PL190599B1 - Tablet featured by instantaneous and prolonged release of one or more active substances - Google Patents

Abstract

A pill characterised by an immediate and prolonged release of one or more active substances, containing at least two overlapping layers, characterised in that: - the first external surface consists of a mix of excipients and the first active substance, whereby the first described layer ensures an immediate release of the described active substance - the second layer, overlapping the first layer, consists of a non-biodegradable, non-reactive porous polymeric matrix, where the second active substance is disperged. 11. Method of obtaining the pill defined in any of the paragraphs 1-10, characterised in that it includes the following stages: a) preparing a granulate of the first active substance from the powdered mix of the above, first substance, a disintegrating agent and one or more additions useful for preparing a layer of the immediate release of the above, first active substance; b) preparing a granulate of the second active substance from a powdered mix of the above, second active substance, from one or more non-reactive polymeric non-biodegradable materials and one or more additions useful for preparing a layer of the prolonged release of the above second active substance; c) joining two granulates through pressing by a known method. The granulates were obtained in a) and b) stages for obtaining pills, whose first layer ensuring the immediate release results from pressing the granulate obtained in a) stage and the second layer overlaps the above mentioned first layer, whereby the above mentioned second layer results from pressing the granulate obtained in b) stage.

Description

The subject of the invention is galenic solid tablet forms with a controlled release of the active substance, intended for the immediate and then prolonged release of the active substance.

The importance of galenic forms of this type is undoubtedly very great. The immediate release of the active substance ensures the practically immediate availability of the active substance in the body, which is especially desirable in patients with acute disease symptoms.

However, in the case of active substances with a short half-life, the therapeutic effect is limited in time. Thus, continuous and regular delivery of the active ingredient is often necessary to ensure the effectiveness of the therapy. To date, a number of systems with immediate and sustained release of the active substance have been developed.

The following patents and patent applications illustrating the prior art WO 96/0311l, US 4,990,335, Ep 352 190, BE 905 282, EP 106 443, EP 36 350, EP 615 444 and EP 220 670 can be mentioned by way of reference. '

In the solutions known to date, the kinetics of release depends on many factors such as enzymatic activity and pH, which varies greatly depending on the individual predispositions of the patients and even depending on whether the stomach of a particular patient is filled with food or is empty. In addition, the pH conditions at different sites in the digestive tract also vary. Hence, the precise prediction of the release profile of a given substance after in vivo administration is difficult for the systems used so far, both in the case of immediate and extended release.

The object of the present invention is to provide tablets which ensure the stability of the release characteristics of the active substances in vivo regardless of the conditions of administration.

The tablets of the invention provide excellent reproducibility of the results, allowing the release rate to be properly controlled in the sustained release step of the active ingredient. The use of the tablets according to the invention makes it possible to optimize the process of delivering the active ingredient to the body taking into account both the patient's tolerance to the drug and the pharmacokinetic and metabolic profiles of the active ingredient.

In addition, the tablets according to the invention are advantageous in terms of combining the active ingredients, since the correct choice of excipients allows the formulation of tablets with higher concentrations of active ingredients.

Hence, it is possible to produce tablets with very high doses and, at the same time, small sizes, which tablets can be taken orally.

The invention relates to multilayer tablets with immediate and sustained release of active substances, comprising at least two superimposed layers, characterized in that:

- a first active condition is seen from the excipient conversion of the first active ingredient, said layer providing immediate release of said active ingredient;

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- the second layer is organized such that, while in contact with the first layer, it consists of a biodegradable, non-reactive porous polymer matrix material in which the second active substance is dispersed.

The second layer is organized such that, while in contact with the first layer, it is either completely covered with or partially covered by the first layer.

In the first case, both layers are concentric.

In the latter case, only one of the surfaces of the second layer is in contact with the first layer: in the following text, such tablet will be referred to as "having parallel layers". The shape of the tablet is irrelevant and may in particular be oval. It should be emphasized that in this case both layers have one outer surface while their other surfaces are in contact with each other.

The tablets according to the invention are preferably two-layer. However, the invention also includes multi-layer tablets which include a combination of the first and second layers in the sense as defined above.

For some active ingredients, there may be problems with the stability of the active ingredient contained in the sustained release matrix. In this case, it is preferable to prepare tablets containing concentric layers.

The kinetics of active ingredient release depends in any case on the exact composition of the layer to be analyzed. The release kinetics can be modified by adjusting the nature and amount of the excipients making up both layers.

One of the characteristics of the first layer is that it easily disintegrates directly at the site of administration into the body. The opposite property characterizes the second layer which is not biodegradable. Its matrix is non-reactive in the sense that it does not react with the surrounding environment. Regardless of changes in pH, the matrix of the second layer maintains its physical and chemical integrity during the period of sustained release of the active ingredient.

The release of the first active substance is immediate, since the first layer disintegrates immediately upon contact with an aqueous environment such as the physiological environment.

