The tablet is very fast and sustained release of active substances

 

Described two-layer tablet for very fast, and then the prolonged release of active substances. The tablet includes two stacked on top of each layer. The first outer layer consists of a mixture of excipients, one or more leavening agents and the active substance. The first layer allows a very rapid release of the active substance. The second layer is in contact with the first layer and consists of a biologically non-biodegradable inert porous polymer matrix, in which the dispersed active substance. Tablets according to the invention is obtained by granulation with subsequent pressing. Preferably, the active ingredient is 2-ethoxymethyl-4(3H)-pteridine. Two-layer tablet according to the invention retain their kinetic characteristics of release of the active substance, regardless of the conditions in vivo. 2 S. and 9 C.p. f-crystals, 6 ill., table 2.

The invention relates to solid Galanova forms like pills controlled release, designed to be extremely fast, and then prolonged release of one or more active substances.

The importance of such galenical forms is neandrogennoy availability, that is especially important in the case where the patient suffers acute conditions.

However, in those cases where the active ingredients have a short duration half-life, therapeutic activity is very short. At the present time for effective treatment often requires continuous and regular introduction of the active substance. For this purpose developed numerous systems with very quick and slow release.

As a reference we can call, for example, the following patents and patent applications describing the state of the art: WO 96/03111, US 4990335, EP 352190, BE 905282, EP 106443, EP 36350, EP 615444 and EP 220670.

However, in known prior art systems, the kinetics of release of the active substance depends on many factors, such as enzymatic activity and pH value, which vary not only from individuals to individuals, but also for the same individual depending on whether they fall in an empty stomach or not. In addition, pH values change throughout the gastrointestinal tract. Thus, for known as prototype systems with very quick and slow release Proc. of the present invention was based on the task to solve the problem with pills, that would've kept their characteristics of release of active substances, regardless of the conditions in vivo.

When using the tablets according to the invention obtained quite good reproducible results, showing that the control over the rate of release can greatly utilitity during phase prolonged release of the active substance. When using the tablets according to the invention it becomes possible to optimize the introduction of the active substance in the organism, taking into account both the tolerability of the active substance by the patient, and the pharmacokinetic and metabolic profiles of the active substance.

In addition, the tablets according to the invention have the advantage from the point of view of the composition of the active substance, as a scientific selection of excipients allows you to prepare tablets with higher concentrations of active ingredients.

Thus, in particular, you can get tablets with very high doses, have a size that is acceptable for oral administration.

More specifically the invention relates to a multilayer tablets for very fast, and then the prolonged release of active substances which consists of a mixture of excipients and the first active substance, and this first layer allows a very rapid release of the first active substance, a second layer which is in contact with the first layer and consists of a biologically indecomposable inert porous polymer matrix, in which the dispersed second active substance.

The second layer in contact with the first layer, either completely or only partially covered by the first layer.

In the first case, two layers are concentric.

In the second case only one of the surfaces of the second layer is in contact with the first layer: next in the context of the present description, this type of pills labelled as containing parallel layers, with the form of tablets is not decisive, in particular, it is ovoid. In this case, it is evident that the two layers have the same outer surface and the second surface are in contact with each other.

Tablets of the invention preferably are double-layered. However, under the scope of the invention also includes a multilayer tablets, if they include a combination of the above first and second layers.

For some active substances incorporated into the matrix slow release can occur about the containing concentric layers.

Kinetics of release of the active substance in all cases depend on the precise structure of the considered layer. The kinetic characteristics of the release can be modified by appropriate selection of the nature and amount of excipients included in both layers.

One of the main characteristics of the first layer is a rapid decay in the introduction. In contrast, the second layer is a biologically indecomposable. Its matrix is inert in the sense that it is not involved in the interaction with the environment. The matrix of the second layer maintains its physical and chemical integrity during the whole time prolonged release of the active substance, regardless of the changes of pH values.

Since the first layer very rapidly disintegrates upon contact with an aqueous medium, such as a physiological environment, it is easy to understand why the release of the first active substance is practically instantaneous.

In the case of the second layer, as part of its matrix is inert (it does not decompose and does not swell in aqueous medium), the release of the second active substance is due to leaching and trim environment dissolves the active ingredient, dispersed in an inert matrix. Because the mechanism of diffusion is slow by nature, you can understand why in this case the release of the active substance is prolonged.

