CN1756538A - Stable oral benzimidazole compositions and processes for their preparation - Google Patents

Abstract

The present invention relates to stable oral benzimidazole compositions and processes for their preparation. The stable oral benzimidazole pharmaceutical composition includes a core, a separating layer, and an enteric coating. The core includes a benzimidazole compound, a substantially water-soluble material and, optionally, one or more pharmaceutically acceptable excipients, wherein the core is not alkaline. The separating layer surrounds the core and includes a substantially water-soluble material and, optionally, one or more pharmaceutically acceptable excipients. The enteric coating surrounds the separating layer. At least one of the core and the separating layer includes the substantially water-soluble material without any pharmaceutically acceptable excipients.

Description

Stable oral benzimidazole compositions and preparation method thereof

Technical field

The present invention relates to stable oral benzimidazole compositions and preparation method thereof.

Background technology

United States Patent (USP) 4255431,4628098 and 4758579 discloses substituted pyridine radicals sulfinyl benzimidazole and can be used as potent gastric acid secretion inhibitor.This compounds is by suppressing H ⁺-K ⁺The active gastric acid inhibitory secretion of ATP enzyme (proton pump).Known this class medicine is in sour environment camber instability.They are also unstable in moist and organic solvent.Like this, in the prescription that this medicine will dose a patient with, and in the process of making this prescription, this prescription must be designed to protect this medicine to avoid the effect of moist and sour environment.Because this medicine degraded rapidly in acidic gastric juice, prescription can be an enteric coating.

The stability problem relevant with benzimidazole compound is familiar with in the art well, has the whole bag of tricks to prepare to contain the stabilized formulations of benzimidazole compound.One of the most general method that wherein is used for stabilizing benzimidazole compounds is to use the core of an alkalescence, a sealing coat and an enteric coating.The common recognition of this area is to use a kind of medium of alkalescence to avoid by acid degradation with the protection benzimidazole compound at in-core.Use the core of an alkalescence, and do not have sealing coat between core is with enteric coating, this in the past to make the stable prescription of benzimidazole compound be invalid.Like this, just a sealing coat need be arranged between core and enteric coating.Between the core of alkalescence and enteric coating, there is the example of a sealing coat in United States Patent (USP) 4786505 and United States Patent (USP) 4853230, description to be arranged.Wherein the sealing coat of Jie Shiing is made up of water-soluble polymer.

United States Patent (USP) 5035899 has disclosed a kind of oral benzimidazole compound preparation, and it is depicted as basic composition is a core, first coatings and second coatings that is slightly soluble in water.It is effective that described core contains a kind of pharmacology, to the unsettled benzimidazole compound of acid.First coating is applied on the core and comprises a kind of filmogen that is slightly soluble in water, this material is selected from ethyl cellulose, polyvinyl acetate and a kind ofly be slightly soluble in water, be suspended in the fine grained in the ground floor, this fine grained that is slightly soluble in water is selected from magnesium oxide, silica anhydride, calcium silicates, magnesium hydroxide, magnesium carbonate, aluminium hydroxide, calcium stearate, magnesium stearate and sucrose fatty acid ester.Second coatings is coated on the ground floor and by a kind of enteric polymer film to be formed.

United States Patent (USP) 6274173 has disclosed a kind of controlled release pharmaceutical compositions, this compositions comprises a kind of sour absence of labile protons pump inhibitor except that pantoprazole, a kind of ball of alkalescence or label, the enteric layer of the water-fast intermediate layer that at least one control active component discharges and the enteric solubility of a periphery.Inferior coatings be depicted as that the control active component discharges and like this active component just be released in a kind of mode of change, that is, the part active component can discharge immediately and partly discharge in the controlled release mode.

United States Patent (USP) 5877192 is disclosed in the treatment gastric acid related disorder, compares with omeprazole, and (-) enantiomer (different omeprazole) of use omeprazole or its pharmaceutically acceptable salt are as the individual variation in the means minimizing blood plasma level.Compare with those omeprazole racemic modifications, use (-) enantiomer of omeprazole can increase the average plasma levels (AUC) of this material, so show higher dosage effectiveness.

According to prior art, directly there is not the prescription of sealing coat with one deck enteric coating in the outside of the benzimidazole compound that has alkaline core, be unsuccessful aspect the stable benzimidazole compound prescription of preparation.For example, WO 00/78284 has disclosed a kind of benzimidazole compound prescription that does not have sealing coat.These prescriptions disclose and use neutral enteric coating, and this enteric coating is applied with the solution form, the pH value at least 6.5 of solution, and preferable range is 7-10.This enteric coating is directly to be applied to the benzimidizole derivatives substrate.This solution optionally adds a kind of plasticizer, can directly be coated on the substrate and need not any intermediate layer.

United States Patent (USP) 6602522 discloses a kind of stable pharmaceutical composition, wherein a kind of oral sour unstable compounds is used as active component.Said composition comprises a core of making sheet and a single coats on core, and this layer coating comprises a kind of enteric coating reagent.This core of making sheet comprise an active component that contains dose therapeutically effective not by coated granules, an optional surfactant, a pharmaceutically acceptable alkaline agent, at least a water-soluble adhesive and at least a water-fast adhesive.This patent has also disclosed a kind of core of making sheet of alkaline medium and enteric coat layer that is applied directly to of having.

Next for making the stable effort of benzimidazole compound be based on the acid core that uses the band sealing coat, sealing coat is made up of water-soluble polymer and other excipient.

United States Patent (USP) 5385739 has disclosed a kind of stable omeprazole microparticle formulations, contains neutral core and active layer of a sugar and starch in the prescription, and quantity is equal substantially, and active layer is made up of the mannitol diluent of omeprazole.This omeprazole active layer contains the carboxyl methyl starch of about 10 weight % and the sodium lauryl sulphate surfactant of about 5 weight %.HYDROXY PROPYL METHYLCELLULOSE is applied on the neutral core as the mannitol diluent of high viscosity adhesive with omeprazole.

United States Patent (USP) 5626875 discloses and uses a kind of inert sugar/starch spherical core, and ground floor of coating is by benzimidazole compound on it, and the mixture of the pharmaceutically acceptable excipient of a kind of water-soluble inert polymer and non-alkaline reaction is formed.Second stratum disjunctum that applies on the ground floor formed by the pharmaceutically acceptable excipient of water-soluble polymer and non-alkaline reaction.Form by enteric coating, be applied on the second layer for the 3rd layer.

