HK1079448B - Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s) - Google Patents

Description

Oral suspension of microcapsules of active ingredients

The present invention relates to the field of modified release of pharmaceutically active ingredients which do not include amoxicillin. In the present specification, the expression "modified release" optionally means that the release of the active ingredient begins once the galenic dosage form is in contact with its dissolution medium (in vivo or in vitro), or that the release of the active ingredient does not begin until a predetermined period of time (for example after 0.5 to several hours). The time required to release 50% of the active ingredient according to the invention is generally a few hours and can be extended, for example from 0.5 to 30 hours.

More specifically, the invention relates to liquid pharmaceutical formulations for oral administration of modified release active ingredients (excluding amoxicillin). These formulations consist of a suspension or dispersion of microcapsules, each of which is formed by a core comprising amoxicillin and a coating surrounding the core. The microcapsules that comprise the dispersed phase of the suspension are designed to provide modified release of the active ingredient (excluding amoxicillin).

Even more particularly, the invention relates to aqueous "multivesicular" suspensions of active principles (excluding amoxicillin) for oral administration, which remain stable throughout the treatment and enable a modified release of the active principles (excluding amoxicillin). These suspensions are of particular value in the following cases:

-forming a dosage form for modified release of the active ingredient at a high therapeutic dose (e.g. 500-;

liquid pediatric or geriatric dosage forms with modified release of the active ingredient (e.g. a re-dissolvable oral suspension in sachets or vials);

-taste masking and/or protection of sensitive active ingredients.

The invention further relates to a specific method for the preparation of microcapsules to be suspended in water.

Oral pharmaceutical formulations for modified release of active ingredients are well known.

Some of these formulations consist of tablets comprising a therapeutically active core coated with a non-digestible material of different thickness.

More recently, microcapsules or microspheres comprising a core of active ingredient coated with layers having different permeability or solubility have appeared. For example, these microcapsules/microspheres are placed into capsules to form a galenic system for the modified release of the active ingredient.

Most modified release pharmaceutical dosage forms comprising a coated core of an active ingredient are solid dosage forms: tablets, capsules, microspheres or microcapsules.

As an example of microcapsules in dry form, mention may be made in particular of the patent EP-B-0709087, in which a (pharmaceutical or food) galenic system is described, preferably in the form of tablets, advantageously disintegrating tablets, or in the form of powders or capsules, characterized in that it comprises reservoir-type microcapsules containing at least one pharmaceutical and/or nutraceutical active ingredient (AP), chosen in particular from antibiotics, and intended for oral administration, characterized in that:

they consist of AP granules each coated with a film coating consisting of:

1-at least one film-forming polymer (P1) insoluble in gastrointestinal liquids, in a quantity of from 50 to 90% by dry weight relative to the total weight of the coating composition, and consisting of at least one water-insoluble cellulose derivative, particularly preferably ethylcellulose and/or cellulose acetate;

2-at least one nitrogen-containing polymer (P2) in an amount of 2 to 25% by dry weight relative to the total weight of the coating composition and consisting of at least one polyacrylamide and/or poly-N-vinylamide and/or poly-N-vinyllactam, polyacrylamide and/or polyvinylpyrrolidone being particularly preferred;

3-at least one plasticizer, in an amount of 2-20% by dry weight relative to the total weight of the coating composition, and consisting of at least one of the following compounds: glycerides, phthalates, citrates, sebacates, cetyl esters, castor oil, salicylic acid and keratan, castor oil being particularly preferred;

4-and at least one surfactant and/or lubricant, in an amount of 2 to 20% by dry weight relative to the total weight of the coating composition, and selected from: anionic surfactants, preferably alkali or alkaline earth metal salts of fatty acids (preferably stearic acid and/or oleic acid); and/or nonionic surfactants, preferably polyethoxylated sorbitan esters and/or polyethoxylated castor oil derivatives; and/or lubricants, such as stearates, preferably calcium, magnesium, aluminum or zinc stearate, or stearyl fumarate, preferably sodium stearyl fumarate; and/or glycerol behenate;

the agent may comprise only one of the above products or a mixture of the above products;

they have a particle size of 50-1000 microns;

-and they are designed to be able to stay in the small intestine for a period of at least about 5 hours, thereby allowing AP to be absorbed during at least part of the retention time in the small intestine.

The said reference relates only to dry pharmaceutical dosage forms based on microcapsules, but no liquid pharmaceutical dosage forms based on microcapsules are mentioned.

These modified release solid pharmaceutical formulations are not always advantageous, especially when they are administered to very small children or elderly patients who have difficulty swallowing.

This occurs when the active ingredient must be administered orally at high doses, e.g. 500 and 1000mg or more, e.g. when the active ingredient is metformin. Obviously such solid galenic systems are not suitable because they are too large and therefore extremely difficult to swallow, especially by young children or elderly people. This may be the reason for poor patient compliance and thus compromise the success of the treatment.

Also, in the case of pediatric dosage forms where the therapeutic dose must be appropriate for the weight of the child, the suspension of the invention is suitable for vials already existing with syringes with kg scales, thus eliminating the need to develop new devices. Thus, modified release dosage forms that are rarely used today become available with the present invention. Such dosage forms have the advantage of reducing the number of daily unit doses and optimizing the therapeutic efficacy between successive dosage units (e.g. in terms of antibiotics, anti-inflammatories, cardiovascular therapy, etc.). Thus, easily prepared controlled release liquid pharmaceutical formulations represent a significant advance.

In this case, it is even more advantageous to use a modified release galenic system consisting of a plurality of microcapsules having a diameter of less than 1000 microns. In fact, in these systems, the active ingredient to be administered is distributed in a large number of microcapsules (typically 10,000 capsules for a 500mg dose) and therefore has the following intrinsic advantages:

the use of mixtures of microcapsules with different modified release profiles results in release profiles with several release pulses, or ensures a constant plasma concentration level of AP by appropriate adjustment of the different fractions.

Avoiding tissue contact with high dose AP (dose dumping). Each microcapsule contains substantially only a greatly reduced amount of active ingredient, thereby avoiding the risk of tissue damage due to local concentrations of aggressive active ingredients that are too high.

It is possible to combine several galenic forms (immediate release or modified release) containing one or more active ingredients in these "multivesicular" systems.

For high dose active ingredients or paediatric applications, it is known that liquid multiparticulate galenic dosage forms, or more specifically colloidal suspensions, are preferred over solid dosage forms for oral administration.