Since the mechanism of decomposition of the first layer is not affected at all or depend only slightly on the nature of the active substance, it is clear that a greater or lesser degree of hydrophilicity of the active substance of the second layer can affect the kinetic characteristics leaching/diffusion.

However, the invention is not limited by the nature of the active substances. Each layer can contain different active ingredients.

However, according to one of specific embodiments of the invention the first and second layers include the same active ingredient.

In particular, the active agents can be selected from any substance from the following groups (to indicate the active substances used international names are not trademarks): - drugs, active against asthma, such as 2-ethoxymethyl-4-(3H)-pteridine, and bronchodilators, such as theophylline, and/or some anti-inflammatory agents or antihistamine prepari neurological, Nephrology, eye or vascular type. As examples, Metformin, hypolipidemic agents, such as phenobarbital or pravastatin and antiatherosclerotic agents in General; - drugs that are active against the treatment of alcoholism, such as acamprosate; - peripheral analgesics, such as derivatives of para-aminophenol, such as paracetamol, salicylidene derivatives such as aspirin, diflunisal, propionic acid derivatives, such as ibuprofen, fenoprofen, Ketoprofen, derived aminoquinoline, such as floctafenine, pyrazolone derivatives, such as norepinephrin; - Central analgesics, such as dextroposition, codeine, morphine, pethidine, dextromoramide, buprenorphine, nalbuphine, pentazocine; - anti-spam tools such as tiemonium, diferin, phloroglucinol, trimebutine, pinaverium, prifinium; - nonsteroidal anti-inflammatory drugs, such as, for example:
derivatives arylpropionic acid, such as Ketoprofen, ibuprofen, naproxen, flurbiprofen, alminoprofen, tiaprofenic acid,
derivatives akriluksusnoy acids such as diclofenac, fentiazac,
derivatives arylcarbamoyl acid, such as finnova acid,
- indole derivatives such as indomethacin and exaltation,
- oxicam, such as piroxicam, tenoxicam,
- pyrazolopyrimidine derivatives such as phenylbutazone,
derivatives of indene, such as sulindac;
- steroid anti-inflammatory drugs, such as corticoide prednizolonovogo, prednizolonovuyu and metilprednisolona type;
antibiotics
-laktamovogo type, such as penicillins,
cephalosporin type, such as cefuroxime,
type inhibitors-lactamases, such as clavulanic acid,
aminoglycoside type, such as neomycin,
macrolide type, such as spiramycin, erythromycin,
tetracycline type, such as minocycline and doxycycline,
sulfa type, such as sulfadiazine,
quinolone-type, such as pefloxacin;
- anti-tuberculosis drugs such as isoniazid, rifampicin, ethambutol, pyrazinamide;
- polyene antifungal agents such as amphotericin b, nystatin,
- imidazolidinone antifungal agents such as miconazole, ketoconazole, fluconazole, flucytosine, griseofulvin;
- anti-virus agents type of zidovudine, acyclovir, Adam, such as acebutolol, celiprolol, atenolol, betaxolol, metoprolol, bisoprolol, propranolol, nadolol, timolol, tertatolol, sotalol, pindolol, penbutolol, carteolol, oxiranyl, labetalol;
- nitrated derivatives, such as isosorbide dinitrate treatment, the Mononitrate of the isosorbide, TETRANITRATE of pentaerythritol, TETRANITRATE erythritol;
- protivovarikoznye tools type sydnonimine, such as molsidomine and linsidomine;
- cardiotonic agents such as ortsiprenalin, or alternatively type digitaline, such as digoxin, digitoxin;
