JP2002532425A - New pharmaceutical formulations - Google Patents

Abstract

The present invention comprises a proton pump inhibitor, ie, an H ⁺ , K ⁺ -ATPase inhibitor, a gastric acid antisecretory prostaglandin analog and optionally an additional drug, such as a calcium channel blocker. It relates to a new oral dosage form, in particular for use in the treatment and prevention of gastrointestinal disorders. More particularly, the present invention relates to a novel dosage form consisting of omeprazole and misoprostol. The present invention also relates to combinations of three categories of drugs: H ⁺ , K ⁺ -ATPase inhibitors, gastric acid antisecretory prostaglandin analogs, and calcium channel blockers. Furthermore, the invention relates to a process for the preparation of the above-mentioned dosage forms and their use in medicine and to blister packs comprising these medicines.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD OF THE INVENTION

 The present invention is particularly directed to H for use in the treatment and prevention of gastrointestinal disorders.⁺, K⁺-AT
Pase inhibitors, gastric acid antisecretory prostaglandin analogs, and optionally
Novel orally administered medicament consisting of an additional agent such as a calcium channel blocker
Regarding dosage form. More particularly, the present invention relates to omeprazole and misoprost
A novel pharmaceutical dosage form comprising The present invention also provides three categories of drugs: H ⁺ , K⁺-ATPase inhibitors, gastric acid antisecretory prostaglandin analogs and
A combination of calcium channel blockers. Furthermore, the present invention produces the above dosage form
And methods for their use in medicine and Bliss comprising these medicines
About Tarpac.

[0002]

[Background Art]

H ⁺ , K ⁺ -ATPase inhibitors such as the proton pump inhibitors known by the generic names of omeprazole, lansoprazole, pantoprazole, rabeprazole and reminoprazole are, for example, EP 5129, EP 174 726, EP 166 287, GB 2
163 747 and WO 90/06925. The expressions H ⁺ , K ⁺ -ATPase inhibitor and proton pump inhibitor are interchangeable within the scope of the present application. Proton pump inhibitors are known to be useful in mammals and humans to suppress gastric acid secretion by controlling gastric acid secretion at the last step of the secretory pathway. They are nonsteroidal anti-inflammatory drugs (NSAIDs)
) To cure gastric and duodenal ulcers in patients undergoing continuous treatment with NSAIDs as a user. WO 96/01735 describes fixed dosage forms consisting of a proton pump inhibitor and an NSAID and their use in treating or preventing gastrointestinal side effects associated with NSAID treatment.

[0003] Prostaglandin analogs such as the compounds known by the common names misoprostol, enoprosteil, enisoprost, rosaprostol and miraprostal have orally active PGE ₁ -having mucoprotective and antisecretory effects. Analogues, these types of compounds are described for example in US 3,965,143 and US 4,178,457. They are mainly used for the prevention of gastric and duodenal ulcers associated with NSAID treatment. Usually they are in separate single unit dosage forms, sometimes containing
It is administered in a fixed dosage form formulated with the SAID.

[0004] Adverse drug reactions have been reported for gastric acid antisecretory prostaglandin analogs. The use of misoprostol can cause, for example, diarrhea, abdominal pain and other gastrointestinal related side effects. The dosing standard for misoprostol sometimes includes frequent ingestion of the dosage form up to four times a day. In addition to the undesirable gastrointestinal side effects of gastric acid antisecretory prostaglandin analogs, this frequent intake is closely related to compliance issues. On the other hand, the proton pump inhibitor omeprazole has few dose-related side effects.

[0005] The combination of two or more active drugs that achieve similar physiological effects, but by different mechanisms, usually can reduce the dose of each single drug and still achieve the desired effect. is there. This will reduce the risk of dose dependent adverse side effects. Furthermore, it is possible that one component may be ineffective due to individual differences in patient response while the other component of the treatment criteria is effective.

[0006] These factors generally relate to the benefit of using two or more anti-ulcer drugs in combination, particularly the benefit of using misoprostol with other anti-ulcer drugs. The administration of two or more different dosage forms to a patient is inconvenient and unsatisfactory to achieve optimal results. It is advantageous to combine different drugs into a single pharmaceutical dosage form to reduce the number of pills a patient takes at each dose, as the major factor for good medical outcome is patient compliance . The effectiveness is further enhanced if one or more drugs can be provided in a long-release formulation.

Previously suggested combination therapies comprising anti-ulcer drugs include, for example, histamine H ₂ -receptor antagonists such as cimetidine or ranitidine in combination with sucralfate. Other proposed treatments include, for example, omeprazole and sucralfate, ranitidine and cimetidine, or ranitidine and misoprostol. See, for example, Van Deventer GM et al., Am J Med 1985; 79: 39-44, and Houston LJ et al., Am J Gastroenterol 1993; 88: 675-679.

[0008] Combination therapy of misoprostol with calcium channel blockers such as verapamil has been proposed and tested in rats for mucoprotective effects by reducing leukotriene synthesis and increasing prostaglandin synthesis. Fedorak
See RN et al., Gastroenterology 1992; 102: 1229-35.

[0009] For the treatment of gastrointestinal disorders, combining the proton pump inhibitor omeprazole and the gastric acid antisecretory prostaglandin analog enprosteil has been described by Tari A et al., D
igestive Diseases and Sciences 1997; 42: 1741-1746 and Meijer JL et al., Di
gestive Diseases and Sciences 1994; 39: 609-616. However, fixed unit dosage forms comprising an H ⁺ , K ⁺ -ATPase inhibitor combined with a gastric acid antisecretory prostaglandin analog have not been suggested before.

[0010] Furthermore, there is no suggestion or description in the prior art of a formulation comprising an H ⁺ , K ⁺ -ATPase inhibitor, a gastric acid antisecretory prostaglandin analog and a calcium channel blocker. To the applicant's knowledge, there is no pharmaceutical dosage form for oral administration comprising such a formulation, especially a blister pack or fixed unit dosage form.

One aspect of the present invention is to provide a fixed unit dosage form for oral administration comprising an H ⁺ , K ⁺ -ATPase inhibitor and a gastric acid antisecretory prostaglandin analog. It is a further aspect of the present invention to provide a dosage form comprising an H ⁺ , K ⁺ -ATPase inhibitor and a gastric acid antisecretory prostaglandin analog, the latter being in a form that provides prolonged release. Such dosage forms reduce the frequency and dosage-related adverse side effects.

[0012] Additional aspects of the invention include H ⁺ , K ⁺ -ATPase inhibitors, gastric acid antisecretory prostaglandin analogs, and components that enhance the action of prostaglandin analogs, such as calcium channel blockers. To provide combination therapy. The formulation may be provided in a fixed unit dosage form.

According to the invention, a fixed dosage form consisting of an H ⁺ , K ⁺ -ATPase inhibitor, a gastric acid antisecretory prostaglandin analog and optionally a calcium channel blocker is in principle a two-layer tablet, or Tablet core or press coated with a coating layer
-Constructed in the form of a coated tablet, different drugs are placed on different parts of the tablet. Alternatively, the dosage form may be two or three each containing one drug.
A tablet or capsule consisting of either a single unit population of different species, or a single population of multi-layer units consisting of a combination of different drugs, or other drugs containing one or two drugs as a unit population Can be constructed as capsules containing as a single unit placed within the same capsule.

[0014] Preferred types of dosage forms according to the invention are described in further detail below in separate headings and in the Examples below. One layer of a two-layer tablet consists of a number of enteric coated pellets dispersed in a pharmaceutically acceptable excipient as a proton pump inhibitor. These pellets can be characterized as immediate release, delayed pulsed release, delayed double pulsed release, delayed multiple pulsed release or extended release, or any combination thereof. When the proton pump inhibitor is constructed as a long-term release part layer, it can be designed in the form of a hydrophilic matrix layer composed of the proton pump inhibitor. In the latter case, appropriate measures must be taken to protect the proton pump inhibitor from contact with acidic solutions.

[0015] Another layer consists of gastric acid antisecretory prostaglandin analogs and, optionally, calcium channel blockers. This layer is formulated to provide immediate or prolonged release of the drug. Extended release properties are achieved by the use of extended release pellets with a membrane coating dispersed in a pharmaceutically acceptable excipient, or by dispersion of the drug in a hydrophilic or hydrophobic matrix with extended release. . Immediate release properties are achieved by using conventional tablet granulation procedures or by incorporating the prostaglandin analog into rapidly dissolving pellets dispersed in a pharmaceutically acceptable excipient. It is also possible to include a proton pump inhibitor pellet in the first layer together with a pellet consisting of a prostaglandin analog, and optionally a calcium channel blocker in the second layer.