Liquid suspensions for modified release of active ingredients are difficult to produce. The main difficulties to be overcome are: the release of the active ingredient into the liquid phase is avoided during storage of the suspension, while it is modified once it has entered the gastrointestinal tract. This is particularly difficult to achieve because the active ingredient needs to be stored in the liquid for an extremely long time compared to the release time required in the gastrointestinal fluids. Furthermore, its extended residence time in the liquid phase during storage must not interfere with the modified release system, i.e. the point at which the active ingredient release profile is reduced and the active ingredient release time is reduced.

Furthermore, for liquid formulations to be fully effective, the following are known to be important:

microcapsules are extremely small (< 1000 microns);

and limits the weight fraction of coating excipients, which is more difficult to achieve in all cases, since the microcapsules have a large specific surface area due to their small size, thus accelerating the release.

With regard to the prior art relating to oral liquid pharmaceutical dosage forms for the modified release of active ingredients, mention should first be made of french patent applications FR- A-2634377; said reference discloses new modified release pharmaceutical dosage forms based on resin/active ingredient complexes coated with an ionomer of opposite polarity to the resin and thus fixed by ionic bonding. The active ingredient is also ionic and has an opposite polarity to the resin. The latter may be sodium polystyrene sulfonate, the ionic coating polymer is selected from acrylic acid and methacrylate polymersThe resin is immersed in an aqueous solution of the active ingredient. The resin particles impregnated with the active ingredient are then coated with an organic solvent solution of an ionic polymer. The resulting microcapsules can be converted into oral suspensions (especially example 2). The use of ionic resins and ionic coating polymers limits their potential for use on ionic active ingredients.

US-B-4,999,189 and US-B-5,186,930 relate to liquid pharmaceutical compositions comprising an ion exchange resin/active ingredient complex suspended in a liquid phase. Administering the tree with a first layer of a high melting pharmaceutically acceptable waxThese granules of the lipid/active ingredient complex are coated and coated with a pharmaceutically acceptable water-insoluble polymer (ethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, or mixtures thereof,Etc.) belonging to the second layer. A plasticizer such as dibutyl sebacate is introduced into this outer layer, which is the second layer. The active ingredient is immobilized by ionic bonding with the ion exchange resin. The liquid phase consists of glucose syrup with a high fructose content and several other components, such as glycerol or propylene glycol.

US-B-5,186,930 differs from the first US patent in that it produces a sufficient amount of first layer (wax) to prevent swelling and cracking of the resin/active ingredient composite particles.

These us patents do not provide any data for evaluating the quality of the modified release of the active ingredient. Furthermore, the use of ion exchange resins as active ingredient supports is rather inconvenient and limited due to the various active ingredients involved. Furthermore, such galenic systems do not provide any convincing stability of the active ingredient to the modified release characteristics and protection thereof.

Aqueous suspensions of microcapsules of active ingredients (e.g. theophylline) having modified release characteristics of the active ingredient (e.g. 12 hours) are disclosed in PCT patent application WO-A-87/07833 and patent US-B-4,902,513. These suspensions are prepared by saturating the aqueous phase with the active ingredient before mixing the active ingredient microcapsules into this phase. The composition of the coating material for microcapsules that allows a modified release of the active ingredient is not described in said reference. Currently, such coating compositions are the determining factor in ensuring that the modified release profile of the microcapsules is maintained after storage in the aqueous phase. It appears that there is no disclosure in the said technical proposal of a way to solve the dual problem of producing a liquid suspension of modified release microcapsules without interfering with the stability of the modified release profile of the active ingredient after the microcapsules have been stored in the liquid phase.

European patent application EP-A-0601508 relates to aqueous suspensions of naxopren for oral administration with modified release profile. The suspension comprises coated particles of naxopren suspended in a syrupy aqueous liquid phase. The technical problem relating to the present invention is to propose a modified release dosage form of naxopren containing a dose of 1000mg and capable of being administered in a single daily dosage unit.

The microparticles consist of naxopren, polyvinylpyrrolidone and lactose (90-300 μm). The coating layer is made of 4 layers. The first layer comprises diethylcellulose/diethylphthalate/polyethylene glycol. The second layer is based on an EUDRAGIT (meth) acrylate/(meth) acrylic acid copolymer. The third layer comprises glyceryl stearate/wax/fatty alcohols and the fourth layer consists of a cellulose acetate/phthalate based enteric coating layer. naxopren was modified in release within 24 hours.

Example 22 of said European patent application EP-A-0601508 contains an indication of the stability of the release profile after 30 days of storage of the liquid suspension.

One disadvantage of this suspension derives from the enteric layer, which prohibits the use of a neutral pH for the suspension, since the layer is designed to disintegrate and become liquid at a neutral pH. Another disadvantage of this enteric layer is that it blocks the release of the active ingredient in the stomach at acidic pH. Currently, for AP, where the absorption window is located in the upper part of the gastrointestinal tract, it is often advantageous to have the active ingredient released in the stomach in order to increase bioavailability. Furthermore, the problem faced by this multi-layer solution is extremely complex and specific to naxopren.

PCT patent application WO-A-96/01628 discloses A liquid pharmaceutical formulation for oral administration with A modified release profile (12 hours) of the active ingredient consisting of moguisteine. The object was to provide a modified release liquid formulation of moguisteine which is easy to measure and swallow, has a release time which avoids multiple dosage units, is stable for a certain period of time in aqueous suspension and is palatable to facilitate compliance, without its manufacture involving the use of toxic substances such as solvents. To achieve this object, the invention of PCT patent application WO-A-96/01628 provides A suspension of moguisteine microcapsules (90-300 μm) in A weakly hydrated liquid phase (essentially based on sorbitol and glycerol), wherein the moguisteine microcapsules are coated with A first hydrophilic layer consisting of cellulose acetate/phthalate and diethyl phthalate, A second hydrophobic layer comprising glyceryl stearate/wax/fatty alcohols and A third hydrophilic layer identical to the first layer.

Such multi-layered dosage forms are extremely complex to prepare and are specific, in particular, to moguisteine.

