HK1087015B - Composition comprising a mixture of active principles, and method of preparation - Google Patents

Description

Composition containing active ingredient mixture and preparation method thereof

The present invention relates to coated granules containing two active ingredients, a process for their preparation, and multiparticulate tablets containing the granules.

Pharmaceutical forms containing both active ingredients in unit dosage form have long been available, such as gelatin capsules or tablets.

In these dosage forms, the first option is to formulate each active ingredient separately.

The two populations are then either compressed without prior mixing into the form of a bilayer tablet, which is technically complex and requires special materials to compress; or mixing before compression, and placing into gelatin capsule or sachet.

A second alternative is to formulate the two active ingredients simultaneously, for example by mixing them, followed by a granulation step, the resulting product being compressed, placed in gelatin capsules or placed in sachets.

These mixtures are often difficult to control because they bring together several populations of active ingredients and excipients that differ in size, mass and form, respectively. This creates an increased risk of separation, resulting in progressive delamination of the two active particle populations during their mixing or during pharmaceutical operations after mixing, such as during compression or placement into gelatin capsules. The amount of both active ingredients in the final unit dosage form varies widely.

The selection of the population of active ingredients and excipients requires extreme care, but is still insufficient to completely eliminate this risk.

In the case of a mixture of active ingredients, the risk of segregation is already high due to the presence of another population, and becomes even more serious if the ratio between the highest dose of active ingredient and the lowest dose of active ingredient is high, in particular equal to or greater than 5, preferably equal to or greater than 10.

To counteract this unfavorable dose ratio and to keep the respective mass ratio of the fractions close to 1, a diluent for granulating the active ingredient is often added to the lowest dose fraction.

The addition of diluents to granular formulations results in an increase in the unit size and weight of the pharmaceutical dosage form to be taken by the patient, which creates another hurdle to be overcome when formulating pharmaceutical products and makes it more difficult for patients with dysphagia to take.

A second difficulty arises in the case where at least one active ingredient, or even both active ingredients, in the active ingredient composition requires a coating to mask its unpleasant taste.

In this case, the size of the particles is increased by the taste-masking polymer coating.

It is therefore desirable to have a composition which does not present the above-mentioned risks of inhomogeneity in terms of quality and size, and where appropriate in terms of content, and which is suitable for any subsequent formulation operation, such as compression, placement in gelatin capsules or coating.

To solve this problem, the applicant has developed a coated granule combining two active ingredients of different natures, respectively a first active ingredient as a component of the whole or part of the core and a second active ingredient as a component of the whole or part of the coating.

In the remainder of the description, "coating" means a coating comprising at least one coating layer. If the coating consists of several layers, each layer should have the same composition and is applied to the core by spraying. It should be noted, however, that since one of the objectives is to obtain coated particles of as small a size as possible, it is preferred that the particles are coated with a single layer. The coating applied around the core is to be distinguished from the additional functional layer which will be obtained later, which represents the additional layer applied on the basic coating.

In other words, according to the invention, the association of two different active ingredients by the same granule makes it possible to solve the above-mentioned problems related to the non-uniformity of the population of the granules used, both in terms of size and shape.

The invention therefore relates to an active ingredient-based coated granule in which both the core and the coating contain an active ingredient, wherein the core contains a first active ingredient and the coating contains a second, essentially different, active ingredient.

The applicant has shown in patent application 02/39981 a substantially spherical particle consisting of a core coated with at least one coating, the core and the coating each containing 80 to 95% by weight of active ingredient, the remainder up to 100% consisting of at least one binder. According to this document, the active ingredient constituting the core is the same as that contained in the coating. Furthermore, only embodiments based on a single active ingredient are described in the examples.

Therefore, in order to solve the problem of uneven content of active ingredient, if the concentration of the two active ingredients in the coated granules is different, the core contains the active ingredient present in the highest dose, while the coating contains the active ingredient present in the lowest dose.