- diuretics, such as furosemide, bumetanide, clopamide, type thiazide, such as hydrochlorothiazide, xipamide, type dianilino acid, such as indapamide, cicletanine, spironolactone, canrenone, amiloride, triamterene;
inhibitors involved in converting enzymes, such as captopril, enalapril, lisinopril, perindopril, enalapril, ramipril, benazepril;
inhibitors of calcium, such as nifedipine, nicardipine, nitrendipin, diltiazem, verapamil, bepridil;
- antihypertensive agents, such as rilmenidine, clonidine, hydrochlorothiazide methyldopa, dihydralazine, prazosin, Oedipal, Minoxidil;
- antiarrhythmic agents such as quinidine, diz is ischemic funds such as naftidrofuryl, Trimetazidine, pentoxifylline, nicergoline, buflomedil, dihydroergotoxine, dihydroergocristine, dihydroergocryptine, moxisylyte, raubasine, vincamine, papaverine, nicotinic acid;
- vancomicina tools such as vitamin P;
- correctors hypotension, such as heptaminol;
- hormones such as thyroid hormones type of levothyroxine;
- drugs that stimulate the gastroduodenal motor function, such as cisapride, domperidone;
- an antiemetic such as metoclopramide, metopimazine, kaliprasad, odansetron, scopolamine;
- antiulcer agents such as ranitidine, famotidine, nizatidine, cimetidine, omeprazole, antiulcer means prostaglandin such as misoprostol, sukralfat, aluminum hydroxide;
- Antidiarrheals such as loperamide, Diphenoxylate, drugs that enhance the growth of bacterial flora and enhance the growth of the yeast flora;
intestinal antiseptics, such as nitrofuran;
- contraceptives, such as astroprojection;
- antianemics means, such as iron;
- antihistamines such as phenothiazines;
- vitamins, such as thiamine, nicotinamide means, such as valparola acid, phenytoin, carbamazepine, tosucceed, progabid, vigabatrin;
- funds from migraines, such as oximoron, indoramin, ergotamine derivatives sporine rye, such as digidroergotamin, methysergide, tricyclic derivatives, such as pizotifen;
- anticoagulants, such as agents that prevent the manifestation of the biological activity of vitamin K;
- anti-Parkinson's disease such as levodopa, selegiline, lisuride, bromocriptine, biperiden, orphenadrine, procyclidine, createpen, scopolamine;
- anxiolytic drug, which is derived from benzodiazepines, such as clotiazepam, tofisopam, oxazepam, alprazolam, lorazepam, bromazepam, diazepam, buspirone, alpidem, hydroxyzine, meprobamate, fearbut;
- antidepressants, such as minupren, desipramine, imipramine, clomipramine, amitriptyline, viloxazine, amineptine, fluvoxamine, fluoxetine, tianeptine, oxaprozin, maprotiline, mianserin, trazodone, modificatin, toloxatone, IMAOs;
hypnotics such as zopiclone, zolpidem and benzodiazepine derivative, such as flunitrazepam, nitrazepam, triazolam, the phenothiazines such as naprosyn, doxylamine, barbiturate derivative is involved valpromide;
- antipsychotics, such as thioxanthen, pimozide, loxapine, carpipramine, the phenothiazines, such as chlorpromazine, thioridazine, fluphenazine, derivatives butyrophenones, such as haloperidol, penfluridol, pipamperone, benperidol, benzamide derivatives, such as sulpiride, amisulpride, tiaprid, sultoprid;
the antimetabolites, such as methotrexate, mercaptopurine, fluorouracil, cytarabine, hydrochloroquine, asparaginase;
- alkylating agents, such as busulfan, pipobroman, procarbazine, nitrogen mustard derivatives, such as chlorambucil, cyclophosphamide, estramustine, melphalan, lomustin, fotemustine;
anticancer steroids, such as methoxyprogesterone, gestonorone, norethisterone, diethylstilbestrol, dienestrol;
and a more General class of peptides with therapeutic activity.