In the present state of the art, the main object of the present invention is to provide aqueous suspensions of microcapsules of active ingredients (excluding amoxicillin) for oral administration according to a modified release profile, wherein the coating layer of the microcapsules is designed such that the release profile is not disturbed and is independent of the immersion time of the microcapsules in the liquid (preferably aqueous) phase. Thus, it is possible to prevent the active ingredient contained in the microcapsules from escaping from the liquid phase during the entire storage of the suspension, while allowing a modified release of the active ingredient once it has entered an environment suitable for causing the release, i.e. in the gastrointestinal tract in vivo, and in vitro under the conditions of a dissolution test carried out just after the microcapsules have been suspended in a solvent (preferably aqueous) phase, which is subjected to the dissolution test under the following conditions: a type II instrument was used, according to European pharmacopoeia, 3 rd edition, in a volume of 900ml in a phosphate buffer medium at pH6.8, at a temperature of 37 ℃.

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

It is another object of the present invention to provide an aqueous liquid suspension of microcapsules of an active ingredient (excluding amoxicillin) in which the fraction of dissolution originating from the microcapsules is less than or equal to 15% and preferably 5% of the total weight of active ingredient present in the microcapsules.

It is another object of the present invention to provide an aqueous liquid suspension of microcapsules of an active ingredient (excluding amoxicillin) wherein one part of the active ingredient is in immediate release form and another part of the active ingredient is in modified release form (microcapsules).

It is another main object of the present invention to provide an aqueous suspension of microcapsules for modified release of active principles (excluding amoxicillin) which allows the active principle to be released according to a release profile which is not reduced by ageing of the suspension.

Another main object of the present invention is to provide an aqueous suspension of microcapsules, made up of individually coated granules of the active principle (excluding amoxicillin) and capable of releasing the active principle according to a prolonged and/or optionally delayed profile, such that the release half-life t_1/2Is 0.5-30 hours.

It is another object of the present invention to provide an oral galenic form formed as a liquid and consisting of a large number (for example of the order of several thousand) of microcapsules, this multiplicity statistically ensuring a good reproducibility of the transport kinetics of AP throughout the gastrointestinal tract, thus improving the control of bioavailability and thus efficacy.

It is a primary object of the present invention to provide an oral liquid galenic form made of multiple coated microcapsules which avoids the use of large amounts of coating material, wherein the weight fraction of coating material is comparable to the weight fraction of the whole form.

It is another principal object of the present invention to provide a modified release aqueous suspension wherein the active ingredient (excluding amoxicillin) is in the form of a plurality of granules each coated with microcapsules and several active ingredients with different release times can be mixed.

Another main object of the present invention is to provide the use of a suspension of microcapsules, preferably aqueous, consisting of granules of active principle(s) (not including amoxicillin) each coated to determine a modified release of the active principle(s) independent of the microcapsule storage in a liquid dosage form in the form of such a suspension, as a means of treating human or veterinary diseases.

Another main object of the present invention is to provide a medicament based on an aqueous suspension of microcapsules preferably consisting of granules of active principle (not including amoxicillin), wherein the active principle (not including amoxicillin) is individually coated to determine a modified release of the active principle, while the modified release profile is not affected by the storage of the microcapsules in a liquid dosage form in the form of such a suspension.

As all the above objectives have been set, the inventors have succeeded in developing a multivesicular galenic system, preferably in the form of an aqueous suspension for modified release of the active principle (excluding amoxicillin), which:

-does not reduce the optionally delayed, modified release profile;

and is stable, easy to prepare, economical and effective.

To achieve the object, the present inventors propose:

-selecting a coating composition that is entirely specific to a particular microcapsule;

and suspending the microcapsules in a liquid phase saturated with the active ingredient (preferably aqueous), or capable of being saturated with the active ingredient upon contact with the microcapsules, preferably aqueous, the amount of solvent used being limited, but sufficient to make the suspension easy to swallow.

The present invention, which meets the above objects, relates in particular to a suspension of microcapsules in an aqueous liquid phase, which allows modified release of at least one active principle (excluding amoxicillin) and is intended for oral administration, characterized in that:

■ it comprises a plurality of microcapsules each consisting of a core containing at least one active principle (excluding amoxicillin) and a film coating:

applied on the core;

controlled modified release of the active ingredient;

and has a composition corresponding to one of the following groups A, B and C:

group A

1A-at least one film-forming polymer insoluble in the gastrointestinal liquids (P1), in a content ranging from 50 to 90% and preferably from 50 to 80% by dry weight relative to the total weight of the coating composition; and consists of at least one water-insoluble cellulose derivative;

2A-at least one nitrogen-containing polymer (P2) in an amount of 2-25% by dry weight, preferably 5-15% by dry weight, relative to the total weight of the coating composition; and consists of at least one polyacrylamide and/or poly-N-vinylamide and/or poly-N-vinyllactam;

3A-at least one plasticizer in an amount of 2-20% by dry weight, preferably 4-15% by dry weight, relative to the total weight of the coating composition; and consists of at least one of the following compounds: glycerides, phthalic acids, citric acid esters, sebacates, cetyl esters and castor oil;

4A-at least one surfactant and/or lubricant in an amount comprised between 2 and 20% by dry weight and preferably between 4 and 15% by dry weight of the total weight of the coating composition and chosen from anionic surfactants and/or nonionic surfactants and/or lubricants; the agent may comprise only one of the above products or a mixture of the above products;

group B

1B-at least one hydrophilic polymer bearing groups which ionize at neutral pH and preferably from cellulose derivatives;

2B-at least one hydrophobic compound different from A;

group C

1C-at least one film-forming polymer insoluble in gastrointestinal fluids;

2C-at least one water-soluble polymer;

3C — at least one plasticizer;

4C-optionally, at least one surfactant/lubricant, preferably selected from the group of:

-an anionic surfactant;

-and/or a non-ionic surfactant;

■ and saturating the liquid phase with the active ingredient or with the active ingredient once in contact with the microcapsules.

The expression "microcapsules of active ingredients" in the present description refers to microcapsules whose core comprises one or more active ingredients and optionally at least one excipient.

This suspension of the invention makes it possible to overcome two main obstacles to the production of aqueous suspensions of microcapsules consisting of individually coated active principle microparticles and capable of modifying the release of the latter, these two obstacles being as follows:

a) limiting the immediate release of the fraction of active ingredient from the microcapsules to a value of less than 15% and preferably 5% of the total weight of active ingredient used in the microcapsules;

b) a modified release system is obtained which is sufficient to facilitate avoiding any alteration or reduction of the release profile of the active ingredient during storage of said aqueous suspension.

