CN1767817A - Oral pharmaceutical preparation for proton pump antagonist - Google Patents

Abstract

The invention relates to novel dosage forms for proton pump antagonists.

Description

The oral drug preparation that is used for proton pump antagonist

Technical field

The present invention relates to be used for the many particle form of proton pump antagonist or the oral drug preparation of tablet form.

Background technology

Irreversible proton pump inhibitor (H ⁺/ K ⁺Atpase inhibitor, PPI), especially for example at EP-A-0005129, disclosed pyridine among EP-A-0166287, EP-A-0174726 and the EP-A-0268956-2-ylmethyl sulfenyl-1H-benzimidazole is because it suppresses H ⁺/ K ⁺The effect of-ATP enzyme has importance to increase the treatment of diseases that causes because of gastric acid secretion.Irreversible proton pump inhibitor be can with cause sour excretory enzyme (H in the stomach ⁺/ K ⁺-ATP enzyme) covalency (therefore irreversible) bonded material [Wurst etc. is for example seen in the description of the mechanism of action, The YaleJournal of Biology and Medicine 69, (1996), 233-243].The example of existing this active component is 5-methoxyl group-2-[(4-methoxyl group-3 on the market, 5-dimethyl-2-pyridine radicals) methyl sulfenyl]-1H-benzimidazole (INN: omeprazole), 5-difluoro-methoxy-2-[(3,4-dimethoxy-2-pyridine radicals) methyl sulfenyl]-(INN: pantoprazole) 2-[3-methyl-4-(2 for the 1H-benzimidazole, 2,2-trifluoro ethoxy-2-pyridine radicals) methyl sulfenyl]-the 1H-benzimidazole (INN: lansoprazole) and 2-{[4-(3-methoxy propoxy)-3-picoline-2-yl] the methyl sulfenyl-1H-benzimidazole (INN: rabeprazole).

Because they have intensive decomposition tendency in neutrality, particularly sour environment, and form the catabolite of altitudinal belt color, so must protect the effect of this irreversible proton pump inhibitor acid and alkali for oral formulations.For highly sour unsettled pyridine-2-ylmethyl sulfenyl-1H-benzimidazole, they also must perhaps with alkaline matter, be processed into tablet core or granule with its alkali metal salt form of sodium salt for example.Have carboxyl because be suitable as the material of enteric coating, can produce enteric coating part even consoluet problem internally, because inside is alkaline environment, and free carboxyl promotes the decomposition of active component.Therefore must between enteric coating and alkaline tablet core or granule, form the intermediate layer (sub-coat) of a sealing.EP-A 0,244 380 proposes, and before applying enteric layer, will comprise the core with the blended active component of alkali compounds or its alkali metal salt earlier, dissolve in water or the pharmaceutically useful nonacid inert substance coating of disintegrate rapidly with one deck at least.This intermediate layer plays a part the pH relief area, spreads hydroxyl that the hydrion of coming in can spread out with alkaline core therein from the outside from effect.In order to increase the buffer capacity in intermediate layer, proposed in the intermediate layer, to add buffer substance.Utilize this method in fact can obtain the preparation of quite stable.But,,, also must use quite thick intermediate layer in order to prevent to produce ugly variable color even have only slight decomposition.In addition, need not do very big effort to avoid the trace moisture content of production period.

As described in when beginning, so-called irreversible proton pump inhibitor has common alkali formula chemical constitution (they are pyridylmethyl iodosobenzene benzimidazole compounds) basically, in addition, also has so-called reversible H ⁺/ K ⁺-atpase inhibitor, they have different alkali formula chemical constitutions, and shown in its title, combine with the enzyme that causes gastric acid secretion is reversible, therefore [mechanism of action is for example seen Wurst etc. to be also referred to as proton pump antagonist or APA (acid pump antagonist), The YaleJournal of Biology and Medicine 69 (1996), 233-243].Reversible proton pump inhibitor has explanation in following patent document for example:

DE-A 3917232，

EP-A-0399287，EP-A-0387821，JP-A-3031280，JP-A-2270873，EP-A-0308917，EP-A-0288989，

EP-A-0228006，EP-A-0204285，EP-A-0165545，EP-A-0125758，EP-A-0120589，EP-A-0509974，

DE-A 3822036，EP-A-0537532，EP-A-0535529，JP-A-3284888，JP-A-3284622，US-A-4,833,149，

EP-A-0261912，WO-A-9114677，WO-A-9315055，WO-A-9315071，WO-A-9315056，WO-A-9312090，

WO-A-9212969，WO-A-9118887，EP-A-0393926，EP-A-0307078，U8-A-5,041,442，EP-A-0266890，

WO-A-9414795，EP-A-0264883，EP-A-0033094，EP-A-0259174，EP-A-0330485，WO-A-8900570，

EP-A-0368158，WO-A-9117164，WO-A-9206979，WO-A-9312090，WO-A-9308190，WO-A-9418189，

DE-A 3011490, US-A-4, and 484,372, EP-A-0068378 and WO-A-9424130,

EP 0841904 B1 has described a kind of pharmaceutical composition, said composition can postpone to discharge reversible proton pump inhibitor and with the active antimicrobial ingredient of being used for the treatment of of its associating by the microbial disease of screw rod.

WO-A-95/27714 relates to tricyclic antidepressants imidazo [1, the 2-a] pyridine of replacement, and they reversibly suppress the gastric acid secretion of external source or interior source excitation.An example that is used for the tablet preparation is disclosed at the 38th page.

WO-A-0245693 discloses the novel formulation that active component is used, and wherein active component is evenly dispersed in the excipient substrate that is made of one or more excipient that are selected from aliphatic alcohol, triglyceride, glycerol partial ester and fatty acid ester basically.It is said that this substrate is particularly suitable for being called that active component of reversible proton pump inhibitor or APA (acid pump antagonist).Mentioned quickly disintegrated tablet in the literary composition based on these preparations.

Summary of the invention

Now find unexpectedly,, when active component is stabilized in the dosage form with alkaline excipient, obtained stable especially peroral dosage form for proton pump antagonist (APA).

Therefore, one aspect of the present invention is the stable peroral dosage form of using for reversible proton pump inhibitor, wherein contain the proton pump antagonist (APA) and the excipient of effective quantity, wherein this proton pump antagonist is stabilized in this dosage form with one or more alkaline excipient.

Also be surprised to find that, for oral administration, by taking proton pump antagonist (APA), the benefit that can obtain to treat with quickly disintegrated dosage form (preferably discharging active component immediately).Particularly, when treatment increases the disease that causes by gastric acid secretion, observe have an effect faster and eliminate pain faster.

Therefore, another aspect of the present invention is a kind of quickly disintegrated dosage form, makes the quickly disintegrated excipient of dosage form when wherein containing the proton pump antagonist (APA) of effective quantity and this dosage form of oral absorption, also contains other excipient in the time of suitably.Preferred this dosage form discharges active component immediately.

According to the present invention, irreversible proton pump inhibitor (H ⁺/ K ⁺-ATP inhibitor, PPI) be can with cause sour excretory enzyme (H in the stomach ⁺/ K ⁺-ATP enzyme) the bonded material of covalency (therefore irreversible) [Wurst etc., The Yale Journalof Biology and Medicine 69,3,1996,233-243 are for example seen in the explanation of the possible mechanism of action].This for example is meant disclosed pyridine-2-base-methyl sulfenyl-1H-benzimidazole compound among EP-A-0005129, EP-A-0166287, EP-A-0174726 and the EP-A-0268956 especially.The example that can mention is 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl sulfenyl]-1H-benzimidazole (INN: omeprazole), 5-difluoro-methoxy-2-[(3,4-dimethoxy-2-pyridine radicals) methyl sulfenyl]-(INN: pantoprazole) 2-[3-methyl-4-(2 for the 1H-benzimidazole, 2,2-trifluoro ethoxy-2-pyridine radicals) methyl sulfenyl]-the 1H-benzimidazole (INN: lansoprazole) and 2-{[4-(3-methoxy propoxy)-3-picoline-2-yl] the methyl sulfenyl-1H-benzimidazole (INN: rabeprazole).

