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

DESCRIPTION

ORAL PHARMACEUTICAL FORMULATION IN THE FORM OF A MICROCapsule PLURALITY FOR PROLONGED RELEASE OF LOW SOLUBILITY ACTIVE PRINCIPLES The subject of the invention is that of modified release pharmaceutical active ingredients (PA) with low solubility.

In the present description, the term modified release indifferently means a release of the active ingredient (s) beginning as soon as the dosage form is contacted with its dissolution medium (in vivo or in vitro). or a release of the active ingredient (s) which only begins after a predetermined period of time ranging for example from 0.5 to several hours. Thus in the sense of the invention, a release prolongation corresponds to a release time of 50% of the active principle (s) which is typically several hours and may extend from 0.25 to 20 hours, for example.

The term low solubility relates to active ingredients whose solubility in water is less than g / L at 25 ° C.

ΡΕ1524968

More precisely, the invention relates to low solubility active ingredient sustained release pharmaceutical formulations, which formulation is comprised of a plurality of microcapsules consisting of a core containing the low solubility active ingredient and coated with a polymer layer which contains controls PA release.

Among the various modified release systems, galenic modified release systems consisting of a plurality of reservoir-type microcapsules with an average diameter of less than 1000 micrometers are particularly advantageous. In fact, in these systems, the dose of active ingredient (s) to be administered is spread over a large number of microcapsules (typically 10,000 for a dose of 500 mg and a diameter of 400 micrometers) and this type of system has Therefore, the following intrinsic advantages:

• The use of a mixture of microcapsules with different modified release profiles makes it possible to produce release profiles which have several release waves or to provide, by means of appropriate adjustment of the different fractions, a constant level of AP plasma concentration;

• the sensitivity to gastric emptying variability is lower because emptying, which occurs here in relation to a large number of particles, is

ΡΕ1524968 statistically more reproducible;

• tissue contact with a high dose of PA is avoided. Each microcapsule actually contains only a very small dose of active ingredient (s). This avoids the risk of tissue deterioration by local overconcentration of aggressive active principle (s);

• It is possible to combine various dosage forms (immediate and / or delayed and / or prolonged release) containing one or more active ingredients in these multi-capsular systems;

• does not induce BP degradation;

• The residence time of the microcapsules in the upper parts of the tract can be extended, which ensures an increased passage time of the active ingredient (s) in front of the absorption windows and thus maximizes the bioavailability of the drug. (or active ingredient (s)).

However, when the solubility of PA is low, the production of a modified release microparticulate form faces significant difficulty.

The diffusion of the active principle through the coating film covering each microcapsule is accomplished by

241524968 action of the dissolved PA concentration gradient between the inside and outside of the microcapsule. In other words, it is the osmotic pressure difference of PA between the inside and outside of the microcapsule which is the engine of release. The internal concentration of PA is the concentration in saturation. The external concentration of PA is thus negligible under usual conditions (called sink). 0 The release motor is therefore directly linked to the concentration in PA saturation, that is, its solubility.

For sparingly soluble PAs, the concentration in PA saturation is low and the diffusion of PA outwards is therefore a priori very slow, even for thin coating films.

<td>It's from</td><td>any mood,</td><td>for films</td><td>coating</td>

<td>with little</td><td>thickness are</td><td>found the</td><td>difficulties</td>

following:

(a) The deposition of a very thin coating film is not uniform: there are gaps next to excessively thick areas, and AP release is not prolonged.

(b) Industrial control of the deposition process with very low thickness becomes very delicate and poorly reproducible.

On the other hand, for coating films

241524968 thicker, PA release is extremely slow or even nonexistent.

The difficulty in modifying the release of poorly soluble PA explains the small number of technical solutions proposed so far.

For solid, microcapsule galenic systems, those consisting of a multiplicity of particles or microcapsules are known, each having an active ingredient (s) coated with a polyvinylpyrrolidone ethylcellulose film layer. magnesium stearate and castor oil, for example. This galenic system is described in PCT application W096 / 11675. These reservoir microcapsules take advantage of their multiplicity, which is a more regular and reproducible gastric emptying time. In addition, its size between 50 and 1000 pm as well as the characteristics of its coating allow to increase its transit time in the upper parts of the gastrointestinal tract and, consequently, to maintain the absorption of the active ingredient (s). ) during all or part of that time of residence in the small intestine. However, the multi-capsule galenic system according to WO-96/11675 can be improved with regard to poorly soluble PAs which can be administered orally, because it does not propose a solution to the problem of diffusion of these poorly soluble PAs through a film. of sufficiently large thickness, for example with several micrometers.

