BR122013000700B1 - "SUSPENSION MICROCAPSULES IN A NET STAGE AQUASA" - Google Patents

Abstract

oral pharmaceutical formulation in the form of aqueous microcapsule suspension allowing modified release of active ingredient (s). The present invention relates to orally administrable liquid pharmaceutical formulations with modified release of active principle (s) excluding amoxylin and comprised of suspensions of coated active principle particles (microcapsules). The microcapsules that make up the dispersed phase of the suspension are designed according to the invention to allow modified release of the active ingredient (s) according to a profile that does not evolve during storage. liquid suspension. To do so, the inventors propose to select a microcapsule-specific coating composition consisting of at least four components which allow these microcapsules to be conserved in water without modifying their modified release properties of the active principle, this liquid phase being otherwise saturated in water. active principle (s).

Description

Patent Descriptive Report for "SUSPENSION OF MICROCapsules IN A WATER LIQUID PHASE".

Divided from PI0309142-2, filed on April 7, 2003. The present invention relates to the modified release of pharmaceutical active ingredients other than amoxicillin. In this report, the term "modified release" indifferently designates a release of the active principle (s) beginning from contact of the galenic form with its dissolution medium (in vivo or in vitro). or a release of the active principle (s) which only begins after a predetermined time ranging for example from 0.5 to several hours. In the sense of the invention, the release time of 50% of the active ingredient (s) is typically several hours, and may extend from 0.5 to 30 hours, for example.

More precisely, the invention relates to orally administrable liquid pharmaceutical formulations with modified release of active ingredient (s) excluding amoxicillin. Such formulations consist of suspensions or dispersions of microcapsules each formed of a core comprising amoxicillin and a coating surrounding said core. The microcapsules constituting the dispersed phase of the suspension are designed according to the invention to allow modified release of the active principle (s) excluding amoxicillin.

More particularly, the invention relates particularly to "multimicapsular" aqueous suspensions of orally administrable active principle (s), excluding amoxicillin, which suspensions are stable throughout the duration of treatment. and which allow modified release of the active ingredient (excluding amoxicillin). These suspensions are especially interesting in the case of: - modified-release forms of active ingredients having high therapeutic doses (for example from 500 to 1000 milligrams and more); - liquid pediatric or geriatric forms with modified release of active ingredients (such as sachets or drinkable suspensions to be reconstituted in vials); - taste masking and / or protection of fragile active ingredients. The invention also relates to a special process for preparing microcapsules for aqueous suspension.

Modified release oral pharmaceutical formulations of active ingredient (s) are well known.

Some of these formulations are tablets comprising a therapeutically active core coated with varying thicknesses of non-digestible materials.

More recently there have appeared microcapsules or microspheres comprising a core of active principle (s) coated in different permeability or solubility layers. Such microcapsules / microspheres are placed, for example, into gelatin gels to form modified release galenic systems of active ingredient (s). Most modified release dosage forms comprising a core of coated active (s) are presented in solid form: tablets, gels, microspheres, or microcapsules. By way of illustration of microcapsules in dry form, mention may be made in particular of EP-B-0 709 087 which describes a galenic (pharmaceutical or dietary) system, preferably in the form of an advantageously disintegrable tablet, powder or It is characterized by the fact that it comprises reservoir-type microcapsules containing at least one medicinal and / or nutritional active ingredient (PA), which are notably chosen among antibiotics, intended for oral administration, characterized by: - the fact that they are made up of PA particles each coated with a coating film of the following composition: 1 - at least one filmogenic polymer (P1) insoluble in the tract fluids, present at a rate of 50 to 90% by weight. dry weight to total weight of the coating composition and comprising at least one non-water soluble cellulose derivative, ethylcellulose and / or cellulose acetate. pulp being especially preferred; 2 - at least one nitrogenous polymer (P2) present at a ratio of 2 to 25% by dry weight to the total mass of the coating composition and consisting of at least one polyacrylamide and / or a poly-N-vinylamide and / or a poly-N-vinyl lactam, polyacrylamide and / or polyvinyl pyrrolidone being especially preferred; 3 - at least one plasticizer present at a ratio of 2 to 20% by dry weight to the total mass of the coating composition and comprising at least one of the following compounds: glycerol esters, phthalates, citrates, sebacates, cetyl alcohol esters, castor oil, salicylic acid and cutin, castor oil being especially preferred; - at least one surfactant and / or lubricant, present at a ratio of 2 to 20% by dry weight in relation to the total mass of the coating composition and chosen from anionic surfactants, preferably alkaline or alkaline earth salts of the fatty acids, stearic and / or oleic acid being preferred, and / or among nonionic surfactants, preferably polyoxyethylenated sorbitan esters and / or polyoxyethylenated castor oil derivatives, and / or lubricating agents. as stearates, preferably calcium, magnesium, aluminum or zinc, or as stearyl fumarate, preferably sodium, and / or glycerol behenate; said agent may comprise a single or a mixture of the above products; - by the fact that they have a particle size of between 50 and 1 000 microns, - by the fact that they are designed to be able to remain within the small intestine for a time of at least about 5 hours, thus allowing the absorption of PA for at least part of its stay in the small intestine.

This document relates only to dry microcapsule-based dosage forms and in no way mentions oral liquid capsule-based dosage forms.