As the active substance may also be selected pharmaceutically acceptable salt of any of the above active substances, are capable of forming salts.

The content of active substance in the first layer should be determined depending on a subject to treatment of disease.

This content may be high, the content of nio from 85 to 95 wt.% in terms of the total weight of the first layer.

The second layer may contain up to 98.5 wt.% the active substance, for example from 1 to 95 wt.%, more preferably from 60 to 80%.

Numerous compositions with a very quick release known in this field, and therefore, experts in the art known technology that allows you to easily manufacture the first layer.

Thus, in particular, parts of the first layer can be chosen in such a way as to ensure rapid disintegration upon contact with water or saline environments.

It is known, for example, that in this type of layer you can turn the baking powder, the role of which consists in the ability to cause the destruction of the tablets in the presence of water or physiological environments.

These leavening agents, usually included in this layer in an amount of from 0 to 15 wt. %, preferably from 2 to 5 wt.%. Examples of such openers are alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal anhydrous silica, croscarmellose sodium, crosspovidone, guar gum, magnesium silicate and aluminum, methylcellulose, microcrystalline cellulose, polacrilin potassium, cellulose, pre-elastometry starch, sodium alginate, nitroglycol starch, make a part of the compounds, able to cause the destruction of the first layer, especially when the latter comes into contact with the acid of the gastric juice. These mixtures usually contain carbonates or bicarbonates of the alkali metal or alkaline earth metal or getsincereboot sodium.

In the layer with a very quick release may include other additives such as diluents, binders, sizing, antioxidants, colorants, sweeteners, corrigentov and podnikatel, wetting agents, Hydrophilidae agents, such as sorbitol and cyclodextrins, agents for regulating the osmotic pressure, such as mannitol, substances to adjust the pH stabilizing agents, such as trehalose and mannitol, adsorbing substances, chelating agents and passivator and resistant to the action of gastric juices excipients for the formation of a film coating type acetylcholine pulp and polymethacrylates.

As an example, can be selected any one of the following diluents: calcium carbonate, calcium sulfate, sucrose, dexterity, dextrin, dextrose, dicalcium phosphate dihydrate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, cellulose, microcrystalline cellulose, is the situation of these substances.

From binders include gum Arabic, tragacanth gum, guar gum, alginic acid, sodium alginate, carboxymethylcellulose sodium, dextrin, gelatin, hydroxyethyl cellulose, hydroxypropylcellulose, liquid glucose, magnesium silicate and aluminum, maltodextrin, povidone, pre elastometry starch, starch and Zein.

The sizing are promoting sliding substances (such as anhydrous colloidal silica, magnesium trisilicate, magnesium silicate, cellulose, starch, talc or tricalcium phosphate) or in another embodiment, represent the agents that contribute to making antifriction properties (such as calcium stearate, glycerylmonostearate, glycerylmonostearate, hydrogenated vegetable oil, paraffin, magnesium stearate, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, fumaric acid, stearic acid or zinc stearate and talc).

As examples of antioxidants include the following compounds: ascorbic acid, ascorbyl palmitate, fumaric acid, propylgallate, sodium ascorbate, and sodium metabisulfite, alpha-tocopherol, malic acid, tert-butyl-4-methoxyphenol (BHA) and VTN.

- benzylaniline, benzethonium chloride and cetrimide, which are cationogenic surfactants;
- glycerylmonostearate, esters of fatty acids and polyoxyethylenesorbitan, poly (vinyl alcohols) and sorbitan, which are nonionic surfactants.

From pH regulators known acidifying agents, for example, citric acid, hydrochloric acid, lactic acid, tartaric acid and alkalizing agents, for example, monoethanolamine, diethanolamine and triethanolamine, sodium citrate, sodium bicarbonate, sodium citrate.

Examples of absorbent substances are bentonite, colloidal anhydrous silica, kaolin, magnesium silicate and aluminum, microcrystalline cellulose, and cellulose.

As chelating agents and passivation can be used citric acid monohydrate, adetola acid, centripetal, monopotassium phosphate, potassium citrate, tartaric acid and the dihydrate of sodium citrate.

Amounts of these additives are similar to those commonly used in this field. Typically, binder prophetic Messiah.

The oil is preferably included in the composition of the first layer in an amount of from 0.01 to 10 wt.%.

Typically, the number of resistant to the action of gastric juices of excipients intended for the formation of a film coating ranges from 0.5 to 9 wt.%.

It should be noted that all of the above additives, with the exception of leavening agents, can also come in similar proportions in the composition of the layer of slow release. In addition, the layer of slow release may include diluents selected from the group comprising glycerylmonostearate, hydrogenated vegetable oils, polymethacrylates, potassium chloride and sodium chloride.

In addition, the layer of slow release may include binders, such as carbomer, ethylcellulose, hydrogenated vegetable oil, hypromellose, methylcellulose and polymethacrylates.

However, the main components of the second layer with slow release are polymeric materials, which makes it inert and biologically indecomposable properties. According to the invention under consideration polymeric materials are insoluble in water (but not the image is RME.