Proton pump antagonist also is called reversible proton pump inhibitor or APA (sour pump antagonist) according to the present invention, for the present invention, be can with the enzyme H that causes gastric acid secretion ⁺/ K ⁺The reversible bonded active component of-ATP enzyme [for example Wurst etc., The Yale Journal of Biology and Medicine 69,3,1996,233-243 are seen in the explanation of the possible mechanism of action of APA].According to the present invention, proton pump antagonist one speech not only comprises active component itself, also comprises its pharmaceutically useful salt and solvate (especially hydras) etc.Mentioned the example of proton pump antagonist in the following document:

EP 33094，EP 204285，EP 228006，EP 233760，EP 259174，EP 266326，EP 266890，EP 270091，

EP 307078，EP 308917，EP 330485，US 4728658，US 5362743，WO 9212969，WO 9414795，

WO 9418199，WO 9429274，WO 9510518，WO 9527714，WO 9603405，WO 9604251，WO 9605177，

WO 9703074，WO 9703076，WO 9747603，WO 9837080，WO 9642707，WO 9843968，WO 9854188，

WO 9909029，WO 9928322，WO 9950237，WO 9951584，WO 9955705，WO 9955706，WO 0001696，

WO 0010999，WO 0011000，WO 0017200，WO 0026217，WO 0029403，WO 0063211，WO 0077003，

WO 0158901，WO 0172754，WO 0172755，WO 0172756，WO 0172757，WO 02034749，WO 02060440，

WO 02060441 and WO 02060442.

The example of the proton pump antagonist that can mention is specified numbering according to its international non-proprietary nomenclature of drug (INN) or its, is following chemical compound:

AG-2000(EP 233760)，AU-461(WO 9909029)，BY112(WO 9842707)，soraprazan(BY359)(WO 0017200)，CP-113411(US 5362743)，DBM-819(WO 0001896)，KR-60436(WO9909029)，pumaprazole(WO 9418199)，SKF-96067(EP 259174)，SKF-96356(EP 307078)，SKF-97574(EP 330485)，T-330(EP 270091)，T-776(EP 270091)，WY-27198(US 4728858)，YH-1885(WO 9605177)，YJA-20379-8(WO 9703074)，YM-19020(EP 266890)

With 2,3-dimethyl-8-(2-ethyl-6-methyl benzyl amino) imidazo [1,2-a] pyridine-6-Methanamide (WO 02060440).

That be worth proposition in this respect especially is compd A U-461, Soraprazan (BYK61359), DBM-819, KR-60436, T-330, YH-1885, YJA 20379-8 and 2,3-dimethyl-8-(2-ethyl-6-methyl-benzyl amino) imidazo [1,2-a] pyridine-6-Methanamide.

In following patent application, address and propose claim for the significant especially class APA of the present invention:

WO 9842707, and WO 9854188, and WO 0017200, and WO 0026217, and WO 0063211, WO0172754, WO 0172755, and WO 0172766, and WO 0172757, and WO 02034749, WO 03014120, and WO 03016310, and WO 03014123, WO 03068774 and WO 03091253.

For the present invention, the example of the APA that can mention is following chemical compound:

(9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7S, 8R,

(7R, 8R, 9R)-and 3-methylol-7,8-dihydroxy-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(9R)-7,8-isopropylidene dioxy-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7S, 8R,

7,8-dihydroxy-9-phenyl-2,3-dimethyl-7H-8,9-dihydropyran be [2,3-c] imidazo [1,2-a] pyridine also,

(9R)-2,3-dimethyl-8-hydroxyl-7-methoxyl group-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7R, 8R,

(9S)-2,3-dimethyl-8-hydroxyl-7-methoxyl group-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7S, 8S,

(9R)-2,3-dimethyl-8-hydroxyl-7-methoxyl group-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7S, 8R,

(9S)-2,3-dimethyl-8-hydroxyl-7-methoxyl group-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7R, 8S,

(9R)-2,3-dimethyl-7-ethyoxyl-8-hydroxyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7R, 8R,

(9R)-2,3-dimethyl-7-ethyoxyl-8-hydroxyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7S, 8R,

(9R)-2,3-dimethyl-8-hydroxyl-7-(2-methoxy ethoxy)-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7R, 8R,

(9S)-2,3-dimethyl-8-hydroxyl-7-(2-methoxy ethoxy)-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7S, 8S,

(9R)-2,3-dimethyl-8-hydroxyl-7-(2-methoxy ethoxy)-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7S, 8R,

(9S)-2,3-dimethyl-8-hydroxyl-7-(2-methoxy ethoxy)-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7R, 8S,

(9R)-2,3-dimethyl-8-hydroxyl-7-(2-propoxyl group)-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7S, 8R,

(9R)-2,3-dimethyl-7,8-dimethoxy-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7R, 8R,

(7R, 8R, 9R)-2, and 3-dimethyl-8-hydroxyl-7-(2-methyl mercapto ethoxy base)-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7S, 8R, 9R)-2, and 3-dimethyl-8-hydroxyl-7-(2-methyl mercapto ethoxy base)-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-2, and 3-dimethyl-8-hydroxyl-7-(2-methylsulfinyl ethyoxyl)-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7S, 8R, 9R)-2, and 3-dimethyl-8-hydroxyl-7-(2-methyl sulfenyl ethyoxyl)-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(9R)-2,3-dimethyl-8-hydroxyl-7-(ethylmercapto group)-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7R, 8R,

(9R)-2,3-dimethyl-8-hydroxyl-7-(ethylmercapto group)-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7S, 8R,

(7R, 8R, 9R)-2, and 3-dimethyl-8-hydroxyl-7-(2,2, the 2-trifluoro ethoxy)-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7S, 8R, 9R)-2, and 3-dimethyl-8-hydroxyl-7-(2,2, the 2-trifluoro ethoxy)-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7S, 8R, 9R)-and 8-acetoxyl group-7-(2-methoxy ethoxy)-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 8-acetoxyl group-7-(2-methoxy ethoxy)-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 8-acetoxyl group-7-methoxyl group-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 8-acetoxyl group-7-ethyoxyl-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 7-(2-methoxy ethoxy)-2,3-dimethyl-8-propionyloxy-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 8-benzoyloxy-7-(2-methoxy ethoxy)-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7S, 8R, 9R)-and 8-benzoyloxy-7-(2-methoxy ethoxy)-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 8-methoxyl group carbon acyloxy-7-(2-methoxy ethoxy)-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7S, 8R, 9R)-and 8-methoxyl group carbon acyloxy-7-(2-methoxy ethoxy)-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 8-benzoyloxy-7-methoxyl group-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7S, 8R, 9R)-and 8-benzoyloxy-7-methoxyl group-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 7-(2-methoxy ethoxy)-2,3-dimethyl-8-(4-nitrobenzoyl acyloxy)-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7S, 8R, 9R)-and 7-(2-methoxy ethoxy)-2,3-dimethyl-8-(4-nitrobenzoyl acyloxy)-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7S, 8R, 9R)-and 7-(2-methoxy ethoxy)-2,3-dimethyl-8-(3-nitrobenzoyl acyloxy)-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 7-(2-methoxyethoxy)-2,3-dimethyl-8-(3-nitrobenzoyl acyloxy)-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7S, 8R, 9R)-and 7-methoxyl group-2,3-dimethyl-8-(3-nitrobenzoyl acyloxy)-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 7-methoxyl group-2,3-dimethyl-8-(3-nitrobenzoyl acyloxy)-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7S, 8R, 9R)-and 7-(2-methoxyethoxy)-2,3-dimethyl-8-(4-methoxybenzoyl oxygen base)-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 7-(2-methoxyethoxy)-2,3-dimethyl-8-(4-methoxybenzoyl oxygen base)-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 7-(2-methoxyethoxy)-2,3-dimethyl-8-(N, N-dimethylaminomethyl carbon acyloxy)-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7S, 8R, 9R)-and 7-(2-methoxyethoxy)-2,3-dimethyl-8-(N, N-dimethylaminomethyl carbon acyloxy)-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7S, 8R, 9R)-and 7-(2-methoxyethoxy)-8-(N, N-diethylamino carbon acyloxy)-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 7-(2-methoxyethoxy)-8-(N, N-diethylamino carbon acyloxy)-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 8-ethylamino carbon acyloxy-7-(2-methoxyethoxy)-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 8-benzoyloxy-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7H-8,9-dihydropyran be [2,3-c] imidazo [1,2-a] pyridine also,

