WO2004099182A1 - Zinc salt of (s)-omeprazole - Google Patents

Zinc salt of (s)-omeprazole Download PDF

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Publication number
WO2004099182A1
WO2004099182A1 PCT/IB2004/001378 IB2004001378W WO2004099182A1 WO 2004099182 A1 WO2004099182 A1 WO 2004099182A1 IB 2004001378 W IB2004001378 W IB 2004001378W WO 2004099182 A1 WO2004099182 A1 WO 2004099182A1
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zinc
omeprazole
salt
process according
used
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PCT/IB2004/001378
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French (fr)
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Yatendra Kumar
Mahavir Singh Khanna
Mohan Prasad
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Ranbaxy Laboratories Limited
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

Abstract

A zinc salt of the S-enantiomer of omeprazole which is (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole is provided. Further, processes for preparing the zinc salt, pharmaceutical compositions comprising the salt and a method of treatment or prevention of gastrointestinal ulcers comprising administration of the salt are provided.

Description

ZINC SALT OF (S) -OMEPRAZOLE

Field of the Invention

A zinc salt of the S-enantiomer of omeprazole which is (S)-5-methoxy-2-[[(4- methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH-benzimidazole is provided. Further, processes for preparing the zinc salt, pharmaceutical compositions comprising the salt and a method of treatment or prevention of gastrointestinal ulcers comprising administration of the salt are provided.

Background of the Invention

Omeprazole is a gastric acid secretion inhibitor, useful as an anti-ulcer agent. United States Patent No. 5,714,504 describes alkaline salts of (S)-omeprazole, such as sodium, magnesium, lithium, potassium, calcium or tetraalkylammonium salts. However, only the preparation of sodium and magnesium salts of (S)-omeprazole has been exemplified, besides (S)-omeprazole freebase in this patent. The potassium salt of (S)- omeprazole has been prepared in WO 98/54171 and WO 00/44744. Commercially magnesium salt of (S)-omeprazole is used for treating and preventing peptic ulcers, gastroesophageal reflux disease (GERD or heartburn), erosive esophagitis, other conditions involving excessive stomach acid production, and for treating bacterial infections caused by helicobacter pylori.

Summary of the Invention

Herein is provided the zinc salt of (S)-omeprazole, that is, (S)-omeprazole zinc.

Another aspect relates to esomeprazole zinc in an amorphous form.

In yet another aspect, a process for preparing (S)-omeprazole zinc is provided, which comprises contacting (S)-omeprazole freebase or its sodium/potassium salt with zinc salt of an acid in a suitable solvent to form (S)-omeprazole zinc, wherein the process is carried out in the presence of a base whenever (S)-omeprazole freebase is used.

Further aspects include methods for treating or preventing gastrointestinal ulcers which comprise administering (S)-omeprazole zinc, or a pharmaceutical composition that comprises (S)-omeprazole zinc, along with pharmaceutically acceptable excipients. The term "(S)-omeprazole zinc," as used herein, means any salt comprised of (S)- omeprazole anions and zinc cations. For instance, solid as well as dissolved forms are included, and so are crystalline and amorphous forms. (S)-omeprazole zinc may exist in an anhydrous and/or solvent-free form or as a hydrate and/or a solvate.

The expression "S-omeprazole," as used herein, refers to an omeprazole-containing material which is substantially free of the R-enantiomer of omeprazole, for example, it has an enantiomeric excess of 80%, or for example an enantiomenc excess of 90%. In some particular embodiments, S-omeprazole is in enantiomeric excess of at least about 95%, or at least about 98%, or at least about 99.5%, or at least about 99. 8%.

Further, the term "(S)-omeprazole zinc," as used herein, encompasses stoichiometric as well as non-stoichiometric ratios of (S)-omeprazole anion and zinc cation. The ratio of (S)-omeprazole to zinc is not required to be 1 : 1 in order to be termed (S)-omeprazole zinc. In a particular embodiment (S)-omeprazole zinc is formed as a salt having a 2:1 molar ratio between (S)-omeprazole anion and zinc cation even when an excess of (S)-omeprazole or an excess of zinc salt of an acid is used in the salt formation.

Brief Description of the Figures

Figure 1 is an X-Ray diffractogram of (S)-omeprazole zinc.

Figure 2 is an infrared spectrum of (S)- omeprazole zinc.

Figure 3 is a differential scanning calorimetry spectrum of (S)-omeprazole zinc.

Figure 4 is an X-Ray diffractogram of (S)-omeprazole zinc.

Figure 5 is an infrared spectrum of (S)- omeprazole zinc.