These polymers can play the role of binder in the composition of the second layer.

Such materials are, in particular, presents a polyvinylchloride, copolymers of vinyl acetate and vinyl chloride, copolymers of Acrylonitrile and vinylidenechloride, polydimethylsiloxane and copolymers, derivationally of (meth)acrylic acid.

Copolymers, derivateservlet of (meth)acrylic acid include copolymers of derivatives of methacrylic acid and copolymers of derivatives of acrylic acid and derivatives of methacrylic acid. As derivatives of (meth)acrylic acid are preferred ethers.

According to a preferred variant of the invention, the biologically indecomposable inert polymeric material chosen from the group comprising copolymers of acrylate and methylmethacrylate, copolymers of methacrylate ethylamine and methyl acrylate, copolymers of methacrylate ethylamine and ethyl acrylate, copolymers of methacrylate ethylamine and methylmethacrylate, copolymers of methacrylate ethylamine and methacrylate, copolymers of methacrylic acid and ethyl acrylate, copolymers of methacrylic acid and methyl methacrylate.

According to the invention "ethylamine" refers to a radical, wybranej and three With1-C4-alkylammonium. Preferably ethylamine denotes trimethylammoniumphenyl radical.

Such products come on the market, for example, by the company Rohm.

Purely as a reference, it should also mention the following substances:
copolymers Eudragit RL 30 D, Eudragit RS 30 D, Eudragit RL PO D, Eudragit RS PO D, Eudragit RL 12.5 D, Eudragit RS 12.5 D, Eudragit RL 100 Dand Eudragit RS 100, which are copolymers of esters of acrylic acid and esters of methacrylic acid with a low content of ammonium groups. These polymers are as a duplicate link to the group:

where R1denotes a hydrogen atom or a metal band, a R2denotes a methyl or ethyl group;
the copolymer Eudragit NE 30 Dthat is a neutral copoly is f">
copolymers Eudragit L 30 D-55and Eudragit L100-55who are the copolymers of methacrylic acid and ethyl acrylate in which the duplicate link has the formula

copolymers Eudragit L 100, Eudragit S 12.5, Eudragit S 100and Eudragit S 12.5who are the copolymers of methacrylic acid and methyl methacrylate, in which the duplicate link has the formula

Of these copolymers are particularly preferred copolymer was NE 30 D. In General, the use of copolymers of esters of methacrylic acid and esters of acrylic acid is preferred for any type of inert matrix.

Molecular weight polymeric material can vary within wide limits depending on the nature of the monomers included in this material.

In the case when the copolymers obtained from the above acrylic is up to 800000.

Preferably, the amount of inert polymeric materials does not exceed 25% of the total weight of the second layer, but not accounted for less than 1% of the total weight of this layer. Preferably, the quantity of polymeric materials ranged from 2.5% to 12% of the total weight of the second layer.

The entire tablet may be a coating of resistant to the action of gastric juices or intersolubility polymer film, resulting in the active substance is released only in the duodenum.

Typically, the polymeric substances used to obtain resistant to the action of gastric juices systems are acatitla cellulose, azeotroping cellulose, trimellitic cellulose or polymers or copolymers of (meth)acrylic acid.

Tablets according to the invention, generally receive a method comprising a granulation with subsequent pressing.

More specifically, the method of production, which is an object of the invention, includes the following stages:
a) obtaining a first granulate of active substance from a powder mixture of the first active ingredient, baking powder and one or more additives suitable for receiving layer for very Bystrov scoobysnack this second mixture of the active substance, of one or more biologically indecomposable inert polymeric materials and one or more additives suitable for receiving layer for prolonged release of this active substance,
C) join by pressing a well-known method of two types of granules obtained in the above stages a) and b), with taking tablets, in which the first layer, which allows for a very quick release, obtained by pressing of the granules obtained in stage a), and in which there is a second layer in contact with the first layer and the second layer is produced by extrusion of granular slow release obtained in stage b).

The first stage (stage a)) is used to obtain a granulate, which is based on the first active ingredient, and this stage after pressing allows you to get the first layer, indicated as a layer with a very quick release.

The second stage (stage b)) is used to obtain a granulate, which is based on the same active substance or other active substance, and this stage after pressing allows you to get the second layer, denoted as layer with prolonged release of ertai polymer matrix.