In the case of the second layer, due to the fact that the matrix that forms it is non-reactive (it does not erode and does not swell in the water environment), the release of the second active substance occurs under the influence of leaching and diffusion. The environmental water environment gradually penetrates into the non-reactive porous matrix, and then gradually the water from the environment dissolves the active substance dispersed in the non-reactive matrix. Since the diffusion mechanism is essentially slow, the release of the active ingredient is sustained.

While the disintegration mechanism of the first layer is independent or little dependent on the nature of the active ingredient, the more or less hydrophilic properties of the active ingredient in the second layer may influence the leaching / diffusion kinetics.

However, the invention is not limited by the nature of the active ingredient. Each layer of knives contain a different active ingredient.

However, it is preferable that the first and second layers contain the same active substance.

Active substances may in particular be selected from any of the following groups (the names of active substances are given in the form of modified international non-proprietary names):

drugs that work in asthma, such as 2-ethoxymethyl-4- (3H) pteridinone, and bronchodilators such as theophylline and / or certain anti-inflammatory or antihistamine types of ketotifen;

- drugs that work in cases of diabetes mellitus and related complications of the neurological, nephrological, ophthalmic or vascular type. Examples include metformin, hypolipidemic agents such as fenofibrate or pravastatin, and antiatherosclerotic agents in general;

- drugs that work in cases of alcohol therapy, such as acamprosate;

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peripheral analgesics, for example para-aminophenol derivatives such as paracetamol, salicylic acid derivatives such as aspirin, diflunisal, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, aminoquinoline derivatives such as floctafenine, pyrazine derivatives such as noramidopyrazine;

centrally acting painkillers such as dextropoxyphene, codeine, morphine, pethidine, dextromoramide, buprenorphine, nalbuphine, pentazocine;

- antispasmodics such as thiemonium, difemerin, floroglucinol, trimebutin, pinaverine, prifmium;

- non-steroidal anti-inflammatory drugs, such as, for example:

- arylpropionic acid derivatives such as ketoprofen, ibuprofen, naproxen, flurbiprofen, alminoprofen, thiaprofenic acid;

- arylacetic derivatives such as diclofenac, fenthiazac;

- aryl carboxylic derivatives such as fenbufen and etodolac;

- anthranilic derivatives or fenamates such as niflumic acid and mefenamic acid;

- indole derivatives such as indomethacin and oxamethacin;

- oxicams such as piroxicam, tenoxicam;

- pyrazole-containing derivatives such as phenylbutazone;

- indene derivatives such as sulindac;

- steroidal anti-inflammatory agents such as corticoids of the prednisone, prednisolone and methylprednisolone type;

- beta-lactam type antibiotics such as penicillins: cephalosporin type such as cefuroxime axetyl, beta-lactamase inhibitor type such as clavulanic acid, aminoglycoside type such as neomycin, macrolide type such as spiromycin, erythromycin, tetracycline type, and minocycline type such as doxocycline sulfamides such as sulfadiazine. the quinolone type such as pefloxacin;

- anti-tuberculosis agents such as isoniazid, rifampicin, ethambutol, pyrazinamide;

- polyene antifungal agents such as amphotericin B, nystatin;

- imidazole-containing antifungal agents such as miconazole, ketoconazole, fluconazole, flucytosine, griseofulvin;

- antivirals containing zidovudine, acyclovir, adamantane such as rimantadine, amantadine and moroxidine;

- beta-blockers such as acebutolol, celiprolol, atenolol, betaxolol, metoprolol, bisoprolol, propanolol, nadolol, timolol, tertatolol, sotalol, pindolol, pentobutolol, karteolol, oxiprenolol, labetalol;

- derivatives containing a nitro group such as isosorbide dinitrate, isosorbide nitrate, pentaerythrityl tetranitrate, erythrityl tetranitrate;

- sydnonimine-type anti-anginal drugs such as molsidomine and linsidomine;

- heart tonic drugs such as orciprenaline or alternatively of the digitalin type such as digoxins, digitoxins;

- diuretics such as furosemide, bumetanide, clopamide, thiazide type such as thiazide hydrochloride, xipamide, thienyl type, indapamide, cycletanine, spironolactone, canrenone, amiloride, triamterene;

- converting enzyme inhibitors such as captopril, enalapril, lisinopril, perinodopril, quinalapril, ramipril, benazepril;

- calcium inhibitors such as nifedipine, nicardipine, nitrendipine, diltiazem, verapamil, bepridil;

- antihypertensive drugs such as rilmenidine, clonidine, methyldopa, dihydralazine, prazosin, uradyipil, minoxidil;

- anti-arrhythmic drugs such as quinidine, disopyramide, cibenzoline, propafenone, flecainide, aprindine, peroxolol, mexiletine, burtilium, amiodarone;