Tablet core consisting of one drug coated with a second drug Each tablet consists of a tablet core containing a proton pump inhibitor, the tablet core being spray coated with a layer consisting of a gastric acid antisecretory prostaglandin analog I do. Tablet cores are prepared as described below under the heading "Press Coated / Coated Tablets". The enteric-coated prepared tablet is further coated with a suspension comprising a prostaglandin analog. Alternatively, the tablet core is coated in the same way as described below for the preparation of the pellets. However, the prepared tablet cores are larger than the core size intended for pellet preparation. That is, preferably the tablet core has a size of 3 to 12 mm in diameter.

Press Coated / Coated Tablets The inner tablet core is prepared by the tableting technique according to known techniques. The tablet core is
Consisting of one active ingredient, preferably a proton pump inhibitor, optionally combined with a calcium channel blocker. The tablet core is coated with an enteric coating layer, optionally after applying a separating layer.
The enteric coating layer protects acid-sensitive proton pump inhibitors from gastric acid. That is, it is a layer that does not dissolve in the gastric acid environment, but dissolves or disintegrates in the small intestine. Further, a further coating layer consisting of the second active ingredient, optionally with a calcium channel blocker, is applied over the enteric coating layer by compression. Either the tablet core or the outer layer can be given the properties of an extended release or immediate release formulation.

Tablets or Capsules Consisting of Multiple Drug-Containing Units Such dosage forms fall primarily into two distinct categories. For example, one group of (i) multiple-coated units and two groups of (ii) units. (i) a population of multi-coated units for tablet or capsule formulations The first category consisting of a population of uniformly constructed units or pellets is optionally in a pharmaceutically acceptable tablet excipient. Distributed. Each unit consists of a proton pump inhibitor as a pharmaceutically active agent and a gastric acid antisecretory prostaglandin analog. These units contain multiple layers, the different active substances being arranged in different layers. The proton pump inhibitor layer is disposed inside the enteric coating layer, and a separation layer may optionally be provided between the proton pump inhibitor layer and the enteric coating layer. The layer consisting of the gastric acid antisecretory prostaglandin analog and optionally the calcium channel blocker is located outside the proton pump inhibitor layer, but can be located inside or outside the enteric coating layer . The layer comprising the proton pump inhibitor can have immediate release or extended release properties, which also applies to the layer comprising the gastric acid antisecretory prostaglandin analog, although extended release is preferred. The prepared drug-containing units can be filled into capsules or mixed with pharmaceutically acceptable tablet excipients and compressed into multi-unit tablets.

(Ii) Two Populations of Units for Tablet or Capsule Formulations The second category is that each population consists of a mixture of two different populations, each of which is an equally structured unit or pellet, and is sometimes pharmaceutically acceptable. Dispersed in an acceptable tablet excipient. As pharmaceutically active drugs, one population consists of proton pump inhibitors and the other population consists of gastric acid antisecretory prostaglandin analogs. Optionally, a third population of units consisting of calcium channel blockers can optionally be included in the mixture. These formulations are based on mixing a population of units consisting of gastric acid antisecretory prostaglandin analogs with a population of units consisting of proton pump inhibitors.
This mixture is filled into capsules or further mixed with pharmaceutically acceptable tablet excipients and compressed into tablets. Tablet excipients may be pre-granulated or simply mixed with the layered unit prior to compression into tablets.

Units consisting of gastric acid antisecretory prostaglandin analogs These units are granulated, extruded and spheronized, coagulated, pelletized directly in a mixer, melt granulated with suitable polymer additives, porous carrier It can be prepared by introduction into or stratification on the starting seed, or by any other suitable technique known in the art. The unit can be formulated to have immediate or extended release characteristics. If appropriate, an additional coating layer can be applied on the unit to provide extended release. In order to prolong the residence time in the stomach of the unit consisting of the gastric acid antisecretory prostaglandin analog, the gastric acid antisecretory prostaglandin analog is formulated into pellets by including the gastric acid antisecretory prostaglandin analog in a hydrophilic matrix together with an appropriate concentration of sodium hydrogen carbonate. Become When the pellets come into contact with an acidic gastric acid environment, they generate small bubbles of carbon dioxide, reducing the density of these pellets and causing them to flow into the stomach. Units with immediate release properties are prepared by incorporating the active into porous amphoteric silica particles or by layering the active on sugar seeds.

Units Consisting of Proton Pump Inhibitors These units are prepared for either immediate, extended or delayed pulsed release of the proton pump inhibitor. WO 97/02020 describes pentoprazole pellets coated with an extended release membrane, a technique which is also suitable for other extended release units. Suitable units for immediate release of proton pump inhibitors are EP 502 556
And particularly designed for use in tablet dosage forms are described in WO 96/01624.
It is described in. These are incorporated herein by reference.

Capsules consisting of two or more drugs in a single unit in combination with multiple units Capsules are composed of one drug or tablet in a single unit, and in the form of two groups, one group and one or one Consists of one or more drugs in the form of two or more single tablets.

Suitable units for a capsule formulation are, as described above, a population of (i) a multilayer unit consisting of a proton pump inhibitor and a gastric acid antisecretory prostaglandin analog or (ii)
) Prepared in two population units. The capsule may be composed of two or three different drugs, ie, a third population of units consisting of calcium channel blockers. A single unit consists of any drug, ie, a proton pump inhibitor, a gastric acid antisecretory prostaglandin analog or, optionally, a calcium channel blocker. If the single unit consists of a gastric acid antisecretory prostaglandin analog, it may also have immediate release or extended release properties. The immediate release single unit is preferably constructed according to principles well known in the art. The extended release single unit is preferably constructed as a hydrophilic matrix unit, or as a hydrophobic matrix unit, or as a membrane coating unit.

Layer application techniques The layer is applied by means of water and / or an organic solvent suitable for the coating operation, by means of a coating or layering operation in a suitable apparatus, for example a coating pan, a coating granulator or a fluidized bed apparatus. . Alternatively, the layers can be applied using powder coating or press coating techniques.

Excipients In the dosage forms claimed, various pharmaceutically acceptable excipients can be used in combination with the active substances. Such excipients include binders, fillers, pH buffering substances, dyes and the like.

Separation Layer Suitable materials for the separation layer include pharmaceutically acceptable compounds such as sugar or polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium There are film forming compounds such as sodium carboxymethylcellulose and the like, used alone or as a mixture. Additives such as plasticizers, colorants, pigments, fillers, anti-adhesives and anti-statics, for example magnesium stearate, titanium dioxide, talc, pH
Buffer substances and other additives are also included in the separation layer. The separation layer is water soluble or configured to disintegrate in water.

Enteric Coating Layer The material of the enteric coating layer is dispersed or dissolved in water or dissolved in a suitable organic solvent. The enteric coating layer polymer is not limited thereto, and one or more of the following polymers can be used separately or in combination and dissolved. For example, methyl acrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, shellac or other suitable intestines well known in the art Soluble coating layer polymer.

Dispersants, colorants, dyes, additional polymers such as poly (ethyl acrylate,
Additives such as methyl methacrylate), anti-adhesives and antifoams can also be included in the separating layer and / or enteric coating layer, or in additional tablet coats as described below. Other compounds can also be added to increase the film thickness and reduce the diffusion of acidic gastric juice into the acid-sensitive core material. The enteric coating layer has a thickness of at least about 10 μm, preferably 20 μm
The above is constructed. The maximum thickness of the applied enteric coating layer is usually limited only by processing conditions.

[0029] The enteric coating layer may also contain a pharmaceutically acceptable plasticizer to obtain the desired mechanical properties. Such plasticizers include, but are not limited to, triacetin, citrate, phthalate, dibutyl sebacate, cetyl alcohol, polyethylene glycol, glycerol monoester, polysorbate or other plasticizers and There is a mixture of them. The amount of plasticizer is preferably optimized for each formulation in relation to the selected polymer, the selected plasticizer and the amount of polymer applied.

