Preformed mnogoagentnye dosage form, method of receipt, the method of inhibiting the secretion of gastric acid or treatment of gastrointestinal diseases in mammals and man

 

(57) Abstract:

The invention relates to pharmacy. Proposed mnogoagentnye tableted dosage form comprising as active substance kislotoneustoichiwami inhibitor of H+K+-ATPase or its alkali salt, or one of its enantiomers or an alkaline salt, method of its manufacture and the use of such dosage forms medicine. The active substance is not destroyed in acidic environments and is stable during storage. 3 C. and 16 h.p. f-crystals, 2 tab.

The invention relates to new pharmaceutical preparations in the form of mnogodetnoi tablet dosage forms containing the active substance in the form of kislotoneustoichiwami inhibitor H+K+-ATPase. New tablet dosage form for oral administration. In addition, this invention relates to a method of manufacture of such drugs and to the use of such drugs in medicine.

Kislotoneustoichiv inhibitors of H+K+-ATPase, also known inhibitor of the gastric proton pump (proton pump) are, for example, the compounds under generic names of omeprazole, lansoprazole, pantoprazole, PARETE are compounds of General formula 1 or their alkali metal salts or one of the enantiomers of this compound or its alkali salt (alkali metal salt).

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where Het1represents a

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or

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Het2represents a

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or

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or

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X denotes

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or

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where N in the benzimidazole part indicates that one of the carbon atoms is replaced with an R6-R9sometimes can be replaced by a nitrogen atom without any substituents,

R1, R2and R3the same or different and selected from hydrogen, alkyl, alkoxygroup, optionally substituted by fluorine, alkylthio, alkoxyalkyl, dialkylamino-, piperidino, morpholinopropan, halogen, phenyl and vinylalcohol.

R4and R5the same or different and selected from hydrogen, alkyl and aralkyl,

R'6represents hydrogen, halogen, trifluoromethyl, alkyl, alkoxygroup,

R6-R9the same or different and selected from hydrogen, alkyl, alkoxygroup, halogen, halogen-alkoxygroup, alkylcarboxylic, alkoxycarbonyl, oxazolyl, triptoreline or adjacent groups R6-R9form a ring structure, which may be optionally substituted,

R10represents hydrogen or forms together with R3alkylenes chain,

R11and R and-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil] -1H - benzimidazole, 5-fluoro-2-[[(4-cyclopropylmethoxy-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole and 5-carbomethoxy-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinil]-1H-benzimidazole.

Examples of the characteristic of interest are compounds of formula 1 are

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The active compound used in tablet dosage form according to this invention can be used in neutral form or in the form of a salt of an alkali metal, such as salts of Mg2+Ca2+, Na+or K+, preferably in the form of salts of Mg2+. These compounds can also be applied in the form of one of the single enantiomers or an alkaline salt.

Some of the above compounds are described, for example, in EP-A1-0005129, EP-A1-174726, EP-A1-166287 and GB 2163747.

These active substances suitable for inhibiting the secretion of gastric acid in mammals and humans. More generally, they can be used for prevention and treatment associated with gastric acid diseases in mammals and humans, including, for example, reflux esophagitis (peptic esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer. In addition, Alenia gastric acid, for example, in patients treated NSAID therapy (treatment with the use of nonsteroidal anti-inflammatory therapy) in patients with non-ulcer dyspepsia in patients with symptoms of gastro-oesophageal reflux disease in patients with ulcerogenic adenoma of the pancreas. They can also be used for patients in intensive care situations, in patients with upper gastrointestinal bleeding prior to surgery and post-surgery to prevent aspiration of gastric acid and to prevent and treat the formation of ulcers induced by stress. In addition, they can be used in the treatment of psoriasis, as well as in the treatment of infections caused by Helicobacter, and related diseases.

However, these active compounds are susceptible to degradation/transformation in acidic and neutral environments. Degradation is catalyzed by the acidic compounds and stabilized in mixtures with alkaline compounds. On the stability of the active substances is also influenced by moisture, organic solvents and to some extent the light.

In respect of the stability properties of these active substances is obvious that the oral solid dosage form must be protected from contact with acidic gastric is, the de pH close to neutral and where it can happen fast absorption (absorption).

Pharmaceutical oral dosage form such kislotoneustoichiv inhibitors H+K+-ATPase best protected from contact with acidic gastric juice by means of a layer Intercollege coverage. In U.S. patent 4853230 described such a drug with intersolubility coating. This product contains alkaline kernel (the Central part), which includes sensitive to acid substance, separating layer and a layer Intercollege coverage. To further increase the stability during storage of the prepared dosage form can sometimes be Packed with desiccant.

There is a need to develop new having intersolubility cover mnogoagentnykh drugs with good chemical and mechanical stability, enable production of a well-functioning and supportive to the patient packages, such as packages in the form of patches. In addition, there is a need for finished dosage forms with improved properties with respect to their acceptance by patients, such as shared and/or dispersability coated tablets. WO 95/01783 describes a tablet containing kislotoneustoichiwami connection omeprazole. However, only covered intersolubility coating mnogoagentnye tablet can be made and shared dispersible. A further advantage is covered intersolubility coating mygoodeye tablet is that it is dispersed into many small units in the stomach with the introduction.

Previous studies describe many different types mnogoagentnykh dosage forms. Usually this type of dosage form is required for finished dosage forms with controlled selection, such as forms with prolonged action. In the typical case mnogoagentnye finished dosage form can be a tablet which disintegrates in the stomach, making available many covered intersolubility coating units, or balls, encased in a capsule (see, for example, EP 0080341 and U.S. patent 4853230).