Furthermore, such suspensions can facilitate the oral administration of drugs with high therapeutic doses, especially with respect to elderly and children, with a significant increase in compliance with and success of treatment.

Furthermore, for AP with a limited absorption window, as described in the introductory part of the present description, a modified release dosage form in the form of a multiparticulate microcapsule is particularly advantageous.

In a preferred embodiment of the invention, groups A, B and C comprising the coating composition are selected from the following:

group A

1A-ethylcellulose and/or cellulose acetate;

2A-polyacrylamide and/or polyvinylpyrrolidone;

3A-castor oil;

alkali metal or alkaline earth metal salts of 4A-fatty acids (preferably stearic acid and/or oleic acid); polyethoxylated sorbitan esters; polyethoxylated castor oil derivatives; stearates, preferably calcium stearate, magnesium stearate, aluminum stearate or zinc stearate; stearyl fumarate, preferably sodium stearyl fumarate; or glyceryl behenate;

may be either alone or in admixture with one another;

group B

◆1B

-cellulose acetate-phthalate;

-hydroxypropyl methylcellulose phthalate;

hydroxypropyl methylcellulose acetate-succinate;

copolymers of (meth) acrylic acid and (meth) acrylic acid alkyl (meth) estersS or L);

-and mixtures thereof;

◆2B

hydrogenated vegetable wax (P60、116)；

Triglycerides (tristearin, tripalmitin,Cutina HR, etc.);

animal and vegetable fats (beeswax, carnauba wax, etc.);

-and mixtures thereof.

Group C

◆1C

Water-insoluble cellulose derivatives, particularly preferably ethyl vitamin and/or cellulose acetate;

-acrylic acid derivatives;

-polyvinyl acetates;

-and mixtures thereof;

◆2C

-a water-soluble cellulose derivative;

-polyacrylamides;

poly-N-vinylamides;

poly-N-vinyl lactams;

polyvinyl alcohols (PVA);

polyoxyethylenes (POE);

-polyvinylpyrrolidones (PVP) (this class of materials is preferred);

-and mixtures thereof;

◆3C

glycerol and esters thereof, preferably from the following subgroups: acetylated glycerides, glycerol monostearate, glycerol triacetate and glycerol tributyrate;

esters of phthalic acid, preferably from the following subgroups: dibutyl phthalate, diethyl phthalate, dimethyl phthalate and dioctyl phthalate;

citric acid esters, preferably from the following subgroups: acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate, and triethyl citrate;

-sebacates, preferably from the following subgroups: diethyl sebacate and dibutyl sebacate;

adipates;

-azelaic acid esters;

-benzoates;

-vegetable oil;

esters of fumaric acid, preferably diethyl fumarate;

-esters of malic acid, preferably diethyl malate;

esters of oxalic acid, preferably diethyl oxalate;

-succinic acid esters, preferably dibutyl succinate;

-butanoates;

-cetyl esters;

-salicylic acid;

-triacetin;

malonic esters, preferably diethyl malonate;

-keratan;

castor oil (particularly preferred);

-and mixtures thereof;

◆4C

alkali or alkaline earth metal salts of fatty acids (preferably stearic acid and/or oleic acid);

-polyethoxylated oils;

-polyoxyethylene/polyoxypropylene copolymers;

-polyethoxylated sorbitan esters;

-polyethoxylated castor oil derivatives;

-stearates, preferably calcium stearate, magnesium stearate, aluminium stearate or zinc stearate;

-stearyl fumarate, preferably sodium stearyl fumarate;

-glyceryl behenate;

-and mixtures thereof.

Preferably, the film coating consists of a single layer, the weight of which is 1-50% and preferably 5-40% of the total weight of the microcapsule. .

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

The suspension of the invention advantageously contains:

30-95% by weight and preferably 60-85% by weight of a liquid phase (advantageously water);

-and 5-70% by weight and preferably 15-40% by weight of microcapsules.

Advantageously, the amount of solvent liquid phase (preferably water) of the active principle (excluding amoxicillin) is such that the proportion of dissolved active principle originating from the microcapsules is less than or equal to 15% by weight, and preferably less than or equal to 5% by weight, based on the total amount of active principle contained in the microcapsules.

In a first embodiment of the invention, after incorporation of the microcapsules into the liquid phase, the liquid phase is at least partially and preferably fully saturated with the active ingredient.

In this embodiment, it is the saturated liquid phase of the active ingredient contained in the microcapsules.

In a second embodiment of the invention, the liquid phase is at least partially and preferably completely saturated with active ingredient(s) (excluding amoxicillin) by means of uncoated active ingredient(s) before incorporation of the microcapsules into said liquid phase. This embodiment is of particular value for amoxicillin administration in that it enables the immediate release fraction to be combined with the modified release fraction.

In practice, the amount of liquid phase saturated with the active ingredient prior to introduction of the microcapsules into the suspension is such that the active ingredient contained in the microcapsules does not or does not actually play a part in the process of saturating the liquid phase. The diffusion of the active ingredient contained in the microcapsules is thus inhibited or practically inhibited.

A preferred feature of the invention enables such liquid oral formulations to be fully effective, the microcapsules having a particle size of less than or equal to 1000 microns, preferably 200-800 microns and particularly preferably 200-600 microns.

The "particle size" of the present invention is understood to mean that at least 75% by weight of the microcapsules have a diameter between the sieve sizes.

Furthermore, in order to improve the efficacy, the coating material for the microcapsules advantageously represents 1 to 50% and preferably 5 to 40% of the total weight of the coated microcapsules. This advantageous feature is that all microcapsules have a large specific surface area due to their small size.

In order to control the in vivo and in vitro release of the active ingredient, the present invention preferably uses a film coating material belonging to group a or C for the microcapsules.

For more specific qualitative and quantitative information on such group A coating compositions, reference may be made to European patent EP-B-0709087, the contents of which forming part of the specification of this publication are incorporated by reference.