U.S. Patent Application Publication No. is a kind of oral Pharmaceutical dosage forms of making sheet of announcement of 20030118650, and it is covered by one deck enteric coating, and contain many unitary in acid medium unsettled benzimidazole compound as active principle.This multiple-unit contains: i) inert core; Ii) one at inert core i) on active layer, it is by unsettled benzimidazole compound in acid medium, a kind of water-soluble inert polymer of non-alkalescence and one or more pharmaceutically acceptable inert excipients are formed; Iii) an intermediate layer comprises one by non-alkalescence, the non-alkaline coating of inertia that water-soluble inert polymer forms and one or more pharmaceutically acceptable inert excipients.The intermediate layer is coated on and covers inert core i) active layer ii) above.

Like this, United States Patent (USP) 5626875 and the U.S. Patent Application Publication No. intermediate layer that has been 20030118650 use, it is made up of water-soluble inert polymer and one or more pharmaceutically acceptable inert excipients of a non-alkalescence.

United States Patent (USP) 6159499 has disclosed a kind of compositions, and it is depicted as the chemical compound that is substantially free of alkaline reaction.Said composition comprises (a) core that contains sour unsettled benzimidazole active principle; (b) intermediate layer around this core of person; (c) enteric layer around this intermediate layer of person.This core comprises and mixes the many nuclears and the active principle that press together then.The form that this active principle is depicted as not with basic salt exists.This patent has also disclosed a kind of method of benzimidazole compound of the stable peroral dosage form for preparing the alkali-free compound of reaction.This method may further comprise the steps (i) a plurality of nuclears and active principle is mixed; (ii) the product of pressing steps (i) is to form a core that comprises active principle; (iii) apply the core of gained with an intermediate layer; And the product that (iv) (iii) obtains with an enteric layer applying step.

United States Patent (USP) 6207198 has disclosed a kind of stable pharmaceutical composition, and it comprises (a) core that contains sour unsettled omeprazole active principle; (b) intermediate layer that comprises at least one polymer; (c) enteric layer.It is the alkali-free compound of reaction that said composition is depicted as.This core is made up of pharmaceutically inert nuclear and active component, and both are pressed together.The omeprazole active principle is depicted as the form with basic salt.The polymer in intermediate layer is depicted as and is selected from saccharide, Polyethylene Glycol, and polyvinylpyrrolidone, polyvinyl alcohol, hydroxy propyl cellulose, hydroxy-methyl cellulose, HYDROXY PROPYL METHYLCELLULOSE, and composition thereof.

WO 99/61022 discloses a kind of stable combination of oral medication, and it is a kind of form of mixture, contains a substituted pyridine radicals sulfinyl benzimidazole and the carrier with gastric acid secretion inhibiting activity.This carrier comprises at least one polymer, and this polymer to small part is made up of the ketopyrrolidine monomeric unit.This patent has also disclosed uses benzimidazole compound and at least one to contain the mixture of polymers of ketopyrrolidine monomeric unit, and this mixture does not contain any alkaline reaction chemical compound with stabilizing benzimidazole compounds.This prescription form of premix, it is not extruded and is beneficial to preparation.

U.S. Patent Application Publication No. is 2002128293 to tell about a kind of stable pharmaceutical composition, and it contains omeprazole and a kind of pharmaceutically acceptable carrier, and carrier comprises at least a water-insoluble polymer of being made up of ketopyrrolidine to small part.This application discloses crosslinked polyvinyl pyrrolidone as the polymer that is insoluble in water and as disintegrating agent.As described below, the inventor has developed a kind of prescription, does not comprise this vinyl pyrrolidone polymer with disintegration properties in sealing coat.

From effective stabilisation of compositions, manufacturing cost and complexity, employed organic solvent considers that to the aspects such as influence of environment there are various shortcomings in prior art.The present invention of relevant stable oral benzimidazole compositions has overcome defective of the prior art.

Summary of the invention

A total aspect the invention provides a kind of stable oral benzimidazole pharmaceutical composition.Said composition comprises a core, a sealing coat, and an enteric coating.Described core comprises benzimidazole compound, a kind of water-soluble substantially material and, optional, one or more pharmaceutically acceptable excipient, wherein said core are not alkaline.Described sealing coat round core and comprise a kind of water-soluble substantially material and, optional, one or more pharmaceutically acceptable excipient.Described enteric coating is round sealing coat.Have at least one to comprise water-soluble substantially material and do not contain pharmaceutically acceptable excipient in core and the sealing coat.

Can comprise one or more following characteristics in the instantiation of this pharmaceutical composition.For example, described benzimidazole compound can be selected from omeprazole, lansoprazole, pantoprazole, one or more in the rabeprazole, and single enantiomer.Described one or more pharmaceutically acceptable excipient can be selected from one or more diluent, disintegrating agent, adhesive and lubricant.

Diluent can be selected from saccharide, sugar alcohols, one or more of cellulose derivative and starch.Saccharide can be selected from dextrose, glucose and lactose.Sugar alcohol can be selected from sorbitol, xylitol and mannitol.Cellulose derivative can be selected from the cellulose and the microcrystalline Cellulose of claying into power.Starch can be selected from corn starch, the starch and the corn starch of pre-gelatinization.Disintegrating agent can be selected from Explotab, one or more in cross-linked carboxymethyl cellulose sodium and the corn starch.

Adhesive can be selected from cellulose derivative, natural gum, one or more in water soluble vinyl pyrrolidone polymer and the saccharide.Cellulose derivative can be a HYDROXY PROPYL METHYLCELLULOSE, one or more in hydroxy propyl cellulose and the methylcellulose.Natural gum can be xanthane gum, one or more in Radix Acaciae senegalis and the tragacanth gum.The water soluble vinyl pyrrolidone polymer can be one or more in the copolymer of polyvinyl pyrrolidone and vinyl pyrrolidone and vinyl acetate.Saccharide can be one or more in sorbitol and the mannitol.

Lubricant can be a magnesium stearate, Talcum, one or more in fumaric acid sodium stearyl ester and the colloidal silica.Substantially water-soluble material can be one or more in water-soluble substantially polymer and the water-soluble substantially excipient.Substantially water-soluble polymer can be selected from HYDROXY PROPYL METHYLCELLULOSE, hydroxy propyl cellulose, polyvinyl pyrrolidone, algin, carbonyl sodium carboxymethylcellulose pyce, and in the copolymer of vinyl pyrrolidone and vinyl acetate one or more.Water-soluble excipient can be a lactose, mannitol, sorbitol, one or more in sucrose and the glucose.