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With regard to the state of the art on poorly soluble modified-ingredient modified release microcapsules, reference should first be made to PCT patent application WO-99/49846 which describes a pharmaceutical preparation consisting of submicron particles (0.05 to 10 pm) combining a poorly soluble active ingredient with a phospholipid compound, a surface charge modifying compound and a block polymer. The purpose of this preparation is to improve the bioavailability and stability of the active ingredient and has applications in injectable forms or for ocular or nasal administration. A prolonged release form is obtained only in the case of intramuscular injection.

PCT patent application WO-OO / 18374 describes an invention of the same type as above: the active principle in the form of submicron particles (&lt;1000 nm) is stabilized by a particle surface-associated compound and mixed with a polymer. This mixture may then be formulated into granules or micropellets and optionally into tablets. The active ingredient is rapidly dissolved and this increase in bioavailability is achieved thanks to the size reduction that allows effective plasma concentration over an extended period.

<td> 0</td><td>request of</td><td>patent</td><td>GB-2 202 143</td><td>describes</td>

<td>rhoids with</td><td>diameter</td><td>higher</td><td>at 0.5 mm and</td><td>preferably</td>

<td>superior than</td><td>0.8 mm,</td><td>containing</td><td>the beginning</td><td>little active</td>

ΡΕ1524968 soluble dispersed in 70 to 99.5% microcrystalline cellulose. This matrix form does not require any coating to control the release of the active ingredient.

JP-8073345 describes a controlled release system comprised of a film coated granulate. The granulate contains a poorly soluble active ingredient at neutral pH and inorganic acids. This system therefore proposes a solution adapted only to the case of poorly soluble basic active ingredients.

Finally, European patent EP-B-0 249 587 relates to a solid preparation which allows for the slow release of a poorly soluble active substance (&lt;0.1 wt%). This controlled release preparation may be presented in the form of gelatin capsules comprising capsules consisting of coated granules. The granules comprise the poorly soluble active ingredient and a solubilizer consisting of the commercial product Cremophor® RH 40 (polyoxyethylenated hydrogenated castor oil: 40 ethylene oxide units) as well as other additives such as polyvinylpyrrolidone, cellulose, starch and lactose. These granules between 700 and 1120 µm are coated with an ethylcellulose coating layer for release control. The constituents of the granules, which are polyvinylpyrrolidone, cellulose, maize starch and lactose, appear to be the elements of the specific hydrophilic gel system of the dosage form according to EP-B-0 249 587. These capsules therefore comprise only one

241524968 constituent (ethylcellulose) in its coating layer, which limits its ability to modify the release of the active ingredient. In particular, it is doubtful that a coating layer consisting solely of ethylcellulose (known to form impermeable films) will allow the release of a poorly soluble, controlled and industrially reproducible PA over a period of several hours, for example.

None of these patent applications describe reservoir-type microparticles or microcapsules wherein prolonged release of the poorly soluble active principle is controlled by their diffusion through a membrane having a thickness sufficient to ensure controlled and industrially reproducible permeability. Nor do they describe how such a system can be realized.

In view of this prior art void, one of the essential objects of the present invention is to propose a modified form of poorly soluble PA release consisting of a plurality of microcapsules, each formed by a core containing the PA and coated with a coating film. .

Another object of the present invention is to provide a plurality of low solubility PA reservoir type microcapsules for oral administration of the latter (s) having the film of

The coating of these microcapsules is of sufficient thickness to ensure controlled and industrially reproducible permeability.

Another essential object of the present invention is to provide a plurality of low PA microcapsules.

<td>soluble</td><td>size</td><td>less than</td><td> 1000</td><td>pm</td>

<td>a</td><td>other</td><td>purpose</td><td>gives</td><td>present invention is</td>

<td>provide</td><td colspan="2">a galenic form</td><td>oral</td><td>and consisting of a</td>

large numbers (eg in the order of several thousand) of microcapsules, ensuring this multiplicity, statistically, a good reproducibility of PA transit kinetics throughout the gastrointestinal tract, thus resulting in better bioavailability control and therefore better efficacy. .