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- anti-bleeding drugs such as naphthidrofuryl, trimetazidine, pentaxifylline, nicergoline, buflomedil, dihydroergotoxin, dihydroergocristine, dihydroergocriptine, moxysilite, raubazine, vinamine, papaverine, nicotinic acid;

- cardiovascular tonics such as vitamin PP;

- low pressure correctors such as heptaminol;

- hormones such as sodium L-thyroxine thyroid hormones;

- drugs that stimulate gastroduodenal motor functions such as cisapride, domperidone;

- antiemetic drugs such as metoclopramide, metopimazine, aliprazide, odansetron, scopolamine;

antiulcer drugs such as ranitidine, famotidine, nizatidine, cimetidine, omeprazole, prostaglandin anti-ulcer drugs such as misoprostol, sucralfate, aluminum hydroxide;

- anti-diarrheal drugs such as leporamide, diphenoxylate, drugs that strengthen the bacterial and fungal flora;

- intestinal antiseptics such as nitrofuran;

- contraceptives such as estroprogestogens;

- anti-anemia drugs such as iron;

- antihistamines such as phenothiazine;

vitamins such as thiamine, nicinamide, pyridoxine, biutin, ascorbic acid, cyanocobalamin, retinol, cholecalciferol;

- antiepileptic drugs such as valoproic acid, phenytoin, carbamazepine, ethosuximide, progabide, vigabatrin;

anti-migraine agents such as oxetorone, indoramine, ergotamine, rice derived ergot such as dihydroergotamine, methysergide, tricyclic derivatives such as pizotifene;

- anticoagulants such as anti-vitamin K type agents;

- anti-parkinsonian drugs such as L-dopa, selegiline, lisuride, bromocriptine, biperiden, orphenadrine, procyclidine, tropatepine, scopolamine;

- benzodiazepine-derived sedatives such as clothiazepam, tofisopam, oxazepam, alprazolam, lorazepam, bromazepam, prazepam, buspirone, alpid, hydroxyzine, meprobamate, febarbamate;

- antidepressants such as quinupramine, desipramine, imipramine, clomipramine, amitriptyline, viloxazine, amineptine, fluvoxamine, fluoxetine, tianeptine, oxaflosan, maprotiline, mianserins, trazodone, medifoxamine, toloxatoninases, inhibitors;

- hypnotics such as zopiclone, zolpidem and benzodiazepine derivatives such as flunitrazepam, nitrazepam, triazolam, phenothiazines such as niaprazine, doxylamine, barbiturate derivatives such as butabarbitol, amobarbital, phenobarbital;

- mood stabilizers such as lithium, valpromide;

- neuroleptics such as thioxanthene, pimozide, loxapine, carpipramine, phenothiazine derivatives such as chlorpromazine, thioridazine, fluphenazine, butyrophenone derivatives such as haloperidol, pentafluridol, pimpamerone, benperidol, benzamide derivatives such as sultiapulpiride, sultiapulpyrid;

- antimetabolites such as methotrexate, mercaptopurine, fluorouracil, cytarabine, hydroxyurea, asparaginase;

- alkylating agents such as busulfan, pipobroman, procarbazine, nitrogen mustards such as chlorambucil, cyclophosphamide, estramustine, melphalan, lomustine, fotemustine;

- anti-tumor steroids such as methoxyprogesterone, gestonorone, norethisterone, diethylstilbestrol, dienestrol;

- and peptides with a therapeutic effect in general.

The active ingredient may also be any physiologically tolerable salt of the above-mentioned active substances, which may be converted into a salt form.

The active ingredient content in the first layer is determined by the condition being treated.

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This content may, for example, be from 1-99% of the total weight of the first layer and thus may be high, even reaching 99.0% by weight, but is preferably 85-95% of the total weight of the first layer.

The second layer may contain up to 98.5% by weight of active ingredient, for example from 1 to 95% by weight, preferably 60 to 80%.

In the field of immediate release compositions, many known techniques can be used.

For example, known solutions are used, in particular, the selection of the components of the first layer in such a way as to ensure its rapid disintegration upon contact with water or physiological fluids.

In particular, it is known to incorporate a tablet disintegrating agent into such layers in the presence of water or physiological fluids.

Such disintegrants usually constitute from 0 to 15% by weight, preferably 2 to 5% by weight of the weight of the first layer. Examples of this type of disintegrating agent are alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose, anhydrous colloidal silica, cross-linked sodium carmellose, cross-linked povidone (Merck Index 12th ed .: 7879), guar gum, magnesium and sodium silicates, microcrystalline cellulose, polycrystalline cellulose , pregelatinized starch, sodium alginate, sodium starch glycolate, starch and disintegrating effervescent mixtures.

Effervescent mixtures with a disintegrating effect are substances capable of rapidly causing disintegration of the first layer, especially upon contact with digestive acids. These mixtures usually contain alkali or alkaline earth metal carbonates or bicarbonates or sodium glycine carbonate.

