CA1264751A - Base addition salts of omeprazole - Google Patents
Base addition salts of omeprazoleInfo
- Publication number
- CA1264751A CA1264751A CA000448761A CA448761A CA1264751A CA 1264751 A CA1264751 A CA 1264751A CA 000448761 A CA000448761 A CA 000448761A CA 448761 A CA448761 A CA 448761A CA 1264751 A CA1264751 A CA 1264751A
- Authority
- CA
- Canada
- Prior art keywords
- omeprazole
- salt
- formula
- compound according
- alkyl group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic 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
- C07D401/02—Heterocyclic 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
- C07D401/12—Heterocyclic 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Compounds Of Unknown Constitution (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Food Preservation Except Freezing, Refrigeration, And Drying (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines Containing Plant Substances (AREA)
- Saccharide Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
- Inorganic Insulating Materials (AREA)
- Cephalosporin Compounds (AREA)
Abstract
Abstract There are disclosed novel salts of the compound known under the generic name omeprazole, having the formula (i) with Li+ , Na+ , K+ , Mg2+ , Ca2+ , Ti4+, N+(R1)4 or
Description
Novel comp_unds __ _ __ , _ _ _ Field of the i_vent on The invention relates to novel salts of the known com-pound omeprazole.
nd _f_the_l ention The compound known under the generic name omeprazole, having the structural formula OCH
3 ~ O CH ,_H3 ~ -S-CH2--1~ ( i ) which is described i.a. in European patent specification 0005129, is being extensively investigated clinically as a gastric acid secretion inhibiting agent.
Omeprazole is useful for inhibiting gastric acid secretion as well as for providing gastrointestinal cytoprotective effects in mammals and man. In a more general sense, omeprazole may be used for prevention and treatment of gastrointestinal inflammatory diseases in mammals and man, including e.g. gastritis, gastric ulcer, and duodenal ulcer. Furthermore, omeprazole may be used for prevention and treatment oE other gastrointestinal disorders where cytoprotective and/or gastric antisecretory effect is desir-
nd _f_the_l ention The compound known under the generic name omeprazole, having the structural formula OCH
3 ~ O CH ,_H3 ~ -S-CH2--1~ ( i ) which is described i.a. in European patent specification 0005129, is being extensively investigated clinically as a gastric acid secretion inhibiting agent.
Omeprazole is useful for inhibiting gastric acid secretion as well as for providing gastrointestinal cytoprotective effects in mammals and man. In a more general sense, omeprazole may be used for prevention and treatment of gastrointestinal inflammatory diseases in mammals and man, including e.g. gastritis, gastric ulcer, and duodenal ulcer. Furthermore, omeprazole may be used for prevention and treatment oE other gastrointestinal disorders where cytoprotective and/or gastric antisecretory effect is desir-
2~ able, e.g. in patients with gastrinomas, in patients with acute upper gastrointestinal bleeding, and in patients with a historyof chronic and excessive alcohol consumption.
, '..
~Z~47~
- la - 23940-461 The term "omeprazole" as used in this specification designates the neutral form of the compound of the formula (i), that is the form as given in the formula (i) without salt forming components present.
. . .
A problem with omeprazole is its stability characteristics. Upon storage without any special precautions being taken, it is degraded at a rate which is higher than desired. At storage during accelerated conditions, that is at +37C and at a relative humidity of 80% for a period of 6 months, about 6% of the substance is converted to degradation products.
While the rate of decomposition of omeprazole at normal storage con-ditions is lower, it is nevertheless desirable to obtain physical forms of omeprazole which exhibit improved stability. This need tor more stable forms of omeprazole is apparent when con-sidering the o~ten considerable time periods involved from the synthesisof the active substance through its incorporation in pharmaceutical preparations, distribution of the finished Droduct to Dharmacies etc. uD
to the consumption of the preparation by the patient. The present in-vention provides such new forms of omeprazole which exhibit improved storage stability.
The invention It has been founcl that the novel alkaline $alts of omeprazole with the structural formula r ~; cH2 S~ 1 n wherein n i5 1,2, or 4; A~ is Li , Na+, K , M92 , Ca2+, Ti4+, N (Rt)~ or H2N-C \ , wherein R is an alkyl qroup containinq 1-4 carbon atoms are more stable durinq storaqe than the corresDondina neutral form of omeprazole. The salts of the formula I are also easier to handle than the neutral form in the manufacture of pharmaceutical dosage units.
~LX~7~
A preferred group of omeprazole salts of the formula I are those where-in An+ is Na , K ,.M92 and Ca2 .
Further preferred salts are those wherein A~ is Na , M92 and Ca2 .
The Na -salt is especially preferred for the preparation of liquid pharmaceutical formulations, e.g. solutions for intravenous administra-tion. The M92 and Ca2 salts are especially preferred for the prepara-tion of tablets. The M92 salt is particularly preferred.
Illustrative examples of the alkyl group Rl are CH3, C2H5, n-C3H7, and n C4Hg.
The novel salts I of the invention are prepared by reacting omeprazole of the formula 5~
, '..
~Z~47~
- la - 23940-461 The term "omeprazole" as used in this specification designates the neutral form of the compound of the formula (i), that is the form as given in the formula (i) without salt forming components present.
. . .
A problem with omeprazole is its stability characteristics. Upon storage without any special precautions being taken, it is degraded at a rate which is higher than desired. At storage during accelerated conditions, that is at +37C and at a relative humidity of 80% for a period of 6 months, about 6% of the substance is converted to degradation products.
While the rate of decomposition of omeprazole at normal storage con-ditions is lower, it is nevertheless desirable to obtain physical forms of omeprazole which exhibit improved stability. This need tor more stable forms of omeprazole is apparent when con-sidering the o~ten considerable time periods involved from the synthesisof the active substance through its incorporation in pharmaceutical preparations, distribution of the finished Droduct to Dharmacies etc. uD
to the consumption of the preparation by the patient. The present in-vention provides such new forms of omeprazole which exhibit improved storage stability.
The invention It has been founcl that the novel alkaline $alts of omeprazole with the structural formula r ~; cH2 S~ 1 n wherein n i5 1,2, or 4; A~ is Li , Na+, K , M92 , Ca2+, Ti4+, N (Rt)~ or H2N-C \ , wherein R is an alkyl qroup containinq 1-4 carbon atoms are more stable durinq storaqe than the corresDondina neutral form of omeprazole. The salts of the formula I are also easier to handle than the neutral form in the manufacture of pharmaceutical dosage units.
~LX~7~
A preferred group of omeprazole salts of the formula I are those where-in An+ is Na , K ,.M92 and Ca2 .
Further preferred salts are those wherein A~ is Na , M92 and Ca2 .
The Na -salt is especially preferred for the preparation of liquid pharmaceutical formulations, e.g. solutions for intravenous administra-tion. The M92 and Ca2 salts are especially preferred for the prepara-tion of tablets. The M92 salt is particularly preferred.
Illustrative examples of the alkyl group Rl are CH3, C2H5, n-C3H7, and n C4Hg.
The novel salts I of the invention are prepared by reacting omeprazole of the formula 5~
3 ~ C 3 ~ ~/ ~ OCH3 with a ~ase capable of releasing the cation An+ (ii) wherein A~ is as defined above, to give a salt of the formula OCH
~ CH3 0 OCH
which salt is thereafter isolated.
Examples of bases capable of releasi~g the cation An~, and examples of reaction conditions are given b~low.
a) Salts of the formula I wherein A is Li, Na or K are prepared by treating omeprazole with LiOH, NaOH or KOH in an aqueous or nonaqueous medium or with LiOR, LiNH2, LiNR2, NaOR, NaNH2, NaNR2, KOR, KNH2 or KNR2, wherein R is an alkyl group containing 1-4 carbon atoms, in a nonaqueous medium.
b) Salts of the formula I wherein A is Mg, Ca, or Ti are prepared by treating omeprazole with Mg(OR)2, Ca(OR)2, CaH2, Ti(OR)4 or TiH4, wherein R is an alkyl group containing 1-4 carbon atoms, in a nonaqueous solvent such as an alcohol (only for the alcoholates), e.g.
ROH, or in an ether such as tetrahydrofuran 5~L
c) Salts of the formula I wherein A is H2N ~ are prepared by treating omeprazole with the strong base NH
H2N-C ~ NH2 2 NH
dissolved in a solvent7 for example an alcohol.
d) A salt of formula I may be converted to another salt of the same formula by exchanging the cation. When both the starting material and the salt obtained as final product are sufficiently soluble, such an ex-change may be performed by using a cation-exchange resin saturated with the cation desired in the product. The exchange may also be per-formed by utilizing the low solubility of a desired salt. By this principleJ for example, Na as a counter ion may be exchanged for Ca2+ or Mg2+.
e) The reaction between the compounds ~i) and (ii) may also be carried out by ion-pair extraction.For example, tetrabutylammonium salts of the invention may be prepared by dissolving the Na -salt in water con-taining tetrabutylammonium sulfate followed by extraction of the tetra-butylammonium salt I into a methylene chloride phase, and subsequent isolation of the tetrabutylammonium salt I. In this manner also other tetraalkylammonium salts I may be prepared.
Illustrative examples of the radical R are CH3, C2H5, n-C3H7, n-C4Hg, i-C4Hg, sec.-C4Hg and tert.-C4Hg.
The invention also relates to pharmaceutical compositions containing a novel salt of omeprazole as active ingredienti to the use of the novel omeprazolesalts for providing gastrointestinal cytoprotective effects in mammals and man; to the use of the novel omeprazole salts in the prevention and treatment of gastrointestinal inflammatory diseases in mammals and man; to the use of the novel omeprazole salts for inhibit-ing gastric acid secretion in mammals and man; to a method for inhibit-ing gastric acid secretion in mammals and man by administering a com-pound of the formula I; to a method for the treatment of gastrointesti-nal inflammatory diseases in mammals and man by administering a com-pound of the formula I; and to a method for providing gastrointesti-nal cytoprotective effects in mammals and man by administering a compound of the formula I.