Overcoat Layer The pellet coated with the enteric coating layer may be further coated with one or more overcoat layers. The overcoating layer is formed by coating the pellets coated with the enteric coating layer with water and / or an organic solvent for the coating or stratification process, using a suitable apparatus such as a coating pan, a coating granulator or a fluidized bed apparatus. Applied by stratification operation. The material of the overcoating layer is a pharmaceutically acceptable compound such as sugar,
It is selected from polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and the like, and used alone or as a mixture. Plasticizer,
Additives such as colorants, dyes, fillers, anti-adhesives and anti-statics, such as magnesium stearate, titanium dioxide, talc and other additives can also be included in the overcoating layer. The maximum thickness of the applied overcoating layer is usually limited only by processing conditions.

Hydrophilic matrix The active substance or drug is embedded in a hydrophilic polymer, optionally with pharmaceutically acceptable excipients. Suitable hydrophilic polymers are, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylhydroxyethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, poloxamer, polyethylene oxide, polyvinylpyrrolidone, polyvinylalcohol, tragacanth, xanthan and guar gum or any Are other suitable hydrophilic polymers. These polymers can be used alone or mixed with one another.

The amount of hydrophilic polymer in the matrix is preferably 15 to 85% w / w (calculated by unit weight) of the hydrophilic polymer selected from the above. A particularly preferred polymer in the hydrophilic matrix unit is hydroxypropyl methylcellulose or polyethylene oxide. Preferred excipients in the matrix are fillers that produce technically good tableting properties,
That is, sodium aluminum silicate, mannitol or calcium phosphate [Emcompress (registered trademark)]. Preferred matrices consist of 15-85% w / w (calculated by unit weight) of a hydrophilic polymer selected as described above, and 80-10% w / w of sodium aluminum silicate or calcium phosphate [Emcompress®]. (Calculated per unit weight).

Hydrophobic Matrix The active substance or drug is embedded in a hydrophobic matrix, optionally with pharmaceutically acceptable excipients. The hydrophobic matrix consists of a hydrophobizing agent and / or a hydrophobic polymer. Suitable materials for the hydrophobic matrix include, for example, cetanol, cetostearyl alcohol, cetyl palmitate, waxes such as carnauba wax, paraffin, magnesium stearate, sodium stearyl fumarate,
And hydrophobizing agents such as medium or long chain glycerol esters alone or in any mixture. Hydrophobic polymers include, for example, polyvinyl chloride, ethyl cellulose, polyvinyl acetate and acrylic acid copolymers, such as Eudragi
th (R) RS and RL. These polymers can be used alone or as a mixture. Further, the polymer may be compounded with a hydrophobizing agent. As a binder for the hydrophobic matrix, either hydrophilic or hydrophobic polymers can be used.

It is important that the matrix consists of at least one component that is soluble in aqueous media, for example intestinal fluid. This component dissolves, leaving a porous network open to the passage of the liquid to dissolve and the dissolved drug. This soluble component can be, for example, sugar. Each of the matrices is 10 to 70% w / w as described above.
(Calculated by unit weight) hydrophobizing agent or hydrophobic polymer, and 10-70% w / w
Or any combination thereof.

[0035] Other preferred matrices consist of slightly soluble or insoluble components as adducts. As such components, add any of the following: sodium aluminum silicate, calcium phosphate, elixir, titanium dioxide, magnesium carbonate, or other neutral or alkaline compounds that are slightly soluble or insoluble in this case with respect to solubility in water. can do. Slightly soluble is defined as described under the heading of the General Information in the European Pharmacopoeia (3rd edition). Such a matrix is preferably 10% to 70% w / w (calculated by unit weight) of a hydrophobizing agent or hydrophobic polymer or a blend thereof, preferably 10% to 70% w / w.
Consists of ~ 70% w / w slightly water soluble or insoluble components. As such a component, sodium aluminum silicate is particularly preferred.

[0036] The final dissolution image may be adjusted by heat treating the hydrophobic matrix unit for a short period of time to achieve the softening temperature of the hydrophobizing agent or higher.

Particles of Oily Materials, eg, Misoprostol One method of preparing free flowing particles of an oily / greasy / sticky material is to convert it to an inorganic material, eg, ceramic hydroxyapatite or amorphous silica. Introducing into the porous particle material. Ceramic hydroxyapatite is
The particle size range is preferably from 5 to 250 μm, more preferably from 80 to 1 μm.
50 μm, nominal hole diameter 50-1000 °, more preferably 500-100
0 ° and a surface area of 40 to 45 m ² / g. Amorphous silica has an intermediate pore diameter of 50 ~
1000 °, more preferably 50-200 °, pore volume 0.8-1.2 ml / g,
The surface area is 500 to 600 m ² / g.

The introduction of the oily material is achieved by known conventional methods, for example by dissolving the oil in a suitable solvent, then adding the porous particulate material and drying the mixture. Alternatively,
The oil is directly mixed with the porous particulate material, or the introduction is performed using phase separation from the particle-containing solution achieved by the addition of a non-solvent. The loaded porous particles are filled into capsules or compressed into tablets. The preparation of small quantities of particles composed of oily materials is also achieved by customary methods, such as layering or coating on inert seeds or extrusion / spheronisation.

Tablet Coat The prepared tablets may optionally be coated with a film forming agent to obtain a smooth surface for the tablet and to increase the stability during packaging and shipping. Such a coat of polymeric material may further be composed of anti-adhesives, colorants and pigments or other additives to obtain a good looking tablet. Tablet coats can consist especially of dyes for protecting the sensitive components.

Active Ingredients I) H ⁺ , K ⁺ -ATPase inhibitors suitable for the therapies and pharmaceutical preparations claimed in the present invention, ie proton pump inhibitors, are of the general formula I

Embedded image [Where Het ₁ is

Embedded image And Het ₂ is

Embedded image And X =

Embedded image

Wherein N in the benzimidazole residue is a carbon atom in the ring substituted by R _{6 to} R ₉ is optionally exchangeable for an unsubstituted N atom, and R ₁ , R ₂ and R ₃ Are the same or different and are selected from hydrogen, alkyl, alkoxy optionally substituted by fluorine, alkylthio, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenyl and phenylalkoxy; R ₄ and R ₅ are the same or different Heterologous, selected from hydrogen, alkyl and arylalkyl; R ₆ ′ is hydrogen, halogen, trifluoromethyl, alkyl or alkoxy; R ₆ -R ₉ are the same or different and are hydrogen, alkyl, alkoxy, halogen,
Haloalkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolinyl, trifluoroalkyl, or a group adjacent to R _{6 to} R ₉ forms a ring structure which may be further substituted; R ₁₀ is hydrogen; or with R ₃ form an alkylene chain, R ₁₁ and R ₁₂ are the same or different, hydrogen, a compound of a halogen or alkyl as)], alkaline salts thereof, one alkali its single enantiomer or enantiomerically Salt.

Compounds of particular interest according to Formula I are

Embedded image

[0043]

Embedded image It is.

Suitable compounds for the preparations according to the invention are in neutral or alkaline salt form, for example the Mg ²⁺ , Ca ²⁺ , Na ⁺ or K ⁺ salt, preferably the Mg ²⁺ salt. These compounds can also be used in the form of one of the single enantiomers or of the alkali salt of the single enantiomer.

Preferred compounds for the pharmaceutical preparation for oral administration of the present invention are omeprazole, a magnesium salt of omeprazole or a magnesium salt of the (−)-enantiomer of omeprazole. Omeprazole and related compounds and their production are EP
5129, EP 124 495, WO 95/01977, WO 94/27988. These are incorporated herein by reference in their entirety.

The compounds are susceptible to degradation / conversion in acidic or neutral media. In general, the decomposition is catalyzed by an acid-reactive compound and the active compound is stabilized by an alkali-reactive compound. Various enteric coated formulations of omeprazole and other proton pump inhibitors are known in the art (eg, US-A 4,853,230,
WO 95/01783 and WO 96/01624). In particular, the latter describes an alternative method for producing pellets coated with an enteric coating layer of omeprazole and similar compounds. These patents are incorporated herein by reference in their entirety.

II) Gastric acid-secreting prostaglandin analogs suitable for the therapies and pharmaceutical formulations claimed in the present invention include, for example,

Embedded image , Misoprostol, Enprosteol, Enisoprost, Rosaprostol, Miraprostal and analogs. The above compounds can also be used in the form of their single enantiomer.

