anticoagulants, antithrombotic, hypo-lipémiants , antiarrhythmics, vasodilators, anti-anginal, antihypertensive, vasoprotectors, fertility promoters, inducers and inhibitors of uterine labor, contraceptives, antibiotics, antifungals, antivirals, anti-cancer, anti-inflammatory, analgesic, anti-epileptic, anti-Parkinson, neuro- leptic, hypnotics, anxiolytics, psychostimulants, anti-migraine, antidepressants, cough suppressants, antihistamines or allergy.

Preferably, the one or PA is (are) selected (s) from the following compounds: prazosin, acyclovir, nifedipine, naproxen, ibuprofen, ketoprofen, fenoprofen, indomethacin, diclofenac, sulpiride, terfenadine, carbamazepine, fluoxetine, alprazolam, famotidine, ganciclovir, spironolactone, acetylsalicylic acid, quinidine, morphine, amoxicillin, paracetamol, metoclopramide, verapamil and mixtures thereof.

Regarding the preparation of microcapsules according to the invention, it refers to microencapsulation techniques available to the skilled person, the main ones are summarized in the article by C. Duverney and JP Benoit in "The chemical news "December 1986. More specifically, the technique in question is microencapsulation by film coating, leading to systems individualized" reservoir "as opposed to matrix systems. For further details, reference is made to EP-B-0953359.

PA particles of desired particle size necessary to achieve the microcapsules according to the invention may be pure PA crystals and / or have undergone a pretreatment by one of the conventional techniques of the art, such as granulation, in presence of at least one conventional binder and / or an agent for modifying the intrinsic solubility characteristics of the PA.

The present invention also provides a drug comprising the microcapsules as defined above. This drug can be in solid form: tablet, capsule, powder, etc. or in liquid form, for example aqueous suspension.

According to the invention, it is also proposed as a solution to the problems mentioned at the beginning of this paper, namely: Modified-release, extended preferably PA poorly soluble in a dosage form easily swallowable, all in perspective therapeutic long, efficient and safe cover, using a plurality of microcapsules:

• each consisting of a heart with at least one active ingredient and a coating film applied on the heart and controlling the prolonged release (or) AP,

• the mean diameter is less than 1000 microns, preferably between 800 and 50 microns and more preferably still between 600 and 100 microns,

• in which the coating film of each microcapsule contains the following components:

→ -I- at least one film-forming polymer (PI) insoluble in the fluids of the gastrointestinal tract; - "-II- At least one water-soluble polymer (P2); -> -III- At least one plasticizer (PL);

- "-IV- And optionally at least one surfactant (SA) lubricant; characterized in that:

> The microcapsule coating film represents at least 3% w / dry w, preferably at least 5% w / w dry of the total mass,

> And their heart contains at least one AP and at least one solubilizing agent having the particularity, as soon as it is placed in aqueous solution at a concentration of 20% w / w at 37 ° C, an increase of more than 50 % the solubility of the AP, for manufacturing a medicament based on at least one AP with low solubility and can be administered orally, swallowable and easily which is released in vivo in a controlled, sustained, and possibly delayed.

According to yet another of its objects, the present invention relates to a method of therapeutic treatment, wherein use is made of a medicament as defined above as a product per se or as a product obtained by the above-described method .

The invention will be better understood in terms of its composition and properties of its obtaining, reading the examples below, given by way of illustration and to bring out the embodiments and benefits of 'invention.

DESCRIPTION OF FIGURES:

- Figure 1 shows the curve of the percentage of dissolved AP (% D) as a function of time (t) in hours (H), microcapsules of Example 1, the dissolution test

TD.

- Figure 2 shows the curve of the percentage of dissolved AP (% D) as a function of time (t) in hours (H), microcapsules of Example 2, the dissolution test TD. - Figure 3 shows the curve of the percentage of dissolved AP (% D) as a function of time (t) in hours (H), microcapsules of Example 3, the dissolution test TD.

example 1

1.1 - Preparation of Spironolactone Microcapsules Step 1: Granules 180 g of spironolactone, 100 g of polyoxyethylene hydrogenated castor oil (40 ethylene oxide units), marketed under the trademark Cremophor RH 40 and 120 g of povidone (Plasdone K29 / 32) are predissolved in a water / acetone / isopropanol (5/57/38 w / w). This solution is then sprayed on 800 g of cellulose spheres Celphere® CP - 305 (ASAHI KASEI; diameter between 300 and 500 microns) in an apparatus in a fluidized air bed Glatt® GPC-G1.

Step 2: Coating

50 g of granules obtained above are coated with 1.60 g of ethylcellulose (Ethocel Premium 7), 0.16 g of dibutyl sebacate, 0.64 g of polyoxyethylene hydrogenated castor oil (40 ethylene oxide units ) marketed under the trademark Cremophor RH 40 and 0.80 g of povidone (Plasdone K29 / 32) dissolved in an acetone / isopropanol mixture (60/40 w / w), in a fluidized air bed apparatus MiniGlatt .

