Oral pharmaceutical dosage form with prolonged release

 

The invention relates to medicine. The claimed pharmaceutical dosage form with prolonged release of an inhibitor of H+To+- ATPase with intersolubility coating, giving a prolonged profile of the concentration of inhibitor N+To+- ATPase in the plasma. Extended profile in the plasma was produced using the pharmaceutical composition, which contains a core material of a hydrophilic or hydrophobic matrix and the inhibitor N+To+- ATPase, and possibly pharmaceutically acceptable excipients. Dosage form can be entered once per day. The invention provides protection of the active substance from degradation occurring in the acidic environment of the stomach. 2 C. and 16 h.p. f-crystals, 6 PL.

Field of invention the Present invention relates to new pharmaceutical dosage forms, containing a proton pump inhibitor such as an inhibitor of H+To+- ATPase. New dosage forms are drugs with intersolubility coating that provides a long lasting and continuous release of an inhibitor of H+To+- ATPase in thin and/or large intestine, which leads to prolongirovannomu p the th release of an inhibitor of H+To+- ATPase preferably for a minimum of 2 and maximum of 12 hours. Further, the present invention relates to the manufacture of such pharmaceutical preparations with protracted release and their application in medicine.

Background of the invention and the prior art are Unstable in the acidic environment of inhibitors of H+To+- ATPase, also known as inhibitor of the gastric proton pump, are for example, compounds known under the generic names of omeprazole, lansoprazole, pantoprazole, rabeprazole and leminoprazole. Some of these compounds are described in EP-A1-0005129, EP-A1-124495, WO 94/27988, EP-A1-174726, EP-A1-1666287 and GB 2163747.

These pharmaceutical substances suitable for inhibiting the secretion of gastric acid in mammals, including humans, by controlling the secretion of gastric acid in the final stage of the journey secretion of acid and thus reduce basal and induced stimulus secretion of gastric acid, regardless of the stimulus. In a more General sense, they can be used for the prevention and treatment of diseases associated with gastric acid in mammals and humans, including for example, reflux esophagitis, gastritis, duodenitis, ulcers VC the value of other gastrointestinal disorders, where desired effect of inhibiting gastric acid, for example in patients when therapy with nonsteroidal anti-inflammatory drugs (NSPs) therapy in patients with non-ulcer dyspepsia patients with symptomatic gastroesophageal reflux disease (GERD). They can also be used in patients in intensive care patients with acute upper gastrointestinal bleeding, pre - and post-operative to prevent aspiration of gastric acid and to prevent and treat stress ulceration. Further, they can be useful in the treatment of psoriasis, in addition, in the treatment of Helicobacter infections and diseases associated with them.

Therapeutic regulation of the secretion of gastric acid is essential in all these conditions, but the degree and duration of inhibition of acid required for optimal clinical effect is not yet fully understood.

In WO 97/48380 (published on 24 December 1997, i.e. after the priority date of this application) the applicant has proposed the injection mode, which gives levels in plasma, prolonged from 2 to 12 hours (using any of several ways), will lead to inhibition the most part protohypericin secretion of acid, leading to improved efficiency in GER, faster healing of stomach ulcers and improved elimination of N. Pylori. The present invention provides pharmaceutical dosage forms that reach such prolonged plasma levels by continuous drug release.

Pharmaceutical dosage form containing omeprazole or other proton pump inhibitor, is better protected from contact with acidic gastric juice by layer Intercollege coverage. Such drugs with intersolubility coating described in US 4786505 and US 4853230. These drugs have a nucleus containing an alkaline salt of a medicinal product, or a core containing the drug together with an alkaline reacting compound, and the core is covered with a water-soluble or bystrorazvivajushchimsja in the water separating layer, and then layer Intercollege coverage. In WO 96/01623 and WO 96/01624 described tableted dosage form of omeprazole and other proton pump inhibitors, where bean with a layer of Intercollege coating is compressed in a tablet dosage form compound units. Significantly in these tablets the drugs that the layer Intercollege portelinha release of the medicinal product, leading to prolonged profile in plasma.

In WO 97/02020 described dosage form of pantoprazole with antibiotic substance, which has a slow release membrane located as an intermediate layer. This membrane contains water-insoluble film-forming agent as important features of the dosage form. In WO 97/02021 described the same type of dosage form for optimaliausio of proton pump inhibitor in combination with an antibiotic substance.

Easier way to get the dosage form with prolonged release compared with the application of a semi-permeable membrane is the manufacture of dosage forms containing matrix unit. Some advantages of such matrices are, for example, a simple technological ways, mainly through the use of conventional equipment for granulating and tableting and sometimes also in relation to the manipulation of solvents, energy and the gain in time production, etc.

Pill use with hydrophilic matrices as a source for sustained release of drug was first described in the early 60's, stubname matrices is also in the handling of the 60's, for example, durali quinidine was sold in 1963.