Example of getting the dosage form with controlled allocation, allocating the active ingredient by diffusion through the membrane described in U.S. patent 4927640, i.e. described mnogoagentnye system containing a small inert kernel (the Central part), pokrytiya such multiple units, molded into tablets as described in Pharmaceutical Researh 10 (1993), p. S-274. Other examples of dosage forms with controlled selection are described, for example, Aulton M. E. (Churchhill Lioingstone Ed. ), Pharmaceutics: The science of dosage form design (1988), p. 316-321.

Even if there are examples in previous studies, showing that beads can be formed into tablets, there are no examples describing any composition such preformed ready form or method of manufacture of the finished dosage form kislotoneustoichiv inhibitors H+K+-ATPase. In practice, when pressing covered intersolubility coated beads containing kislotoneustoichiv substances in tablets having problems. If the layer Intercollege coverage does not stand the balls pressing into tablets, sensitive active substance will be destroyed penetrating acidic gastric juice, i.e., the acid Intercollege precipitation layer is insufficient in the tablet after pressing. The above problems are well illustrated in the sample below.

Further, the tablets of the controlled allocation of having intersolubility coated particles described in Drugs Made in Germany, 37, No. 2 (1994), p. 53. E is metacrilate (NE30D) suitable for having intersolubility coating particles, compressed into tablets, as coating polymers. The standard Example III shows that this recommendation is not applicable in the manufacture mnogoagentnykh tablet dosage forms is sensitive to acid agents, such as omeprazole. Resistance to acid these balls, pressed into tablets, is too low. Cited reference Drugs Made in Germany also asserts that the use of a copolymer L30D-55 without the addition copolymer NE30D as a layer Intercollege coverage will lead to getting covered balls that will not be able to withstand the forces of compression applied during the tabletting process. With reference to this statement it has been unexpectedly discovered that beads coated with L30D-55, in accordance with this invention (see Examples) can be compressed into tablets with fulfilling the necessary conditions, including acceptable resistance to acids such pills.

The applicant did not know any suitable practical examples mnogodetnoi tablet dosage form containing kislotoneustoichiwami inhibitor of H+K+-ATPase.

Description of the invention

The applicant has unexpectedly found that tablets of this izobreteny hibitor H+K+-ATPase or one of its single enantiomers or an alkaline salt can be made by pressing these units in tablets, without significantly affecting the properties of the layer Intercollege coverage. As explained above, if this layer Intercollege coating damaged during extrusion coated with this layer units, resistance to acid layer Intercollege coating manufactured in tablets will be insufficient and made pills will not meet the standard requirements with intersolubility coating products, such as, for example, as defined in United States Pharmacopeia, included here as a complete reference. Interest kislotoneustoichiv inhibitors of H+K+-ATPase for a new dosage form of this invention shown in paragraph 2 of the claims, and particularly preferred compounds are listed in paragraph 3 of the claims.

One purpose of this invention is the provision of pharmaceutical mnogodetnoi tabletirovannoj dosage forms containing kislotoneustoichiwami inhibitor of H+K+-ATPase or one of its enantiomers or an alkaline salt, coloroado. Layer (s) Intercollege coating covering the individual units of the active substance has properties such that the pressing of these units in the tablet does not have a significant influence on the resistance to acid separately covered intersolubility layer units. The active substance is protected from degradation and dissolution in acidic environments and has good stability during long-term storage, Intersolubility covering layer separate units quickly destroyed/dissolved in near-neutral or alkaline environments.

Another purpose of this invention is the provision of pharmaceutical mnogodetnoi tablet dosage form containing kislotoneustoichiwami inhibitor of H+K+-ATPase or one of its enantiomers or an alkaline salt, which is easily divided into units and easy for handling. Such mnogodenek tablet dosage form can be atomized into liquid water and given to patients with impaired swallowing and apply in Pediatrics. Such a suspension of dispersed units with stoem Intercollege coverage of the appropriate size can be used for oral administration and for feeding through nasal Iovanna dosage form, contains the active substance in the form of kislotoneustoichiwami inhibitor H+K+-ATPase or one of its enantiomers or an alkaline salt has the following characteristics. Separately covered intersolubility layer unit containing the active substance and sometimes alkaline substances, mixed with excipients for tablets and pressed into mnogodenek tablet dosage form. The expression "individual (separate) unit" means a small granules, particles, pellets or beads, hereafter referred to as balls.

The process of compaction (compression) for the manufacture of mnogodetnoi tablet dosage form should not have a significant impact on the acid-covered intersolubility layer of balls. In other words, the mechanical properties such as ductility and stiffness, thickness, Intercollege covering layer (s) must ensure that the requirements have intersolubility floor products made in the United States Pharmacopeia, performed and that the acid is not reduced by more than 10% during the balls pressing into tablets.

Ductility/hardness layers Intercollege cover MoEP tester type HMV 2000.

Acid resistance (acid resistance) is defined as the number of active substances in tablets or beads after incubation with simulated gastric fluid, USP, or with 0.1 M HCl (aqueous) compared with untreated pellets or balls, respectively. The test is carried out as follows. Tablets or pellets are subjected to the action of simulated gastric fluid at 37 ° oC. the Tablets disintegrate and release covered intersolubility layer of balls on Wednesday. After two hours the beads were removed and examined for the content of the active substance by means of liquid chromatography high resolution (HPLC, IHVR). Presented values of kislotostojkuju represent averages from at least three separate definitions.