Figure 6' is a differential scanning calorimetry spectrum of (S)-omeprazole zinc.

Figure 7 is an X-Ray diffractogram of (S)-omeprazole zinc.

Figure 8 is an infrared spectrum of (S)- omeprazole zinc.

Figure 9 is a differential scanning calorimetry spectrum of (S)-omeprazole zinc.

(S)-omeprazole zinc obtained in amorphous form is non-hygroscopic. Amorphous form may be advantageous in comparison with the crystalline form as it can be obtained in a finely powdered form with better solubility properties.

Examples of bases which may be used in the process for preparing (S)-omeprazole zinc using (S)-omeprazole freebase include alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkali metal bicarbonates such as sodium bicarbonate, and ammonium hydroxide.

The zinc salt of an acid to be used in the process can be the salt of any inorganic or organic acid. Examples of such salts include zinc chloride, zinc nitrate, zinc sulphate, zinc phosphate, zinc carbonate, zinc oxalate, zinc acetate, zinc lactate, zinc succmate, zinc citrate, and zinc tartrate.

Examples of suitable solvents for carrying out the process include water, ketones such as acetone and methyl isobutyl ketone, esters such as ethyl acetate and isopropyl acetate, chlorinated hydrocarbons such as methylene chloride and ethylene dichloride, cyclic ethers such as dioxaii and tetrahydrofuran, alcohols such as methanol, ethanol and isopropanol, nitriles such as acetonitrile, dipolar aprotic solvents such as dimethylsulfoxide and dimethylformamide, and mixtures thereof.

In water the reactants are more soluble than the (S)-omeprazole zinc product. In this way, the salt-forming reaction is accompanied by spontaneous precipitation of the produced zinc salt out of the solution.

Alternatively, the precipitation may be facilitated by reducing the volume of the solution and/or by adding an antisolvent, that is, a solvent in which the (S)-omeprazole zinc is insoluble or sparingly soluble. The precipitation can also be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated.

Examples of anti solvents that may be added to precipitate out (S)-omeprazole zinc include lower alkyl ethers such as diethyl ether, and diisopropyl ether; hydrocarbons such as hexane and heptane and mixture(s) thereof.

The (S)-omeprazole freebase or its sodium/potassium salt to be used in the preparation processes can be obtained by methods known in the art including those described in United States Patent Nos. 5,714,504, 5,948,789, and US 6,162,816, and International Patent Applications WO 00/44744, WO 98/54171, WO92/08716. The starting (S)-omeprazole freebase or its sodium/potassium salts may be obtained as a solution directly from a reaction in which (S)-omeprazole is formed, and used as such.

The precipitated zinc salt may be isolated in a solid state by conventional methods such as filtration or centrifugation, optionally followed by washing and/or drying.

(S)-omeprazole zinc is a useful proton pump inhibitor and an antibacterial, and thus can be used to treat any condition that would be benefited by administration of a gastric acid secretion inhibitor, h particular, (S)-omeprazole zinc can be used for the treatment or prophylaxis of gastric acid-related diseases and gastrointestinal inflammatory diseases in mammals and man, such as erosive or ulcerative gastroesophageal reflux disease (GERD), gastric ulcer, duodenal ulcer, reflux esophagitis, and gastritis. Furthermore, it may be used for treatment of other gastrointestinal disorders where gastric antisecretory effect is desirable, for example in patients on NSAID therapy, in patients with gastrinomas, and in patients with acute upper gastrointestinal bleeding. It may also be used in patients in intensive care situations, and pre- and postoperatively to prevent acid aspiration and stress ulceration. Further, (S)-omeprazole zinc may be useful in the treatment of helicobacter infections and diseases related to these.

The salt can be administered as a component of a pharmaceutical composition. Accordingly, in a further aspect, there is provided a pharmaceutical composition that comprises (S)-omeprazole zinc and pharmaceutically acceptable carriers, diluents or excipients and optionally other therapeutic ingredients. The salt may be conveniently formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms. Any suitable route of administration may be employed for example, peroral or parental.

In the following section preferred embodiments are described by way of examples to illustrate the process of the invention. However, these are not intended in any way to limit the scope of the present invention. Several variants of these examples would be evident to persons ordinarily skilled in the art. Examples

General Experimental Details - Powder XRD

X-Ray Diffraction (XRD) patterns were taken with an diffractometer manufactured by Rigaku Corporation, specifically the model RU-H3R. The goniometer was a CN2155A3, and the X-Ray tube was equipped with Cu target anode. The settings for the divergence slits were 1 0, for the receiving slit 0.15mm, and for the scatter slit 1 0. The operating power was 40 KV, 100 mA, the scanning speed was 2 deg/min step: 0.02 deg, and the wavelength was 1.5406 A.