Definition another possible form of the liquid suspension of the invention consists in: an in vitro release profile was obtained using a type II instrument, according to european pharmacopoeia version 3, in phosphate buffered medium ph6.8 and at 37 ℃, such that:

the proportion of active ingredient released in 15 minutes before the dissolution test PI.ltoreq.15, preferably PI.ltoreq.5;

releasing the remaining active ingredient of the microcapsules during a period of time such that 50% by weight of the AP is released (t)_1/2) As defined below (in hours): t is more than or equal to 0.5_1/230 or less, preferably 0.5 or less t_1/2≤20，

The suspension of the invention is characterized with respect to in vitro dissolution profile by:

-an initial in vitro release profile Pfi obtained in accordance with european pharmacopoeia version 3 in phosphate buffered medium at ph6.8 and at 37 ℃ using a type II instrument, just after suspension of the microcapsules in a solvent (preferably aqueous) phase;

10 days after suspension of the microcapsules in the solvent (preferably aqueous) phase, an in vitro release profile Pf, obtained using a type II instrument, in phosphate buffered medium at ph6.8 and at 37 ℃, according to european pharmacopoeia version 3₁₀；

The two in vitro release profiles were similar.

The release profiles were compared as suggested in the following documents: european office drug product evaluation (EMEA) -part of human drug evaluation-/patent drug product Committee (CPMP) -London, 29 months 7 1999, CPMP/QWP/604/96: attention is directed to the instructional opinions on improving the quality of the released product: a: an oral dosage form; b:transdermal dosage form-chapter 1 (quality) -appendix 3: similarity factor f₂To obtain a similarity factor f₂Values > 50 and can therefore be considered similar.

These advantageous properties of the suspensions according to the invention enable the oral administration of high doses of active ingredients without difficulty and without impairing the modified release and optionally the sustained release manner of the active ingredient.

According to another advantageous physico-chemical characteristic of the invention, the pH of the liquid suspension according to the invention may optionally be acidic or neutral.

It may be of great value to add at least one rheology modifier to the suspension. In particular, it may be one or more selected "viscosity agents" -these are conventional in the pharmaceutical industry and are disclosed inter alia in the Handbook of pharmaceutical excipients (Handbook of pharmaceutical excipients), am. pharmaceutical Association, Arthur H. KIBBE, 2000, ISBN0917330-96X. Europe.0-85369-. Examples which may be mentioned are:

water-soluble cellulose derivatives (hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, etc.);

-polyethylene glycols;

-alginates and derivatives thereof;

-carrageenan;

-agar;

-gelatin;

-maltodextrin;

-polydextrose;

-guar, carob, acacia, xanthan, gellan and other gums;

-polyvinyl alcohol;

-povidone;

-pectin;

-silica gel;

-native and modified starches and derivatives thereof;

-a glucan;

-and the like.

It is also suitable to introduce into the suspension at least one agent for improving the solubility of the active ingredient in the liquid phase of a solvent, preferably aqueous, such as salts, sugars, glycerol and the like. In fact, in the case of very soluble active ingredients, these solutes can limit the release of the active ingredient from the microcapsules, which can be achieved by reducing the saturation concentration of the active ingredient in the aqueous phase.

With regard to suspensions of all qualities of oral galenic form which are easy to swallow, stable and palatable, it is advantageous that it contains at least one further additive selected from the group comprising surfactants, colouring agents, dispersing agents, preservatives, taste-modifying agents, flavouring agents, sweeteners, antioxidants and mixtures thereof.

Examples of such additives which may be mentioned are those commonly used in the pharmaceutical industry and are disclosed inter alia in the Handbook of pharmaceutical excipients (Handbook of pharmaceutical excipients), am. pharmaceutical Association, Arthur H.KIBBE, 2000, ISBN0917330-96X. Europe.0-85369-; or, in the case of emulsifiers, they are described on page 5, lines 14 to 19 of EP-A-0273890; or, in the case of thickeners, they are indicated on page 5, lines 19 to 20 of EP-A-0601508.

The active ingredient used to prepare the controlled release suspensions of the invention may be selected from at least one of the following active substances: antiulcer agents, antidiabetics, anticoagulants, antithrombotic agents, hypolipidemic agents, antiarrhythmics, vasodilators, antianginal agents, antihypertensives, vascular protectants, procreation inducers, birth control inducers and inhibitors, contraceptives, antibiotics, antifungals, antivirals, anticancer agents, anti-inflammatory agents, analgesics, antiepileptics, antiparkinson agents, neuroleptics, hypnotics, anxiolytics, psychostimulants, antimigraine agents, antidepressants, antitussives, antihistamines, and antiallergic agents.

Without being limited thereto, the invention is more particularly applicable to pharmaceutically active ingredients which have to be administered orally in high doses, for example 500 and 1000mg or more, and to suspensions for pediatric use.

The active ingredient is preferably selected from the following compounds: pentoxifylline, prazosin, acyclovir, nifedipine, diltiazemNaproxen, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, indomethacin, diclofenac, fentiazac acid, estradiol valerate, metoprolol, sulpiride, captopril, cimetidine, zidovudine, nicardipine, terfenadine, atenolol, salbutamol, carbamazepine, ranitidine, enalapril, simvastatin, fluoxetine, altizolam, famotidine, ganciclovir, famciclovir, spironolactone, 5-aminosalicylic acid, quinidine, perindopril, morphine, pentazocine, metformin, acetaminophen, omeprazole, metoclopramide, atenolol, salbutamol, morphine, verapamil, erythromycin, caffeine, furosemide, cephalosporins, montelukast, valacivir, ascorbate, diazepam, ciprofloxacin, theophylline, ciprofloxacin, vancomycin, aminoglycosides, penicillins (excluding amoxicillin) and mixtures thereof.

Another aspect of the invention relates to a pharmaceutical characterized in that it comprises a suspension of modified-release microcapsules of an active ingredient as defined above.

More specifically, the invention further relates to a pharmaceutical, or more precisely a galenic pack, characterized in that it comprises a kit for preparing a suspension as defined above, said kit comprising:

-microcapsules containing the active ingredient in substantially dry form, for saturating the liquid phase with the active ingredient once the two phases are brought into contact;

-and/or a mixture of microcapsules containing the active ingredient in a quantity precisely necessary for modified release, in substantially dry form, and an uncoated active ingredient for immediate release, the quantity of uncoated active ingredient being necessary and sufficient to saturate the liquid phase with the active ingredient once the saturated dose of active ingredient has been brought into contact with the liquid phase;

and a liquid phase and/or at least part of the components used for its preparation;

and/or instructions for preparing the suspension.

Such a dosage form of the drug of the invention enables a patient to easily prepare a modified release suspension that is stable for at least several days, particularly in the form of a modified release. It is thereby ensured that the patient possesses a medicament which is easy to administer orally and which is fully effective from a therapeutic point of view.

