HK1082195B

HK1082195B - Orally-dispersible multilayer tablet

Info

Publication number: HK1082195B
Application number: HK06103220.0A
Authority: HK
Inventors: Pascal Oury; Gael Lamoureux; Catherine Herry; Yann Prevost
Original assignee: Ethypharm
Priority date: 2003-06-06
Filing date: 2004-06-04
Publication date: 2014-05-30

Description

The present invention relates to a multilayer orodispersible tablet and its preparation process.

Orodispersible tablet means a tablet intended to disintegrate or solubilize in the mouth, without chewing, in contact with saliva, in less than 60 seconds, preferably in less than 40 seconds, forming a suspension of particles, easy to swallow.

The breakdown time is the time between the time the tablet is placed on the tongue and the time the suspension is swallowed as a result of the breakdown or dissolution of the tablet.

This type of tablet is for example described in documents EP 548356, EP 636364, EP 1003484, EP 1058538, WO 98/46215, WO 00/06126, WO 00/ 27357 and WO 00/51568.

When ingested, the active substance particles release the active substance into the lower gastrointestinal tract.

The orodispersible tablet is very suitable for outpatient treatment, particularly for some patients, especially the elderly or young children, who have swallowing difficulties such that they are uncomfortable or even unable to swallow tablets or capsules even with simultaneous fluid intake.

It is estimated that 50% of the population experience such difficulties, with the possible consequence of not taking the prescribed medication and thus a strong impact on the effectiveness of treatment (H. Seager, 1998, J. Pharm. Pharmacol. 50, 375-382).

Of course, these problems are exacerbated when multiple medications are taken throughout the day, thus increasing the number of times.

Orodispersible tablets containing fixed combinations of active substances would be a solution to improve adherence to long-term treatment for chronic diseases, particularly in older patients and children.

Attempts have already been made to make such tablets, for example by compressing a single mixture comprising both compression excipients and active substances.

A first technical difficulty is to achieve homogeneity of the levels of each active substance throughout the forming process, in this case the compression of the powder mixture comprising all the components of the tablet.

Powder mixtures are generally complex to control because they consist of several populations of particles of active substances and excipients, each with its own characteristics of size, density or shape.

This heterogeneity results in an increased risk of segregation, which results in a gradual unmixing of certain particle populations during storage or in the hopper for the compressor.

The final unit form then has a highly variable content of each active substance and significantly different intrinsic hardness, decomposition or palatability characteristics in the same batch.

Careful selection of active substance and excipient populations is not sufficient to eliminate this risk completely.

In addition, other solutions, applicable to orodispersible tablets, have been proposed to improve the unit of content, for example by the Applicant in patent application FR 03 01308 (not yet published), but these are not completely satisfactory in limiting the risks of incompatibility.

A second technical difficulty in the manufacture of tablets containing a combination of active substances is the choice of active substances and excipients which can be used together, because of the risk of incompatibility between the active substances themselves or between an active substance and excipients, which increases when the number of components present in the tablet is higher.

In order to reduce these risks of incompatibility, solutions have been proposed, including the preparation of multilayer tablets, which have been described for many years (Abstract from Galen Pharmacy, Le Hir, 3rd ed., p. 269, Evaluation of bilayer tablet machines - A case study.

For example, WO 03/017985 describes a multilayered dispersible tablet for oral use, which is a tablet containing clavulanate and amoxicillin in two layers made from two separate formulations. WO 94/06416 describes tablets containing at least three layers, two of which contain the same or a different active substance each, and which are prepared by compressing at least three granules. US 5.236.713 describes a controlled release preparation for a periodic release of an active ingredient, which is a multilayered preparation. JP 2000/336027 describes a method to avoid the release of two layers of particles in a single tablet by adjusting the ratio of the granules to the tablet by means of a multilayer preparation.

However, none of the above documents describes a multi-layer orodispersible tablet, i.e. intended to disintegrate or dissolve easily in the mouth by saliva.

Multi-layer tablets are composed of at least two layers that are bound together by a surface.

The layers of the tablet have their own composition and are successively formed by a compression cycle, which limits both the risks of heterogeneity of content and of physicochemical incompatibility.

However, this type of tablet requires adjustments in formulation to ensure cohesion of the different layers.

This is usually achieved by applying high compressive forces resulting in tablets with hardness values often well above 100 N, or by the presence of a binder in at least one of the layers of the tablet, in an amount effective in promoting adhesion between the layers.

In addition, the preparation of a multilayer tablet requires repeated application of compressive forces on each powder mixture.

These conditions are therefore not favourable, either for tablets intended to be rapidly disintegrated or for active substances which require a prior masking of their bitterness by means such as polymer coating, which are considered particularly sensitive to compression and the use of which is incompatible with the application of high compression forces, which increases the risk of film rupture.

Therefore, to date, only multi-layer tablets, in the form of suction tablets or lozenges, are available in solid forms for disintegration in the mouth for the administration of local active substances, limited to the oral mucosa and oropharynx and requiring no masking of taste other than the simple addition of sweeteners.

A well-known example of such tablets for sublingual administration is Solutricine® vitamin C marketed in France by THERAPLIX which is a triple-layer tablet containing tyrothrycin and ascorbic acid.

These multi-layered suction tablets have a high hardness to ensure adhesion of the layers, and have a stay time in the oral cavity of several minutes, corresponding to the time during which the tablet gradually disintegrates.

The main mechanisms of tablet decomposition, erosion and solubilization, are then directly dependent on the size of the tablet and its surface in contact with the saliva.

In addition to the constraints they pose, the solutions proposed to date for formulating combinations of active substances cannot therefore be applied to orodispersible tablets, especially when the taste of the active substances used must be masked.