(7S, 8R, 9R)-and 8-benzoyloxy-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7H-8,9-dihydropyran be [2,3-c] imidazo [1,2-a] pyridine also,

(7R, 8R, 9R)-and 8-[4-(methoxycarbonyl group) benzoyloxy]-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7H-8,9-dihydropyran be [2,3-c] imidazo [1,2-a] pyridine also,

(7S, 8R, 9R)-and 8-[4-(methoxycarbonyl group) benzoyloxy]-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-7H-8,9-dihydropyran be [2,3-c] imidazo [1,2-a] pyridine also,

(9R)-2,3-dimethyl-7-methoxyl group-8-methoxyl group acetoxyl group-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7S, 8R,

(7R, 8R, 9R)-and 8-(N, N-diethylamino carbon acyloxy)-2,3-dimethyl-7-methoxyl group-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7S, 8R, 9R)-and 8-(N, N-diethylamino carbon acyloxy)-2,3-dimethyl-7-methoxyl group-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 7-methoxyl group-8-methoxyl group carbon acyloxy-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7S, 8R, 9R)-and 7-methoxyl group-8-methoxyl group carbon acyloxy-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(9R)-2,3-dimethyl-8-formyloxy-7-methoxyl group-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7R, 8R,

(9R)-2,3-dimethyl-8-formyloxy-7-methoxyl group-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7S, 8R,

(7R, 8R, 9R)-and 8-benzoyloxy-2,3-dimethyl-7-methoxyl group-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(9R)-2,3,8-trimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7R, 8S,

(9R)-2,3-dimethyl-8-benzyl-7,8-dihydroxy-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7S, 8S,

(7R, 8S, 9R)-2,3, and 8-trimethyl-7,8-0,0-isopropylidene-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(9R)-2,3,8-trimethyl-7-(2-methoxyethoxy)-8-hydroxyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7S, 8S,

(9R)-2,3,8-trimethyl-7-methoxyl group-8-hydroxyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7S, 8S,

(9R)-2,3,7-trimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7R, 8R,

(7R, 8R, 9R)-2,3,7-trimethyl-7,8-[1,3] dioxole also-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(8S, 9R)-2,3-dimethyl-8-hydroxyl-7-methylene-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(9R)-2,3,7-trimethyl-7,8-dihydroxy-9-phenyl-7H-8,9-dihydropyran be [2,3-c] imidazo [1,2-a] pyridine also for 7S, 8R,

(9R)-2,3,7-trimethyl-7,8-dihydroxy-9-phenyl-7H-8,9-dihydropyran be [2,3-c] imidazo [1,2-a] pyridine also for 7R, 8R,

(9R)-2,3-dimethyl-7,8-dihydroxy-7,9-diphenyl-7H-8,9-dihydropyran be [2,3-c] imidazo [1,2-a] pyridine also for 7S, 8R,

(9R)-2,3-dimethyl-7-(2 ', 2 '-dimethyl vinyl)-7,8-dihydroxy-9-phenyl-7H-8,9-dihydropyran be [2,3-c] imidazo [1,2-a] pyridine also for 7S, 8R,

(9R)-2,3-dimethyl-7,8-O-isopropylidene-9-phenyl-7-vinyl-7H-8,9-dihydropyran be [2,3-c] imidazo [1,2-a] pyridine also for 7R, 8R,

(9R)-2,3-dimethyl-8-hydroxyl-7-(2-methoxyethoxy)-9-phenyl-7H-8,9-dihydropyran be [2,3-c] imidazo [1,2-a] pyridine also for 7R, 8R,

(9R)-2,3-dimethyl-8-hydroxyl-7-(2-methoxyethoxy)-9-phenyl-7H-8,9-dihydropyran be [2,3-c] imidazo [1,2-a] pyridine also for 7S, 8R,

(9R)-2,3-dimethyl-8-hydroxyl-7-ethyoxyl-9-phenyl-7H-8,9-dihydropyran be [2,3-c] imidazo [1,2-a] pyridine also for 7R, 8R,

(9R)-2,3-dimethyl-8-hydroxyl-7-ethyoxyl-9-phenyl-7H-8,9-dihydropyran be [2,3-c] imidazo [1,2-a] pyridine also for 7S, 8R,

(9R)-2,3-dimethyl-8-hydroxyl-7-(2-methoxy propoxyl group)-9-phenyl-7H-8,9-dihydropyran be [2,3-c] imidazo [1,2-a] pyridine also for 7R, 8R,

(9R)-2,3-dimethyl-8-hydroxyl-7-(2-methoxy propoxyl group)-9-phenyl-7H-8,9-dihydropyran be [2,3-c] imidazo [1,2-a] pyridine also for 7S, 8R,

(9R)-2,3-dimethyl-8-hydroxyl-7-(2-propoxyl group)-9-phenyl-7H-8,9-dihydropyran be [2,3-c] imidazo [1,2-a] pyridine also for 7R, 8R,

(9R)-2,3-dimethyl-8-hydroxyl-7-(2-propoxyl group)-9-phenyl-7H-8,9-dihydropyran be [2,3-c] imidazo [1,2-a] pyridine also for 7S, 8R,

(9R)-2,3-dimethyl-8-hydroxyl-7-butoxy-9-phenyl-7H-8,9-dihydropyran be [2,3-c] imidazo [1,2-a] pyridine also for 7R, 8R,

(9R)-2,3-dimethyl-8-hydroxyl-7-butoxy-9-phenyl-7H-8,9-dihydropyran be [2,3-c] imidazo [1,2-a] pyridine also for 7S, 8R,

(9R)-7,8-dihydroxy-6-methoxy-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7S, 8R,

(9R)-7,8-dihydroxy-6-methoxy-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7R, 8R,

(7S, 8R, 9R)-and 8-hydroxyl-7-methoxyl group-6-methoxy-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 8-hydroxyl-7-methoxyl group-6-methoxy-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 8-hydroxyl-7-(2-methoxy ethoxy)-6-methoxy-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7S, 8R, 9R)-and 8-hydroxyl-7-(2-methoxyethoxy)-6-methoxy-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 8-hydroxyl-7-ethyoxyl-6-methoxy-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7S, 8R, 9R)-and 8-hydroxyl-7-ethyoxyl-6-methoxy-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

7,8-dihydroxy-2,3-dimethyl-9-(3-thienyl)-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

7-hydroxyl-2,3-dimethyl-9-(3-thienyl)-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

9-(3-furyl)-7-hydroxyl-2,3-dimethyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 8-hydroxyl-7-[2-(2-methoxyethoxy) ethyoxyl]-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(7S, 8R, 9R)-and 8-hydroxyl-7-[2-(2-methoxyethoxy) ethyoxyl]-2,3-dimethyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also,

(9R)-7,8-dihydroxy-2-methyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7R, 8R,

(7S, 8R, 9R)-and 8-hydroxy-2-methyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 8-hydroxy-2-methyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 3-bromo-8-hydroxyl-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 3-chloro-8-hydroxyl-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 3-bromo-7-hydroxyl-8-(2-methoxyethoxy)-2-methyl-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 3-chloro-8-hydroxyl-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7H-8, the 9-dihydropyran is [2,3-c] imidazo [1,2-a] pyridine also,

(7R, 8R, 9R)-and 8-hydroxyl-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7H-8, the 9-dihydropyran is [2,3-c] imidazo [1,2-a] pyridine also,

(9R)-7,8-dihydroxy-2-methyl-9-phenyl-7H-8,9-dihydropyran be [2,3-c] imidazo [1,2-a] pyridine also for 7R, 8R,

(9R)-7,8-dihydroxy-2-methyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7S, 8R,

(7R, 8R, 9R)-and 8-hydroxyl-7-methoxyl group-2-methyl-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7S, 8R, 9R)-and 8-hydroxyl-7-methoxyl group-2-methyl-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 3-methylol-8-hydroxyl-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 3-methylol-8-hydroxyl-7-(2-hydroxyl-oxethyl)-2-methyl-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(9R)-2,3-dimethyl-8-hydroxyl-7-(2-hydroxyl-oxethyl)-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7R, 8R,