The material of the Central part (core)

The core material for separately covered intersolubility layer may be composed according to different principles. Include interbedded with the active substance, sometimes mixed with alkaline compounds can be used as a core material for further processing.

These inclusions, which should be interbedded with the active substance, can be wagoners is alone or in mixtures, or water-soluble materials containing various inorganic salts, sugar, unique substances and other materials individually or in mixtures. Further inclusions can contain the active substance in the form of crystals, agglomerates, pressed materials, etc. the size of the materials inclusion is not essential to this invention and can vary between approximately 0.1 and 2 mm Turn on covered active substance is produced by layering or suspension, or a detergent solution using, for example, granulating or installation for coating spray.

Before coating material incorporating the active substance can be mixed with other components. Such components may include binders, surfactants, fillers, dezintegriruetsja agents, alkaline additives or other pharmaceutically acceptable ingredients separately or in mixtures. Binders are, for example, cellulose, such as hypromellose, hydroxypropylcellulose and sodium carboxymethylcellulose, polyvinylpyrrolidone, sugar, starches and other pharmaceutically acceptable substances with adhesive properties. Suitable x surfactants, such as, for example, sodium lauryl sulfate.

Alternatively, an inhibitor of H+K+-ATPase or one of its selected enantiomers or an alkaline salt, sometimes mixed with alkaline compounds and, in addition, mixed with suitable components, can be formed in the core material. These core materials can be obtained by extrusion/spheronization (the formation of spherical particles), the formation of lumps or pressing using different settings. The size of the prepared materials nucleus is approximately 0.1 to 4 mm and preferably 0.1 to 2 mm, Made of the materials of the core can then be covered with additional layers of ingredients containing the active substance, and/or can be used for further processing.

The active substance is mixed with pharmaceutical components to obtain the preferred properties for manipulating and processing and a suitable concentration of the active substance in the final mixture. You can use pharmaceutical components such as fillers, binders, lubricants, dezintegriruetsja agents, surfactant and other pharmaceutically acceptable additives.

Active substances may be selected from (but not only of them) of such substances, as salts of sodium, potassium, calcium, magnesium and aluminium, phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; soosazhdennykh aluminum hydroxide/sodium bicarbonate; substances normally used in antacid preparations such as hydroxides of aluminum, calcium and magnesium; magnesium oxide or composite substances, such as Al2O36MgO12H2O, (Mg6Al2(OH)16CO34H2O), MgOAl2O32SiO2nH2O or similar compounds; organic pH-superyoshi substances, such as trihydroxypyrimidine, basic amino acids and their salts or other similar, pharmaceutically acceptable regulating the pH of a substance.

Alternatively, as mentioned above, the core material can be prepared by spray drying or by spraying with freezing.

The active substance is in the form of kislotoneustoichiwami inhibitor H+K+-ATPase formula 1 or one of its enantiomers or an alkaline salt. These compounds have an asymmetric center at the sulfur atom, i.e. they exist as two optical isomers (enantiomers). As pure enantiomers, racemic mixtures (50% each is authorized forms according to this invention.

Layer Intercollege coatings (layers)

Before applying the layer (s) Intercollege coating on the core material in the form of a separate balls these balls can sometimes be covered by one or more separating layers containing pharmaceutical excipients, sometimes involving alkaline compounds such as, for example, pH-buferiruemoi connection. This (these) layer (s) separated (separated) the core material from the outer layer (s), which is the layer Intercollege coverage.

The separating layer (s) may be deposited on the core material by means of coating or layering in suitable units, such as a mold, a granulator to cover, or in the apparatus with fluidized bed using water and/or organic solvents for the coating process. Alternatively, the separating layer or layers can be deposited on the core material using the method of coating in powder form. Materials for the separating layers are pharmaceutically acceptable compounds such as, for example, sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropylcellulose, methylcellulose, these are the values or as mixtures. In the separating layer or layers may also include additives such as plasticizers, dyes, pigments, fillers, antiadhesive and antistatic agents such as magnesium stearate, titanium dioxide, talc and other additives.

When this optional layer or layers applied to the core material, it can be of different thickness. The maximum thickness of the optional separating layer is usually limited only by the processing conditions. The separating layer or layers may serve as a diffusion barrier and can act as a zone, regulating pH. Buffer properties of the separation layer can be further strengthened by the introduction in the layer or layers of substances selected from the group of compounds usually used in antacid preparations such as, for example, magnesium oxide, hydroxide or magnesium carbonate, aluminum hydroxide or calcium carbonate or aluminum silicate or calcium; composite compounds of aluminum/magnesium, such as Al2O36MgOCO212H2O, (Mg6Al2(OH)16CO34H2O), MgOAl2O32SiO2nH2O, soosazhdenie aluminum hydroxide/sodium bicarbonate or similar compounds; or other pharmaceutically acceptable regulating the pH is connected to the x weak inorganic or organic acids; or suitable organic bases, including basic amino acids and their salts. To increase the thickness of the layer or layers and, therefore, enhance the diffusion barrier can be added talc or other compounds. Sometimes damage the separating layer (or layers) is not essential for the invention. However, this separating layer or layers can improve the chemical stability of the active substance and/or physical properties of the new mnogodetnoi tablet dosage form.