Stage b) is used to produce tablets by successive pressing of the granules obtained in the above stage (a) and (b).

Stages a) and b) include granulation powder form amorphous or kristallicheskikh particles. This granulation conduct a well-known method such as by wet granulation.

Method of granulation includes five major steps: (I) mixing the various components in dry form, (II) wetting, (III) the relevant granulation, (IV) drying and then (V) classification, i.e., separation by size.

Mix in the dry mixture of the powder of the excipients included in the composition of the granulate.

Moisture is added to the powder mixture of the various components of the wetting liquid, which can be water, With1-C4-alkanol, an aqueous solution of the binder or alcohol solution of the binder. According to the invention, the term "alcohol solution binder" includes both alcohol and water-alcohol solution in which the solvent is a mixture of one or more1-C4-alkanols or mixtures of water and one or more1-C4-alkanols. PR is a planetary type mixer, in the tub for mixing, in a mixer extrusion or vortex type or in the mixer-granulator rapid type.

At the stage a) acceptable wetting liquid is water, C1-C4-alkanol, an aqueous solution of the binder or alcohol solution of a binder as defined above, which is usually recommended for use in this field.

At the stage b) as the wetting liquid can be used an aqueous dispersion or organic solution not biologically decomposable (s) polymer (s) material (s). This achieves a more homogeneous distribution of the matrix. The term "organic solvent" in the context of the invention should be understood, the solution is not biologically decomposable (s) polymer (s) material (s) in an organic solvent, which is either a mixture of one or more1-C4-alkanols, or a mixture of one or more (C1-C4-alkyl)(C1-C4-alkyl)ketones, and one or more1-C4-alkanols. According to the invention preferred1-C4-alkanol is isopropanol. Similarly, when a mixture of ketone(s) and alcohol (s), I preferred the ove acrylic and/or methacrylic acid, the dispersion or solution should preferably have a viscosity of from 10 to 300 MPas, more preferably from 15 to 200 MPaC.

According to a preferred variant of the invention, the classification is carried out by sieving through a sieve with mesh size of 0.5 to 1.5 mm, preferably from 0.8 to 1.5 mm

The preferred size of the cells used in each of the stages a) and b) 1.25 mm

However, the invention is not limited by wet granulation. Thus, in particular, can be applied to other existing methods for the granulation method such as dry granulation.

The last stage (stage b)) to obtain tablets. Association granules spend the conventional method using the pellets obtained in stages a) and b).

In the case of two-layer tablets containing concentric layers, this stage includes (I) pressing in the first chamber for pressing the entire granular slow release obtained in stage b), to obtain core tablets, (II) compressing the second chamber for pressing parts, preferably 50 wt.% granulate with a very quick release, received vis higher in stage (I), (IV) careful pressing with centering the core in the second chamber for pressing, (V) adding the remaining portion of the granules with a very fast release of the second chamber for granulation and (VI) joint crushing of the granules with a very quick release with tablet obtained above in stage (IV).

In the case of two-layer tablets containing parallel layers, stage b) includes (I) careful pressing of the entire granular slow release in the chamber for pressing, and then (II) adding an entire granulate with a very quick release in this chamber for pressing and adjust its position on the tablet, obtained above in stage (I), and (III) the final stage of pressing tablets.

The relative proportions of granules with a very quick release and slow release is not decisive according to the invention.

Tablets according to the invention can be oral or vaginal route. They give you the ability to very quickly be released first to the current matter, and then the release of the second active ingredient, which is not necessarily identical to the first, occurs within 2-12 hours

Multilayer tablet according to the invention assursante are available for sale. In addition, if production is possible by appropriate selection of biologically non-biodegradable inert polymeric materials to modify the dissolution profiles in a very large range and with high accuracy depending on specific requirements.

According to a preferred variant of the invention, the use of polymer materials related to products from the Eudragit series that come to market by the Rhm. These materials are copolymers derived from methacrylic and/or acrylic acid. Due to the variety of properties of these copolymers is possible to change the profile of release of active substances.

In addition, these copolymers give get tablets very high capacity in relation to the composition (the ability to have high levels of active ingredients) and the ability to pressing.