A further essential object of the present invention is to provide a plurality of (soluble) poorly soluble PA microcapsules for oral administration of the latter (s) according to such a prolonged and / or possibly delayed release profile as such. the half-release time ti / 2 is between 0.25 and 20 hours.

A further essential object of the present invention is to provide an oral modified release form wherein the PA (s) are in the form of a plurality of individually coated particles to form microΡΕ1524968 capsules and in which various active ingredients may be mixed in the form. microcapsules, released at different release times.

Having set out the above objectives among others, the inventors had the merit of developing a sparingly soluble multi-capsular PA extended release galenic system:

• allows you to adjust the PA half-release time between 0.25 and 20 hours, • is reproducible and easy to implement industrially thanks to a ratio of coating film mass to particle mass greater than 3% by weight dry weight / dry weight, preferably greater than 5% dry weight / dry weight, and most preferably between 3 and 40% dry weight / dry weight.

To this end, the inventors have had the merit of developing, after numerous trials, microcapsules of specific structure which enable the above objectives to be met, among others.

Thus, the invention relates to microcapsules allowing modified release of at least one poorly soluble PA intended for oral administration and of the following type:

241524968 • each consisting of a core having at least one active ingredient and a coating film applied over the core which controls the sustained release of the PA (s), whose mean diameter is less than 1000 micrometers, preferably comprised of between 800 and 50 micrometers and most preferably between 600 and 100 micrometers, wherein the coating film of each microcapsule contains the following compounds:

-I- at least one film-insoluble polymer (Pi) insoluble in gastrointestinal tract fluids

-A- -II- at least one water soluble polymer (P2) -&gt; -III- at least one plasticizer (PL)

And optionally at least one lubricating surfactant (TA);

characterized by:

&gt; its coating film represents at least 3% dry weight / dry weight, preferably at least 5% dry weight / dry weight of its total mass,

Núcleo1524968&gt; its core contains at least one PA and at least one solubilizing agent with the characteristic that, as soon as it is placed in an aqueous solution at a concentration of 20% w / w at 37 ° C, it increases the solubility of the PA by more than 50%

&gt; the solubilizing agent (s) present in the core with the PA gives the core in which properties are incorporated such that the behavior of the bare (uncoated) core ) in a given TD dissolution assay defined in the examples below is as follows: 80% PA release in less than two hours, preferably in less than one hour.

Interestingly, this unique microcapsule structure with a core comprising a solubilizing agent and a P1 / P2 / PL / (TA) -based coating is designed to significantly improve the solubility of PA in aqueous solution. To achieve this, the microcapsules according to the invention are in fact prepared in such a way as to facilitate surface wetting of the PA crystals with water.

The solubility of the active ingredient is for example determined by introducing PA into an aqueous solution containing the solubilizing agent. The solution is stirred at 37 ° C for 6 hours and then filtered through a 0.2 µm pore diameter filter. Solubilized PA content is assessed by HPLC chromatography or any other appropriate analytical technique.

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Preferably, the coating film components P1, P2 and PL satisfy the following characteristics:

Dry weight mass fraction of P1 in relation to the total mass of the coating from 40 to 90% and preferably from 50 to 80%;

• dry weight P2 / P1 + P2 mass fraction comprised between 15 and 60% and preferably between 15 and 55%;

• dry weight mass fraction PL / P1 + PL between 1 and 30% and preferably between 5 and 25%.

In an advantageous embodiment, the coating film comprises component TA in a ratio of 2 to 20% and preferably from 4 to 15% of the total dry coating weight.

Preferably, the coating film represents 3 to 40% dry weight / dry weight of the total microcapsule mass.

According to preferred embodiments of the invention, the PA-containing core and solubilizing agent may have one of the following structures:

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Structure The core consists of a microsphere approved for chronic oral administration, composed for example and without limitation of cellulose derivatives and / or hydrophilic compounds such as sucrose and / or dextrose, etc. This neutral core may be coated with a layer comprising a mixture of PA and at least one solubilizing agent as defined hereinbelow.