There is therefore a real need for orodispersible tablets which allow the combination of different active substances, possibly coated, without the disadvantages of heterogeneity of content or incompatibility.

The applicant found, against all odds, that it was possible to obtain a multilayer orodispersible tablet.

Thus, the present invention relates to a tablet which is orodispersible and which consists of at least two layers superimposed and joined together, two of these layers each containing at least one active substance.

In its broadest sense, the present invention relates to tablets as defined in the attached claims.

Each layer contains a mixture of compression excipients.The mixture of excipients includes:at least one soluble agent less one disintegrating agent and/or at least one inflating agent.

The number of layers is limited by the resulting thickness of the tablet which should be acceptable to the patient and generally not exceed three.

In a first variant of the invention the orodispersible tablet is a two-layer tablet containing at least one active substance in each layer.

In a second variant of the invention, the orodispersible tablet is a trilayer tablet.

In this case, all three layers may contain an active substance or one of the layers may contain only excipients.

It is advantageous to interpose the excipient-only layer between the two layers, each containing at least one active substance.

According to one variant of the invention, the active substance of two layers is the same base molecule but differs in the nature of the salt or base used, or in its crystalline state polymorphic or amorphous, the solubility and/or pharmacokinetic characteristics of the molecule present in one layer being different from those of the molecule present in another layer.

According to another variant of the invention, the active substance present in each layer is chemically identical, but is shaped differently in each layer, so that in vitro and in vivo release rates are significantly different.

For example, the active substance is in the form of particles with modified release properties, e.g. prolonged, so as to release efficiently over a period of 8 to 24 hours, or delayed to release the active substance at a specific absorption site or to prevent its degradation in an unfavourable pH environment.

In this variant, the active substance of the other layer is present in an immediate form, possibly coated if the molecule requires a simple taste masking, or modified according to a different release profile from the first layer.

These release or taste masking characteristics can be achieved by any known method to achieve this result, but preferably by a polymer coating around the particle of active substance.

The plasma profile resulting from administration of such a tablet to a patient shows several peaks in plasma concentrations, corresponding to different release rates of particles from each layer, as these particles were swallowed simultaneously after disintegration of the orodispersible tablet.

The active substance (s) may be selected from any family of compounds, for example from the gastrointestinal sedatives, antacids, analgesics, anti-inflammatories, coronary vasodilators, peripheral and brain vasodilators, anti-infectious agents, antibiotics, antivirals, antiparasitics, anticancer agents, anxiolytics, neuroleptics, central nervous system stimulants, antidepressants, antihistamines, antidiarrheals, laxatives, nutritional supplements, immunosuppressants, hypocholesteroids, hormones, enzymes, anticoagulants, anti-decorative agents, anti-fungal agents, anti-diarrheal agents, anti-hypertensive agents, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagul

Err1:Expecting ',' delimiter: line 1 column 206 (char 205)

The pharmaceutically acceptable salts of the present invention may be synthesized from the basic therapeutic compound containing an acid or base fraction by conventional processes, and generally such salts may be prepared by reaction of free acid or base forms with a predetermined amount of the appropriate base or acid in water or in an organic solvent or in a mixture of water and organic solvent.

The lists of appropriate salts are listed in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418.

Err1:Expecting ',' delimiter: line 1 column 56 (char 55)

The multi-layer orodispersible tablet of the invention is particularly suitable for the combination administration of medicinal products as it reduces the number of units a patient needs to take each day and improves adherence to treatment in people with difficulty swallowing.

The associations are particularly studied by pharmaceutical laboratories, the ones mentioned below being examples without any limiting character.

Combinations of active substances are particularly useful in the field of analgesia, when a synergistic effect is sought, for example by combining morphine, oxycodone, hydrocodone or tramadol with a second analgesic such as ibuprofen or paracetamol or in the field of anti-inflammatories, by combining ketoprofen and naproxen, or diclofenac with misoprostol.

It is also possible to administer an opioid painkiller, e.g. oxycodone or morphine, with an opioid receptor antagonist, such as naloxone or naltrexone, to prevent drug abuse by drug users.

In the field of anti-ulcer medicines, the preferred combination is an anti-ulcer agent, such as a proton pump inhibitor such as omeprazole or lansoprazole, an H-2 receptor inhibitor such as famotidine or ranitidine or an antacid.

In the field of cholesterol lowering and antidiabetic drugs, it is possible to combine molecules belonging to different families, including fibrates, for example, fenofibrate, biguanides, such as metformin, or statins, such as atorvastatin or simvastatin.

Other areas are particularly studied, such as effective drugs for the AIDS virus and anticancer drugs.

The active substance, which may be between 20 μm and 1000 μm in size, may be in the form of powder or microcrystals, or in the form of granules obtained by dry, wet or hot granulation, or in the form of granules obtained by mounting on neutral media, or extrusion-sferonisation.

In the following description, the term active particle will be used to refer to any of these forms in which the active substance can be used.

The active substance, initially in powder or microcrystals, is used as a dry granule and as a solution or suspension in an aqueous or organic solvent for mounting on inert media.

The inert medium may consist of any excipient which is chemically and pharmaceutically inert, exists in particulate, crystalline or amorphous form, for example sugar derivatives such as lactose, sucrose, hydrolysed starch (maltodextrins) or cellulose.

Mixtures such as sucrose and starch, or cellulose-based are also used for the preparation of spherical inert media.

The unit particle size of the inert medium may be between 50μm and 500μm, preferably between 90μm and 150μm.

The active particle may also include one or more excipients selected from the group consisting of binders, diluents, antistatic agents, micro-pH modifying agents and mixtures thereof.