The choice of such copolymers will also determine the possibility of applying a film coating on tablets made with the use of excipients materials such as Eudragit, to obtain resistant to the action of gastric juices coating.

On the other hand, these copolymers are absolutely inert in relation to the organization the mechanism (in particular, changes of pH values), which results in reliability, safety, high quality, reproducibility, and better portability impacts with the introduction of tablets according to the invention.

Below the invention is illustrated in the examples. When used with reference to appended Fig.1-6.

Example 1
(a) Receiving and composition of the granulate with a very quick release
The active substance is a 2-ethoxymethyl-4(3H)-pteridine, which are outlined below as EMF.

To obtain a granulate with a very quick release, indicated below as GLI-1, using the following ingredients, combined in the following proportions in terms of mass%:
EMF - 94,12
Polyvinylpyrrolidone 30 - 2,94
Crosslinked carboxymethylcellulose - 2,94
All of 100.00
The active substance, polyvinylpyrrolidone 30 and the carboxymethyl cellulose is introduced into the mixer-granulator for mixing for 3 minutes

Then in a mixer-granulator enter wetting liquid, i.e. water with an installed osmotic pressure, until then, until you get a properly designed granules and agglomerates. Then the whole product is dried (drying oven or in a fluidized bed air layer) and classify t is r /> Use the same active ingredient as in example 1.

Used biologically non-biodegradable polymeric material is Eudragit NE 30 Dsupplied by the company
To obtain granular slow release indicated below as GLP-1, using the following ingredients, combined in the following proportions in terms of mass %:
EMF - 71,70
Finely powdered lactose - 17,20
Eudragit NE 30 D- 8,80
Talc - 1,10
Magnesium stearate - 1,20
All of 100.00
The active ingredient and the lactose is introduced into the mixer-granulator for mixing for 3 minutes Then the mixture is gradually introduced as the wetting fluid Eudragit NE 30 Dthat is an aqueous dispersion of a neutral copolymer of ethyl acrylate and methyl methacrylate. If necessary, add purified water to obtain the correctly formulated granules comprising agglomerates. Then the granulate is dried in a fluidized air layer and classified using sieves with mesh size of 1.25 mm Then obtained above grasa concentric layers, and the so-called tablets with parallel layers
Described below contains parallel layers of the tablet And G is obtained by carrying out the following stages using teletrauma machine, equipped with egg-shaped molds:
(I) careful pressing in the chamber for pressing the entire granular slow release from example 1B),
(II) adding to this chamber for pressing the entire granulate with a very quick release from example 1A) on the tablet obtained in stage (1),
(III) subsequent pressing of the whole mixture, consisting of a granulate with a very quick release from example 1A) and tablets obtained above in stage (I).

Described below containing concentric layers pills D is obtained by carrying out the following stages:
(a) pressing in the first chamber for pressing the entire granular slow release from example 1B) to obtain core tablets
(b) compressing the second chamber for pressing part (approximately half) of the granulate with a very quick release from example 1A),
(C) transferring the tablets obtained in stage (a), the second chamber for pressing,
(g) careful pressing centered tablets obtained by stagename from example 1A) into the second chamber for pressing and
(e) joint crushing of the granules with a very quick release from example 1A) and tablets obtained above in stage (d).

The following table 1 shows data on the relative quantities of the used pellets for each tablet.

Example 2
The dissolution profiles of the tablets made according to example 1
The dissolution profiles of the tablets made according to the previous example, determined by UV spectrometry.

Test tablets at 37oTo contribute in the reactor, which is equipped with a system for temperature control and efficient system for mixing and pre-loaded with 1 l of water with an installed osmotic pressure. During the whole experiment the temperature in the reactor is maintained at 37oC.

After a certain period of time t take samples of the medium contained in the reactor, filtered through a filter with pore size of 0.48 μm and analyzed by UV spectrometry.

Conditions analysis using UV spectrometry
The optical density of the samples collected, which are diluted with a known volume of water established by the osmotic pressure is measured at 313 nm.

The number q prisutstvie active substance, i.e. the ECM with a known concentration. By simple calculation, you can determine the total amount of active substance released in the reactor at time t.

The dissolution profile for the tested tablets get, building a graph of the calculated quantities of the active substance in the function from the time of collection.