In an advantageous embodiment, the dosage ratio between the active ingredient present in the highest dose (first active ingredient) and the active ingredient present in the lowest dose (second active ingredient) is equal to or greater than 5, preferably equal to or greater than 10.

The coated particles contain two active ingredients which may be selected from any compound family, such as gastro-intestinal sedatives, antacids, analgesics, anti-inflammatory agents, coronary vasodilators, peripheral and cerebral vasodilators, anti-infectives, antibiotics, antiviral agents, antiparasitics, anticancer agents, anxiolytics, neuroleptics, central nervous system stimulants, antidepressants, antihistamines, antidiarrheals, laxatives, nutritional supplements, immunosuppressants, hypocholesterolemic agents, hormones, enzymes, antispasmodics, antianginals, drugs affecting heart rhythm, drugs for treating arterial hypertension, antimigraine drugs, drugs affecting blood coagulation, antiepileptics, muscle relaxants, drugs for treating diabetes, drugs for treating thyroid dysfunction, diuretics, appetite suppressants, anti-asthmatics, expectorants, drugs, Antitussives, mucus regulators, decongestants, hypnotics, antiemetics, hematopoietics, uricosuric agents, plant extracts and contrast agents, or any other family of compounds, the active ingredient incorporated in the tablet may be selected from the same or different families of compounds.

The pharmaceutical industry has studied in particular compositions comprising drugs of the same or different families for the treatment of serious pathological conditions requiring a combined prescription of several characteristic products, since they facilitate adherence to the treatment by reducing the number of units to be taken by the patient and sometimes allow a synergistic effect to be obtained.

The combination of active ingredients is particularly useful in the analgesic field where it is desirable to provide a synergistic effect in treating pain by combining two analgesics of appropriate potency, for example oxycodone with acetaminophen, hydrocodone with acetaminophen, acetaminophen with tramadol, or using a combination of an opioid analgesic (e.g. oxycodone) and an opioid receptor antagonist (e.g. naloxone or naltrexone), to avoid improper use of the drug due to drug addiction.

In the context of antiulcer agents, preferred compositions are those in which an antacid is combined with an antiulcer agent, such as an antacid in combination with omeprazole or lansoprazole, an antacid in combination with famotidine or ranitidine.

In a preferred combination, fenofibrate is combined with metformin or fenofibrate with simvastatin in the context of a hypocholesterolemic and antidiabetic agent.

Other fields have been studied in particular, such as pharmaceutical products effective against AIDS or anticancer drugs.

The composition of the coated granules according to the invention will vary with the particle size of the active ingredient used and the content of each active ingredient in the final coated granule.

In a first embodiment, the core comprises 100% by weight of the first active ingredient, while the coating comprises 60 to 99% by weight, preferably 80 to 99% by weight, of the second active ingredient, the remainder up to 100% consisting of at least one binder and optionally an antistatic agent.

In this first embodiment, the remainder up to 100% of the coating may also consist of binder only.

In a second embodiment, the core comprises 60 to 99% by weight, preferably 80 to 99% by weight, of the first active ingredient, and the coating comprises 60 to 99% by weight, preferably 80 to 95% by weight, of the second active ingredient, the remainder up to 100% of the core and of the coating consisting of at least one binder and optionally an antistatic agent.

In this second embodiment, the remainder up to 100% by weight of the core and the coating may consist solely of binder, which may be the same or different.

As mentioned above, in all cases it is possible to add antistatics to the suspensions or solutions used for coating.

The choice of binder will depend not only on its ability to bind the particles of active ingredient to each other in the coated core, but also on the desired functional properties of the coated core, whether or not a subsequent functional coating is present. The term "functional properties" particularly, but not exclusively, means taste masking and properties which modify or do not modify the release of the active ingredient.

In practice, the binder is chosen in particular from cellulose polymers, acrylic polymers, polyvinylpyrrolidone, vinylpyrrolidone copolymers, polyvinyl alcohol, alginic acid, sodium alginate, starch, pregelatinized starch, sucrose and its derivatives, guar gum, polyethylene glycol and mixtures thereof.