For clinical use the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. The pharmaceu~ical formulation contains a compound of the invention in combination with a pharmaceutically acceptable carrier. The carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule. These pharmaceutical prepara-tions are a further object of the invention. Usually the amount of active compound is between 0.1-95% by weight of the preparation, between 0.2-?0% by weight in preparations for parenteral use and between 1 and 50% by weight in preparations for oral administration.
In the preparation of pharmaceutical formulations containing a compound of the present invention in the form of dosage units for oral admini-stration the compound selected may be mixed with a solid, powdered carrier, e.g. lactose, saccharose, sorbitol, mannitol, starch, amylo-pectin, cellulose derivatives or gelatin, as well as with lubricating agents e.g. magnesium stearate, calcium stearate, sodium steryl fuma-rate and polyethylene glycol waxes. The mixture is then processed into granules or pressed into tablets. Since the compounds of the invention are susceptible to degradation in acid to neutral media, the above-men-tioned granules or tablets are preferably coated with an enteric coating which protects the active compound from acid degradation as long as the dosage form remains in the stornach. The enteric coating is chosen among pharmaceutically acceptable enteric-coating materials e.g. beeswax.
shellac or anionic film-forming polymers such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, partly methyl esteri-fied methacrylic acid polymers and the like, if preferred in combination with a suitable plasticizer. To this coating various dyes may be added in order to distinguish among tablets or granules with different active compounds or with different amounts of the active compound present.
~L2~5~
Soft gelatine capsules may be prepared with capsules containing a mix-ture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Soft gelatine capsules are preferably enteric coated as described above.
Hard gelatine capsules may contain enteric-coated granules of the active compound. Hard gelatine capsules may also contain the active compound in combination with a solid powdered carrier e.g. lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine; the hard gelatine capsules are pre-ferably enteric coated as described above.
Dosage units for rectal administration may be prepared in the form ofsuppositories which contain the active substance mixed with a neutral fat base, or they may be prepared in the fonm of a gelatine rectal cap-sule which contains the active substance in a mixture with a vegetableoil, paraffin oil or other suitable vehicle for gelatine rectal cap-sules, or they may be prepared in the form of a ready-made micro enema, or they may be prepared in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing from 0.2% to 20% by weight of the active ingredient and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose and thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable sol-vent, preferably in a concentration from 0.1% to 10% by weight. These solutions may also contain stabilising agents and/or buffering agents and may be manufactured in unit dose ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
Sodium salts of the invention are preferably used in the preparation of parenteral formulations.
The typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the in-dividual requirement of each patient, the manner of administration and the disease. In general, oral and parenteral dosages will be in the range of 5 to 400 mg per day of active substance.
The following examples will further illustrate the invention.
Example 1. Preparation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2--pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium salt (omeprazole sodium salt).
Omeprazole (10009, 2.gO mol) was added to a solution of NaOH (1169, 2.90 mol) in deionized water (25l). After stirring for 5 min methylene chlor-ide (5l) was added and stirring was continued for 10 min. The two phases were separated. The aqueous phase was washed with methylene ' chloride (5l), filtered clear (Celite ~and concentrated by evaporation under reduced pressure to about 2 ltotal volume. Absolute ethanol (6~) was added and the evaporation was continued until dryness. Ethyl acetate (7~) was added, the mixture WdS stirred under reflux for 30 min. After cooling and standing over night the resulting slurry was stirred with an additional amount (2l) of ethyl acetate and filtered. The filter cake was washed with diethyl ether and dried under reduced pressure at 40C
over night giving o,neprazole sodium salt (9759, 92%), mp 208-210C, NMR:
~(D20): 1.85(s,3H), 2.1(s,3H), 3.5(s,3H), 3.85(s,3H), 4.75(s,2H), 6.85 (ddglH), 7.2(d,1H), 7.55(d,1H), 8.15(d,1H).
Example 2. Preparation of omeprazole sodium salt.
Omeprazole (13009, 3.77 mol) was added under vigorous mechanic stirring to a mixture of tetrahydrofuran (13l) and 50% aqueous NaOH (2969, 3.7 mol) and stirring was then continued fsr 45 min. Trichloroethylene (5.7l) was added and stirring was continued over night at room tempera-ture. The mixture was cooled to +5C and then stirred for 3h. The pre-cipitate was filtered off and the filter cake was washed with trichloro-ethylene (5l) and dried under reduced pressure at 50C giving o.neprazole ft~D ~
sodium salt (13149, 95~), mp 208-210C.
Example 3. Preparation of omeprazole potassium salt.
Omeprazole (10.09, 0.0290 mol) was added to a solution of KOH (1.609.
0.0285 mol) in deionized water and then methylene chloride (50ml) was added. The mixture was stirred vigorously for 15 min. The phases were separated and the aqueous phase was washed with methylene chloride (50ml) and filtered clear (Celite). Evaporation to dryness gave a crystalline residue. Recrystallisation from ethyl acetate yielded omeprazole patassium salt, mp. 148-150C (soluble in water).
Example 4. Preparation of di-omeprazole calcium salt dihydrate.
Anhydrous CaC12 (17.99, 0.161 mol) dissolved in deionized water (200 ml) was added dropwise under viogorous stirring to a solution of omepra-zole sodium salt (1259, 0.340 mol) in deionized water (1250 ml) andthen stirring was continued for lh at room temperature. The precipitate was centrifugated down and washed with deionized water until no Cl was detectable (AgN03). After drying in the air and grinding, the cry-stals were dried in vacuum at 40 for 20h yielding omeprazole calcium salt dihydrate (1049, 80%), mp 182-184C, NMR: o~CDC13~1 drop of DMSO-d6) 2.0(s,3H), 2.15(s,3H), 3.6(s,3H), 3.7(s,3H), 4.5(s,2H), 6.7(dd,1H), 7.1(d,1H), 7.6(d,1H, 8.15(s,1H).
_xample 5. Preparation of di-omeprazole magnesium salt dihydrate.
Anhydrous MgC12 (16.29, 0.17 mol) dissolved in deionized water (625 ml) was added dropwise under vigorous stirring to a solution of omeprazole sodium salt (1259, 0.340 mol) in deionized water(l560ml) and then the stirring was continued for lh at room temperature. The precipitate was centrifugated down and then washed with deionized water until no Cl was detectable (AgN03). Drying in the air, grinding and drying in vacuum at 40 for 24h yielded omeprazole magnesium salt dihydrate (1119, 87%) mp 177-178C.
Example 6. Preparation of di-Omeprazole magnesium salt.
Magnesium (0.359, 0.0145 mol) was reacted with absolute methanol (lOml) (in the presence of one drop of CC14) to give a solution of Mg(OCH3)2 in methanol solution. More methanol (lOml) was added and the solution lo was added dropwise to a solution of omeprazole (10 a ! 0.029 m) in rnethanol (200 ml) and the mixture was then stirred for 30 min at room temperature. Evaporation gave a crystalline solid of the di-omeprazole magnesium salt, mp. 178-180.
Example 7. Preparation of omeprazole tetrabutylammonium salt.
Omeprazole sodium salt (3.89, 0.010 mol) was added to a mixture of tetrabutylammonium hydrogensulphate (3.5g, 0.010 mol) and NaOH (0.42 9, 0.0105 mol) in deionized water (15ml). Methylene chloride (lOml) was added and the mixture was shaken in a separatory funnel. After sepa-ration of the phases the organic phase was dried and the solvent evapo-rated off giving omeprazole tetrabutylammonium salt (3.59, 60%)~ NMR:
o~(CDC13): 0.8-1.15(m,12H), 1.15-1.6(m,16H), 2.25(s,3H), 2.3(s,3H), 2.75-3.15(m,8H), 3.75(s,3H), 3.9(s,3H), 4.7(d,1H), 5.05(d,1H), 6.8 (dd,lH), 7~3(d,1H), 7.7(d,1H), 8.35(s,1H).
Example 8. Preparation of omeprazole guanidinium [C (NH2)3] salt.
A solution of guanidine (0.0029 mol)[prepared from guanidinium nitrate and KOH] in ethanol (50ml) was added to a solution of omeprazole (l.Og, 0.0029 mol) and the resulti~g solution was stirred for 15 min.
The solvent was evaporated giving omeprazole guanidinium salt, mp 110-112C (soluble in water).
Example 9. Preparation of tetra-omeprazole titanium salt.
Titanium tetraisopropylate (1.039, 0.0036 mol) was added to a solution of omeprazole in dry isopropanol (250ml) and the mixture was stirred under N2 at room temperature for 4h. (A white precipitate was formed).
Evaporation of the solvent followed by washing 3 times with light pet-roleum and drying in vacuum gave a white-crystalline powder of tetra-omeprazole titanium salt, mp >260C.
Example 10. Preparation of omeprazolelit~lium salt.Omeprazole (3.0 9, 0.0087 mol) was added to a solution of LiOH (0.207 9, 0.00865 mol) in deionized water and then methylene chloride (25 ml) was added. The mix~ure was stirred vigorously for 15 min. The phases were separated and the aqueous phase was washed with methylene chloride (25 ml) and filtered clear (Celite). Evaporation to dryness gave a cry-stalline omeprazole lithium salt, mp. 198-200C (soluble in water).
fi~751 NMR:c~(CDC13) 1.65 (s,3H), 1.8 (s,3H), 3.45 (s,3H), 3.4 (s,3H),
~ CH3 0 OCH
which salt is thereafter isolated.