Such modified release solid pharmaceutical formulations are not always advantageous, notably when they are administered to very young children or very elderly patients who have difficulty swallowing. This is the case where the active ingredients in question should be administered orally at high doses, for example from 500 to 1000 milligrams and more, as is the case for metformin for example. Of course, such solid galenic systems are inadequate because they are too bulky and therefore very difficult to swallow, notably by young children or the elderly. This can lead to poor compliance by patients and as a result endanger the success of therapeutic treatment. The same is true for pediatric forms in which the therapeutic dose is to be adjusted according to the mass of the child, the suspensions of the invention are adapted to vials fitted with existing kg-graduated syringes and therefore do not require the development of a new device. Modified release forms hitherto little used for children are henceforth accessible through the invention. The advantages of such forms are the reduction in the number of daily shots and the optimization of treatment effectiveness between each shot (eg antibiotics, anti-inflammatory drugs, cardiovascular treatments, etc.). Thus, an easy-to-prepare controlled release liquid pharmaceutical formulation would constitute significant progress.

In such a case, it would be even more advantageous to perform modified release galenic systems consisting of a plurality of microcapsules with a diameter of less than 1000 microns. Indeed, in such systems, the dose of active ingredient (s) to be administered is distributed among a large number of microcapsules (typically 10,000 for a dose of 500 mg) and therefore has the following intrinsic advantages: • The execution of a mixture of microcapsules with different modified release profiles allows the release of profiles that have several release waves or that, by means of the appropriate adjustment of the different fractions, a constant AP plasma concentration level. • High-dose tissue contact with PA is avoided. Each microcapsule actually contains only a very small dose in active principle (s). There is thus a release of the risk of tissue deterioration by local overconcentration of aggressive active principle (s). • It is possible to combine various galenic forms (immediate or modified release) that comprise one or several active principles in these "multi-capsular" systems. Liquid multiparticulate dosage forms, more precisely colloidal suspensions, which are preferred to solid forms for heavily dosed active ingredients or pediatric orally administrable applications are known. Performing modified-release liquid suspensions of active ingredient (s) is delicate. The main difficulty to be resolved is to prevent the release of the active ingredient (s) into the liquid phase during storage of the suspension, while allowing a modified release from entry into the gastrointestinal tract. This goal is especially delicate to achieve as the active ingredient (s) are stored in a liquid for a very long time relative to the desired release time in the gastrointestinal tract fluids. . On the other hand, its prolonged stay in the liquid storage phase should not disturb the system with modified release to the point of causing a change in the profile and release time of the active principle (s).

On the other hand, in order for these liquid formulations to be fully effective, it is known to be important: that the microcapsules are very small in size (<1000 microns), and that the mass fraction in coating excipients is limited, this modality It is even more delicate to obtain since, due to their very small size, the microcapsules have a large specific surface, which accelerates the release.

With regard to the prior art for oral, modified-release oral dosage forms of active ingredients, it is appropriate to first mention the French patent application FR-A-2 634 377 which discloses a new modified-release dosage form based on a resin / active ingredient complex, coated with an ionic polymer of polarity opposite to the polarity of the resin and fixed to it by ionic bonding. The active ingredient is also ionic and has a polarity opposite to the polarity of the resin. The latter may be sodium polystyrene sulfonate and the coating ionic polymer is chosen from the acrylic and methacrylic acid ester polymers (EUDRAGIT®). The resin is impregnated with an aqueous solution of the active ingredient. The impregnated resin particles of active principle are then coated with an organic tonic polymer solution. The microcapsules thus obtained may be placed as a drinkable suspension (notably example 2). The use of tonic resin and polymer coating limits the application possibilities to ionic active principles.

US-B-4,999,189 and US-B-5,186,930 refer to liquid pharmaceutical compositions comprising ion exchange ion resin / active ingredient complexes suspended in a liquid phase. Such resin / active ingredient complex particles are coated with a first layer of high melting pharmaceutically acceptable wax and a second outer layer of a pharmaceutically acceptable water-insoluble polymer (ethylcellulose or methylcellulose and hydroxypropyl methylcellulose, hydroxyethyl cellulose , Eudragit® ...). A plasticizer such as dibutylcebacate may be introduced into this second outer layer. The active principle is fixed by ionic bonding over the ion exchange resin. The liquid phase consists of a high fructose glucose syrup and various other ingredients such as glycerin or propylene glycol. US-B-5,186,930 is distinguished from the first by the fact that it provides for a sufficient amount of first layer (wax) to prevent the expansion and cracking of particles of complex resin / active ingredients.

These US patents do not provide any element that allows one to appreciate the quality of the modified release of active ingredients. On the other hand, the fact that employing ion exchange resins as support for the active principle is uncomfortable and limiting in terms of the variety of active principles concerned. Moreover, this galenic system is not convincing about the stability and preservation of the modified release properties of the active ingredient. PCT patent application WO-A-87/07833 and US-B-4,902,513 disclose aqueous suspensions of active principle microcapsules (e.g. theophylline) with modified release of the active principle (12h for example). These suspensions are prepared by saturating the aqueous phase with the active ingredient for this purpose before incorporating the active ingredient microcapsules into that aqueous phase. The composition of the microcapsule shell, which allows modified release of the active ingredient, is not described in these documents. However, this coating composition is crucial to ensure the maintenance of the modified release profile of the microcapsules after preservation in the aqueous phase. It is clear that the described technical proposal does not disclose the means of solving the double problem of making a liquid suspension of a modified release microcapsular form, without impairing the stability of the modified release profile of the active principle at the end of storage of the microcapsules in liquid phase. European patent application EP-A-0 601 508 relates to an aqueous suspension for oral administration of naxoprene according to a modified release profile. Such a suspension comprises coated Naxoprene microgranules suspended in a syrupy aqueous liquid phase. The technical problem underlying this invention is the provision of a modified release form of naxoprene, dosed at 1000 mg and administrable in a single daily intake.