Pharmaceutical form prolonged-release formulation containing various drugs in the matrix, have been described in the prior art. However, none of these matrix dosage forms as such are not suitable for an inhibitor of H+To+- ATPase.

Some matrix of the pharmaceutical form prolonged-release hydrophilic matrix described in the literature, for example in the Journal of Pharmaceutical Sciences, vol.84, 3, March 1995, in which Kim describes dosage forms containing theophylline or diltiazem hydrochloride. U.S. patent 5273758 describes dosage forms containing, for example, clemastine fumarate. EP 0249587 describes the preparations felodipina. Dosage forms, containing a derivative of benzodiazepine described by Franz et al in the Journal of Controlled Release 1987, 5, 159-72. Dosage forms containing hydrophobic matrix with extended-release have been described, e.g., Romero et al in International Journal of Pharmacy 1991, 73, 239-48.

Tablets with prolonged-release with additional coating layer were also described, for example, Sangalli et al in International Journal of Pharmaceutics, 91 (1993), 151-6. Given as examples of drugs are of metoprolol by tartrate hole in the center of the tablet, the opening of the original surface area for dissolution of the inner core, that is, dissolution of the active drug.

Quite complex dosage form has been described in U.S. patent 5178867. Dosage forms have a core containing the drug, this core is covered with a semi-permeable wall (supporting its physical integrity during the lifetime of the dosage form), having at least one hole drilled in it, as the output passage for the dissolved drug. It was also mentioned that the layer Intercollege coating may be applied to limit delivery of the drug in the stomach and to ensure the release of the drug in the small intestine. This dosage form is much more difficult to manufacture than the matrix unit. There is not a detailed description of the received dosage forms containing the compound-proton pump inhibitor and validation of such dosage forms to ensure that the acidic gastric fluid does not penetrate through the semi-permeable membrane, and that the active substance is delivered intact to the site of absorption.

None of this is Stateline to acid substance, such as a proton pump inhibitor, from the destruction that occurs upon contact with acidic, such as the environment found in the stomach.

Description of the invention Thus, the present invention relates to the preparation with intersolubility coating with properties extended release containing hydrophilic or hydrophobic matrix, which is an inhibitor of H+To+- ATPase, or one of its single enantiomer, or alkaline salt is an inhibitor of H+To+- ATPase, or one of its single enantiomers.

The present invention offers a solution to the problem of creating a simplified way such dosage forms with prolonged release containing sensitive to acid inhibitor of H+To+- ATPase, such as omeprazole or other proton pump inhibitor. The specific problem is that the pharmaceutical dosage form according to the present invention must meet certain requirements in terms of resistance to gastric acid products with intersolubility coating defined in the USP (23rd edition). This dosage form should be protected intersolubility coating to ensure the, where it can be absorbed.

In accordance with the present invention extended profile in the plasma is provided by the introduction of a once daily dosage form with intersolubility coating that releases the proton pump inhibitor over an extended period of time, preferably for a minimum period of 2 hours and a maximum period of 12 hours. Thus, the full dose will be delivered within 2 hours or maximum within 12 hours. Therapeutic effect of omeprazole and similar substances can be improved by providing an extended release profile in plasma and by providing such a dosage form for administration once a day.

These preparations with protracted release show improved patient compliance with the mode of administration, which consistently give two or more than two standard doses for one day.

Detailed description of the invention the Dosage form, giving a prolonged release formulation of the present invention provide a unit in the form of tablets, coated intersolubility coating. Alternatively, the units are tablets, coated intersolubility drug form compound units.

Individual units, i.e. tablets or pills may be created as the core material may deposited on a seed/sphere, and the core material contains a hydrophilic or hydrophobic matrix containing the active drug and the possible pharmaceutically acceptable excipients, and possible surrounding the separating layer, and finally a layer Intercollege coverage.

The core material.

The core material for the units, i.e. tablets or separate tablets may be prepared in accordance with different principles. The core material may be homogeneous or heterogeneous.

I) Homogeneous material of the core If the core material is homogeneous, it has a homogeneous distribution of the active substance around the core material.

The active substance is mixed with substances, forming a hydrophilic or hydrophobic matrix and possibly pharmaceutically acceptable excipients. The core material should be free from acidic substances. Thus, the hydrophilic or hydrophobic matrix in combination with other material in the core should not give an acidic reaction in the core material, which would be harmful to sensitive to acid connection-proton pump inhibitor. The microenvironment in the equipment is not less than pH 8, when water is absorbed in the particles of the mixture or when water is added in small amounts to the mixture.

The active substance can be mixed with additional components to obtaining preferred for handling and processing properties and a suitable concentration of the active substance in the final mixture. Such components may include binders, surfactants, lubricants, slip agents, fillers, alkaline additives or other pharmaceutically acceptable ingredients, separately or in mixtures.