Examples of bases capable of releasi~g the cation An~, and examples of reaction conditions are given b~low.
a) Salts of the formula I wherein A is Li, Na or K are prepared by treating omeprazole with LiOH, NaOH or KOH in an aqueous or nonaqueous medium or with LiOR, LiNH2, LiNR2, NaOR, NaNH2, NaNR2, KOR, KNH2 or KNR2, wherein R is an alkyl group containing 1-4 carbon atoms, in a nonaqueous medium.
b) Salts of the formula I wherein A is Mg, Ca, or Ti are prepared by treating omeprazole with Mg(OR)2, Ca(OR)2, CaH2, Ti(OR)4 or TiH4, wherein R is an alkyl group containing 1-4 carbon atoms, in a nonaqueous solvent such as an alcohol (only for the alcoholates), e.g.
ROH, or in an ether such as tetrahydrofuran 5~L
c) Salts of the formula I wherein A is H2N ~ are prepared by treating omeprazole with the strong base NH
H2N-C ~ NH2 2 NH
dissolved in a solvent7 for example an alcohol.
d) A salt of formula I may be converted to another salt of the same formula by exchanging the cation. When both the starting material and the salt obtained as final product are sufficiently soluble, such an ex-change may be performed by using a cation-exchange resin saturated with the cation desired in the product. The exchange may also be per-formed by utilizing the low solubility of a desired salt. By this principleJ for example, Na as a counter ion may be exchanged for Ca2+ or Mg2+.
e) The reaction between the compounds ~i) and (ii) may also be carried out by ion-pair extraction.For example, tetrabutylammonium salts of the invention may be prepared by dissolving the Na -salt in water con-taining tetrabutylammonium sulfate followed by extraction of the tetra-butylammonium salt I into a methylene chloride phase, and subsequent isolation of the tetrabutylammonium salt I. In this manner also other tetraalkylammonium salts I may be prepared.
Illustrative examples of the radical R are CH3, C2H5, n-C3H7, n-C4Hg, i-C4Hg, sec.-C4Hg and tert.-C4Hg.
The invention also relates to pharmaceutical compositions containing a novel salt of omeprazole as active ingredienti to the use of the novel omeprazolesalts for providing gastrointestinal cytoprotective effects in mammals and man; to the use of the novel omeprazole salts in the prevention and treatment of gastrointestinal inflammatory diseases in mammals and man; to the use of the novel omeprazole salts for inhibit-ing gastric acid secretion in mammals and man; to a method for inhibit-ing gastric acid secretion in mammals and man by administering a com-pound of the formula I; to a method for the treatment of gastrointesti-nal inflammatory diseases in mammals and man by administering a com-pound of the formula I; and to a method for providing gastrointesti-nal cytoprotective effects in mammals and man by administering a compound of the formula I.
For clinical use the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. The pharmaceu~ical formulation contains a compound of the invention in combination with a pharmaceutically acceptable carrier. The carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule. These pharmaceutical prepara-tions are a further object of the invention. Usually the amount of active compound is between 0.1-95% by weight of the preparation, between 0.2-?0% by weight in preparations for parenteral use and between 1 and 50% by weight in preparations for oral administration.
In the preparation of pharmaceutical formulations containing a compound of the present invention in the form of dosage units for oral admini-stration the compound selected may be mixed with a solid, powdered carrier, e.g. lactose, saccharose, sorbitol, mannitol, starch, amylo-pectin, cellulose derivatives or gelatin, as well as with lubricating agents e.g. magnesium stearate, calcium stearate, sodium steryl fuma-rate and polyethylene glycol waxes. The mixture is then processed into granules or pressed into tablets. Since the compounds of the invention are susceptible to degradation in acid to neutral media, the above-men-tioned granules or tablets are preferably coated with an enteric coating which protects the active compound from acid degradation as long as the dosage form remains in the stornach. The enteric coating is chosen among pharmaceutically acceptable enteric-coating materials e.g. beeswax.
shellac or anionic film-forming polymers such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, partly methyl esteri-fied methacrylic acid polymers and the like, if preferred in combination with a suitable plasticizer. To this coating various dyes may be added in order to distinguish among tablets or granules with different active compounds or with different amounts of the active compound present.
~L2~5~
Soft gelatine capsules may be prepared with capsules containing a mix-ture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Soft gelatine capsules are preferably enteric coated as described above.
Hard gelatine capsules may contain enteric-coated granules of the active compound. Hard gelatine capsules may also contain the active compound in combination with a solid powdered carrier e.g. lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine; the hard gelatine capsules are pre-ferably enteric coated as described above.
Dosage units for rectal administration may be prepared in the form ofsuppositories which contain the active substance mixed with a neutral fat base, or they may be prepared in the fonm of a gelatine rectal cap-sule which contains the active substance in a mixture with a vegetableoil, paraffin oil or other suitable vehicle for gelatine rectal cap-sules, or they may be prepared in the form of a ready-made micro enema, or they may be prepared in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing from 0.2% to 20% by weight of the active ingredient and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose and thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable sol-vent, preferably in a concentration from 0.1% to 10% by weight. These solutions may also contain stabilising agents and/or buffering agents and may be manufactured in unit dose ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
Sodium salts of the invention are preferably used in the preparation of parenteral formulations.
The typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the in-dividual requirement of each patient, the manner of administration and the disease. In general, oral and parenteral dosages will be in the range of 5 to 400 mg per day of active substance.
The following examples will further illustrate the invention.
Example 1. Preparation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2--pyridinyl)-methyl]sulfinyl]-lH-benzimidazole sodium salt (omeprazole sodium salt).
Omeprazole (10009, 2.gO mol) was added to a solution of NaOH (1169, 2.90 mol) in deionized water (25l). After stirring for 5 min methylene chlor-ide (5l) was added and stirring was continued for 10 min. The two phases were separated. The aqueous phase was washed with methylene ' chloride (5l), filtered clear (Celite ~and concentrated by evaporation under reduced pressure to about 2 ltotal volume. Absolute ethanol (6~) was added and the evaporation was continued until dryness. Ethyl acetate (7~) was added, the mixture WdS stirred under reflux for 30 min. After cooling and standing over night the resulting slurry was stirred with an additional amount (2l) of ethyl acetate and filtered. The filter cake was washed with diethyl ether and dried under reduced pressure at 40C
over night giving o,neprazole sodium salt (9759, 92%), mp 208-210C, NMR:
~(D20): 1.85(s,3H), 2.1(s,3H), 3.5(s,3H), 3.85(s,3H), 4.75(s,2H), 6.85 (ddglH), 7.2(d,1H), 7.55(d,1H), 8.15(d,1H).
Example 2. Preparation of omeprazole sodium salt.
Omeprazole (13009, 3.77 mol) was added under vigorous mechanic stirring to a mixture of tetrahydrofuran (13l) and 50% aqueous NaOH (2969, 3.7 mol) and stirring was then continued fsr 45 min. Trichloroethylene (5.7l) was added and stirring was continued over night at room tempera-ture. The mixture was cooled to +5C and then stirred for 3h. The pre-cipitate was filtered off and the filter cake was washed with trichloro-ethylene (5l) and dried under reduced pressure at 50C giving o.neprazole ft~D ~
sodium salt (13149, 95~), mp 208-210C.
Example 3. Preparation of omeprazole potassium salt.
Omeprazole (10.09, 0.0290 mol) was added to a solution of KOH (1.609.
0.0285 mol) in deionized water and then methylene chloride (50ml) was added. The mixture was stirred vigorously for 15 min. The phases were separated and the aqueous phase was washed with methylene chloride (50ml) and filtered clear (Celite). Evaporation to dryness gave a crystalline residue. Recrystallisation from ethyl acetate yielded omeprazole patassium salt, mp. 148-150C (soluble in water).
Example 4. Preparation of di-omeprazole calcium salt dihydrate.
Anhydrous CaC12 (17.99, 0.161 mol) dissolved in deionized water (200 ml) was added dropwise under viogorous stirring to a solution of omepra-zole sodium salt (1259, 0.340 mol) in deionized water (1250 ml) andthen stirring was continued for lh at room temperature. The precipitate was centrifugated down and washed with deionized water until no Cl was detectable (AgN03). After drying in the air and grinding, the cry-stals were dried in vacuum at 40 for 20h yielding omeprazole calcium salt dihydrate (1049, 80%), mp 182-184C, NMR: o~CDC13~1 drop of DMSO-d6) 2.0(s,3H), 2.15(s,3H), 3.6(s,3H), 3.7(s,3H), 4.5(s,2H), 6.7(dd,1H), 7.1(d,1H), 7.6(d,1H, 8.15(s,1H).
_xample 5. Preparation of di-omeprazole magnesium salt dihydrate.
Anhydrous MgC12 (16.29, 0.17 mol) dissolved in deionized water (625 ml) was added dropwise under vigorous stirring to a solution of omeprazole sodium salt (1259, 0.340 mol) in deionized water(l560ml) and then the stirring was continued for lh at room temperature. The precipitate was centrifugated down and then washed with deionized water until no Cl was detectable (AgN03). Drying in the air, grinding and drying in vacuum at 40 for 24h yielded omeprazole magnesium salt dihydrate (1119, 87%) mp 177-178C.
Example 6. Preparation of di-Omeprazole magnesium salt.
Magnesium (0.359, 0.0145 mol) was reacted with absolute methanol (lOml) (in the presence of one drop of CC14) to give a solution of Mg(OCH3)2 in methanol solution. More methanol (lOml) was added and the solution lo was added dropwise to a solution of omeprazole (10 a ! 0.029 m) in rnethanol (200 ml) and the mixture was then stirred for 30 min at room temperature. Evaporation gave a crystalline solid of the di-omeprazole magnesium salt, mp. 178-180.
Example 7. Preparation of omeprazole tetrabutylammonium salt.