The binding agent is present in proportions of up to 15% by weight, preferably up to 10% by weight in relation to the weight of uncoated particles and may be chosen from the group comprising, inter alia, cellulosic polymers, acrylic polymers, povidones, copovidones, polyvinyl alcohols, alginic acid, sodium alginate, starch, pre-gelatinised starch, sucrose and its derivatives, guar gum, polytetylene glycols and mixtures thereof.

The diluent is present in proportions up to 95% by weight, preferably up to 50% by weight in relation to the weight of uncoated particles and may be chosen from the group comprising in particular cellulosic derivatives and preferably microcrystalline cellulose, polyols and preferably mannitol, starches alone, sugar derivatives such as lactose and mixtures thereof.

The antistatic agent is present in proportions up to 10% by weight, preferably up to 3% by weight in relation to the weight of uncoated particles and may be chosen from the group comprising colloidal silica, in particular that marketed under the brand name Aerosil®, and preferably precipitated silica, in particular that marketed under the brand name Syloïd® FP244, micronized or unmicronized talc and mixtures thereof.

The micro-pH modifier in the environment may be an acidic or alkaline compound.

The acidic agent may be any mineral or organic acid, in the form of a free acid, acid anhydride or acid salt.

This acid is chosen from the group comprising, inter alia, tartaric acid, citric acid, maleic acid, fumaric acid, malic acid, adipic acid, succinic acid, lactic acid, glycolic acid, alpha hydroxyacids, ascorbic acid and amino acids, as well as their salts and derivatives.

The alkaline compound is selected from the group comprising potassium carbonate, lithium, sodium, calcium, ammonium or L-lysine carbonate, arginine carbonate, sodium glycine carbonate, sodium amino acid carbonates, anhydrous sodium perborate, effervescent perborate, sodium perborate monohydrate, sodium percarbonate, sodium dichlorisocyanate, sodium hypochlorite, calcium hypochlorite, and mixtures thereof.

For the purposes of the present invention, the carbonate is either a carbonate, a sesquicarbonate or a hydrogen carbonate.

The amount of micro-pH modifying agent in the environment shall be between 0,5 and 20% by weight of uncoated particles, preferably between 5 and 15%, and preferably between 5 and 10% by weight of uncoated particles.

Where appropriate, the powder, microcrystals or particles of the active substance may be coated with a functional layer, the composition of which is chosen according to the desired characteristics, including taste masking and/or modified, delayed or prolonged release.

The coating composition shall be chosen according to the physico-chemical characteristics of each active substance and shall consist of at least one coating polymer.

The coating polymer may be insoluble or soluble only at certain pH values and is preferably chosen from the group comprising cellulosic polymers, acrylic polymers, vinyl polymers and mixtures thereof.

The preferred choice of cellulosic polymers shall be ethyl cellulose, hydroxypropyl cellulose (HPC) and hydroxypropyl methyl cellulose (HPMC), cellulose acetate, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose succinate phthalate, cellulose acetate, cellulose acetate trimethyllite, cellulose acetate butyrate, carboxymethyl cellulose, alone or in a mixture.

The acrylic polymers are ammonium methacrylate copolymer (Eudragit® RL and RS), polyacrylate (Eudragit® NE) and polymethylated (Eudragit® E), the methacrylic acid copolymer, marketed under the trade name Eudragit® L100 or Eudragit® L30D, Eudragit® being a registered trade mark of RÖHM.

Other polymers are for example shellac, polyvinyl acetate phthalate, or any other polymer, used alone, in combination, or combined separately.

The coating composition is preferably applied by spraying a solution, suspension or colloidal dispersion of the coating polymer in a solvent or a mixture of solvents to form a continuous film covering the entire surface of each particle, regardless of its surface condition, in sufficient quantity to allow, for example, an effective masking of the taste when taking the medicinal product and during the entire time the coated particles remain in the oral cavity.

The thickness of the film, which is generally between 5 μm and 75 μm, is most often dependent on the solubility of the active substance at the pH of the saliva and the more or less pronounced bitterness of the saliva.

The polymer is applied to the surface of particles of active substances in proportions up to 60%, preferably up to 20%, calculated as weight gain in relation to the mass of coated particles.

The solvent used to spray the coating polymer may be water, an organic solvent such as ethanol, isopropanol, acetone, methylene chloride or a mixture of solvents.

The coating composition also includes, optionally, a plasticizer, a surfactant, an antistatic agent and/or a lubricant.

The plasticizer shall be used in a proportion of not more than 40%, preferably between 15 and 30%, expressed by weight in relation to the dry weight of the polymer and selected from the group comprising triethyl citrate, acetyltributyl citrate, triacetine, tributyl citrate, diethyl phthalate, polyethylene glycols, polysorbates, mono- and diacetyl glycerides and mixtures thereof.

The surfactant is chosen from anionic, cationic, non-ionic or amphoteric surfactants.

The antistatic agent shall be used in a proportion of not more than 10% by weight, preferably between 0 and 3% by weight, preferably less than 1% by weight, calculated on the dry weight of the polymer, in the group comprising micronized or non-micronized talc, colloidal silica (Aerosil®200), treated silica (Aerosil®R972) or precipitated silica (Syloid® FP244) and mixtures thereof.

The lubricant shall be used in a proportion of not more than 10% by weight, preferably between 0 and 3% and preferably less than 1% by weight, calculated on the dry weight of the polymer and selected from the group comprising magnesium stearate, stearic acid, sodium stearyl fumarate, polyoxyethylene glycols, sodium benzoate and mixtures thereof.

The size of coated particles is usually between 50μm and 1000μm, preferably between 100μm and 800μm, and still preferably between 200 and 500μm, and is determined by conventional methods, e.g. by a set of calibrated mesh-opening sieves, or by laser diffraction.