The specified core material can be produced either by direct extrusion of the mixed ingredients, or by granulation of the ingredients with subsequent pressing of the dried granulated material.

In direct extrusion, the ingredients are mixed and pressed with conventional tabletting equipment.

For granulating there are different ways of granulation mentioned in the literature, dry methods, such roller pressing (Chilsonator), and wet methods using a granulating solution with or without added binders. A variant of the wet method is the implementation of the granules is arousih solutions can be used organic solvents, aqueous solutions or pure water. For reasons of environmental protection preferred clean water. However, for some materials used as components of hydrophilic matrices, technical properties of the manufactured pellets can be better when using organic solvents, such as alcohols, especially for hydroxypropylmethylcellulose.

For granulation of hydrophobic components of the matrices is also preferable to apply alcohol solution in the wet granulation methods. As binding agent in such solution, as the polymer forming the matrix can be selected one or more than one polymer of the following.

As a General principle, the active ingredients together with the polymers forming the matrix, and possibly pharmaceutically acceptable excipients are mixed and granularit. The dried granules possibly mixed with pharmaceutically acceptable excipients, and then pressed into tablets using conventional equipment.

The size made of materials of the core is approximately between 2 and 14 mm, preferably between 3 and 9 mm for drugs in tablet form, and between 0.1 and 4 mm, preferably between 0.1 and 2 mm for drugs in the form of drag the area, for example, the seed or the area not containing the active substance. These grain or the field is surrounded by a layer of a hydrophilic or hydrophobic matrix containing the active substance in the matrix, possibly included pharmaceutically acceptable excipients.

The grain, or the field can be soluble or insoluble. Perhaps a grain or sphere (inner zone) can be coated with an inert layer to prepare a smooth surface before the layer containing active substance and a hydrophilic or hydrophobic erosive substance(s), put on a seed/sphere.

Insoluble grains/sphere can contain various oxides, cellulose, organic polymers and other substances, individually or in mixtures. Water-soluble granules/sphere may contain various inorganic salts, sugars and other substances, individually or in mixtures. The grain size can vary between approximately 0.1 and 2 mm Grains coated with a layer of the matrix containing the active substance are manufactured by applying a layer or powder, or solution/suspension, using, for example, equipment for granulating or coating spray application method/layering.

Pharmaceutically acceptable additives.

Binders for hydrophobic matrix can be selected from among a hydrophobic erosive matrices listed below.

Additives listed among the following components that are suitable for both hydrophilic and hydrophobic matrix.

Suitable alkaline additives can be selected from, but not limited to, such substances as sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; soosazhdenie aluminum hydroxide/sodium bicarbonate; substances normally used in antacid preparations such as hydroxides of aluminum, calcium and magnesium; magnesium oxide or complex substances, such as Al2O3MDOCO2N2O (SB6Al2(OH)16CO34H2O), MaoAl2O32SiO2mo2O or similar compounds; organic pH-buffering substances such as trihydroxypyrimidine substances.

Suitable surfactants are groups pharmaceutically acceptable nonionic surfactants, such as Polysorbate 80, or ionogenic surface-active substances, such as, for example, sodium lauryl sulfate.

The lubricating substances are, for example, magnesium stearate, sodium fumarate (PruvTM), and cetylpalmitate.

Fillers are, for example, a silicate of sodium, lactose, calcium phosphate and others.

Moving substances are, for example, talc and Aerosil.

Antioxidants can be added if necessary.

The active substance.

Compounds of interest for new dosage forms with prolonged release of the present invention, are compounds of the General formula I, their alkali metal salts, one of their single enantiomers or an alkaline salt of one enantiomer
where Het1represents a

or

Het2represents a

or

X=

or

Examples of specific compounds of formula I are






Connection, suitable for use in preparations with protracted release of the present invention, can be used in neutral form or in the form of alkaline salts, such as, for example, salt of Mg2+Ca2+, Na+or+preferably Sol MD2+. Connections can also be used in the form of one of their single enantiomers or an alkaline salt of the single enantiomer.

The preferred compounds for oral pharmaceutical preparations of the present invention are omeprazole, a magnesium salt of omeprazole or a magnesium salt of (-)-enantiomer of omeprazole. Omeprazole and rodstvennye compounds and their preparations are described in EP 5129, EP 124495, WO 95/01977, WO 94/27988, fully included here by reference.

The above connection is subject to degradation/transformation in acidic and neutral environments. Usually catalyze the degradation of the acid-reactive compound, and stabilize the active substance is alkaline reacting compounds. There are different drugs with a layer of different Intercollege coatings containing omeprazole and other proton pump inhibitors, describes the development of production methods for the preparation of tablets coated with a layer of Intercollege coverage, containing omeprazole and similar compounds. These patents are incorporated here fully by reference.

Hydrophilic matrix.

