Pharmaceutical dosage forms for oral administration containing a proton pump inhibitor and a means of non-steroidal anti-inflammatory therapy

 

(57) Abstract:

The invention relates to a pharmaceutical dosage form for oral administration containing a proton pump inhibitor and one or more means of nonsteroidal anti-inflammatory therapy in the form of a metered dose of the drug, in which the proton pump inhibitor is protected intersolubility coating, means non-steroidal anti-inflammatory therapy, to a method for producing a dosage form and method for the treatment of side effects in the gastrointestinal tract as a result of treatment by means of a non-steroidal anti-inflammatory therapy. Dosage the drug is in the form of tablets with intersolubility coated, capsule or tablet dosage form with a complex structure. Dosage forms with complex structure are the most preferred. New dosed drug is particularly useful for the treatment of side effects in the gastrointestinal tract as a result of treatment by means of a non-steroidal anti-inflammatory therapy. 6 C. and 22 C.p. f-crystals.

The present invention relates to new pharmaceutical preparations for oral administration designed anti-inflammatory therapy SNPT (NSAID). The preparations according to the present invention contain kislotoustojchivy the proton pump inhibitor in combination with one or more means of nonsteroidal anti-inflammatory therapy in the form of a new dosage form, particularly a tablet dosage form.

Background of the invention

Funds non-steroidal anti-inflammatory therapy (SDPT), in particular acetylsalicylic acid are the most commonly prescribed and taken drugs in the world. Despite therapeutic advantages SNPT, their application is often necessary to limit because of the high probability of the occurrence of side effects, mainly violations in the upper part of the gastrointestinal tract such as peptic ulcers and indigestion.

The probability of formation of stomach ulcers during treatment SNPT increased 40-50 times, and the probability of formation of duodenal ulcers has increased 8-10 times (McCarty DM. Gastroenterology 1989; 96:662). The likelihood of complications of ulcers, such as bleeding and perforation of the stomach, increased by 1.5-5 times (Hawkey C. BMJ 1990; 300:278). In addition, the symptoms of digestive disorders OBS health in the UK SNPT account for 25% of cases of harmful reactions caused by drugs, but in the US the average is 21%. Therefore, adequate treatment to avoid side effects in the gastrointestinal tract under the influence SNPT.

Attempts to change the structure SNPT in order to eliminate such side effects are still unsuccessful. The most effective solution to the problem of treatment and prevention of diseases of the upper section of the gastrointestinal tract caused by SNPT, such as ulcers and digestive disorders in subjects in need of constant care SNPT is receiving SNPT in combination with the anti - weaponname drugs recommended for the treatment and/or prevention of side effects caused SNPT in the gastrointestinal tract, such as prostaglandin analogues, antagonists H2receptors or proton pump inhibitors.

Risk factors contributing to the occurrence of side effects in the upper part of the gastrointestinal tract under the influence SNPT are, for example, advanced age, existed before peptic ulcers and/or bleeding, high dose SNPT, simultaneous treatment is serious complication as bleeding or perforation should undergo preventive treatment in connection with the admission SNPT.

Funds non-steroidal anti-inflammatory therapy is primarily used for the treatment of chronic diseases, such as rheumatoid arthritis and osteoarthritis, which often affects older people. Such treatment is especially important for elderly and debilitated subjects, which is especially great the likelihood of life-threatening complications associated with treatment SNPT, such as bleeding or perforation. It is known that 50% of all deaths from peptic ulcers account for subjects receiving SNPT, and 68% of these subjects are people older than 75 years (Catford: Health Trends 1986; 18:38). This is confirmed by another study, which allows to conclude that SNPT causes first of all deaths of people older than 75 years (Guess. J Clin Epidemiol 1988; 41:35). The importance of this mode of treatment is further confirmed by the discovery that the majority of peptic ulcers caused by taking SNPT, there are no symptoms until the very moment of their occurrence.

Found that omeprazole, which is a known inhibitor of the proton pump capable of preventing erosion of the stomach is e studies have shown, that omeprazole can cure stomach ulcers and duodenal ulcers as subjects, constantly receiving SNPT, and subjects not taking this drug (Walan A. N Engl J Med 1989; 320: 69). These results became the basis for the revision of the recommendations on the prescription dose of omeprazole for the treatment of gastric ulcers and duodenal ulcers while taking SNPT approved by the health services in the UK and Sweden.

Recent studies confirm that omeprazole significantly reduces the probability of formation of stomach ulcers, duodenal ulcers, and digestive disorders in subjects, constantly receiving SNPT.

In the European patent N 0426479 describes tableted compositions containing SNPT, such as ibuprofen, and means inhibiting the formation of acid in the stomach, such as cimetidine, etc. In these compositions do not provide for the protection of the active substance, if an inhibitor of acid in the stomach is islamochristiana connection, such as a proton pump inhibitor.

In the proposed treatment regimens using SNPT and kislotoustoichivoje of proton pump inhibitor different active substances stijene good results in the course of conservative treatment. Therefore, the reception of two or more different pills creates certain inconveniences for the needy of the subject and allows you to get the most optimal results. The present invention provides new drugs for oral administration, containing two or more different active substances in the form of a single dosage forms, preferably tablets.

Some anti-ulcer drugs, such as proton pump inhibitors, subject to destruction and transformation in acidic and neutral environments, as mentioned above. From the point of view of stability, it is obvious that one of the active substances, which is a proton pump inhibitor should be protected from contact with acidic gastric juice by using Intercollege coverage. Describes the different drugs with intersolubility coating containing proton pump inhibitors (see, for example, an application for a U.S. patent N 4786505 (AB Hassle)).

It is difficult to obtain a dosage form containing a sufficiently large number of active substances. A combination of the active drug substances with different physical properties creates additional problems. When and granules with intersolubility coating, containing kislotoustojchivy a proton pump inhibitor, pressed into tablets. If intersolubility coating cannot withstand the pressure generated in the process of pressing the granules into tablets, sensitive active substance is destroyed by contact with acidic gastric juice, that is acid Intercollege layer of granules is insufficient after pressing tablets.

A brief statement of the substance of the invention

The present invention relates to dosage forms for oral administration, i.e. tablet dosage forms with complex structure, tablets with intersolubility coating, multilayer tablets, or capsules filled with several pharmaceutically active substances. The active compounds are preferably kislotoustojchivy proton pump inhibitor and one or more means of nonsteroidal anti-inflammatory therapy, with at least a proton pump inhibitor is protected intersolubility coating. These new dosage forms simplify the scheme of medical treatment and facilitate compliance with the sick mode and regimens.

Description contains kislotoustojchivy the proton pump inhibitor in the form of granules (1) with intersolubility coated in a mixture with the rapidly disintegrating granular substance, containing SNPT (2). On the tablet applied film coating (13).

Fig. 2 is a cross section of a tablet dosage form with a complex structure, containing kislotoustojchivy the proton pump inhibitor in the form of granules (1) with intersolubility coating and SNPT as cyclodextrine complex (3) in a rapidly disintegrating granular substance (4). On the tablet applied film coating (13).

Fig. 3 is a cross section of tablets with two different layers of which one layer contains kislotoustojchivy the proton pump inhibitor in the form of granules (1) with intersolubility coated in a mixture with excipients (5), and the other layer contains SNPT (6) in the gel-forming matrix with prolonged action. Different layers are separated from each other by a separating layer (12), and a tablet applied film coating (13).

Fig. 4 is a cross section of a tablet dosage form with a complex structure, containing kislotoustojchivy the proton pump inhibitor in the form of granules (1)with intersolubility coating and SNPT in the form of granules (7) with intersolubility coated in a mixture with excipients (5). On the tablet applied film coating (13).

Fig. 5 is a cross Seca in a mixture with one or more SNPT (9) and excipients (5). The pill caused intersolubility floor (11), and between the core tablet and intersolubility layer is separating layer (10).

Fig. 6 - the pill, the core of which consists of kislotoustoichivoje of proton pump inhibitor in the form of granules (1) with intersolubility coated in a mixture with the rapidly disintegrating granular substance (4) and covered with a layer SNPT and granulated substances (2). The pill caused pigmented coating (13).