The usually preferred particle size distribution of coated particles, determined by one of the above methods, shall be such that at least 80% by weight of the coated particle population is between 90 μm and 500 μm, and preferably between 150 μm and 500 μm, and with a D50 value between 200 and 400 μm.

The mixture of excipients present in each of the layers of the tablet is sometimes referred to in the following description as compression excipients as opposed to excipients used for the formulation of the active substance particles.

This mixture must necessarily contain at least one soluble agent, at least one disintegrating agent and/or at least one inflating agent.

The soluble agent is selected from sugars such as sucrose, lactose, fructose, dextrose, or polyols with less than 13 carbon atoms such as mannitol, xylitol, sorbitol, maltitol, lactitol, erythritol, alone or in a mixture.

The solvent is used in a proportion of 20 to 90% by weight, preferably 30 to 60% by weight, calculated by weight of each layer of the tablet.

The soluble agent shall be used in its directly compressible form, with an average particle diameter of 100 μm to 500 μm, or in the form of a powder with an average particle diameter of less than 100 μm, the powder being used alone or in combination with the directly compressible product.

Each layer of the tablet may contain a single soluble agent or a mixture of at least two soluble agents, the soluble agent being used in any case as either a directly compressible form or a non-directly compressible powder.

The tablet may contain the same soluble agent in each layer or the same mixture of soluble agents, but the composition may also vary from one layer to another, either in terms of the nature of the soluble agent, the particle size of the soluble agent, or, in the case of a mixture, the ratio of each fraction.

In a first advantageous embodiment of the tablet of the invention, each layer of the tablet contains a single soluble agent used in its directly compressible form.

In a second advantageous embodiment of the tablet of the invention, each layer of the tablet contains a mixture comprising a soluble agent in its directly compressible form and the same soluble agent in powder form, the respective proportions of the directly compressible form and the powder being between 99/1 and 20/80, preferably between 80/20 and 20/80.

In a third advantageous embodiment of the tablet of the invention, the tablet contains the same soluble agent or mixture of soluble agents in each of the layers that compose it.

The decomposition agent shall be selected from the group comprising in particular cross-linked sodium carboxymethylcellulose, referred to in the trade name croscarmellose, cross-linked polyvinylpyrrolidones, referred to in the trade name crospovidones, and mixtures thereof.

The decomposing agent shall be used in a ratio of 1 to 20% by weight, preferably 5 to 15% by weight in the case of a mixture, with each decomposing agent being between 0,5 and 15% by weight, preferably 5 to 10% by weight, calculated by weight ratio of each layer of the tablet.

The inflating agent shall be selected from the group comprising microcrystalline cellulose, starches, modified starches such as carboxymethylamidone or sodium glycolateamidone, alginic acid or sodium alginate and mixtures thereof.

The inflating agent is used in a proportion of between 1 and 15% by weight, calculated from the weight of each layer of the tablet.

In addition to the excipients mentioned above, each layer of the orodispersible tablet of the invention may optionally contain a lubricant, a permeable agent, an antistatic agent, a water-insoluble diluent, a binder, a sweetener, a flavoring agent, a dye, adjuvants.

The lubricant shall be selected from the group comprising magnesium stearate, stearic acid, sodium stearyl fumarate, polyoxyethylene glycols, sodium benzoate, a pharmaceutically acceptable oil, preferably dimethicone or liquid paraffin, and mixtures thereof.

The lubricant shall be used in a proportion of up to 2% by weight, preferably between 0.02 and 2% by weight, and preferably between 0.5 and 1% by weight, calculated by weight of each layer of the tablet.

In the first variant, the lubricant is incorporated entirely into the compression excipient mixture; in the second variant, at least a fraction of this lubricant is sprayed on the walls of the matrix and the punches at the time of compression, the said lubricant function being then in the form of a powder, or a liquid.

The quantities of lubricant used in the internal and/or external phase shall be carefully adjusted to avoid any excess affecting the cohesion of the layers at the time of final compression.

The permeable agent shall be selected from the group comprising, in particular, silica with a high affinity for aqueous solvents, such as the precipitated silica better known by the brand name Syloïd®, maltodextrins, β-cyclo-dextrins and mixtures thereof.

The permeable agent is used in a proportion of up to 5% by weight, calculated by the weight of each layer of the tablet.

The antistatic agent may be chosen from the group comprising micronized or non-micronized talc, colloidal silica (Aerosil®200), treated silica (Aerosil®R972) or precipitated silica (Syloid® FP244) and their mixtures.

The antistatic agent is used in a proportion of up to 5% by weight, calculated by the weight of each layer of the tablet.

The water-insoluble diluent may be selected from dicalcium phosphate, tricalcium phosphate or microcrystalline cellulose.

Its role is to enhance the action of the disintegrating agent by increasing the insoluble charge in the tablet.It is used in a proportion of up to 20% by weight, preferably less than 10% by weight, calculated in relation to the weight of each layer of the tablet.

The binder is used in dry form and may be a starch, sugar, polyvinylpyrrolidone or carboxymethylcellulose, alone or in a mixture.

It is preferably used in a single layer of the tablet and in a proportion of up to 15% by weight, preferably less than 10% by weight, calculated by the weight of the layer in which it is found.

The sweetener may be selected from the group comprising, inter alia, aspartame, potassium acesulfame, sodium saccharinate, neohesperidin dihydrochalcone, sucralose, monoammonium glycyrrhizinate and mixtures thereof.

Flavourings and colouring agents are those commonly used in pharmacy for the preparation of tablets.

In a particularly preferred embodiment, each layer is of a different colour from the one to which it is attached, so that the layered structure of the tablet is immediately visible.