In the preparation of the core or coating, the binder is sprayed in a solvent selected from water and organic solvents, such as ethanol, isopropanol or acetone, alone or in a mixture.

As mentioned above, the core and the coating contain antistatic agents, which may in principle be present in amounts of up to 10%, preferably up to 3%, by weight of the core, and up to 10%, preferably up to 3%, by weight of the coating, and they may be selected from the group consisting of micronized or non-micronized talc, colloidal silica ((C) (R))200) Treated silica (a)R972) or precipitated silica (FR244), and mixtures thereof.

By virtue of this structure consisting of a core and a coating covering the core in a substantially spherical form, the granules according to the invention can then advantageously be coated with an additional functional layer whose composition is selected according to the desired taste-masking and/or active ingredient-releasing properties.

The composition of the additional functional layer is selected according to the physicochemical properties of the active ingredients and comprises at least one coating polymer.

The coating polymer is preferably selected from the group consisting of cellulosic polymers, acrylic polymers and mixtures thereof.

Among the cellulose polymers, ethyl cellulose, hydroxypropyl cellulose (HPC) and hydroxypropylmethyl cellulose (HPMC) are preferably selected, used alone or as a mixture.

Among the acrylic polymers, preference is given to selecting aminomethacrylate copolymers (A)RL and RS), polyacrylates: (NE) and polymethacrylate (A), (B), (C), (E)，Is thatThe registered trademark of (1).

The additional functional layer is applied by spraying a solution, suspension or colloidal dispersion of a coating polymer in a solvent or solvent mixture to form a continuous film covering the entire surface of each particle, regardless of the particle surface finish, in an amount sufficient to achieve effective taste masking, for example, upon administration of the pharmaceutical product and throughout the period of time that the coated particles remain in the oral cavity.

The thickness of the film is typically 5-75 μm, which generally depends mainly on the solubility of the active ingredient (second active ingredient) contained in the coating at the saliva pH and its more or less pronounced bitter character.

The polymer of the additional functional layer applied to the surface of the coated granules according to the invention may be up to 40%, preferably up to 20%, calculated on the weight increase of the coated agglomerates.

The solvent chosen for spraying the coating polymer contained in the additional functional layer may be water, an organic solvent (e.g. ethanol, isopropanol or acetone), or a mixture of solvents.

The additional functional layers may optionally also contain plasticizers, surfactants, antistatic agents, lubricants.

The plasticizer is used in an amount of up to 40%, preferably 15-30%, relative to the dry weight of the polymer, and is selected from the group consisting of triacetic acid citrate, acetyltributyl citrate, triacetin, tributyl citrate, diethyl phthalate, polyethylene glycol, polysorbates, mono-and di-acetylated glycerides, and mixtures thereof.

The surfactant is selected from anionic, cationic, nonionic and amphoteric surfactants.

Antistatic agents are used in amounts of up to 10%, preferably 0-3%, most preferably less than 1%, relative to the dry weight of the polymer, and are selected from the group consisting of micronized or non-micronized talc, colloidal silica: (200) Treated silica (a)R972) or precipitated silica (FP244), and mixtures thereof.

The lubricant is used in an amount of up to 10%, preferably 0-3%, most preferably less than 1%, relative to the dry weight of the polymer, and is selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium benzoate, and mixtures thereof.

The size of the coated particles is preferably in the range 50 μm to 2mm, preferably 100-800 μm, more preferably 200-500 μm, as determined by conventional means, for example using a series of calibrated mesh sizes, or by laser diffraction.

Pharmaceutical or cosmetic compositions comprising such coated particles are also an object of the present invention.

Such coated particles, which may be coated with an additional functional layer, may be used in any dosage form intended for oral administration, but are particularly suitable where the selected dosage form involves contacting the coated particles with saliva.

Particularly preferred pharmaceutical forms are powders intended for oral administration, packaged in the form of small sachets, or drinkable suspensions in liquid form, or reconstitutable suspensions by the extemporaneous addition of a volume of water, or tablets, especially multiparticulate tablets which are dispersible in the mouth or in a small volume of water.