Detailed description of the invention

The purpose of this invention is to provide a tablet dosage form with a complex structure for oral administration containing antiulcer agent, preferably kislotoustojchivy the proton pump inhibitor in the form of a separate structural units with intersolubility coated compressed tablet with one or more SNPT and excipients. Intersolubility coating that protects the individual structural units kislotoustoichivoje of proton pump inhibitor, has properties such that pressing said structural units pill no significant effect on acid resistance of separate organization which provides good stability of the active substances during long-term storage.

An alternative received the tablet consists of different layers, of which one layer contains kislotoustojchivy the proton pump inhibitor in the form of compacted structural units with intersolubility the floor, and the other layer contains one or more SNPT.

New dosage form preferably is a tablet dosage form with a complex structure, containing structural units kislotoustoichivoje substances with intersolubility coating and other granular active substance (or several active substances), which forms the remaining part of the compressed tablet, as shown in Fig. 1.

Alternative different active substances can be mixed with each other and pressed in the usual tablet with intersolubility coating, see Fig. 5, or both active substances are in the form of granules with intersolubility the floor, pressed in a tablet form with a complex structure with preferably rapidly disintegrating granules of inert excipients, as shown in Fig. 4.

Other possible options are described in the examples of the dosage form with a complex structure, which contain the (a) complex in order to achieve the best bio-availability, see Fig. 2, or b) the gel-forming matrix, allowing to obtain the drug slow release SNPT, see Fig. 3. Another option is a dosage form with a complex structure, containing a proton pump inhibitor in the form of a separate structural units with intersolubility coating, compressed into a tablet, which is applied by spraying a separate layer SNPT. This tablet cover pigmented film coating to protect SNPT, see Fig. 6, as some SNPT are light-sensitive and require the application of the light protection cover.

In accordance with another variant of different active substances are mixed in the dry state and fill them capsule. In the last drug kislotoustojchivy the proton pump inhibitor has the form of structural units with intersolubility coating, and SNPT has the form of granules or alternative form of structural units with a modified mode of release, such as a structural unit with intersolubility coating or structural units with coating for modified release.

SNPT can be obtained in the form of drugs with immediate effect, delayed or prolonged action. olcu some SNPT are light-sensitive substances, the drug is preferably protects the pigmented film coating, as shown in Fig. 6, or through the inclusion of pigment in one of the coatings applied to tablet dosage form.

Another purpose of this invention is to provide a divided dosage forms, such as scored tablets.

Another purpose of this invention is to provide a tablet dosage form with a complex structure, which is divided and easy to handle. Some tablet dosage forms with complex structure can be atomized in a slightly acidic aqueous liquid and to provide subjects with impaired swallowing and young children. Such a dispersed suspension of the structural units of granules of appropriate size can be used for oral administration, and for feeding through a nasogastric tube.

Below are other active components used in the dosage forms of the present invention.

The active substance

Antiulcer agent is preferably kislotoustojchivy a proton pump inhibitor. These proton pump inhibitors are, for example, to connect the
or or

X=

or

where N in the benzimidazole means that one of the carbon atoms is replaced with an R6-R9not necessarily can be replaced by a nitrogen atom without any substituents;

R1, R2and R3have the same or different values, and they are chosen from the group comprising hydrogen, alkyl, alkoxy, optionally substituted by fluorine, alkylthio, alkoxyalkyl, dialkylamino, piperidino, morpholino, halogen, phenyl, funeralcare;

R4and R5have the same or different values, and they are chosen from hydrogen, alkyl and aralkyl;

R'6is hydrogen, halogen, trifluoromethyl, alkyl and alkoxy;

R6-R9have the same or different values, they are chosen from the group comprising hydrogen, alkyl, alkoxy, halogen, halogenoalkane, alkylsulphonyl, alkoxycarbonyl, oxazolyl, triptorelin, or adjacent groups R6-R9form a ring structure, which may be further substituted;

R10is hydrogen or forms alkylenes circuit with R3;

R11and R12have the same or different values, and they are chosen from the group comprising hydrogen, halogen or alkyl, the alkyl group, CNS is licencie alkyl group, such as cycloalkenyl.

Examples of proton pump inhibitors of the formula I are:

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Lanzoprazol

Pantoprazole

Alprazol

Leminoprazole

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< / BR>
< / BR>
< / BR>
< / BR>
Omeprazole

< / BR>
Kislotoustoytchive proton pump inhibitors included in the dosage forms according to this invention, can be used in neutral form or in the form of salts of alkaline metal such as, for example, salts of Mg2+Ca2+, Na+TO+or Li+preferably salts of Mg2+. In addition, the above compounds can be used, if desired, in the form of a racemic mixture, in the form of pure enantiomers or alkali metal salts of the individual enantiomers.

Suitable proton pump inhibitors are considered, for example, in applications to the European patent EP-A1-0005129, EP-A1-174726, EP-A1-166287, application great Britain N 2163747 and applications WO 90/06925, WO 91/19711, WO 91/19712, and other particularly suitable compounds are described in applications WO 95/01977 and WO 94/27988.

In the dosage forms of the present invention can use a number SNPT in combination with a suitable proton pump inhibitor and optionally with pharmaceutically plengkung acid and ndimethylacetamide, derivatives of salicylic acid and derivatives of pyrazolidine.

In addition, the drug of the present invention may contain other funds non-steroidal anti-inflammatory therapy, for example, SNPT election in respect of cyclooxygenase 2 and NO-releasing SNPT (de Soldato P, NO-releasing NSAD:s, A new class of safer antiinflammatory analgesic and anti-pyrretic agents; The IV International meeting on side-effects of antiifinflammatory drugs 7-9, 1995).

The following examples show some suitable SNPT: acetylsalicylic acid, indomethacin, diclofenac, piroxicam, tenoxicam, ibuprofen, naproxen, Ketoprofen, nabumetone, Ketorolac, azapropazone, mefenamovaya acid, telenova acid, sulindac, diflunisal, tiaprofenic acid, derivatives podofillotoksina, acemetacin, aceclofenac, droxicam, oxaprozin, floctafenine, phenylbutazone, proglumetacin, flurbiprofen, tolmetin, fenbufen.

Active SNPT can be used in standard form or in the form of salts, hydrates, esters, and so on, you Can use a combination of two or more of the above drugs. Preferred SNPT for new dosage forms are diclofenac, ibuprofen, naproxen and piroxicam.

The process of compaction (compaction) to obtain a tablet dosage form with a complex structure should not significantly affect the acid resistance of the granules with intersolubility coating containing kislotoustojchivy a proton pump inhibitor. In other words, the mechanical properties such as ductility and hardness, and thickness is resolubilized coating, in accordance with which the acid should not decrease by more than 10% during the pressing of the granules into tablets.

The acid resistance is determined by the amount of proton pump inhibitor tablets or granules after exposure to artificial gastric juice, by definition, the United States Pharmacopeia or 0.1 M HCl solution (aqueous solution) compared respectively with not subjected to tablets and granules. The test is performed as follows. Individual tablets or granules are immersed in artificial gastric juice at a temperature of 37oC. the Tablets rapidly disintegrate and release pellets with intersolubility coating in this environment. After two hours of granules with intersolubility coating is removed and examined for the content of the proton pump inhibitor by using liquid chromatography high resolution.

Here are other typical components used in the dosage forms of the present invention.

Substance core - for pellet and structural units with intersolubility coating

The substance of the core for the individual granules with intersolubility coating you can get different with the e crystals, which caused a proton pump inhibitor optionally in a mixture with alkaline substances.

The seed crystals, which cause the proton pump inhibitor may be not water-soluble crystals of different oxides, cellulose, organic polymers and other materials, used alone or as mixtures, or they may be water-soluble crystals, representing different inorganic salts, sugar, perfect crystals and other materials, used alone or as mixtures. In addition, the seed crystals may contain a proton pump inhibitor in the form of crystals, agglomerates, pressed substances and so on, the Size of these crystals is not significant for the present invention and can vary from about 0.1 to 2 mm Crystals coated proton pump inhibitor, obtained by the coating of powder or solution/suspension, for example, using equipment for coating spray.