Adjuvants may also be added to the mixture, and are chosen from the group comprising decay accelerators, e.g. amino acids or proteins, pH adjusting agents, systems to produce a boiling point, in particular carbon dioxide generators of the type used as pH adjusting agents, or surfactants.

In a coating containing a pharmaceutically active substance, the proportion of excipient mixtures to the active substance, whether coated or not, is usually between 0.4 and 10 and preferably between 1 and 5 parts by weight.

In an advantageous embodiment of the tablet of the invention, each layer of the tablet contains the same excipients so that the disintegration of the tablet of the invention gives a sensation in the mouth identical to that of an orodispersible tablet monolayer of the same qualitative composition, and the patient does not perceive any difference in the rate of disintegration between the different layers constituting the tablet.

The quantitative composition of each layer is adjusted to take into account the levels of each active substance.

The maximum mass ratio between the thickest layer and the lightest layer is 10/1.

If the dose ratio of the highest and lowest dosage active substance is greater than 10, the amount of diluent is adjusted so that the weight ratio between the layers is reduced to 10.

Tablets may be between 6 mm and 18 mm in diameter.

They may be round, oval, oblong, have a flat, concave or convex surface, and may have engravings.

Biconvex punches are used to advantage.

Tablets generally weigh between 0.1 and 2.0 grams.

The invention also relates to the method of preparation of the multilayer tablets described above.

The process according to the invention consists of the following steps: 1. preparation of at least two types of particles of active substances, possibly coated; 2. preparation of at least two dry mixtures, each containing the compression excipients and at least one type of particles of active substance; 3. pre-compression of at least one of the powder mixtures obtained above; 4. application of another mixture to the above mixture; 5. pre-compression, possibly; 6. final compression on the previously obtained pre-formed layers; Steps 4 and 5 may be repeated at least once depending on the number of layers of the tablet.

In the case of a two-layer tablet, the process according to the invention consists of the following steps: preparation of two types of active substance particles, possibly coated; preparation of two dry mixtures, each comprising the compression excipients and the active substance particles prepared above; pre-compression of one of the above mixtures in order to preform the lower layer of the tablet; application on the preformed layer of the second mixture; possibly pre-compression of the second mixture in order to preform the upper layer of the final tablet; compression.

In the case of a trilayer tablet, the process according to the invention includes the following steps: preparation of at least two types of active substance particles, possibly coated; preparation of three dry mixtures, each containing the excipients for compression, at least two of which also contain the active substance particles prepared above;pre-compression of one of the above mixtures in order to preform the lower layer of the tablet;application on the preformed layer of a second mixture;pre-compression of the second mixture in order to preform the intermediate layer of the compressed mixture on the preformed layer of the third mixture; possibly pre-compression of the mixture in order to preform the upper layer of the final compressed tablet; third compression.

In a preferred method of production, the preparation of each mixture itself consists of two steps, the first step being the mixing of the active substance, whether coated or not, with all the compression excipients except the internal lubricant, followed by a second step, in which the lubricant is added to the first mixture in whole or in part, the remaining part being then sprayed on the punches and/or on the inner face of the compression dies.

When all the lubricant is sprayed on the punches and/or on the inner face of the compression dies the second stage of the mixture is of course then removed.

The pre-compression and compression steps are carried out on an alternative or rotary compressor.

The purpose of precompression is, first, to preform the layer by stacking the powder bed in the compression matrix and, second, to degase the powder bed by rearranging the particles in such a way as to avoid the appearance of cleavage at the time of final compression, which may occur either between the layers, by failure of adhesion, or in the layer itself.

In a tablet where the layers are not of equal relative importance in mass and/or thickness, the first preformed layer is the one with the largest mass or thickness.

The stresses exerted during the pre-compression stage can range from 0.5 to 5 kN, and are generally 5 to 10 times lower than the stresses exerted during the final compression.

The stresses exerted during the compression step may vary from 5kN to 50kN, preferably from 5kN to 15kN.

The pre-compression forces applied to the powder beds can be regulated in two ways: the first is by adjusting the compression force according to the variations measured by the machine at the heights of the powder bed in the matrix; the second is by adjusting the filling volume according to the pressure measured by the punches.

The hardness of these tablets is between 1 and 6 kp, measured according to the European Pharmacopoeia method (2.9.8), with 1 kp being equal to 9.8 N.

The hardness of the multi-layer tablet is adjusted to achieve a crumbliness, as measured by the European Pharmacopoeia method, of less than 1% by weight and to allow a time of disintegration of the tablet in the mouth by saliva of less than 60 seconds, preferably less than or equal to 40 seconds.

If the tablet of the invention contains an active substance in a coated form, either to mask the taste or to delay or prolong release, the compression shall be so performed that an identical dissolution profile is maintained between the coated active substance particles before and after compression, which must be understood as not differing by more than 15% in absolute value from the percentage of active substance released at each sampling time under the same in vitro dissolution conditions.

The present invention will be better understood by means of examples of the manufacture of tablets conforming to the invention.

Excipients used

Mannitol M 300 directly compressible : PARTECK® marketed by MERCKMannitol 60 powder : Pearlitol® 160C marketed by Roquette FrèresCrospovidone : Kollidon® CL marketed by BASFSucralose : marketed by McNeillAspartame : marketed by NutrasweetRootbeer mint aroma and vanilla biscuit aroma: marketed by PharmaromeMagnesium stearate: marketed by Peter Graven

Equipment

The mixer is a 60 1 or 200 L SONECO or BSI type overturning mixer.

The compressor used in examples 1, 2 and 3 is a COURTOY R292F press with 55 type B stations, of which only 28 stations were used.

The machine has a dual feed system and can be used as a dual output for high speed compression of single-layer tablets or as a single output for the manufacture of double-layer tablets.