Omeprazole sodium salt (3.89, 0.010 mol) was added to a mixture of tetrabutylammonium hydrogensulphate (3.5g, 0.010 mol) and NaOH (0.42 9, 0.0105 mol) in deionized water (15ml). Methylene chloride (lOml) was added and the mixture was shaken in a separatory funnel. After sepa-ration of the phases the organic phase was dried and the solvent evapo-rated off giving omeprazole tetrabutylammonium salt (3.59, 60%)~ NMR:
o~(CDC13): 0.8-1.15(m,12H), 1.15-1.6(m,16H), 2.25(s,3H), 2.3(s,3H), 2.75-3.15(m,8H), 3.75(s,3H), 3.9(s,3H), 4.7(d,1H), 5.05(d,1H), 6.8 (dd,lH), 7~3(d,1H), 7.7(d,1H), 8.35(s,1H).
Example 8. Preparation of omeprazole guanidinium [C (NH2)3] salt.
A solution of guanidine (0.0029 mol)[prepared from guanidinium nitrate and KOH] in ethanol (50ml) was added to a solution of omeprazole (l.Og, 0.0029 mol) and the resulti~g solution was stirred for 15 min.
The solvent was evaporated giving omeprazole guanidinium salt, mp 110-112C (soluble in water).
Example 9. Preparation of tetra-omeprazole titanium salt.
Titanium tetraisopropylate (1.039, 0.0036 mol) was added to a solution of omeprazole in dry isopropanol (250ml) and the mixture was stirred under N2 at room temperature for 4h. (A white precipitate was formed).
Evaporation of the solvent followed by washing 3 times with light pet-roleum and drying in vacuum gave a white-crystalline powder of tetra-omeprazole titanium salt, mp >260C.
Example 10. Preparation of omeprazolelit~lium salt.Omeprazole (3.0 9, 0.0087 mol) was added to a solution of LiOH (0.207 9, 0.00865 mol) in deionized water and then methylene chloride (25 ml) was added. The mix~ure was stirred vigorously for 15 min. The phases were separated and the aqueous phase was washed with methylene chloride (25 ml) and filtered clear (Celite). Evaporation to dryness gave a cry-stalline omeprazole lithium salt, mp. 198-200C (soluble in water).
fi~751 NMR:c~(CDC13) 1.65 (s,3H), 1.8 (s,3H), 3.45 (s,3H), 3.4 (s,3H),
4.2 (s,2H), 6.6 (dd,lH), 6.95 (d,lH), 7.45 (d,lH), 7.75 (s,lH).
The NMR data given in the examples are measured at 90 MHz.
Incorporation of the novel omeprazole salts of the present invention in plarmaceutical preparations is exemplified in the following examples.
Example 11. Syrup A syrup containing 1% (weight per volume) of active substance was pre-pared from the following ingredients:
I Omeprazole sodium salt 1.0 9 Sugar, powder 30.0 9 II Saccharine 0.6 9 Glycerol 5.0 9 Flavouring agent 0.059 Ethanol 5.0 9 Sorbic acid 0.5 9 Sodium dihydrogen phosphate q.s. to pH= 9.0 9 Distilled water q.s. to a final volume of 100 ml I Powdered omeprazole sodium salt was carefully dry mixed with pow-dered sugar, dried in a vacuum oven over-night and dispensed into bottles each containing 31.0 gram of the powder mixture.
II A solution of saccharine, glycerol, flavouring agent, ethanol, sodium dihydrogen phosphate, sorbic acid and water was prepared, and dispensed into vials. When mixed with the powder mixture of omeprazole sodium salt and sugar the final volume was 100 ml.
Solvent vial II is to be added to powder mixture vial I just prior to use. The formed suspension is stable for ten days when stored at re-frigerator temperature.
The salt given above may be replaced with another salt of the invention.
12~7~L
Example 12. Enteric-coated tablets An enteric-coated tablet containing 20 mg of active compound was pre-pared from the following ingredients:
I Omeprazole magnesium salt 200 9 Lactose 700 9 Methyl cellulose 6 9 Polyvinylpyrrolidone cross-linked50 g Magnesium stearate 15 9 Distilled water q.s.
II Cellulose acetate phthalate 200 9 Cetyl alcohol 15 9 Isopropanol 2000 g Methylene chloride 2000 9 I Omeprazole magnesium salt, powder, was mixed with lactose, and granulated with a water solution of methyl cellulose. The wet mass was forced through a sieve and the granulate dried in an oven. After drying the granulate was mixed with polyvinylpyrroli-done and magnesium stearate. The dry mixture was pressed into tab-let cores (10 000 tablets), each tablet containing 20 mg of active substance, in a tabletting machine using 6 mm diameter punches.
II A solution of cellulose acetate phthalate and cetyl alcohol in isopropanol/methylene chloride was sprayed onto the tablets I in an Accela Cota~, Manesty coating equipment. A final tablet weight of 110 mg was obtained.
Example 13. Solution for intravenous administration -A parenteral formulation for intravenous use, containing 4 mg of active compound per ml, was prepared from the following ingredients:
7 S ~L
I Omeprazole sodium salt 4.26 9 Sterile water 200 ml II Polyethylene glycol 400 for injection 400 9 Sodium dihydrogen phosphate 1.5 9 Sterile water to a final volume of1000 ml I Omeprazole sodium salt 4.26 9, corresponding to 4.0 9 of omepra-zole, was dissolved in sterile water to a final volume of 200 ml.
The solution was filtered through a 0.22 ~ filter and dispensed into sterile vials, each vial containing 2.0 ml. The vials were placed in a freeze drier with a shelf temperature of -40C. When the solution in the vials had frozen, the solution was freeze dried. After drying the vials were stoppered.
II A solution of polyethylene glycol and sodium dihydrogen phosphate in sterile water was prepared, filtered through a 0.22 ,u filter, dispensed into sterile vials and the vials closed with a rubber stopper. The vials were sterilised in an autoclave at +120C for twenty minutes. Immediately before use 10.0 ml of solvent II is added to vial I. The clear solution contains 4 mg of omeprazole per millilitre.
Test of the stability of omeprazole salts of the invention The stability of omeprazole sodium salt, of the invention, obtained according to Example 1, was compared with the stability of the neutral form of omeprazole. Both test compounds were stored for six months at + 37C and at a relative humidity of 80%. Thereafter, the amount of degradation products which had formed was measured. The result is given in Table 1 below.
'f~6~L7~i~L
Table 1. Stability of neutral omeprazole and of omeprazole sodium salt after six months storage at ~ 37~C and 80Yo relative humidity
The NMR data given in the examples are measured at 90 MHz.
Incorporation of the novel omeprazole salts of the present invention in plarmaceutical preparations is exemplified in the following examples.
Example 11. Syrup A syrup containing 1% (weight per volume) of active substance was pre-pared from the following ingredients:
I Omeprazole sodium salt 1.0 9 Sugar, powder 30.0 9 II Saccharine 0.6 9 Glycerol 5.0 9 Flavouring agent 0.059 Ethanol 5.0 9 Sorbic acid 0.5 9 Sodium dihydrogen phosphate q.s. to pH= 9.0 9 Distilled water q.s. to a final volume of 100 ml I Powdered omeprazole sodium salt was carefully dry mixed with pow-dered sugar, dried in a vacuum oven over-night and dispensed into bottles each containing 31.0 gram of the powder mixture.
II A solution of saccharine, glycerol, flavouring agent, ethanol, sodium dihydrogen phosphate, sorbic acid and water was prepared, and dispensed into vials. When mixed with the powder mixture of omeprazole sodium salt and sugar the final volume was 100 ml.
Solvent vial II is to be added to powder mixture vial I just prior to use. The formed suspension is stable for ten days when stored at re-frigerator temperature.
The salt given above may be replaced with another salt of the invention.
12~7~L
Example 12. Enteric-coated tablets An enteric-coated tablet containing 20 mg of active compound was pre-pared from the following ingredients:
I Omeprazole magnesium salt 200 9 Lactose 700 9 Methyl cellulose 6 9 Polyvinylpyrrolidone cross-linked50 g Magnesium stearate 15 9 Distilled water q.s.
II Cellulose acetate phthalate 200 9 Cetyl alcohol 15 9 Isopropanol 2000 g Methylene chloride 2000 9 I Omeprazole magnesium salt, powder, was mixed with lactose, and granulated with a water solution of methyl cellulose. The wet mass was forced through a sieve and the granulate dried in an oven. After drying the granulate was mixed with polyvinylpyrroli-done and magnesium stearate. The dry mixture was pressed into tab-let cores (10 000 tablets), each tablet containing 20 mg of active substance, in a tabletting machine using 6 mm diameter punches.
II A solution of cellulose acetate phthalate and cetyl alcohol in isopropanol/methylene chloride was sprayed onto the tablets I in an Accela Cota~, Manesty coating equipment. A final tablet weight of 110 mg was obtained.
Example 13. Solution for intravenous administration -A parenteral formulation for intravenous use, containing 4 mg of active compound per ml, was prepared from the following ingredients:
7 S ~L
I Omeprazole sodium salt 4.26 9 Sterile water 200 ml II Polyethylene glycol 400 for injection 400 9 Sodium dihydrogen phosphate 1.5 9 Sterile water to a final volume of1000 ml I Omeprazole sodium salt 4.26 9, corresponding to 4.0 9 of omepra-zole, was dissolved in sterile water to a final volume of 200 ml.
The solution was filtered through a 0.22 ~ filter and dispensed into sterile vials, each vial containing 2.0 ml. The vials were placed in a freeze drier with a shelf temperature of -40C. When the solution in the vials had frozen, the solution was freeze dried. After drying the vials were stoppered.