The immediate release layer may also contain other additives such as diluents, binders, lubricants, antioxidants, dyes, sweeteners, flavors, acidifiers, moisturizers, hydrophilizing agents such as sorbitol and cyclodextrins, osmotic pressure regulating agents such as mannitol, pH correctors. , stabilizing agents such as trehalose and mannitol, adsorbants, chelating and sequestering agents, and excipients that are film resistant to digestive agents such as, for example, cellulose acetylphthalates and polymethacrylates.

By way of example, some of the diluents which may be used alone or as a mixture thereof are listed below: calcium carbonate, calcium sulfate, sucrose, dextrates, dextrin, dextrose, dicalcium phosphate dihydrate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, cellulose , microcrystalline cellulose, sorbitol, starches, pregelatinized starch, talc, tricalcium phosphate and lactose.

The following substances can be mentioned among the binders: gum acacia, gum tragacanth, guar gum, alginic acid, sodium alginate, sodium carboxymethyl cellulose, dextrin, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, liquid glucose, magnesium and aluminum silicate, scallatin dextrin and zein.

Lubricants may be lubricants (such as anhydrous colloidal silica, magnesium trisilicate, magnesium silicate, cellulose, starch, talc or tricalcium phosphate) or alternatively anti-fading agents (such as calcium stearate, glycerol monostearate, glycerol palmitostearate, vegetable hydrogenated , paraffin, magnesium stearate, polyethylene glycol, sodium benzoate, sodium lauryl sulfonate, fumaric acid, stearic acid or zinc stearate and talc).

As examples of known antioxidants, the following compounds may be mentioned: ascorbic acid, ascorbyl palmitate, fumaric acid, propyl gallate, sodium ascorbate and sodium metabisulfite, alpha-tocopherol, malic acid, BHA and BTH.

The preferred wetting agents are:

- sodium docusate (sodium dioctyl sulfosuccinate) and sodium lauryl sulfonate, which are anionic surfactants;

- benzalkonium chloride, benzethonium chloride (Merck Index 12th Ed .: 1102), cetrimide (Merck Index 12th Ed .: 2068) which are cationic surfactants;

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- glycerol monooleate, polyoxyethylene fatty acid esters of sorbitan derivatives (Merck Index 12th ed.: 7742), (poly) vinyl alcohol and sorbitan derivatives which are nonionic surfactants.

Among the pH regulators, acidifying agents such as citric acid, hydrochloric acid, lactic acid, tartaric acid and alkalizing agents such as monoethanolamine, diethanolamine, triethanolamine, potassium citrate, sodium bicarbonate, sodium citrate dihydrate can be mentioned.

Examples of adsorbents are bentonite, anhydrous colloidal silica, kaolin, magnesium and aluminum silicates, microcrystalline cellulose and cellulose.

As chelating agents and sequestering agents, citric acid monohydrate, EDTA edetic acid, disodium phosphate, monosodium phosphate, potassium citrate, tartaric acid and sodium citrate dihydrate are used.

The amounts of the mentioned additives are within the limits normally used. Typically, the binder comprises 0.5 to 25% by weight, preferably 2 to 5% by weight of the first layer.

Lubricants are preferably 0.01 to 10% by weight of the first layer.

As a guide, the amount of the digestive-resistant film excipients is in the range 0.5 to 9% by weight.

It should be noted that all of the above-mentioned additives, with the exception of the disintegrant, can also be added to the sustained release layer, the proportions of these components then remaining the same as before. The sustained release layer may further contain diluents such as glycerol palmitostearate, hydrogenated vegetable oils, polymethacrylates, potassium chloride, and sodium chloride.

In addition, binders such as carboxypolymethylene (Carbomer: Merck Index 12th Ed. 1878), ethyl cellulose, hydrogenated vegetable oils, hydroxypropyl methyl cellulose, methyl cellulose and polymethacrylates may be added to the sustained release layer.

The basic material of the second sustained release layer, however, is a polymeric material which gives this layer its non-reactive and bio-degradable nature. The polymeric materials according to the invention are polymers or copolymers which are insoluble in water (but do not form a gel when submerged in an aqueous medium), which are unaffected by the body and are excreted in this form from the body.

These polymers can act as a binder for the second layer.

Such materials are, in particular, polyvinyl chlorides, copolymers of vinyl acetate and vinyl chloride, copolymers of acetonitrile and vinylidene chloride, polydimethylsiloxanes and copolymers derived from meth (acrylic) acids.

Methacrylic acid copolymers include copolymers of methacrylic acid derivatives and copolymers of acrylic acid derivatives and methacrylic acid derivatives. Esters are preferred as meth (acrylic) acid derivatives.