The active substance, i.e. the drug is embedded in a hydrophilic polymer may together with pharmaceutically acceptable excipients. Suitable hydrophilic polymers are, for example, hypromellose, hydroxypropylcellulose, metilgidroxiatilzelllozu, hydroxyethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, polyethylene oxides, polyvinyl alcohols, tragakant and xanthan gum. These polymers can be used individually or in mixtures with each other.

The amount of hydrophilic polymer in the matrix is preferably 15-80% (per unit weight), and the selected hydrophilic polymer(s) among the above.

Particularly preferred polymers in the matrix unit with hydrophilic matrix are hypromellose or oxides.

Preferred excipients in the matrix are the fillers, which can lead to a good technical properties tabletiruemoj, that is a silicate of sodium, mannitol or calcium phosphate (EmcompessTM). Predpokazah above, and 10-60%.about. (per unit weight) of silicate of sodium or calcium phosphate (EmcompressTM).

Hydrophobic matrix.

The active substance, i.e. the drug is embedded in a hydrophobic matrix, possibly together with pharmaceutically acceptable excipients. Hydrophobic matrix contains a hydrophobic agent and/or a hydrophobic polymer. A suitable material for hydrophobic matrix are, for example, water agents, such as cetanol, cetosteatil alcohol, cetylpalmitate, waxes, such as Carnauba wax, paraffin, magnesium stearate, sodium fumarate and glycerol esters of medium or long chain, individually or in any mixtures. Examples of hydrophobic polymers are, for example, polyvinyl chloride, ethylcellulose, polyvinyl acetate and copolymers of acrylic acid, such as EudragithTMRS and RL. The polymers can be used individually or as mixtures.

As binders for hydrophobic matrix can be used either hydrophilic or hydrophobic polymers.

It is important that the matrix contains at least one component that is soluble in such environments as intestinal fluid. This component dissolves and leaves porarily component can be itself the active drug or a soluble component, such as sugar. Preferably the soluble component is present in an amount of not less than 2% wt./wt. (per unit weight) and up to 60%.

Preferably, the matrix contains not less than 10% wt./wt. (per unit weight) and up to 80% water-repellent agent or a hydrophobic polymer, both described earlier, or any combination thereof.

Another preferred matrix contains as an additive slightly soluble or less soluble component. As such components, you can add any of the following: sodium aluminosilicate, calcium phosphate, Aerosil, titanium dioxide, carbonates of magnesium or other neutral or alkaline compounds which are slightly soluble or less soluble, here, with respect to solubility in water. "Slightly soluble" is defined according to the European Pharmacopoeia (3rd edition) under the heading "General notes" (the"General notices"). This matrix contains 10-80 wt.%. /Mac. (per unit weight) water-repellent agent or a hydrophobic polymer, or any of their combinations, together with 10-60% poorly soluble or less soluble component. As such a component is particularly preferred is sodium aluminosilicate.

The final dissolution profile can in period with the achievement of temperatures equal to or above the softening temperature of hydrophobic agents. Such processing is best done after applying Intercollege coverage.

The layer(s) intersolubility shell and the separating layer(s).

Before applying the layer Intercollege coating on the core material of pills or tablets may be covered by one or more than one separating layer containing pharmaceutical excipients, possibly including alkaline compounds such as, for example, a pH-buffering compounds. This separating layer separates the active ingredient in pills or tablets from the outer layer Intercollege coverage.

The separating layer can be applied using the procedures of coating or layering in a suitable equipment, such as drazhirovochnuyu boiler, pellet coating, centrifugal granulator apparatus with suspended layer (including the type Wuster), using water and/or organic solvents for the coating process. As an alternative, the layer(s) may be deposited using methods of powder coating or coating process.

Suitable substances for separating SL is irreligion, polyvinyl alcohol, polyvinyl acetate, hydroxypropylcellulose, methylcellulose, ethylcellulose, hypromellose, sodium carboxymethyl cellulose and other used individually or in mixtures. Additives such as plasticizers, dyes, pigments, fillers, agents against adhesion and antistatic agents, such as, for example, magnesium stearate, titanium dioxide, talc, pH buffering agents and other additives may also be included in the separating layer.

When the separating layer is deposited on pills or pills, it may have a different thickness. The maximum possible thickness of the separating layer is usually limited only by the terms of method. The separating layer can serve as a diffusion barrier and can act as a pH buffer zone. Possible separating layer can improve the chemical stability of the active substance and/or physical properties of the dosage form.

Finally, units, i.e. tablets or pills, coated with one or more than one layer Intercollege coating using a suitable method of coating. Substance layer Intercollege coverage may be dispersed or dissolved either in water or in suitable organic dissolve the N. of the following, separately or in combination: for example, solutions or dispersions of copolymers of methacrylic acid, acatitla cellulose phthalate of hydroxypropylmethylcellulose, acetolactate hydroxypropylmethylcellulose, polivinilatsetatftalat, acetotartrate cellulose, karboksimetiltselljulozy, shellac or other suitable layer Intercollege coating polymer(s).