II A solution of polyethylene glycol and sodium dihydrogen phosphate in sterile water was prepared, filtered through a 0.22 ,u filter, dispensed into sterile vials and the vials closed with a rubber stopper. The vials were sterilised in an autoclave at +120C for twenty minutes. Immediately before use 10.0 ml of solvent II is added to vial I. The clear solution contains 4 mg of omeprazole per millilitre.
Test of the stability of omeprazole salts of the invention The stability of omeprazole sodium salt, of the invention, obtained according to Example 1, was compared with the stability of the neutral form of omeprazole. Both test compounds were stored for six months at + 37C and at a relative humidity of 80%. Thereafter, the amount of degradation products which had formed was measured. The result is given in Table 1 below.
'f~6~L7~i~L
Table 1. Stability of neutral omeprazole and of omeprazole sodium salt after six months storage at ~ 37~C and 80Yo relative humidity
5 Test compound Amount of degradation products forrned (per cent calculated on original amount of omeprazole) neutral omeprazole 6 10 omeprazole sodium salt 0.4 As is seen in Table 1 the omeprazole sodium salt of the invention gave rise to substantially lower amounts of degradation products than the neutral forrn of omeprazol. This shows the improved stability of the novel omeprazole salts of the invention.
Claims (11)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A compound of the formula An+ (I) wherein n is 1, 2, or 4; and An+ is Li+, Na+, K+, Mg2+, Ca2+, Ti4+, wherein R1 is an alkyl group containing 1-4 carbon atoms.
2. A compound according to claim 1 wherein An+ is Na+, K+, Mg2+ or ca2+.
3. A compound according to claim 1 wherein An+ is Na+.
4. A compound according to claim 1 wherein An+ is Mg2+.
5. A process for the preparation of a compound of the formula I
An+ (I) wherein n is 1, 2, or 4; and An+ is Li+, Na+, K+, Mg2+, Ca2+, Ti4+, and wherein R1 is an alkyl group containing 1-4 carbon atoms, which process comprises reacting omeprazole of the formula (i) (i) a) with LiOH, NaOH or KOH in an aqueous or nonaqueous medium or with LiOR, LiNH2, LiNR2, NaOR, NaNH2, NaNR2, KOR, KNH2 or KNR2, wherein R is an alkyl group containing 1-4 carbon atoms, in a nonaqueous medium, to obtain a salt of the formula I wherein A is Li, Na or K;
b) with Mg(OR)2, Ca(OR)2, CaH2, Ti(OR)4 or TiH4, wherein R
is an alkyl group containing 1-4 carbon atoms, in a nonaqeous solvent to obtain a salt of the formula I wherein A is Mg, Ca, or Ti;
c) with the strong base dissolved in a solvent, to obtain the salt of the formula I wherein A is , or converting a salt of formula I into another salt of formula I by exchanging the cation, and isolating the salt so obtained.
An+ (I) wherein n is 1, 2, or 4; and An+ is Li+, Na+, K+, Mg2+, Ca2+, Ti4+, and wherein R1 is an alkyl group containing 1-4 carbon atoms, which process comprises reacting omeprazole of the formula (i) (i) a) with LiOH, NaOH or KOH in an aqueous or nonaqueous medium or with LiOR, LiNH2, LiNR2, NaOR, NaNH2, NaNR2, KOR, KNH2 or KNR2, wherein R is an alkyl group containing 1-4 carbon atoms, in a nonaqueous medium, to obtain a salt of the formula I wherein A is Li, Na or K;
b) with Mg(OR)2, Ca(OR)2, CaH2, Ti(OR)4 or TiH4, wherein R
is an alkyl group containing 1-4 carbon atoms, in a nonaqeous solvent to obtain a salt of the formula I wherein A is Mg, Ca, or Ti;
c) with the strong base dissolved in a solvent, to obtain the salt of the formula I wherein A is , or converting a salt of formula I into another salt of formula I by exchanging the cation, and isolating the salt so obtained.
6. A process according to claim 5 wherein omeprazole is reacted with NaOH, NaNH2, or NaNR2 and wherein R is an alkyl group containing 1-4 carbon atoms.
7. A process according to claim 5 wherein omeprazole is reacted with Mg(OR)2 and wherein R is an alkyl group containing 1-4 carbon atoms.
8. A pharmaceutical composition comprising as active ingredient an effective amount of a compound according to claim 1, 2 or 3 in admixture with pharmaceutically acceptable diluent or carrier.
9. A pharmaceutical composition comprising as active ingredient an effective amount of a compound according to claim 4 in admixture with pharmaceutically acceptable diluent or carrier.
10. A method for making a pharmaceutical composition, which method comprises incorporating a compound according to claim 1, 2 or 3 as active ingredient in the composition.
11. A method for making a pharmaceutical composition, which method comprises incorporating a compound according to claim 4 as active ingredient in the composition.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8301182.5 | 1983-03-04 | ||
| SE8301182A SE8301182D0 (en) | 1983-03-04 | 1983-03-04 | NOVEL COMPOUNDS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1264751A true CA1264751A (en) | 1990-01-23 |
Family
ID=20350251
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000448761A Expired - Lifetime CA1264751A (en) | 1983-03-04 | 1984-03-02 | Base addition salts of omeprazole |
Country Status (43)
| Country | Link |
|---|---|
| US (1) | US4738974A (en) |
| EP (1) | EP0124495B1 (en) |
| JP (1) | JPS59167587A (en) |
| KR (1) | KR870001005B1 (en) |
| AT (1) | ATE24907T1 (en) |
| AU (1) | AU563842B2 (en) |
| BG (2) | BG44538A3 (en) |
| CA (1) | CA1264751A (en) |
| CS (1) | CS241150B2 (en) |
| DD (1) | DD221459A5 (en) |
| DE (2) | DE3462036D1 (en) |
| DK (1) | DK160044C (en) |
| DZ (1) | DZ615A1 (en) |
| ES (2) | ES8500934A1 (en) |
| FI (1) | FI83649C (en) |
| GB (1) | GB2137616B (en) |
| GR (1) | GR79828B (en) |
| HK (1) | HK13590A (en) |
| HR (1) | HRP930428B1 (en) |
| HU (1) | HU193557B (en) |
| IE (1) | IE57326B1 (en) |
| IL (1) | IL70985A (en) |
| IS (1) | IS1363B6 (en) |
| JO (1) | JO1425B1 (en) |
| LT (1) | LT2253B (en) |
| LU (1) | LU90677I2 (en) |
| LV (2) | LV5503A3 (en) |
| MA (1) | MA20050A1 (en) |
| MY (1) | MY102052A (en) |
| NL (1) | NL300027I2 (en) |
| NO (2) | NO160204C (en) |
| NZ (1) | NZ207348A (en) |
| PH (1) | PH21352A (en) |
| PL (1) | PL142748B1 (en) |
| PT (1) | PT78191B (en) |
| RO (1) | RO88721A (en) |
| SA (1) | SA92120418B1 (en) |
| SE (1) | SE8301182D0 (en) |
| SG (1) | SG1490G (en) |
| SI (1) | SI8410397A8 (en) |
| SU (1) | SU1314953A3 (en) |
| YU (1) | YU43345B (en) |
| ZA (1) | ZA841202B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6048981A (en) * | 1998-04-22 | 2000-04-11 | Torcan Chemical Ltd. | Magnesium omeprazole and process for its preparation |
| US6077541A (en) * | 1997-11-14 | 2000-06-20 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US6174548B1 (en) | 1998-08-28 | 2001-01-16 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US6733778B1 (en) | 1999-08-27 | 2004-05-11 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US8809542B2 (en) | 2000-08-04 | 2014-08-19 | Takeda Pharmaceutical Company Limited | Salts of benzimidazole compound and use thereof |
Families Citing this family (154)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5869513A (en) * | 1985-05-24 | 1999-02-09 | G. D. Searle & Co. | 2- (1H-benzimidazol-2-ylsulfinyl)methyl!benzenamines |
| AU5768886A (en) | 1985-05-24 | 1986-11-27 | G.D. Searle & Co. | 2-((1-h-benzimidazol-2-ylsulfinyl)methyl)benzenamines |
| US5433959A (en) | 1986-02-13 | 1995-07-18 | Takeda Chemical Industries, Ltd. | Stabilized pharmaceutical composition |
| CA1327010C (en) * | 1986-02-13 | 1994-02-15 | Tadashi Makino | Stabilized solid pharmaceutical composition containing antiulcer benzimidazole compound and its production |
| US6749864B2 (en) * | 1986-02-13 | 2004-06-15 | Takeda Chemical Industries, Ltd. | Stabilized pharmaceutical composition |
| JPS62277322A (en) * | 1986-02-13 | 1987-12-02 | Takeda Chem Ind Ltd | Stabilized pharmaceutical composition and production thereof |
| GB2189699A (en) * | 1986-04-30 | 1987-11-04 | Haessle Ab | Coated acid-labile medicaments |
| GB2189698A (en) * | 1986-04-30 | 1987-11-04 | Haessle Ab | Coated omeprazole tablets |
| US4687775A (en) * | 1986-07-17 | 1987-08-18 | G. D. Searle & Co. | 2-[(Imidazo[1,2-a]pyridinylmethyl)sulfinyl]-1H-benzimidazoles |