A preferred solution according to the invention are the bio-degradable non-reactive polymeric materials from the group of copolymers of ethyl acrylate and methyl methacrylate, copolymers of ethyl ammonium methacrylate and methyl acrylate, copolymers of ethyl ammonium methacrylate and ethyl acrylate, copolymers of ethyl ammonium methacrylate and methyl methacrylate copolymers and methyl methacrylate copolymers, methyl methacrylate copolymers and methyl methacrylate copolymers. ethyl acrylate, methacrylic acid and methyl methacrylate copolymers.

According to the invention, "ethylammonium" means alternatively an ammonioethyl (C 1 -C 4) alkylammonioethyl, di (C 1 -C 4) alkylammoniumethyl or tri (C 1 -C 4) alkylammonioethyl residue. Preferably, the ethylammonium moiety is a trimethylammonium ethyl group.

Materials of this type are commercially available, for example distributed by the company Rohm.

The following preparations can be mentioned as examples.

- copolymers of Eudragit RL 30 D®, Eudragit RS 30 D®, Eudragit RL PO® and Eudragit RS PO®, Eudragit RL 12.5®, Eudragit RS 12.5®, Eudragjt RL 100® and Eudragit RS 100®, which are copolymers of acrylic acid esters and low ammonium methacrylic. These polymers contain the following repeating unit represented by formula 1, wherein Ri is hydrogen or methyl and R2 is methyl or ethyl;

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- Eudragit NE 30 D® copolymer which is a neutral copolymer of ethyl acrylate and methyl methyldine in which the repeating unit has the structure given by formula 2;

- copolymer of Eudragit L 30 D-55® and Eudragit L 100-55®, which is a copolymer of methacrylic acid and ethyl acrylate, in which the repeating unit has the structure represented by the formula 3;

- copolymer of Eudragit L 100®, Eudragit L 12.5® and Eudragit S 100® Eudragit S 12.5®, which are copolymers of methacrylic acid and methyl methacrylate, in which the repeating unit has the structure expressed by formula 4.

Among the above-mentioned polymers, the NE 30 D® copolymer has proved to be particularly preferred. Generally, compared to other materials, copolymers of methacrylic acid esters and acrylic acid esters are the preferred non-active matrix material.

The molecular weight of the polymeric material can vary greatly depending on the nature of the monomer that makes up the material.

For polymers derived from the above-mentioned acrylic and / or methacrylic acid, the molecular weight is in the range 100,000 to 1,000,000, preferably between 130,000 and 800,000.

It is desirable that the content of polymeric material does not exceed 25% of the total weight of the second layer and not less than 1% of the total weight of that layer. Preferably, the content of polymeric material is between 2.5% and 12% of the total weight of the second layer.

The entire tablet may be covered with a digestive or gut-resistant thin film such that the active ingredient is only released in the duodenal transport.

Polymeric substances commonly used in the preparation of digestive-resistant systems are cellulose acetals, cellulose acatopyrionates, cellulose trimethylitonate (1,2,4-benzenetricipoxylate) or (meth) acrylic acid polymers or copolymers.

The tablets of the invention are prepared in a conventional manner, including a compression step prior to granulation.

In particular, the preparation method according to the invention comprises the steps of:

a) preparing a granule of a first active ingredient from a powdered mixture of said first active ingredient, an anti-integrating agent and one or more additives advantageous for preparing an immediate release layer of said first active ingredient;

b) preparing a granule of a second active substance from a powdered mixture of said second active substance, from one or more non-reactive polymeric biodegradable materials and from one or more additives advantageous for the preparation of a sustained release layer of said second active substance;

c) combining, in a known manner, the two granules obtained in steps a) and b) above, such that tablets are obtained, the first layer of which provides an immediate release resulting from the compression of the granules obtained in step a), and a second layer organized so as to be in contact with the above-mentioned first layer, the above-mentioned second layer being produced by pressing the sustained release granulate obtained in step b).

The task of the first step (step a)) is to form a granulate whose base substance is the first active substance, whereby a first layer is obtained by pressing, known as an immediate release layer.

The task of the second stage (stage b)) is to confine the granules with the substance. The same active substance or a different active substance, whereby a second layer, known as a sustained release layer, is obtained by sprinkling. The components of this layer are the components of the previously defined non-active polymer matrix.

Step c) consists in forming the tablet by compressing the granules obtained in the previous steps a) and b).

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Steps a) and b) involve granulating powders consisting of amorphous or crystalline grains. This granulation is carried out by known methods, for example by wet granulation.

The granulation method comprises five basic steps: (i) dry blending the components, (ii) wetting, (iii) proper granulation, (iv) drying followed by (v) sorting.

Dry mixing consists in mixing powdered excipients that are part of the granulate.

Wetting consists in adding to the powdered mixture of various components-, wetting liquids, which may be water, alkanols (C 1 -C 4), an aqueous binder solution or an alcohol binder solution. The term alcoholic detergent solution according to the invention includes both alcoholic solutions and hydroalcoholic solutions in which the solvent is a mixture of one or more alkanols (C 1 -C 4) or a mixture of water and one or more alkanols (C 1 -C 4). A preferred (Ci-C4) alkanol is isopropanol. The wetting operation is carried out in a mixer-kneader, a powder mixer or a high speed mixing granulator.