One or more layers Intercollege coating applied to the core material or core material covered with separating layer or layers, using a suitable method of coating. Material layer Intercollege coverage may be dispersed or dissolved either in water or in suitable organic solvents. As the polymer layer Intercollege coating can be used with one or more, separately or in combination, of the following polymers: for example, solutions or dispersions of copolymers of methacrylic acid, acetate-cellulose phthalate, phthalate of hydroxypropylmethylcellulose, acetate-succinate of hydroxypropylmethylcellulose, polyvinyl acetate-phthalate, azeta ocrite polymers.

Layers Intercollege coatings contain pharmaceutically acceptable plasticizers to obtain the desired mechanical properties, such as ductility and hardness of the layers Intercollege coverage. Such plasticizers are (but are not limited to, triacetin, esters of citric acid, esters of phthalic acid, dibutylsebacate, cetyl alcohol, polyethylene glycols, polysorbates or other plasticizers.

The amount of plasticizer optimize for each formula a layer Intercollege coating on the selected polymer layer selected from plasticizers and applied amount of these polymers in such a way that the mechanical properties, i.e., ductility and hardness of the layers Intercollege coating, for example, expressed in the form of hardness Vickers adjusted in such a way that the acid balls, covered with a layer Intercollege coverage does not decrease significantly during the pressing of these beads into tablets. The amount of plasticizer is usually more than 10% by weight of polymer layer Intercollege coating, preferably 15-50%, and more preferably 20-50%. In the layer Intercollege coating additives may be incorporated, that is s and protivovspenivayushchie agents. Other compounds can be added to increase film thickness and to reduce the diffusion of acidic gastric juice in sensitive to acid material.

To protect sensitive to acid agents, such as inhibitors of H+K+-ATPase, and to get a reasonable kislotostojkuju mnogodetnoi tableted dosage form according to this invention the layer Intercollege coating gives a thickness of approximately not less than 10 μm, preferably more than 20 μm. The maximum thickness of the applied Intercollege coverage (in the form of a layer or layers) is typically limited only by the treatment conditions.

The layer of protective coating

Beads coated with the layer or layers Intercollege coating can be further coated with one or more protective layers. These protective layers can be deposited on the coated intersolubility layer of balls by means of coating methods in appropriate units, such as mold, granulator, or apparatus with fluidized bed using water and/or organic solvents for the coating process. The materials for the layers of the protective coating are supplied with liviniere, hydroxypropylcellulose, methylcellulose, ethylcellulose, hypromellose, sodium carboxymethylcellulose, and others, used alone or as mixtures. In the protective layers may also include additives such as plasticizers, dyes, pigments, fillers, antiadhesive and antistatic agents, such as magnesium stearate, titanium dioxide, talc and other additives. Described protective layer may, in addition, to prevent potential agglomeration covered intersolubility layer, the shielding layer Intercollege coating against cracking during the compaction process and accelerate the process of tableting. The maximum thickness of the deposited protective layer or layers is limited only by the treatment conditions.

Tablets

Covered intersolubility layer balls mixed with fillers tablets and pressed into mnogodenek tableted dosage form according to this invention. Covered intersolubility layer balls with a protective layer or without it mixed with excipients for tablets, such as carriers, binders, dezintegriruetsja agents, lubricants and other pharmaceutically acceptable add the smooth surface of the tablet and further improving the stability of the tablet during packaging and transportation. Such covering pill, the layer may optionally contain additives, such as antiadhesive, dyes and pigments, or other additives, to obtain tablets with good appearance.

The number of covered intersolubility layer of balls is less than 75 percent by weight of the total weight of the tablet and predpochtitelno less than 60%. By selecting a small covered intersolubility layer of balls in the finished dosage form of the present invention, the number of such balls in each tablet can be maintained high, which, in turn, makes the tablet share to maintain the accuracy of dosing.

Mechanical properties, i.e., ductility and hardness Intercollege layer of covering material to kislotostojkuju mnogodetnoi tablet dosage form. Ductility/hardness of the surface layer Intercollege coatings can be characterized as preliminary parameter, such as Vickers hardness, measured on the coated intersolubility layer the balls before pressing them into pellets. The Vickers hardness can be measured using an instrument Shimadzu micro identation hardness tester tupe HMV 2000 (Micro Hardness Testing Marchines for vickers and knoop Hardness JIS B 7734-1984 and JIS Z 2251-1980). Posestvo the applied layer of the coating, and mechanical properties of the material, this covering layer. To obtain a well-functioning covered intersolubility layer of balls with a reasonable amount of material Intercollege layer, in which the balls can be compressed into tablets with no significant effect on acid, the preferred surface layer Intercollege coatings with hardness Vickers hardness of less than 8. If intersolubility layer of sediment covered with a protective layer, the hardness Vickers should be characterized prior to application of the protective layer. Solid protective layer with a Vickers hardness of more than 8) can be deposited on plastic and soft (hardness Vickers hardness of less than 8) intersolubility layer with persistent acid resistance during compaction.

Thus, the finished dosage form of the present invention consists of a core material containing the active substance, sometimes mixed with alkaline compounds, and fillers. Adding alkaline material may not be necessary, however, this substance may further increase the stability of the active substance. The core material is sometimes covered by one or more separating layers, sometimes containing alkaline Washakie layers Intercollege coverage, making these beads are insoluble in acidic media, but disintegrating/dissolving in near-neutral and alkaline environments, such as liquid present in the proximal part of the small intestine, where it is desirable dissolving tablets. Covered intersolubility layer of beads can be optionally covered with a protective layer before pressing them in mnogodenek tablet dosage form.