| US4772619A (en) * | 1986-07-17 | 1988-09-20 | G. D. Searle & Co. | [(1H-benzimidazol-2-ylsulfinyl)methyl]-2-pyridinamines |
| US4721718A (en) * | 1986-08-18 | 1988-01-26 | G. D. Searle & Co. | 2-[(imidazo[1,2-a]pyridin-3-ylmethyl)sulfinyl]-1H-benzimidazoles useful in the treatment and prevention of ulcers |
| JP2536173B2 (en) * | 1988-08-18 | 1996-09-18 | 武田薬品工業株式会社 | Injection |
| AU617217B2 (en) * | 1988-09-20 | 1991-11-21 | Hisamitsu Pharmaceutical Co., Inc. | Novel dibenz(b,e)oxepin derivatives |
| SE8804629D0 (en) | 1988-12-22 | 1988-12-22 | Ab Haessle | NEW THERAPEUTICALLY ACTIVE COMPOUNDS |
| IE64199B1 (en) * | 1988-12-22 | 1995-07-12 | Haessle Ab | Compound with gastric acid inhibitory effect and process for its preparation |
| JP2694361B2 (en) * | 1989-02-09 | 1997-12-24 | アストラ アクチエボラグ | Antibacterial agent |
| US4965269A (en) * | 1989-12-20 | 1990-10-23 | Ab Hassle | Therapeutically active chloro substituted benzimidazoles |
| US5049674A (en) * | 1989-12-20 | 1991-09-17 | Aktiebolaget Hassle | Therapeutically active fluoro substituted benzimidazoles |
| US5274099A (en) * | 1989-12-20 | 1993-12-28 | Aktiebolaget Hassle | Therapeutically active fluoro substituted benzimidazoles |
| SE9002206D0 (en) | 1990-06-20 | 1990-06-20 | Haessle Ab | NEW COMPOUNDS |
| ES2026761A6 (en) * | 1990-10-31 | 1992-05-01 | Genesis Para La Investigacion | A process for the preparation of omeprazol. |
| WO1994002141A1 (en) * | 1992-07-28 | 1994-02-03 | Astra Aktiebolag | Injection and injection kit containing omeprazole and its analogs |
| SE9301830D0 (en) | 1993-05-28 | 1993-05-28 | Ab Astra | NEW COMPOUNDS |
| US6875872B1 (en) | 1993-05-28 | 2005-04-05 | Astrazeneca | Compounds |
| SE9302395D0 (en) * | 1993-07-09 | 1993-07-09 | Ab Astra | NEW PHARMACEUTICAL FORMULATION |
| SE9302396D0 (en) * | 1993-07-09 | 1993-07-09 | Ab Astra | A NOVEL COMPOUND FORM |
| TW359614B (en) * | 1993-08-31 | 1999-06-01 | Takeda Chemical Industries Ltd | Composition containing benzimidazole compounds for rectal administration |
| TW280770B (en) | 1993-10-15 | 1996-07-11 | Takeda Pharm Industry Co Ltd | |
| EE03305B1 (en) | 1994-07-08 | 2000-12-15 | Astra Aktiebolag | Multiparticulate tableted dosage form I |
| GB9423968D0 (en) * | 1994-11-28 | 1995-01-11 | Astra Ab | Resolution |
| CN1042423C (en) * | 1995-05-25 | 1999-03-10 | 常州市第四制药厂 | Aomeilazole salt hydrate for gastric acid inhibitor and its preparing method |
| US5840737A (en) | 1996-01-04 | 1998-11-24 | The Curators Of The University Of Missouri | Omeprazole solution and method for using same |
| US6645988B2 (en) | 1996-01-04 | 2003-11-11 | Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
| US6489346B1 (en) | 1996-01-04 | 2002-12-03 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
| US6699885B2 (en) | 1996-01-04 | 2004-03-02 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and methods of using same |
| SE508669C2 (en) * | 1996-04-26 | 1998-10-26 | Astra Ab | New procedure |
| SE510666C2 (en) * | 1996-12-20 | 1999-06-14 | Astra Ab | New Crystal Modifications |
| SE9702000D0 (en) * | 1997-05-28 | 1997-05-28 | Astra Ab | New pharmaceutical formulation |
| SE510650C2 (en) | 1997-05-30 | 1999-06-14 | Astra Ab | New association |
| US6747155B2 (en) | 1997-05-30 | 2004-06-08 | Astrazeneca Ab | Process |
| SE510643C2 (en) * | 1997-06-27 | 1999-06-14 | Astra Ab | Thermodynamically stable omeprazole sodium form B |
| SI9700186B (en) | 1997-07-14 | 2006-10-31 | Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, D.D. | Novel pharmaceutical preparation with controlled release of active healing substances |
| SE9704869D0 (en) * | 1997-12-22 | 1997-12-22 | Astra Ab | New pharmaceutical formulaton II |
| SE9704870D0 (en) * | 1997-12-22 | 1997-12-22 | Astra Ab | New pharmaceutical formulation I |
| DE19801811B4 (en) * | 1998-01-19 | 2004-12-23 | Stada Arzneimittel Ag | Pharmaceutical preparation for oral administration |
| DK173431B1 (en) | 1998-03-20 | 2000-10-23 | Gea Farmaceutisk Fabrik As | Pharmaceutical formulation comprising a 2 - [[(2-pyridinyl) methyl] sulfinyl] benzimidazole with anti-ulcer activity and progress |
| SE9803772D0 (en) | 1998-11-05 | 1998-11-05 | Astra Ab | Pharmaceutical formulation |
| IL142703A (en) * | 1998-11-10 | 2006-04-10 | Astrazeneca Ab | Crystalline form of omeprazole |
| UA72748C2 (en) | 1998-11-10 | 2005-04-15 | Astrazeneca Ab | A novel crystalline form of omeprazole |
| SE9900274D0 (en) * | 1999-01-28 | 1999-01-28 | Astra Ab | New compound |
| IL130602A0 (en) | 1999-06-22 | 2000-06-01 | Dexcel Ltd | Stable benzimidazole formulation |
| US6780880B1 (en) | 1999-08-26 | 2004-08-24 | Robert R. Whittle | FT-Raman spectroscopic measurement |
| US6312723B1 (en) | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Pharmaceutical unit dosage form |
| US6312712B1 (en) | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Method of improving bioavailability |
| US6262086B1 (en) | 1999-08-26 | 2001-07-17 | Robert R. Whittle | Pharmaceutical unit dosage form |
| US6369087B1 (en) | 1999-08-26 | 2002-04-09 | Robert R. Whittle | Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
| US6316020B1 (en) * | 1999-08-26 | 2001-11-13 | Robert R. Whittle | Pharmaceutical formulations |
| US6262085B1 (en) | 1999-08-26 | 2001-07-17 | Robert R. Whittle | Alkoxy substituted Benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
| US6326384B1 (en) | 1999-08-26 | 2001-12-04 | Robert R. Whittle | Dry blend pharmaceutical unit dosage form |
| US6268385B1 (en) | 1999-08-26 | 2001-07-31 | Robert R. Whittle | Dry blend pharmaceutical formulations |
| US6228400B1 (en) | 1999-09-28 | 2001-05-08 | Carlsbad Technology, Inc. | Orally administered pharmaceutical formulations of benzimidazole derivatives and the method of preparing the same |
| SE9903831D0 (en) * | 1999-10-22 | 1999-10-22 | Astra Ab | Formulation of substituted benzimidazoles |
| CA2290893C (en) | 1999-11-16 | 2007-05-01 | Bernard Charles Sherman | Magnesium omeprazole |
| DE19959419A1 (en) | 1999-12-09 | 2001-06-21 | Ratiopharm Gmbh | Stable pharmaceutical preparations comprising a benzimidazole and process for their preparation |
| US7732404B2 (en) | 1999-12-30 | 2010-06-08 | Dexcel Ltd | Pro-nanodispersion for the delivery of cyclosporin |
| US20030212274A1 (en) * | 2000-05-15 | 2003-11-13 | Bakthavathsalan Vijayaraghavan | Novel amorphous form of omeprazole salts |
| US6306435B1 (en) | 2000-06-26 | 2001-10-23 | Yung Shin Pharmaceutical Industrial Co. Ltd. | Oral pharmaceutical preparation embedded in an oily matrix and methods of making the same |
| CA2386716C (en) * | 2002-05-17 | 2012-07-24 | Bernard Charles Sherman | Magnesium salt of s-omeprazole |
| MY137726A (en) | 2000-11-22 | 2009-03-31 | Nycomed Gmbh | Freeze-dried pantoprazole preparation and pantoprazole injection |
| US8206741B2 (en) | 2001-06-01 | 2012-06-26 | Pozen Inc. | Pharmaceutical compositions for the coordinated delivery of NSAIDs |
| MXPA04007169A (en) * | 2002-01-25 | 2004-10-29 | Santarus Inc | Transmucosal delivery of proton pump inhibitors. |
| WO2003074514A1 (en) | 2002-03-05 | 2003-09-12 | Astrazeneca Ab | Alkylammonium salts of omeprazole and esomeprazole |
| TW200410955A (en) | 2002-07-29 | 2004-07-01 | Altana Pharma Ag | Novel salt of (S)-PANTOPRAZOLE |
| AU2003262992A1 (en) * | 2002-08-30 | 2004-03-19 | Reddy's Laboratories Limited | Amorphous hydrates of esomeprazole magnesium and process for the preparation thereof |
| BR0315574A (en) * | 2002-10-22 | 2005-09-20 | Ranbaxy Lab Ltd | Amorphous form of esomeprazole, pharmaceutical composition containing it and process for its preparation |
| EP1581196A4 (en) * | 2002-12-23 | 2007-08-22 | Celltech Americas Inc | Acid labile drug compositions |
| CA2517005A1 (en) * | 2003-02-20 | 2004-09-02 | Santarus, Inc. | A novel formulation, omeprazole antacid complex-immediate release for rapid and sustained suppression of gastric acid |
| KR20050123096A (en) * | 2003-02-24 | 2005-12-29 | 미쯔비시 웰 파마 가부시키가이샤 | The enantiomer of tenatoprazole and the use thereof in therapy |