(9R)-3,9-diphenyl-8-hydroxyl-7-(2-methoxyethoxy)-2-methyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7R, 8R,

(9R)-7,8-dihydroxy-2-methoxy-3-methyl-9-phenyl-7,8,9,10-imidazolidine be [1,2-h] [1,7] benzodiazine also for 7R, 8R,

(7S, 8R, 9R)-and 8-hydroxyl-7-(2-methoxyethoxy)-2-methoxy-3-methyl-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 8-hydroxyl-7-(2-methoxyethoxy)-2-methoxy-3-methyl-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7S, 8R, 9R)-and 7-ethyoxyl-8-hydroxyl-2-methoxy-3-methyl-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(7R, 8R, 9R)-and 7-ethyoxyl-8-hydroxyl-2-methoxy-3-methyl-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine also,

(8S)-2,3-dimethyl-8-phenyl-7,8-dihydro-6H-9-oxa--1,3a-diazacyclo pentadiene be [a] naphthalene-5-carboxylic acid diformamide also,

8-[(1S, 2S)-2,3-dihydro-2-hydroxyl-1-indenes oxygen base-6-(N, N-dimethylamino carbonyl)-2,3-dimethyl-imidazo [1,2-a] pyridine,

6-(N, N-dimethylamino carbonyl)-4-(2,6-dimethylbenzyl amino)-1,2-dimethyl-1H-benzimidazole,

And the pharmaceutically useful salt of these chemical compounds.

An example of the preferred proton pump antagonist that can propose be chemical compound (7R, 8R, 9R)-2,3-dimethyl-8-hydroxyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9, the 10-imidazolidine is [1,2-h] [1,7] benzodiazine (INN:soraprazan) also.

For the present invention, proton pump antagonist can exist with the form of itself or with its salt and/or solvate forms such as (for example hydras).Most of reversible proton pump inhibitors are alkali compoundss.Specially suitable salt is all acid-addition salts.It is to be noted the pharmaceutically useful salt of inorganic and organic acid that usually in pharmaceutical technology, uses especially.Suitable is and the water solublity and the water-insoluble salt of acid, the example of acid has hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, acetic acid, citric acid, the D-gluconic acid, benzoic acid, 2-(4-(2-hydroxybenzoyl)) benzoic acid, butanoic acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, pamoic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxyl-2-naphthoic acid, these acid with etc. the quantity or the different quantity of mol ratio be used to prepare salt, this depends on that this acid is monoacid or polyprotic acid, and wishes to obtain which kind of salt.

Dosage form of the present invention preferably is used for the solid dosage forms of oral many particle form (multiple-units dosage pattern) or tablet form.The example that can mention is tablet, coated tablet, colored tablet, pill, microplate capsule or granule capsule particularly.An embodiment preferred comprises having film-coated tablet and pill or colored tablet.In film-coated situation, peplos does not preferably hinder the quick disintegrate of dosage form.At proton pump antagonist is the situation of photosensitive material, and tablet of the present invention or pill contain the film coating that a protection active component exempts from photolysis.Special preferably painted at this film coating of this situation.In another embodiment, comprise a kind of coloring agent in the process of preparation tablet core or pill, solid dosage forms is colored.Opposite with the dosage form described in the EP-0841904-B1, dosage form of the present invention is not display delay release preferably, but discharge active component immediately.Therefore the present invention preferably discharges the rapidly disintegrating dosage form (discharging solid oral dosage form immediately) of active component immediately.The maximum disintegration time of this dosage form in water (37 ℃) is preferably 15,10,5,4 or 3 minutes.When using in temperature is 15-25 ℃ water, disintegration time preferably is no more than 15,10,5,4 or 3 minutes (disintegration time of tablet can be according to the pharmacopeia monograph, preferably measures according to disclosed standard step among the European Pharmacopoeia the 4th edition).After 15 minutes, dosage form preferably discharges the active component more than or equal to 60% in the hydrochloric acid of 0.1N, more preferably greater than or equal 75%, be preferably greater than especially or equal 80%, especially be preferably greater than or equal 85%.In an embodiment preferred, the active component that this dosage form discharged after 15 minutes is more than or equal to 90%, and preferably the active component that discharged after 30 minutes is more than or equal to 95% (labelled amount).

In an embodiment of the present invention, rapidly disintegrating dosage form of the present invention demonstrates the character that meets " being used to prepare the tablet (dispersible tablet) of the suspension that will take " or " being used to prepare the tablet of the solution that will take " regulation among the pharmacopeia monograph European Pharmacopoeia the 4th edition.According to the present invention, also preferred especially quickly disintegrated solid dosage forms, it European Pharmacopoeia the 4th edition for " dispersible tablet " described experimental condition under (in temperature is 15-25 ℃ cold water), demonstrating maximum disintegration time is 10,5,4 or 3 minutes, and does not stay residue on the sieve of screen size 710 μ m.

In an embodiment preferred, dosage form of the present invention is a rapidly disintegrating dosage form, and its disintegration time in 37 ℃ of water is no more than 5 minutes, and the dissolving after 15 minutes in 0.1N hydrochloric acid (active component release) is more than or equal to 85%.

The characteristics of dosage form of the present invention are quick disintegrates, discharge active component rapidly, and have for treatment because gastric acid secretion increases the type of action (for example having an effect rapidly) of the disease the best that causes.Also observing proton pump antagonist stability in the dosage form that contains alkaline excipient of the present invention improves.

The alkaline excipient that is fit to the present invention and can be used for stablize proton pump antagonist in dosage form of the present invention is the material with alkaline reaction, and they are pharmaceutically useful, the proton pump antagonist in the energy stabilizer type.They particularly are selected from faintly acid pharmaceutically useful alkali metal, alkaline-earth metal or earth metal salt, pharmaceutically suitable alkaline-earth metal and the hydroxide of earth metal and oxide, or those chemical compounds of pharmaceutically useful alkaline buffer system.The example that can mention has sodium carbonate, calcium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, aluminosilicate magnesium, magnesium silicate, magnesium aluminate, brucite (synthesizing), magaldrate and calcium hydroxide, amino acid whose basic salt, sodium hydroxide, Tris, trisodium citrate, sodium hydrogen phosphate and sodium phosphate, and their mixture.

According to the present invention, preferably sodium carbonate, sodium hydrogen phosphate, sodium phosphate and the buffer system formed by sodium hydrogen phosphate and potassium hydroxide.

Alkalescence excipient preferably other excipient or the carrier with fractionized and active component and suitably the time fully mixes, and makes that tight (directly) contacts between alkaline excipient and the active component.Also can use the excipient granule that has flooded alkaline buffer system.

The addition of alkalescence excipient preferably, when the mixture of 100mg active component and desired excipient is dissolved in the 50mL water, its basicity is not less than pH7, be preferably pH8-11.5, be preferably pH8-11.0 especially, especially be preferably the essence of pH8.5-10.5. according to alkaline excipient, its content can be 0.1-30% weight (based on the weight fraction of finished dosage forms) for example.In an embodiment preferred, the content of alkaline excipient is lower than 20% weight, particularly is lower than 15% weight, especially is lower than 10% weight (based on the percetage by weight of finished dosage forms).

Other excipient that can use in dosage form of the present invention is to cause the quickly disintegrated excipient of dosage form when this dosage form of oral absorption.These excipient preferably contain one or more materials that is selected from filler or carrier and disintegrating agent.Can also exist one or more to belong to the excipient of binding agent, lubricant, coloring agent, spice, flavoring agent and surfactant.

Be fit to filler of the present invention or carry this particularly for example following filler: calcium carbonate (MagGran for example ^Cc or Destab ^95) and sodium carbonate, sugar alcohol such as mannitol (Perlltor for example ^Or Parteck ^M), sorbitol (Karion for example ^), xylitol or maltose alcohol, starch such as corn starch, potato starch and wheaten starch, microcrystalline Cellulose, saccharide such as glucose, lactose, fructose, sucrose and dextrose.Particularly preferably be microcrystalline Cellulose and/or mannitol.