Core can comprise water-soluble substantially material and without any pharmaceutically acceptable excipient.Sealing coat can comprise water-soluble substantially material and without any pharmaceutically acceptable excipient.

The aspect that another is total the invention provides a kind of stable oral benzimidazole pharmaceutical composition.Said composition comprises a core and an enteric coating.Described core contains benzimidazole compound, a kind of water-soluble substantially material and, optional, one or more pharmaceutically acceptable excipient, wherein said core are not alkaline.Described enteric coating is round core and directly contact with it.This prescription does not have sealing coat between core and enteric coating.

Can comprise one or more following characteristics in the instantiation of this pharmaceutical composition.For example, described benzimidazole compound can be selected from omeprazole, lansoprazole, pantoprazole, one or more in the rabeprazole, and single enantiomer.The pharmaceutically acceptable excipient of one or more of described core can be selected from one or more diluent, disintegrating agent, adhesive and lubricant.

Diluent can be selected from saccharide, sugar alcohols, one or more of cellulose derivative and starch.Saccharide can be selected from dextrose, glucose and lactose.Sugar alcohol can be selected from sorbitol, xylitol and mannitol.Cellulose derivative can be selected from the cellulose and the microcrystalline Cellulose of claying into power.Starch can be selected from corn starch, the starch and the corn starch of pre-gelatinization.Disintegrating agent can be selected from Explotab, one or more in cross-linked carboxymethyl cellulose sodium and the corn starch.Adhesive can be selected from cellulose derivative, natural gum, one or more in water soluble vinyl pyrrolidone polymer and the saccharide.Cellulose derivative can be a HYDROXY PROPYL METHYLCELLULOSE, one or more in hydroxy propyl cellulose and the methylcellulose.Natural gum can be xanthane gum, one or more in Radix Acaciae senegalis and the tragacanth gum.The water soluble vinyl pyrrolidone polymer can be one or more in the copolymer of polyvinyl pyrrolidone and vinyl pyrrolidone and vinyl acetate.Saccharide can be one or more in sorbitol and the mannitol.

Lubricant can be a magnesium stearate, Talcum, one or more in fumaric acid sodium stearyl ester and the colloidal silica.

The aspect that another is total the invention provides a kind of method for preparing stable oral benzimidazole pharmaceutical composition.This method comprises core of preparation, with a sealing coat parcel core, with an enteric parcel core or sealing coat.The preparation method of core is with benzimidazole compound, substantially water-soluble material and, choose wantonly, one or more pharmaceutically acceptable excipient are dispersed in and obtain a kind of disperse system in a kind of aqueous medium, this disperse system of spray drying, and be squeezed into core with one or more pharmaceutically acceptable mixed with excipients.Described core use by water-soluble substantially material and, optional, the sealing coat parcel that pharmaceutically acceptable excipient forms.Have at least one to comprise water-soluble substantially material and do not contain any pharmaceutically acceptable excipient in described core and the sealing coat.

Can comprise one or more following characteristics in the instantiation of this preparation method.For example, described benzimidazole compound can be selected from omeprazole, lansoprazole, pantoprazole, one or more in the rabeprazole, and an one enantiomer.The pharmaceutically acceptable excipient of one or more of described core can be selected from one or more diluent, disintegrating agent, adhesive and lubricant.

Diluent can be selected from saccharide, sugar alcohols, one or more of cellulose derivative and starch.Disintegrating agent can be selected from Explotab, one or more in cross-linked carboxymethyl cellulose sodium and the cereal starch.Adhesive can be selected from cellulose derivative, natural gum, one or more in water soluble vinyl pyrrolidone polymer and the saccharide.Lubricant can be a magnesium stearate, Talcum, one or more in fumaric acid sodium stearyl ester and the colloidal silica.

The aspect that another is total the invention provides the excretory method of a kind of gastric acid inhibitory.This method comprises takes a kind of pharmaceutical composition, and this pharmaceutical composition comprises (a) core, comprises benzimidazole compound, water-soluble substantially material and, optional, one or more pharmaceutically acceptable excipient, its SMIS are not alkaline; (b) sealing coat around core, and comprise water-soluble substantially material and, optional, one or more pharmaceutically acceptable excipient and (c) enteric coating round sealing coat.Have at least one to comprise water-soluble substantially material and do not contain pharmaceutically acceptable excipient in core and the sealing coat.

Can comprise one or more following characteristics in the instantiation of this method, or any characteristic that is described in this.For example, described benzimidazole compound can be selected from omeprazole, lansoprazole, pantoprazole, one or more in the rabeprazole, and single enantiomer.

The aspect that another is total the invention provides the excretory method of a kind of gastric acid inhibitory.This method comprises takes a kind of pharmaceutical composition, this pharmaceutical composition comprises (a) core, contain benzimidazole compound, substantially water-soluble material and, optional, one or more pharmaceutically acceptable excipient, its SMIS is not alkaline, with (b) one round core and the enteric coating that directly contacts with it, wherein this prescription does not have sealing coat between core and enteric coating.

Can comprise one or more following characteristics in the instantiation of this method, or any characteristic that is described in this.For example, described benzimidazole compound can be selected from omeprazole, lansoprazole, pantoprazole, one or more in the rabeprazole, and single enantiomer.

One or more specific embodiment of the present invention will present in the following description.Other characteristic of the present invention, purpose and advantage are obvious in description and claims.

Detailed Description Of The Invention

In order to seek to develop stable benzimidazole dosage form, the inventor has developed several benzimidazole dosage forms and their preparation method.For example, the inventor has developed a kind of stable benzimidazole dosage form, and it comprises a core, a sealing coat and an enteric coating.Described core comprises benzimidazole compound, a kind of water-soluble material and optional pharmaceutically acceptable excipient.Being characterized as of described core is not alkaline.Described sealing coat is deposited over, or with other method be wrapped on the core and also comprise a kind of water-soluble material and, optional, one or more pharmaceutically acceptable excipient.Described enteric coating is round sealing coat.Have at least one to comprise water-soluble substantially material and do not contain pharmaceutically acceptable excipient in core and the sealing coat.

The inventor has also developed a kind of stable benzimidazole dosage form, and it comprises a core and an enteric coating, and described enteric coating is deposited over or is wrapped on the core with other method.Described core contains benzimidazole compound, a kind of water-soluble material and, optional, one or more pharmaceutically acceptable excipient.In addition, the feature of described core is not alkaline.