An orally dispersible tablet is defined as a tablet which disintegrates or dissolves upon contact with saliva in the mouth, without chewing, within 60 seconds, preferably within 40 seconds, to form a suspension of particles, which may or may not be coated, and which is easy to swallow.

The disintegration time corresponds to the period from when a tablet is placed in the mouth in contact with saliva to when a suspension formed by disintegration or dissolution of the tablet in contact with saliva without chewing is swallowed.

Such tablets are described, for example, in documents EP 548356, EP 636364, EP 1003484, EP 1058538, WO 98/46215, WO 00/06126, WO 00/27357 and WO 00/51568, but the granules of the invention can also be used in other formulations equivalent to those described in the above documents.

Initially, such coated granules are released into the oral cavity after the tablets are disintegrated or dissolved by the action of saliva, and then the active ingredient is rapidly released in the gastrointestinal tract, the stomach or the duodenum.

An orally dispersible tablet is formed from the granules of the invention and an excipient mixture comprising at least a disintegrant, a soluble diluent, a lubricant and optionally a swelling agent, an osmotic agent, sweetener and flavor.

The relative proportion of the excipient mixture to the coated particles is generally from 0.4 to 10, preferably from 1 to 5, parts by weight.

The disintegrant is chosen in particular from croscarmellose sodium, commercially available as croscarmellose, crosslinked polyvinylpyrrolidone and mixtures thereof.

The amount of disintegrant is 1-20%, preferably 5-15% by weight of the tablet. In the case of mixtures, each disintegrant represents 0.5 to 15%, preferably 5 to 10%, by weight of the tablet.

The diluent may in particular be chosen from soluble agents with binding properties, preferably polyols of less than 13 carbon atoms, lactose, cellulose derivatives, preferably microcrystalline cellulose.

Preferred polyols of less than 13 carbon atoms are selected from mannitol, xylitol, sorbitol and maltitol.

The diluent is used in an amount of 20 to 90%, preferably 30 to 50%, relative to the weight of the tablet.

The soluble diluent is in the form of a directly compressible product with particles having an average diameter of 100-500 μm, or in the form of a powder with particles having an average diameter of less than 100 μm, which powder can be used alone or in admixture with the directly compressible product.

In a preferred embodiment, the polyols are used in the form of directly compressible products.

In a second preferred embodiment, the directly compressible polyol and the polyol in powder form are mixed, in which case the polyols may be the same or different, and the ratio of directly compressible polyol to pulverulent polyol is from 99/1 to 20/80, preferably from 80/20 to 20/80.

The lubricant is selected from magnesium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium benzoate, and mixtures thereof.

The lubricant is used in an amount of 0.02 to 2%, preferably 0.5 to 1%, relative to the weight of the tablet.

The lubricant is dispersed in the tableting excipient mixture and sprayed, either completely or partially, onto the tablet surface during compression.

The swelling agent is selected from microcrystalline cellulose, starch and modified starch.

The swelling agent is used in an amount of 1.0 to 15% relative to the weight of the tablet.

The penetrating agent is chosen in particular from silicas having a strong affinity for water-based solvents, such as precipitated silicas, the trade names of which are more well knownMaltodextrin, beta-cyclodextrin and mixtures thereof.

The osmotic agent is used in an amount of 0.5-5.0% relative to the weight of the tablet.

The antistatic agent may be chosen from micronized or non-micronized talc, colloidal silica (II) ((III))200) Treated silica (a)R972) or precipitated silica (FP244), and mixtures thereof.

The antistatic agent is used in an amount of 0.5-5.0% relative to the weight of the tablet.

The sweetening agent can be chosen in particular from aspartame, acesulfame potassium, saccharin sodium, neohesperidin, dihydrochalcone, sucralose, monoammonium glycyrrhizinate and mixtures thereof.