The microcapsules constituting the solid phase of the suspension according to the invention can be prepared by those skilled in the art by means of the microencapsulation techniques available, the main techniques being summarized in the article "L' acauli chimique", published by c.duverney and j.p.bensoit at 12 months 1986. More precisely, the technology described is microencapsulated by a film coating, resulting in a separate "reservoir" system with respect to the matrix system.

For further details reference may be made to EP-B-0953359 cited above.

To produce the active principle (excluding amoxicillin) based core of the microcapsules of the invention, it is advantageous to use active principle particles of the desired size as starting material. The granules may be crystals of the active ingredient, which are pure, and/or have been pretreated by techniques commonly used in the art, such as granulation, in the presence of small amounts of at least one conventional binder and/or agent for improving the inherent solubility of AP.

The invention may be more clearly understood from the standpoint of composition, characteristics and preparation by means of the following examples which are given for illustrative purposes only and which represent variants and advantages of the invention.

Description of the drawings

FIG. 1 shows the initial dissolution profile and the dissolution profile after 10 days of storage of the suspension of example 1, the% dissolution D being a function of the time in hours (t).

FIG. 2 shows the initial dissolution profile and the dissolution profile after 19 days of storage of the suspension of example 2, the% dissolution D being a function of the time in hours (t).

FIG. 3 shows the initial dissolution profile and the dissolution profile after 12 days of storage of the suspension of example 3, the% dissolution D being a function of the time in hours (t). The suspension was combined with 29% free metformin and 71% encapsulated metformin.

Example 1

Preparation of acyclovir microcapsule

1000g of acyclovir and 30g ofDry-mixed for 5 minutes. The mixture was granulated with water. The granules were dried in a vented oven at 40 ℃ and then classified with a 500 μm sieve. The 200-500 μm fraction was selected.

In a Glatt GPC-G1 air fluidized bed apparatus, 27.3G of ethylcellulose, 3.7G of castor oil, 3.7G of magnesium stearate and 2.9G of ethyl cellulose dissolved in 60/40w/w acetone/isopropanol mixture are used700g of the granules obtained above were coated. The product temperature: at 40 ℃.

Preparation of the suspension:

0.58g of the microcapsules obtained above was put into 37ml of phosphate buffer solution of pH 6.8.

And (3) testing:

the suspension was stored at room temperature for 10 days. After 10 days, the suspension was analyzed for dissolution rate using a type II instrument according to the 3 rd edition European pharmacopoeia, using a phosphate buffer medium of pH6.8, a volume of 900ml, a temperature of 37 ℃, with stirring on a blade at 100rpm, UV detection at 252 nm.

The results are shown in FIG. 1.

The distribution is obviously the same: similarity factor f₂Greater than 50. The microcapsules remain highly effective in aqueous suspensions.

Example 2

Preparation of spironolactone microcapsules:

step 1: granules

First 45G spironolactone, 25G PEG 40-hydrogenated castor oil and 30G povidone were dissolved in a water/acetone/isopropanol mixture (5/57/38w/w) in a Glatt GPC-G1 air fluidized bed apparatus. The solution was then sprayed onto 800g of cellulose spheres (300- & 500 μm diameter).

Step 2: coating film

50G of the granulate obtained above were coated in a Glatt GPC-G1 air fluidized bed apparatus with 1.44G of ethylcellulose, 0.16G of castor oil, 0.64G of poloxamer 188 and 0.96G of povidone dissolved in an acetone/isopropanol mixture (60/40 w/w).

Preparation of the suspension:

0.07g of the microcapsules obtained above was put into 0.165ml of phosphate buffer solution at pH 6.8.

And (3) testing:

the suspension was stored at room temperature for 19 days. After 19 days, the suspension was analyzed for dissolution rate using a type II instrument according to the 3 rd edition of European pharmacopoeia, using a phosphate buffer medium of pH6.8, a volume of 1000ml, a temperature of 37 ℃, with stirring on a blade at 100rpm, UV detection at 240 nm.

The results are shown in FIG. 2.

The distribution is obviously the same: similarity factor f₂Greater than 50. The microcapsules remain extremely effective in aqueous suspensions.

Example 3

Preparation of metformin microcapsules:

192.4G of ethylcellulose, 26G of castor oil, 26G of magnesium stearate and 20.8G of magnesium stearate dissolved in 60/40w/w acetone/isopropanol mixture are used in a Glatt GPC-G1 air fluidized bed apparatus740g of the metformin crystals (200-500 μm fraction) obtained above were coated. The product temperature: at 40 ℃.

Preparation of suspension (29% free and 71% encapsulated):

50g of the microcapsules obtained above were dry-mixed with 15g of metformin crystals and 0.7g of xanthan gum in a 100ml glass flask. Then 34.3g of pure water was added to the powder mixture. After manual stirring, a suspension is obtained which very slowly gives rise to a sediment.

The total metformin titer in the suspension was 0.52 g/ml.

And (3) stability test:

the suspension was stored at room temperature for 12 days. After 12 days, the suspension was analyzed for dissolution rate using a type II instrument according to the 3 rd edition European pharmacopoeia, using a phosphate buffer medium of pH6.8, a volume of 900ml, a temperature of 37 ℃, with stirring on a blade at 100rpm, UV detection at 232 nm.

The results are shown in FIG. 3.

The distribution is obviously the same: similarity factor f₂Greater than 50. The microcapsules remain extremely effective in aqueous suspensions.

And (3) uniformity test:

the suspension was stirred manually and then 6 portions of 5ml samples were taken with a graduated syringe. The content of metformin in each sample was determined by HPLC and is as follows:

sample number	Content of metformin (in g) in 5ml of suspension
		1	2.58
2	2.60
		3	2.62
4	2.59
		5	2.60
6	2.63

It was observed that the samples were extremely homogeneous and the dose corresponded to a prediction of 2.60g for a 5ml sample.

The formulation can thus be administered without the risk of overdosing or underdosing.