The content (based on the percetage by weight of finished dosage forms) of filler in dosage form of the present invention is preferably 1-99% weight.The content of filler is preferably 30-95% weight, is preferably 60-90% weight especially.

Be fit to the especially preferably insoluble polyvinylpyrrolidone of disintegrating agent of the present invention (insoluble PVP, crosslinked polyvinylpyrrolidone), carboxymethyl starch sodium, sodium carboxymethyl cellulose, alginic acid and can satisfy the various starch (for example starch 1500) of disintegrating agent function.

In rapidly disintegrating dosage form of the present invention, the content of disintegrating agent (based on the percetage by weight of dosage form of the present invention) is 0.5-30% weight.The content of disintegrating agent is preferably 1-15% weight.The content of disintegrating agent is preferably 1-5% weight especially.

The examples of suitable lubricants that can mention is sodium stearyl fumarate, magnesium stearate, calcium stearate, stearic acid, Talcum and silica sol (Aerosil).

The content of lubricant in the rapidly disintegrating dosage form of the present invention (with the percetage by weight on the basis of finished dosage forms) is 0.1-5% weight.The content of lubricant is preferably 0.2-3% weight.The content of lubricant is preferably 0.5-2% weight especially.

Being fit to binding agent of the present invention is polyvinylpyrrolidone (PVP, Polyvidon ^K25, Polyvidon ^K90) or PVP and polyvinyl acetate (as Kolloidon ^64) mixture, gelatin, corn starch paste, pre-swollen starches (Starch ^1500, Uni-Pure ^WG220), hydroxypropyl emthylcellulose (HPMC) or hydroxypropyl cellulose (L-HPC).

The content of binding agent (based on the percetage by weight of finished dosage forms of the present invention) can be up to 10% weight, preferably is up to 5% weight.

The suitable surfactant that can mention is sodium lauryl sulphate or Tween ^20, Tween ^60 or Tween ^80.

Dosage form of the present invention preferably contains the mixture of at least a alkaline excipient, a kind of filler or carrier, a kind of disintegrating agent and a kind of lubricant.

For the present invention, the preferred dosage form that can mention be contain microcrystalline Cellulose as filler or carrier and sodium carbonate as alkaline excipient, and contain that class dosage form of disintegrating agent and lubricant.In another embodiment, dosage form of the present invention contains the mixture of at least a alkaline excipient, a kind of filler or carrier, a kind of disintegrating agent, a kind of binding agent and a kind of lubricant.The preferred dosage form that can mention is the dosage form that contains a kind of mixture in this respect, and this mixture contains mannitol and microcrystalline Cellulose as filler or carrier, and sodium carbonate also contains binding agent and disintegrating agent in addition as alkaline excipient.Can be used as another dosage form that the preferred dosage form of this respect mentions is the dosage form that contains a kind of mixture, and this mixture contains microcrystalline Cellulose, sodium carbonate, carboxymethyl starch sodium and magnesium stearate.

If desired, can also there be one or more flavoring agents (for example spice or sweeting agent) in the dosage form of the present invention.Can realize for example improvement of taste by this.These materials add with usual amounts.

If desired, can also use suitable coloring agent, for example, ferrum oxide, indigo carmine E132 or titanium dioxide.They can directly be processed into the mixture of active component obtaining painted dosage form, or be coated on the dosage form as film-coated composition.

In the situation of coated dosage form of the present invention (for example coated tablet), suitable film coating is to be fit to film-coated material.The example that can mention is a cellulose esters, for example hydroxypropyl emthylcellulose (HPMC) and hydroxypropyl cellulose (L-HPC), polyvinyl alcohol, phthalic acid ester or polymethacrylates (Eudragits for example ^), can be when needing to wherein adding plasticizer (for example, propylene glycol, Polyethylene Glycol, sodium citrate) and/or other additive and excipient (for example, buffer agent, alkali, preferred aluminium hydroxide or pigment).In film-coated situation, its content (based on the weight % of finished dosage forms) is 1-20% weight, is preferably 2-5% weight.In the situation that contains the reversible proton pump inhibitor of heliosensitivity, preferably dosage form of the present invention is applied painted film coating or dyestuff directly is incorporated in the dosage form.For the preparation of painted dosage form, the film-coated example that can mention is OPADRY ^(OPADRY for example ^GREEN or OPADRY II ^GREEN).OPADRY ^GREEN contains the mixture of hydroxypropyl emthylcellulose/hypromellose, titanium dioxide, Polyethylene Glycol/PEG, iron oxide yellow and indigo carmine E132, and OPADRY II ^GREEN contains the mixture of polyvinyl alcohol, titanium dioxide, Polyethylene Glycol/PEG, iron oxide yellow, iron oxide black and indigo carmine E132.

In an embodiment preferred of the present invention, comprise in the dosage form (7R, 8R, 9R)-2,3-dimethyl-8-hydroxyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-imidazolidine also [1,2-h] [1,7] benzodiazine (INN:soraprazan) or its officinal salt and/or hydrate are as proton pump antagonist, and sodium carbonate is as alkaline excipient, and microcrystalline Cellulose, carboxymethyl starch sodium and magnesium stearate are as excipient.In another embodiment, dosage form is a kind of film coating tablet.Preferred especially this dosage form contains painted film coating.The disintegration time that this dosage form is preferably measured in 37 ℃ of water is no more than 5 minutes, and the dissolving in 0.1N hydrochloric acid after 15 minutes (active component release) is more than or equal to 85%.

Dosage form of the present invention particularly prepares by proton pump antagonist and mixed with excipients according to the method preparation that the technical staff knows.In this respect, preferably active component is fully mixed with alkaline excipient.In the situation of tablet, quickly disintegrated dosage form is preferably done excipient and active component in the preparation and is mixed, and if desired, active component and a part of filler or carrier can be pre-mixed.Can use conventional blender, for example forced action type mixing machine or free-falling formula blender carry out married operation.Another kind of probability is the granule of this each component of dosage form of preparation, then with its compacting in flakes.The goods that obtain in this way can be suppressed on suitable tablet machine subsequently.If desired, also can carry out precommpression.In the situation of coated tablet, can use the common equipment (for example coating pan or rotary drum coating machine) of this type of purposes to apply desired film coating in a usual manner.Preferred water is as granulating and coating liquid.In the situation of painted dosage form, coloring agent preferably is dispersed in the granule, perhaps dry mixed, humidifying or granulating or be suspended in dyestuff (pigment)/granulating liquid then.

In the situation of pill, rapidly disintegrating dosage form preferably is sprayed on the inoculum pill by the active agent preparation with alkalization and prepares, perhaps with extruder/spheronizator preparation.

Embodiment

Following formulation Example describes the present invention in detail, but is not limitation ot it.

Embodiment 1

Film coated tablet:

1. The not preparation of coated cores

a)Soraprazan 10.0mg

B) sodium carbonate (anhydrous) 5.1mg

C) microcrystalline Cellulose (for example: 137.2mg Avicel pH102)

D) microcrystalline Cellulose (for example: 7.5mg Avicel pH101)

E) Sodium Hydroxymethyl Stalcs 8.5mg

F) magnesium stearate 1.7mg

170.0mg

With a) with d) in the forced action type mixing machine, mix.This mixture and b), c) and e) in the forced action type mixing machine, mix.Subsequently with f) in free-falling formula mixer, mix.In suitable tablet machine, press sheet mixture is pressed into core.

II. Rete

g)Opadry II green 5.0mg

175.0mg

The g that in suitable coating device, obtains in I) is coated in tablet core in the heart.

Embodiment 2

Film coated tablet:

I. The not preparation of coated cores

a)Soraprazan 10.0mg

B) sodium phosphate 5.1mg

C) microcrystalline Cellulose (as: Avicel pH101) 83.5mg

D) mannitol 51.0mg

E) carboxymethyl starch sodium 5.1mg

F) starch 1500 13.6mg

G) magnesium stearate 1.7mg

170.0mg

II. Rete

h)Opadry II green 3.1mg

173.1mg

Embodiment 3

Film coated tablet:

I. The not preparation of coated cores:

a)Soraprazan 20.0mg

B) sodium phosphate (anhydrous) 10.2mg

C) microcrystalline Cellulose (as: Avicel pH102) 114.6mg

D) microcrystalline Cellulose (as: Avicel pH101) 15.0mg

E) carboxymethyl starch sodium 8.5mg

F) magnesium stearate 1.7mg

170.0mg

With a) with d) in the forced action type mixing machine, mix.This mixture and b), c) and e) in the forced action type mixing machine, mix.Subsequently in free-falling formula mixer with f) mix.In suitable tablet machine, this press sheet mixture is made core.