In Fig.1 and 2 shows the dissolution profiles obtained for the above described tablets A-D.

Example 3
Working according to the method described in example 1, receive contains parallel layers of the tablet E-And, the composition of which is given in table 2.

The composition of the granules with a very quick release, i.e., GLI-2, below, %:
EMF - 91,5
Polyvinylpyrrolidone 30 - 4,0
Crosslinked carboxymethylcellulose - 4,0
Magnesium stearate - 0,5
Just 100,0
These pellets get according to example la).

The compositions of granules slow release below, %:
GLP-2
EMF - 71,7
Finely powdered lactose - 16,0
Eudragit RSPO - 10,0
Talc - 1,1
Magnesium stearate - 1,2
Just 100,0
GLP-3
EMF - 71,7
Finely powdered lactose - 17,2
Eudragit RS30D - 8,8
Talc - 1,1
Magnesium stearate - 1,2
Just 100,0
GLP-4
EMF - 71,7
Fine on the receive according to example 1B).

Example 4
Curves of dissolution for tablets E-And receive from the graphs according to the method described in example 2. These curves are presented in Fig.3-6.


Claims

1. Two-layer tablet for very fast, and then the prolonged release of active substances, comprising two superimposed on each layer, characterized in that the first outer layer consists of a mixture of excipients, one or more leavening agents and the active substance, and that the first layer allows a very rapid release of the active substance, a second layer in contact with the first layer consists of a biologically non-biodegradable inert porous polymer matrix, in which the dispersed active substance.

2. Tablet p. 1, characterized in that the biologically non-biodegradable inert polymer matrix contains one or more biologically non-biodegradable inert polymeric materials selected from the group comprising polyvinylchloride, copolymers of vinyl acetate/vinyl chloride, copolymers derived from acrylic and/or methacrylic acid, copolymers of Acrylonitrile/vinylidenechloride and polydimethylsiloxane.

3. Tablet under item 2, the, Lucaya copolymers of acrylate esters and methacrylate, copolymers of methacrylate ethylamine and methyl acrylate, copolymers of methacrylate ethylamine and ethyl acrylate, copolymers of methacrylate ethylamine and methylmethacrylate, copolymers of methacrylate ethylamine and methacrylate, copolymers of methacrylic acid and ethyl acrylate, copolymers of methacrylic acid and methyl methacrylate.

4. Tablet under item 2 or 3, characterized in that the biologically non-biodegradable inert polymeric materials are present in the second layer in an amount of from 1 to 25 wt. %.

5. The tablet according to any one of the preceding paragraphs, characterized in that the porous polymer matrix comprises from 1 to 95 wt. % active ingredient.

6. The tablet according to any one of the preceding paragraphs, characterized in that one or more leavening agents in the first layer is chosen from the group comprising alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal anhydrous silica, croscarmellose sodium, crosspovidone, guar gum, magnesium silicate and aluminum, methylcellulose, microcrystalline cellulose, polacrilin potassium, cellulose, pre-elastometry starch, sodium alginate, nitrilic is 7. The tablet according to any one of the preceding paragraphs, characterized in that the first layer contains from 1 up to 99.0 wt. % active ingredient.

8. Two-layer tablet p. 1, characterized in that the second layer has an upper surface and a lower surface, and only one of these surfaces is in contact with the first layer.

9. Two-layer tablet p. 1, wherein the first layer and the second layer are concentric.

10. A method of producing a tablet according to any one of paragraphs. 1-9, comprising the following stages: a) obtaining a granulate of active substance from a powder mixture of this active ingredient, baking powder and one or more additives suitable for receiving layer for a very quick release of this active substance, b) obtaining a granulate of active substance from a powder mixture of this active substance, one or more biologically non-biodegradable inert polymeric materials and one or more additives suitable for receiving layer for prolonged release of this active ingredient, in Association by pressing a well-known method of two types of granules obtained in the above stage (a) and (b)with receiving what W granulate, obtained in stage a), and in which there is a second layer in contact with the first layer and the second layer is produced by extrusion of granular slow release obtained in stage b).

11. The tablet according to any one of paragraphs. 1-10, characterized in that the active substance take 2-ethoxymethyl-4(3H)-pteridine.

 

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