Flavors and dyes are those flavors and dyes that are conventionally used in pharmacy to prepare tablets.

The invention also relates to a method for preparing the coated granule.

The method of the invention comprises the following steps:

-preparing a core containing a first active ingredient,

-coating the core thus obtained by spraying a solution containing the second active ingredient and at least one binder,

-drying.

In a first preferred embodiment, the particles are prepared according to the following steps:

granulating a first active ingredient in powder form with a binder in the form of an aqueous or organic solution or a solvent mixture and then drying,

-coating the core thus obtained by spraying a solution or suspension containing the second active ingredient and at least one binder,

-drying.

In a second preferred embodiment, the particles are prepared according to the following steps:

-selecting crystallites with a particle size of 50 μm to 400 μm constituting the first active ingredient,

coating the microparticles by spraying a solution or suspension containing the second active ingredient and at least one binder,

-drying.

According to this embodiment, the spraying can be carried out in different or the same devices.

For granulation, high-energy granulators, planetary mixers or fluidized air beds can be conveniently used.

In the case of granulation in a fluidized-air bed, a powder mixture containing the active ingredient and optionally diluents and antistatic agents is introduced into the apparatus and then granulated by spraying a solution or suspension of the excipient containing at least one binder onto the powder mixture.

When the two active ingredients are incompatible with each other, so that accelerated degradation of one of them is observed, an optional polymeric layer can be applied between the core containing the first active ingredient and the coating containing the second active ingredient to separate the two active ingredients. This layer is then made of a polymer which can be used as a binder, preferably the same polymer as that used as binder in a certain step of the preparation of the granules, the amount of polymer applied being not more than 15%, preferably not more than 5%, calculated on the weight increase of the substance to be coated.

If the organoleptic properties of the granules are indeed necessary, an additional step of coating the coated granules thus obtained is carried out by spraying an additional functional layer which masks the taste and is subsequently dried.

All steps of the process of the invention can be carried out in a sugar-coated pan or in a perforated pan, or in a fluidized air bed.

In a preferred embodiment of the process of the invention, all the steps for preparing the coated core and for applying the additional layer are carried out in a fluidized air bed.

The fluidized air bed is equipped with spray nozzles, the direction and location of which can be selected.

This choice makes it possible to control the kinetics of particle growth and to avoid sticking phenomena, which are related to the nature of the active ingredient, to the ingredients of the sprayed binding or coating composition, and to the various parameters of the process (temperature, air pressure, solution flow rate).

According to an advantageous embodiment, the binder used to prepare the granules and the polymer used to mask the taste of the granules are the same.

The invention also relates to a process for preparing multiparticulate tablets containing coated particles.

The method of the invention comprises the following steps:

dry mixing the granules obtained according to the above process with a compression excipient,

-compressing the mixture to obtain a unit form.

Compression of the mixture may be performed on an alternating or rotary tablet press.

The pressure applied in the pressing step may be 5 to 50kN, preferably 5 to 15 kN.

The hardness of these tablets, measured according to the method of the European pharmacopoeia (2.9.8), is preferably between 1 and 10kP, more preferably between 1 and 5kP, 1kP being equal to 9.8N.

Preferably, the hardness of the multiparticulate tablet is adapted to achieve a friability of less than 2% as measured according to the methods of the european pharmacopoeia, while maintaining the same dissolution profile as that of the coated particles alone, and the disintegration time of the tablet in the mouth may be less than or equal to 60 seconds, preferably less than or equal to 40 seconds.

The tablet may have a diameter of 6-17 mm. They may be circular, oval or rectangular, with flat or concave surfaces and optionally grooved.

In the case of tablets which are dispersible in the mouth, it is also possible to use "Polo" (horse ball) shaped punches.

The mass of the tablet is 0.1-2.0 g.

The present invention will be more clearly understood from the preparation examples of the coated granules and multiparticulate tablets of the present invention. These examples are given solely as illustrations and advantageous embodiments of the invention and are not to be construed as limiting the invention in any way.