A kind of method for preparing described stable benzimidazole prescription comprises the preparation core and applies this core.In order to prepare this core, benzimidazole compound, water-soluble material and, optional, one or more pharmaceutically acceptable excipient are dispersed in the purified water to obtain a kind of disperse system.This disperse system of spray drying, and with optional pharmaceutically acceptable mixed with excipients extruding formation core.By a sealing coat parcel, substantially water-soluble material and optional pharmaceutically acceptable excipient be made of then by described sealing coat for this core.This core that is wrapped is then by an enteric coating parcel.Perhaps, described core can be wrapped up by enteric coating and not contain described sealing coat.

Suitable benzimidazole compound comprises by the excretory any substituted benzimidazole compound of any mechanism energy gastric acid inhibitory, thereby can be used in the multiple gastrointestinal upset of treatment.Described benzimidazole compound can comprise, for example, and one or more omeprazoles, lansoprazole, rabeprazole, pantoprazole, leminoprazole, one or more in the Jennifer Parilla azoles (pariprazole), and single enantiomer, pharmaceutically acceptable salt, solvate, hydrate, or its mixture.Described benzimidazole compound can be crystalline or amorphous salt.In the weight of prescription, described benzimidazole compound amount can from 1% to 80%, preferred 5%-35%.

The core of using in this relates to any structure, comprises isolatedly or center on by barrier coating or equivalent, or does not have barrier coat, but isolated or center on by an enteric coating.Described core can be a sheet, ball, capsule, powder or its form of mixtures." sheet " used in this can comprise one or more small pieces, microplate or sheet." ball " used in this can comprise one or more granules, beadlet, ball, bolt or its mixture.The preferred right and wrong alkalescence of described core.Described core can contain one or more pharmaceutically acceptable excipient, comprises one or more adhesive, diluent, disintegrating agent, lubricants and solubilizing agent/wetting agent.

Benzimidazole compound in the core can be non-crystal or crystalline.Described benzimidazole compound also can also be mixed into core by spray drying together together with water-soluble polymer.Described core can contain one or more water solublity presheafs between inert nuclear and medicated layer.These one or more presheafs are different with sealing coat (or inferior coating).

Suitable diluent comprises one or more saccharides, such as dextrose, glucose and lactose; Comprise one or more sugar alcohols such as sorbitol, xylitol and mannitol; Comprise cellulose and microcrystalline Cellulose that one or more cellulose derivatives are for example clayed into power; Comprise one or more starch such as corn starch, the starch and the corn starch of pre-gelatinization.The preferable range of diluent is to decide according to the formulation types that is disclosed among each the prepared embodiment that comprises in this in the prescription.

Suitable adhesive comprises one or more cellulose derivatives such as HYDROXY PROPYL METHYLCELLULOSE, hydroxy propyl cellulose and methylcellulose; Comprise for example xanthane gum of one or more natural gum, Radix Acaciae senegalis and tragacanth gum; The copolymer that comprises one or more water soluble vinyl pyrrolidone polymers such as polyvinyl pyrrolidone and vinyl pyrrolidone and vinyl acetate; Comprise one or more saccharides such as sorbitol, mannitol or analog.The preferable range of adhesive is to decide according to the formulation types that is disclosed among each the prepared embodiment that comprises in this in the prescription.

Suitable disintegrants can comprise one or more Explotab, cross-linked carboxymethyl cellulose sodium, cereal starch and other suitable disintegrants.Suitable wetting agent comprises one or more sodium lauryl sulfates, polymerization sorbate 80, and equivalent.Examples of suitable lubricants/fluidizer comprises one or more magnesium stearate, Talcum, fumaric acid sodium stearyl ester, colloidal silicon dioxide and equivalent.Disintegrating agent in the prescription, the preferable range of wetting agent and lubricants are to decide according to the formulation types that is disclosed among each the prepared embodiment that comprises in this.

The sealing coat of using in this relates to core with the isolated layer of enteric coating.Described sealing coat is made with water-soluble substantially material, and these materials can dissolve or form gel when contacting with water or after the contact.These materials can comprise water-soluble substantially polymer and/or water-soluble substantially excipient.Just capsule shells is used as sealing coat, additional the using of one or more sealing coats chosen wantonly.In this prescription, enteric coating can directly be deposited on stratification on the capsule shells.Substantially water-soluble excipient can be selected from glucose, lactose, mannitol, sorbitol, sucrose, dextrose or equivalent.Substantially water-soluble polymer can be selected from HYDROXY PROPYL METHYLCELLULOSE, hydroxy propyl cellulose, polyvinyl pyrrolidone, sodium alginate, the copolymer of carbonyl sodium carboxymethylcellulose pyce and vinyl pyrrolidone and vinyl acetate.Preferably, these polymer are HYDROXY PROPYL METHYLCELLULOSE, hydroxy propyl cellulose or polyvinyl pyrrolidone.The preferable range of water-soluble substantially polymer is according to the formulation types that prepared in the prescription, and is tangible for a person skilled in the art on the basis that each specific embodiment of description discloses.

Described enteric coating comprises one or more cellulose acetate phthalate phthalic acids, HYDROXY PROPYL METHYLCELLULOSE, the phthalic acid polyvinyl acetate, carboxy methyl ethyl cellulose, methyl methacrylate/methacrylic acid copolymer is Eudragit NE30D as the known trade mark by Rohm Pharma listing, EudragitL, Eudragit S, the chemical compound of Eudragit L 100 55, and composition thereof.Described enteric coating can also contain plasticizer such as glycerol triacetate, triethyl citrate, certain herbaceous plants with big flowers diacid tributyl (sebecate), diethyl phthalate, Polyethylene Glycol and inert excipient such as Talcum, titanium dioxide, colloidal silica, HYDROXY PROPYL METHYLCELLULOSE, cross-linking polyethylene pyrrolidone etc.

Following embodiment illustrates stable oral benzimidazole prescription that is disclosed in various embodiments of whole description discussion and preparation method thereof.Described embodiment only provides and illustrates prescription and preparation method thereof and do not limited by it.The various versions of these prescriptions are expected in the scope of the present invention and appended claim.

