HK1079447A - Oral pharmaceutical formulation in the form of aqueous suspension of microcapsules for modified release of amoxicillin - Google Patents

Description

Oral pharmaceutical formulation in the form of a microencapsulated aqueous suspension with modified release of amoxicillin

The present invention relates to the field of modified release of pharmaceutically active ingredients. In the present specification, the expression "modified release" means that the release of the active ingredient begins once the galenic 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 after a predetermined period of time (for example from 0.5 to several hours). According to the invention, the time required to release 50% of the active ingredient is generally a few hours and can be extended, for example, from 0.5 to 30 hours.

More precisely, the invention relates to liquid pharmaceutical formulations for oral administration with modified release of amoxicillin (β -lactam family antibiotics). 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. According to the invention, the microcapsules that constitute the dispersed phase of the suspension are designed to provide a modified release of amoxicillin.

The invention further relates to dry pharmaceutical formulations of aqueous suspensions for re-dissolution at the start of treatment. These re-dissolved aqueous suspensions remain stable throughout the treatment and provide for modified release of amoxicillin.

These suspensions are of particular value in the following cases:

-increasing the interval between two dosage units, for example once every 12 hours instead of once every 8 hours;

and facilitates the oral administration of amoxicillin-based drugs. Indeed, a large number of patients prefer to drink liquid pharmaceutical suspensions and also prefer not to swallow one or more tablets. Thereby improving compliance. This is of particular value in people who are not able to swallow the usually larger tablets, i.e. infants, children and elderly;

-simultaneously improving the taste of the suspension.

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

Numerous types of microcapsules in dry form are known. In the EP-B-0709087 patent, in particular, 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 2-20% by dry weight based on 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.

Oral pharmaceutical formulations for modified release of amoxicillin are currently available only in tablet form. Different formulations of such tablets are described in patents WO-A-94/27557, WO-A-95/20946, WO-A-95/28148, WO-A-96/04908, WO-A-00/61115, WO-A-00/61116, WO-A-01/47499 and WO-A-02/30392. These tablets are relatively large, such as the tablet of example 1 of the WO-A-02/30392 patent, and have A total weight of 1600mg for A1000 g dose. These tablets cannot be administered to dysphagic patients, even to children or infants, who in any case cannot swallow such tablets, and furthermore, for them, the dosage to be administered must be adapted to their body weight.

For such applications, the choice of multi-dose suspensions or solutions is preferred over tablets as pharmaceutical dosage forms.

Pharmaceutical suspensions or solutions of amoxicillin meet this need. Examples of these are the formulations described in patent applications WO-A-98/35672 or WO-A-98/35672. Efforts to improve these suspensions have been directed to the stability of the suspensions (patent application WO-A-00/50036), the gastrointestinal tolerability (patent application WO-A-97/06798 & WO-A-00/03695) or the taste improvement (patent application WO-A-98/36732).

However, none of these known suspensions is capable of providing a modified release of amoxicillin which is essential to increase the duration of action of amoxicillin and to treat certain indications, such as pneumonia due to drug-resistant streptococci. To meet this requirement, patent application WO-A-97/09042 describes A formulation containing more than the usual amount of amoxicillin, in which the amoxicillin is in immediate release form.

Liquid suspensions for modified release of amoxicillin are difficult to manufacture. The main difficulty to overcome is to avoid the release of amoxicillin into the liquid phase during storage of the suspension, while allowing its modified release once it has entered the gastrointestinal tract. This objective is particularly difficult to achieve because amoxicillin needs to be stored in the fluid for an extremely long time (treatment period, i.e., about 10 days) compared to the release time required in the gastrointestinal fluids (several hours, up to 12 hours). Furthermore, its prolonged residence time in the liquid phase during storage must not interfere with the modified release system, i.e. not cause a decrease in the active ingredient release profile and a decrease in the amoxicillin release time.

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

very small (1000 microns) microcapsules;

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

The prior art concerning oral liquid pharmaceutical dosage forms with modified release of the active ingredient should be mentioned first of all in PCT patent application WO-A-87/07833 and patent US-B-4,902,513, which disclose aqueous suspensions of microcapsules of an active ingredient (e.g. theophylline) having modified release characteristics (e.g. 12 hours) of the active ingredient. 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 microcapsules 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 containing a 1000mg dose of naxopren which can be administered in a single daily dosage unit.

The microcapsule is composed 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 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. The Naxopren undergoes a modified release over 24 hours.