General Experimental Details - FT Infrared

Infrared spectra were taken with a Perkin Elmer, 16 PC, with scan parameters of 16 scans, 4.0 cm"1, according to the USP 25, general test methods page 1920. Infrared absorption spectra were obtained by the potassium bromide pellet method.

General Experimental Details - Differential Scanning Calorimetry

Differential Scanning Calorimetry was done by the model DSC821 e, manufactured by Mettler Toledo, with sample weights of 3-5 mg, and the sample temperature range of 25-100° C, heating rate of 1° C/min, nitrogen flow of 80.0 mL/min, with one hole in the crucible.

Example 1 : A first preparation of (S)-omeprazole zinc

(-)-5 -methoxy-2-[ [(4-methoxy-3 , 5 -dimethyl-2-pyridinyl)-methyl] sulfinyl] - 1H- benzimidazole, zinc salt was prepared as follows.

The potassium salt of (S)-omeprazole ( 5.0g) was stirred in acetone (50ml) at 25 to 30°C and anhydrous zinc chloride (1.8 g) was added. The reaction mixture was stirred for 1 to 2 hours. The solid that separated out was filtered through filter aid under vacuum and the wet cake was washed with acetone (20ml). The filtrate was concentrated under reduced pressure at 40-45°C to a semisolid material. Methanol (50 ml) was added, the suspension stirred further for 1-2 hours at 20-25°C. The solid obtained was filtered, washed with methanol and air dried at 40 to 45°C for 7 to 8 hours to get (S)-omeprazole zinc (5.2g). HPLC Purity = 98.56 %, Chiral Purity by HPLC= 99.89 %. MC% w/w by KF = 3.35 %, Zn content (w/w): 10.99%; Powder XRD, IR in KBr and DSC spectra are as shown in Figure 1, 2 and 3 respectively, as shown in the accompanying drawings.

Example 2:

(-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-lH- benzimidazole, zinc salt was also prepared as follows.

The potassium salt of (S)-omeprazole (5g,) was dissolved in water (60ml) at at 25- 30° C to get a clear solution. Anhydrous zinc chloride (1.8g) dissolved in water (5ml) was slowly added to the above solution in 10 minutes at 25-30°C. The reaction mixture was further stirred for 1 to 2 hours, the obtained solid was filtered and washed with water. The product was air dried at 40 to 45°C for 8 to 10 hours to get (S)-omeprazole zinc (4.9g).

MC% w/w by KF = 3.31 %, Zn content (w/w): 9.42%; XRD, IR spectra, and DSC spectra are as shown in Figure 4, 5 and 6 respectively, as shown in the accompanying drawings.

Example 3:

(-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfmyl]-lH- benzimidazole, zinc salt was also prepared as follows.

The potassium salt of (S)-omeprazole (5g,) was dissolved in water (60ml) at at 25- 30° C to get a clear solution. Zinc sulphate heptahydrate (3.8 g) dissolved in water (10ml) was slowly added to the above solution in 10 minutes at 25-30°C. The reaction mixture was further stirred for 1 to 2 hours, the obtained solid was filtered and washed with water. The product was air dried at 40 to 45°C for 8 to 10 hours to get (S)-omeprazole zinc (4.2g).

ΗPLC Purity = 98.97 %, Chiral Purity by ΗPLC= 99.92%. MC% w/w by KF = 0.10 %. XRD and IR spectra are similar to those shown for Example 1 in Figure 1 and 2 respectively. Example 4:

(-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfmyl]-lH- benzimidazole, zinc salt was also prepared as follows.

The potassium salt of (S)-omeprazole ( lOO.Og) was stirred in acetone (1500ml) at 25 to 30°C and zinc sulphate pentahydrate (75.0 g ) was added. The reaction mixture was stirred for 5-6 hours. The solid that separated out was filtered through filter aid under vacuum and the wet cake was washed with acetone (200ml). The filtrate was concentrated under reduced pressure at 40-45°C to a semisolid material. Methanol (400 ml) was added, the solution so obtained was stirred with activated carbon (5.0 g) for another 30 minutes at 20-25°C. The carbon was filtered off and the filtrate concentrated under vacuum to a semisolid material. Water (500ml) was then added and the mixture was stirred at 25 to 30°C for 2 to 3 hours. Solid thus obtained was filtered, washed with water and air dried at 40 to 45°C for 7 to 8 hours to get (S)-omeprazole zinc (59.0).