Embodiment 1:

S.No	Composition	Weight (milligram/unit)
			A)	The medicine layer of lamination on the inertia label
1	The inertia label of mannitol/lactose/microcrystalline Cellulose (the about 7.0-9.0 millimeter of diameter)	145.0
			2	Omeprazole	20.0
3	Polyvinyl pyrrolidone (PVP-K30)/hydroxy propyl cellulose (HPC-L)/HYDROXY PROPYL METHYLCELLULOSE (HPMC)/mannitol	7.0
			4	# ammonium hydroxide	qs
5	Purified water	qs
			B)	Sealing coat (optional)

1	Hydroxy propyl cellulose (HPC-L)/HYDROXY PROPYL METHYLCELLULOSE (HPMC)/mannitol	8.6
			2	Purified water	qs
C)	Enteric coating
			1	Acryl EZE TM*	18.0
2	Purified water	qs
				Or
1	Eudragit L30D-55	38.15
			2	Liquid Macrogol	1.15
3	Talcum	4.06
			4	Titanium dioxide	1.35
5	Purified water	qs

Evaporate in the # preparation process

* Acryl EZE ^TM*Being the registered trade mark of Colorcon, is a kind of prescription that is used to disperse enteric coating.

Process:

PVP-K30/HPC-L/HPMC/ mannitol (a kind of or its mixture) is soluble in water, and adds ammonium hydroxide.Omeprazole added and be distributed in the above-mentioned mixture and disperse.With traditional coating machine this disperse system is applied to inert tablet.Suitable polymers/excipient is applied the benzimidazole sheet that so makes with traditional coating machine.At last, this sheet applies with the enteric coating prescription.

Embodiment 2:

S.No	Composition	Weight (milligram/unit)
			A)	The core ball
1	Non Pariel seed (microcrystalline Cellulose/sugar)	190.68
			B)	Preformed layer (optional)
1	Hydroxy propyl cellulose (HPC-L)/HYDROXY PROPYL METHYLCELLULOSE (HPMC)	9.52
			2	Purified water	qs
C)	Medicine layer

1	Esso draws azoles (Esomeprazole)	40.0
			2	Hydroxy propyl cellulose (HPC-L)/mannitol	20.0
3	# ammonium hydroxide	qs
			4	Purified water	qs
D)	Sealing coat
			1	Hydroxy propyl cellulose (HPC-L)/HYDROXY PROPYL METHYLCELLULOSE (HPMC)	26.0
2	Purified water	qs
			E)	Enteric coating
1	Acryl EZE TM*	85.80
			2	Purified water	qs
	Or
			1	Eudragit L30D-55	114.39
2	Liquid Macrogol	3.43
			3	Talcum	12.12
4	Titanium dioxide	4.04
			5	Purified water	qs

Evaporate in the # preparation process

* Acryl EZE ^TM*Being the registered trade mark of Colorcon, is a kind of prescription that is used to disperse enteric coating.

Process:

HPMC/HPC-L is water-soluble and be applied on the Non Pariel seed.The HPC-L/ mannitol under agitation is dissolved in purified water.Continue to stir, in above-mentioned mixture, add ammonium hydroxide.Under constantly stirring, draw azoles (Esomeprazole) to be dispensed in the mixture Esso and make.Adding in the multiplexer NonPariel seed at a fluid bed draws the coating of azoles (Esomeprazole) disperse system to form ball with Esso.Adding multiplexer with suitable polymers/excipient with a fluid bed, is enteric coating then, is coated on the above-mentioned ball.

Embodiment 3:

S.No	Composition	Weight (milligram/unit)
			A)	The medicine layer of lamination on the inertia label

1	The inert tablet core of mannitol (about 2.0-5.0 millimeters of diameter)	57.5
			2	Rabeprazole	10.0
3	Polyvinyl pyrrolidone (PVP-K30)/hydroxy propyl cellulose (HPC-L)/HYDROXY PROPYL METHYLCELLULOSE (HPMC)	2.25
			4	# ammonium hydroxide	qs
5	Purified water	qs
			B)	Sealing coat
1	Hydroxy propyl cellulose (HPC-L)/HYDROXY PROPYL METHYLCELLULOSE (HPMC)	2.25
			2	Purified water	qs
C)	Encapsulation layer
			1	Acryl EZE TM*	5.0
2	Purified water	qs

Evaporate in the # preparation process

* Acryl EZ ^TM*Being the registered trade mark of Colorcon, is a kind of prescription that is used to disperse enteric coating.

Process:

Soluble in water and the adding ammonium hydroxide of PVP-K30/HPC-L/HPMC.Rabeprazole is added and be distributed in the above-mentioned mixture.With traditional coating machine this disperse system is applied to inert tablet.With traditional coating machine suitable polymers is coated on the benzimidazole sheet that makes.At last, this tablet Acryl EZE enteric coating.A plurality of are filled in the hard gelatine capsule.

Embodiment 4:

S.No	Composition	Weight (milligram/unit)
			A)	Medicine layer
1	Non Pariel seed	160
			2	Lansoprazole	30
3	HYDROXY PROPYL METHYLCELLULOSE	17

4	Purified water	q.s.
			B)	Sealing coat
1	HYDROXY PROPYL METHYLCELLULOSE	38
			2	Talcum	8
3	Titanium dioxide	11
			4	Purified water	q.s.
C)	Enteric coating
			1	Monophalic acid ester of hydroxypropyl/Eudragit L100-55/Eudragit L30D-55	48
2	Liquid Macrogol	9.2
			3	Talcum	20.5
4	Titanium dioxide	0.75
			5	Purified water	q.s.
6	Acetone	q.s.

Process:

Medicine layer

1. HYDROXY PROPYL METHYLCELLULOSE is disperseed lansoprazole after water-soluble.

2. Non Pariel seed is loaded into fluid bed and adds in the multiplexer, the dispersion of spray step 1 is to obtain the medicine layered pills then.

Sealing coat

1. HYDROXY PROPYL METHYLCELLULOSE is disperseed Pulvis Talci and titanium dioxide after water-soluble.

2. the medicine layered pills is loaded into fluid bed and adds in the multiplexer, the solution with above-mentioned steps 1 applies then.

Enteric coating

The preparation of Monophalic acid ester of hydroxypropyl coating disperse system:

1. with Talcum, titanium dioxide and Polyethylene Glycol are dispersed in the acetone.

2. Monophalic acid ester of hydroxypropyl is dissolved in the acetone.

3. the disperse system that the disperse system of step 1 is added step 2 adds entry then and mixes.

With the ball of above-mentioned enteric coating disperse system coating sealing coat, and the ball of enteric coating is filled in the hard gelatine capsule.

Embodiment 5:

S.No	Composition	Weight (milligram/unit)
			A)	Medicine layer
1	Non Pariel seed	160
			2	Lansoprazole	30
3	HYDROXY PROPYL METHYLCELLULOSE	17
			4	Purified water	q.s.
B)	Sealing coat
			1	HYDROXY PROPYL METHYLCELLULOSE	57
2	Purified water	q.s.
			C)	Enteric coating
1	Monophalic acid ester of hydroxypropyl/Eudragit L100-55/Eudragit L30D-55	48
			2	Liquid Macrogol	9.2
3	Talcum	20.5
			4	Titanium dioxide	0.75
5	Purified water	q.s.
			6	Acetone	q.s.

