CN1116092A - Pharmaceutical composition - Google Patents
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- CN1116092A CN1116092A CN 94116369 CN94116369A CN1116092A CN 1116092 A CN1116092 A CN 1116092A CN 94116369 CN94116369 CN 94116369 CN 94116369 A CN94116369 A CN 94116369A CN 1116092 A CN1116092 A CN 1116092A
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Abstract
The present invention consists of ulcer activeness resisting benzimidazole compound and water soluble amide medicinal composite. In accordance with said invention, the ulcer activeness resisting water non-soluble benzimidazole compound can be solubilized and the stable medicinal composite can be provided. The invented solid medicinal composite can be dissolved temporarily in the aseptic distillated water or infusion (for example the physiological saline, glucose solutione tc.) for using conveniently as injection solution.
Description
The present invention relates to a kind of Pharmaceutical composition, it comprises benzimidazole compound and the water miscible amide with antiulcer activity.Pharmaceutical composition of the present invention can be used as anti-ulcer medicament.
Therefore some benzimidazole compound is owing to have anti-gastric acid secretion and the activity of protection gastric mucosa, as the therapeutic agent of ulcer and/or prevent that the preventive drug of ulcer recurrence from attracting much attention gradually.
For the intravenously administrable compositions of above-claimed cpd is provided, someone has recommended such method, the sterile water solution that is about to the omeprazole sodium salt filters and lyophilization, again described lyophilized products is remake (EP-A-124495) in the mixture of the filtration sterilization of PEG400, sodium dihydrogen phosphate and the aquesterilisa of injection stage temporarily, but the active agent stability in said composition is not exclusively satisfactory.
Contain the 2-[(pyridine radicals that (a) can be used as antiulcer agent) methylsulfinyl] benzimidazoles compound and (b) at least a injection that is selected from the solvent of ethanol, propylene glycol and Polyethylene Glycol be known (USP 5223515), do not appear in the newspapers as yet but nicotiamide and described benzimidazole compound together are used for injection.
Main purpose of the present invention provides high stability Pharmaceutical composition.
By following explanation, this purpose of the present invention and other purpose and advantage will be conspicuous to those skilled in the art.
The present inventor studies the several years to the problems referred to above, the benzimidazole compound that discovery has an antiulcer activity is soluble in amide for example in the aqueous solution of nicotiamide or Benzoylamide, and very stable in such solution, and find by described chemical compound being dissolved in such amide aqueous solution and with this solution lyophilization or compositions that spray drying obtained is not added lustre in time and storage period is long and have the good water property made again.These find to have formed after further study the present invention.
The invention provides: 1) a kind of Pharmaceutical composition, it comprises benzimidazole compound and the water miscible amide with antiulcer activity, 2) according to above-mentioned 1) compositions, benzimidazole compound wherein is the compound or its salt of following formula representative:
The A ring can randomly be substituted R in the formula
1, R
3And R
7Identical or different, be hydrogen, alkyl or alkoxyl, R
2Be can randomly substituted alkyl, and n be 0 or 1,3) according to above-mentioned 2) compositions, R wherein
1And R
3Identical or different, be hydrogen, alkyl or alkoxyl, R
2Be C
1-4Alkyl, it can be randomly by (1) halogen or (2) C
1-4Alkoxyl replaces, and R
7It is hydrogen atom; 4) according to above-mentioned 1) compositions; wherein said benzimidazole compound is 2-[2-[3-methyl-4-(2; 2; the 2-trifluoro ethoxy) pyridine radicals] methylsulfinyl] benzimidazole; 5) according to above-mentioned 1) compositions, wherein said water-soluble amide is the chemical compound of following formula representative:
R in the formula
4Be hydrogen, amino, can randomly substituted alkyl, can randomly substituted aryl or can randomly substituted nitrogen heterocyclic ring group, R
5And R
6Identical or different, be hydrogen or alkyl, 6) according to above-mentioned 5) compositions, R wherein
4Be can randomly substituted nitrogen heterocyclic ring group, R
5And R
6Identical or different, it is hydrogen or alkyl, 7) according to above-mentioned 5) compositions, wherein said water-soluble amide is a nicotiamide, 8) according to above-mentioned 1) compositions, it also comprises at least a sugar, 9) according to above-mentioned 8) compositions, wherein said sugar is sugar alcohol, 10) according to above-mentioned 1) compositions, it is a lyophilized products, 11) according to above-mentioned 1) compositions, it is an aqueous solution, 12) according to above-mentioned 11) compositions, wherein said aqueous solution is an injection, and 13) according to above-mentioned 10) compositions, it prepares by comprising the benzimidazole compound with antiulcer activity and the alkaline aqueous solution lyophilization of water-soluble amide.Benzimidazole compound with antiulcer activity used in this invention comprises for example 2-[(pyridine radicals)-methylsulfinyl or-methyl mercapto] benzimidizole derivatives and salt thereof.Preferred chemical compound is the compound or its salt of formula (I) representative:
The A ring can randomly be substituted R in the formula
1, R
3And R
7Identical or different, be hydrogen, alkyl or alkoxyl, R
2Be can randomly substituted alkyl, and n be 0 or 1.