Materials and methods of analysis

Excipients used

Mannitol: sold by Roque TE220SD。

Microcrystalline cellulose:sold by FMCpH 102。

Colloidal silica: sold by BASF244FP。

HPMC: sold by SHIN-ETSU603。

Methacrylate ester copolymer:for sale100。

Aspartame: nutarsweet products.

Method of dissolution at pH 1.2

→ the device: USP type II

→ blade speed: 50rpm

→ volume: 900ml

→ temperature: 37.0 +/-0.5 DEG C

→ detection: UV spectrophotometer, hydrocodone bitartrate 210nm, oxycodone hydrochloride 280nm, acetaminophen 298 nm.

→ dissolution medium: 0.1N HCl.

Example 1: coated particles combining oxycodone hydrochloride and acetaminophen

An aqueous solution containing 30.8g oxycodone hydrochloride ("oxycodone") and 8.0g (corresponding to 25% by weight of the oxycodone) of hydroxypropylmethylcellulose ("HPMC") as binder was sprayed onto 1000g of paracetamol crystals having an average size of 350 μm in a fluidized air bed of the GPCG-3 type equipped with a hurter nozzle ("bottom spray").

In a fluidized bed of GLATT GPCG-3 air equipped with a Verster insert, by spraying a solution containing colloidal silica in an amount corresponding to 10% by dry weight of the polymerE100 alcoholic solution, coating 1038g of granules obtained after the above assembly step.

In total, 20% by weight, calculated as the weight gain of the starting material particles, was applied to the particlesE100。

The final formulation of the coated granules is shown in table 1:

TABLE 1

Example 2: orodispersible tablet comprising 325mg paracetamol and 10mg oxycodone hydrochloride Tablet formulation

The coated granules obtained in example 1 were mixed with excipients according to Table 2, and the resulting mixture was then tableted on a SVIAC PR6 tablet press equipped with 6 flat punches of 15mm diameter to give a unit dose containing on average 325mg of acetaminophen and 10mg of oxycodone.

The final formulation of the tablets thus obtained is shown in table 2: TABLE 2

The tablet had the following characteristics (table) 3:

TABLE 3

Weight (mg)	1050
		Hardness (kP)	3.5
Friability (%)	0.6
		Disintegrating in the mouth(s)	25

Dissolution tests were carried out in a medium at pH 1.2, as described previously, in order to determine the in vitro release kinetics of each of the two active ingredients (table 4):

TABLE 4

Time (minutes)	% w/w liberated paracetamol	% w/w Release of oxycodone hydrochloride
			2.5	45	80

Time (minutes)	% w/w liberated paracetamol	% w/w Release of oxycodone hydrochloride
			15	100	100
30	100	100
			60	100	100

Example 3: coated particles combining hydrocodone bitartrate and acetaminophen

An aqueous solution containing 30.8g hydrocodone bitartrate ("hydrocodone") and 9.2g hydroxypropylmethylcellulose ("HPMC") as binder (corresponding to 30% by weight of hydrocodone) was sprayed onto 1000g of paracetamol crystals having an average size of 350 μm in a fluidized air bed of the type GPCG-3 equipped with a hurter nozzle ("bottom spray").

In a fluidized bed of GLATT GPCG-3 air equipped with a Verster insert, by spraying a solution containing colloidal silica in an amount corresponding to 10% by dry weight of the polymerE100 alcoholic solution, coating 1039g of the granules obtained after the above assembly step.

In total, 20% by weight, calculated as the weight gain of the starting material particles, was applied to the particlesE100。

The final formulation of the coated granules is shown in table 5:

TABLE 5

Example 4: an oral preparation containing 325mg of acetaminophen and 10mg of hydrocodone bitartrate Dispersible tablet

The coated granules obtained in example 3 were mixed with excipients according to Table 5 and the mixture thus obtained was then compressed on a SVIAC PR6 tablet press equipped with 6 flat punches of 15mm diameter to give unit doses containing on average 325mg paracetamol and 10mg hydrocodone.