Above-mentionedly be applicable to embodiment 5 for embodiment 4 described processes.

Embodiment 6:

S.No	Composition	Weight (milligram/unit)
			A)	Medicine layer
1	The sugar ball	160
			2	Lansoprazole (littleization)	30
3	HYDROXY PROPYL METHYLCELLULOSE	17
			4	Purified water	q.s.
B)	Sealing coat
			1	HYDROXY PROPYL METHYLCELLULOSE	32.2

2	Talcum	13.8
			3	Titanium dioxide	11.0
4	Purified water	q.s.
			C)	Enteric coating
1	EUDRAGIT L100-55 (1: 1) 30% disperse system	170
			2	Liquid Macrogol	5.1
3	Talcum	18
			4	Titanium dioxide	5.9
5	Purified water	q.s.
			D)	Mix
1	Talcum	0.3
			2	Colloidal silica	0.3

Process:

Medicine layer

1. HYDROXY PROPYL METHYLCELLULOSE is disperseed lansoprazole after water-soluble.

2. sugared ball is loaded into fluid bed and adds in the multiplexer, the dispersant of spray step 1 is to obtain the medicine layered pills then.

Sealing coat

1. HYDROXY PROPYL METHYLCELLULOSE is disperseed Talcum and titanium dioxide after water-soluble.

2. the medicine layered pills is loaded into fluid bed and adds in the multiplexer, the solution with above-mentioned steps 1 applies then.

Enteric coating

The preparation of Monophalic acid ester of hydroxypropyl coating disperse system:

1. with Talcum, titanium dioxide and Polyethylene Glycol are dispersed in the water.

2. the disperse system with above-mentioned steps 1 is added to methacrylic acid: in the disperse system of ethyl acrylate copolymer, stirred 30 minutes.

With the ball of above-mentioned enteric coating disperse system coating sealing coat, and the ball of enteric coating is filled in the hard gelatine capsule.

Embodiment 7:

S.No	Composition	Weight (milligram/unit)
			A)	The core ball
1	Non Pariel seed	130
			2	Hydroxy propyl cellulose (HPC-L)	6.5
3	Purified water	q.s.
			B)	Medicine layer
1	Omeprazole	40
			2	Hydroxy propyl cellulose (HPC-L)	5
3	# ammonium hydroxide	qs
			4	Purified water	q.s.
C)	Sealing coat
			1	Mannitol	18.15
2	Purified water	q.s.
			D)	Enteric coating
1	Eudragit L30D-55	114.39
			2	Liquid Macrogol	3.43
3	Talcum	12.12
			4	Titanium dioxide	4.04
5	Purified water	q.s.
			6	Colloidal silica	0.44

Evaporate in the # preparation process

Process:

Be sprayed at then on the Non Pariel seed hydroxy propyl cellulose is water-soluble.

Hydroxy propyl cellulose under agitation is dissolved in purified water, continues to stir, add ammonium hydroxide again.Then, under constantly stirring, omeprazole is dispensed in the mixture that makes.A fluid bed add in the multiplexer NonPariel seed with the coating of omeprazole disperse system to form ball.The ball that makes like this applies with mannitol, adds multiplexer enteric coating prescription with a fluid bed then.At last, with ball with insert hard gelatine capsule after colloidal silica mixes.

Embodiment 8:

S.No	Composition	Weight (milligram/unit)
			A)	The core ball
1	Non Pariel seed	130
			2	Hydroxy propyl cellulose (HPC-L)	4.75
3	Polyethylene glycol 6000	0.47
			4	Talcum	1.28
5	Purified water	qs
			B)	Medicine layer
1	Omeprazole	40
			2	Hydroxy propyl cellulose (HPC-L)	5
3	# ammonium hydroxide	qs
			4	Purified water	q.s.
C)	Sealing coat
			1	Mannitol/hydroxy propyl cellulose (HPC-L)/HYDROXY PROPYL METHYLCELLULOSE (HPMC)	18.15
2	Purified water	q.s.
			D)	Enteric coating
1	Eudragit L30D-55	114.39
			2	Liquid Macrogol	3.43
3	Talcum	12.12
			4	Titanium dioxide	4.04
5	Purified water	q.s.
			6	Colloidal silica	0.44

Process:

Hydroxy propyl cellulose and polyethylene glycol 6000 is water-soluble.Talcum is dispensed in the aforesaid solution, then the disperse system that obtains is sprayed on the Non Pariel seed.Hydroxy propyl cellulose under agitation is dissolved in purified water, adds ammonium hydroxide in continuing to stir.Then, under constantly stirring, omeprazole is distributed in the above-mentioned mixture.Add in the multiplexer at a fluid bed above-mentioned disperse system is sprayed onto on the Non Pariel seed to form ball.The ball that makes like this adds multiplexer enteric coating prescription with a fluid bed then with mannitol/HPC-L/HPMC coating.At last, with ball with insert hard gelatine capsule after colloidal silica mixes.

Embodiment 9:

S.No	Composition	Weight (milligram/unit)
			A)	Spray drying
1	Omeprazole	20.0
			2	Mannitol	80.0
3	Polyvinyl pyrrolidone (PVP-K30)/hydroxy propyl cellulose (HPC-L)/HYDROXY PROPYL METHYLCELLULOSE (HPMC)	3.0
			4	# ammonium hydroxide	qs
5	Purified water	qs
			B)	Sheet
1	Mannitol (Pearlitol SD 200 TM)	63.5
			2	The fumaric acid sodium stearyl ester	3.50
C)	Sealing coat (optional)
			1	Hydroxy propyl cellulose (HPC-L)/HYDROXY PROPYL METHYLCELLULOSE (HPMC)/mannitol	8.5
2	Purified water	qs
			D)	Encapsulation layer
1	Hydroxy propyl cellulose (HPC-L)/HYDROXY PROPYL METHYLCELLULOSE (HPMC)	26.0
			2	Purified water	qs
E)	Encapsulation layer
			1	Acryl EZE TM*	18.0
2	Purified water	qs
				Or
1	Eudragit L30D-55	38.15

2	Liquid Macrogol	1.15
			3	Talcum	4.06
4	Titanium dioxide	1.35
			5	Purified water	qs

Evaporate in the # preparation process

* Acryl EZE ^TM*Being the registered trade mark of Colorcon, is a kind of prescription that is used to disperse enteric coating.