Structure B The core is composed of a PA single crystal coated with a layer containing the solubilizing agent defined below.

Core C is a granulate composed of a mixture of the PA (s), one or more granulation excipients known to the person skilled in the art and one or more solubilizing agents as defined below.

Apart from making it possible to solve the technical problem which underlies the invention, one of the many advantageous features of these solubilizing agents is that they belong to the family of pharmaceutical excipients approved for chronic oral administration by most of the relevant authorities throughout the world.

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Furthermore, these solubilizers are selected such that they do not induce PA degradation.

These solubilizing agents are preferably non-exhaustively selected from the following families:

(a) hydrophilic polymers, preferably:

polyvinylpyrrolidone, polyvinyl alcohol, hydrophilic cellulose derivatives preferably hydroxypropylcellulose and / or carboxymethylcellulose, maltodextrins, polyethylene glycol (PEG);

(b) surfactants, preferably:

- polyoxyethylene-polyoxypropylene copolymers,

- polyoxyethylenated hydrogenated castor oil,

- sodium dodecyl sulphate,

- sucrose and sorbitan esters,

- phospholipids,

- polyethylene glycol (PEG) stearate,

- disodium pamoate,

- polyoxyethylenated oils,

- polysorbates;

241524968 (c) or else of 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 + PA] is greater than or equal to 5% and preferably from 10 to 98%.

Preferably Pi is selected from the group of the following products:

• non-water soluble cellulose derivatives, preferably ethyl cellulose and / or cellulose acetate, • acrylic derivatives, • poly (vinyl acetates), and • mixtures thereof.

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

• water soluble cellulose derivatives, • polyacrylamides, • poly-N-vinylamides, • poly-N-vinyl lactams, • polyvinyl alcohols (APV), • polyoxyethylenes (POE);

ΡΕ1524968 • polyvinylpyrrolidones (PVP) (the latter being preferred), • and mixtures thereof.

Preferably, the PL is selected from the following product group:

• glycerol and its esters, preferably from the following subgroup: acetylated glycerides, glyceryl monostearate, glyceryl triacetate, glyceryl tributyrate • phthalates, preferably from the following subgroup: diethyl phthalate, dimethyl phthalate, dioctyl phthalate • citrates, preferably from the following subgroup: tributyl acetylcitrate, triethyl acetylcitrate, tributyl citrate, triethyl citrate, • sebacates, preferably from the following subgroup: diethyl sebacate, dibutyl sebacate, • adipates, • azelates, • benzoates, • vegetable oils, • fumarates, preferably diethyl fumarate, • malates, preferably diethyl malate, • oxalates, preferably diethyl oxalate, • succinates, preferably dibutyl succinate, • butyrates, • cetyl alcohol esters,

Sal1524968 • salicylic acid, • triacetin, • malonates, preferably diethyl malonate, • cutin, • castor oil (particularly preferred), • and mixtures thereof.

Preferably, TA is selected from the following product group:

Anionic surfactants, preferably from the alkaline or alkaline earth fatty acid subgroups, with stearic acid and / or oleic acid being preferred, and / or nonionic surfactants, preferably from the following subgroup:

o polyoxyethylenated oils preferably polyoxyethylenated hydrogenated castor oil, polyoxyethylene-polyoxypropylene copolymers, polyoxyethylenated sorbitan esters, polyoxyethylenated castor oil derivatives, stearates, preferably calcium, magnesium, aluminum or zinc, stearyl fumarates preferably sodium, glyceryl behenate, and mixtures thereof.

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This preparation according to the invention makes it possible to realize a multimicapsular form of modified soluble PA release, and the PA release time can be reproducibly adjusted between 0.25 and 20 hours using a coating film which can be classify as a diffusion coating film which is sufficiently thick.

On the other hand, for poorly soluble PAs whose absorption window is limited, this plurality of microcapsules (typically 10,000 for a dose of 500 mg and an average diameter of 400 micrometers) has the following intrinsic advantages:

• The use of a mixture of microcapsules with different delayed and controlled release profiles allows the production of release profiles which have several release waves or ensure, by appropriate adjustment of the different fractions, a constant level of AP plasma concentration.

• The variability of gastric emptying is lower, since emptying, when it occurs above a large number of particles, is statistically more reproducible.