These chemical compounds are for example being stated in the following patent literature: USP4,045,563, USP4,255,431, USP4,359,465, USP4,472,409, USP4,508,905, JP-A-59181277, USP4,628,098, USF4,738,975, USP5,045,321, USP4,786,505, USP4,853,230, USP4,769,456, USP5,045,552, EP-A-295603, USP5312824, EP-A-166287 and EP-A-519365 etc.
About above-mentioned formula (I), the substituent group that can be on the A ring randomly exists comprise halogen, can substituted alkyl, can substituted cycloalkyl, can substituted alkenyl, can substituted alkoxyl, cyano group, carboxyl, alkoxy carbonyl group, alkoxycarbonyl alkyl, carbamoyl, carbamoyl alkyl, hydroxyl, hydroxy alkyl, acyl group, carbamoyloxy, nitro, acyloxy, aryl, aryloxy group, alkylthio group and alkyl sulphinyl etc.
Now specifically describe described each substituent group.
Described halogen for example can be fluorine, chlorine, bromine or iodine.Preferred halogen is fluorine and chlorine, and best is fluorine.
Described alkyl group that can substituted alkyl comprises the straight or branched alkyl group (for example methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl group, nonyl, decyl etc.) of 1 to 10 carbon atom.Preferred group is C
1-6The straight or branched alkyl.Preferred group is C
1-3The straight or branched alkyl.Substituent group on such alkyl group comprises halogen, nitro, cyano group, hydroxyl, carboxyl, amidino groups, guanidine radicals, carbamoyl and can be by alkyl, acyl group etc. one or dibasic amino etc.
Described group of naphthene base that can substituted cycloalkyl comprises C
3-7Group of naphthene base.Such group of naphthene base specifically is cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and suberyl.Described group of naphthene base can be replaced by following groups for example separately: halogen, nitro, cyano group, hydroxyl, carboxyl, amidino groups, guanidine radicals, carbamoyl and can be by alkyl, acyl group etc. one or dibasic amino etc.
Described alkenyl group that can substituted alkenyl preferably includes C
2-16Straight or branched thiazolinyl group.Therefore described alkenyl group specifically comprises pi-allyl, vinyl, crotyl, 2-amylene-1-base, 3-amylene-1-base, 2-hexene-1-base, 3-hexene-1-base, 2-methyl-2-propylene-1-base and 3-methyl-2-butene-1-base etc.Preferred group is C
2-6The straight or branched thiazolinyl.Preferred group is C
2-4The straight or branched thiazolinyl.Described alkenyl group can be replaced by following radicals for example: halogen, nitro, cyano group, amidino groups, guanidine radicals and can be by alkyl, acyl group etc. one or dibasic amino etc.Described alkenyl group comprises about the isomer of this pair key (E and Z-type).
Describedly can comprise C by substituted alkoxy grp
1-10Alkoxy grp etc.For example described alkoxy grp specifically comprises methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isoamoxy, neopentyl oxygen, hexyloxy, heptan oxygen base, octyloxy, ninth of the ten Heavenly Stems oxygen base, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.C preferably
1-6Alkoxy grp.C more preferably
1-3Alkoxy grp.Described alkoxy grp can be replaced by following radicals for example: halogen, nitro, amidino groups, guanidine radicals and can be by alkyl, acyl group etc. one or dibasic amino etc.
Can be used as the fontanel element that substituent group is present on described alkyl group, group of naphthene base, alkenyl group or the alkoxy grp and comprise chlorine, bromine, fluorine and iodine.
The moieties that can replace the alkyl amino of abovementioned alkyl group, group of naphthene base, alkenyl group or alkoxy grp preferably includes C
1-6Straight or branched alkyl etc., thereby specifically comprise methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, isopentyl, n-hexyl, isohesyl etc., wherein particularly preferably be C
1-4The straight or branched alkyl.
The acyl moiety that can replace the acylamino-of abovementioned alkyl group, group of naphthene base, alkenyl group or alkoxy grp for example comprises the acyl group derived from organic carboxyl acid.C preferably
1-6Alkanoyl, for example formoxyl, acetyl group, propiono, bytyry, isobutyryl, valeryl, isovaleryl, valeryl, caproyl etc.It is desirable to C especially
1-4Alkanoyl.
Can be in 1 to 6 scope at the substituent number on abovementioned alkyl group, group of naphthene base, alkenyl group or the alkoxy grp, preferred 1 to 3.