Process:

Soluble in water and the adding ammonium hydroxide of mannitol and PVP-K30/HPC-L/HPMC.Omeprazole is added and be distributed in the above-mentioned mixture.With above-mentioned disperse system spray drying, spray-dired capsule mixes with Pearlitol, and is lubricated to form mixture with the fumaric acid sodium stearyl ester, then with this mixture compacting in flakes.Suitable polymers/excipient is applied the benzimidazole sheet that so makes with traditional coating machine.At last, this sheet applies with enteric coating prescription encapsulation.

Embodiment 10:

S.No	Composition	Weight (milligram/unit)
			A)	The medicine coating
1	Pantoprazole	30
			2	HYDROXY PROPYL METHYLCELLULOSE (mix and use)	15
3	HYDROXY PROPYL METHYLCELLULOSE (being coated with application)	15
			4	Purified water
B)	Tabletting (conversion) as small pieces
			1	Coated pantoprazole	60
2	Mannitol	20
			3	Crospovidone	157
4	Microcrystalline Cellulose	157
			5	Talcum	2
6	The fumaric acid sodium stearyl ester	2
			7	Colloidal silica	2
C)	Enteric coating

1	HYDROXY PROPYL METHYLCELLULOSE phthalic acid ester/Eudragit L100-55	21.04
			2	Liquid Macrogol	4.11
3	Talcum	9.19
			4	Titanium dioxide	0.35
5	Purified water	q.s.
			6	Acetone	q.s.

Process:

The medicine coating

1. pantoprazole and HYDROXY PROPYL METHYLCELLULOSE (mix and use) are mixed, granulate to obtain wet group with purified water then.

2. should the group of wetting pass through 30 mesh sieves.

3. HYDROXY PROPYL METHYLCELLULOSE (being coated with application) is dissolved in purified water.

4. the wet group of sieving that step 2 is obtained is loaded into fluid bed and adds multiplexer, and the spray solution with step 3 gets on to obtain the pantoprazole of coating again.

Tabletting

1. with coated pantoprazole, mannitol, microcrystalline Cellulose and crospovidone mix in suitable blender.

2. magnesium stearate and colloidal silica are added in the mixture of step 5.

3. with the mixture tabletting of step 6.

Enteric coating

The preparation of Monophalic acid ester of hydroxypropyl coating disperse system:

1. with Talcum, titanium dioxide and Liquid Macrogol are dispensed in the acetone.

2. Monophalic acid ester of hydroxypropyl is dissolved in the acetone.

3. the disperse system with step 1 joins in the disperse system of step 2, adds water then and mixes.

The tablet that so makes is applied with enteric coating disperse system encapsulation, and the suitable sheet number that will contain the unit required dosage then is packed in the hard gelatine capsule.Several specific form of the present invention is illustrated and describes, and various modification of the present invention and combinations to describing in detail in this description obviously can not deviate from spirit of the present invention and leave scope of the present invention.Other optional inessential component be introduced in the described mixture, to reach the purpose attractive in appearance and/or that make of adoring.These inessential components comprise stain, diluent, lubricant, and fluidizer. there is any to be expected in addition, that is exactly any one characteristic of creative variation as described herein or property combination can be got rid of outside claim specifically arbitrarily, and is depicted as the restriction negating.Therefore, should not think restriction, unless additional claim is arranged to invention.

Claims (46)

1. stable oral benzimidazole pharmaceutical composition is characterized in that described compositions comprises:

(a) include the core of benzimidazole compound, a kind of water-soluble substantially material and, optional, one or more pharmaceutically acceptable excipient, wherein said core are not alkaline;

(b) sealing coat around core, comprise a kind of water-soluble substantially material and, optional, one or more pharmaceutically acceptable excipient and

(c) enteric coating round sealing coat wherein, has at least one to comprise water-soluble substantially material and do not contain any pharmaceutically acceptable excipient in core and the sealing coat.

2. compositions as claimed in claim 1 is characterized in that described benzimidazole compound is selected from omeprazole, lansoprazole, pantoprazole, one or more in the rabeprazole, and single enantiomer.

3. compositions as claimed in claim 1 is characterized in that, described one or more pharmaceutically acceptable excipient are selected from one or more diluent, disintegrating agent, adhesive and lubricant.

4. compositions as claimed in claim 3 is characterized in that described diluent is selected from saccharide, sugar alcohols, one or more in cellulose derivative and the starch.

5. compositions as claimed in claim 4 is characterized in that described saccharide is selected from dextrose, one or more in glucose and the lactose.

6. compositions as claimed in claim 4 is characterized in that described sugar alcohol is selected from sorbitol, one or more in xylitol and the mannitol.

7. compositions as claimed in claim 4 is characterized in that described cellulose derivative is selected from one or more in pulverous cellulose and the microcrystalline Cellulose.

8. compositions as claimed in claim 4 is characterized in that described starch is selected from corn starch, the starch of pre-gelatinization and in the corn starch one or more.

9. compositions as claimed in claim 3 is characterized in that described disintegrating agent is selected from Explotab, one or more in cross-linked carboxymethyl cellulose sodium and the corn starch.

10. compositions as claimed in claim 3 is characterized in that described adhesive is selected from cellulose derivative, natural gum, one or more in water-soluble vinyl pyrrolidone polymer and the saccharide.

11. compositions as claimed in claim 10 is characterized in that, described cellulose derivative comprises HYDROXY PROPYL METHYLCELLULOSE, one or more in hydroxy propyl cellulose and the methylcellulose.

12. compositions as claimed in claim 10 is characterized in that, described natural gum comprises xanthane gum, one or more in Radix Acaciae senegalis and the tragacanth gum.

13. compositions as claimed in claim 10 is characterized in that, described water soluble vinyl pyrrolidone polymer comprises one or more in the copolymer of polyvinyl pyrrolidone and vinyl pyrrolidone and vinyl acetate.

14. compositions as claimed in claim 10 is characterized in that, described saccharide comprises one or more in sorbitol and the mannitol.

15. compositions as claimed in claim 3 is characterized in that, described lubricant comprises magnesium stearate, Talcum, one or more in fumaric acid sodium stearyl ester and the colloidal silica.

16. compositions as claimed in claim 1 is characterized in that, described water-soluble substantially material comprises one or more in water-soluble substantially polymer and the water-soluble substantially excipient.