| CA2516600C (en) * | 2003-03-24 | 2011-04-05 | Eisai Co., Ltd. | Process for production of sulfoxide proton pump inhibitors in the amorphous state |
| WO2004099182A1 (en) * | 2003-05-05 | 2004-11-18 | Ranbaxy Laboratories Limited | Zinc salt of (s)-omeprazole |
| EP1633736A1 (en) * | 2003-05-05 | 2006-03-15 | Ranbaxy Laboratories Limited | Barium salt of benzimidazole derivative |
| US8993599B2 (en) * | 2003-07-18 | 2015-03-31 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| AR045062A1 (en) * | 2003-07-18 | 2005-10-12 | Santarus Inc | PHARMACEUTICAL FORMULATIONS TO INHIBIT THE SECRETION OF ACID AND METHODS TO PREPARE AND USE THEM |
| MXPA06000524A (en) * | 2003-07-18 | 2006-08-11 | Santarus Inc | Pharmaceutical formulation and method for treating acid-caused gastrointestinal disorders. |
| DE602004011946T2 (en) * | 2003-07-23 | 2009-03-19 | Nycomed Gmbh | ALKALISALS OF PROTON PUMP INHIBITORS |
| CN100457104C (en) * | 2003-07-23 | 2009-02-04 | 尼科梅德有限责任公司 | Alkaline salts of proton pump inhibitors |
| SE0302381D0 (en) * | 2003-09-04 | 2003-09-04 | Astrazeneca Ab | New salts I |
| SE0302382D0 (en) | 2003-09-04 | 2003-09-04 | Astrazeneca Ab | New salts II |
| TWI372066B (en) | 2003-10-01 | 2012-09-11 | Wyeth Corp | Pantoprazole multiparticulate formulations |
| US20070292498A1 (en) * | 2003-11-05 | 2007-12-20 | Warren Hall | Combinations of proton pump inhibitors, sleep aids, buffers and pain relievers |
| SE0400410D0 (en) | 2004-02-20 | 2004-02-20 | Astrazeneca Ab | New compounds |
| WO2005082888A1 (en) * | 2004-03-01 | 2005-09-09 | Milen Merkez Ilac Endustrisi A.S. | Process for the preparation of magnesium salt of omeprazole |
| US8815916B2 (en) * | 2004-05-25 | 2014-08-26 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US8906940B2 (en) * | 2004-05-25 | 2014-12-09 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US20050267159A1 (en) * | 2004-05-28 | 2005-12-01 | Aaipharma, Inc. | Magnesium complexes of S-omeprazole |
| PT1748998E (en) * | 2004-05-28 | 2010-03-24 | Hetero Drugs Ltd | A novel stereoselective synthesis of benzimidazole sulfoxides |
| FR2871800B1 (en) * | 2004-06-17 | 2006-08-25 | Sidem Pharma Sa Sa | SODIUM SALT S-TENATOPRAZOLE MONOHYDRATE AND THERAPEUTIC APPLICATION |
| JP5457632B2 (en) | 2004-06-24 | 2014-04-02 | アストラゼネカ・アクチエボラーグ | Process for making modified forms of crystals for use in the manufacture of sodium salt of esomeprazole |
| US20060024362A1 (en) * | 2004-07-29 | 2006-02-02 | Pawan Seth | Composition comprising a benzimidazole and process for its manufacture |
| CA2575718C (en) | 2004-08-06 | 2010-12-14 | Eisai R & D Management Co., Ltd. | Salts of benzimidazole derivative with amines and process for manufacturing the same |
| WO2006067599A2 (en) | 2004-12-23 | 2006-06-29 | Ranbaxy Laboratories Limited | Stable oral benzimidazole compositions and process of preparation thereof |
| US20060160783A1 (en) * | 2004-12-30 | 2006-07-20 | Transform Pharmaceuticals, Inc. | Novel omeprazole forms and related methods |
| EP1845982A2 (en) * | 2005-02-02 | 2007-10-24 | Ranbaxy Laboratories Limited | Stable oral benzimidazole compositions prepared by non-aqueous layering process |
| US20090298884A1 (en) * | 2005-05-06 | 2009-12-03 | Glenmark Generics Ltd. | Esomeprazole Strontium Salt, Process For Its Preparation and Pharmaceutical Compositions Containing Same |
| US7803817B2 (en) | 2005-05-11 | 2010-09-28 | Vecta, Ltd. | Composition and methods for inhibiting gastric acid secretion |
| US7981908B2 (en) | 2005-05-11 | 2011-07-19 | Vecta, Ltd. | Compositions and methods for inhibiting gastric acid secretion |
| EP1907375B1 (en) * | 2005-06-08 | 2013-07-24 | LEK Pharmaceuticals d.d. | Crystalline solvate of omeprazole sodium |
| WO2006134605A1 (en) * | 2005-06-15 | 2006-12-21 | Hetero Drugs Limited | Amorphous esomeprazole hydrate |
| US20070043085A1 (en) * | 2005-08-19 | 2007-02-22 | Glenmark Pharmaceuticals Limited | Process for the preparation of amorphous form of neutral esomeprazole |
| CA2626085C (en) * | 2005-10-26 | 2011-12-06 | Hanmi Pharm. Co., Ltd. | S-omeprazole strontium or hydrate thereof, method for preparing same, and pharmaceutical composition comprising 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 |
| EP1785135A1 (en) * | 2005-11-10 | 2007-05-16 | Laboratorios Del Dr. Esteve, S.A. | New stabilized galenic formulations comprising lansoprazole and their preparation |
| EP1801110A1 (en) | 2005-12-22 | 2007-06-27 | KRKA, tovarna zdravil, d.d., Novo mesto | Esomeprazole arginine salt |
| ES2281292B1 (en) * | 2006-03-08 | 2008-06-16 | Quimica Sintetica S.A. | NEW SALTS OF ESOMEPRAZOL. PROCEDURE OF PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT UNDERSTAND THEM. |
| CN101460481A (en) * | 2006-06-07 | 2009-06-17 | 阿斯利康(瑞典)有限公司 | Novel method for preparation of ammonium salts of esomeprazole |
| US7786309B2 (en) | 2006-06-09 | 2010-08-31 | Apotex Pharmachem Inc. | Process for the preparation of esomeprazole and salts thereof |
| ES2511792T3 (en) | 2006-07-25 | 2014-10-23 | Vecta Ltd. | Compositions and methods for the inhibition of gastric acid secretion using derivatives of small dicarboxylic acids in combination with IBP |
| US20090092658A1 (en) * | 2007-10-05 | 2009-04-09 | Santarus, Inc. | Novel formulations of proton pump inhibitors and methods of using these formulations |
| GB2459393B (en) | 2006-10-05 | 2010-09-08 | Santarus Inc | Novel capsule formulation for the proton pump inhibitor omeprazole |
| WO2008057802A2 (en) | 2006-10-27 | 2008-05-15 | The Curators Of The University Of Missouri | Compositions comprising at least one acid labile proton pump inhibiting agents, optionally other pharmaceutically active agents and methods of using same |
| CA2673665C (en) | 2006-12-22 | 2017-03-21 | Ironwood Pharmaceuticals, Inc. | Method and compositions for treating esophageal disorders |
| US20080194307A1 (en) * | 2007-02-13 | 2008-08-14 | Jeff Sanger | Sports-based game of chance |
| CA2678702A1 (en) | 2007-02-21 | 2008-08-28 | Cipla Limited | Process for the preparation of esomeprazole magnesium dihydrate |
| US8492551B2 (en) * | 2007-06-07 | 2013-07-23 | Aurobindo Pharma. Ltd. | Process for preparing an optically active proton pump inhibitor |
| EP2195309A4 (en) * | 2007-10-08 | 2013-04-24 | Hetero Drugs Ltd | Polymorphs of esomeprazole salts |
| CA2716367C (en) | 2008-02-20 | 2015-05-26 | The Curators Of The University Of Missouri | Composition comprising a combination of omeprazole and lansoprazole, and a buffering agent, and methods of using same |
| US8911787B2 (en) | 2008-02-26 | 2014-12-16 | Ranbaxy Laboratories Limited | Stable oral benzimidazole compositions and process of preparation thereof |
| WO2009137648A1 (en) * | 2008-05-09 | 2009-11-12 | Aptapharma, Inc. | Multilayer proton pump inhibitor tablets |
| US20090280173A1 (en) * | 2008-05-09 | 2009-11-12 | Ishwar Chauhan | Multilayer Omeprazole Tablets |
| EP2147918A1 (en) * | 2008-07-21 | 2010-01-27 | LEK Pharmaceuticals D.D. | Process for the preparation of S-omeprazole magnesium in a stable form |
| CH699302B1 (en) * | 2008-08-11 | 2012-03-15 | Mepha Gmbh | An oral pharmaceutical formulation for omeprazole containing a specific release layer. |
| JP4906817B2 (en) * | 2008-08-29 | 2012-03-28 | セイコークロック株式会社 | Decoration device and clock |
| EP2344139A1 (en) | 2008-09-09 | 2011-07-20 | AstraZeneca AB | Method for delivering a pharmaceutical composition to patient in need thereof |
| EP2346854A4 (en) * | 2008-11-18 | 2012-10-17 | Hetero Research Foundation | Optical purification of esomeprazole |
| WO2010122583A2 (en) | 2009-04-24 | 2010-10-28 | Rubicon Research Private Limited | Oral pharmaceutical compositions of acid labile substances |
| AU2010266026B2 (en) * | 2009-06-25 | 2014-08-07 | Nuvo Pharmaceuticals (Ireland) Designated Activity Company | Method for treating a patient in need of aspirin therapy |
| EP2445499A4 (en) | 2009-06-25 | 2013-02-27 | Astrazeneca Ab | Method for treating a patient at risk for developing an nsaid-associated ulcer |
| US8748619B2 (en) | 2009-11-12 | 2014-06-10 | Hetero Research Foundation | Process for the resolution of omeprazole |