ΗPLC Purity = 99.69 %, Chiral Purity by ΗPLC= 99.96 %. MC% w/w by KF = 3.44 %, Zn content (w/w): 6.04%; Powder XRD, IR in KBr and DSC spectra are as shown in Figure 7, 8 and 9 respectively, as shown in the accompanying drawings.

Claims

We Claim:
1. The zinc salt of (S)-omeprazole.
2. The salt according to claim 1, which is in amorphous form.
3. A process for preparing (S)-omeprazole zinc, comprising contacting (S)- omeprazole freebase or its sodium/potassium salt with zinc salt of an acid to form (S)-omeprazole zinc, wherein the process is carried out in the presence of a base whenever (S)-omeprazole freebase is used.
4. The process according to claim 3, wherein the zinc salt of an inorganic acid is used.
5. The process according to claim 4, wherein the zinc salt is selected from the group consisting of zinc chloride, zinc nitrate, zinc phosphate, zinc carbonate, and zinc sulphate.
6. The process according to claim 3, wherein the zinc salt of an organic acid is used.
7. The process according to claim 6, wherein the zinc salt is selected from the group consisting of zinc oxalate, zinc acetate, zinc lactate, zinc succinate, zinc citrate, and zinc tartrate.
8. The process according to claim 3, wherein the base is selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates and ammonium hydroxide.
9. The process according to claim 8, wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate.
10. The process according to claims 3, wherein the solvent is selected from the group consisting of water, ketones, alcohols, esters, cyclic ethers, chlorinated hydrocarbons, nitriles, dipolar aprotic solvents, and mixtures thereof.
11. The process according to claim 11 , wherein the solvent is selected from the group consisting of water, acetone, methyl isobutyl ketone, acetonitrile, dimethylsulfoxide, dimethylformamide, and mixtures thereof.
12. The process according to claim 3, wherein (S)-omeprazole zinc precipitates out spontaneously from the solvent.
13. The process according to claim 3, wherein amorphous form of (S)-omeprazole zinc is obtained.
14. A method for treating or preventing gastrointestinal inflammatory diseases, which comprises administering (S)-omeprazole zinc.
15. A method of inhibiting gastric acid secretion comprising administering (S)- omeprazole zinc.
16. The method according to claim 14 or 15, wherein (S)-omeprazole zinc is used for treatment or prophylaxis of gastric acid-related diseases and gastrointestinal inflammatory diseases selected from the group consisting of erosive or ulcerative gastroesophageal reflux disease (GERD), gastric ulcer, duodenal ulcer, reflux esophagitis, and gastritis.
17. The method according to claim 14 to 16, wherein amorphous form of the (S)- omeprazole zinc is used.
18. A pharmaceutical composition comprising (S)-omeprazole zinc and pharmaceutically acceptable carriers, diluents or excipients.
19. The pharmaceutical composition according to claim 19, wherein amorphous form of the (S)-omeprazole zinc is used.
PCT/IB2004/001378 2003-05-05 2004-05-04 Zinc salt of (s)-omeprazole WO2004099182A1 (en)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006073779A1 (en) * 2004-12-30 2006-07-13 Transform Phamaceuticals, Inc. Novel omeprazole forms and related methods
EP1726305A1 (en) * 2005-05-25 2006-11-29 Ratiopharm GmbH Zinc salt of omeprazole and its enantiomers
WO2007049914A1 (en) * 2005-10-26 2007-05-03 Hanmi Pharm. Co., Ltd. S-omeprazole strontium or hydrate thereof, method for preparing same, and pharmaceutical composition comprising same
EP1801110A1 (en) 2005-12-22 2007-06-27 KRKA, tovarna zdravil, d.d., Novo mesto Esomeprazole arginine salt
WO2007079784A1 (en) * 2005-12-22 2007-07-19 Ratiopharm Gmbh Enantioselective preparation of benzimidazole derivatives and their salts
WO2007089511A2 (en) 2006-01-27 2007-08-09 Yale University Fast acting inhibitor of gastric acid secretion
KR100818753B1 (en) * 2005-10-26 2008-04-01 한미약품 주식회사 S-omeprazole strontium or hydrate thereof, method for preparing same and pharmaceutical composition comprising same
WO2008092939A2 (en) 2007-01-31 2008-08-07 Krka, Tovarna Zdravil, D.D., Novo Mesto Process for the preparation of optically pure omeprazole via salt formation with a chiral amine or treatment with an entiomer converting enzyme and chromatographic separation
WO2009017624A2 (en) * 2007-07-26 2009-02-05 Yale University Compositions with enhanced bioavailability and fast acting inhibitor of gastric acid secretion
WO2015153552A1 (en) * 2014-03-31 2015-10-08 Yale University Fast acting inhibitor of gastric acid secretion with enhanced activity