Additives such as dispersing agents, dyes, pigments, additional polymers such as poly(acrylate, methacrylate), agents against sticking and preventing foaming, can also be included in the layer Intercollege coverage. Other compounds can be added to increase film thickness and to reduce the diffusion of acidic gastric juices into the material, sensitive to acid. The layer(s) Intercollege coating has a thickness of approximately at least 10 μm, preferably more than 20 μm. The maximum thickness of the applied layer(s) Intercollege coverage is usually limited only by the conditions of the method.

Layers Intercollege coating may also contain pharmaceutically acceptable plasticizers to obtain the desired mechanical properties. Such plasticizers ablauts milovy alcohol, the glycols, complex monetary glycerin, Polysorbate or other plasticizers and mixtures thereof. The amount of plasticizer is preferably optimized for each composition in the selected polymer(s) selected plasticizer(s) and the applied amount of the specified polymer(s).

The final dosage form
Tablet or dragee covered intersolubility shell, possibly mixed with excipients of the tablets are loaded into a capsule or compressed into tablet dosage form compound units. Prepared tablets intersolubility coating may cover film-forming agent(s) to obtain a smooth surface tablets and additional improve the strength of the tablet during packaging and transportation. Such a coating layer tablets may optionally contain additives, such as agents against sticking, dyes and pigments or other additives to obtain tablets with good appearance.

Dosage forms according to the invention suitable for oral administration. The dose will depend on the nature and severity of the disease to be treated. The dose may vary depending on age, weight and response of the individual who will in most cases benefit from doses which is a little below average. In the treatment of other conditions will be used doses higher than average. The dosage form can also be used in combination with other medicinal forms containing, for example, NSPs, agents contractility, antibacterial substances and/or antacids.

The standard dose of proton pump inhibitor is administered at least once a day. Oral pharmaceutical preparation will maintain prolonged release pharmaceutical substances for a minimum of 2 and maximum of 12 hours, preferably will be maintained for a minimum of 4 and maximum of 8 hours. Such a drug with prolonged release may contain up to 500 mg, preferably doses contain about 5-100 mg and more preferably 10-80 mg

Examples
The invention is described in more detail in the following not limiting examples.

Example 1.

Matrix tablets are extended release, containing Omeprazole-MD (approximately 20 mg).

Granules for core tablets were manufactured in accordance with the following composition (in mass units):
Omeprazole-MD - 45
The polyethylene oxide (mol. mass Ave is more in the mixer, then add ethanol uniform stream. The mass is dried in a drying oven at 50oC.

After grinding in a vibrating mill through a 1.0 mm sieve obtained granules are mixed with the lubricant tablets, in accordance with the following composition (in mass units):
Granules for kernel-tablets - 235
Stearyl the sodium fumarate (Pruv) - 1
Mixing is carried out in the mixer Kenwood (Kenwood mixer and the mixture is pressed into tablets (6 mm diameter) with an average weight of 123 mg, tablet machine with a single punch (Diaf).

The rate of dissolution test, analysis of individual tablets, using dissolving units 2 (mixer) United States Pharmacopeia, equipped with stationary basket and operating at 100 rpm and 37oC. Environment dissolution is phosphate buffer pH 6.8.

The resulting rate of release (n=2) shown in the table.1.

Prepared tablets can be further processed in accordance with Example 3 or 4, i.e. on the pill cause intersolubility floor.

Example 2
Matrix tablets with prolonged-release formulation containing MD-salt of S-omeprazole (approximately 32 mg).

Granules for kernels tablets izgotavlivaeyutsya 50 cps - 80
Ethanol 95% (wt./about.) - 356
Polyvinylpyrrolidone K-90 - 40
The powders are mixed in a mixer, after which the ethanol add a uniform stream. The mass is dried in a drying oven at 50oC.

After grinding in a vibrating mill through a 1.0 mm sieve obtained granules are mixed with the lubricant tablets in accordance with the following composition (in mass units):
Granules for kernel-tablets - 380
The sodium fumarate (Pruv) - 4
Mixing is carried out in the Kenwood mixer, after which the mixture is pressed into tablets (7 mm diameter) with an average weight of 175 mg, tablet machine with a single punch (Diaf).

Prepared tablets can be further processed according to Example 3 or 4, i.e. on the pill cause intersolubility floor.

Example 3
Matrix tablets with prolonged-release intersolubility coating containing MD-salt of S-omeprazole (approx. 32 mg).

Tablets of example 2 cover first separating layer in the apparatus for coating fluidized bed using covering suspension of the following composition (in mass units):
tO of 99.5% (wt./about.) - 85
Purified water - 85
process and coating process continues until while the average weight of the tablets will not be 181 mg.