Way

The method of manufacture of this dosage form is a further aspect of the present invention. Pharmaceutical methods may be preferably processes on the basis of water, and there are various descriptions given in the examples below.

The use of the drug

The drug of the present invention is particularly advantageous for reducing the secretion of gastric acid. It is administered from one to several times a day. A typical daily dose of the active substance varies and depends on various factors such as the individual needs of patients, the route of administration and type of disease. In the total daily dosage is in the range of 1-1000 mg of active substance. The drug of the present invention is also applicable to dispersion in the aqueous liquid with neitralnogo up.

The invention is illustrated in more detail by the following examples.

Example 1

Material bark

Lansoprazole - 400g

Spherical inclusions sugar 400 g

The hypromellose - 82 g

Sodium lauryl sulfate, 3 g

Purified water - 1600

The separating layer

The core material is 400 grams

Hydroxypropylcellulose - 40g

Talc - 69 d

Magnesium stearate 6 g

Purified water (800 g)

Layer Intercollege coating

Beads coated with the separating layer 400 g

Copolymer of methacrylic acid and 200 g

Triethylcitrate - 60g

Mono - and diglycerides 10 grams

Polysorbate 80 1 g

Purified water - 420 g

Tablets

Covered intersolubility coated balls 80 grams

Microcrystalline cellulose - 191 g

Layering the suspension is carried out in the apparatus with fluidized bed using the bottom spray. Lansoprazole is sprayed on a spherical inclusion of sugar from water suspension containing the dissolved buffer. The size of a sugar spherical inclusions is in the range of 0,25-0,35 mm

The obtained core material cover with a separating layer in the apparatus with fluidized bed solution hydroxypropylcellulose on balls, covered with separating layer in the apparatus with fluidized bed. Hardness Vickers covered intersolubility layer tablets measure up to the value of 2.

Covered intersolubility layer balls and microcrystalline cellulose are mixed and pressed into tablets using tablet press machine single punch, use all the stamps 10 mm. High power stamp set 5 and the hardness of the tablets was measured on the device Schleuniger to determine hardness. Hardness was 168-185 N.

Example 2

Material bark

Pantoprazole - 600 g

Mannitol - 1000 grams

Microcrystalline cellulose - 300 grams

Hydroxypropylcellulose - 100 g

Sodium dodecyl sulfate - 8 g

Purified water - 802 g

The separating layer

The core material is 400 grams

The hypromellose - 48g

Purified water - 960 g

Layer Intercollege coating

Beads coated with the separating layer 200 grams

Copolymer of methacrylic acid, 100 g of

Triethylcitrate 30 grams

Mono - and diglycerides - 5 g

Polysorbate 80 - 0.5 g

Purified water - 309 g

Tablets

Beads coated with intersolubility layer 200 grams

Microcrystalline cellulose - 299 g

Stereolove. Pantoprazole, mannitol, microcrystalline cellulose and hydroxypropylcellulose mixed in dry form. Fluid granulation is added to the powder mixture and the mass is mixed in a raw form.

The wet mass is pushed through an extruder equipped with sieves with openings of 0.5 mm Extrudate is processed in order to obtain spherical particles on the friction drive device to obtain spherical particles. The core material is dried in a drying plant with fluidized bed and sorted. The obtained core material cover with a separating layer in the installation of a fluidized bed using hypromellose solution/water.

Layer Intercollege coating applied to beads coated with a separating layer of an aqueous dispersion of methacrylic acid copolymer, plasticized by triethylcitrate, to which was added a dispersion of mono - and diglycerides/Polysorbate. The beads are dried in the installation of the fluidized bed.

Covered intersolubility layer balls, microcrystalline cellulose and sodium fumarate are mixed and pressed into tablets having a weight corresponding to 20 mg of active substance, with the use of tablet press machine with the circle of inclusion sugar 500 grams

The hypromellose - 150 grams

Colloidal silicon dioxide - 3 g

Purified water - 1400 g

The separating layer

The core material 500 grams

Hydroxypropylcellulose - 40g

Talc - 67 g

Magnesium stearate 6 g

Purified water (800 g)

Layer Intercollege coating

Beads coated with the separating layer 500 grams

Copolymer of methacrylic acid and 200 g

Triethylcitrate - 60g

Purified water - 392 g

Tablets

Covered intersolubility layer balls - 400 grams

Microcrystalline cellulose - 871 g

Fumarate sodium 3 g

Pantoprazole, part of hydroxypropylmethylcellulose and colloidal silicon dioxide are mixed in dry form with the formation of the powder mixture. Spherical inclusions of sugar (0.25 to 0.35 mm) cover this powder in a centrifugal granulator to cover the fluidized bed by spraying solution hydroxypropylmethylcellulose (6 wt.%).

The obtained core material is dried and cover with separating layer in a centrifugal granulator to cover the fluidized bed. For layering Intercollege coating using setup fluidized bed.

Covered intersolubility the internal machine, equipped with 6 pairs 10 mm round punches. The amount of active substance is approximately 20 mg.

Example 4

The core material

Leminoprazole - 200 grams

The inclusion of silica - 200 grams

The hypromellose - 35 grams

Sodium lauryl sulfate 2 grams

Purified water - 700 g

The separating layer

The core material is 400 grams

The hypromellose - 32 g

Purified water - 700 g

Layer Intercollege coating

Beads coated with the separating layer 400 g

Copolymer of methacrylic acid - 250g

The polyethylene glycol 400 - 50 g

Mono - and diglycerides 10 grams

Polysorbate 80 1 g

Purified water - 650g

Tablets

Covered intersolubility layer balls - 500 grams

Microcrystalline cellulose - 1496

Fumarate sodium to 2 grams

Layering the suspension is performed in the apparatus with fluidized bed. Leminoprazole sprayed on the inclusion of silicon dioxide (size range of 0.15-0.30 mm) of the water suspension containing the dissolved binder and surfactant ingredient.