The microgranules are made up of naxoprene, polyvinylpyrrolidone, and lactose (90-300 μιτι). Their coating is made of 4 layers. The first comprises: diethylcellulose / diethylphthalate / polyethylene glycol. The second is based on (meth) acrylates / (meth) acrylic copolymers EUDRA-GIT. The third comprises glycerol / wax stearate / fatty alcohols. And the fourth is an enteric coating based on cellulose acetate / phthalate. Naxoprene release intervenes in a modified manner within 24 hours. Example 22 of this European patent application EP-A-0 601 508 comprises a demonstration of the stability of the release profile after 30 days of storage of the liquid suspension.

One of the drawbacks of this suspension results from the enteric layer which prevents the use of a pH neutral suspension as this layer is designed to disintegrate and become liquid at that neutral pH. Another drawback of this enteric layer is that it blocks the release of the acidic active ingredient in the stomach. Now, for PAs whose absorption window is located in the upper parts of the gastrointestinal tract, it is often advantageous to release the active ingredient in the stomach to increase bioavailability. On the other hand, it is a very complex multi-layer solution which is moreover specific to naxoprene. PCT patent application WO-A-96/01628 discloses a liquid pharmaceutical formulation for oral administration according to a modified (12-hour) release profile of an active ingredient consisting of mo-guistein. The aim is to propose an easy-to-measure, ingested, modified-release liquid mo-guistein formulation that has a release duration that allows multiple shots to be avoided, which is stable in aqueous suspension over time, which it is tasty to promote compliance and whose manufacture does not involve the use of toxic substances such as solvents. To achieve this goal, the invention according to PCT patent application WO-A-96/01628 proposes a suspension in a poorly hydrated (essentially sorbitol and glycerin) liquid phase of microgranules (90-300 pm). moguistein coated with a first hydrophilic layer consisting of cellulose acetate / phthalate and diethylphthalate; with a second hydrophobic layer comprising glycerol / wax stearate / fatty alcohols; and with a third hydrophilic layer identical to the first.

This multilayered form is very complex to prepare and, moreover, is specific to moguistein.

In this state of the art, the present invention aims to propose an aqueous suspension of microcapsules of active principle (s) excluding amoxicillin for oral administration of the latter (s) according to a modified release profile, in which the coating of the microcapsules is designed such that the release profile is not disturbed and does not depend on the time of maceration of the microcapsules in the liquid (preferably aqueous) phase. Thus, the release of the active ingredient (s) contained in the microcapsules into the liquid phase throughout the storage of the suspension would be avoided, while allowing a modified release of the (or ) active principle (s) from entry into an environment that allows the onset of release, namely in vivo in the gastrointestinal tract and in vitro under the conditions of a dissolution test performed just after the suspension of the microcapsules in the phase. solvent (preferably aqueous) with the aid of a Type II apparatus according to the European Pharmacopoeia 3rd Edition in a pH 6.8 phosphate buffer medium at a volume of 900 ml at a temperature of 37 ° C Ç.

Another object of the present invention is to provide an aqueous liquid suspension of active ingredient (s) (excluding amoxicillin) microcapsules comprising a single layer coating film.

Another object of the present invention is to provide an aqueous liquid suspension of microcapsules of active principle (s) (excluding amoxicillin), in which the dissolved fraction from the microcapsules is less than or equal to 15%. preferably 5% by weight of the total mass of active ingredients present in the microcapsules.

Another object of the present invention is to provide an aqueous liquid suspension of active ingredient (s) (excluding amoxicillin) microcapsules in which a portion of the active ingredient (s) is under the immediate release form and the other part of the active principle (s) is in the modified release form (microcapsules).

Another essential objective of the present invention is to provide an aqueous suspension of modified active ingredient release microcapsules (excluding amoxicillin) which enables the active ingredient to be released according to a release profile that is not altered by the aging time of the active ingredient. suspension.

Another essential object of the present invention is to provide an aqueous microcapsule suspension made of individually coated active principle (s) (excluding amoxicillin) particles, which allows the release of the latter (s). according to a prolonged and / or possibly delayed profile such that the half-release time is between 0.5 and 30 hours.

Another object of the present invention is to propose an oral galenic form that is liquid and consists of a large number (for example of the order of several thousand) of microcapsules, such multiplicity ensuring statistically good reproducibility of PA transit kinetics throughout the gastrointestinal tract, resulting in better control of bioavailability and therefore better efficacy.

An essential object of the present invention is to propose a liquid, oral dosage form formed by a plurality of coated microcapsules which avoids the use of large amounts of coating, the coating mass fraction being comparable to that of monolithic forms.

Another essential object of the present invention is to provide a modified release aqueous suspension in which the active principle (s) (excluding amoxicillin) is in the form of a plurality of individually coated particles to form microcapsules and allowing the mixing of various active ingredients, released according to different release times.

Another essential object of the present invention is to propose the use, as a means of treating human or veterinary diseases, of a (preferably aqueous) suspension of microcapsules composed of particles of active principle (s) (with exclusion of amoxicillin) individually coated in order to determine the modified release of the active ingredient (s), without the storage in this liquid form of microcapsules in suspension having an impact on the modified release profile.

A further essential object of the present invention is to propose a medicament based on a preferably aqueous suspension of microcapsules consisting of individually coated particles (excluding amoxicillin) in order to determine the modified release. of the active principle (s), without the storage in this liquid form of the microcapsules in suspension having an impact on the modified release profile.