The tablets covered with a separating layer, cover layer Intercollege coverage in the same equipment as for the previous stage of the coating. Used covering solution has the following composition (in mass units):
Phthalate of hydroxypropylmethylcellulose (HP-55) - 19
Cetanol - 1
Acetone - 182
Ethanol (95% wt./about.) - 78
Total: 280 parts
100 grams of pellets covered with separating layer process and the coating process continues as long as the average weight of the tablets will not be 194 mg.

The tablet is exposed to 0.1 M HCl for 2 hours. Resistance to acid is defined as 98%.

Example 4
Matrix tablets with prolonged-release intersolubility coating containing MD-salt of S-omeprazole (approximately 32 mg).

Tablets obtained from Example 2, directly cover with a layer of Intercollege coating apparatus with fluidized bed. Used covering solution has the following composition (in mass units):
Phthalate of hydroxypropylmethylcellulose (HP-55) - 19
Cetanol - 1
Aceto who will not stop until while the average weight of the tablets will not be 187 mg.

The tablet is exposed to 0.1 M HCl for 2 hours. Resistance to acid is defined as 99%.

Example 5
Matrix tablets with prolonged-release formulation containing MD-salt of S-omeprazole (approx. 45 mg).

Granules for kernels tablets produced in accordance with the following composition (in mass units):
MD salt of S-omeprazole - 45
The polyethylene oxide (mol.weight approx. 4000000), PolyoxWSR 301 - 145
The aluminosilicate sodium - 50
Propylgallate - 0,1
Ethanol of 99.5% (wt./about.) - 140
The powders are mixed and moistened with ethanol in the mixer, after which the mass is dried in a drying oven at 50oC.

After grinding in a vibrating mill through a 0.1 mm sieve obtained granules are mixed with the lubricant tablets in accordance with the following composition (in mass units):
Granules for kernel-tablets - 232
The sodium fumarate (Pruv) - 1
The ingredients are mixed, then the mixture is pressed into pellets (10 mm diameter) with an average weight of 241 mg, tablet machine with a single punch (Diaf).

The rate of dissolution test as described in example 1. Polychloroethene, containing MD-salt of S-omeprazole (approx. 45 mg).

Granules for nuclei pellets were obtained in accordance with the following composition (in mass units):
MD salt of S-omeprazole - 45
The polyethylene oxide (mol. weight approx. 4000000), PolyoxWSR 301 - 72,5
The polyethylene oxide (mol. weight approx. 100000), PolyoxWSR N10 - - 72,5
The aluminosilicate sodium - 50
Propylgallate - 0,1
Ethanol of 99.5% (wt./about.) - 140
The powders are mixed and moistened with ethanol in the mixer, after which the mass is dried in a drying oven at 50oC.

After grinding in a vibrating mill through a 1.0 mm sieve obtained granules were mixed with the lubricant tablets in accordance with the following composition (in mass units):
Granules for kernel-tablets - 234
The sodium fumarate (Pruv) - 1
The ingredients are mixed, then the mixture is pressed into pellets (10 mm diameter) with an average weight of 241 mg, tablet machine with a single punch (Diaf).

The rate of dissolution test as described in Example 1 above. The resulting rate of release (n=2) shown in the table.3.

Example 7
Matrix tablets with prolonged visvobodi edusim composition (in mass units):
MD salt of S-omeprazole - 45
The polyethylene oxide (mol. weight approx. 100000), PolyoxWSR N10 - 145
The aluminosilicate sodium - 50
Propylgallate - 0,1
Ethanol of 99.5% (wt./about.) - 140
The powders are mixed and moistened with ethanol in the mixer, after which the mass is dried in a drying oven at 50oC.

After grinding in a vibrating mill through a 1.0 mm sieve obtained granules are mixed with the lubricant tablets in accordance with the following composition (in mass units):
Granules for kernel-tablets - 29
Stearyl the sodium fumarate (Pruv) - 1
The ingredients are mixed, then the mixture is pressed into pellets (10 mm diameter) with an average weight of 241 mg, tablet machine with a single punch (Diaf).

The rate of dissolution test as described in example 1.

The resulting rate of release (n=2) shown in the table.4.

Example 8
Matrix tablets with prolonged-release formulation containing MD-salt of S-omeprazole (approx. 45 mg).

Granules for kernels tablets made in accordance with the following composition (in mass units):
MD salt of S-omeprazole - 80
The hypromellose 50 cps - 300
Polyvinylpyrrolidone K-90 and then moisturize with a solution of PVP in the mixer. Then the resulting mass is dried in a drying oven at 50oC.

After grinding in a vibrating mill through a 1.0 mm sieve obtained granules are mixed with the lubricant tablets in accordance with the following composition (in mass units):
Granules for kernel-tablets - 412
The sodium fumarate (Pruv) - 4
The ingredients are mixed, then the mixture is pressed into tablets (diameter 9 mm), having an average mass of 265 mg, tablet machine with a single punch (Diaf).