• Contact with PA (dose dumping) is avoided.

in fact not a dose tissues with a high dose

Each microcapsule does not contain much reduced AP. This avoids the risk of tissue deterioration by local overconcentration of aggressive BP.

• The residence time of the microcapsules in the upper tract can be extended, which ensures an increase in AP passage time before absorption windows and thus maximizes AP bioavailability.

The poorly soluble PAs used for the preparation of the preferably controlled modified release microcapsules according to the invention may be selected from at least one of the following major active substance varieties:

antiulcer, antidiabetic, anticoagulant, antithrombotic, hypolipemic, antiarrhythmic, vasodilating, anti-anginal, antihypertensive, vasoprotective, fertility enhancers, inducers and inhibitors of uterine labor, contraceptives, antibiotics, antifungals, anti-antiviral, anti-cancer, anti-cancer, anti-ulcer , analgesics, anti-epileptics, antiparkinsonians, neuroleptics, hypnotics, anxiolytics, psycho-stimulants, anti-migraines, antidepressants, antitussives, antihistamines or antiallergics.

Preferably the PA (s) is selected from the following compounds: Prazosine, Acyclovir,

ΡΕ1524968 nifedipine, naproxen, ibuprofen, ketoprofen, fenoprofen, indomethacin, diclofenac, sulpiride, terfenadine, carbamazepine, fluoxetine, alprazolam, famotidine, ganciclovir, spironolactone, acetylsalicyl acid, quinidine, aminaphamine, methuphamine

Referring to the preparation of microcapsules according to the invention, reference is made to microencapsulation techniques accessible to the skilled artisan, of which the main ones are summarized in the article by C. DUVERNEY and JP BENOIT in L'actualité chimique, December 1986. More precisely, the technique considered is film-coated microencapsulation, leading to individualized reservoir systems as opposed to matrix systems. For further details, see EP-B-0 953 359.

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

The present invention is also directed to a medicament comprising the microcapsules as defined hereinabove.

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This medicine may be in solid form: tablet, gelatin 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 referred to at the beginning of the present disclosure, namely: modified, preferably prolonged, release of sparingly soluble PA in a readily swallowed dosage form, all from a cover perspective long, effective and safe therapy, the use of a plurality of microcapsules:

Each consisting of a core having at least one active ingredient and a coating film applied over the core controlling the sustained release of the PA (s), the average diameter of which is less than 1000 micrometers, preferably between 800 and 50 micrometers and most preferably between 600 and 100 micrometers, wherein the coating film of each microcapsule contains the following components:

At least one film-insoluble polymer (Pi) insoluble in gastrointestinal tract fluids

ΡΕ1524968 -&gt; -II- at least one water soluble polymer (P2)

-A -III- at least one plasticizer (PL)

And optionally at least one lubricating surfactant (TA);

characterized by:

&gt; The microcapsule coating film represents at least 3% dry weight / dry weight, preferably at least 5% dry weight / dry weight of its total mass. Its core contains at least one PA and at least one agent. solubilizer with the particularity that it is then placed in an aqueous solution at a concentration of 20% w / w at 37 ° C, to increase PA solubility by more than 50%&gt; the solubilising agent (s) present in the nucleus with the PA gives the nucleus in which it is incorporated The properties of such bare core (uncoated) behavior in a given TD dissolution assay defined in the examples below are as follows: 80% PA release in less than two hours, preferably in less than one hour for the manufacture of a medicinal product based on at least one

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4

Poorly soluble, oral-swallowable, easy-to-swallow, sustained and optionally delayed in vivo release.

According to yet another object, the present invention relates to a method of therapeutic treatment, wherein a medicament as defined above is used as a product per se or as a product obtained by the process described above.

The invention will be better understood in terms of its composition and properties and its achievement by reading the examples below, which are given by way of illustration only and which make it possible to highlight the embodiments and advantages of the invention.

DESCRIPTION OF THE FIGURES:

Figure 1 represents the curve of the percentage of dissolved PA (% D) versus time (t) in hours (Η) of the microcapsules of example 1 in the TD dissolution assay.

Figure 2 represents the curve of the percentage of dissolved PA (% D) versus time (t) in hours (Η) of the microcapsules of example 2 in the TD dissolution assay.

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Figure 3 represents the curve of the percentage of dissolved PA (% D) versus time (t) in hours (Η) of the microcapsules of example 3 in the TD dissolution assay.

Example 1

1.1 - Preparation of spironolactone microcapsules:

Step 1: Grainy

180 g spironolactone, 100 g polyoxyethylenated hydrogenated castor oil (40 units of ethylene oxide) marketed under the brand name Cremophor® RH 40 and 120 g povidone (Plasdone® K29 / 32) are previously solubilized in a water / acetone mixture / isopropanol (5/57/38 m / m). This solution is then sprayed onto 800 g of Celphere® CP-305 cellulose spheres (ASAHI KASEI; diameter 300 to 500 pm) in a Glatt® GPC-G1 fluid bed apparatus.

Step 2: Coating g of previously obtained granules are coated with 1.60 g of ethylcellulose (Ethocel® 7 Premium),

0.16 g of dibutyl sebacate, 0.64 g of polyoxyethylenated hydrogenated castor oil (40 units of

Ileno1524968 ethylene), marketed under the brand name Cremophor® RH 40 and 0.80 g of povidone (Plasdone® K29 / 32) dissolved in an acetone / isopropanol (60/40 m / m) mixture in a miniGlatt fluid bed apparatus .

1.2 - Composition of microcapsules:

Table 1

<td>Components</td><td>% in large scale</td><td>Formulation of production (in g)</td>

<td>Spironolactone Granules</td><td> 94,00</td><td></td>

<td>- Cellulose spheres</td><td> (62,7)</td><td> 50</td>

<td>- Plasdone® K29 / 32</td><td> (9,4)</td><td></td>

<td>- Cremophor® RH 40</td><td> (7,8)</td><td></td>

<td>- Spironolactone</td><td> (14,1)</td><td></td>

<td>Coating</td><td> 6, 00</td><td></td>

<td>- Ethocel® 7 Premium</td><td> (3,0)</td><td></td>

<td>- Plasdone® K29 / 32</td><td> (1,5)</td><td> 3,2</td>

<td>- Cremophor® RH 40</td><td> (1,2)</td><td></td>

<td>- Dibutyl Sebacate</td><td> (0,3)</td><td></td>

1.3 - Increased solubility

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

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1.4 - Dissolution Test (TD):

The release kinetics of spironolactone are determined by a dissolution test (Type II apparatus according to European Pharmacopoeia 3^The phosphate buffer medium pH 6.8, volume 1000 mL, temperature 37 ° C, paddle stirring 100 revolutions / min, UV detection 240 nm).

The TD assay is first performed with uncoated granules and then with microcapsules comprising these granules.

TD test result:

Uncoated granules: release is complete (greater than 97% dissolution) at = 1 hour.

Microcapsules: The result is shown in the attached FIG.

The microcapsule composition described above gives a modified release profile for 8 hr for very poorly soluble spironolactone (0.02 g / l). The membrane represents 6% of the weight of the microcapsule, which ensures a reproducible release profile in an industrial process.

ΡΕ1524968

Example 2

2.1 - Preparation of spironolactone microcapsules:

Step 1: Grainy

180 g spironolactone, 100 g polyoxyethylenated hydrogenated castor oil (40 units of ethylene oxide) marketed under the brand name Cremophor® RH 40 and 120 g povidone (Plasdone® K29 / 32) are previously solubilized in a water / acetone mixture / isopropanol (5/57/38 m / m). This solution is then sprayed onto 800 g of cellulose spheres (300 to 500 µm in diameter) in a Glatt® GPC-G1 fluidized bed apparatus.