Before applying the proton pump inhibitor on the crystals, if desired, mixed with other components. Such components may include a binder, the surface is acceptable ingredients, used separately or as mixtures. Binders are, for example, such polymers as hypromellose, hydroxypropylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone or sugar, starches or other pharmaceutically acceptable substances with cohesive properties. Suitable surfactants are the pharmaceutically acceptable non-ionic or ionic surfactants, such as sodium lauryl sulfate.

Alternative substance core can be obtained from the proton pump inhibitor mixed with alkaline substances, and then with acceptable components. Specified substance core can be obtained by extrusion and stereopathy, clumping or pressing using a known process equipment. Substance core gain in the amount of from about 0.1 to 4 mm, preferably from 0.1 to 2 mm On the resulting material of the core can then apply additional ingredients containing a proton pump inhibitor, and/or used for further processing.

The proton pump inhibitor is mixed with pharmaceutical components to obtain necessary is against using such pharmaceutical components, as fillers, binders, lubricants, disintegrators, surfactants, and other pharmaceutically acceptable additives.

In addition, the proton pump inhibitor may be mixed with alkaline pharmaceutically acceptable substance (or substances). Such substances include, but are not limited to, sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other acceptable weak inorganic or organic acids; coprecipitate aluminum hydroxide and sodium bicarbonate; substances normally used in antacid preparations such as hydroxides of aluminum, calcium and magnesium; magnesium oxide and composite materials, such as Al2O36MgO CO212H2O, (Mg6Al2(OH)16CO34H2O, MgO Al2O32SiO2nH2O or similar compounds; organic pH-buffering substances such as trihydroxypyrimidine, basic amino acids and their salts or other pharmaceutically acceptable pH-buffering substances.

Alternative to the above is the substance of the core can be obtained by a method of drying or freezing spray.

ENT is otdelnyh granules, these granules can be covered by one or more separation layers consisting of pharmaceutical excipients, optionally containing alkaline compounds such as pH buffering compounds. Such a separating layer separates the substance of the core from the outer layers, representing intersolubility coverage. The separating layer that protects the substance of the core of the proton pump inhibitor should be water-soluble or rapidly disintegrating in water.

One or more barrier layers can be applied to the substance of the core using methods of applying coatings or films using appropriate equipment, such as a device for coating, granulation coating or apparatus with a fluidized bed, in which the coating using water and/or organic solvents. As an option, one or more barrier layers can be applied to the substance of the core through the coating of the powder material. For the separation of the layers using pharmaceutically acceptable compounds such as, for example, sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl sleep is the sodium carboxymethyl cellulose, the water-soluble salts of polymers for intersolubility coatings and the like, used alone or as mixtures. In the separation layer may be incorporated additives such as plasticizers, dyes, pigments, fillers, substances that prevent adhesion and antistatic agents, such as, for example, magnesium stearate, titanium dioxide, talc and other additives.

Optional separating layer applied to the substance of the core, may have a different thickness. The maximum thickness of the separation layer is usually limited only by the terms of the technological process. The separating layer may serve as a diffusion barrier and to be pH-buffer zone. pH-Buffering properties of the separation layer can be further enhanced by the introduction of substances selected from the group of compounds usually used in antacid preparations such as, for example, oxide, hydroxide or magnesium carbonate, hydroxide, carbonate or silicate of aluminum or calcium; composite compounds of aluminum and magnesium, such as, for example, Al2O36MgO CO212H2O, (Mg6Al2(OH)16CO34H2O), MgAl2O32SiO2nH2O, coprecipitate aluminum hydroxide and sodium bicarbonate Il is reavie, potassium, calcium, magnesium and aluminium salts of phosphoric, carbonic, citric acid or other acceptable weak inorganic or organic acids; or acceptable organic bases, including basic amino acids and their salts. You can add talc or other compounds to increase the thickness of the layer and, thus, to make a more durable barrier diffusion. Optional separating layer is not significant to this invention. However, the separation layer can improve the chemical stability of the active substance and/or physical properties of the new tablet dosage form with a complex structure.

Alternative separation layer can be obtained on the spot by the interaction Intercollege polymer coating on the substance of the core, with the alkaline reagent substance core. Thus obtained spacer layer is a water-soluble salt formed by the interaction of the polymer included in the composition Intercollege coating with an alkaline reagent in place of salt.

On the substance of the core or on the substance of the core with a separator is rite. Substance Intercollege coverage may be dispersed or dissolved in water or in an acceptable organic solvents. As one or more polymers for Intercollege coating, applied separately or in combination, you can use the following substances, for example, solutions or dispersions of copolymers of methacrylic acid, acatitla cellulose phthalate of hydroxypropylmethylcellulose, acetolactate hydroxypropylmethylcellulose, polyvinyl acetate phthalate, acetotartrate cellulose, karboksimetiltselljulozy, shellac and other acceptable polymers for Intercollege coverage.

Intersolubility coating may contain pharmaceutically acceptable plasticizers to be used to obtain the required mechanical properties such as ductility and hardness intersolubility coatings. Such plasticizers include, but are not limited to, for example, triacetin, esters of citric acid, esters of phthalic acid, dibutylsebacate, cetyl alcohol, polyethylene glycols, polysorbates or other plasticizers.

The amount of plasticizer must be optimized for each structural formulas of enterocolitis and used quantities of the selected polymer, so the mechanical properties, i.e., ductility and hardness Intercollege coating, for example, expressed as the hardness Vickers hardness can be adjusted so that the acid resistance of the granules with intersolubility coating does not substantially deteriorated during the pressing of the granules into tablets. The amount of plasticizer is usually more than 10 weight. percent of the polymer for Intercollege coating, preferably this amount is from 15 to 50% and more preferably 20-50%. Intersolubility coating may also contain additives such as dispersing agents, dyes, pigments, polymers, such as poly(acrylate, methacrylate), substances that prevent adhesion, and antifoams. To increase the film thickness and decrease the diffusion of acidic gastric juice in islamochristiana substance can be added to other compounds. To protect islamochristiana substance, in particular, a proton pump inhibitor, and get acceptable acid dosage form according to this invention, the thickness of Intercollege coverage must be equal to at least about 10 μm, preferably more than 20 μm. The maximum thickness of the applied what filem dissolution.

Intersolubility coating can also be used for applying a layer SNPT. Alternative intersolubility coating, described above, can also be used as Intercollege coverage for conventional tablets containing composition of the proton pump inhibitor and one or more SNPT, and core tablets may also be coated with one of the above-described separation of the layers, which allows to separate the core tablets from Intercollege coverage.

Protective coating

For pellets with intersolubility coating can optionally apply one or more protective coatings. A protective cover should be water-soluble or rapidly disintegrating in water. The protective coating may be applied to granules with intersolubility coating using methods of applying coatings or films on the appropriate equipment, such as a device for coating, granulation coating or apparatus with a fluidized bed, in which the coating or film using water and/or organic solvents. Substances for protective coatings selected from pharmaceutically acceptable compounds such as, for example, is over, methylcellulose, ethylcellulose, hypromellose, sodium carboxymethyl cellulose and others, used alone or as mixtures. The protective coating may also contain additives such as plasticizers, dyes, pigments, fillers, substances that prevent adhesion, antistatic agents, such as, for example, magnesium stearate, titanium dioxide, talc and other additives. The specified protective coating may further prevent possible agglomeration of the granules with intersolubility coating, it can protect intersolubility floor from cracking during extrusion and to improve the tabletting process. The maximum thickness of the protective coating is usually limited to the process conditions and the desired dissolution profile. The protective coating can also be used as a film coating of tablets.

Receiving means nonsteroidal anti-inflammatory therapy (SNPT)

Active substance representing one or more funds non-steroidal anti-inflammatory therapy (SDPT), mixed in a dry state with an inert excipients, one or more fillers are perhaps the disintegrator.Oteri drying is less than 3 wt.%.

After that, the dry mass is crushed to obtain granules of the desired size, in particular, less than 4 mm and preferably less than 1 mm is Acceptable inert excipients for granulated SNPT are, for example, sodium glycolate starch, corn starch, crosslinked polyvinylpyrrolidone, low molecular weight substituted hydroxypropylcellulose, microcrystalline cellulose, mannitol and anhydrous colloidal silicon dioxide (Aerosil), and the like. A dry mixture containing SNPT, mixed with acceptable granulating fluid, which may contain, for example, polyvinylpyrrolidone, hydroxypropylcellulose, polyethylene glycol, hydroxypropylcellulose and optionally wetting agents such as sodium lauryl sulfate dissolved in distilled water, acceptable alcohol or mixtures thereof.