The compressor used in examples 4 and 5 is a FETTE PT3090 press equipped with 61 type B and 49 type D stations.

EXAMPLE 1: Orodispersible tablet with two layers containing 500 mg of paracetamol and 65 mg of caffeine. 1/ Mixtures

The first powder mixture (layer A) is prepared according to the formula in Table 1.

	FORMULA (%p/p)
PARACETAMOL ENROBE	46,9
MANNITOL M300	21,5
MANNITOL 60	21,5
KOLLIDON CL	6,9
SUCRALOSE	1,0
ROOTBEER MINT FLAVOR	1,0
BISCUIT VANILLA FLAVOR	0,2
MAGNESIUM STEARATE	1,0
TOTAL	100

The coated particles of paracetamol are obtained by granulation and coating in a fluidised air bed.

The particle size distribution is determined by laser diffraction and has the following characteristics: 98% by weight of coated particles are between 150μm and 500μm in size.

A flavoured premixture consisting of mannitol 60, Kollidon CL, sucralose and flavourings shall be prepared by mixing the various ingredients in the proportions given in Table 1 for 15 min to 10 rpm.

Add to this first mixture mannitol M300 and coated paracetamol granules in the proportions given in Table 1.

The mixing time is 20 minutes at 10 rpm.

Add lubricant to the resulting mixture by mixing (lubrication step) for 2 minutes at 10 rpm.

The second mixture, comprising the coated caffeine and the compression excipients given in Table 2, is prepared strictly according to the same protocol as described above for the first mixture.

	FORMULA (%p/p)
CAFEINE ENROBEE	42,3
MANNITOL M300	23,2
MANNITOL 60	23,2
KOLLIDON CL	7,4
SUCRALOSE	1,1
ROOTBEER MINT FLAVOR	1,1
BISCUIT VANILLA FLAVOR	0,2
GREEN COLOR	0,5
MAGNESIUM STEARATE	1,0
TOTAL	100

The caffeine-coated particles are also obtained by granulation and coating in a fluidised air bed.

The particle size distribution of these particles, determined by laser diffraction, has the following characteristics: 96% by weight of coated particles are between 150μm and 500μm in size.

2/ Compression of the

The compressor is a COURTOY R292F press with 55 type B presses, of which only 28 were used.

The first layer A (1200 mg mass) is pressed with a pre-compression force of 4.8 kN, the thickness is determined to obtain a mass of 1200 mg.

Mix B (mass 200 mg) is then introduced into the matrix on the surface of layer A.

A pre-compression of 2,3 kN is applied, before the final compression of the two layers successively formed under a force of 15,3 kN, to target a hardness of 50 to 60 N.

The punches used are round, flat and chamfered, with a diameter of 16.5 mm.

The bicontact tablets so prepared have a theoretical mass of 1400 mg and are dosed with 500 mg paracetamol and 65 mg caffeine.

The final formula of each tablet is as follows (Table 3): - What?

These tablets have the following physical and chemical characteristics (Table 4):

	MOYENNE (CV)
Poids (mg)	1400,1
(n=16)	(2,7%)
Dureté(N)	44,7
(n=10)	(16,3%)
Désintégration en bouche	Min : 20 s
(n= 6)	Max : 35 s

EXAMPLE 2 :Orally dispersed bi-layer tablet containing 325 mg of paracetamol and 37.5 mg of tramadol hydrochloride (Tramadol HCl).

A batch of 14000 double-coated tablets is prepared as follows.

1/ Mixed

All mixtures shall be prepared according to the same protocol as in example 1.

Coated paracetamol has granulometer characteristics identical to those of example 1.

The first mixture (COUPLE A, mass 800 mg) comprises on the one hand paracetamol coated with 20% (calculated as coating weight relative to coated particle weight) of a mixture of Eudragit® E100/Eudragit® NE30D polymers in a ratio of 67/33, and on the other hand the compression excipients in the proportions given in Table 5.

	FORMULE % (p/p)
PARACETAMOL ENROBE	46,0
MANNITOL M300	20,6
MANNITOL 60	20,6
KOLLIDON CL	9,4
ASPARTAME	1,9
ROOTBEER MINT FLAVOR	0,9
MAGNESIUM STEARATE	0,6
TOTAL	100

The second mixture (COUPLE B) comprises tramadol hydrochloride coated with 35% (calculated as coating weight relative to coated particle weight) of N7 ethyl cellulose and compressing excipients in the proportions given in Table 6.

Tramadol coated particles are obtained by granulation and coating in a fluidised air bed.

The particle size distribution of these particles, determined by laser diffraction, has the following characteristics:

D10%, D50% and D90% values equal to 187 μm, 330 μm and 530 μm respectively. - What?

	FORMULE % (p/p)
TRAMADOL HCL ENROBE	28,3
MANNITOL M300	27,3
MANNITOL 60	27,3
KOLLIDON CL	12,4
ASPARTAM	2,5
ROOTBEER MINT FLAVOR	1,2
GREEN COLOR	0,5
MAGNESIUM STEARATE	0,5
TOTAL	100

2/ Compression of the

Compression shall be carried out using the same equipment as in example 1.

The theoretical mean dose of each tablet is 325 mg paracetamol and 37.5 mg tramadol HCl.

The compressor is equipped with round, flat, chamfered punches with a diameter of 15 mm.

Layer A (mass 800 mg) is pressurised with a pre-compression force of 1,6 kN.

The powder mixture from layer B (mass 200 mg) is then introduced onto the surface of the pre-treated layer A.

A pre-compression force of 0,8 kN is applied, before the final compression of the two successive layers, under a force of 10 kN to target a hardness of 50 N.