The final formulation of the tablets thus obtained is shown in table 6:

TABLE 6

These tablets have the following characteristics (table 7):

TABLE 7

Weight (mg)	1400
		Hardness (kP)	4.0
Friability (%)	0.4
		Disintegrating in the mouth(s)	30

Dissolution tests were carried out in a medium at pH 1.2, as described previously, in order to determine the in vitro release kinetics of each of the two active ingredients (table 8):

TABLE 8

Time (minutes)	% w/w liberated paracetamol	% w/w liberated hydrocodone bitartrate
			2.5	35	80
15	75	100
			30	90	100
60	100	100

Claims (13)

1. A pharmaceutical coated granule based on active ingredient, wherein both the core and the coating contain active ingredient, the core contains 60-99% by weight of a first active ingredient and the coating contains 60-99% by weight of a second, different active ingredient, the remaining up to 100% by weight of the core and the coating consisting of at least one binder and optionally an antistatic agent, wherein the ratio of the amount of the first active ingredient to the amount of the second active ingredient is equal to or greater than 5; the coating layer is directly coated on the core; the size of the coated granule is 50 μm-2 mm.

2. The coated pharmaceutical particle of claim 1, wherein the coating and up to 100% of the remainder of the core are comprised of the binder, and the binder in the coating and the core is the same or different.

3. The pharmaceutical coated granule according to claim 1 or 2, wherein the binder is selected from the group consisting of cellulose polymers, acrylic acid polymers, polyvinylpyrrolidone, vinylpyrrolidone copolymers, polyvinyl alcohol, alginic acid, sodium alginate, starch, pregelatinized starch, sucrose, guar gum and polyethylene glycol, used alone or in a mixture.

4. The coated pharmaceutical granule according to claim 1 or 2, wherein the core and/or the coating further comprises at least one antistatic agent in an amount of up to 10% by weight of the core and up to 10% by weight of the coating.

5. A pharmaceutical coated granule according to claim 1 or 2, comprising in addition to the coating an additional functional layer, the composition of which is selected according to the desired taste masking and/or active ingredient release.

6. The pharmaceutical coated granule according to claim 5, wherein the additional functional layer is composed of at least one coating polymer selected from the group consisting of cellulose polymers and acrylic polymers, alone or in a mixture.

7. A pharmaceutical composition comprising the pharmaceutically coated granules according to any one of claims 1 to 6.

8. The pharmaceutical composition of claim 7 in the form of a tablet.

9. A process for the preparation of granules coated with an active ingredient, the core of the granules containing a first active ingredient and the coating containing a second active ingredient, wherein the ratio of the amount of the first active ingredient to the amount of the second active ingredient is equal to or greater than 5; the coating layer is directly coated on the core; the coated particles have a size of 50 μm to 2mm, the method comprising the steps of:

-preparing a core containing 60-99% by weight of a first active ingredient,

-coating the core thus obtained by spraying a solution or suspension consisting of 60-99% by weight of the second active ingredient and of at least one binder and optionally of an antistatic agent,

-drying.

10. The method of claim 9, wherein the step of preparing the core comprises granulating the first active ingredient in powder form with a binder in the form of an aqueous or organic solution or solvent mixture, followed by drying.

11. The method of claim 9, wherein the preparation of the core comprises selecting crystallites having a size of 50-400 μm to constitute the first active ingredient.

12. The method according to claim 9, comprising the additional step of coating with an additional functional layer, the ingredients of which are selected according to the desired taste masking and/or active ingredient release properties, wherein the additional layer consists of at least one coating polymer selected from the group consisting of cellulosic polymers, acrylic polymers and mixtures thereof.

13. The method of claim 9, wherein the binder is selected from the group consisting of cellulosic polymers, acrylic polymers, polyvinylpyrrolidone, vinylpyrrolidone copolymers, polyvinyl alcohol, alginic acid, sodium alginate, starch, pregelatinized starch, sucrose, guar gum, and polyethylene glycol, used alone or in a mixture.