Example 22 of said European patent application EP-A-0601508 contains ｃA demonstration 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 amoxicillin, which has an absorption window in the upper part of the gastrointestinal tract, it is necessary to release it for efficient absorption once it reaches the stomach. Furthermore, the multilayer solutions solving this problem are extremely complex and specific for 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. It is an object 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 in aqueous suspension for a certain period of time and is palatable to facilitate compliance, while its manufacture does not involve 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 (90-300 μm) of moguisteine microcapsules 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 for moguisteine.

In the present state of the art, the main object of the present invention is to provide aqueous suspensions or formulations of amoxicillin microcapsules according to a modified release profile for oral administration of amoxicillin, 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 amoxicillin contained in the microcapsules from escaping from the liquid phase during the entire storage of the suspension and to modify the release once it has entered the environment suitable for causing the release, i.e. in the gastrointestinal tract in vivo, under the conditions of the dissolution test carried out just after the microcapsules have been suspended in a solvent (preferably aqueous) phase, in vitro, wherein the dissolution test is carried out under the following conditions: a type II instrument was used, according to European pharmacopoeia, 3 rd edition, in a volume of 900ml in phosphate buffer medium at pH6.8, at a temperature of 37 ℃.

It is a further object of the present invention to provide an aqueous liquid suspension comprising amoxicillin microcapsules formed as a film coating from a single layer.

It is a further object of the present invention to provide an aqueous liquid suspension of microcapsules of amoxicillin in which the fraction derived from dissolution of the microcapsules is less than or equal to 15% and preferably 5% of the total weight of amoxicillin present in the microcapsules.

It is a further object of the present invention to provide an aqueous liquid suspension of microcapsules of amoxicillin in which a portion of the amoxicillin is in immediate release form and another portion of the amoxicillin is in modified release form (microcapsules).

It is another principal object of the present invention to provide an aqueous suspension of microcapsules for modified release of amoxicillin which allows for release of amoxicillin with a release profile which does not degrade upon aging of the suspension.

Another main object of the present invention is to provide an aqueous suspension of microcapsules, made of coated granules of amoxicillin alone and capable of releasing the latter according to a prolonged and/or optionally delayed profile, so that the release half-life t_1/2Is 0.5-30 hours.

Another object of the present invention is to provide an oral galenic form which is liquid and consists of a large number (for example of the order of several thousand) of microcapsules, this multiplicity ensuring statistically good reproducibility of the kinetics of AP transport throughout the gastrointestinal tract, thus improving the control of bioavailability and therefore 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 amoxicillin is in the form of a plurality of individual particles coated with microcapsules and wherein several active ingredients with different respective release times can be combined.

Another main object of the present invention is to provide the use of a suspension of microcapsules (preferably aqueous) consisting of granules of amoxicillin, each coated to define a modified release of amoxicillin, as a means of treating human or veterinary disease, without the modified release profile of amoxicillin being affected by the storage of the microcapsules in a liquid dosage form in the form of such a suspension.

Another main object of the present invention is to provide a drug based on an aqueous suspension of microcapsules preferably consisting of amoxicillin granules, wherein the amoxicillin is individually coated to determine a modified release of the active ingredient, 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.

Since 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 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 completely specific to the microcapsules;

-suspending the microcapsules in a (preferably aqueous) liquid phase saturated with amoxicillin or capable of being saturated with amoxicillin once in contact with the microcapsules, using an amount of solvent (preferably water) limited to the solvent used, but sufficient to make the suspension easy to swallow.

The invention thus meeting the above objectives relates in particular to a suspension of microcapsules in an aqueous liquid phase, said suspension being intended for oral administration and providing a modified release of amoxicillin, characterized in that:

■ it comprises a plurality of microcapsules each consisting of a core containing amoxicillin and a film coating which:

● is applied to the core;

● control the modified release of amoxicillin;

● 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 a content ranging from 2 to 20% and preferably from 4 to 15% by dry weight relative to the total weight of the coating composition, and chosen from anionic surfactants and/or non-ionic 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 the liquid phase is saturated with amoxicillin or by contacting the microcapsules with amoxicillin to saturate the liquid phase.

The expression "microcapsules of amoxicillin" in the present description refers to microcapsules comprising amoxicillin and optionally at least one other active ingredient and/or at least one excipient in the core.

This suspension of the invention makes it possible to overcome the two main obstacles of producing an aqueous suspension of microcapsules consisting of amoxicillin microparticles coated individually and capable of modifying the release of the latter, which are as follows:

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

b) a modified release system is obtained which is sufficient to avoid any alteration or decrease in the amoxicillin release profile during storage of the aqueous suspension.