II. Rete

g)Opadry II green 5.0mg

175.0mg

In suitable film coating device with g) be coated in the tablet core that obtains among the I in the heart.

Embodiment 4

Film coated tablet:

I. The not preparation of coated cores:

a)Soraprazan 20.0mg

B) sodium carbonate (anhydrous) 10.2mg

C) microcrystalline Cellulose (as: Avicel pH102) 274.4mg

D) microcrystalline Cellulose (as: Avicel pH101) 15.0mg

E) carboxymethyl starch sodium 17.0mg

F) magnesium stearate 3.4mg

340.0mg

With a) with d) in the forced action type mixing machine, mix.This mixture and b), c) and e) in the forced action type mixing machine, mix.Subsequently in free-falling formula mixer with f) mix.In suitable tablet machine, press sheet mixture is pressed into core.

II. Rete

g)Opadry II green 7.5mg

347.5mg

In suitable film coating device with g) be coated in the tablet core that obtains among the I in the heart.

Embodiment 5

Film coated tablet:

I. The not preparation of coated cores:

a)Soraprazan 20.0mg

B) sodium carbonate (anhydrous) 5.1mg

C) microcrystalline Cellulose (as: Avicel pH102) 119.7mg

D) microcrystalline Cellulose (as: Avicel pH101) 15.0mg

E) carboxymethyl starch sodium 8.5mg

F) magnesium stearate 1.7mg

With a) with d) in the forced action type mixing machine, mix.This mixture and b), c) and e) in the forced action type mixing machine, mix.Subsequently in free-falling formula mixer with f) mix.In suitable tablet machine, press sheet mixture is pressed into core.

II. Rete

g)Opadry II green 5.0mg

175.0mg

In suitable film coating device with g) be coated in the tablet core that obtains among the I in the heart.

Embodiment 6

Film coated tablet:

a)Soraprazan 5.0mg

B) mannitol 50.0mg

C) microcrystalline Cellulose (as: Avicel pH101) 20.0mg

d)Uni Pure ^WG 220 3.0mg

E) alkaline cushion 2.0mg

Granular mass80.0mg

F) disintegrating agent 4.0mg

G) magnesium stearate 0.25mg

The tablet core mass84.25mg

H) film coating 4.0mg

The quality of thin membrane coated tablet88.25mg

Embodiment 7

Film coated tablet:

a)Soraprazan 5.0mg

B) mannitol 50.0mg

C) microcrystalline Cellulose (as: Avicel pH101) 20.0mg

d)Uni Pure ^WG 220 3.0mg

E) alkaline cushion 2.0mg

Granular mass80.0mg

F) disintegrating agent 4.0mg

G) magnesium stearate 0.25mg

The tablet core mass84.25mg

H) film coating 4.0mg

The quality of film-coat tablet88.25mg

Embodiment 8

Film coated tablet:

a)Soraprazan 5.0mg

B) mannitol 50.0mg

C) microcrystalline Cellulose (as: Avicel pH101) 20.0mg

d)Uni Pure ^WG 220 3.0mg

E) sodium carbonate 1.2mg

Granular mass79.2mg

F) Explotab 4.0mg

G) magnesium stearate 0.25mg

The tablet core mass83.45mg

H) film coating (PVA yl) 3.55mg

The quality of film-coat tablet87.00mg

Embodiment 9

Film coated tablet:

a)Soraprazan 20.0mg

B) mannitol 124.0mg

C) microcrystalline Cellulose (as: Avicel pH101) 52.0mg

d)Uni Pure ^WG 220 8.2mg

E) sodium carbonate 3.3mg

Granular mass207.5mg

F) Explotab 11.0mg

G) magnesium stearate 0.7mg

The tablet core mass219.2mg

H) film coating (PVA yl) 9.8mg

The quality of film-coat tablet229.00mg

	Embodiment 10	Embodiment 11	Embodiment 12	Embodiment 13
					The transparent coating of soraprazan natrium carbonicum calcinatum sodium hydrogen phosphate microcrystalline cellulose (Avicel PH101) microcrystalline cellulose (Avicel PH112) the sweet mellow wine Ac-Di-Sol Uni-Pure WG 220 indigo carmine E132 iron oxide yellow dolomol transparent sub-coat HPMC of sub-coat PVA HPMC/FeO coats PVA/FeO and coats PVA/FeO/ indigo carmine E132 film coated tablet total	5.00mg 2.40mg 20.00mg 49.27mg 4.25mg 1.60mg 0.43mg 0.30mg 0.25mg 83.50mg	5.00mg 2.40mg 20.00mg 49.27mg 4.25mg 1.60mg 0.43mg 0.30mg 0.25mg 83.50mg	5.00mg 2.40mg 13.00mg 31.00mg 2.75mg 1.60mg 0.25mg 3.00mg 59.00mg	5.00mg 2.40mg 13.00mg 31.00mg 2.75mg 1.60mg 0.25mg 3.00mg 59.00mg

	Embodiment 14	Embodiment 15	Embodiment 16	Embodiment 17
					The transparent coating of soraprazan natrium carbonicum calcinatum sodium hydrogen phosphate microcrystalline cellulose (Avicel PH101) microcrystalline cellulose (Avicel PH112) the sweet mellow wine Ac-Di-Sol Uni-Pure WG 220 indigo carmine E132 iron oxide yellow dolomol transparent sub-coat HPMC of sub-coat PVA HPMC/FeO coats PVA/FeO and coats PVA/FeO/ indigo carmine E132 film coated tablet total	5.00mg 2.40mg 20.00mg in 50.00mg 4.25mg 1.60mg 0.25mg 0.855mg 4.47mg 88.83mg	5.00mg 2.40mg 20.00mg 50.00mg 4.25mg 1.60mg 0.25mg 0.855mg 4.47mg 88.83mg	5.00mg 1.20mg 20.00mg 50.00mg 3.95mg 1.60mg 0.25mg 4.10mg 86.10mg	5.00mg 1.20mg 20.00mg 50.00mg 3.95mg 1.60mg 0.25mg 4.10mg 86.10mg

Core:	Embodiment 18	Embodiment 19	Embodiment 20
				Soraprazan natrium carbonicum calcinatum hexameta phosphoric acid sodium microcrystalline cellulose (Avicel PH102) microcrystalline cellulose (Avicel PH101) microcrystalline cellulose (Avicel PH112) sweet mellow wine sodium carboxymethyl starch pregelatinized starch (starch 1500) dolomol core amounts to	10.0mg 5.1mg 137.2mg 7.5mg 8.5mg 1.7mg 170.0mg	10.0mg 5.1mg 137.2mg 7.5mg 8.5mg 1.7mg 170.0mg	10.0mg 5.1mg 7.5mg 137.2mg 8.5mg 1.7mg 170.0mg
Rete:
				Opadry green 03F21409 Opadry ll green 85F21399 film coated tablet amounts to	5.0mg 175.0mg	5.0mg 175.0mg	5.0mg 175.0mg

Core:	Embodiment 21	Embodiment 22	Embodiment 23
				Soraprazan natrium carbonicum calcinatum hexameta phosphoric acid sodium microcrystalline cellulose (Avicel PH102) microcrystalline cellulose (Avicel PH101) microcrystalline cellulose (Avicel PH112) sweet mellow wine sodium carboxymethyl starch pregelatinized starch (starch 1500) dolomol core amounts to	10.0mg 5.1mg 7.5mg 137.2mg 8.5mg 1.7mg 170.0mg	10.0mg 5.1mg 83.5mg 51mg 5.1mg 13.6mg 1.7mg 170.0mg	10.0mg 2.89mg 2.21mg 83.5mg 51mg 5.1mg 13.6mg 1.7mg 170.0mg
The component of wet granulation
				Rete:
Opadry green 03F21409 Opadry ll green 85F21399 film coated tablet amounts to	5.0mg 175.0mg	3.1mg 173.1mg	4.4mg 174.4mg