III) Calcium channel blockers optionally used in combination with proton pump inhibitors and gastric acid antisecretory prostaglandin analogs are known, for example, by the following generic names: verapamil, felodipine, nifedipine and nisoldipine ing.

Use of the formulation The dosage form according to the invention is suitable for oral administration. The dose will depend on the nature and severity of the disease being treated. Dosage will also vary with age, weight, and individual patient response. It is advantageous for children and patients with liver disease, and patients under long-term treatment, to generally start with a slightly lower than average dose. Higher doses are used for treatment of other conditions. This dosage form may also be used in combination with other dosage forms comprising, for example, calcium channel blockers, NSAIDs, or anti-ulcer agents.

The dosage form according to the invention, when used alone, is a gastric acid antisecretory prostaglandin analog
It is particularly advantageous for patients experiencing gastrointestinal side effects caused by the body. This new
Such dosage forms are administered once or several times a day, preferably once or twice a day.
The typical daily dose of the active substance depends on a variety of factors, such as the individual needs of the patient,
And depend on the type and disease of the disease. Generally, each dosage form is H⁺, K ⁺ -ATPase inhibitor 1 to 200 mg and gastric acid antisecretory prostaglandins
Consists of 80-1000 μg of rim. Preferably each dosage form is H⁺, K⁺-ATPase inhibition
5-80 mg of harmful agent and 100-800 μ of gastric acid antisecretory prostaglandin analog
g, more preferably H⁺, K⁺-ATPase inhibitor 10 to 40 mg and gastric acid resistance
Consists of 150-600 μg of secreted prostaglandin analog. Particularly preferred arrangement
Omeprazole and misoprostol from the range of 15: 1 to 400: 1
For example, omeprazole 20 mg and misoprostol 200 μg,
Is a combination of omeprazole 20 mg and misoprostol 400 μg. Place of the latter
If so, it is preferred that misoprostol be present in the form of an extended release formulation.

Optionally, the calcium channel blocker is present in an amount of 1-100 mg. Multi-unit preparations, ie capsules or tablet dosage forms, are also suitable for dispersion in aqueous liquids of slightly acidic pH. Dispersions may be prepared immediately prior to oral administration or supplied via a nasogastric tube.

EXAMPLES The present invention is further described by the following non-limiting examples. Example 1 Bilayer tablet consisting of misoprostol and omeprazole (magnesium salt) Principle: One layer consists of 400 μg misoprostol in a hydrophilic matrix, the other layer is an enteric coating mixed with tablet excipients It consists of 20 mg of omeprazole (magnesium salt) in the form of a coated pellet.

[0053] Extended release granules of misoprostol were prepared according to the following formulation. Misoprostol 0.4 parts by weight Ethanol 95% (w / v) 410 parts by weight Hydroxypropyl methylcellulose 50 cps 400 parts by weight Sodium stearyl fumarate 4 parts by weight Misoprostol was dissolved in half of ethanol. While mixing this solution,
Poured over powdered HPMC. The remaining ethanol was added to obtain a lump of appropriate hardness. The mass is dried under mild conditions and the particle size of the dried granules is 0.8 mm for all granules.
Until it has passed through the sieve. 1% (w / w) sodium stearyl fumarate was mixed.

An enteric-coated pellet comprising omeprazole magnesium salt was prepared according to the following formulation. Core material Magnesium omeprazole 12.00 kg Spherical sugar [non-pareil (registered trademark)] 12.00 kg Hydroxypropyl methylcellulose 1.8 kg Purified water 35.4 kg Separation layer core material (see above) 23.50 kg Hydroxypropyl cellulose 2.35 kg Talc 4.03 kg Magnesium stearate 0.34 kg Purified water 48.00 kg

Enteric coating Coated pellets (see above) 29.00 kg Methacrylic acid copolymer (30% suspension) 38.70 kg Triethyl citrate 3.48 kg Mono and diglycerides (NF) 0.58 kg Polysorbate 80 0.06 kg purified water 22.68kg overcoating enteric coating applied pellets 44.7kg hydroxypropylmethylcellulose 0.58 kg Mg- stearate 0.017kg purified water 11.6kg

The suspension coating was performed in a fluidized bed apparatus. Magnesium omeprazole was sprayed onto non-pareil from an aqueous suspension containing the dissolved binder and magnesium omeprazole. The prepared core material was coated with a separating layer material in a fluidized bed apparatus.
The enteric coating was sprayed on the coated pellets in a fluid bed apparatus. Enteric coated pellets were coated with an overcoat in the same type of equipment. The overcoated pellets were classified by sieving.

Tableting excipients for mixing with enteric coated pellets were prepared by uniformly mixing the following ingredients: Tableting excipient Microcrystalline cellulose (especially coarse grade PH 102) 12.12 g Microcrystalline cellulose PH 101 6.06 g Crosslinked polyvinylpyrrolidone 1.82 g Total amount: 20.00 g Tablets are 9 x 17 mm oval punches (oval) 404 mg of misoprostol-containing granules are pre-compacted on a tablet machine fitted with a tablet-shaped tablet) and then filled with a mixture consisting of 100 mg of omeprazole pellets (see above) and 200 mg of tableting excipient mix. , Compressed. A two-layer tablet with 91% acid resistance (average of 4 tablets) was obtained. The release of omeprazole at pH 6.8 from tablets pre-exposed in 0.1 M HCl for 2 hours was 89% within 30 minutes as determined by spectrophotometry.

Example 2 Enteric Coated Pellets Consisting of Magnesium S-omeprazole Coated with Misoprostol Principle: Enteric Coated Pellets Consisting of Approximately 225 mg of Magnesium S-omeprazole at about 3.6 mg / g of Misoprostol Coated with an external rapid dissolution layer consisting of a stall.

[0059] Pellets coated with an enteric coating of magnesium S-omeprazole were prepared according to the following recipe. Core material S-omeprazole Mg-salt 20.0 kg Non-pareil® 25.0 kg Hydroxypropyl methylcellulose (HPMC) 3.0 kg Polysorbate 80 0.4 kg Purified water 93.6 kg Separation layer core material (see above) 50. 0 kg hydroxypropylcellulose 5.5 kg talc 20.5 kg magnesium stearate 1.4 kg purified water 193.8 kg enteric coated pellets (see above) 30.0 kg methacrylic acid copolymer (30% suspension) 30.0 kg citrus Triethyl acid 0.9 kg Mono and diglyceride (NF) 0.5 kg Polysorbate 80 0.05 kg Purified water 12.9 kg

The suspension coating was performed in a fluid bed apparatus. The magnesium salt of S-omeprazole was sprayed onto non-pareil from an aqueous suspension containing the binder dissolved. The prepared core material was coated with a separating layer material in a fluidized bed apparatus. The enteric coating was sprayed on the coated pellets in a fluid bed apparatus. Enteric coated pellets were classified by sieving.

The enteric coated pellets were further coated with a solution of HPMC and misoprostol in a fluid bed apparatus using the following composition. Enteric coated pellets (see above) 100 g solution; EtOH 95% (w / v) 125 g misoprostol 0.46 g purified water 125 g hydroxypropylmethylcellulose (HPMC) 6 cps 5.3 g colloidal silica [Aerosil® 0.5 g) Misoprostol was first dissolved in ethanol and then water was added. HPMC
Were mixed and dissolved. Finally, Aerosil® was dispersed in the solution. The obtained pellets were classified by sieving. The acid resistance of the prepared pellets is 99.6
%Met. The prepared pellets were mixed with tablet excipients and compressed into multi-unit tablets as described in Example 5, or filled into capsules suitable for the desired dose.