| EP2345408A3 (en) | 2010-01-08 | 2012-02-29 | Dr. Reddy's Laboratories Ltd. | Acid labile drug formulations |
| FR2967353B1 (en) * | 2010-11-16 | 2013-08-16 | Centre Nat Rech Scient | QUINOLINONE DERIVATIVES |
| CN102351846B (en) * | 2011-09-07 | 2012-08-22 | 周晓东 | Novel omeprazole sodium compound and medicinal composition thereof |
| WO2013081566A1 (en) | 2011-11-25 | 2013-06-06 | Mahmut Bilgic | A formulation comprising benzimidazole |
| BR112014016085A8 (en) | 2011-12-28 | 2017-07-04 | Pozen Inc | Enhanced compositions and methods for delivery of omeprazole plus acetylsalicylic acid |
| CN104203938A (en) | 2012-01-21 | 2014-12-10 | 朱比兰特生命科学有限公司 | Process for the preparation of 2-pyridinylmethylsulfinyl benzimidazoles, their analogs and optically active enantiomers |
| EA201591338A1 (en) | 2013-01-15 | 2016-01-29 | Айронвуд Фармасьютикалз, Инк. | GASTRORETENTIVE MEDICAL FORM OF SECRESTRANATE OF BILIC ACIDS, SLOWLY RELEASED FOR ORAL APPLICATION |
| NZ711754A (en) * | 2013-02-13 | 2020-05-29 | Redhill Biopharma Ltd | Pharmaceutical compositions for the treatment of helicobacter pylori |
| GB201306720D0 (en) | 2013-04-12 | 2013-05-29 | Special Products Ltd | Formulation |
| EP2933002A1 (en) | 2014-04-11 | 2015-10-21 | Sanovel Ilac Sanayi ve Ticaret A.S. | Pharmaceutical combinations of dabigatran and proton pump inhibitors |
| EP2929885A1 (en) | 2014-04-11 | 2015-10-14 | Sanovel Ilac Sanayi ve Ticaret A.S. | Pharmaceutical combinations of rivaroxaban and proton pump inhibitors |
| CN104045627A (en) * | 2014-05-21 | 2014-09-17 | 丽珠医药集团股份有限公司 | Purification method of omeprazole |
| WO2016126625A1 (en) | 2015-02-03 | 2016-08-11 | Ironwood Pharmaceuticals, Inc. | Methods of treating upper gastrointestinal disorders in ppi refractory gerd |
| US20170042806A1 (en) | 2015-04-29 | 2017-02-16 | Dexcel Pharma Technologies Ltd. | Orally disintegrating compositions |
| US10076494B2 (en) | 2016-06-16 | 2018-09-18 | Dexcel Pharma Technologies Ltd. | Stable orally disintegrating pharmaceutical compositions |
| WO2024075017A1 (en) | 2022-10-04 | 2024-04-11 | Zabirnyk Arsenii | Inhibition of aortic valve calcification |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1234058A (en) * | 1968-10-21 | 1971-06-03 | ||
| US4045564A (en) * | 1974-02-18 | 1977-08-30 | Ab Hassle | Benzimidazole derivatives useful as gastric acid secretion inhibitors |
| SE416649B (en) * | 1974-05-16 | 1981-01-26 | Haessle Ab | PROCEDURE FOR THE PREPARATION OF SUBSTANCES WHICH PREVENT Gastric acid secretion |
| CA1085392A (en) * | 1976-03-25 | 1980-09-09 | Masayuki Narisada | Arylmalonamido-1-oxadethiacephalosporins |
| SE7804231L (en) * | 1978-04-14 | 1979-10-15 | Haessle Ab | Gastric acid secretion |
| US4359465A (en) * | 1980-07-28 | 1982-11-16 | The Upjohn Company | Methods for treating gastrointestinal inflammation |
| US4472409A (en) * | 1981-11-05 | 1984-09-18 | Byk Gulden Lomberg Chemische Fabrik Gesellschaft Mit Beschrankter Haftung | 2-Pyridylmethyl thio(sulfinyl)benzimidazoles with gastric acid secretion inhibiting effects |
-
1983
- 1983-03-04 SE SE8301182A patent/SE8301182D0/en unknown
-
1984
- 1984-02-16 IL IL70985A patent/IL70985A/en not_active IP Right Cessation
- 1984-02-17 ZA ZA841202A patent/ZA841202B/en unknown
- 1984-02-24 DK DK099584A patent/DK160044C/en not_active IP Right Cessation
- 1984-02-28 DE DE8484850066T patent/DE3462036D1/en not_active Expired
- 1984-02-28 AT AT84850066T patent/ATE24907T1/en active
- 1984-02-28 DE DE2001199022 patent/DE10199022I2/en active Active
- 1984-02-28 EP EP84850066A patent/EP0124495B1/en not_active Expired
- 1984-02-28 BG BG8464457A patent/BG44538A3/en unknown
- 1984-02-29 NO NO840772A patent/NO160204C/en not_active IP Right Cessation
- 1984-03-01 PH PH30317A patent/PH21352A/en unknown
- 1984-03-01 IS IS2887A patent/IS1363B6/en unknown
- 1984-03-02 DD DD84260523A patent/DD221459A5/en unknown
- 1984-03-02 PL PL1984246492A patent/PL142748B1/en unknown
- 1984-03-02 NZ NZ207348A patent/NZ207348A/en unknown
- 1984-03-02 GB GB08405511A patent/GB2137616B/en not_active Expired
- 1984-03-02 AU AU25257/84A patent/AU563842B2/en not_active Expired
- 1984-03-02 SI SI8410397A patent/SI8410397A8/en unknown
- 1984-03-02 GR GR73990A patent/GR79828B/el unknown
- 1984-03-02 ES ES530242A patent/ES8500934A1/en not_active Expired
- 1984-03-02 HU HU84845A patent/HU193557B/en unknown
- 1984-03-02 RO RO84113806A patent/RO88721A/en unknown
- 1984-03-02 CA CA000448761A patent/CA1264751A/en not_active Expired - Lifetime
- 1984-03-02 PT PT78191A patent/PT78191B/en unknown
- 1984-03-02 YU YU397/84A patent/YU43345B/en unknown
- 1984-03-02 IE IE514/84A patent/IE57326B1/en not_active IP Right Cessation
- 1984-03-02 JP JP59038921A patent/JPS59167587A/en active Granted
- 1984-03-02 ES ES000530242D patent/ES8500934B9/en active Active
- 1984-03-02 FI FI840851A patent/FI83649C/en not_active IP Right Cessation
- 1984-03-02 SU SU843710408A patent/SU1314953A3/en active
- 1984-03-02 CS CS841515A patent/CS241150B2/en unknown
- 1984-03-03 KR KR1019840001074A patent/KR870001005B1/en not_active IP Right Cessation
- 1984-03-03 JO JO19841425A patent/JO1425B1/en active
- 1984-03-04 DZ DZ847097A patent/DZ615A1/en active
- 1984-03-05 MA MA20272A patent/MA20050A1/en unknown
-
1986
- 1986-04-21 US US06/854,739 patent/US4738974A/en not_active Expired - Lifetime
-
1987
- 1987-09-26 MY MYPI87001982A patent/MY102052A/en unknown
-
1990
- 1990-01-10 SG SG14/90A patent/SG1490G/en unknown
- 1990-02-22 HK HK135/90A patent/HK13590A/en not_active IP Right Cessation
-
1992
- 1992-03-09 SA SA92120418A patent/SA92120418B1/en unknown
-
1993
- 1993-03-22 HR HRP-397/84A patent/HRP930428B1/en not_active IP Right Cessation
- 1993-06-30 LV LV930867A patent/LV5503A3/en unknown
- 1993-09-06 LT LTRP947A patent/LT2253B/en not_active IP Right Cessation
-
1994
- 1994-02-25 BG BG98585A patent/BG60837B2/en unknown
-
1996
- 1996-07-18 LV LV960280A patent/LV5801B4/en unknown
-
2000
- 2000-10-05 NO NO2000010C patent/NO2000010I1/en unknown
- 2000-11-15 LU LU90677C patent/LU90677I2/en unknown
- 2000-11-17 NL NL300027C patent/NL300027I2/en unknown
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6077541A (en) * | 1997-11-14 | 2000-06-20 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US6096340A (en) * | 1997-11-14 | 2000-08-01 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US6780435B2 (en) | 1997-11-14 | 2004-08-24 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US6048981A (en) * | 1998-04-22 | 2000-04-11 | Torcan Chemical Ltd. | Magnesium omeprazole and process for its preparation |
| US6174548B1 (en) | 1998-08-28 | 2001-01-16 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US6855336B2 (en) | 1998-08-28 | 2005-02-15 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US6733778B1 (en) | 1999-08-27 | 2004-05-11 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| US8809542B2 (en) | 2000-08-04 | 2014-08-19 | Takeda Pharmaceutical Company Limited | Salts of benzimidazole compound and use thereof |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1264751A (en) | Base addition salts of omeprazole | |
| US5039808A (en) | Therapeutically active cyclopropyl substituted compound | |
| EP0277738B1 (en) | Anhdrous, crystalline sodium salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide | |
| AU636866B2 (en) | Therapeutically active substituted benzimidazole and process for its preparation | |
| EP0173664A2 (en) | Biologically active benzimidazole compounds and process for their preparation | |
| AU639429B2 (en) | Compound with gastric acid inhibitory effect and process for its preparation | |
| AU665043B2 (en) | Substituted benzimidazoles, process for their preparation as well as their use | |
| AU641465B2 (en) | 2((2-pyridinyl)methyl) sulfinyl)-1H-Benzimidazole derivatives | |
| JPH06500789A (en) | Imidazole derivatives, their production methods and pharmaceutical compositions | |
| BG62228B2 (en) | Anhydrous crystalline sodium salt of 5-cholr-3-(2-tenoyl)-2-oxindole-1-carboxamide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |