Microcapsules with modified release of active principles with low solubility for oral delivery

Translation of description of equivalent WO 2004010984 A2

MICROCAPSULES RELEASE PRINCIPLES MODIFIED SOLUBLE ACTIVE LITTLE FOR ADMINISTRATION PER OS

The scope of the present invention is that of modified release systems of medicinal active principles and / or nutritional (PA), for administration by the oral route.

The present invention thus relates to microcapsules for the administration _/^ Er bone and containing at least one AP with low solubility. The invention also relates to medicaments containing these microcapsules mentioned above and the use of the latter for the manufacture of medicaments.

In this presentation, expression'V / èerαtton modified "means either 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 release corresponds to a time to release 50% of the (or) principle (s) active (s) which is typically several hours and can range from 0.25 to 20 hours, for example. the term "poor 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

PA.

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 in any case, for the coating films of small thicknesses, it is then 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.

This technical problem is even more difficult to solve than this should not be at the expense of other specifications required for a pharmaceutical system for radministration PA orally, are among others, cumulatively and for a wide range of AP, the following :

- Slow transit in the upper parts of the gastrointestinal tract, reflected by an in vivo absorption profile on a significantly longer period than allowed by the natural transit (+/- 3 hours 1)

- Absence of irritation of the mucous membrane,

- Limited mass of the dosage form corresponding to a dose,

- Reduced cost.

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.

In the field of microcapsules with modified release of active ingredients anti-hyperglycemic, we should mention the French patent application FR-A-2816840 which discloses microcapsules whose heart consists of metformin crystals coated with a membrane control the release of the metformin comprising stearic acid (50%) or castor oil (10%) and ethyl cellulose (respectively 50 and 90%). The pharmaceutical system for oral radministration of antihyperglycemic active principles must result in an effective therapeutic coverage over 24 hours by overcoming bypass problems of absorption window and localized massive release of active ingredient. This technical proposal still be improved, insofar as it does not solve the problem of poorly soluble PA mentioned above

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 nm) 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 granulate contains a sparingly soluble active ingredient at 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 a coating layer of ethylcellulose, allowing the control of 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 thus behave one 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 microcapsules or microparticles for which sustained release of the active principle with low solubility is controlled by its diffusion through a membrane having a thickness sufficient to provide controlled permeability and industrially reproductible.- 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 radministration of this (or these) last (s), the coating film of these microcapsules having a thickness sufficient for 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 thousand) of microcapsules, this multiplicity statistical-ment ensuring good reproducibility of the transit kinetics of PA 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 \_\a 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 several active ingredients in multimicrocapsular form, released under different respective release times.

Having set themselves all the above objectives, among others, the inventors had the merit of developing a pharmaceutical system multimicrocapsular extended to AP with low solubility release, orally, which, besides the properties addressed in the objectives above, has cumulatively and for a wide range of PA, the following specifications, among others:

- Absence of irritation of the mucous membrane - high AP content

- Reduced cost,

- 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 ratio of the mass of the coating film to the mass of the particle top 3% w / w dry, preferably greater than 5% w / w dry, and even more preferably between

3 and 40% p / ρ sec.

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.

To this end, the present invention relates to a galenic system formed by microcapsules allowing the modified release of at least one AP with low solubility in water, isolation or anti-hyper glycemic, intended 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 for the release of modified (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);

- "-in- And optionally at least one surfactant (SA) lubricant; excluding or not of coating films consisting of enteric compositions and coating films of following composition:

1 - at least one film-forming polymer (PI) insoluble in the tract fluids, present in an amount from 50 to 90, preferably 50 to 80% by weight of solids relative to the total mass of the coating composition and composed of at least one water-insoluble derivative of cellulose, namely ethylcellulose and / or cellulose acetate;

2 - at least one nitrogenous polymer (P2) present in an amount of 2 to 25, preferably 5 to 15% by weight of solids relative to the total mass of the coating composition and composed of at least one polyacrylamide and / or a poly-N-vinylamide and / or unpoly-

N-vinyllactam, namely polyacrylamide and / or polyvinylpyrrolidone;

3 - at least one plasticizer present in an amount of 2 to 20, preferably 4 to 15% by weight of solids relative to the total weight of the coating composition and constituted by at least one of the following compounds: glycerol esters, phthalates, citrates, sebacates, cetyl alcohol esters, castor oil, salicylic acid and cutin;

4 - and at least one surfactant and / or lubricant present in an amount of 2 to 20, preferably 4 to 15% by weight of solids relative to the total mass of the coating composition and chosen from anionic surfactants , namely the alkali or alkaline earth salts of fatty acids, stearic and / or oleic acid being preferred, and / or from nonionic surfactants, namely polyoxyethylenated sorbitan esters and / or castor oil derivatives polyoxyethylenated and / or from lubricants such as stearates of calcium, magnesium, aluminum or zinc, or such as sodium stearylfumarate and / or glycerol behenate; said agent to comprise just one or a mixture of the abovementioned products;

characterized:> in that their coating film represents at least 3% w / dry w, preferably at least 5% w / dry w of total particle mass,> and in that 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%.

It is to the credit of the Applicant to have developed quite surprising and unexpected, such a dosage system for dissemination of AP with low solubility through a coating film of the microcapsules and thick enough without breaking the cost.

Choosing a higher stripping rate or equal to 3% by dry weight relative to the total weight of the microcapsule, is a particularly inventive arrangement, which goes against the current technical opinion widely held in this field. It is the same with regard to quantitative data for PI, P2 & PL.

According to a particularly preferred embodiment of the invention, the coating film is 3 to 40% w / w on dry total mass of the microcapsules.

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 cellulose derivatives,

• polyacrylamides,

• poly-N-vinylamides,

• poly-N-vinyl lactams,

• polyvinyl alcohols (AFN) • polyoxyethylenated (POE)

• polyvinylpyrrolidones (PNP) (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, glycérolmono-stearate, glyceryl triacetate, glyceryl tributyrate, phthalates, preferably from the following subgroup: dibutyl phthalate, diétliylphfhalate, diméthylphfhalate, 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.

According to an advantageous variant, the film emobage 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, TA is selected from the group of following products:

• anionic surfactants, preferably from the subgroup of alkali or alcalmoterreux 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 polyoxyethylenated derivatives of castor oil, o stearates, preferably calcium, magnesium, aluminum or zinc, o stéarylfumarates, preferably sodium, o glyceryl behenate, o and mixtures thereof.

Advantageously, the microcapsules are designed so as to stay in the upper parts of gastrointestinal tract for at least about 5 hours, preferably at least about 8 hours, thus allowing the absorption of the AP during a prolonged period.

According to a particular embodiment of the microcapsules to APs with low solubility according to the invention and according to another embodiment quantitative expression, the coating film comprises from 35 to 75% PI ethylcellulose, from 20 to 50% of P2 polyvinylpyrrolidone from 5 to 15% PL.

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 in 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, antiépi-leptic, antiparkinsonian agents, neuroleptics, hypnotics, anxiolytics, psychostimulants, anti-migraine, antidepressants, cough suppressants, antihista-Miniques 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.

Alternatively, the AP consists of at least one nutritional supplement and / or dietetic, preferably chosen from vitamins, amino acids, trace elements, antioxidants 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. DUNERNEY 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 long therapeutic coverage, efficient and safe to use a plurality of microcapsules allowing the modified release of at least one AP with low solubility in water, isolation or anti-hyperglycemic agents, intended to be administered by way oral, these microcapsules having the following characteristics:

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

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

• their coating film 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; IP components, P2 and PL of the coating film satisfy the following characteristics:> => dry weight mass fraction of PI relative to the total weight of

F 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%. • and this coating film represents at least 3% w / dry w, preferably at least 5% w / w dry mass of the total;

excluding or not of coating films consisting of enteric compositions and coating films of following composition: 1 - at least one film-forming polymer (PI) insoluble in the tract fluids, present in an amount from 50 to 90, preferably 50 to 80% by weight of solids relative to the total mass of the coating composition and composed of at least one water-insoluble cellulose derivative, namely V ethylcellulose and / or cellulose acetate;

2 - at least one nitrogenous polymer (P2) present in an amount of 2 to 25, preferably 5 to 15% by weight of solids relative to the total mass of the coating composition and composed of at least one polyacrylamide and / or a poly-N-vinylamide and / or unpoly- N-vinyllactam, namely polyacrylamide and / or polyvinylpyrrolidone;

3 - at least one plasticizer present in an amount of 2 to 20, preferably 4 to 15% by weight of solids relative to the total weight of the coating composition and constituted by at least one of the following compounds: glycerol esters, phthalates, citrates, sebacates, cetyl alcohol esters, castor oil, salicylic acid and cutin;

4 - and at least one surfactant and / or lubricant present in an amount of 2 to 20, preferably 4 to 15% by weight of solids relative to the total mass of the coating composition and chosen from anionic surfactants , namely the alkali or alcalmoterreux salts of fatty acids, stearic and / or oleic acid being preferred, and / or from nonionic surfactants, namely polyoxyethylenated sorbitan esters and / or castor oil derivatives polyoxyethylenated and / or from lubricants such as stearates of calcium, magnesium, aluminum or zinc, or such as sodium stearylfumarate and / or glycerol behenate; said agent to comprise just one or a mixture of the abovementioned products;

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 dissolution (% D) of active principle AP, depending on the time (t) in hours (H), microcapsules of Example 1, the dissolution test described in the examples that follow.

- Figure 2 shows the curve of the percentage dissolution (% D) of active principle AP, depending on the time (t) in hours (H), microcapsules of Example 2, the dissolution test described in the examples that follow.

EXAMPLES

example 1

Preparation of microcapsules Acyclovir:

Step 1: Granules 970 g of acyclovir and 30 g of povidone (Plasdone® K29 / 32) are premixed dry in the bowl of a high shear granulator (Lodige® M5MRK) for 5 minutes. This powder mixture is then granulated with water (200 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 700 g of granules obtained above are coated in an apparatus in a fluidized air bed Glatt® GPCGl by 50.65 g of ethylcellulose (Ethocel Premium 7), 50.65 g of povidone (Plasdone K29 / 32), 12.35 g of magnesium stearate and 9.88 g of castor oil dissolved in an acetone / isopropanol mixture (60/40 w / w) ,.

Composition of microcapsules:

<img id="imgf000015_0001" he="51" wi="157" file="imgf000015_0001.tif" img-format="tif" img-content="table" orientation="portrait" inline="yes" /> Test

The Acyclovir release kinetics is determined by a dissolution test (type II device according to the European Pharmacopoeia 3rd edition, phosphate buffer medium pH 6.8, volume 900 ml, temperature 37 ° C, stirring blades 100 rev / min, detection UV 268 nm).

result:

Figure 1 attached shows the dissolution profile obtained by these microcapsules.

The microcapsule composition described above allows to obtain a dissolution profile wherein 80% of acyclovir released in 3 hours.

example 2

Preparation of amoxicillin microcapsules:

Step 1: Granules 970 g of amoxicillin trihydrate and 30 g of povidone (Plasdone® K29 / 32)) are premixed dry in the bowl of a high shear granulator (Lodige® M5MRK) for 5 minutes. This powder mixture is then granulated with water (200 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

700 g of granules obtained above are coated in a fluidized air bed apparatus

Glatt® GPCGl per g of ethyl cellulose (Ethocel 7 Premium) g of povidone

(Plasdone® K29 / 32) and 0.96 g of castor oil dissolved in an acetone / isopropanol mixture (60/40 w / w) Composition of microcapsules:

<img id="imgf000016_0001" he="46" wi="154" file="imgf000016_0001.tif" img-format="tif" img-content="table" orientation="portrait" inline="no" /> test:

The arnoxicillme the release kinetics is détenninée by a dissolution test (type II apparatus according to European Pharmacopoeia 3rd edition, phosphate buffer medium pH 6.8, volume 900 ml, temperature 37 ° C, stirring blades 100 rev / min, detection A 240 nm).

result:

Figure 2 attached shows the dissolution profile obtained for these microcapsules.

The microcapsule composition described above allows to obtain a dissolution profile wherein 80% of amoxicillin released in 4 hours.