Example 3 One layer of omeprazole (magnesium salt) in the form of pellets coated with an enteric coating mixed with 400 μg of misoprostol and 10 mg of felodipine in a hydrophilic matrix and another with tablet excipients 2.) Two-layer tablet consisting of 20 mg Long-term release granules consisting of misoprostol and felodipine were prepared according to the following formulation. Parts by weight misoprostol 0.4 felodipine 10 polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) 10 ethanol 95% (w / v) 400 hydroxypropyl methylcellulose 50 cps 400 sodium stearyl fumarate 4

[0063] Misoprostol is dissolved in half the volume of ethanol. Another solution is made by dissolving 10 parts felodipine and 10 parts Cremophor RH 40 in 60 parts ethanol. Pour these solutions onto powdered HPMC with mixing. Further ethanol (about 140 parts) is added to obtain a lump of appropriate hardness. The mass is dried on the tray (under mild conditions). The particle size of the dried granules was reduced until all granules passed through a 0.8 mm sieve. Then 1% (w / w) of sodium stearyl fumarate is mixed. Enteric coated pellets consisting of omeprazole magnesium salt were prepared and mixed with tableting excipients according to Example 1. A bilayer tablet consisting of 400 μg misoprostol, 10 mg felodipine and 20 mg omeprazole was prepared as described in Example 1.

The tablets are coated with a solution of HPMC and PEG with the pigment dispersed therein in a suitable coating device, for example a rotary drum coater, using the following composition: Tablets (see above) 724 parts by weight Solution; purified water 122 parts by weight Hydroxypropylmethylcellulose (HPMC) 6 cps 14 parts by weight Polyethylene glycol (PEG) 6000 4 parts by weight Titanium dioxide 2 parts by weight Yellow iron oxide 2 parts by weight The coating is the average tablet weight Until it increases by 14-20 mg.

Example 4 Capsule Formulation Consisting of Pantopyrazole and Misoprostol Pellets (40 mg Pentopyrazole and 200 μg Misoprostol) Pellets coated with an enteric coating of pentopyrazole are prepared according to the following formula. Core material Pentopyrazole 100 g Non-pareil® 200 g Hydroxypropylcellulose LF 25 g Purified water 607 g Separation layer core material (see above) 200 g Hydroxypropylcellulose LF 20 g Talc 34.3 g Magnesium stearate 2.9 g Purified water 400 g Enteric Coating Coated pellets (see above) 200 g Methacrylic acid copolymer (30% suspension) 333 g Triethyl citrate 30 g Mono and diglyceride (NF) 5 g Polysorbate 80 0.5 g Purified water 281.5 g Suspension coating is applied in a fluidized bed apparatus carry out. Pantopyrazole is sprayed onto non-pareil from an aqueous suspension containing the dissolved binder. The prepared core material is coated with a separating layer material in a fluidized bed apparatus. The enteric coating is sprayed on the coated pellets in a fluid bed apparatus. The pellet was classified by sieving.

Misoprostol pellets are prepared by coating inert spherical sugar in a fluid bed apparatus according to the following recipe. Spherical sugar [Non-pareil (registered trademark)] 100 g solution; EtOH 95% (w / v) 125 g misoprostol 0.46 g purified water 125 g hydroxypropyl methylcellulose (HPMC) 6 cps 5.34 g colloidal silica [Aerosil (registered trademark) )] 0.50 g Firstly dissolve misoprostol in ethanol and then add water. HPMC
Is mixed and dissolved. Finally, Aerosil® is dispersed in the solution. The obtained pellets were classified by sieving.

Capsule filling; enteric coated 266 mg pantopyrazole pellets and 20
The pellet (ie, about 55 mg) corresponding to 0 μg of misoprostol is filled into a No. 1 hard gelatin capsule.

Example 5 Multi-unit Tablets Consisting of Lansoprazole and Misoprostol Pellets (60 mg Lansoprazole and 200 μg Misoprostol) Lansoprazole pellets are prepared according to the following formula. Core material Lansoprazole 370 g Non-pareil® 400 g Hydroxypropyl methylcellulose 76 g Sodium lauryl sulfate 2.8 g Purified water 1360 g Separation layer core material (see above) 400 g Hydroxypropyl cellulose 40 g Talc 68.6 g Magnesium stearate 5.7 g Purified water 800 g enteric coating coated pellets (see above) 400 g methacrylic acid copolymer (30% suspension) 667 g (dry material content 200 g) triethyl citrate 60 g mono and diglyceride (NF) 10 g polysorbate 80 1 g purified water 420 g overcoat Enteric coated pellets 500 g Hydroxypropyl methylcellulose 6.5 g Mg-stearate 0.2 g Purified water 1 0g

The enteric coated pellets of lansoprazole are prepared as in Example 1 using lansoprazole instead of omeprazole. Tablet mg / tablet Pellets composed of lansoprazole (see above) Approximately 285 Pellets composed of misoprostol (see Example 4) about 55 microcrystalline cellulose PH 102 205 microcrystalline cellulose PH 101 205 crosslinked polyvinylpyrrolidone 30 sodium stearyl fumarate 4 first And microcrystalline cellulose and polyvinylpyrrolidone are uniformly mixed. The lubricant sodium stearyl fumarate is then mixed, then the lansoprazole pellets and misoprostol pellets are added and mixed until uniform. Compression into tablets is carried out on a tableting machine equipped with a 9x21 mm oval punch.

Example 6 Two-layer tablet miso consisting of delayed pulsed release pellets containing 200 μg of misoprostol in one layer and 10 mg of S-omeprazole (magnesium salt) in another layer mixed with tableting excipients A granule composed of Prostol is prepared according to the following formulation. Parts by weight misoprostol 0.2 ethanol 95% (w / v) 300 purified water 110 hydroxypropylmethylcellulose 6 cps 50 microcrystalline cellulose PH 101 350 sodium stearyl fumarate 4 Misoprostol is dissolved in 200 parts of ethanol. This solution was added to HPMC
And pour over microcrystalline cellulose powder with mixing. A sufficient amount of a mixture consisting of 100 parts of ethanol and 110 parts of water is then added and mixed until a lump of sufficient hardness is obtained. The mass is dried under mild conditions. The particle size of the dried granules is reduced until all granules have passed through a 0.8 mm sieve. Then a 1% (w / w) solution of sodium stearyl fumarate is added.

Preparation of Delayed Pulsed Release Pellets Consisting of Magnesium Salt of S-omeprazole (Pellet Concentration Approximately 44 mg / g) Preparation of Core Material (Drug Coated Spheres) A drug-containing suspension is made according to the following recipe. S-omeprazole Mg-salt 100 g HPMC, 6 cps 15 g polysorbate 80 2 g purified water 323 g HPMC is dissolved in water with stirring, then polysorbate 80 and drug are added. This suspension is sprayed onto 290 g of spherical sugar (Non-pareil) in a fluidized bed. The weight of the product is about 395 g.

Application of the swelling layer A water-free suspension containing a substance having a high swelling property with water is prepared according to the following formula. Low-substituted hydroxypropylcellulose (L-HPC) 162 g Hydroxypropylcellulose LF (HPC-LF) 74 g Talc 354 g EtOH (99.5%) 3100 g Dissolve HPC-LF in ethanol with stirring, then talc and swelling agent L- Add HPC. This suspension is sprayed onto the 175 g drug-containing pellet described above in a fluid bed equipped with a Wurster. The weight of the product is usually about 710 g.

Application of Latency Control Layer (Semipermeable Membrane) A coating suspension is prepared according to the following recipe. Ethyl cellulose, 10 cps 10 g Talc 23 g EtOH (99.5%) 1000 g Ethyl cellulose is dissolved in ethanol with stirring, and then talc is added. This suspension is sprayed onto 150 g of the above-mentioned pellets (0.61-0.71 mm obtained by sieving) in a fluid bed fitted with a Wurster. The weight of the obtained pellet is usually about 175 g.

Application of an enteric coating layer The above-mentioned pellets are provided with an enteric coating layer in a fluidized bed with the following coating dispersion. Eudragit L30 D-55 (30% w / w dispersion) 73.3 g Triethyl citrate (TEC) 6.6 g Glycerol monostearate (GMS) 0.3 g Polysorbate 80 0.03 g Purified water 40.4 g Polysorbate 80 and glycerol A uniform coating dispersion is prepared by dispersing monostearate in water. Dissolve the triethyl citrate in the Eudragit dispersion and then mix the two dispersions to obtain a coating dispersion. The coating dispersion is sprayed onto 120 g pellets in a fluid bed equipped with a Wurster. Enteric coated pellets usually weigh about 140 g.