In a preferred embodiment of the present invention, the coating composition selected from group A, B and group C consists 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 (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 glycerol behenate;

can be used alone or in mixtures with one another;

group B

◆1B

-cellulose acetate-phthalate;

-hydroxypropyl methylcellulose phthalate;

hydroxypropyl methylcellulose acetate-succinate;

copolymers of (meth) acrylic acid and alkyl (meth) acrylates (EUDRAGIT)^*S or L);

-and mixtures thereof;

◆2B

hydrogenated vegetable wax (Dynasan)^*P60、Dynasan^*116)；

Triglycerides (tristearin, tripalmitin, Lubritab)^*Cutina HR, etc.);

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

-and mixtures thereof.

Group C

◆1C

Water-insoluble cellulose derivatives, particularly preferably ethylcellulose 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 (this material is particularly preferred);

-and mixtures thereof;

◆4C

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

-polyethoxylated oils, preferably polyethoxylated hydrogenated castor oil;

polyoxyethylene/polyoxypropylene copolymers;

polyethoxylated sorbitan esters;

polyethoxylated castor oil derivatives;

stearates, preferably calcium stearate, magnesium stearate, aluminum stearate or zinc stearate;

stearyl fumarate, preferably sodium stearyl fumarate;

glycerol behenate;

and mixtures thereof.

In an advantageous form of the invention, the coating contains a wax selected from the melting point T_fCompounds at temperatures of > 40 ℃ and preferably > 50 ℃.

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 comprises water; 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 the solvent liquid phase of amoxycillin, preferably water, is such that the proportion of dissolved amoxycillin 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 amoxycillin contained in the microcapsules.

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

In this embodiment, the liquid phase is saturated with amoxicillin contained in the microcapsules.

In a second embodiment of the invention, the liquid phase is at least partially and preferably fully saturated with amoxicillin (by means of uncoated amoxicillin) prior to incorporating the microcapsules into the 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 fact, this amount of saturating the liquid phase with amoxicillin prior to introducing the microcapsules into the suspension renders the amoxicillin contained in the microcapsules ineffective or practically ineffective in the process of saturating the liquid phase. The diffusion of amoxicillin contained in the microcapsules is thereby 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" according to the invention is understood to mean the diameter between the sieve numbers in the proportion of microcapsules of at least 75% by weight.

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 required in particular by the fact that: all microcapsules have a large specific surface area (due to their small size) and thus accelerate release.

In order to control the in vivo and in vitro release of amoxicillin, the present invention preferably employs 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 obtaining an in vitro release profile in phosphate buffered medium at pH6.8 and at 37 ℃ according to european pharmacopoeia version 3, using a type II instrument, such that:

the ratio PI of amoxicillin released from the microcapsules during the first 15 minutes of the dissolution test is less than or equal to 15, preferably PI less than or equal to 5;

the amoxicillin remaining in the microcapsules is released over a period of time such that there is a release time (t) of 50% by weight amoxicillin_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 using a type II instrument, according to european pharmacopoeia version 3, in phosphate buffered medium at pH6.8 and at a temperature of 37 ℃, just after suspension of the microcapsules in a solvent (preferably aqueous) phase;

10 days after suspension of the microcapsules in a solvent (preferably aqueous) phase, an in vitro release profile Pf obtained using a type II instrument, according to european pharmacopoeia version 3, at pH6.8 in phosphate buffered medium and at a temperature of 37 ℃₁₀；

The two in vitro release profiles were similar.

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

These advantageous properties of the suspension of the invention enable amoxicillin to be administered orally without difficulty and without compromising the manner of modified release and optionally sustained release.

According to another advantageous physico-chemical characteristic of the invention, the pH of the liquid suspension according to the invention may be optionally 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 amoxicillin in the liquid phase of a solvent, preferably aqueous, such as salts, sugars, glycerol, etc.

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.

Another feature of the invention relates to a pharmaceutical product characterized in that it comprises a suspension of modified release microcapsules of amoxicillin 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 amoxicillin in substantially dry form, once the solid and liquid phases are brought into contact, for saturating the liquid phase with amoxicillin;

-and/or a mixture of microcapsules containing amoxicillin in substantially dry form in an amount necessary for modified release, with immediate release uncoated amoxicillin, wherein the dosage of uncoated amoxicillin must be sufficient to saturate the liquid phase with amoxicillin once the saturated dosage of amoxicillin has been contacted 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 suspension of the modified release form that is stable (especially in terms of modified release) for at least several days. 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' acualiteichique", published by c.duverney and j.p.bensoit, 12 months 1986. More precisely, the technology described is microencapsulated by a film coating, thus obtaining a separate "storage" system with respect to the matrix system.