Core:	Embodiment 24	Embodiment 25	Embodiment 26
				Soraprazan natrium carbonicum calcinatum hexameta phosphoric acid sodium microcrystalline cellulose (Avicel PH102) microcrystalline cellulose (Avicel PH101) microcrystalline cellulose (Avicel PH112) sweet mellow wine sodium carboxymethyl starch pregelatinized starch (starch 1500) dolomol core amounts to	10.0mg 5.1mg 83.5mg 51mg 5.1mg 13.6mg 1.7mg 170.0mg	10.0mg 2.89mg 2.21mg 83.5mg 51mg 5.1mg 13.6mg 1.7mg 170.0mg	10.0mg 5.1mg 83.5mg 51.0mg 5.1mg 13.6mg 1.7mg 170.0mg
The component of wet granulation
				Rete:
Opadry green 03F21409 Opadry ll green 85F21399 film coated tablet amounts to	4.8mg 174.8mg	3.3mg 173.3mg	5.0mg 175.0mg

Core:	Embodiment 27	Embodiment 28	Embodiment 29
				Soraprazan natrium carbonicum calcinatum hexameta phosphoric acid sodium microcrystalline cellulose (Avicel PH102) microcrystalline cellulose (Avicel PH101) microcrystalline cellulose (Avicel PH112) sweet mellow wine sodium carboxymethyl starch pregelatinized starch (starch 1500) dolomol core amounts to	10.0mg 5.1mg 83.5mg 51.0mg 5.1mg 13.6mg 1.7mg 170.0mg	10.0mg 5.1mg 83.5mg 51.0mg 5.1mg 13.6mg 1.7mg 170.0mg	10.0mg 5.1mg 83.5mg 51.0mg 5.1mg 13.6mg 1.7mg 170.0mg
The component of wet granulation
				Rete:	NGa 5	NGa 8	NGa 9
Opadry green 03F21409 Opadry ll green 85F21399 film coated tablet amounts to	5.0mg 175.0mg	5.0mg 175.0mg	5.0mg 175.0mg

The disintegration time of the tablet of embodiment 1 is measured

Film coated tablet carries out slaking test European Pharmacopeeia the 4th edition under about " dispersible tablet " described experimental condition.Observe tablet disintegrate in 3 minutes in 15-25 ℃ of water.Form 3 dispersions and dumpable by sieve (710).

Stability test

Make Soraprazan and comprise or the development thing of the various excipient of alkali-free excipient, store down, analyze its impurity, obtain following result at 50 ℃:

Mixture	Soraprazan, mannitol	Soraprazan, magnesium stearate	Soraprazan, corn starch	Soraprazan, corn starch, mannitol, magnesium stearate, sodium carbonate
					Total impurities (AU%)	5,29	5,01	6,67	3,76

Mixture	Soraprazan, corn starch, magnesium stearate, sodium bicarbonate	Soraprazan, mannitol, magnesium stearate, sodium bicarbonate
			Total impurities (AU%)	3,68	3,74

For the development thing that contains alkaline excipient, observed impurity is obviously less.

Industrial usability

Proton pump antagonist and salt thereof have valuable industrial available pharmacological properties. They are particularly to warm-blooded animal, and especially the people demonstrates significant gastric acid secretion inhibitory action and excellent pipe intestinal protection effect. The compounds of this invention characteristics in this respect are high selectivities of effect, and are active in the favourable acting duration, particularly preferred intestines, do not have obvious side effect, and high therapeutic index.

For the present invention; " stomach and intestine protective effect " refers to gastrointestinal disease; especially gastrointestinal inflammation and damage preventing and (for example treating; gastric ulcer; duodenal ulcer; gastritis; the indigestion that hyperhydrochloria or medicine are relevant; heart-burn and acid belch; serious peptic esophagitis; send out again the prevention of peptic esophagitis and duodenal ulcer; peptic esophagitis; pancreatogenic canker syndrome; unite to eliminate the pathogen helicobacter pylori with Amoxicillin and CLA or with CLA and metronidazole or with Amoxicillin and metronidazole, long-term treatment is to prevent sending out again of serious peptic esophagitis. Ulcer and gastroduodenal erosion that prevention and treatment are brought out by the NSAID thing), these diseases can be caused by microorganism (for example helicobacter pylori), bacteriotoxin, medicine (for example some antiphlogistic and antirheumatic drug), chemicals (such as ethanol), hydrochloric acid in gastric juice or tense situation.

Because these performances, the formulation that contains proton pump antagonist and/or its officinal salt of the present invention is specially adapted to human and veterinary drug, in particular for treating and/or preventing stomach trouble and enteropathy.

Therefore the invention still further relates to formulation of the present invention is used for the treatment of and/or prevents above-mentioned illness.

The present invention comprises that also use formulation of the present invention treats and/or prevents above-mentioned illness. In this situation, formulation of the present invention can be used as it is (for example by the oral absorption of patient), perhaps is dispersed or dissolved in the water before use. What be particularly suitable for this purposes is the rapidly disintegrating dosage form of the present invention of the standard that meets European Pharmacopeeia the 4th edition (" tablet that is used for the solution that preparation will take " or " tablet that is used for the suspension that preparation will take "). The solution or the suspension that obtain after in being scattered in suitable decentralized medium or solvent can be taken by the patient subsequently. This can be beneficial to for for example taking the problematic patient of solid dosage forms. Another may be to take these solution or suspension with pipe (for example nasogastric tube, stomach tube). This is particularly conducive to uses formulation of the present invention to the patient of the patient who accepts intensive care, dysphagia, bedfast patient and children.

Formulation of the present invention can be from other medicines or in different compositions, or in a kind of composition, unite use. With the proton pump antagonist that contains of the present invention as the combination of the formulation of active component, be worth to propose be with the antimicrobial acivity composition and with the combination of NSAID (non-steroid class disappear material medicine). Should mention especially the combination with the antimicrobial agents that for example is used for controlling microorganism helicobacter pylori (H.Pylori). The further example of the composition that can mention is: tranquilizer (benzene diaza class for example, diazepam), antispasmodic (for example bietamiverine or camylofin), anticholinergic drug (for example Oxyphencyclimine or phencar-bamide), local anesthetic (for example totokaine or procaine) also comprises enzyme, vitamin or amino acid in the time of suitably. In this respect should the lay special stress on The compounds of this invention and the drug regimen that suppresses the acid secretion, for example, antiacid, H2 blocking agent (such as Cimetidine, ranitidine), H⁺/K ⁺-ATP enzyme inhibitor (for example class difficult to understand is drawn azoles, Pantoprazole), or with so-called periphery anticholinergic drug (for example, pirenzepine, Telenzepine) and the gastrin antagonists combination, so that adduction ground or synergy ground strengthen main effect and/or elimination or reduce side effect.

The example of suitable antimicrobial acivity composition (anti-helicobactor pylori activity thing) has been described among the EP-A 0282131. The example that being suitable for of can mentioning controlled the antimicrobial agents of microorganism helicobacter pylori be for example bismuth salt (as, BISMUTH SUBCITRATE, basic bismuth salicylate, two hydroxide bismuth citrate (III) potassium ammoniums, the oxidation bismuth nitrate, three (four oxygen, two aluminic acids), two bismuths), especially beta-Lactam antibiotic, for example PCs (as, benzylpenicillin, phenoxymethyl penicillin, propicillin, the azidocillin, dicloxacillin, the flucloxacillin, OXA, the Amoxicillin, Bacampicillin, the ampicillin, the mezlocillin, Piperacillin or azlocillin), cephalosporins (cefadroxil for example, Cefaclor, cefalexin, Cefixime, cephalo skin suffering, cefetamet, Ceftibuten, Cefpodoxime, cefotetan, Cefazolin, cefoperazone, Ceftizoxime, CTX, cefotaxime, Cefamandole, Cefepime, Cefoxitin, cefodizime, Cefsulodin, ceftriaxone, Cefotiam or Cefmenoxime) or other beta-Lactam antibiotic (for example, AZT, Loracarbef or Meropenem); Enzyme inhibitor, for example Sulbactam; Tetracyclines, for example tetracycline, terramycin, minocycline or Doxycycline; Glucosaminide, for example, TOB, gentamicin, neomycin, streptomysin, amikacin, Netilmicin, paromomycin or spectinomycin; Acid amides alcohols antibiotic, for example chloramphenicol or Thiamphenicol; Lincomycin class and macrolide antibiotic, for example clindamycin, lincomycin, erythromycin, CLA, spiramvcin, ROX or azithromycin; Polypeptide antibiotics, for example polymyxin e, PB, teicoplanin or vancomycin; Rotate mould inhibitor, for example, Norfloxacin, cinoxacin, Ciprofloxacin, pipemidic acid, Enoxacin, acidum nalidixicum, Pefloxacin, fleraxacin or Ofloxacin; Nitro glyoxaline, for example metronidazole; Or other antibiotic, for example phosphonomycin or Fusidic Acid. At reversible proton pump inhibitor aspect the composition administration of multiple active antimicrobial ingredient, be worth to propose especially be for example with the composition of bismuth salt and/or tetracycline and metronidazole, or with Amoxicillin or CLA and metronidazole, and the combination compound of Amoxicillin and CLA associating.