Claims (39)

1. Suspension of microcapsules in an aqueous liquid phase, which allows modified release of at least one active principle not comprising amoxicillin, and is intended for oral administration, characterized in that:

■ which comprises a plurality of microcapsules each consisting of a core containing at least one active ingredient excluding amoxicillin and a film coating which:

● is applied to the core;

● control the modified release of the active ingredient;

● and has a composition corresponding to one of the following groups A, B and C:

group A

1A-at least one film-forming polymer insoluble in the gastrointestinal liquid, in an amount of from 50 to 90% by dry weight of the coating composition; and consists of at least one water-insoluble substituted cellulose;

2A-at least one nitrogen-containing polymer in an amount of 2-25% by dry weight, based on the total weight of the coating composition; and consists of at least one polyacrylamide and/or poly-N-vinylamide and/or poly-N-vinyllactam;

3A-at least one plasticizer in an amount of 2-20% by dry weight based on the total weight of the coating composition; and consists of at least one of the following compounds: glycerides, phthalates, citrates, sebacates, cetyl esters and castor oil;

4A-at least one surfactant and/or lubricant, in an amount of 2-20% by dry weight, based on the total weight of the coating composition, chosen from anionic surfactants and/or nonionic surfactants and/or lubricants; the reagent comprises only one of the products or the mixture of the products;

group B

1B-at least one hydrophilic polymer bearing groups which ionize at neutral pH;

2B-at least one hydrophobic compound different from A;

group C

1C-at least one film-forming polymer insoluble in gastrointestinal fluids;

2C-at least one water-soluble polymer;

3C — at least one plasticizer;

4C-optionally, at least one surfactant/lubricant;

■ it comprises:

● 30-95% by weight of a liquid phase;

● and 5-70% by weight of microcapsules;

■ and the liquid phase is saturated with the active ingredient or with the active ingredient when contacting the microcapsules.

2. The suspension according to claim 1, characterized in that the group a component, the content of film-forming polymer insoluble in gastrointestinal fluids, is comprised between 50 and 80% by dry weight of the total weight of the coating composition; a nitrogen-containing polymer in an amount of 5-15% by dry weight based on the total weight of the coating composition; a plasticizer in an amount of 4-15% by dry weight based on the total weight of the coating composition; surfactant and/or lubricant in an amount of 4-15% by dry weight based on the total weight of the coating composition.

3. Suspension according to claim 1, characterized in that group B1B is selected from substituted celluloses.

4. Suspension according to claim 1, characterized in that when a surfactant/lubricant is present in the group C composition, the surfactant/lubricant is selected from the group consisting of:

-an anionic surfactant;

-and/or a non-ionic surfactant.

5. The suspension of claim 1, characterized in that A, B and group C constituting the coating composition are selected from the group consisting of:

group A

1A-ethylcellulose and/or cellulose acetate;

2A-polyacrylamide and/or polyvinylpyrrolidone;

3A-castor oil;

alkali metal or alkaline earth metal salts of 4A-fatty acids; polyethoxylated sorbitan esters; polyethoxylated castor oil compounds; a stearate; stearyl fumarate; or glyceryl behenate;

they are used alone or in a mixture;

group B

◆1B

-cellulose acetate-phthalate;

-hydroxypropyl methylcellulose phthalate;

hydroxypropyl methylcellulose acetate-succinate;

(meth) acrylic acid/(meth) acrylic acid alkyl (meth) ester copolymer;

-and mixtures thereof;

◆2B

-hydrogenated vegetable wax;

-triglycerides;

animal and vegetable fats;

-and mixtures thereof;

group C

◆1C

-water insoluble substituted cellulose;

-an acrylic polymer;

-polyvinyl acetate;

-and mixtures thereof;

◆2C

-water-soluble substituted cellulose;

-polyacrylamide;

poly-N-vinyl amide;

poly-N-vinyl lactam;

-polyvinyl alcohol;

-polyoxyethylene;

-polyvinylpyrrolidone;

-and mixtures thereof;

◆3C

-glycerol and its esters;

-a phthalate;

-a citric acid ester;

-sebacate;

-an adipate ester;

-azelaic acid ester;

-benzoic acid esters;

-vegetable oil;

-a fumarate;

-malate;

-an oxalate ester;

-a succinic acid ester;

-a butyrate ester;

-cetyl alcohol ester;

-triacetin;

malonic ester;

-castor oil;

-and mixtures thereof;

◆4C

-alkali or alkaline earth metal salts of fatty acids;

-polyethoxylated oils;

-polyoxyethylene/polyoxypropylene copolymers;

-polyethoxylated sorbitan esters;

-polyethoxylated castor oil compounds;

-a stearate salt;

-stearyl fumarate;

-glyceryl behenate;

-and mixtures thereof.

6. Suspension according to claim 5, characterized in that the group A constituting the coating composition is selected from the following:

4A-stearic acid and/or oleic acid; calcium stearate, magnesium stearate, aluminum stearate, or zinc stearate; sodium stearyl fumarate;

they are used alone or in the form of a mixture.

7. Suspension according to claim 5, characterized in that the group B constituting the coating composition is selected from the following:

◆2B

-beeswax, carnauba wax;

-and mixtures thereof.

8. Suspension according to claim 5, characterized in that the group C constituting the coating composition is selected from the following:

◆1C

-ethyl cellulose and/or cellulose acetate;

◆2C

-polyvinylpyrrolidone;

◆3C

acetylated glycerides, glycerol monostearate, glycerol triacetate and glycerol tributyrate;

dibutyl phthalate, diethyl phthalate, dimethyl phthalate and dioctyl phthalate;

acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate and triethyl citrate;

-diethyl sebacate and dibutyl sebacate;

-diethyl fumarate;

-diethyl malate;

-diethyl oxalate;

-dibutyl succinate;

-malonic acid diethyl ester;

-castor oil;

-and mixtures thereof;

◆4C

alkali or alkaline earth metal salts of stearic acid and/or oleic acid;

-polyethoxylated hydrogenated castor oil;

-calcium stearate, magnesium stearate, aluminium stearate or zinc stearate;

-sodium stearyl fumarate;

-and mixtures thereof.

9. The suspension according to claim 1, characterized in that the composition of the coating composition is as follows:

-ethyl cellulose and/or cellulose acetate;

-polyvinylpyrrolidone;

-castor oil;

polyethoxylated hydrogenated castor oil.

10. Suspension according to claim 1, characterized in that the group C constituting the coating composition comprises at least one surfactant/lubricant.

11. The suspension of claim 1, characterized in that said film coating consists of a single layer.

12. Suspension according to claim 1, characterized in that it comprises:

-60-85% by weight of a liquid phase;

-and 15-40% by weight of microcapsules.