In some cases, you can resort to machining to obtain a complex between SNPC and integrated foaming agent, such as beta - hydroxypropylcellulose similar to that described in the following example 3. It is known that cyclodextrine complexes SNPT increase bioavailability SNPT, see, for example. Drug Dev. Ind. Pharm. 19(7), 843-852, (1993)�the first polymer. Acceptable gelling hydrophilic polymers are, for example, hypromellose, polyoxyethylene (polyethylene glycol), hydroxypropylcellulose, hydroxyethyl cellulose and xanthan gum. The granules may also contain buffer substances. See, for example, the following example 4. Some SNPT cause irritation of the mucous membrane of the stomach, so it is better to put protective intersolubility floor and get in the form of granules with intersolubility the floor.

Tablets with a complex structure

Granules with intersolubility coating containing a proton pump inhibitor, is mixed with granules containing SNPT, and excipients for tablets. From this mixture, compressed tablet dosage form with a complex structure. On the pressed tablet can be applied film coating to make the surface of the tablet is smooth and increase its stability during packaging and transportation. This film-coated tablets may further contain additives such as substances that prevent the sticking, dyes and pigments, or other additives, giving the tablet an attractive appearance and protect from light sensitive components.

such excipients for tablets, as fillers, binders, disintegrators, lubricants, and other pharmaceutically acceptable additives, and pressed into tablets. Acceptable lubricants in the tabletting process are, for example, sodium fumarate, magnesium stearate and talc.

Alternative SNPT can be mixed in the dry state with the granules with intersolubility coating containing a proton pump inhibitor, possibly together with an inert excipients and compressed into tablets (direct pressing), or from different active substances can form separate layers, and SNPT may be included in the layer with controlled release.

In addition, as SNPT, and the proton pump inhibitor in the form of granules with intersolubility coating can be mixed with inert excipients and compressed into a tablet. On the pressed tablet can be applied film coating to give it an attractive look.

As another possible option in tablet dosage form with a complex structure, containing a proton pump inhibitor can be coated by spraying of a suspension or solution containing SNPT. The obtained tablet then put the pigmented pleno is blecki, preferably less than 60%. Increasing the dosage form with a complex structure, the number of granules containing SNPT, it is possible to reduce the fraction of granules with intersolubility coating containing a proton pump inhibitor. Choosing for the preparation of the present invention small granules with intersolubility coating, it is possible to increase the number of pellets in each tablet, which, in turn, allows you to share the tablet with maintaining the accuracy of dispensing.

Thus, the preferred tablet with a complex structure consists of granules with intersolubility coating containing one active substance in the form of kislotoustoichivoje of proton pump inhibitor, optionally in a mixture with one or more alkaline agents, which are compressed into a tablet together with granules containing SNPT, and the optional excipients for tablets. The proton pump inhibitor is not necessary to add an alkaline reagent, but this substance may further increase the stability of the proton pump inhibitor, besides some alkaline reagents can interact with the substance Intercollege coating, forming a separation layer. Intersolubility pokrytiya in almost neutral and alkaline environments such as, for example, the liquid present in the proximal small intestine, where it is desirable dissolution of the proton pump inhibitor. SNPT may be released in the stomach. For pellets with intersolubility coating can be further coated before they are compressed into a tablet, they can have one or more separation layers between substance core and intersolubility the floor.

The method of obtaining

An additional object of this invention is a method for dosage forms. After receiving the granules by spraying method of proton pump inhibitor on the seed crystals or by extrusion and stereopathy or granulation, for example, by means of rotary granulation homogeneous granules, these granules first does not necessarily cause a separation layer, and then intersolubility floor or separation layer is formed on the result of the interaction between alkaline substance pith and substance Intercollege coverage. The coating is applied as described above and in the following examples. A method of producing granules containing SNPT, and granules SNPT with intersolubility coating also op what applies water-based.

Granules with intersolubility coated with a protective coating or without it, mixed with pre-obtained granules SNPT, excipients and other pharmaceutically acceptable additives and pressed into tablets. Alternative different active substances in the form of powders can be mixed in the dry state until smooth with excipients for tablets, wet and pressed in the usual tablet before applying the optional separating layer and Intercollege coverage. SNPT you can also enter in the coating on the dosage form with a complex structure, containing a proton pump inhibitor, or CNPC and the proton pump inhibitor in the form of granules with intersolubility coating mixed with inert excipients for tablets and pressed into tablet dosage form with a complex structure.

From different active substances can also be formed of two separate layers, one layer containing SNPT, can be a drug with controlled release. As another possible option kislotoustojchivy the proton pump inhibitor in the form of granules with intersolubility coating can be introduced into the capsule together with SNPT in view of the SS="ptx2">

The use of the drug

Dosage forms according to this invention is particularly effective for treating the side effects of SNPT in the gastrointestinal tract, which typically occur at constant reception of funds non-steroidal anti-inflammatory therapy. New dosage forms take one or more times per day, preferably once or twice a day. The usual daily dose of active substances can be different depending on such factors as the individual needs of the subjects, the mode of administration and the nature of the disease. Typically, each dosage form contains about 0.1 - 200 mg of proton pump inhibitor and 0.1-1000 mg SNPT. Each dosage form preferably contains 10-80 mg of proton pump inhibitor and 10-800 mg SNPT, more preferably 10-40 mg of proton pump inhibitor and 10-500 mg SNPT. Particularly preferred preparations contain, for example, 10 mg of omeprazole and 50 mg of diclofenac sodium, 10 mg of omeprazole and 250 mg of naproxen, 10 mg of omeprazole and 10 mg piroxicam or 10 mg of omeprazole and 400 mg of ibuprofen.

Tablets drug with a complex structure can also dispersing in water with a slightly acidic pH before oral priamosusm examples.

Examples

Example 1

Rapidly disintegrating tablet dosage form with a complex structure, containing magnesium-omeprazole and ibuprofen.

Substance core

Magnesium-omeprazole - 12,00 kg

Perfect crystals - 12,00 kg

The hypromellose - 1.8 kg

Distilled water - 35,4 kg

The separating layer

The substance of the core (in accordance with the above) - 23,50 kg

Hydroxypropylcellulose - 2,35 kg

Talc - 4,03 kg

Magnesium stearate - 0,34 kg

Distilled water - 48,00 kg

Intersolubility floor

Granules with a separating layer (in accordance with the above) - 38,70 kg

Copolymer of methacrylic acid (30% suspension) - 38,70 kg

Triethylcitrate - 3,48 kg

Mono - and diglycerides (NF) - 0,58 kg

Polysorbate 80 - 0.06 kg

Distilled water - 22,68 kg

Aditee floor

Granules with intersolubility coating (in accordance with the above) - 44.7 kg

The hypromellose is 0.58 kg

Magnesium stearate - 0,017 kg

Distilled water - 11.6 kg

Tablet mg/tablet

Granules with a protective coating containing omeprazole - 47,85

Ibuprofen - 400

Microcrystalline of all the I - 26,7

Distilled water - 297

Fumarate sodium - 4,0

Suspension floor get in apparatus with fluidized bed. Magnesium-omeprazole applied by spraying on an inert perfect crystals from water suspension containing the dissolved binder.

The obtained substance core in the apparatus with fluidized bed cause separation layer from a solution of hydroxypropylcellulose containing talc and magnesium stearate. Intersolubility coating consisting of a copolymer of methacrylic acid, mono - and diglycerides, triethylcitrate and Polysorbate, is applied by spraying granules (coated with a separating layer in the apparatus with fluidized bed. In the apparatus of the same type on the beads with intersolubility coating is applied a coating of the suspension hydroxypropylmethylcellulose and magnesium stearate. The obtained granules are sorted by the screening.

Granulating fluid tablets get by dissolving 26.7 parts of lauryl sodium and 33.3 parts of polyvinylpyrrolidone K-25 267 parts of distilled water. 400 parts of ibuprofen, 226 parts microcrystalline cellulose and 10.4 parts of crosslinked polyvinylpyrrolidone are mixed in a dry state. To powder the Ute 30 parts of water to reach the required amount.