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

To produce the cores of the microcapsules of the invention based on amoxicillin, it is advantageous to use as starting material particles of amoxicillin of the desired size. The granules may be crystals of amoxicillin which are pure and/or have been pre-treated by techniques commonly used in the art (e.g. granulation) in the presence of small amounts of at least one conventional binder and/or agent for improving the inherent solubility of amoxicillin.

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 12 days of storage of the suspension of example 1, where the% dissolution is a function of time in hours.

● FIG. 2 shows the initial dissolution profile and the dissolution profile after 12 days of storage of the suspension of example 2, where the% dissolution is a function of time in hours.

Example 1

Preparation of amoxicillin microcapsule

First in a high shear granulator (L * dige)^*M5MRK) 970g of amoxicillin trihydrate and 30g of povidone (Plasdone)^*K29/32) were dry mixed for 5 minutes. The powdery mixture was then granulated with water (200 g). The granules were dried in a vented oven at 40 ℃ and then classified with a 500 μm sieve. The fraction of 200-500 μm was selected by sieving.

107.6G of ethylcellulose (Ethocel 7 Premium), 35.3G of povidone (Plasdone) dissolved in an acetone/isopropanol mixture (60/40 w/w) are used in a Glatt GPC-G1 air fluidized bed apparatus^*K29/32) and 10.8g castor oil 700g of the granulate obtained above were coated.

Preparation of the suspension:

12.2g of the microcapsules obtained above were dry mixed with 0.3g of xanthan gum in a 100ml glass flask. 87.5g of purified water were then added to the powder mixture. After manual stirring, a suspension is obtained which very slowly gives rise to a sediment.

The amoxicillin titer in the suspension is 0.1 g/ml.

And (3) stability test:

the suspension prepared above 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 272 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.

And (3) uniformity test:

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

sample number	Content of Amoxicillin in 5ml suspension (in g)
		1	0.51
2	0.49
		3	0.52
4	0.50
		5	0.50
6	0.51

It was observed that the samples were extremely homogeneous and the dose corresponded to the expected value of 0.5g for 5ml samples.

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

Example 2

Preparation of amoxicillin microcapsule

First in a high shear granulator (L * dige)^*M5MRK) 970g of amoxicillin trihydrate and 30g of povidone (Plasdone)^*K29/32) were dry mixed for 5 minutes. The powder was then mixed with water (200g)Granulating the mixture. The granules were dried in a vented oven at 40 ℃ and then classified with a 500 μm sieve. The fraction of 200-500 μm was selected by sieving.

61g of Aquacoat ECD30, 2.6g of Povidone (Plasdone) dispersed in water were used in a Glatt GPCG1 air fluidized bed apparatus^*K29/32) and 16.4g triethyl citrate were used to coat 920g of the granulate obtained above.

Preparation of the suspension:

10.9g of the microcapsules obtained above were dry mixed with 0.3g of xanthan gum in a 100ml glass flask. 88.8g of purified water was then added to the powder mixture. After manual stirring, a suspension is obtained which very slowly gives rise to a sediment.

The amoxicillin titer in the suspension is 0.1 g/ml.

And (3) stability test:

the suspension prepared above 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 272 nm.

The results are shown in FIG. 2.

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

Claims (18)

1. Suspension of microcapsules in an aqueous liquid phase, said suspension being intended for oral administration and allowing a modified release of amoxicillin, characterized in that:

■ it comprises a plurality of microcapsules each consisting of a core containing amoxicillin and a film coating which:

● is applied to the core;

● control the modified release of amoxicillin;

● 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, 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 and preferably 4-15% by dry weight of the total coating composition; and is selected from anionic surfactants and/or non-ionic 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, preferably selected 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 following products:

-an anionic surfactant;

-and/or a non-ionic surfactant;

■ and the liquid phase has been saturated with amoxicillin or has been saturated with amoxicillin by contacting the microcapsules.