13. Suspension according to claim 1, characterized in that the liquid phase is water.

14. Suspension according to claim 1, characterized in that the amount of the solvent liquid phase of the active ingredient is such that the proportion of the active ingredient originating from the dissolution of the microcapsules is less than or equal to 15% by weight, based on the total weight of the active ingredient contained in the microcapsules.

15. Suspension according to claim 14, characterized in that the proportion of active ingredient deriving from the dissolution of the microcapsules is less than or equal to 5% by weight, based on the total weight of active ingredient contained in the microcapsules.

16. Suspension according to claim 14, characterized in that the solvent liquid phase is water.

17. Suspension according to claim 1, characterized in that the liquid phase is at least partially saturated with the active ingredient after the microcapsules have been incorporated into the liquid phase.

18. Suspension according to claim 17, characterized in that the liquid phase is completely saturated with the active ingredient after the microcapsules have been incorporated into the liquid phase.

19. Suspension according to claim 17, characterized in that the saturation of the active ingredient is carried out by the active ingredient contained in the microcapsules.

20. Suspension according to claim 1, characterized in that the liquid phase is at least partially saturated with the uncoated active ingredient before incorporating the microcapsules into said liquid phase.

21. Suspension according to claim 20, characterized in that the liquid phase is completely saturated with the uncoated active ingredient before incorporating the microcapsules into said liquid phase.

22. Suspension according to claim 1, characterized in that the microcapsules have a particle size of less than or equal to 1000 microns.

23. Suspension according to claim 22, characterized in that the microcapsules have a particle size of 200 and 800 microns.

24. Suspension according to claim 23, characterized in that the microcapsules have a particle size of 200-600 microns.

25. Suspension according to claim 1, characterized in that the film coating represents 1-50% of the total weight of the coated microcapsules.

26. Suspension according to claim 25, characterized in that the film coating represents 5-40% of the total weight of the coated microcapsules.

27. Suspension according to claim 25, characterized in that the in vitro release profile obtained using a type II instrument according to the european pharmacopoeia version 3 in phosphate buffered medium at ph6.8 and at a temperature of 37 ℃ is as follows:

the proportion PI of the active ingredient released in the first 15 minutes of the dissolution test is less than or equal to 15;

releasing the remaining active ingredient during a period of time such that 50% by weight of the active ingredient is released over a time period (t)_1/2) As defined below: t is not more than 0.5 hour_1/2Less than or equal to 30 hours.

28. Suspension according to claim 27, characterized in that the in vitro release profile obtained using a type II instrument according to the european pharmacopoeia version 3 in phosphate buffered medium at ph6.8 and at a temperature of 37 ℃ is as follows:

the proportion PI of the active ingredient released in the first 15 minutes of the dissolution test is less than or equal to 5;

releasing the remaining active ingredient during a period of time such that 50% by weight of the active ingredient is released over a time period (t)_1/2) As defined below: t is not more than 0.5 hour_1/2Less than or equal to 20 hours.

29. The suspension of claim 1, characterized in that:

-an initial in vitro release profile Pfi obtained in accordance with european pharmacopoeia version 3 in phosphate buffered medium at ph6.8 and at a temperature of 37 ℃ using a type II instrument, just after suspension of the microcapsules in the solvent phase;

10 days after suspension of the microcapsules in the solvent phase, an in vitro release profile Pf obtained using a type II instrument, according to the european pharmacopoeia version 3, in phosphate buffered medium at ph6.8 and at a temperature of 37 ℃₁₀；

The two in vitro release profiles were similar.

30. The suspension of claim 29, characterized in that the solvent is aqueous.

31. Suspension according to claim 1, characterized in that its pH is acidic or neutral.

32. Suspension according to claim 1, characterized in that it comprises at least one rheology modifier.

33. Suspension according to claim 1, characterized in that it comprises at least one agent for modifying the solubility of the active ingredient in the liquid phase of the solvent.

34. The suspension of claim 33, characterized in that the solvent is aqueous.

35. Suspension according to claim 1, characterized in that it contains at least one additive chosen from surfactants, colorants, dispersants, preservatives, flavors, seasonings, sweeteners, antioxidants and mixtures thereof.

36. Suspension according to claim 1, characterized in that the active ingredient belongs to at least one of the following active substance groups: antiulcer agents, antidiabetics, anticoagulants, antithrombotic agents, hypolipidemic agents, antiarrhythmics, vasodilators, antianginal agents, antihypertensives, vascular protectants, procreation inducers, birth control inducers and inhibitors, contraceptives, antibiotics, antifungals, antivirals, anticancer agents, anti-inflammatory agents, analgesics, antiepileptics, antiparkinson agents, neuroleptics, hypnotics, anxiolytics, psychostimulants, antimigraine agents, antidepressants, antitussives, antihistamines, and antiallergic agents.

37. The suspension according to claim 36, characterized in that said active ingredient is selected from the group consisting of: pentoxifylline, prazosin, acyclovir, nifedipine, diltiazemNaproxen, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, indomethacin, diclofenac, fentiazac acid, estradiol valerate, metoprolol, sulpiride, captopril, cimetidine, zidovudine, nicardipine, terfenadine, carbamazepine, ranitidine, enalapril, simvastatin, fluoxetine, azinazolam, famotidine, ganciclovir, famciclovir, spironolactone, 5-aminosalicylic acid, quinidine, perindopril, pentazocine, metformin, acetaminophen, omeprazole, metoclopramide, atenolol, salbutamol, morphine, verapamil, erythromycin, caffeine, furosemide, cephalosporins, montelukast, valaciclovir, ascorbate, diazepam, theophylline, ciprofloxacin, vancomycin, aminoglycosides, penicillins excluding amoxicillin, and mixtures thereof.

38. Pharmaceutical, characterized in that it comprises a suspension according to claim 1.

39. Medicament, characterized in that it comprises a kit for the preparation of the suspension according to claim 1, said kit comprising:

-microcapsules containing an active ingredient in substantially dry form, for saturating the liquid phase with the active ingredient contained, once the solid and liquid phases are brought into contact;

-and/or a mixture of microcapsules containing the active ingredient in a quantity just necessary for modified release, in substantially dry form, and an uncoated active ingredient for immediate release, wherein the dose of uncoated active ingredient is necessary and sufficient to saturate the liquid phase with active ingredient once the saturated dose of active ingredient has been brought into contact with the liquid phase;

and a liquid phase and/or at least part of the components used for its preparation; and/or instructions for preparing the suspension.