In this batch of 14 000 tablets, each tablet has the following final composition (Table 7):

These tablets have the following physical and chemical characteristics (Table 8): - What?

	MOYENNE (CV)
Poids (mg)	1005,1
(n=16)	(0.42%)
Dureté (N)	40.7
(n=10)	(5.6%)
Désintégration in vitro	Min : 12 s
(n= 6)	Max : 28 s
Désintégration en bouche (n =3)	20 à 35 s
Teneur en Paracétamol	326, 7
(n = 3)	(0,9%)
Teneur en tramadol	41,7
(n = 3)	(1,6)

EXAMPLE 3: Orodispersible tablet with two layers containing 200 mg ibuprofen and 37.5 mg of tramadol hydrochloride (Tramadol HCl).

A batch of 14000 double-coated tablets is prepared as follows.

1/ Mixtures

All mixtures are prepared according to the same protocol as in example 1.

The coated particles of ibuprofen are obtained by granulation and coating in a fluidised air bed.

The particle size distribution of these particles, determined by laser diffraction, has the following characteristics: A D50 value of 258 μm, 2% by weight for particles less than 90 μm and 1% by weight for the same particles greater than 500 μm.

The first mixture (COUPLE A) comprises ibuprofen coated with 13,7% (calculated as coating weight relative to coated particulate weight) of N7 ethyl cellulose and compressing excipients in the proportions given in Table 9. - What?

	FORMULE % (p/p)
IBUPROFENE ENROBE	32,0
MANNITOL M300	27,0
MANNITOL 60	27,0
KOLLIDON CL	9,9
ASPARTAM	2,5
ROOTBEER MINT FLAVOR	1,0
MAGNESIUM STEARATE	0,6
TOTAL	100

The second mixture (COUPLE B) comprises, on the one hand, tramadol hydrochloride coated with 35% (calculated as coating weight relative to coated particle weight) ethyl cellulose N7, and, on the other hand, the compression excipients in the proportions shown in Table 10.The coated tramadol particles have size characteristics identical to those of Example 2. - What?

	FORMULE % (p/p)
TRAMADOL HCL ENROBE	28,3
MANNITOL M300	28,4
MANNITOL 60	28,4
KOLLIDON CL	10,4
ASPARTAM	2,6
ROOTBEER MINT FLAVOR	1,0
GREEN COLOR	0,5
MAGNESIUM STEARATE	0,4
TOTAL	100

2/ Compression of the

The theoretical mean dose is 200 mg ibuprofen and 37.5 mg tramadol HCl.

The first layer A (mass 800 mg) is pressurised with a pre-compression force of 1,6 kN.

The powder mixture from layer B (mass 200 mg) is then introduced into the matrix on the surface of the pre-formed layer A.

A pre-compression force of 0,8 kN is applied before the final compression of the two layers successively formed under a compression force of 10 to 12 kN, with a target hardness of 50 N.

Each tablet has the following final composition (Table 11):

These tablets have the following physical and chemical characteristics (Table 12): - What?

	MOYENNE (CV)
Poids (mg)	998, 5
(n=20)	(0,4%)
Dureté (N)	50,9
(n=10)	(8,0%)
Désintégration in vitro	Min : 14 s
(n= 6)	Max : 20 s
Désintégration en bouche	30 à 35 s
(n = 3)
Teneur en ibuprofène	205, 1
(n = 3)	(0,6%)
Teneur en tramadol	38,3
(n = 3)	(0,3%)

EXAMPLE 4 : Orodispersible tablet with two layers containing 500 mg of paracetamol and 65 mg of caffeine: 1/ Mixtures

The first powder mixture (layer A) is prepared according to the formula in Table 13. - What?

	FORMULE (% p/p)
PARACETAMOL ENROBÉ	47,2
MANNITOL M300	21,6
MANNITOL 60	21,6
KOLLIDON CL	6,9
SUCRALOSE	1,1
ROOTBEER MINT FLAVOUR	1,0
BISCUIT VANILLA FLAVOUR	0,2
STEARATE DE MAGNESIUM INTERNE	0,4
TOTAL	100

The second mixture consists of coated caffeine and compression excipients in the proportions shown in Table 14. - What?

	FORMULE (% p/p)
CAFÉINE ENROBÉE	42,5
MANNITOL M300	23,3
MANNITOL 60	23,3
KOLLIDON CL	7,5
SUCRALOSE	1,2
ROOTBEER MINT FLAVOUR	1,1
BISCUIT VANILLA FLAVOUR	0,2
GREEN COLOUR	0,5
STEARATE DE MAGNESIUM	0,4
TOTAL	100

The two mixtures are prepared according to the same protocol as in example 1.

The paracetamol and caffeine coated particles have the same particle size characteristics as in example 1

2/ Compression of the

33 stations (out of 49 D-type stations on the PT 3090 compressor) are equipped with round dimple-shaped pins 17 mm in diameter.

Magnesium stearate external lubrication is used to lubricate the punches and dies.

The first layer A (mass 1800 g) is pressed with a pre-compression force of 2,2 kN, the thickness being determined to have a mass of 1200 g.

Mix B (mass 200 g) is then introduced into the matrix on the surface of layer A.

A pre-compression of 11,2 kN is applied before the final compression of the two successive layers, under a force of 15,3 kN, to target a hardness of 70 N.

89 438 tablets are prepared with a maximum tablet manufacturing rate of 80000 tablets/ hour.

The tablets thus prepared have a theoretical mass of 1400 mg and contain a dose of 500 mg paracetamol and a dose of 65 mg caffeine.