The dosage of active component depends primarily on the essence of employed proton pump antagonist in the formulation of the present invention. For example the exemplary dosage of disclosed proton pump antagonist can be for being the about 0.01-20 of daily dose in WO-A-9418199, and preferably about 0.05-5, particularly 0.1-1.5mg/kg body weight can be the form of a plurality of single doses as required. In the situation of compound S oraprazan, contain dosage in the formulation example of the present invention and be 2,2.5,5,10,15,20 or the proton pump antagonist of 40mg.

The active antimicrobial ingredient that should emphasize is erythromycin, azithromycin, CLA, clindamycin, rifampin, ampicillin, mezlocillin, Amoxicillin, tetracycline, minocycline, Doxycycline, Imipenem, Meropenem, cefalexin, cefuroxime axetil, cefpodoxime proxetil, Cefaclor, cefadroxil, Ciprofloxacin, Norfloxacin, Ofloxacin and Pefloxacin.

Can ben active antimicrobial ingredient be CLA and Amoxicillin.

For the present invention, that administering drug combinations refers to fix and particularly freely associating, namely, proton pump antagonist and active antimicrobial ingredient or be present among the dosage device, or being present in proton pump antagonist and the anti-plain active component of little life among the dosage device of separation following the mode that links to each other closely or with bigger time interval administration, the bigger time interval means and is no more than 24 hours. For using with the dosage device that separates, preferably be provided in the common packing. For example, two kinds of dosage devices are packaged together in the bubble eye, bubble eye is in known manner according to relative configuration, mark and/or painted design of two kinds of dosage devices, so that the time (therapeutic regimen) that each component of two kinds of dosage devices should be taken is open-and-shut to the patient.

Dosage device means especially such as tablet, coated tablet or pill, and the formulation such as microplate capsule, formulation is advantageously designed to make two kinds of active components, and (proton pump antagonist is a side, active antimicrobial ingredient is the opposing party) discharge or be supplied in the body in the mode that reaches the optimum activity component distributing, thus reach optimum efficiency.

Claims (26)

1. the dosage form that is used for proton pump antagonist (APA) wherein contains the proton pump antagonist and the excipient of effective quantity, and proton pump antagonist wherein is stabilized in this dosage form with one or more alkaline excipient.

2. the dosage form of claim 1, its neutral and alkali excipient exists with the form of segmentation and fully mixes with proton pump antagonist.

3. claim 1 or 2 dosage form is characterized in that, when this dosage form of oral absorption, cause the quick disintegrate of this dosage form, and also have other excipient in addition in due course.

4. the dosage form of claim 1 to 3 is characterized in that, this dosage form is to be selected from tablet, coated tablet, pill, microplate capsule and granule capsule.

5. the dosage form of claim 4 is characterized in that it comprises coated tablet.

6. the dosage form of claim 3 is characterized in that, it comprises the rapidly disintegrating dosage form (discharging solid oral dosage form immediately) that discharges active component immediately.

7. the dosage form of claim 3, it is characterized in that, it comprises the rapidly disintegrating dosage form of release of active ingredients (discharging solid oral dosage form immediately) immediately, and this dosage form disintegration time under " dispersible tablet " described experimental condition in Europeanpharmacopoeia (European Pharmacopoeia) the 4th edition is no more than 5 minutes.

8. the dosage form of claim 3, it is characterized in that, it comprises the rapidly disintegrating dosage form of release of active ingredients (discharging solid oral dosage form immediately) immediately, this dosage form in European pharmacopoeia the 4th edition under " dispersible tablet " described experimental condition, disintegrate in 3 minutes.

9. the dosage form of claim 7 is characterized in that, after 15 minutes, the active component that discharges is more than or equal to 85% in 0.1N hydrochloric acid for it.

10. the dosage form of claim 3 is characterized in that, exists one or more materials that are selected from filler and disintegrating agent as causing the quickly disintegrated excipient of tablet.

11. the dosage form of claim 10 is characterized in that, has at least a filler and at least a disintegrating agent.

12. the dosage form of claim 11 is characterized in that, has microcrystalline Cellulose.

13. the dosage form of claim 1 to 3 is characterized in that, also has one or more other excipient that are selected from lubricant, spice, coloring agent, correctives and surfactant.

14. the dosage form of claim 1, it is characterized in that, this alkalescence excipient is to be selected from sodium carbonate, calcium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, aluminosilicate magnesium, magnesium silicate, magnesium aluminate, brucite (synthesizing), aluminum magnesium hydroxide, calcium hydroxide, aminoacid basic salt, sodium hydroxide, Tris, trisodium citrate, sodium hydrogen phosphate and sodium phosphate, or their mixture.

15. the dosage form of claim 14 is characterized in that containing sodium carbonate.

16. the dosage form of claim 14 is characterized in that, the buffer system that contains sodium hydrogen phosphate, sodium phosphate or be made up of sodium hydrogen phosphate and sodium hydroxide.

17. the dosage form of claim 1, it is characterized in that, there are a kind of AU-461 of being selected from, soraprazan (BYK61359), DBM-819, KR-60436, T-330, YH-1885, YJA 20379-8 and 2, the chemical compound of 3-dimethyl-8-(2-ethyl-6-methyl benzyl amino) imidazo [1,2-a] pyridine-6-Methanamide is as irreversible proton pump inhibitor.

18. the dosage form of claim 17, it is characterized in that, exist (7R, 8R, 9R)-2,3-dimethyl-8-hydroxyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-imidazolidine also [1,2-h] [1,7] benzodiazine (INN soraprazan) or its officinal salt and/or hydrate be as proton pump antagonist.

19. the dosage form of claim 9, wherein contain (7R, 8R, 9R)-2,3-dimethyl-8-hydroxyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-imidazolidine also [1,2-h] [1,7] benzodiazine (INN soraprazan) is as proton pump antagonist, and sodium carbonate is as alkaline excipient, and microcrystalline Cellulose, carboxymethyl starch sodium and magnesium stearate are as excipient.

20. the dosage form of claim 19, this dosage form is a film coated tablet.

21. the dosage form of claim 20 wherein contains a coloured film coating.

22. prepare the method for the dosage form of one of aforementioned claim, comprise with active component and the well-mixed step of alkaline excipient.

23. quickly disintegrated dosage form wherein contains the proton pump antagonist (APA) and the excipient of effective quantity, this excipient causes the quick disintegrate of dosage form when the described dosage form of oral absorption, also can randomly contain other excipient.

24. demonstrating, the dosage form of claim 23, this dosage form discharge proton pump antagonist (APA) immediately.

25. the dosage form of claim 24, the disintegration time that it is measured in 37 ℃ of water is no more than 5 minutes, and the active component that discharges after 15 minutes in 0.1N hydrochloric acid is more than or equal to 85%.

26. the dosage form of claim 23, it is characterized in that, exist (7R, 8R, 9R)-2,3-dimethyl-8-hydroxyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-imidazolidine also [1,2-h] [1,7] benzodiazine (INN soraprazan) or its officinal salt or solvate be as proton pump antagonist.