The wet mass is dried in a furnace at a temperature of 60oC for about 6 hours. Dry granules are crushed so that they passed through a sieve with a mesh size of 0.8 mm

Pellets of omeprazole with intersolubility the floor, crushed granules of ibuprofen, 47,6 part of microcrystalline cellulose, about 4.0 parts of sodium fumarate and 90 parts of cross-linked polyvinylpyrrolidone are mixed and pressed into tablets using a tabletting machine with 15 mm punches. The hardness of tablets weight 886 mg, measured in the apparatus of Lanigera is from 5.3 to 5.9 KP. Time raspadaemosti defined in artificial gastric juice (USP without enzymes), 49-52 sec (n = 2).

Example 2

Rapidly disintegrating tablet dosage form with a complex structure, containing a magnesium salt of S-omeprazole and naproxen

Substance core

The magnesium salt of S-omeprazole 120 g

Perfect crystals - 150 grams

Polysorbate 80 - 2.4 g

The hypromellose - 18 g

Distilled water - 562 g

The separating layer

The substance of the core (in accordance with the above) - 200 grams

Hydroxypropylcellulose 30 grams

Talc - 51,4 g

Magnesium stearate - 4.3 g
accordance with the above) - 250 g

Copolymer of methacrylic acid, 30% suspension - 333,7 g

Triethylcitrate 30 grams

Mono - and diglycerides (NF) - 5.0 g

Polysorbate 80 (tween 80) - 0.5 g

Distilled water - 195,8

Protective coating

Granules with intersolubility coating - 371 g

Nutricosmetics - 5.0 g

Distilled water - 191 g

Tablet mg/tablet

Granules with a protective coating containing 55 magnesium salt of S - omeprazole - 55

Naproxen - 250

Microcrystalline cellulose - 150

Hydroxypropylcellulose, low molecular weight substituted - 40

Polyvinylpyrrolidone K-90 - 5,0

Distilled water - 250

Suspension floor get in the apparatus with fluidized bed. The magnesium salt of S-omeprazole is applied by spraying in an inert sugar crystals (perfect crystals) from a water suspension containing the dissolved binder and Polysorbate 80.

The obtained substance core in the apparatus with fluidized bed cause separation layer from a solution of hydroxypropylcellulose containing talc and magnesium stearate. Intersolubility coating consisting of a copolymer of methacrylic acid, mono - and diglycerides, triethylcitrate and the policy of this type granules with intersolubility coating is applied a solution of sodium carboxymethyl cellulose. Granules with a protective coating sorted by screening.

5 parts of polyvinylpyrrolidone K-90 is dissolved in 150 parts of distilled water to obtain a granulating fluid. Naproxen, microcrystalline cellulose and low substituted hydroxypropylcellulose mixed in a dry state. To the powder mixture add the granulating liquid and the resulting mass is mixed in a wet condition. Add 100 parts of water to reach the required amount.

The wet mass is dried in a furnace at a temperature of 60oC for about 5-6 hours. Dry granules are crushed so that they passed through a sieve with a mesh size of 1.0 mm

Granules with intersolubility coating is mixed with the crushed granules and compressed into tablets using a tabletting machine with h,5 mm punches. The average hardness of the tablets weighing 500 mg, measured along the largest axis) in the apparatus of Lanigera, equal to 9.4 KP. Time raspadaemosti determined in distilled water at a temperature of 37oC, equal to 15-30 seconds (n = 2).

Example 3

Rapidly disintegrating tablet dosage form with a complex structure, containing pantoprazole and piroxicam- -- hydroxypropylmethylcellulose (LF) - 25 g

Distilled water - 607 g

The separating layer

The substance of the core (in accordance with the above) - 200 grams

Hydroxypropylcellulose (LF) - a 20 g

Talc - 34.3 g

Magnesium stearate - 2.9 g

Distilled water 400 g

Intersolubility floor

Granules with a separating layer (in accordance with the above) - 200 grams

Copolymer of methacrylic acid, 30% suspension - 333 g

Triethylcitrate 30 grams

Mono - and diglycerides (NF) - 5.0 g

Polysorbate 80 - 0.5 g

Distilled water - 281,5 g

Tablet mg/tablet

Granules containing pantoprazole - 133

Piroxicam - 20

Hydroxypropylcellulose, (90%) - 72

Microcrystalline cellulose - 276

Crosslinked polyvinylpyrrolidone - 36,8

Distilled water - 2

Fumarate sodium - 3,9

Suspension floor get in the apparatus with fluidized bed. Pantoprazole is applied by sputtering in an inert sugar crystals (perfect crystals) from a water suspension containing the dissolved binder.

The obtained substance core in the apparatus with fluidized bed cause separation layer from a solution of hydroxypropylcellulose containing talc job, triethylcitrate and Polysorbate, is applied by spraying granules (with a separating layer in the apparatus with fluidized bed. The granules are sorted by the screening.

Piroxicam add to --hydroxypropylcellulose during machining and wetting by water. The resulting mass is dried in a drying oven at a temperature of 50oC and then crushed so that it passed through a sieve with a mesh size of 0.8 mm

Piroxicam -- -hydroxypropylcellulose, microcrystalline cellulose, crosslinked polyvinylpyrrolidone and sodium fumarate are mixed in a dry state, and then this mixture is mixed with granules of pantoprazole. Tablets are pressed into a tablet machine h,5 mm punches. The average hardness of tablets weight 577 mg, measured in the apparatus of Lanigera along the largest axis equal 16,7 KP, and it can vary from 14.8 to 18.7 KP. Time raspadaemosti determined in water is approximately 4 minutes.

Tablet cover pigmented dispersion as in example 7.

Example 4

Two-layer tablet dosage form, in which one layer is a rapidly decaying part and contains 20 mg of lansoprazole in the form of granules with enteroscope the El, containing 250 mg of naproxen.

Granules lansoprazole with intersolubility coating

Substance core

Lanzoprazol - 400g

Perfect crystals - 400g

The hypromellose (LF) - 80 g

Sodium lauryl sulfate, 3 g

Distilled water - 1360 grams

The intermediate coating

The substance of the core (in accordance with the above) - 100 g

The hypromellose - 9 g

Polyethylene glycol 6000 to 1 g

Ethanol, 95% - 250 g

Distilled water - 250 g

Intersolubility floor

Granules with an intermediate coating (in accordance with the above) - 100 g

Phthalate of hydroxypropylmethylcellulose - 39.9

Acetyltributyl 8 grams

Cetanol - 2.1 g

Ethanol, 95% - 162 g

Acetone - 378 g

Suspension floor get in the apparatus with fluidized bed. Lanzoprazol applied by spraying in an inert perfect crystals from water suspension containing the dissolved binder and wetting agent.

The obtained substance core in a specially-designed apparatus with fluidized-bed Wurster put intermediate coating of talc suspended in the solution hydroxypropylmethyl is ethylcellulose.

Intersolubility coating is applied in a similar device out of solution forming substances intersolubility layer in organic solvents.

Tablet mg/tablet

Granules containing lanzoprazol - 94

Microcrystalline cellulose - 181,8

Crosslinked polyvinylpyrrolidone - 18,2

Naproxen - 250

Polyoxyethylene (molecular weight approximately equal 4000000) - 200

The aluminosilicate sodium - 50

L-arginine - 190

Ethanol, 95% (weight to volume), about 280

Naproxen, polyox WSR 301L-arginine and sodium aluminosilicate mixed in a dry state. To the powder mixture add the granulating liquid and ethanol, and then the resulting mass is mixed in a wet condition. The wet mass is dried in a furnace at a temperature of 60oC for about 8 hours. Dry granules are crushed so that they passed through a sieve with a mesh size of 1.0 mm

In the process of manufacturing tablets first pre-pressed 690 mg of granules containing naproxen, and then, on the upper surface of this layer is applied based on one tablet 281 mg of a mixture containing 81 mg of granules lansoprazole, 181,8 mg microcrystalline cellulose and 18.2 mg stitched watering the layer tablets. The hardness of the tablets measured in the apparatus of Lanigera along the largest axis, equal to about 14 KP.