Having set the above objectives among others, the inventors had the merit of developing a multi-capsular galenic system in suspension form, preferably aqueous, with modified release of active principle (s) excluding amoxicillin: change the modified release profile, possibly delayed, - and that is stable, easy to prepare, economical and of high performance.

To do this, the inventors proposed: - selecting an absolutely special coating composition for the microcapsules, - and suspending the microcapsules in a liquid (preferably aqueous) saturated in principle active or saturable in principle (s) active in contact with the microcapsules while employing a limited amount of solvent (preferably water), yet sufficient for the suspension to be easily swallowed.

Thus, the invention which fulfills the above objectives, among others, relates to a suspension of microcapsules in an aqueous liquid phase, which allows the modified release of at least one active ingredient (excluding amoxicillin) and which is intended to be orally administered, characterized in that: ■ it comprises a plurality of microcapsules each consisting of a core comprising at least one active ingredient (excluding amoxicillin) and a coating film: • applied over the core , • which regulates the modified release of the active principle (s), • and which has a composition that corresponds to one of the following three families A, B, C: ■ => Family A: ♦ 1A - at least one liquid-insoluble film-forming polymer (P1) present at a ratio of 50 to 90, preferably 50 to 80 dry weight to total weight of the coating composition and consisting of: at least one non-water soluble cellulose derivative; ♦ 2A - at least one nitrogenous polymer (P2) present at a ratio of 2 to 25, preferably 5 to 15% dry weight to total weight of the coating composition and consisting of at least one polyacrylamide and / or a poly-N-vinylamide and / or a poly-N-vinyl lactam; ♦ 3A - at least one plasticizer present at a ratio of 2 to 20, preferably from 4 to 15% by dry weight to the total mass of the coating composition and comprising at least one of the following compounds: glycerol esters, phthalates, citrates, sebacates, cetyl alcohol esters, castor oil; ♦ 4A - at least one surfactant and / or lubricant present at a ratio of 2 to 20, preferably 4 to 15% by dry weight to total weight of the coating composition and chosen from anionic surfactants, and / or among nonionic surfactants, and / or among lubricating agents; said agent may comprise a single or a mixture of the above products; ■ => Family B: ~ 1B - at least one hydrophilic polymer carrying neutral pH ionized clusters, preferably chosen from cellulose derivatives; ~ 2B - at least one hydrophobic compound, other than A; => Family C: ♦ 1C - at least one film-forming polymer insoluble in gastrointestinal tract fluids, ♦ 2C - at least one water-soluble polymer, ♦ 3C - at least one plasticizer, ♦ 4C - and possibly at least one surfactant / lubricant preferably selected from the group of the following products: anionic surfactants, and / or nonionic surfactants; ■ and by the fact that the liquid phase is saturated or saturated in active principle (s) in contact with the microcapsules.

For the purposes of this report, "microcapsules of active principle (s)" means microcapsules having a nucleus comprising the active principle (s) and possibly at least one excipient.

This suspension according to the invention allows to overcome the two main obstacles to the realization of an aqueous suspension of microcapsules consisting of individually coated microparticles of active ingredients and allowing the modified release of the latter, these two obstacles being: a) limit the fraction of active ingredients immediately released from the microcapsules at a value of less than 15% and preferably 5% by weight of the total mass of active ingredients employed in the microcapsules, (b) obtain a modified release system sufficiently robust to prevent any evolution or alteration of the release profile of the active ingredient (s) during the storage time of the aqueous suspension.

In addition, this suspension facilitates the oral administration of medicinal products with high therapeutic doses and this, notably in relation to the elderly and children, the gain in compliance and treatment success is significantly high.

On the other hand, for PAs whose absorption window is limited, it is especially advantageous that the modified release form is a plurality of microcapsules as indicated in the preamble of this report.

According to a preferred embodiment of the invention, families A, B, C in which the constituents of the coating composition are chosen are as follows: => Family A: ♦ 1A - ethylcellulose and / or cellulose acetate; ♦ 2A - polyacrylamide and / or polyvinyl pyrrolidone; ♦ 3A - castor oil; ♦ 4A - alkaline or alkaline earth salt of fatty acids, stearic and / or oleic acid being preferred, polyoxyethylenated sorbitan ester derived from polyoxyethylenated castor oil, preferably calcium, magnesium, aluminum or zinc stearate, stearyl fumarate, preferably sodium glycerol behenate; taken alone or in a mixture with each other; => Family B: ♦ 1B ~ cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate ~ hydroxypropril methylcellulose acetate succinate; (meth) acrylic acid and (meth) acrylic acid alkyl (methyl) ester copolymer (EUDRAGIT® S or L), and mixtures thereof, ♦ 2B ~ hydrogenated vegetable waxes (Dynasan® P60, Dynasan® 116), ~ triglycerides (trystearine, tripalmitin, Lubritab®, Cutina HR, ...), ~ animal and vegetable fats (beeswax, carnauba wax, ~ and mixtures thereof. ■ => Family C: ♦ 1C ~ non- Water soluble cellulose, ethyl cellulose and / or cellulose acetate are especially preferred, - acrylic derivatives, polyvinylacetates, and mixtures thereof.