The obtained core material cover with a separating layer in the apparatus with a fluidized bed of mortar used gileadi in the apparatus with fluidized bed. Covered intersolubility layer balls and excipients for tablets are mixed and pressed into tablets as described in Example 2.

Example 5

Layer Intercollege coating

Beads coated with the separating layer (preparation and composition as described in Example 1) 500 grams

Copolymer of methacrylic acid - 250g

Polyethylene glycol 6000 75 g

Mono - and diglycerides - 12.5 g

Polysorbate 80 - 1.2 grams

Purified water - 490 g

Tablets

Covered intersolubility layer balls - 600 g

Microcrystalline cellulose - 1395

Fumarate sodium 5 g

Covered intersolubility layer balls, microcrystalline cellulose and sodium fumarate are mixed and pressed into tablets as described in Example 3.

Example 6

Layer Intercollege coating

Beads coated with the separating layer (preparation and composition as described in Example 1) - 400 g

Phthalate of hydroxypropylmethylcellulose - 400g

Diethylphthalate - 80 g

Ethanol - 1600

Acetone - 4000 g

Tablets

Beads coated with intersolubility layer 500 grams

Microcrystalline cellulose - 1500 g

Magnesium stearate 5 g

Layering Intercollege cover vypolnyu cellulose and magnesium stearate are mixed and pressed into tablets, as described in Example 3.

Example 7

The core material

Lansoprazole - 400g

Spherical inclusions of sugar (small) - 400 g

The hypromellose of 80 grams

Purified water - 1600

The separating layer

The core material is 800 grams

Hydroxypropylcellulose 80 grams

Talc - 137 g

Magnesium stearate - 11 g

Purified water - 1600

Beads coated with the separating layer 800 g

Layer Intercollege coating

Copolymer of methacrylic acid - 400 grams

Triethylcitrate 120 g

Mono - and diglycerides 8 grams

Polysorbate 80 1 g

Purified water (800 g)

Tablets

Covered intersolubility layer balls - 1000 grams

Dibasic calcium phosphate (anhydrous) - 1760

Microcrystalline cellulose - 440 g

Magnesium stearate - 16 g

Layering the suspension is performed in the apparatus with fluidized bed. Lansoprazole is sprayed on a spherical inclusion of sugar from water suspension containing the dissolved binder.

The prepared core material is covered separating layer in the fluidized bed with a solution of hydroxypropylcellulose containing talc and magnesium stearate. Layer Intercollege coating is sprayed in the form of di is m layer of balls, dibasic anhydrous calcium phosphate in granular form, microcrystalline cellulose and magnesium stearate are mixed and compressed into tablets as described in Example 3. High power stamp set at approximately 30 kN.

Example 8

Tablets

Covered intersolubility layer balls (preparation and composition as in Example 1) - 1.00 kg

Microcrystalline cellulose - 1.45 kg

Anhydrous, lactoba - 0.14 kg

Starch - 0,23 kg

Povidone - 0,18 kg

Purified water - 0,836 kg

Povidone is dissolved in water. Microcrystalline cellulose, anhydrous lactose and starch are mixed in a dry form. Add a solution of povidone, performing mixing wet. The wet mass is dried in a thermostat. Granulated mass grind in mixer granulator.

Covered intersolubility layer balls and cooked granulate are mixed and pressed into a shaped and having labels tablets using a rotary tablet press machine, equipped with 16 pairs of oval, 8.5 x 17 mm, tablet dies.

Example 9

The protective layer

Covered intersolubility layer balls (preparation and composition as in Example 7) - 400 g

Hydroxypropylmethylcellulose cellulose - 233 g

In the apparatus with fluidized bed solution hydroxypropylmethylcellulose sprayed on the coated intersolubility layer balls. Hardness Vickers covered intersolubility layer the balls before applying the protective layer is equal to 2, and the Vickers hardness measured on covered with a protective layer of balls equal to 11. Covered with a protective layer of beads are mixed with microcrystalline cellulose and pressed into tablets as described in Example 2.

Example 10

The core material

Pantoprazole - 100 g

Spherical inclusions sugar - 200 grams

Hydroxypropylcellulose - 25g

Purified water - 607 g

The separating layer

The material of the core 200 g

Hydroxypropylcellulose - 20 g

Talc - 34 grams

Magnesium stearate 3 g

Purified water - 400g

Layer Intercollege coating

Beads coated with the separating layer 200 grams

Copolymer of methacrylic acid, 100 g of

Triethylcitrate 30 grams

Mono - and diglycerides - 5 g

Polysorbate 80 - 0.5 g

Purified water - 282 g

Tablets

Covered intersolubility layer balls - 100 gr.

Microcrystalline cellulose - 232 grams

Fumarate sodium 1 g

Layering the suspension is performed in the apparatus of soup dissolved binder.

The obtained core material cover with a separating layer in the apparatus with fluidized bed. Layer Intercollege coating is applied by spraying an aqueous suspension of beads coated with the separating layer, in the apparatus of the fluidized bed.