The solubility of naproxen were tested in phosphate buffer with a pH of 6.8. The following results are obtained:

1 hour dissolved - 14%

3 hours dissolved - 34%

5 hours dissolved - 58%

7 hours dissolved - 79%

24 hour dissolved - 102%

Example 5

Rapidly disintegrating tablet dosage form with a complex structure, containing magnesium-omeprazole and piroxicam.

Substance core (omeprazole)

Magnesium-omeprazole - 5,00 kg

Perfect crystals - 10,00 kg

The hypromellose - 0.75 kg

Distilled water - 19,65 kg

The separating layer (omeprazole)

The substance of the core (in accordance with the above) - 14,60 kg

Hydroxypropylcellulose - 1,46 kg

Talc - 2.5 kg

Magnesium stearate - 0.21 kg

Distilled water - 29,2 kg

Intersolubility floor (omeprazole)

Granules with a separating layer (in accordance with the above) - 9,00 kg

Copolymer of methacrylic acid (30% suspension) - 15,00 kg

Triethylcitrate - 1.35 kg

Mono - and diglycerides (NF) - 0.22 kg

Polysorbate 80 - 0,02 kg

Distilled is nsiproperties - 0.18 g

Magnesium stearate - 0,005 kg

Distilled water is 3.6 kg

Suspension floor get in the apparatus with fluidized bed. Magnesium-omeprazole applied by spraying on an inert sugar crystals (perfect crystals) from a water suspension containing the dissolved binder.

The obtained substance core in the apparatus with fluidized bed cause separation layer from a solution of hydroxypropylcellulose containing talc and magnesium stearate. Intersolubility coating consisting of a copolymer of methacrylic acid, mono - and diglycerides, triethylcitrate and Polysorbate, is applied by spraying the granules with an intermediate coating apparatus with fluidized bed. In the apparatus of the same type on the beads with intersolubility coating is applied a coating of the suspension hydroxypropylmethylcellulose and magnesium stearate. Granules with a protective coating sorted by screening.

Substance core (piroxicam)

Piroxicam, very finely chopped - 35 grams

Sugar crystals - 100g

The hypromellose 6 CP - 25 g

Distilled water - 250 g

Ethanol 99% (weight to volume) - 250 g

Intersolubility floor (peat the coating suspension of the following composition to obtain a product contains 163 mg/g of the active substance:

Acetosella hydroxypropylmethylcellulose (LF) - 14,38 parts

Triethylcitrate - 2,87 parts

Sodium dodecyl sulfate - 0,43 parts

Talc - 4,32 parts

Distilled water - 183,3 parts

Suspension floor get in the apparatus with fluidized bed. Very finely ground piroxicam is applied by sputtering in an inert perfect crystals from water suspension containing the dissolved binder.

Intersolubility floor, consisting of acetolactate hydroxypropylmethylcellulose, triethylcitrate, sodium lauryl sulphate and talc, is applied by spraying the granules piroxicam in the apparatus with fluidized bed.

Tablets (1000 pieces)

Granules containing omeprazole - 95,7 g

Granules containing piroxicam the 122.7 g

Microcrystalline cellulose - 240 g

Crosslinked polyvinylpyrrolidone - 20 g

Hydroxypropylcellulose, low molecular weight substituted - 40g

Fumarate sodium - 4,6 g

Microcrystalline cellulose, low molecular weight substituted hydroxypropylcellulose and crosslinked polyvinylpyrrolidone is mixed until homogeneous. Then mix the granules with entereth the mixture is pressed into tablets using a tabletting machine with 8,5x16 mm punches. The hardness of tablets by weight of 523 mg, measured in the apparatus of Lanigera is from 8 to 9 KP. Time raspadaemosti determined in water at a temperature of 37oC, is less than 1 minute.

These tablets are coated with a pigmented dispersion as in example 7.

Example 6

Rapidly disintegrating tablet with intersolubility coating containing magnesium-omeprazole and diclofenac.

Tablets (2000 pieces)

Magnesium-omeprazole (20 mg omeprazole) - 45,0 g

Sodium diclofenac (corresponding to 20 mg of diclofenac) with 43.2 g

Microcrystalline cellulose - 110 g

Crosslinked polyvinylpyrrolidone - 50 g

Hydroxypropylcellulose, low molecular weight substituted - 50 g

Fumarate sodium - 8, 6 grams

Distilled water, about 170 grams

Omeprazole diclofenac, microcrystalline cellulose, low molecular weight substituted hydroxypropylcellulose, 30 g of crosslinked polyvinylpyrrolidone and 5.6 g of sodium fumarate are mixed and, while continuing to mix, add water. Granular substance is dried in a drying oven at a temperature of 60oC for about 1.5 hours. Dry granular substance is crushed so that it passed cerana and 3.0 g of sodium fumarate. From this mixture is pressed to tablets weighing 153 mg using a tabletting machine with 7 mm punches. The average hardness of the tablets is equal to 7.4 KP (n = 6). Time raspadaemosti in water at a temperature of 37oC is 1 minute 20 seconds (n = 1).

In a specially-designed apparatus with fluidized-bed Wurster on the pill cause a separation layer, consisting of hydroxypropylmethylcellulose and talc.

Applying a separation layer

Tablets of 7 mm - 100,1 g

Dispersion for coating:

The hypromellose 6 CP - 5.5 g

Talc - 1,15 g

Et OH 99% (weight to volume) to 46.7 g

Distilled water to 46.7 g

The obtained coated tablets next put intersolubility floor in the same device.

Application Intercollege coating

Tablets with the separation layer 100 g

Dispersion for coating:

Copolymer of methacrylic acid, 30% suspension of 26.4 g (7,92 g dry matter)

The polyethylene glycol 400 - 0.9 grams

Titanium dioxide - 0,83 g

Iron oxide, reddish-brown - 0.28 g

Distilled water - 55,1 g

At the stage of applying Intercollege coating weight of tablets increases is included in the composition Intercollege coverage, protect the active substance from exposure to light.

Example 7

Rapidly disintegrating tablet dosage form with a complex structure, consisting of a magnesium-omeprazole, internal coating containing sodium diclofenac, and protective pigmented coating to protect the active substance from exposure to light.

Pellets of magnesium-omeprazole with intersolubility coating according to example 5.

Tablet mg/tablet

Granules containing omeprazole - 83,3

Microcrystalline cellulose - 181,4

Crosslinked polyvinylpyrrolidone - 3,7

Fumarate sodium - 0,4

Granules are obtained as in example 5.

Microcrystalline cellulose, crosslinked polyvinylpyrrolidone and granules containing omeprazole, mixed in a dry state. 3 Quiroga to the resulting mixture add the sodium fumarate.

This mixture is pressed into tablets using a tabletting machine with 9 mm punches. The hardness of tablets by Weight of 269 mg, measured in the apparatus of Lanigera is from 8 to 9 KP.

The tablets are coated in the fluidized bed from below solution, while the average weight of the tablet becomes equal to 298 mg

Sodium-dicl the NII weight to volume) - 113,6 weight.parts

Distilled water - 113,6 weight.parts

At the last stage on these tablets are coated with pigmented suspension in the same apparatus. Suspension for coating has the following composition:

The hypromellose 6 CP - 10.0 weight.parts

The polyethylene glycol, molecular weight 6000 - 2,5 weight.parts

TiO2- 1,83 weight.parts

Iron oxide, yellow - 0,40 weight.parts

Ethanol 99% (weight to volume) - 85 weight.parts

Distilled water is 85 weight.parts

The average mass of the obtained tablets equal 303 mg. Time raspadaemosti determined in water at a temperature of 37oC is less than 4 minutes (n = 4).

Example 8

Encapsulated product containing magnesium-omeprazole and piroxicam.

Capsules

Pellets of omeprazole with intersolubility coating (method of obtaining a composition in accordance with example 5), or 95.7 mg/capsule

Granules piroxicam with intersolubility coating (method of obtaining a composition in accordance with example 5) the 122.7 mg/capsule

The obtained granules are filled hard gelatin capsules, size 3. Before filling capsules granules, optional add nebolshaya is about 20 mg.