A suitable wetting agent for step a) is water, an alkanol (C 1 -C 4), an aqueous binder solution or an alcoholic binder solution as defined above and in accordance with the general recommendations in the art for carrying out such operations.

In step b), an aqueous dispersion or an organic solution of the biodegradable polymeric material (s) may be used as the wetting agent. This results in a better homogeneity of the matrix. The term "organic solution" as used herein means a solution of semi-degradable polymeric material (s) in an organic solvent which is either a mixture of one or more alkanols (C 1 -C 4) or a mixture of one or more ketones ((C 1 -C 4) -C4) alkyl- (Ci-C4) alkyl) and one or more (Ci-C4) alkanols. A preferred (C 1 -C 4) alkanol according to the invention is isopropanol. When a mixture of ketones and alkanols is used, a mixture of isopropanol and acetone is preferred.

In the case where the polymeric material is a copolymer derived from acrylic and / or methacrylic acid, the viscosity of the solution dispersion is preferably between 10 and 300 mPa, more preferably between 15 and 200 mPa.

A preferred form of sorting according to the invention is passing through a screen with a mesh size of between 0.5 and 1.5 mm, preferably between 0.8 and 1.5 mm.

A particularly preferred mesh size for both steps a) and b) is 1.25 mm.

The invention is not limited to wet granulation, however. Thus, other known granulation methods, such as the dry granulation method, can be used for this purpose.

The last step c) leads to the formation of tablets. Combining the granules obtained in steps a) and b) is carried out in a conventional manner.

In the case of bilayer tablets having concentric layers, this step comprises (i) compressing, in a first compression chamber, all the sustained release granules obtained in step b) to obtain a tablet core; (ii) pressing in the second compression chamber a portion, preferably 50% by weight, of the immediate release granulate obtained in step a) as described above; (iii) introducing and locating the tablet core obtained in the above-mentioned step (i) in the above-mentioned second compression chamber; (iv) performing a gentle compression process while centering the core in the above-mentioned second compression chamber; (v) adding the remainder of the immediate release granules to the above-mentioned second compression chamber; and (vi) combined compressing the immediate release granules onto a tablet formed in the above-mentioned step (iv).

In the case of a bilayer tablet having parallel layers, step c) comprises (i) gently compressing all of the sustained release granules in a compression chamber; and then (ii) adding all of the immediate release granules to the above-mentioned compression chamber and centering it on the tablet obtained in step (i) and (iii) final compression of the tablet discussed above.

According to the invention, the correct proportions of immediate release granule and sustained release granule are not of the greatest importance.

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The tablets of the invention may be administered orally or vaginally. They allow an immediate release of a first active ingredient followed by a second active ingredient which may alternatively be identical to the first active ingredient over a period of 2 to 12 hours.

The multilayer tablets according to the invention are particularly advantageous because their preparation is simple and conventional excipients are used in such a process. Moreover, by appropriately selecting the non-reactive polymeric biocompatible material, the dissolution curves can be profiled to a great extent to suit precisely defined needs.

A preferred embodiment of the invention is the use of the commercially available Eudragit polymeric material, which is manufactured by the Rohm company. The Eudragit series materials are copolymers derived from methacrylic and / or acrylic acid. Due to the variety of properties of these copolymers, it is possible to control the release profiles of the active ingredients.

In addition, these copolymers give the tablets obtained in this way an excellent tablet forming ability (possibility to incorporate large amounts of active ingredients) and make them compressible.

In the case of tablets with Eudragit excipients, the choice of copolymers also makes it possible to coat them with a film in order to obtain a coating resistant to digestive factors.

On the other hand, these copolymers are absolutely inert towards the organism, which enables the release of the active ingredient regardless of the influence of the organism's environment (especially changes in pH), and thus in relation to the effects associated with the administration of the tablet according to the invention, ensuring reliability and safety , quality, repeatability and better tolerance.

The examples below illustrate the invention better. Refer to Figures 1 and 2 for these examples.

Example 1

a) Preparation and formulation of immediate release granules.

The active ingredient is 2-ethoxymethyl-4 (3H) -pteridinone, which is hereinafter referred to as EMP *.

The components used to prepare the immediate release granules, which are hereinafter referred to as GLI-1, were the following substances in percent by weight:

EMP 94.12% polyvinylpyrrolidone 30 2.94% cross-linked carboxymethylcellulose_2.94%

Total 100.00%

The active ingredient, polyvinylpyrrolidone and carboxymethylcellulose are introduced into the granulating mixer and mixed for 3 minutes.