17. compositions as claimed in claim 16, it is characterized in that, described water-soluble substantially polymer is selected from HYDROXY PROPYL METHYLCELLULOSE, hydroxy propyl cellulose, polyvinyl pyrrolidone, sodium alginate, sodium carboxy methyl cellulose, and in the copolymer of vinyl pyrrolidone and vinyl acetate one or more.

18. compositions as claimed in claim 17 is characterized in that, described water-soluble excipient comprises lactose, mannitol, sorbitol, one or more in sucrose and the glucose.

19. compositions as claimed in claim 1 is characterized in that, described core comprises water-soluble substantially material and without any pharmaceutically acceptable excipient.

20. compositions as claimed in claim 1 is characterized in that, described sealing coat comprises water-soluble substantially material and without any pharmaceutically acceptable excipient.

21. a stable oral benzimidazole pharmaceutical composition is characterized in that described compositions comprises:

(a) include the core of benzimidazole compound, a kind of water-soluble substantially material and, optional, one or more pharmaceutically acceptable excipient, wherein said core be not alkaline and

(b) enteric coating that centers on core and directly contact with core does not have the sealing coat between core and enteric coating in the wherein said prescription.

22. compositions as claimed in claim 21 is characterized in that, described benzimidazole compound is selected from omeprazole, lansoprazole, pantoprazole, one or more in the rabeprazole, and single enantiomer.

23. compositions as claimed in claim 21 is characterized in that, the pharmaceutically acceptable excipient of one or more of described core is selected from diluent, disintegrating agent, one or more in adhesive and the lubricant.

24. compositions as claimed in claim 23 is characterized in that, described diluent is selected from saccharide, sugar alcohols, one or more in cellulose derivative and the starch.

25. compositions as claimed in claim 24 is characterized in that, described saccharide is selected from dextrose, one or more in glucose and the lactose.

26. compositions as claimed in claim 24 is characterized in that, described sugar alcohol is selected from sorbitol, one or more in xylitol and the mannitol.

27. compositions as claimed in claim 24 is characterized in that, described cellulose derivative is selected from one or more in pulverous cellulose and the microcrystalline Cellulose.

28. compositions as claimed in claim 24 is characterized in that, described starch is selected from corn starch, the starch of pre-gelatinization and in the corn starch one or more.

29. compositions as claimed in claim 23 is characterized in that, described disintegrating agent is selected from Explotab, one or more in cross-linked carboxymethyl cellulose sodium and the corn starch.

30. compositions as claimed in claim 32 is characterized in that, described adhesive is selected from cellulose derivative, natural gum, one or more in water-soluble vinyl pyrrolidone polymer and the saccharide.

31. compositions as claimed in claim 30 is characterized in that, described cellulose derivative comprises HYDROXY PROPYL METHYLCELLULOSE, one or more in hydroxy propyl cellulose and the methylcellulose.

32. compositions as claimed in claim 30 is characterized in that, described natural gum comprises xanthane gum, one or more in Radix Acaciae senegalis and the tragacanth gum.

33. compositions as claimed in claim 30 is characterized in that, described water-soluble vinyl pyrrolidone polymer comprises one or more in the copolymer of polyvinyl pyrrolidone and vinyl pyrrolidone and vinyl acetate.

34. compositions as claimed in claim 30 is characterized in that, described saccharide comprises one or more in sorbitol and the mannitol.

35. compositions as claimed in claim 23 is characterized in that, described lubricant comprises magnesium stearate, Talcum, one or more in fumaric acid sodium stearyl ester and the colloidal silica.

36. a method for preparing stable oral benzimidazole pharmaceutical composition, its step comprises:

(a) with benzimidazole compound, substantially water-soluble material, and optional, one or more pharmaceutically acceptable excipient are dispersed in and obtain a kind of disperse system in the aqueous medium, this disperse system of spray drying, and with one or more pharmaceutically acceptable mixed with excipients extruding;

(b) the sealing coat coating core that forms with water-soluble substantially material and optional pharmaceutically acceptable excipient; Then

(c), have at least one to comprise water-soluble substantially material and do not contain any pharmaceutically acceptable excipient in its SMIS and the sealing coat with enteric applying coating step (a) or the product that (b) obtains.

37. preparation method as claimed in claim 36 is characterized in that, described benzimidazole compound is selected from omeprazole, lansoprazole, pantoprazole, one or more in the rabeprazole, and single enantiomer.

38. preparation method as claimed in claim 36 is characterized in that, the pharmaceutically acceptable excipient of one or more of described core is selected from diluent, disintegrating agent, one or more in adhesive and the lubricant.

39. preparation method as claimed in claim 38 is characterized in that, described diluent is selected from saccharide, sugar alcohols, one or more in cellulose derivative and the starch.

40. preparation method as claimed in claim 38 is characterized in that, described disintegrating agent is selected from Explotab, one or more in cross-linked carboxymethyl cellulose sodium and the corn starch.

41. preparation method as claimed in claim 38 is characterized in that, described adhesive is selected from cellulose derivative, natural gum, one or more in water-soluble vinyl pyrrolidone polymer and the saccharide.

42. preparation method as claimed in claim 38 is characterized in that, described lubricant comprises magnesium stearate, Talcum, one or more in fumaric acid sodium stearyl ester and the colloidal silica.

Take a kind of pharmaceutical composition 43. the excretory method of gastric acid inhibitory, this method comprise, this pharmaceutical composition comprises:

(a) include the core of benzimidazole compound, water-soluble substantially material and, optional, one or more pharmaceutically acceptable excipient, its SMIS are not alkaline;

(b) sealing coat around core, comprise water-soluble substantially material and, optional, one or more pharmaceutically acceptable excipient and

(c) enteric coating round sealing coat,

Wherein, have at least one to contain water-soluble substantially material and do not contain pharmaceutically acceptable excipient in core and the sealing coat.

44. method as claimed in claim 43 is characterized in that, described benzimidazole compound is selected from omeprazole, lansoprazole, pantoprazole, one or more in the rabeprazole, and single enantiomer.

Take a kind of pharmaceutical composition 45. the excretory method of gastric acid inhibitory, this method comprise, this pharmaceutical composition comprises:

(a) include the core of benzimidazole compound, water-soluble substantially material and, optional, one or more pharmaceutically acceptable excipient, its SMIS are not alkaline;

(b) enteric coating that centers on core and directly contact with core, wherein said prescription does not have sealing coat between core and enteric coating.

46. method as claimed in claim 45 is characterized in that, described benzimidazole compound is selected from omeprazole, lansoprazole, pantoprazole, one or more in the rabeprazole, and single enantiomer.