Example 9

Encapsulated product containing a magnesium salt of S-omeprazole and naproxen.

Capsules

Granules with intersolubility coating (method of obtaining a composition in accordance with example 2) is 55.2 mg/capsule

Granulated naproxen (the method of obtaining a composition in accordance with example 2) - 445 mg/capsule

The obtained granules and pellets with intersolubility coating filled hard gelatin capsules, size 00. Before filling capsules granules, it is not necessary to add a small amount of lubricant. The number of S-omeprazole in each capsule is about 10 mg, and naproxen is approximately 250 mg.

Example 10

Rapidly disintegrating tablet dosage form with a complex structure, containing magnesium-omeprazole and sodium diclofenac.

Substance core

Magnesium-omeprazole - 5 kg

Spherical crystals of sugar - 10 kg

The hypromellose - 0.75 kg

Distilled water is 19.7 kg

The separating layer

Substance core - 10.2 kg

Hydroxypropylcellulose - 1.02 kg

Talc - 1.75 kg

Magnesium stearate - 0,146 kg

Distilled water - 21,4 Kirilovich acid (30% suspension) - 19.8 kg

Triethylcitrate - 1,79 kg

Mono - and diglycerides (NF) - 0,297 kg

Polysorbate 80 - 0.03 kg

Distilled water - 11,64 kg

Protective coating

Granules with intersolubility coating - 20,0 kg

The hypromellose - 0,238 kg

Magnesium stearate - 0,007 kg

Distilled water - 6,56 kg

Tablets

Granules with a protective coating containing omeprazole - 82,4

Sodium-diclofenac - 50,0

Microcrystalline cellulose - 261

Crosslinked polyvinylpyrrolidone - 5,6

Fumarate sodium - 0,56 2 Suspension floor get in the apparatus with fluidized bed. Magnesium-omeprazole applied by spraying onto the spherical crystals of sugar from water suspension containing the dissolved binder. The size of spherical crystals of sugar equal to 0.25-0.35 mm, the resulting substance core is covered with a solution of hydroxypropylcellulose containing talc and magnesium stearate. Intersolubility coating consisting of a copolymer of methacrylic acid, mono - and diglycerides, triethylcitrate and Polysorbate, is applied by spraying the pellets covered with separating layer in the apparatus with fluidized bed. In a similar apparatus for pellets with intersolubility coating h is a covering sorted by screening.

Granules with intersolubility and protective coatings, sodium diclofenac, microcrystalline cellulose, crosslinked polyvinylpyrrolidone and sodium fumarate are mixed in a dry state and pressed into tablets using a tabletting machine with a Cam and 11 mm punches. The amount of omeprazole in each tablet is about 10 mg, and the amount of sodium diclofenac is approximately 50 mg of the Measured hardness of the tablets is 80 N.

Example 11

Rapidly disintegrating tablet dosage form with a complex structure, containing magnesium-omeprazole and piroxicam.

Substance core

Magnesium-omeprazole - 10,00 kg

Spherical crystals of sugar - 10,00 kg

The hypromellose - 1.5 kg

Distilled water - 29,9 kg

The separating layer

Substance core - 20,00 kg

Hydroxypropylcellulose - 2.0 kg

Talc - 3.43 kg

Magnesium stearate - 0,287 kg

Distilled water - 41,0 kg

Intersolubility floor

Pellets covered with separating layer is 24.5 kg

Copolymer of methacrylic acid (30% suspension) - 32,7 kg

Triethylcitrate - 2,94 kg

Mono - and diglycerides (NF) - 0.49 kg

Polysorbate 80 - 0,049 kg

Diest is prophylatically - 0.49 kg

Magnesium stearate - 0,0245 kg

Distilled water - 11.6 kg

Tablet mg/tablet

Granules with a protective coating containing omeprazole - 94,9

Piroxicam - 20,0

Microcrystalline cellulose - 280

Crosslinked polyvinylpyrrolidone - 5,6

Fumarate sodium - 0,56

Pellets of magnesium-omeprazole with intersolubility and receive protective coatings as in example 10.

Granules with intersolubility and protective coatings, piroxicam, microcrystalline cellulose, crosslinked polyvinylpyrrolidone and sodium fumarate are mixed in a dry state and pressed into tablets using a tabletting machine with a Cam and 11 mm punches. The amount of omeprazole in each tablet is about 20 mg, and the amount of piroxicam approximately 20 mg of the Measured hardness of the tablets is 110 N.

Results

"Acid resistance", i.e.% of active substance remaining after exposure to 0.1 n HCl solution for 2 hours - Pills

Example 1 - 95%

Example 2 - 95%

Example 3 - 99%

Example 4 - 91%

Example 5 - 92%

Example 6 - 96%

Example 7 - 93%

Example 10 - 91%

Example 11 - 91%

The most preferred implementation, intersolubility coating, containing a proton pump inhibitor, can also be obtained as described in the following examples.

Example 12

Obtain granules with intersolubility coating by extrusion and stereopathy.

Substance core

Magnesium-omeprazole - 600 g

Mannitol - 1000 grams

Microcrystalline cellulose - 300 grams

Hydroxypropylcellulose - 100 g

Sodium dodecyl sulfate - 6 grams

Distilled water - 802 g

The separating layer

The substance of the core (in accordance with the above) - 400 g

The hypromellose - 48g

Distilled water - 960 g

Intersolubility floor

Pellets covered with separating layer (in accordance with the above) - 200 grams

Copolymer of methacrylic acid - 100 g

Triethylcitrate 30 grams

Mono - and diglycerides (NF) - 5 grams

Polysorbate 80 - 0.5 g

Distilled water - 309 g

Sodium lauryl sulfate dissolved in distilled water to obtain a granulating fluid. Magnesium-omeprazole, mannitol, microcrystalline cellulose and hydroxypropylcellulose mixed in a dry state. To the powder mixture add the granulating liquid and the resulting mass is stirred into the wet status is the give a spherical shape on the friction plate in sporoobrazujushchimi apparatus. Substance core is dried in a fluidized bed dryer and sorted. In the apparatus with fluidized bed resulting substance core cover the separation layer from a solution of hydroxypropylmethylcellulose and water.

Intersolubility coating applied on the pellets covered with separating layer of an aqueous dispersion of a copolymer of methacrylic acid, powdercoated triethylcitrate, to which is added a dispersion of mono - and diglycerides and Polysorbate. The granules are dried in the apparatus with fluidized bed.

Example 13

Obtain granules with intersolubility coating by applying a powder on a spherical crystals of sugar.

Substance core

Magnesium-omeprazole - 1500 g

Spherical crystals of sugar - 1500 g

The hypromellose - 420 g

Aerosil8 grams

Distilled water - 4230 g

The separating layer

The substance of the core (in accordance with the above) - 500 grams

Hydroxypropylcellulose - 40g

Talc - 67 g

Magnesium stearate 6 g

Distilled water 800 g

Intersolubility floor

Pellets covered with separating layer (in accordance with the above) - 500 grams

Apolzon, part of hydroxypropylmethylcellulose and Aerosilmixed in a dry state to obtain powder. On a spherical sugar crystals (0.25 to 0.40 mm) put the powder in a centrifugal granulator for coating in the fluidized bed while spraying solution hydroxypropylmethylcellulose (6 wt.% respect).

The resulting substance core is dried and cover with a separating layer in a centrifugal granulator for coating in the fluidized bed. Intersolubility coating is applied in the apparatus of the fluidized bed.

Example 14

Obtain granules with intersolubility based coating crystals of silicon dioxide.

Substance core

Magnesium-omeprazole - 8,00 kg

Silicon dioxide - 8,00 kg

The hypromellose - 1,41 kg

Sodium dodecyl sulfate - 0.08 kg

Distilled water - 28,00 kg

The separating layer

The substance of the core (in accordance with the above) - 10,00 kg

The hypromellose - 0,80 kg

Distilled water - 10,00 kg

Intersolubility floor

Pellets covered with separating layer (in accordance with the above) - 300 grams

The copolymer of methacry the Distilled water - 463 g

Suspension floor get in the apparatus with fluidized bed. Magnesium-omeprazole applied by spraying on the crystals of silicon dioxide from a water suspension containing the dissolved binder and surfactant. The resulting substance core cover the separation layer from a solution of hydroxypropylmethylcellulose in the apparatus with fluidized bed. Intersolubility coating consisting of a copolymer of methacrylic acid, mono - and diglycerides, polyethylene glycol 400 and Polysorbate, is applied by spraying the pellets covered with separating layer in the apparatus with fluidized bed.