Covered intersolubility layer beads and fillers tablets are mixed and pressed into tablets weighing approximately 600 mg using vodnoshlamovoj tablet press machine using round (12 mm) stamps. High power stamp set on 5 kN, and the hardness of the tablets is measured in the unit Schleuniger for determining hardness equal to 200-220 N.

Example 11

Layer Intercollege coating

The core material (without a separating layer) - 500 grams

Copolymer of methacrylic acid and 500 grams

Triethylcitrate - 150 grams

Mono - and diglycerides - 25g

Polysorbate 80 - 2.5 grams

Purified water - 978 g

Tablets

Covered intersolubility layer balls - 800 grams

Microcrystalline cellulose - 1860

Fumarate sodium and 7 grams

The core materials are given as in Example 1 and in Example 10. Covered intersolubility layer beads and fillers tablets pressed as described in Example 3.

Example 12

The core material The separating layer

The core material - 100 g

Povidone - 5 g

Purified water - 150 g

Layer Intercollege coating

Beads coated with the separating layer - 100 g

Copolymer of methacrylic acid, 50 g of

Triethylcitrate - 15 g

Talc - 15 g

Purified water - 125 grams

Tablets

Covered intersolubility layer balls - 125 grams

Microcrystalline cellulose - 300 grams

Layering the suspension is performed in the apparatus with fluidized bed. Ariprazole sprayed on a spherical inclusion of sugar from water suspension containing the dissolved binder. The obtained core material cover with a separating layer in the apparatus with fluidized bed. Intersolubility layer is applied by spraying water dispersion into balls, covered with separating layer in the apparatus with fluidized bed.

Covered intersolubility layer balls and microcrystalline cellulose are mixed and pressed into tablets as described in Example 1.

Example 13

Layer Intercollege coating

Beads coated with the separating layer 200 grams

Acetate-succinate of hydroxypropylmethylcellulose - 100 g

Tritylated 30 grams

Purified water - 309 g

Ethanol - 720 g
BR>
Crosspovidone - 5 g

Fumarate sodium 1 g

Beads coated with the separating layer are given as in Example 7.

Layer Intercollege coating is applied in the fluidized bed from a solution of water/ethanol. Hardness Vickers covered intersolubility layer of sediments measured to a value of 5. Covered intersolubility layer beads and fillers tablets are mixed and pressed into tablets as in Example 2.

Example 14

Layer Intercollege coating

Beads coated with the separating layer 200 grams

Copolymer of methacrylic acid and 200 g

Triethylcitrate - 60g

Mono - and diglyceride 10 grams

Polysorbate 80 1 g

Purified water - 391 g

The protective layer

Covered intersolubility layer balls - 471 g

The hypromellose 6 grams

Magnesium stearate - 0.2 g

Purified water 120 g

Tablets

Covered with a protective layer of balls - 140 g

Microcrystalline cellulose - 114

Fumarate sodium 0.4 g

Beads coated with the separating layer is obtained in accordance with Example 7.

Layer Intercollege coating and a protective layer is applied by spraying the balls in the apparatus with fluidized bed. Covered C is the first stamp, 12 mm). High power stamp set of 6 kN.

Example 15

Layer Intercollege coating

Beads coated with the separating layer 200 grams

Copolymer of methacrylic acid and 40 g

Triethylcitrate 12 grams

Mono - and diglycerides - 2 g

Polysorbate 80 - 0.2 g

Purified water is 78 grams

The protective layer

Covered intersolubility layer balls - 200 grams

The hypromellose 4 grams

Magnesium stearate 0.1 g

Tablets

Covered with a protective layer of balls - 69 d

Microcrystalline cellulose - 230 g

Fumarate sodium - 0.7 g

Beads coated with the separating layer is obtained in accordance with Example 7.

Intersolubility layer and a protective layer is applied by spraying the balls in the apparatus with fluidized bed. The amount of material Intercollege layer in this example corresponds to the thickness of Intercollege cover approximately 20 μm. Covered with a protective layer of precipitation and fillers tablets pressed with the use of vodnoshlamovoj tablet press machine (round stamp, 10 mm). The weight of the tablets approximately 330 mg.

Example 16

Layer Intercollege coating

Covered with separating layer balls - 500 grams

Aceturate intersolubility layer balls - 100 g

Microcrystalline cellulose - 300 grams

Crosspovidone 8 grams

Fumarate sodium 1 g

Beads coated with the separating layer are given as in Example 7.

Layer Intercollege coating is applied by spraying in a fluidized bed from a solution in a mixture of acetone/ethanol. Covered intersolubility layer beads and fillers tablets are mixed and pressed into tablets as in Example 2.

The results of the tests on the acid covered intersolubility layer of balls and CT are presented in Table I.

Comments:

Unexpectedly acid tablets shows that intersolubility the coating layer of the present invention sufficiently resists the pressing.

Reference example I

Tablets

Precipitation omeprazole covered intersolubility layer 180 grams

Microcrystalline cellulose - 219 g

Fumarate sodium 1 g

Balls of omeprazole Loseccapsules 40 mg mixed with microcrystalline cellulose and sodium fumarate and pressed into tablets using vodnoshlamovoj tablet press machine. Hardness Vickers covered intersolubility layer of the beads measure to Vela>/P>Reference example II

Tablets

Balls lansoprazole covered intersolubility layer (content Lanzo30 mg capsules) 276 g

Microcrystalline cellulose - 644 g

Balls lansoprazole is mixed with microcrystalline cellulose and tabletirujut in vodnoshlamovoj tablet press machine. Hardness Vickers covered intersolubility layer the balls measure up to size 18. Tool for tabletting round with a diameter of 12 mm Power stamp set by 3.6 kN.