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

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2.2 - Composition of microcapsules:

Table 2

<td>Components</td><td>% in large scale</td><td>Formulation of production (in g)</td>

<td>Spironolactone Granules</td><td> 94,00</td><td></td>

<td>- Cellulose spheres</td><td> (62,7)</td><td> 50</td>

<td>- Plasdone® K29 / 32</td><td> (9,4)</td><td></td>

<td>- Cremophor® RH 40</td><td> (7,8)</td><td></td>

<td>- Spironolactone</td><td> (14,1)</td><td></td>

<td>Coating</td><td> 6,00</td><td></td>

<td>- Ethocel® 7 Premium</td><td> (2, 7)</td><td></td>

<td>- Plasdone® K29 / 32</td><td> (1,8)</td><td> 3,2</td>

<td>- Lutrol F-68</td><td> (1,2)</td><td></td>

<td>- Castor oil</td><td> (0,3)</td><td></td>

2.3 - TD test:

The release kinetics of spironolactone are determined by a dissolution test (Type II apparatus according to European Pharmacopoeia 3^The phosphate buffer medium pH 6.8, volume 1000 mL, temperature 37 ° C, paddle stirring 100 revolutions / min, UV detection 240 nm).

TD test result:

The result is shown in FIG. 2 attached.

ΡΕ1524968

The microcapsule composition described above gives a modified release profile over 8 h for very poorly soluble spironolactone (0.02 g / l). The membrane represents 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 g of spironolactone, 2.5 g of polyoxyethylenated hydrogenated castor oil (40 units of ethylene oxide) marketed under the brand name Cremophor® RH 40, 12.5 g of povidone (Plasdone® K29 / 32) and 200 g of lactose are dry premixed in a laboratory granulator (Mi-PRO / Pro-C-ept) for 5 minutes. This powdery mixture is then granulated with water (20 g). The granules are dried at 40 ° C in a ventilated oven and then calibrated with a 500 pm screen. The 200-500 pm fraction is selected by sieving.

Step 2: Coating g of previously obtained granules are

241524968 coated with 1.88 g ethylcellulose (Ethocel® 7 Premium), 0.23 g polyethoxylated hydrogenated castor oil (40 units of ethylene oxide) marketed under the brand name Cremophor® RH 40 and 0.90 g of povidone ( Plasdone® K29 / 32) dissolved in an acetone / isopropanol mixture (60/40 m / m) in a miniGlatt fluid bed apparatus.

3.2 - Composition of microcapsules:

Table 3

<td>Components</td><td>% in large scale</td><td>Formulation of production (in g)</td>

<td>Spironolactone Granules</td><td> 93, 00</td><td></td>

<td>- Lactose</td><td> (74,40)</td><td> 50</td>

<td>- Plasdone® K29 / 32</td><td> (4,65)</td><td></td>

<td>- Cremophor® RH 40</td><td> (0,93)</td><td></td>

<td>- Spironolactone</td><td> (13,02)</td><td></td>

<td>Coating</td><td> 7,00</td><td></td>

<td>- Ethocel® 7 Premium</td><td> (3,50)</td><td></td>

<td>- Plasdone® K29 / 32</td><td> (1,68)</td><td> 3, 76</td>

<td>- Cremophor® RH 40</td><td> (1,40)</td><td></td>

<td>- Castor oil</td><td> (0,42)</td><td></td>

3.3 - Test:

The release kinetics of spironolactone are determined by a dissolution test (apparatus of

ΡΕ1524968

II according to the European Pharmacopoeia 3^The phosphate buffer medium pH 6.8, volume 1000 mL, temperature 37 ° C, paddle stirring 100 revolutions / min, UV detection 240 nm).

TD test result:

The result is shown in FIG. 3 attached.

The microcapsule composition described above gives a 12 h modified release profile of very poorly soluble spironolactone (0.02 g / l). The membrane represents 7% of the weight of the microcapsule, which ensures a reproducible release profile in an industrial process.

Example 4

The ability of the solubilising agent formed by Cremophor® RH 40 to solubilize an active ingredient formed by spironolactone is tested according to the following solubility determination method:

PA is introduced into an aqueous solution containing the solubilizing agent. The solution is stirred at 37 ° C for 6 hours and then filtered through a 0.2 µm pore diameter filter. Solubilized PA content is assessed by HPLC. The results are presented in table 4 below.

ΡΕ1524968

Table 4

<td>Cremophor® RH 40% w / w at 37²Ç</td><td>(Spironolactone) dissolved in solution mg / mL</td>

<td> 0</td><td> &lt;0,1</td>

<td> 1</td><td> 0,1</td>

<td> 2</td><td> 0,2</td>

<td> 5</td><td> 0,4</td>

<td> 10</td><td> 0,8</td>

<td> 20</td><td> 1,4</td>

Lisbon, March 3, 2008