Preparation of Tablets Tableting excipients for mixing with enteric coated pellets are prepared by uniformly mixing the following ingredients: Tableting excipient; microcrystalline cellulose (especially coarse grade PH 102) 12.12 g microcrystalline cellulose PH 101 6.06 g crosslinked polyvinylpyrrolidone 1.82 g total amount: 20.00 g Compression into tablets is 9 x 21 mm oval Using a tableting machine equipped with a punch (to make oval tablets). Tablets are prepared by first pre-compacting 404 mg of misoprostol-containing granules, then filling with a mixture consisting of pellets consisting of about 270 mg S-omeprazole magnesium salt (see above) and 270 mg of tableting excipient mix. I do.

Example 7 An enteric coated tablet consisting of 45 mg of omeprazole (magnesium salt) in a hydrophilic matrix, having an outer rapidly dissolving coat on the enteric coat layer, the outer coat being about 220 μg of miso Granules for prolonged release tablet core consisting of tablet omeprazole Mg-salt (about 45 mg) consisting of Prostol are made according to the following composition (parts by weight). Omeprazole Mg-salt 80 Hydroxypropyl methylcellulose 50 cps 300 Polyvinylpyrrolidone (PVP) K-90 40 Ethanol 99.5% (w / v) 400 PVP is dissolved in alcohol. The other two components are mixed and then moistened with the PVP-solution in a mixer. Next, the obtained mass is dried in an oven at 50 ° C. After pulverization in an oscillating mill, the mixture is passed through a 1.0 mm sieve, and the obtained granules are mixed with a tablet lubricant according to the following composition (parts by weight). After mixing the tablet core granules 412 sodium stearyl fumarate [Pruv®] 4 ingredients, the mixture is compressed into tablets (diameter 9 mm) having an average weight of 265 mg on a tablet machine.

Tablets Coated with Separation Layer The resulting tablets are first coated with the separation layer with a coating suspension of the following composition, for example in a rotary drum coating apparatus. Ethanol 99.5% (w / v) 85 parts by weight Purified water 85 parts by weight Hydroxypropyl methylcellulose 6 cps 10 parts by weight Talc, pulverized 2 parts by weight Total amount: 182 parts Tablet coating is continued until the average tablet weight becomes about 274 mg. .

Enteric Coating The tablets coated with the separating layer are coated with the enteric coating layer in the same equipment as in the previous coating step. The coating solution used has the following composition: Hydroxypropyl methylcellulose phthalate [HP-55 (registered trademark)] 19 parts by weight Cetanol 1 part by weight Acetone 182 parts by weight Ethanol 95% (w / v) 78 parts by weight Total amount: 280 parts The tablets coated with the separation layer were treated, Coating is continued until the average tablet weight is about 293 mg.

Enteric Coated Tablets Coated with a Misoprostol Layer Enteric coated omeprazole Mg-salt is applied by a solution of HPMC and misoprostol, for example in a rotating drum coating apparatus, using the following composition: Coating.

Dispersion EtOH 95% (w / v) 125 parts by weight Misoprostol 0.46 parts by weight Purified water 125 parts by weight Hydroxypropyl methylcellulose (HPMC) 6cp 5.34 parts by weight Colloidal silica (Aerosil RTM) 0.3 parts by weight 50 parts by weight Misoprostol is first dissolved in ethanol and then water is added. HPMC
And dissolve. Finally, Aerosil® is dispersed in the solution. Coating is continued until the average tablet weight is about 296 mg.

Example 8 Tablet Enteric Coated of 20 mg Omeprazole (Magnesium Salt) in a Hydrophilic Matrix, Having a Hydrophilic Matrix Outer Layer on the Enteric Coat, 200 μg Outer Layer Consists of misoprostol. Granules consisting of omeprazole Mg-salt are prepared according to the following formula. mg / tablet omeprazole Mg-salt 22.5 ethanol 95% (w / v) 90 hydroxypropylmethylcellulose (HPMC) 50 cps 50 hydroxypropylmethylcellulose (HPMC) 1000 cps 40 polyvinylpyrrolidone (PVP) K-90 6.5 PVP in ethanol Dissolve. The solution is poured onto a mixed powder of HPMC and omeprazole Mg-salt powder with constant stirring. The mass obtained is dried at 50 ° C. on a tray in a drying oven. After grinding through a 0.8 mm sieve, the granules obtained are mixed with a tablet lubricant according to the following composition. Granules 119 g Sodium stearyl fumarate [Pruv (registered trademark)] 1 g

Mixing is performed in a mixer such as Kenwood until uniform. It is then compressed on a tablet press to a diameter of 6 mm with an average weight of 120 mg. The tablets are coated with a separating layer using a solution of HPMC with the following composition, for example by coating in a fluidized bed coater or a rotating drum coater. EtOH 95% (w / v) 125 parts by weight Purified water 125 parts by weight Hydroxypropyl methylcellulose (HPMC) 6 cps 5.3 parts by weight HPMC is dissolved in an ethanol / water mixture. The coating has an average tablet weight
Continue until 4 mg increase (i.e., 12 mg for an average starting weight of 120 mg)
Up to 4 mg).

The obtained tablets coated with a separation layer are enterically coated with the same equipment as in the previous coating step. The coating solution has the following composition: Hydroxypropyl methylcellulose phthalate (HP-55) 16 parts by weight Cetanol 1 part by weight Acetyl tributyl citric acid 1 part by weight Acetone 153 parts by weight Ethanol (95% w / v) 65 parts by weight Total amount: 236 parts by weight Tablets have an average tablet weight of 133 mg. Coating until The resulting enteric-coated extended release omeprazole Mg-salt tablet is dry coated in a suitable tablet machine with granules consisting of HPMC and misoprostol prepared using the following composition. Misoprostol 0.2 parts by weight Ethanol 95% (w / v) 200 parts by weight Hydroxypropyl methylcellulose (HPMC) 50 cps 200 parts by weight Misoprostol is first dissolved in ethanol. Then, this solution was added to HPMC
Pour while mixing over the powder. The mass is dried under mild conditions. The resulting dried granules are ground in an oscillating granulator equipped with a 1.0 mm screen. For the preparation of each dry-coated extended release tablet, 200 mg of misoprostol consisting of enteric coated omeprazole Mg-salt tablets and extended release granules are used and compressed with a 10 mm diameter punch.

Example 9 Capsule formulation consisting of 20 mg of pantoprazole and 400 μg of misoprostol, the latter being in a hydrophilic matrix plug The pantoprazole pellets were prepared as described in Example 5 using pantoprazole instead of lansoprazole Prepare. Long-term release plugs composed of misoprostol first make granules according to the following formula. Misoprostol 0.4 parts by weight Ethanol 95% (w / v) 110 parts by weight Hydroxypropyl methylcellulose 50 cps 118 parts by weight Misoprostol is dissolved in 110 parts of ethanol. The solution is poured onto the HPMC powder with mixing. The mass is dried under mild conditions. The particle size of the dried granules is reduced until it passes through a 0.8 mm sieve. Then, the lubricant sodium stearyl fumarate is mixed according to the following formula. The above granules 118.4 parts by weight Sodium stearyl fumarate 1.6 parts by weight Total amount: 120.0 parts by weight Mixing is carried out in a mixer until uniform. It is then compressed on a tablet press into 6 mm diameter plugs (tablets) having an average weight of 120 mg. Capsule filling: A pellet consisting of one plug as described above and 95 mg of pantoprazole is filled into size 1 hard gelatin capsules.

Example 10 Double-pulse release enteric coated coated tablets of S-omeprazole magnesium salt (2 × about 15 mg), having an outer rapidly dissolving coat on the enteric coating and an outer layer the granules granules for tablet core consisting of misoprostol 220μg is prepared according to the following formulation. Parts by weight S-omeprazole Mg-salt 229 microcrystalline cellulose, Avicel PH 101 151 microcrystalline cellulose, especially coarse grade, Avicel PH 102 400 L-HPC 256 PVP-XL 302 sodium lauryl sulfate (SLS) 30 purified water 1060 granulation solution Is prepared by dissolving SLS in 460 parts of purified water. The above-mentioned powders are mixed in a mixer and the solution is then added in a regular flow. Next, about 600 parts of water are added with constant mixing, resulting in a lump of sufficient hardness. The mass is dried in a drying oven at 50 ° C. overnight.

Preparation of tablet cores After grinding through a 1.0 mm sieve, the granules obtained were converted into tablet lubricants according to the following composition:
Mix with salt and an added amount of swelling substance. Parts by weight Granules for a uniform tablet core 400 Salt (pass through 0.3 mm) 80 Sodium stearyl fumarate [Pruv®] 8 Crosslinked polyvinylpyrrolidone (PVP-XL) 20 Mix until uniform, eg a mixer such as Kenwood Implemented in It is then compressed on a tablet press into tablets having a mean weight of 126 mg and a diameter of 6 mm.