♦ 2C, water-soluble cellulose derivatives, polyacrylamides, poly-N-vinylamides, poly-N-vinyl lactams, polyvinyl alcohols (APV), polyoxyethylenes (POE), polyvinylpyrrolidones ( PVP) (the latter being preferred), and mixtures thereof;

♦ 3C-glycerol and its esters, preferably in the following subgroup: acetylated glycerides, glyceromonostearate, glyceryltriacetate, glyceroltributy rat, phthalates, preferably in the following subgroup: dibutylphthalate, diethylphthalate, dimethylphthalate, dioctylphthalate, - citrate in the following subgroup: acetyltributylcitrate, acetyltriethylcitrate, tributylcitrate, triethylcitrate, sebacates, preferably in the following subgroup: diethylsebate, dibutylsebacate, ~ adipates, ~ azelates, ~ benzoates, ~ vegetable oils, ~ fumarates preferably diethyl fumarate, malates, preferably diethylmalate, oxalates, preferably diethyloxalate, succinates, preferably dibutyl succinate, butyrates, cetyl alcohol esters, salicylic acid, triacetin, malonates, preferably diethylmalonate, cutin, castor oil (the latter being especially preferred), and mixtures thereof. ras;

♦ 4C - alkaline or alkaline earth salts of fatty acids, stearic and / or oleic acid being preferred, polyoxyethylenated oils, preferably polyoxyethylenated hydrogenated castor oil, polyoxyethylene polyoxypropylene copolymers, sorbitan esters polyoxyethylenates, polyoxyethylenated castor oil derivatives, stearates, preferably calcium, magnesium, aluminum or zinc, stearyl fumarates, preferably sodium, glycerol behenate, and mixtures thereof.

Preferably, the coating film is comprised of a single layer whose mass represents from 1 to 50% by weight, preferably from 5 to 40% by weight, of the total mass of the microcapsules.

According to a preferred feature of the invention, the liquid phase is aqueous, and most preferably it is comprised of at least 20% water, and even better at least 50% by weight of water.

Such a suspension according to the invention advantageously comprises: 30 to 95% by weight, preferably 60 to 85% by weight of liquid phase (advantageously water), 5 to 70% by weight, preferably 15 to 40% by weight. weight of microcapsules.

Advantageously, the amount of solvent liquid phase (preferably water) of the active principle (s) (excluding amoxicillin) is such that the proportion of the principle (s) dissolved active material (s) from the microcapsules is less than or equal to 15%, preferably 5% by weight with respect to the total mass of the active principle (s) contained within of the microcapsules.

According to a first embodiment of the invention, the liquid phase is at least in part, preferably fully saturated in active principle (s) (excluding amoxicillin) following the incorporation of microcapsules in that liquid phase.

According to this embodiment, saturation in active principle (s) is operated with the aid of the active principle (s) contained within the microcapsules.

According to a second embodiment of the invention, the liquid phase is at least in part, preferably fully saturated in active principle (s) (excluding amoxicillin) with the aid of principle (s). unencapsulated active material (s) prior to incorporation of the microcapsules into this liquid phase. This embodiment is especially interesting for administration of amoxicillin because it allows the association of an immediate release fraction and a modified release fraction.

In practice, this is the same as saturating the liquid phase in active principle (s) prior to the introduction of the microcapsules into the suspension, so that the active principle contained within the microcapsules contributes, or almost nothing, to the saturation of the phase. net. The diffusion of the active principle contained within the microcapsules is therefore suppressed or almost suppressed.

According to a preferred feature of the invention which enables such a liquid oral formulation to be fully effective, the microcapsules have a particle size of less than or equal to 1,000 microns, preferably between 200 and 800 microns, and most preferably between 200 and 600 microns. microns.

By "granulometry" is meant in the sense of the invention a proportion of at least 75% by weight of microcapsules having a diameter within the considered range of sieve size.

Still with a view to improving efficacy, the coating amount of the microcapsules advantageously represents from 1 to 50%, preferably 5 to 40%, of the weight of the coated microcapsules. This advantageous feature should be further acquired as microcapsules, because of their small size, have a large specific surface, which accelerates release.

In order to control the in vivo release of the active ingredient (s) in vitro, it is preferable according to the invention to employ a microcapsule coating film of the A or C family.

For further detailed data on the qualitative and quantitative plan for this family A coating composition, reference will be made to European patent EP-B-0 709 087, the contents of which are incorporated in this report by reference.

Another means of defining the liquid suspension according to the invention may be to show an in vitro release profile performed with the aid of a type II apparatus according to the European Pharmacopoeia 3rd edition in a pH phosphate buffer medium. 6,8, and at a temperature of 37 ° C, such that:> the PI ratio of active principle (s) released from the microcapsules during the first 15 minutes of the dissolution test is such that: PI <15 preferably PI <5,> release of the remaining active principle (s) into the microcapsules is effected at such a time that the release time of 50% by weight of PA ( ti / 2) is defined as follows (in hours): 0.5 <ti / 2 <30 preferably 0.5 <ti / 2 <20.

Still with regard to its in vitro dissolution properties, the suspension according to the invention is characterized by the fact that: - The initial in vitro release profile Pfi, performed just after the suspension of the microcapsules in the solvent phase ( preferably aqueous), with the aid of a Type II apparatus according to European Pharmacopoeia 3rd Edition in a pH 6.8 phosphate buffer medium at a volume of 900 ml at a temperature of 37 ° C C, - The in vitro release profile Pfio, performed 10 days after the suspension of the microcapsules in the solvent phase (preferably aqueous), with the aid of a type II apparatus, according to the European Pharmacopoeia 3rd edition in a phosphate buffer medium pH 6.8 at a temperature of 37 ° C are similar.