Example 9
Matrix tablets with prolonged-release formulation containing MD-salt of S-omeprazole (approx. 45 mg).

Granules for kernels tablets made in accordance with the following composition (in mass units):
MD salt of S-omeprazole - 74
The hypromellose 50 cps - 210
The hypromellose 10000 cps - 90
Polyvinylpyrrolidone K-90 - 40
Ethanol of 99.5% (wt./about.) - 400
Polyvinylpyrrolidon (PVP) dissolved in alcohol. Other ingredients are mixed and then moisturize with a solution of PVP in the mixer. Then the resulting mass is dried in a drying oven at 50oC.

After grinding in a vibrating mill through a 1.0 mm sieve obtained granules are mixed with Sublette - 378
The sodium fumarate (Pruv) - 4
Mixing is carried out in the mixer, and the mixture is pressed into tablets (diameter 9 mm), having an average mass of 261 mg, tablet machine with a single punch (Diaf).

The rate of dissolution test in phosphate buffer pH 6.8 as described in example 1.

The resulting rate of release (n=6) are shown in table.5.

Example 10
Matrix tablets with prolonged-release formulation containing MD-salt of S-omeprazole (approx. 55 mg).

Granules for kernels tablets receive in accordance with the following composition (in mass units):
MD salt of S-omeprazole - 40
Polyvinyl alcohol mol. mass. 22000, the degree of hydrolysis of 97.5-99.5% pure - 160
Polyvinylpyrrolidone K-90 - 14
Ethanol of 99.5% (wt./about.) - 49
Polyvinylpyrrolidone (PVP) dissolved in alcohol. The other two ingredients are mixed and then moisturize with a solution of PVP in the mixer. Then the resulting mass is dried in a drying oven at 50oC.

After grinding in a vibrating mill through a 1.0 mm sieve obtained granules are mixed with the lubricant tablets in accordance with the following composition (in mass units):
Granules for kernel-pill - 215
The sodium fumarate (Pruv

The rate of dissolution test in phosphate buffer pH 6.8 as described in example 1.

The resulting rate of release (n=2) shown in the table.6.9


Claims

1. The pharmaceutical dosage form is an inhibitor of H+To+-ATPase with prolonged-release intersolubility coating, characterized in that this dosage form contains the core material of the hydrophilic or hydrophobic matrix of the matrix and is an inhibitor of H+To+-ATPase, where the specified core material caused separating layer, provided that the separating layer is not formed water-insoluble film-forming agent, an inhibitor of H+To+-ATPase is a compound of formula I, its alkali salt, or one of its single enantiomers or an alkaline salt of one of the enantiomers of the compounds of formula

where Het1represents a

or

Het2represents a

or

X=
6-R9may can be replaced by a nitrogen atom without any substituents;
R1, R2and R3are the same or different and selected from hydrogen, alkyl, alkoxy, possibly substituted by fluorine, alkylthio, alkoxyalkyl, dialkylamino, piperidino, morpholino, halogen, phenyl, funeralcare;
R4and R5are the same or different and selected from hydrogen, alkyl and arylalkyl;
R'6represents hydrogen, halogen, trifluoromethyl, alkyl or alkoxy;
R6-R9are the same or different and selected from hydrogen, alkyl, alkoxy, halogen, halogenoalkane, alkylcarboxylic, alkoxycarbonyl, oxazolyl, triptorelin, or adjacent groups R6-R9form a ring structure, which may be optionally substituted;
R10represents hydrogen or forms alkylenes circuit with R3and
R11and R12are the same or different and selected from hydrogen, halogen or alkyl.

2. Dosage form under item 1, characterized in that the inhibitor of H+To+-ATPase is a compound selected from the group consisting of about the 3. Dosage form under item 2, wherein the alkaline salt is a magnesium salt.

4. Dosage form under item 1, characterized in that the inhibitor of H+To+-ATPase is a compound selected from the group consisting of lansoprazole, pantoprazole, their alkaline salts, their single enantiomer and its alkali metal salts.

5. Dosage form according to any one of paragraphs.1-4, characterized in that the core material further comprises pharmaceutically acceptable excipients.

6. Dosage form according to any one of paragraphs.1-5, characterized in that the core material further comprises an alkaline additive.

7. Dosage form according to any one of paragraphs.1-6, characterized in that the core material contains a seed with a layer of an inhibitor of H+To+-ATPase and hydrophilic or hydrophobic matrix and possibly pharmaceutically acceptable excipient.

8. Dosage form according to any one of paragraphs.1-7, characterized in that the core material creates a microenvironment around the inhibitor+To+-ATPase is not less than pH=7.

9. Dosage form according to any one of paragraphs.1-8, characterized in that the hydrophilic matrix contains a hydrophilic polymer selected from the group consisting of hydroxypropylcellulose, of sodium carboxymethyl cellulose, methyl cellulose, polyethylene oxides, polyvinylpyrrolidone, polyvinyl alcohols, tragakant and xanthan gum or any mixtures thereof.