The final composition of each tablet is as follows:

Formule unitaire (mg)
COUCHE A
PARACETAMOL ENROBÉ	556,9
MANNITOL M300	259,2
MANNITOL 60	259,2
KOLLIDON CL	83,0
SUCRALOSE	12,7
ROOTBEER MINT FLAVOUR	11,9
BISCUIT VANILLA FLAVOUR	2,4
STEARATE DE MAGNESIUM	4,7
S/TOTAL COUCHE A	1200,00

COUCHE B
CAFÉINE ENROBÉE	84,6
MANNITOL M300	46,4
MANNITOL 60	46,4
KOLLIDON CL	14,8
SUCRALOSE	2,3
ROOTBEER MINT FLAVOUR	2,1
BISCUIT VANILLA FLAVOUR	0,4
GREEN COLOUR	1,0
STEARATE DE MAGNESIUM	2,0
S/TOTAL COUCHE B	200,00
MASSE TOTALE DU COMPRIMÉ	1400,00

These tablets have the following physical and chemical characteristics (Table 16): - What?

	MOYENNE (CV)
Poids (mg)	1390,2
(n = 20)	(1,9%)
Dureté (N)	70,7
(n = 10)	(5,4%)
Désintégration en bouche	30 s
(n = 6)

EXAMPLE 5 : Orodispersible tablet with two layers containing 325 mg of paracetamol and 37.5 mg of tramadol hydrochloride (tramadol HCl): 1/ Mixed

All mixtures shall be prepared in accordance with the first step of Example 2. The paracetamol and tramadol coated particles have the same particle size characteristics as in example 2.

2/ Compression of the

The punches are round, convex (radius 25 mm) with a diameter of 16 mm.

The compressor (FETTE PT 3090) is equipped with 61 round convex prongs (radius 25 mm) with a diameter of 16 mm.

Layer A (mass 800 mg) is pressurised with a pre-compression force of 2,3 kN.

A pre-compression force of 13,0 kN is applied before the final compression of the two successive smoked layers, under a force of 37,1 kN, to target a hardness of 50 N.

93777 tablets are prepared with a maximum tablet manufacturing rate of 110 000 tablets/ hour.

The bicontact tablets so prepared have a theoretical mass of 1000 mg and contain a dose of 325 mg paracetamol and a dose of 37.5 mg tramadol HCl.

Each tablet has the following final composition (Table 17): - What?

Formule unitaire (mg)
COUCHE A
PARACETAMOL ENROBÉ	368,5
MANNITOL M300	164,5
MANNITOL 60	164,5
KOLLIDON CL	75,2
ASPARTAME	15,0
ROOTBEER MINT FLAVOUR	7,5
STEARATE DE MAGNESIUM	4,8
S/TOTAL COUCHE A	800,0

COUCHE B
TRAMADOL HCl ENROBÉ	56,6
MANNITOL M300	54,6
MANNITOL 60	54,6
KOLLIDON CL	24,7
ASPARTAME	5,0
ROOTBEER MINT FLAVOUR	2,5
GREEN COLOUR	1,0
STEARATE DE MAGNESIUM	1,0
S/TOTAL COUCHE B	200,0
MASSE TOTALE DU COMPRIMÉ	1000,0

The tablets have the following physical and chemical characteristics (Table 18):

	MOYENNE (CV)
Poids (mg)	991,4
(n = 20)	(0,6%)
Dureté (N)	51,7
(n = 10)	(5,8%)
Friabilité (%)	0,06
(n = 10)
Désintégration en bouche	20 s
(n = 6)

Claims

Tablet characterized in that it consists of at least two superimposed and integral layers, two of the said layers each comprising at least one active substance and wherein said tablet has a hardness of 1 kp (9.8 N) to 6 kp (58.8 N), a friability of less than 1% by weight, and is intended to be disintegrated or dissolved in the mouth, without chewing, on contact with saliva, in less than 60 seconds, forming a particle suspension that is easy to swallow.
Tablet according to claim 1, characterized in that it comprises 2 or 3 layers.
Tablet according to claim 1 or claim 2, characterized in that each layer comprises a mixture of excipients comprising:
- at least one soluble agent selected from the group comprising sugars, polyols with less than 13 carbon atoms, and mixtures thereof, and

- either at least one disintegrant, or at least one disintegrating agent and at least one swelling agent.
Tablet according to anyone of claims 1 to 3, characterized in that it comprises three layers, only the two outer layers comprising at least one active substance.
Tablet according to anyone of claims 1 to 4, characterized in that each layer further comprises a lubricant, a permeabilizing agent, an antistatic agent, a water-insoluble diluent, a binder, a sweetener, a flavouring, a colorant, adjuvants, alone or as mixtures.
Tablet according to claim 5, characterized in that the adjuvants are selected from the group comprising disintegration accelerators, pH adjusters, systems for generating carbon dioxide, surfactants, alone or as mixtures.
Tablet according to anyone of claims 1 to 6, characterized in that at least one of the active substances is in a modified-release form.
Tablet according to anyone of claims 1 to 7, characterized in that at least one of the active substances is in a crystalline form, or in the form of cores, comprising a coating for the purpose of taste masking.
Process for preparing the tablet according to anyone of claims 1 to 8, comprising the following steps:
1. preparation of at least two types of particles of optionally coated active substances ;

2. preparation of at least two dry mixtures each comprising tableting excipients and at least one type of particles of active substance ;

3. pre-compression of at least one of the powder mixtures obtained above with a compression force ranging from 0.5 to 5 kN ;

4. application of another mixture to the above mixture ;

5. optional pre-compression with a compression force ranging from 0.5 to 5 kN ;

6. final compression on the pre-formed layers previously obtained with a compression force ranging from 5 to 50 kN, steps 4 and 5 possibly being repeated at least once depending on the number of layers of the tablet.