2. The suspension of claim 1, characterized in that A, B and group C in the coating composition are as follows:

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 alkali metal or alkaline earth metal salts of stearic acid and/or oleic acid; polyethoxylated sorbitan esters; polyethoxylated castor oil derivatives; stearates, preferably calcium stearate, magnesium stearate, aluminium stearate or zinc stearate; stearyl fumarate, preferably sodium stearyl fumarate; or glycerol 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 (beeswax, carnauba wax, etc.);

-and mixtures thereof.

Group C

◆1C

Water-insoluble cellulose derivatives, particularly preferably ethylcellulose 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 its esters, preferably selected from: acetylated glycerides, glycerol monostearate, glycerol triacetate and glycerol tributyrate;

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

citric acid esters, preferably selected from: acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate, and triethyl citrate;

-sebacates, preferably from: 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 (this material is particularly preferred);

-and mixtures thereof;

◆4C

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

-polyethoxylated oils, preferably polyethoxylated hydrogenated castor oil;

polyoxyethylene/polyoxypropylene copolymers;

polyethoxylated sorbitan esters;

polyethoxylated castor oil derivatives;

stearates, preferably calcium stearate, magnesium stearate, aluminum stearate or zinc stearate;

stearyl fumarate, preferably sodium stearyl fumarate;

glycerol behenate;

and mixtures thereof.

3. Suspension according to claim 1 or 2, characterized in that said film coating consists of a single layer.

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

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.

5. Suspension according to claim 1, characterized in that the amount of the solvent liquid phase of amoxicillin (preferably water) is such that the proportion of dissolved amoxicillin 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 amoxicillin contained in the microcapsules.

6. Suspension according to claim 1, characterized in that the liquid phase is at least partially and preferably completely saturated with amoxicillin incorporated in microcapsules in said liquid phase.

7. A suspension according to claim 6 characterised in that saturation of amoxycillin is achieved by the active ingredient contained in the microcapsules.

8. Suspension according to claim 1, characterized in that the liquid phase is at least partially and preferably completely saturated with uncoated amoxicillin before incorporating the microcapsules into said liquid phase.

9. 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 1000 microns, preferably 200-800 microns and particularly preferably 200-600 microns.

10. Suspension according to any one of claims 1 to 9, characterized in that the film coating represents 1 to 50% and preferably 5 to 40% of the total weight of the coated microcapsules.

11. Suspension according to any one of claims 1-10, characterized in that an in vitro release profile is obtained using a type II instrument according to the european pharmacopoeia, 3 rd edition, in phosphate buffer medium at ph6.8 and at a temperature of 37 ℃, namely:

the ratio PI of amoxicillin released in the first 15 minutes of the dissolution test is less than or equal to 15, preferably PI less than or equal to 5;

the remaining amoxicillin is released over a period of time such that 50% by weight of the AP is released over a time period (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。

12. Suspension according to any one of claims 1 to 11, characterized in that:

-an initial in vitro release profile Pfi obtained according to european pharmacopeia 3 rd edition in phosphate buffer medium at ph6.8 and at a temperature of 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, according to the european pharmacopoeia version 3, in phosphate buffer medium at ph6.8 and at a temperature of 37 ℃₁₀；

The two in vitro release profiles were similar.

13. Suspension according to any one of claims 1 to 12, characterized in that its pH is either acidic or neutral.

14. Suspension according to any one of claims 1 to 13, characterized in that it comprises at least one rheology modifier.

15. Suspension according to any one of claims 1 to 14, characterized in that it comprises at least one agent for modifying the solubility of amoxicillin in the solvent (preferably aqueous) liquid phase.

16. Suspension according to any one of claims 1 to 15, characterized in that it contains at least one additive chosen from surfactants, colorants, dispersants, preservatives, taste modifiers, flavors, sweeteners, antioxidants and mixtures thereof.

17. Pharmaceutical, characterized in that it comprises a suspension according to any one of claims 1 to 16.

18. Pharmaceutical, characterized in that it comprises a kit for the preparation of a suspension according to any one of claims 1 to 16, said kit comprising:

-microcapsules containing amoxicillin in substantially dry form, wherein the liquid phase is saturated with amoxicillin once the solid and liquid phases are in contact; and/or

-a mixture of substantially dry form microcapsules containing just the necessary amount of amoxycillin for modified release, and immediate release uncoated amoxycillin, wherein the dosage of uncoated amoxycillin must be sufficient to saturate the liquid phase with amoxycillin, once the saturated dosage of amoxycillin has been contacted with the liquid phase;

-a liquid phase and/or at least part of the components for its preparation, and/or instructions for the protocol for preparing the suspension.