The wetting fluid and osmotic water are then introduced and the addition continued until well-formed agglomerate granules are obtained. Then the whole is dried (in an oven or a fluidized bed) and sorted on a sieve with a mesh size of 1.25 mm.

b) Preparation and formulation of sustained release granules.

The active ingredient remains as in example 1.

Eudragit NE 30 D® produced by the company Rohm is used as the non-reactive polymeric biodegradable material.

The components used to prepare the extended release granulate, which is hereinafter referred to as GLP-1, were the following substances in percent by weight:

EMP 71.70% fine lactose powder 17.20% o

Eudragit NE 30 D® 8.80% talc 1.10% magnesium stearate_1.20%

Total 100.00%

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The active ingredient and the lactose are introduced into the grapulation mixer and mixed for 3 minutes.

Eudragit N E 30 D, which is in the form of an aqueous suspension in a neutral copolymer of ethyl acrylate and methyl methacrylate, is then gradually introduced into the mixture as a wetting fluid. Purified water is added if necessary to obtain well-formed aggregates containing granules. The granules are then dried in a fluidized air bed and sorted on a sieve with a mesh size of 1.25 mm. Then talc and magnesium stearate are mixed with the obtained granules for 40 seconds.

c) Obtaining Uιbtetea zwiewymoy kowcektryce.ne and IzP zakysU ΙρΖΜek containing parallel layers.

The below-mentioned tablets, which contain layers A to D, are obtained in the subsequent steps discussed below by operating in a compression apparatus equipped with oval-shaped dies:

(i) by gently compressing in the compression chamber all of the sustained release granules in Example 1b; and (ii) by adding, in the same compression chamber, all of the immediate release granules obtained in example 1a are present on the tablet obtained in step (i); and (iii) by successively compressing all of the immediate release granules from example Ia and the tablet obtained in step (i) discussed above.

The following tablet, containing the concentric layers E, is obtained in the following steps:

a) compressing in the first compression chamber all of the sustained release granules obtained in Example 1b to obtain a tablet core;

b) compacting in a second compression chamber a portion (about half) of the immediate release granulate obtained in Example 1a;

c) transferring the tablet obtained in step a) to the above-mentioned second compression chamber;

d) gently compressing while centering the tablet obtained in step a) in the above-mentioned second compression chamber;

z) adding the remainder of the immediate release granules obtained in Example 1a to the second compression chamber, and

f) simultaneously compressing the immediate release granulate obtained in example Ia and the tablet obtained in the above mentioned step d).

Table 1 below shows the respective amounts of granules used to prepare each tablet.

Table 1

Tablet (pattern) GLI granules (mg) GLP granules (mg) Unit weight of tablets (mg) AND 425.0 558.0 983.0 B 531.2 697.5 1228.7 C. 318.7 976.3 1295.0 D 318.7 697.5 1016.2 E. 531.2 558.0 1089.2

Example 2

The dissolution curves of the tablets obtained according to the procedure described in Example 1. The dissolution curves of the tablets obtained in the previous example were determined by UV spectrometry.

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At a temperature of 37 ° C, the test tablet is introduced into the reactor, previously filled with osmotic water and equipped with a temperature-regulating system and an efficient stirrer.

The temperature of the reactor is kept at 37 ° C throughout the experiment, with continued agitation.

At constant time intervals t, samples of the solution are taken from the reactor, filtered on a 0.45 porosity filter and analyzed by UV spectrometry.

Uv spectrometry analysis conditions.

The optical density of the test samples is measured at 313 nm, diluted to known volumes with osmotic water.

The amount of active ingredient q present in the sample is determined by comparison with the optical density of a control solution of the active ingredient EMP with a known concentration. A simple calculation makes it possible to find the total amount released in the reactor at time t.

A test tablet dissolution curve is obtained by plotting a function curve of the calculated amount of active ingredient versus the sampling time.

The accompanying curves of Fig. 1 and Fig. 2 show the curves made for tablets A to E.

Example 3

By following the procedure described in Example 1, the tablets shown in Table 2 were obtained, having the layers parallel to F to I.

Table 2

Pill Type of immediate release granules Immediate-release granules (mg) Type of extended release granules Extended Release Granules (mg) F. GLI-2 327.9 GLP-2 836.8 G. GLI-2 546.4 GLP-3 697.35 H. GLI-2 327.9 GLP-4 697.35 1 GLI-2 437.15 GLP-4 557.9

The composition of GLI-2 immediate release granules is as follows:

EMP 91.5% polyvinylpyrrolidone 30 4.4% cross-linked carboxymethylcellulose 4.4% magnesium stearate 0.5%

Total 100.00%

This granulate was prepared following the procedure described in example 1a. The composition of the extended release granules is as follows:

GLP-2

EMP 71.1% fine lactose powder 16.6%

Eudragit RSPO 10.0.0 »talc 14% magnesium stearate_1

Total 100.00%

GLP-3

EMP 71.1% fine lactose powder 17.2%

Eudragit RS 30 D 8.8% talc 14% magnesium stearate_12%

Total 11 ^ 0, l ^ (^ '/

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GLP-4

EMP 71.7% fine lactose powder 17.2%

Eudragit RSPO 8.8% talc 1.1% magnesium stearate_1.2%

Total 100.00%

These granules are prepared following the procedure described in Example 1b. Example 4

The dissolution curves of tablets F to I are plotted according to the procedure described in Example%.