Application of Latency Control Layer (Semi-permeable Membrane) EtOH 99.5% (w / v) 291 parts by weight Ethylcellulose N-10 11 parts by weight Talc, pulverized 7 parts by weight Total amount: 309 parts Tablet coated Coating is continued until the average tablet weight is 134 mg.

Application of the Drug-Containing Layer The resulting tablets are coated in the same device as described above with a coating suspension of the following composition: S-omeprazole Mg-salt 20 parts by weight Hydroxypropyl methylcellulose 6 cps 13 parts by weight Ethanol 99% 128 parts by weight Purified water 128 parts by weight Total amount: 289 parts The tablets are coated and the coating is continued until the average tablet weight is 162 mg.

The tablets obtained are first coated with a separating layer using a coating suspension of the following composition, for example in a rotary drum coating apparatus. EtOH 99.5% (w / v) 85 parts by weight Purified water 85 parts by weight Hydroxypropyl methylcellulose 6 cps 10 parts by weight Talc, micronized 2 parts by weight Total amount: 182 parts Tablet coating is continued until the average tablet weight reaches 166 mg.

Application of Enteric Coating Layer The resulting tablets are coated with the enteric coating layer in the same equipment as in the previous coating step. The coating solution has the following composition: Hydroxypropyl methylcellulose phthalate (HP-55) 16 parts by weight Cetanol 1 part by weight Acetone 153 parts by weight Ethanol (95% w / v) 65 parts by weight Total amount: 235 parts by weight Tablets are coated, and the coating has an average tablet weight of 177 mg. Continue until. Enteric coated double pulse release S-omeprazole Mg-salt tablets are coated with a solution of HPMC and misoprostol using, for example, the following composition in a fluid bed coater or a rotary drum coater. Tablet (see above) 100 parts by weight Solution: EtOH 95% (w / v) 125 parts by weight Misoprostol 0.46 parts by weight Purified water 125 parts by weight Hydroxypropyl methylcellulose (HPMC) 6 cps 5.34 parts by weight Colloidal silica [ Aerosil (R)] 0.50 parts by weight Misoprostol is first dissolved in ethanol and then water is added. HPMC
And dissolve. Finally, Aerosil® is dispersed in the solution. Coating is continued until the average tablet weight increases by 3 mg (180 mg for a starting average weight of 177 mg).

Example 11 A pellet consisting of 200 μg of misoprostol and a pellet consisting of 20 mg of omeprazole (magnesium salt) was mixed with a tableting excipient into one layer, the other layer comprising 30 mg of nifedipine in a hydrophilic matrix. The extended release granules composed of the two-layer tablet nifedipine were prepared according to the following formulation. Nifedipine 30g Polyoxyl 40 Hydrogenated castor oil 30g Ethanol (99.5 w / v) 300g Ethyl cellulose N-10 20g Propyl gallate 0.06g Hydroxypropyl methylcellulose 50cps 175g Sodium aluminum silicate 75g Sodium stearyl fumarate 6g Nifedipine hydrogenated polyoxyl 40 Fill castor oil and propyl gallate in ethanol. The mixture is heated and stirred until a solution is formed, keeping the temperature of the mixture / solution at a maximum of 70 ° C. Then, ethyl cellulose is added and dissolved. The resulting solution is poured with mixing onto a mixture of HPMC and sodium aluminum silicate powder. The mass is dried in an explosion-proof drying cabinet and then ground in an oscillating granulator equipped with a sieve having a 1 mm opening. The resulting granules are mixed with the lubricant sodium stearyl fumarate for 2 minutes.

[0092] Perret was subjected to enteric coating layer consisting of omeprazole magnesium salt Tsu DOO was prepared as described in Example 1. Misoprostol pellets are prepared by dissolving misoprostol in ethanol and then mixing this solution with porous silica particles according to the following formula. 0.16 parts by weight of misoprostol Silica particles, porous, about 150 μm in diameter 53.14 parts by weight Ethanol (99.5 w / v) 42.5 parts by weight The mass is dried under mild conditions. 1 g of the obtained misoprostol pellets
Contains about 3.75 mg of misoprostol per. Tableting excipients for mixing omeprazole and misoprostol pellets are prepared by uniformly mixing the following ingredients:

Tableting excipient Microcrystalline cellulose, especially coarse grade 12.12 parts by weight of PH 102 6.06 parts by weight of microcrystalline cellulose 1.82 parts by weight of crosslinked polyvinylpyrrolidone 1.82 parts by weight Total amount: 20.00 parts by weight Compression is carried out on a tableting machine fitted with a 9 x 17 mm oval punch (to make oval tablets). Tablets were first pre-compressed with 336 mg of nifedipine-containing granules, then filled with a mixture consisting of 100 mg of omeprazole magnesium salt (see above), 53 mg of misoprostol-containing pellets and 200 mg of tableting excipient mix. To make a total tablet weight of 689 mg. Tablets are HPMC to protect nifedipine in the tablets against photolytic degradation
And PEG in a fluidized bed coating apparatus or a rotating drum coater according to the following composition. Tablets (see above) 336 parts by weight Solution; purified water 122 parts by weight Hydroxypropylmethylcellulose (HPMC) 6 cps 14 parts by weight Polyethylene glycol (PEG) 6000 4 parts by weight Titanium dioxide 2 parts by weight Yellow iron oxide 2 parts by weight Coating is average tablet weight Until it increases by 15-20 mg.

Example 12 Enteric coated pellets consisting of about 225 mg / g S-omeprazole magnesium salt and about 3.5 mg / g misoprostol pellets located in the external extended release layer The resulting enteric coated pellets were prepared as described in Example 2. Enteric coated pellets are coated with a solution of HPMC and misoprostol in a fluid bed apparatus using the following composition. Enteric coated pellets (see above) 100 parts by weight Solution; EtOH 95% (w / v) 300 parts by weight Purified water 50 parts by weight Misoprostol 0.46 parts by weight Hydroxypropyl methylcellulose (HPMC) 50 cps 5.34 parts by weight Colloidal silica [Aerosil®] 0.50 parts by weight Misoprostol is first dissolved in ethanol and then water is added. next,
Mix and dissolve HPMC. Finally, Aerosil® is dispersed in the solution. The obtained pellets are classified by a sieve. The prepared pellets may be compressed into multi-unit tablets as described in Example 5 or filled into capsules suitable for the desired dose.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 9/32 A61K 9/32 9/44 9/44 9/46 9/46 9/54 9/54 31 / 4439 31/4439 31/5575 31/5575 A61P 1/04 A61P 1/04 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH) , GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS , JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Per Johan・ Lundberg Sweden S-431 83 Melndall. AstraZeneca. R & D Melndall (72) Inventor Ork Pilbrandt S-431 83 Sweden Melndall. AstraZeneca. R & D Melndard F-term (reference) 4C076 AA36 AA40 AA44 AA45 AA47 AA53 AA60 BB01 CC16 CC44 DD09 DD28 DD41 DD42 DD43 DD46 EE11 EE16 EE30 EE31 EE33 FF25 FF27 FF28 FF31 FF20 GG20 MA4 MA24 MA08 ZA66 ZB21 ZC41 4C086 AA01 AA02 BC39 DA03 MA02 MA03 MA04 MA35 MA37 MA52 NA06 NA14 ZA66 ZB21 ZC41

Claims (37)