10. Dosage form under item 9, characterized in that the hydrophilic matrix additionally contains a filler, such as sodium aluminosilicate.

11. Dosage form according to any one of paragraphs.1-8, characterized in that the hydrophobic matrix contains a hydrophobic polymer and a hydrophobic agent and hydrophobic agent selected from the group consisting of cetanol, cetosteatil alcohol, cetylpalmitate, waxes, such as Carnauba wax, paraffin, magnesium stearate, sodium fumarate and esters of glycerol with medium or long chain individually, or mixtures thereof.

12. Dosage form under item 11, wherein the hydrophobic polymer is selected from the group consisting of polyvinyl chloride, ethyl cellulose, polyvinyl acetate and copolymers of acrylic acid.

13. Dosage form under item 11 or 12, characterized in that the hydrophobic matrix further comprises a poorly soluble or less soluble component selected from the group consisting of a silicate of sodium, calcium phosphate, Aerosil, titanium dioxide and the carbonate is ri which carry out the following stages: a) the core material, containing an inhibitor of H+To+-ATPase, and a hydrophilic or hydrophobic matrix matrix, and possibly pharmaceutically acceptable excipient, shape, b) a separating layer is applied on the core material, in) put a layer of Intercollege coverage.

15. Dosage form according to any one of paragraphs.1-13, characterized in that a continuous release is supported for at least 2 hours and up to 12 hours

16. Dosage form according to any one of paragraphs.1-13 for use in therapy.

17. Dosage form according to any one of paragraphs.1-13 for the manufacture of drugs with improved inhibition of the secretion of gastric acid.

18. Dosage form according to any one of paragraphs.1-13 for the manufacture of drugs with improved therapeutic effect in the treatment of gastrointestinal disorders associated with excessive secretion of acid.

 

Same patents:

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

The invention relates to the production and use of the product containing the antibiotic, medicine and veterinary medicine for the treatment of local microbial infections in the hard and soft tissues with a slow release of the active substance

The invention relates to medicine, more specifically to pharmaceutical compositions for the treatment of diseases of the pancreas and digestive disorders associated with liver disease

The invention relates to pharmaceutical industry and relates to solid dosage forms prolongirovannogo steps and the method of obtaining

The invention relates to pharmacology, and relates to pharmaceutical drug omeprazole

The invention relates to the field of medicine

The invention relates to the field of medicine and relates to a method of producing an oral pharmaceutical preparation comprising an inert core and the active layer, dissolving or disintegrating in water obtained from water or water-alcohol suspesions solution containing the active substance having anti-ulcer effect of formula I, II or III), and at least one filler, and gasterosteidae external coating obtained from a solution containing the polymer for Intercollege coating and at least one filler, by drawing on the inert core of the active layer by spraying an aqueous or aqueous-alcoholic suspension solution, drying of the active layer, obtained at the previous stage, and coating the core with an active layer of a solution containing the polymer for Intercollege coating and filler

The invention relates to the field of medicine and for the creation of drug - diclofenac sodium

The invention relates to novel oral pharmaceutical dosage forms, containing a proton pump inhibitor, that is an inhibitor of H+, K+-ATPase
Antibacterial // 2213558
The invention relates to the field of pharmaceutical industry and relates to pelletized forms of antibiotics

The invention relates to the field of medicine

The invention relates to the field of medicine and relates to pharmaceutical compositions for the treatment of complex and coronary heart disease, myocardial infarction, myocardiodystrophy, rhythm disturbances associated with the use of cardiac glycosides

The invention relates to medicine, namely to the pharmaceutical industry for the production of drugs therapeutic and prophylactic purposes, and can be used for the prevention and auxiliary treatment for liver diseases

The invention relates to medicine, in particular to pharmacological agents and treatment joints

Centuries-old medical experience shows that virtually every man occasionally pain in the back and joints of the limbs (Nordemar P

The invention relates to medicine, namely to the development of new dosage forms of the biologically active peptide compounds

The invention relates to the use of certain salts monoalkyl esters of fumaric acid individually or in combination with dialkylamino to obtain microtablets for the treatment of psoriatic arthritis, neurodermatitis, psoriasis and regional enteritis (Crohn's disease)
Psychotropic drug // 2210360
The invention relates to medicine, namely the creation of medicines used in psychiatric and neurological practice for the treatment of neurotic and neurosis-like States, as well as chronic alcoholism

The invention relates to pharmaceutical preparations 8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6] cyclohepta[1,2-b] pyridine, known as descarboethoxyloratadine (DCL)
The invention relates to a new process for the preparation of omeprazole, which is effective as an inhibitor of the secretion of gastric acid and is useful as an antiulcer agent
Up!