The release profiles compared according to the recommendations of the European Agency for the Evaluation of Medicinal Products - The Human Medicines Evaluation Age - 'The European Agency for the Evaluation of Medicinal Products (EMEA) - Human Medicines Evolution Unit - / Committee for Proprietary Medicinal Products (CPMP) - London, 29 July 1999 CPMP / QWP / 604/96: note for guidance on quality of modified release products: A: oral dosage forms B: transdermal dosage forms - secti-on I (quality) - Annex 3: Similarity factor Í2 ", lead to a value of similarity factors zz> 50 and can therefore be declared similar.

These advantageous features of the suspension according to the invention make it possible to easily orally administer high doses of active principle (s) without impairing the modified and possibly delayed mode of release of the active principle.

According to another of its advantageous physicochemical characteristics, the pH of the liquid suspension according to the invention may be either acidic or neutral.

It may be absolutely interesting to add to the suspension at least one rheology modifying agent. These may in particular be one or more "viscosifying" agents chosen from those commonly employed in the pharmaceutical industry and notably those disclosed in "Handbook of pharmaceutical excipients - 3rd Edition, Am. Pharmaceutical Association, Arthur KIBBE, 2000" , ISBN 0917330-96-X. Europe. 0-85369-381-1 ". Examples include water-soluble cellulose derivatives (hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose ...); - polyethylene glycol; - alginates and their derivatives; - carrageenans; - the agar; - gelatin; - maltodextrins; - polydextrose; - guar, carob, acacia, xanthan, gelane, ... - polyvinyl alcohol; - povidone; - pectins; - silica gel; - native, modified starches and derivatives thereof; - the dextrans - etc ...

It may also be wise to introduce into the suspension at least one solubility modifying agent of the active ingredient in the liquid-solvent (preferably aqueous) phase, such as salts, sugars, glycerol, etc. In fact, in the case of very active ingredients soluble, these solutes may limit the active principle output of the microcapsules by lowering the concentration to the saturation of the active principle in the aqueous phase.

In order to give the suspension all the qualities of an oral, swallowable, stable and appetizing galenic form, it is advantageous that it comprises at least one other additive chosen from the group comprising surfactants, dyes, dispersing agents, preservatives, flavor agents, aromas, sweeteners, antioxidants are their mixtures. Examples of such additives include those commonly employed in the pharmaceutical industry and notably those disclosed in the "Handbook of pharmaceutical excipients - 3rd Edition, Am. Pharmaceutical Association, Arthur KIBBE, 2000, ISBN 0917330-96-X. Europe. 0-85369-381-Γ or for emulsifiers, those described on page 5, lines 14 to 29 of EP-A-0 273 890, or for thickeners, those indicated on page 5 lines 19 and 20 of EP-A-0 601 508.

The active ingredients used for the preparation of the controlled release suspensions according to the invention may be chosen from at least one of the following broad varieties of active substances: antiulcer, antidiabetic, anticoagulant, antithrombic, hypolypemic, vasodilatory antianginal, antianginal, anti -hypertensors, vasoprotective agents, fertility promoters, uterine labor inducers and inhibitors, contraceptives, antibiotics, antifungals, antivirals, anticancer, anti-inflammatory drugs, analgesics, antiepileptics, antipar-kinsonians, neuroleptics, hypnotics, anxiolytics, psychostimulants, psychostimulants, psychostimulants, psychostimulants antidepressants, antitussives, antihistamines or antiallergics.

Without limitation, the invention applies more particularly to pharmaceutical active ingredients which should be administered orally at high doses, for example from 500 to 1000 milligrams or more, and to pediatric suspensions.

Preferably, the active ingredient (s) is chosen from the following compounds: pentoxifylline, Prazosin, Acyclovir, Nifedipine, Diltiazem, Naproxen, Ibuprofen, Flurbiprofen, Ketoprofen, Phenoprofen, Indomethacin, Diclofenac , fentiazac, estradiol valerate, metoprolol, sulpiride, captopril, cimetidine, zidovudine, nicardipine, terfenadine, atenoiol, salbuta-mol, carbamazepine, ranitidine, enalapril, simvastatin, fluoxetine, alprazo-lam, famotidyrone, famcidyrone wing, quinidine, perindopril, morphine, pentazocine, metformin, paracetamol, omeprazole, me-toclopramide, atenoiol, salbutamol morphine, verapamil, erythromycin, caffeine, furosemide, cephalosporins, montelucast, valaciclovir, salts of ascorepine, ascorbic acid, salts ciprofloxacin, vancomycin, aminoglycosides, penicillins (except amoxicillin) and mixtures thereof.

In another aspect, the present invention relates to a medicament characterized in that it comprises a modified release microcapsule suspension of active principle (s) as defined above.

More specifically, the invention also relates to a medicament, or more precisely a galenic conditioning, characterized in that it comprises a suspension preparation kit as defined above, which kit comprises: - microcapsules in substantially dry form containing the (ies) active principle (s) to allow saturation of the liquid phase in active principle (s) once the solid and liquid phases are brought into presence; - and / or a mixture of substantially dry microcapsules comprising the fair dose in principle (s) required for the modified release as well as a necessary and sufficient amount of non-active ingredient (s). coated (s) with immediate release to allow saturation of the liquid phase in active principle (s), after placement in the presence of saturation dose of active principle (s) and phase liquid; - and the liquid phase and / or at least part of the ingredients useful for its preparation and / or the suspension preparation protocol.

Such a presentation of the medicament according to the invention allows patients to easily prepare the modified release suspension in a stable form, especially in terms of modified release, and for at least several days. The patient is thus assured of having a drug which is easily orally administrable and perfectly therapeutic.