Reference example III

The core material

Omeprazole magnesium - 15,0 kg

Spherical inclusions sugar - 15,0 kg

The hypromellose - 2.25 kg

Purified water 40 kg

The separating layer

The core material - 15,0 kg

Hydroxypropylcellulose - 1.5 kg

Talc - 2.57 m)

Magnesium stearate - 0.21 kg

Purified water, 30 kg

Layer Intercollege coating

Beads coated with the separating layer 200 grams

Material Intercollege layer is used, as described in Drugs made in Germany, 37, No. 2 (1994), p. 53 table I, the product N 9. The amount of coating polymer, as calculated in the link, is 40% (weight/weight).

The protective layer

Covered anterocollis is a - 80 g

Tablets

Covered with a protective layer of balls 75 g

Microcrystalline cellulose - 174 g

Fumarate sodium - 0.6 grams

Layering the suspension is performed in the apparatus with fluidized bed. Omeprazole magnesium is sprayed on a spherical inclusion of sugar from water suspension containing the dissolved binder. The separating layer, Intercollege coating and a protective layer is applied by spraying the balls in the apparatus with fluidized bed. The protective layer is applied to prevent adhesion of balls prior to pelletizing. Covered with a protective layer of beads and fillers tablets tabletirujut as in Example 1. High power stamp set on 5 kN.

The results of the tests on the acid covered intersolubility layer of balls and pressed tablets are presented in Table II.

Review:

As can be seen from the data presented, investigated intersolubility layer of these products, including two best-selling products (reference examples I and II), did not have the mechanical properties required to withstand pressing into tablets.

1. Preformed mnogoagentnye dosage form containing the active is a and its alkali metal salts, characterized in that the individually coated with intersolubility layer units core material containing the active substance, optionally mixed with alkaline compounds, mixed with fillers tablets and compressed into tablets, and the layer Intercollege coating has such mechanical properties that pressing individual pieces, mixed with fillers in mnogodenek tableted dosage form, has no significant effect on acid covered intersolubility layer units.

2. Tableted dosage form under item 1, characterized in that the active substance is a compound of General formula 1, or its alkali salt, or one of its enantiomers or an alkaline salt

< / BR>
where Het1represents a

< / BR>
or

< / BR>
Het2represents a

< / BR>
or

< / BR>
or

< / BR>
X denotes

< / BR>
or

< / BR>
where N in the benzimidazole residue of the molecule indicates that one of the carbon atoms is replaced with an R6-R9not necessarily replaced by a nitrogen atom without any substituents;

R1, R2and R3- same or different and selected from hydrogen, alkyl, alkoxyl, halogen, phenyl and vinylalcohol;

R4and R5- same or different and selected from hydrogen, alkyl and aralkyl;

R'6represents hydrogen, halogen, trifluoromethyl, alkyl and alkoxygroup;

R6-R9- same or different and selected from hydrogen, alkyl, alkoxygroup, halogen, halogenlampe, alkylcarboxylic, alkoxycarbonyl, oxazolyl, triptoreline or adjacent groups R6-R9form a ring structure, which may be optionally substituted;

R10represents hydrogen or forms together with R3alkylenes chain;

R11and R12- same or different and selected from hydrogen, halogen or alkyl, with the exception of the compounds 5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole, 5-fluoro-2[[(4-cyclopropylmethoxy-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole and 5-carbomethoxy-6-methyl-2[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinil]-1H-benzimidazole, or a single enantiomer, or their alkaline salts.

3. Tableted dosage form under item 1, characterized in that the active substance is one of the following connections:

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

5. Tableted dosage form under item 4, characterized in that it has a Vickers hardness of less than 8.

6. Tableted dosage form under item 1, characterized in that the acid separately covered intersolubility layer units is not reduced by more than 10% during tableting.

7. Tableted dosage form under item 1, characterized in that the layer Intercollege coating contains a plasticizer.

8. Dosage form under item 1, characterized in that intersolubility coating has a thickness of at least 10 microns.

9. Tableted dosage form under item 1, characterized in that the separately covered intersolubility layer unit is additionally covered with a protective layer containing pharmaceutically acceptable excipients.

10. Tableted dosage form under item 1, characterized in that it is shared.

11. Tableted dosage form under item 1, characterized in that it I is m units, containing the active substance.

12. Tableted dosage form under item 1, characterized in that the separating layer is located under intersolubility layer.

13. Tableted dosage form under item 12, characterized in that the separating layer contains pharmaceutically acceptable excipients that are soluble or insoluble, but disintegrate in the water and not necessarily alkaline compounds.

14. Tableted dosage form under item 1, characterized in that the core material is the inclusion of the filled active material.

15. Tableted dosage form according to p. 12, wherein the inclusions have a size of 0.1 - 2 mm

16. Tableted dosage form according to PP. 1 - 15 as an inhibitor of the secretion of gastric acid or the treatment of gastrointestinal inflammatory diseases in mammals and man.

17. A method of obtaining a preformed mnogodetnoi dosage form under item 1, according to which units of material containing the active substance are mixed, if necessary, with alkaline compounds can then be covered with separating layers, put intersolubility pokrytie intersolubility layer unit of the active substance optionally covered with a protective layer before pressing.

19. Method of inhibiting secretion of gastric acid or treatment of gastrointestinal diseases in mammals and man by introducing a therapeutically effective dose mnogodetnoi tableted dosage form according to any one of paragraphs.1 - 16.

 

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