Example 15

Obtain granules with intersolubility coating

Intersolubility floor

Pellets covered with separating layer (a method of obtaining a composition in accordance with example 12) - 500 grams

Copolymer of methacrylic acid - 250g

Polyethylene glycol 6000 75 g

Mono - and diglycerides (NF) - 12.5 g

Polysorbate 80 - 1.2 grams

Distilled water - 490 g

Example 16

Obtain granules with intersolubility the floor.

Intersolubility floor

Pellets covered with separating layer (the method of preparation and composition with the 95% - 1000 g

Acetone - 2500 g

Example 17

Obtain granules with intersolubility the floor.

Substance core

Omeprazole - 225 g

Mannitol - 1425 g

Hydroxypropylcellulose - 60g

Microcrystalline cellulose 40 g

Anhydrous lactose 80 grams

Sodium lauryl sulfate 5 g

The dihydrate dinatriumfosfaatti 8 grams

Distilled water 350 g

The separating layer

The substance of the core (in accordance with the above) - 300 grams

Hydroxypropylcellulose - 30 kg

Talc - 51

Magnesium stearate 4 grams

Intersolubility floor

Pellets covered with separating layer (in accordance with the above) - 300 grams

Copolymer of methacrylic acid - 140 g

Triethylcitrate - 42 g

Mono - and diglycerides (NF) - 7 grams

Polysorbate 80 - 0.7 g

The dry ingredients intended for obtaining the substance of the core, thoroughly mix in the mixer. Add the granulating liquid, after which the resulting mixture is stirred and granularit until you get the desired consistency. The wet mass is forced through a sieve of the extruder, and the obtained granules give a spherical shape in stereopathetic. Substance core is dried in the apparatus with a fluidized bed of the tion layer and intersolubility coating in accordance with the description, in the preceding examples.

Getting active substance

Magnesium-omeprazole, is used in some of the examples are in accordance with the method described in the application WO/95/01977, salts of the single enantiomers of omeprazole receive as described in the application WO/94/27988, and get omeprazole in accordance with a method described in the application for the European patent N EP-A10005129. These documents are included in this description of the invention as reference materials.

1. Pharmaceutical dosage form for oral administration, containing kislotoustojchivy a proton pump inhibitor, at least one tool nonsteroidal anti-inflammatory therapy (SDPT) and, optionally, pharmaceutically acceptable excipients, characterized in that it is a dosage form which contains at least two pharmaceutically active substance and in which at least the proton pump inhibitor is protected intersolubility the floor.

2. Dosage form under item 1, characterized in that it is a tablet.

3. Dosage form under item 1, characterized in that it is a capsule.

4. Dosage form under item 1, otlichayushchim intersolubility coverage for proton pump inhibitor.

5. Dosage form under item 1, characterized in that it contains a proton pump inhibitor and one tool nonsteroidal anti-inflammatory therapy.

6. Dosage form under item 1, wherein the proton pump inhibitor is omeprazole, its alkali metal salt of S-omeprazole or its alkali metal salt.

7. Dosage form under item 1, wherein the proton pump inhibitor is lanzoprazolom, one of its single enantiomers or its pharmaceutically acceptable salt.

8. Dosage form under item 1, wherein the proton pump inhibitor is pantoprazole or one of its single enantiomers or its pharmaceutically acceptable salt.

9. Dosage form according to any one of paragraphs.6 and 5, characterized in that the means nonsteroidal anti-inflammatory therapy is ibuprofen, diclofenac, piroxicam or naproxen or pharmaceutically acceptable salt.

10. Dosage form under item 1, characterized in that the amount of the proton pump inhibitor is 10 to 80 mg and the number SNPT is 10 to 800 mg.

11. Dosage form under item 1, characterized in that the number of tabletirovannaya dosage form under item 2, wherein the tablet consists of two separate layers of which one layer contains a proton pump inhibitor, and the other layer contains one or more SNPT.

13. Tableted dosage form under item 2, characterized in that it is tableted dosage form with a complex structure, containing a proton pump inhibitor in the form of individual granules with intersolubility coated, laminated together with granules containing SNPT, tablet, and intersolubility coating applied to the individual granules, has such mechanical properties that tableting these pellets, together with pellets containing SNPT, and, optionally, pharmaceutically acceptable excipients no significant effect on acid resistance of the individual granules with intersolubility the floor.

14. Tableted dosage form according to p. 13, characterized in that the acid resistance of the granules with intersolubility coverage is not reduced by more than 10% during the pressing of these granules in tablet dosage form with a complex structure.

15. Tableted dosage form according to p. 13, characterized in that intersolubility 16. Tableted dosage form according to p. 13, characterized in that the granules with intersolubility coating is additionally applied protective coating containing pharmaceutically acceptable excipients.

17. Tableted dosage form according to p. 13, characterized in that it is a tablet, dispersible with obtaining a water suspension containing SNPT and granules of proton pump inhibitor with intersolubility the floor.

18. Tableted dosage form under item 2, characterized in that it is a tablet consisting of two separate layers of which one layer contains a proton pump inhibitor in the form of granules with intersolubility coating, laminated to a layer together with excipients for tablets, and the other layer contains one or more SNPT with prolonged action.

19. Tableted dosage form under item 18, characterized in that the layer containing one or more SNPT is a gel-forming matrix with prolonged action.

20. Tableted dosage form under item 2, characterized in that it is a tablet with intersolubility coating consisting of a mixture of proton pump inhibitor and granules, with the between the core tablet and intersolubility the floor.

21. Tableted dosage form under item 2, characterized in that it is a pill that contains granules of proton pump inhibitor with intersolubility coating, compressed into a tablet, which is applied to the separation layer containing one or more SNPT, and, optionally, a pigmented film coating.

22. Tableted dosage form under item 2, wherein the tablet consists of two types of granules with intersolubility coating granules of the same type contain a proton pump inhibitor, and granules of a different type contain SNPT, which is compressed in a tablet together with excipients for tablets.

23. Tableted dosage form under item 2, wherein the tablet consists of granules with intersolubility coating containing a proton pump inhibitor containing SNPT coated film with prolonged action, which is compressed into a tablet together with excipients for tablets.

24. A method of obtaining a dosage form containing a proton pump inhibitor and one or more SNPT in the capsule, wherein the proton pump inhibitor get in the form of granules with intersolubility polybiolinum coating, or granules SNPT coated with prolonged action, optionally, a mixture of the above-mentioned granules mixed with pharmaceutically acceptable excipients and administered in a capsule.

25. A method of obtaining a dosage form containing a proton pump inhibitor and one or more SNPT in tablet dosage form with a complex structure, characterized in that the proton pump inhibitor get in the form of granules with intersolubility coated and mixed with the obtained granules SNPT and, optionally, with pharmaceutically acceptable excipients for tablets, and then dry the mixture is pressed into a tablet with a complex structure without a substantial change in kislotostojkuju Intercollege coverage.

26. A method of obtaining a dosage form containing a proton pump inhibitor and one or more SNPT in tablet dosage form with a complex structure, characterized in that the proton pump inhibitor get in the form of granules with intersolubility coating, SNPT receive in the form of granules with a coating that is coated with prolonged action or intersolubility coating obtained pellet army, containing a proton pump inhibitor and one or more SNPT in the tablet with intersolubility coating, wherein the proton pump inhibitor is mixed with SNPT and pharmaceutically acceptable excipients, after which the mixture is pressed into a tablet, on which is applied intersolubility coating and, optionally, cover the separation layer before applying Intercollege coverage.

28. Treatment of side effects in the gastrointestinal tract as a result of treatment by means of a non-steroidal anti-inflammatory therapy in mammals and humans, in particular, in the upper part of the gastrointestinal tract, as a result of treatment SNPT through the introduction of the needy to the subject a therapeutically effective dose of a tablet dosage form with a complex structure according to any one of paragraphs.1 - 28.

 

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