In the preparation of the microcapsules which constitute the solid phase of the suspension according to the invention, this sends to professionally accessible microencapsulation techniques, the main ones of which are summarized in the article by C.DUVERNEY and JP BENOIT in Tactualité chimique ", December 1986. More precisely, the technique considered is wrap-around microencapsulation, which leads to individualized "reservoir" systems as opposed to matrix systems.

For further details, reference will be made to the above-mentioned patent EP-B-0 953 359.

For the construction of the nucleus based on active principle (s) (excluding amoxicillin) of the microcapsules according to the invention, it is advantageous to use as particle size active particle size (s) of particle size. desired. These may be crystals of pure active principle (s) and / or which have been pre-treated by one of the conventional techniques in the art, such as granulation, in the presence of a small amount of at least a classical binding agent and / or an agent that modifies the intrinsic solubility characteristics of PA. The invention will be better understood in terms of its composition, its properties and its achievement by reading the examples below, which are given by way of illustration only and which highlight the embodiments and advantages of the invention.

Description of figures: • Figure 1 shows the initial dissolution profiles and after 10 days of storage of the suspension according to example 1, in% dissolved (D) as a function of time (t) in hours. • Figure 2 shows the initial dissolution profiles and after 19 days of storage of the suspension according to example 2, in% dissolved (D) as a function of time (t) in hours. • Figure 3 shows the initial dissolution profiles and after 12 days of storage of the suspension according to example 3, in% dissolved (D) as a function of time (t) in hours. This suspension combines 29% free Metformin and 71% encapsulated Metformin.

Example 1 Preparation of acyclovir microcapsules: 1000 g acyclovir and 30 g povidone® are dry blended for 5 minutes. The mixture is granulated with water. The pellets are dried at 40 ° C in a ventilated oven, and then calibrated in a 500 pm grid. The 300-500 pm fraction is selected. 700 g of granules obtained above are coated with 27.3 g of ethylcellulose, 3.7 g of castor oil, 3.7 g of magnesium stearate and 2.9 g of povidone® dissolved in an acetone / iso-propanol mixture. 60/40 m / m in a Glatt GPC-G1 fluidized bed apparatus. Product temperature: 40 ° C.

Suspension preparation: 0.58 g of microcapsules obtained above are placed in 37 ml of pH 6.8 phosphate buffer.

Test: The above suspension is stored for 10 days at room temperature. At the end of 10 days, the suspension is analyzed under dissolution. Type II apparatus according to European Pharmacopoeia 3rd edition, phosphate buffer medium, pH 6.8, volume 900 ml, temperature 37 ° C, stirring vane 100 rpm, UV detection 252 nm. The result is shown in the attached figure 1. It is evident that the profiles are identical: similarity factor fi greater than 50. The microcapsules remain high performance in aqueous suspension.

Example 2 Preparation of spironolactone microcapsules: Step 1: Granulated 45 g spironolactone, 25 g PEG 40-hydrogenated castor oil and 30 g Povidone are previously solubilized in a water / acetone / isopropanol mixture (5/57 / 38 m / m). This solution is then sprayed onto 800 g of cellulose spheres (diameter 300 to 500 μιτι) in a Glatt GPC-G1 fluidized bed apparatus.

Step 2: Coating 50 g of granules obtained above are coated with 1.44 g of ethylcellulose, 0.16 g of castor oil, 0.64 g of poloxamer 188 and 0.96 g of povidone dissolved in an acetone / isopropanol (60/40 m / m) in a miniGlatt fluidized bed apparatus.

Suspension preparation: 0.07 g of microcapsules obtained above are placed in 0.165 ml of pH 6.8 phosphate buffer.

Test: The above suspension is stored for 19 days at room temperature. At the end of 19 days, the suspension is analyzed under dissolution. Type II apparatus according to the European Pharmacopoeia 3rd edition, pH 6.8 phosphate buffer medium, volume 1000 ml, temperature 37 ° C, stirring vane 100 rpm, UV detection 240 nm. The result is shown in the attached figure 2. It is evident that the profiles are identical: similarity factor h greater than 50. The microcapsules remain in high performance in aqueous suspension.

Example 3 Preparation of Metformin Microcapsules: 740 g of Metformin crystals (200-500 pm fraction) are coated with 182.4 g of ethylcellulose, 26 g of castor oil, 26 g of magnesium stearate and 20.8 g of povidone® dissolved in a 60/40 m / m acetone / isopropanol mixture in a Glatt GPG-G1 fluidized bed apparatus. Product temperature: 40 ° C.

Suspension preparation (29% free form and 71% encapsulated form): 50 g of microcapsules obtained above are dry mixed with 15 g of Metformin crystals and 0.7 g of xanthan gum in a 100 ml glass vial . 34.3 g of purified water is then added to the powder mixture. After manual shaking, a very slowly settling slurry is obtained. The total titer in metformin in the suspension is 0.52 g / ml.

Stability test: The above suspension is stored for 12 hours at room temperature. At the end of 12 days, the suspension is analyzed under dissolution. Type II apparatus according to European Pharmacopoeia 3rd edition, phosphate buffer medium with pH 6.8, volume 900 ml, temperature 37 ° C, stirring vane 100 rpm, UV detection 232m. The result is shown in the attached figure 3. It is evident that the profiles are identical: f2 similarity factor greater than 50. The microcapsules remain in high performance in aqueous suspension.

Homogeneity test: The above suspension is stirred by hand and then with the aid of a graduated syringe 6 5 ml samples are taken. The metformin content of each collection is determined by HPLC and reported below: It is found that the collections are very homogeneous and that the dosage corresponds to the expected value of 2.60 g for 5 ml.

Such a formulation may therefore be administered without risk of over or under dosing.