1.2 - Composition of microcapsules:

Table 1

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1.3 -increasing solubility

In an aqueous solution at pH 6.8 and containing 20% ​​by weight Cremophor^® RH 40, the solubility at 25 ° C of spironolactone, which without solubilizing agent is of the order of 38 mg / 1, is multiplied by a factor of 5.

1.4 - Dissolution Test (TD^{^}) The release kinetics of spironolactone is determined by a dissolution test (type II device according to the European Pharmacopoeia 3rd edition, medium phosphate buffer pH 6.8, 1000 ml volume, temperature 37 ° C, stirring blades 100 rev / min, UV detection 240 nm). TD test is first carried out on non-coated granules, and then on microcapsules comprising these granules.

TD test result:

Granules uncoated: release is complete (greater than 97%&gt; dissolution) at t = 1 hour.

- Microcapsules: The result is shown in the attached FIG.l.

The microcapsule composition described above allows to obtain a modified-release profile over 8 h spironolactone very low solubility (0.02 g / 1). The membrane 6% of the weight of the microcapsule, which ensures a reproducible release profile in an industrial process.

example 2

2.1 - Preparation of Spironolactone Microcapsules

Step 1: Granules 180 g of spironolactone, 100 g of polyoxyethylene hydrogenated castor oil (40 ethylene oxide units), marketed under the trademark Cremophor RH 40 and 120 g of povidone (Plasdone K29 / 32) are predissolved in a water / acetone / isopropanol (5/57/38 w / w). This solution is then sprayed on 800 g of cellulose spheres (diameter between 300 and 500 microns) in an apparatus in a fluidized air bed Glatt® GPC-G1.

Step 2: Coating 50 g of granules obtained above are coated with 1.44 g of ethylcellulose (Ethocel Premium 7), 0.16 g of castor oil, 0.64 g of polyoxyethylene-polyoxypropylene copolymers (Lutrol® F -68) and 0.96 g of povidone (Plasdone K29 / 32) dissolved in an acetone / isopropanol mixture (60/40 w / w), in an apparatus in a fluidized air bed miniGlatt®.

2.2 - Composition of microcapsules: Table 2

<img id="imgf000016_0001" he="76" wi="159" file="imgf000016_0001.tif" img-format="tif" img-content="table" orientation="portrait" inline="no" />

2.3 - TD Test:

The release kinetics of spironolactone is determined by a dissolution test (type II device according to the European Pharmacopoeia 3rd edition, medium phosphate buffer pH 6.8, 1000 ml volume, temperature 37 ° C, stirring blades 100 rev / min, UV detection 240 nm).

TD test result:

The result is shown in Fig.2 attached

The microcapsule composition described above allows to obtain a modified-release profile over 8 h spironolactone very low solubility (0.02 g / 1). The membrane 6% of the weight of the microcapsule, which ensures a reproducible release profile in an industrial process.

example 3

3.1 - Preparation of Spironolactone Microcapsules

Step 1: Granules 35 g of spironolactone, 2.5 g of polyoxyethylene hydrogenated castor oil (40 ethylene oxide units), marketed under the trademark Cremophor RH 40 12.5 g of Povidone (Plasdone® K29 / 32) and 200 g of lactose are dry-mixed beforehand in a laboratory granulator (Mi-PRO / Pro-C-ept) for 5 minutes. This powder mixture is then granulated with water (20 g). The granules are dried at 40 ° C. in a ventilated oven and then graded on a 500 microns. is selected by sieving the fraction 200- 500 microns.

Step 2: Coating 50 g of granules obtained above are coated with 1.88 g of ethylcellulose (Ethocel Premium 7), 0.23 g of castor oil, 0.75 g of polyoxyethylene hydrogenated castor oil (40 units ethylene oxide), marketed under the trademark Cremophor RH 40 and 0.90 g of povidone (Plasdone K29 / 32) dissolved in a mixture acetone / isopropanol (60/40 w / w), in an apparatus in bed fluidized air MiniGlatt.

3.2 - Composition of microcapsules

Table 3

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3.3 -Test:

The release kinetics of spironolactone is determined by a dissolution test (type II device according to the European Pharmacopoeia 3rd edition, medium phosphate buffer pH 6.8, 1000 ml volume, temperature 37 ° C, stirring blades 100 rev / min, UV detection 240 nm). TD test result:

The result is shown in the FIG.3 attached

The microcapsule composition described above allows to obtain a modified-release profile over 12 hours, spironolactone very low solubility (0.02 g / 1). The membrane represents 7% by weight of the microcapsule, which ensures a reproducible release profile in an industrial process.

example 4

The ability of solubilizing formed by Cremophor® RH 40 agent to solubilize an active principle consisting of spironolactone, is tested according the method of measurement of the solubility following: The AP is introduced into an aqueous solution containing solubilizing agent. The solution was stirred at 37 ° C for 6 hours then filtered through a filter of 0.2 .mu.m pore diameter. The content of solubilized AP is evaluated by HPLC. The results are given in Table 4 below.

Table 4

<img id="imgf000018_0001" he="54" wi="159" file="imgf000018_0001.tif" img-format="tif" img-content="table" orientation="portrait" inline="yes" />