[Claims] 1. A pharmaceutical dosage form for oral administration comprising an H ⁺ , K ⁺ -ATPase inhibitor and a gastric acid antisecretory prostaglandin analog and optionally a pharmaceutically acceptable excipient, wherein at least A dosage form in the form of a fixed unit dosage form consisting of two pharmaceutically active ingredients. 2. The dosage form according to claim 1, wherein the dosage form is a tablet preparation. 3. The dosage form according to claim 1, wherein the dosage form is a capsule preparation. 4. The H ⁺ , K ⁺ -ATPase inhibitory compound is protected by an enteric coating layer and optionally a separating layer separating the H ⁺ , K ⁺ -ATPase inhibitor from the enteric coating layer. The dosage form according to any one of claims 1 to 3, which is applied below. 5. The dosage form according to claim 1, wherein the fixed dosage form comprises a calcium channel blocker in addition to the H ⁺ , K ⁺ -ATPase inhibitor and the gastric acid antisecretory prostaglandin analog. 6. The dosage form according to claim 1, wherein the H ⁺ , K ⁺ -ATPase inhibitor is omeprazole, an alkali salt thereof, one of its single enantiomers, or an alkali salt thereof. . 7. The dosage form according to claim 6, wherein the H ⁺ , K ⁺ -ATPase inhibitor is a magnesium salt of omeprazole. 8. The dosage form according to claim 6, wherein the H ⁺ , K ⁺ -ATPase inhibitor is a magnesium salt of S-omeprazole. 9. The dosage form according to claim 1, wherein the H ⁺ , K ⁺ -ATPase inhibitor is lansoprazole or one of its single enantiomers or a pharmaceutically acceptable salt thereof. . 10. The agent according to claim 1, wherein the H ⁺ , K ⁺ -ATPase inhibitor is pantoprazole or one of its single enantiomers or a pharmaceutically acceptable salt thereof. form. 11. The gastric acid antisecretory prostaglandin analog is one of misoprostol, enisoprost, enprosteel or one of the single enantiomers thereof, or a pharmaceutically acceptable salt thereof. The dosage form according to any one of the above. 12. The method according to claim 1, wherein the amount of the H ⁺ , K ⁺ -ATPase inhibitor ranges from 1 to 200 mg, and the amount of the gastric acid antisecretory prostaglandin analog ranges from 80 to 1,000 μg. The dosage form according to any of the above. 13. The amount of the H ⁺ , K ⁺ -ATPase inhibitor in the range of 5 to 80 mg,
13. The dosage form according to any of claims 1 to 12, wherein the amount of gastric acid antisecretory prostaglandin analog ranges from 100 to 800 g. 14. The tablet is composed of two different layers, the first layer being H⁺, K ⁺ A second layer consisting of ATPase inhibitors, gastric acid antisecretory prostaglandins
3. The tablet dosage form according to claim 2, comprising an edge. 15. A tablet formulation comprising: a) H ⁺ , K ⁺ -ATP in the form of pellets coated with an enteric coating layer.
A multi-unit tablet dosage form comprising b) gastric acid antisecretory prostaglandin analogs, and optionally c) pharmaceutically acceptable excipients, compressed together into tablets, coated with individual pellets. The enteric coating layer, even if tableted together with the gastric acid antisecretory prostaglandin analog and optionally a pharmaceutically acceptable excipient, can be used to reduce the acid resistance of the pellet coated with the enteric coating layer. 3. A tablet dosage form according to claim 2 having mechanical properties that do not significantly affect. 16. The tablet dosage form according to claim 15, wherein the enteric coating of the individual pellets comprises a plasticized enteric coating layer material. 17. The tablet dosage form according to claim 15, wherein the pellets coated with the enteric coating layer are further coated with an overcoating layer consisting of a film-forming polymer and a pharmaceutically acceptable excipient. 18. The tablet dosage form according to claim 15, wherein the tablet is dividable. 19. The tablet dosage form according to claim 2, wherein at least a portion of the tablet is in the form of an extended release formulation. 20. The tablet of claim 1 wherein the extended release portion of the tablet is a hydrophilic matrix.
9. The tablet dosage form according to 9. 21. The extended release portion of the tablet is a hydrophobic matrix.
9. The tablet dosage form according to 9. 22. The tablet is composed of two different layers, the first layer comprising an H ⁺ , K ⁺ -ATPase inhibitor in the form of a pellet coated with an enteric coating layer, wherein the first layer comprises 3. A tablet dosage form according to claim 2 wherein the tablet dosage form is compressed into one layer and the second layer provides a prolonged release of the introduced gastric acid antisecretory prostaglandin analog. 23. A tablet comprising an enteric coated layered pellet of an H ⁺ , K ⁺ -ATPase inhibitor further coated with a layer comprising a gastric acid antisecretory prostaglandin analog, wherein the layered pellet is formed into a tablet. The tablet dosage form according to claim 2, which is compressed into a tablet together with the preparation. 24. The tablet dosage form of claim 23, wherein the pellets are coated with a pigmented film coating layer before being compressed into tablets, or the compressed tablets are coated with a pigmented tablet coat. . 25. The tablet is composed of two types of layered pellets, the first type being a pellet consisting of an H ⁺ , K ⁺ -ATPase inhibitor coated with an enteric coating layer and the second type being a pellet. 3. The tablet dosage form of claim 2, wherein the tablet dosage form comprises a gastric acid antisecretory prostaglandin analog, and all pellets are compressed into tablets with tablet excipients. 26. A tablet comprising a pellet coated with an enteric coating layer comprising an H ⁺ , K ⁺ -ATPase inhibitor and a pellet comprising a gastric acid antisecretory prostaglandin analog introduced into a matrix. 23. The tablet dosage form of claim 22, which provides for prolonged release of the prostaglandin analog. 27. The capsule is composed of two types of layered pellets, the first type being a pellet consisting of an H ⁺ , K ⁺ -ATPase inhibitor coated with an enteric coating layer and the second type being a pellet. The dosage form according to claim 3, wherein the type is a pellet consisting of a gastric acid antisecretory prostaglandin analog, wherein all the pellets and optionally a pharmaceutically acceptable excipient are filled in a capsule. H ⁺ in 28. capsules, a K ⁺ -ATP-ase inhibitor and one or more fixed dosage form production method of consisting of gastric acid antisecretory prostaglandin analogue, H ^+, K ⁺ -ATPase inhibitors are prepared in the form of pellets coated with an enteric coating layer, gastric acid antisecretory prostaglandin analogs are prepared in the form of pellets coated with an extended release film coating layer, and the pellets are mixed. And optionally adding pharmaceutically acceptable excipients and filling the mixture into capsules. 29. A process for the preparation of a fixed dosage form comprising an H ⁺ , K ⁺ -ATPase inhibitor and one or more gastric acid antisecretory prostaglandin analogs in a multi-unit tablet dosage form. , H ⁺ , K ⁺ -ATPase inhibitors are prepared in the form of pellets coated with an enteric coating layer, and these pellets are treated with gastric acid antisecretory prostaglandin analogs and optionally pharmaceutically acceptable tablet excipients. A pellet comprising the agent, and then compressing the mixture into a multi-unit tablet without significant change in the acid resistance of the pellet coated with the enteric coating. 30. A process for the preparation of a fixed dosage form comprising an H ⁺ , K ⁺ -ATPase inhibitor and one or more gastric acid antisecretory prostaglandin analogs in a multi-unit tablet dosage form. , H ⁺ , K ⁺ -ATPase inhibitors are prepared in the form of pellets coated with an enteric coating layer, and gastric acid antisecretory prostaglandin analogs are prepared in the form of pellets coated with a coating layer which is an extended release layer. Prepared in
Mixing these pellets, optionally with pharmaceutically acceptable tablet excipients, and then compressing the mixture without causing a significant change in the acid resistance of the pellets coated with the enteric coating. 31. A method for treating and preventing gastrointestinal diseases by administering a therapeutically effective dose of a dosage form according to any of claims 1-27 to a host in need thereof. 32. Use of a dosage form according to any of claims 1-27 in a host in need thereof for the administration of a therapeutically effective dose of a dosage form according to any of claims 1-27 to a gastric acid antisecretory prostaglandin analogue drug in mammals and humans. How to avoid gastrointestinal side effects usually associated with treatment. 33. Use of a dosage form according to any of claims 1 to 27 in the manufacture of a medicament for the treatment or prevention of a gastrointestinal disorder. 34. Use of a dosage form according to any of claims 1-27 in the manufacture of a medicament for avoiding the gastrointestinal side effects normally associated with gastric acid antisecretory prostaglandin analog treatment. 35. An H ⁺ , K ⁺ -ATPase inhibitor in the treatment of gastric acid disease,
Combination of gastric acid antisecretory prostaglandin analog and calcium channel blocker. 36. A blister pack comprising an H ⁺ , K ⁺ -ATPase inhibitor drug and a gastric acid antisecretory prostaglandin analog drug. 37. The blister pack according to claim 36, further comprising a drug which is a calcium channel blocker.