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4738974A (en) * 1983-03-04 1988-04-19 Aktiebolaget Hassle Base addition salts of omeprazole
US5714504A (en) * 1993-05-28 1998-02-03 Astra Aktiebolag Compositions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4738974A (en) * 1983-03-04 1988-04-19 Aktiebolaget Hassle Base addition salts of omeprazole
US5714504A (en) * 1993-05-28 1998-02-03 Astra Aktiebolag Compositions

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006073779A1 (en) * 2004-12-30 2006-07-13 Transform Phamaceuticals, Inc. Novel omeprazole forms and related methods
EP1726305A1 (en) * 2005-05-25 2006-11-29 Ratiopharm GmbH Zinc salt of omeprazole and its enantiomers
WO2007049914A1 (en) * 2005-10-26 2007-05-03 Hanmi Pharm. Co., Ltd. S-omeprazole strontium or hydrate thereof, method for preparing same, and pharmaceutical composition comprising same
US8586752B1 (en) 2005-10-26 2013-11-19 Hanmi Science Co., Ltd Crystalline S-omeprazole strontium hydrate, method for preparing same, and pharmaceutical composition containing same
US7576219B2 (en) 2005-10-26 2009-08-18 Hanmi Pharm. Co., Ltd Crystalline S-omeprazole strontium hydrate, method for preparing same, and pharmaceutical composition containing same
US8106076B2 (en) 2005-10-26 2012-01-31 Hanmi Holdings Co., Ltd. Crystalline S-omeprazole strontium hydrate, method for preparing same, and pharmaceutical composition containing same
KR100818753B1 (en) * 2005-10-26 2008-04-01 한미약품 주식회사 S-omeprazole strontium or hydrate thereof, method for preparing same and pharmaceutical composition comprising same
EP2269999A1 (en) 2005-10-26 2011-01-05 Hanmi Pharm. Co., Ltd. Method for preparing crystalline s-omeprazole strontium hydrate
US8513426B2 (en) 2005-10-26 2013-08-20 Hanmi Science Co., Ltd Crystalline S-omeprazole strontium hydrate, method for preparing same, and pharmaceutical composition containing same
EP1801110A1 (en) 2005-12-22 2007-06-27 KRKA, tovarna zdravil, d.d., Novo mesto Esomeprazole arginine salt
WO2007079784A1 (en) * 2005-12-22 2007-07-19 Ratiopharm Gmbh Enantioselective preparation of benzimidazole derivatives and their salts
US20140154339A1 (en) * 2006-01-27 2014-06-05 John P. Geibel Fast Acting Inhibitor of Gastric Acid Secretion
US9034391B2 (en) 2006-01-27 2015-05-19 Yale University Compositions with enhanced bioavailability and fast acting inhibitor or gastric acid secretion
WO2007089511A3 (en) * 2006-01-27 2008-04-10 Univ Yale Fast acting inhibitor of gastric acid secretion
WO2007089511A2 (en) 2006-01-27 2007-08-09 Yale University Fast acting inhibitor of gastric acid secretion
CN101374526B (en) 2006-01-27 2013-08-07 耶鲁大学 Fast acting inhibitor of gastric acid secretion
US8512761B2 (en) 2006-01-27 2013-08-20 Yale University Fast acting inhibitor of gastric acid secretion
WO2008092939A2 (en) 2007-01-31 2008-08-07 Krka, Tovarna Zdravil, D.D., Novo Mesto Process for the preparation of optically pure omeprazole via salt formation with a chiral amine or treatment with an entiomer converting enzyme and chromatographic separation
WO2008092939A3 (en) * 2007-01-31 2009-01-29 Krka Tovarna Zdravil D D Novo Process for the preparation of optically pure omeprazole via salt formation with a chiral amine or treatment with an entiomer converting enzyme and chromatographic separation
WO2009017624A3 (en) * 2007-07-26 2009-03-26 Univ Yale Compositions with enhanced bioavailability and fast acting inhibitor of gastric acid secretion
WO2009017624A2 (en) * 2007-07-26 2009-02-05 Yale University Compositions with enhanced bioavailability and fast acting inhibitor of gastric acid secretion
WO2015153552A1 (en) * 2014-03-31 2015-10-08 Yale University Fast acting inhibitor of gastric acid secretion with enhanced activity

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