These curves are shown in Figs. 3 to 6.

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R,

-CKj-C — CHjC -

C = o C = o I o

AND

CH, Cl · ^. CH, cr

OR,

CH,

CH, formula 1 —CH.-CH-CH.-C—

I and

C = O C = O I I

OCjH, OH, formula 2

CH, —CHyC-CHyCHc = 0.1-0OH OCH, formula 3

CH. I ’—CHj - ^ - CHj-C—

C = O C = O I I OH OCH, formula 4

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Fig. 2

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DISSOLUTION OF THE TABLET (%)

Fig. 3

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DISSOLVED PRODUCT (mg)

Fig. 4

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DISSOLVED PRODUCT (mg)

Fig. 5

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DISSOLVED PRODUCT (mg)

Fig. 6

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DISSOLVED PRODUCT (mg)

PRAY PSODUKT (n *)

Fig. 1

Publishing Department of the UP RP. Mintage 50 copies. Price PLN 4.00.

Claims (12)

Patent claims A tablet for immediate and prolonged-release release of one or more active substances, comprising at least two overlapping layers, characterized in that: - a first outer layer consists of a mixture of excipients and a first active ingredient, said first layer providing immediate release of said active ingredient; - the second layer, placed in contact with the first layer, consists of a biodegradable, non-reactive porous polymer matrix in which a second active substance is dispersed. 2. A tablet according to claim 1 The method of claim 1, wherein the second active ingredient is identical to the first active ingredient. 3. A tablet according to claim 1 3. The process of claim 1 or 2, characterized in that the biocompatible, non-reactive porous polymer matrix comprises one or more bi-degradable non-reactive polymeric materials selected from polyvinylchlorides, vinyl acetate / vinyl chloride copolymers, acrylic and / or methacrylic acid copolymers, chlorinitrile / chlorinitrile copolymers vinylidene and polydimethylsiloxanes. 4. A tablet according to claim 1 3. A method according to claim 3, characterized in that the copolymers derived from acrylic and / or methacrylic acids are selected from the group consisting of copolymers of ethyl acrylate esters of methyl methacrylate, copolymers of ethyl ammonium methacrylate and methyl acrylate, copolymers of ethyl ammonium methacrylate and ethyl acrylate, copolymers of methacrylate methacrylate methacrylate methyl, copolymers of ethyl ammonium methacrylate and ethyl methacrylate, copolymers of methacrylic acid and ethyl acrylate, copolymers of methacrylic acid and methyl methacrylate. 5. A tablet according to claim 1 The method of claim 3, characterized in that the bio-degradable non-reactive polymer material is present in said second layer in an amount of from 1 to 25% by weight. 6. A tablet according to claim 1 The method of claim 1 or 2, characterized in that the porous polymer matrix comprises 1 to 95% by weight of said second active ingredient. 7. A tablet according to claim 1 The method of claim 1 or 2, characterized in that said first layer comprises one or more disintegrants selected from alginic acid, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, anhydrous colloidal silica, cross-linked sodium carmellose, cross-linked povidone, guar gum, magnesium and sodium methyl silicates, microcrystalline cellulose, potassium polyacrylate, cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate, starch and effervescent mixtures with a disintegrating effect. 8. A tablet according to claim 1 The method of claim 1 or 2, characterized in that said first layer contains from 1 to 99% by weight of said first active ingredient. 9. A tablet according to claim 1 2. Having two layers, characterized in that said second layer has a bottom and an upper surface, only one of the surfaces being in contact with the first layer. 10. A tablet according to claim 1 2. Having two layers, characterized in that said first layer and said second layer are concentric. A method of preparing a tablet as defined in any one of claims 1 to 10, comprising the steps of: a) preparing a granulate of an active substance from a powdered suspension of said first active substance, a disintegrating agent and one or more additives advantageous for preparing an immediate release layer of said first active substance; 190 599 b) preparing a granule of a second active substance from a powdered mixture of said second active substance, from one or more non-reactive polymeric biodegradable materials, and from one or more additives suitable for preparing a sustained release layer of said second active substance; c) joining by compression in a known manner the two granules obtained in steps a) and b) to obtain tablets, the first immediate release layer of which results from the compression of the granulate obtained in step a) and the second layer is in contact with said first layer, said second layer resulting from the compression of the granules obtained in step b). 12. A tablet according to claim 1 The method of claim 1 or 2, characterized in that said second layer comprises 2-ethoxymethyl-4 (3H) -pterizinone as active substance.