Claims (16)

1. Suspension of microcapsules in an aqueous liquid phase allowing modified release of at least one active ingredient (excluding amoxicillin) and intended for oral administration, characterized in that: oo comprises a plurality of microcapsules, each containing - consisting of a nucleus comprising at least one active ingredient (excluding amoxicillin) and a coating film that: s is applied to the nucleus, S controls the modified release of active ingredient (s), and > at least one film-forming insoluble polymer in the gastrointestinal tract fluids present in an amount of from 50 to 90% by dry weight, preferably from 50 to 80% by dry weight, based on the total weight of the coating, and selected from the group consisting of water-insoluble cellulose derivatives, acrylic derivatives and polyvinyl acetates, at least one water-soluble polymer present in an amount of 2 to 25% by dry weight, preferably 5 to 15% by dry weight, based on the total weight of the coating composition, and selected from the group consisting of water-soluble cellulose derivatives, alcohols polyvinyl (PVA) and polyoxyethylenes (POE), at least one plasticizer present in an amount of 2 to 20% dry weight, preferably 4 to 15% dry weight, based on the total weight of the coating composition, and selected glycerol esters, glycerol esters, phthalates, citrates, sebacates, adipates, azelates, benzoates, vegetable oils, fumarates, malates, oxalates, succinates, butyrates, cetyl alcohol esters, triacetin and malonates; and o the initial in vitro release profile obtained shortly after suspension of the microcapsules in the solvent phase and the initial in vitro release profile obtained 10 days after suspension of the microcapsules in the solvent phase using a type II apparatus according to The 3rd edition of the European Pharmacopoeia, in a phosphate buffered medium with pH 6.8, at a temperature of 37 ° C, are similar. Suspension according to claim 1, characterized in that: at least one film-forming polymer insoluble in the gastrointestinal tract fluids is selected from ethyl ethyl cellulose and cellulose acetate; and the at least one plasticizer is selected from acetylated glycerides, glycerol monostearate, glyceryl triacetate and glycerol tributyrate; dibutyl phthalate, diethyl phthalate, dimethyl phthalate and dioctyl phthalate; acetyltributyl citrate, acetyltriethyl citrate, tributyl citrate and triethyl citrate; diethyl sebacate and dibutyl sebacate; diethyl fumarate; diethyl malate; diethyl oxalate; dibutyl succinate; diethyl malonate; and castor oil. Suspension according to claim 1 or 2, characterized in that the at least one water-soluble polymer is a water-soluble cellulose derivative selected from hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Suspension according to any one of claims 1 to 3, characterized in that the coating film further comprises at least one compound selected from the group consisting of: alkali metal or alkaline earth metal fatty acid salts preferably stearic acid and / or oleic acid; o polyoxyethylenated oils, preferably polyoxyethylenated hydrogenated castor oil; o polyoxyethylene-polyoxypropylene copolymers; o polyoxyethylenated sorbitan esters; o polyoxyethylenated castor oil derivatives; o stearates, preferably calcium, magnesium, aluminum or zinc stearates; o stearyl fumarates, preferably sodium stearyl fumarates; and 00 glycerol beenate. Suspension according to any one of claims 1 to 4, characterized in that the coating film consists of a single layer. Suspension according to claim 1, characterized in that it contains 30 to 95 wt.%, Preferably 60 to 85 wt.%, Of liquid phase; and 5 to 70% by weight, preferably 15 to 40% by weight, of microcapsules. Suspension according to claim 1, characterized in that the amount of solvent liquid phase for active principle (s) is such that the proportion of dissolved active principle (s) which come from the microcapsules is less than or equal to 15 wt.%, preferably less than or equal to 5 wt.%, based on the total mass of active ingredient (s) contained within the microcapsules. Suspension according to Claim 1, characterized in that the liquid phase is at least in part, preferably fully saturated with active principle (s) following the incorporation of the microcapsules in this liquid phase. Suspension according to any one of claims 1 to 8, characterized in that the microcapsules have a particle size of less than or equal to 1,000 microns, preferably from 200 to 800 microns, and more preferably from 200 to 600 microns. . Suspension according to any one of claims 1 to 9, characterized in that the coating film represents from 1 to 50% by weight, preferably from 5 to 40% by weight, of the total mass of the coated microcapsules. Suspension according to Claim 10, characterized in that it has an in vitro release profile obtained using a type II apparatus according to the 3rd edition of the European Pharmacopoeia in a phosphate buffered medium with a pH of 6; 8 and at a temperature of 37 ° C, wherein: o the proportion of PI of active principle (s) released during the first 15 minutes of the dissolution test is such that PI <15, preferably PI <5; 00 the remaining active principle (s) (PA) is released for a period such that the 50% by weight of PA release time (t-1/2) ) is defined as follows (in hours): 0.5 <t / 2 <30, preferably 0.5 <t-1/2 <20. Suspension according to any one of claims 1 to 11, characterized in that it comprises at least one rheology modifying agent. Suspension according to any one of claims 1 to 12, characterized in that it comprises at least one solubility modifying agent of the active principle (s) in the solvent (preferably aqueous) liquid phase. Suspension according to any one of claims 1 to 13, characterized in that it contains at least one additive selected from the group comprising surfactants, colorants, dispersants, preservatives, flavor enhancers, flavorings, sweeteners, anti-oxidants and your mixtures. Suspension according to any one of claims 1 to 14, characterized in that the active ingredient (PA) is selected from the following compounds acyclovir, spironolactone and metformin. Suspension according to any one of claims 1 to 14, characterized in that the active ingredient (PA) is ibuprofen.