The alkyl group of described replacement specifically comprises trifluoromethyl, trifluoroethyl, difluoromethyl, trichloromethyl, methylol, 1-ethoxy, 2-ethoxy, methoxy ethyl, ethoxyethyl group, 1-methoxy ethyl, 2-methoxy ethyl, 2; 2-dimethoxy-ethyl, 2,2-diethoxy ethyl and 2-diethyl phosphoryl ethyl etc.Preferably difluoromethyl, trifluoromethyl and methylol.Better is trifluoromethyl.
The group of naphthene base of described replacement specifically comprises 2-amino-cyclopropane-1-base, 4-hydroxy-cyclopentane-1-base and 2,2-difluoro Pentamethylene .-1-base etc.
The alkenyl group of described replacement specifically comprises 2,2-dichloroethylene, 3-hydroxyl-2-propylene-1-base, 2-methoxy-ethylene base etc.
The alkoxy grp of described replacement specifically comprises difluoro-methoxy, trifluoromethoxy, 2,2,2-trifluoro ethoxy, 2-methoxy ethoxy, 4-chlorine benzyloxy, 2-(3, the 4-Dimethoxyphenyl) ethyoxyl etc.Difluoro-methoxy preferably.
The alkoxyl of described alkoxy carbonyl group partly comprises C
1-7Alkoxyl (for example methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isoamoxy, neopentyl oxygen, hexyloxy, heptan oxygen base etc.).
The alkoxyl of described alkoxycarbonyl alkyl partly comprises C
1-4Alkoxyl (for example methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy etc.) etc.The moieties of described alkoxycarbonyl alkyl comprises C
1-4Alkyl (for example methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group etc.) etc.That can mention especially has methoxycarbonyl group methyl, 2-methoxycarbonyl group ethyl, 2-methoxycarbonyl group propyl group, ethoxycarbonylmethyl group, 2-ethoxycarbonyl-ethyl, 1-methoxycarbonyl group propyl group, the third oxygen carbonyl methyl, a butoxy carbonyl methyl etc.
The moieties of described carbamoyl alkyl comprises C
1-4Alkyl (for example methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group etc.).
The moieties of described hydroxy alkyl comprises C
1-7Alkyl (for example methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, neopentyl, hexyl, heptyl etc.).
The acyl moiety of described acyl group and acyloxy comprises C respectively
1-4Alkanoyl, for example formoxyl, acetyl group, propiono, bytyry, isobutyryl etc.
The aryl moiety of described aryl and aryloxy group comprises C respectively
6-12Aryl (for example phenyl, naphthyl etc.).
The moieties of described alkylthio group or alkyl sulphinyl comprises C
1-6Alkyl (for example methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, neopentyl, hexyl etc.).
Preferred 1 to 4 of substituent number on the A ring that replaces, more preferably 1 to 2.Described substituent position on this phenyl ring can for example be 4-and 5-position.Preferred 5-position.
This preferred A ring is the A ring that can randomly be replaced by following radicals: i) halogen, ii) can substituted alkyl, and iii) can substituted cycloalkyl, iv) can substituted alkenyl, or v) can substituted alkoxyl.
By R
1, R
3Or R
7The alkyl of representative comprises C
1-10The straight or branched alkyl is comprising methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl group, nonyl, decyl etc.C wherein
1-6The straight or branched alkyl is preferred.It is desirable to C especially
1-3The straight or branched alkyl.
By R
1, R
3Or R
7The alkoxyl of representative comprises C
1-10Alkoxyl is comprising methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isoamoxy, neopentyl oxygen, hexyloxy, heptan oxygen base, octyloxy, the ninth of the ten Heavenly Stems oxygen base, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.C preferably
1-6Alkoxyl, that better is C
1-3Alkoxyl.
By R
2The hydrocarbyl portion of the randomly substituted hydrocarbyl group of representative comprises C
1-13Alkyl, for example C
1-6Straight or branched alkyl (for example methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, amyl group, isopentyl, hexyl etc.), C
2-6Alkenyl (for example vinyl, pi-allyl, crotyl, methacrylic, 3-cyclobutenyl, pentenyl, 4-pentenyl, 5-hexenyl etc.), C
2-6Alkynyl (for example acetenyl, propargyl, 2-butyne-1-base, 3-crotonylene-Ji, 1-pentyne-3-base, 3-pentyne-1-base, 4-pentyne-2-base, 3-hexin-1-etc.), C
3-6Cycloalkyl (for example cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc.), C
3-6Cycloalkenyl group (for example cyclobutane base, cyclopentenyl, cyclohexenyl group, cyclohexadienyl etc.), and C
7-13Aralkyl (for example benzyl, 1-phenethyl, 2-phenethyl etc.), and C
6-10Aryl (for example phenyl, naphthyl etc.) etc.Wherein preferred C
1-6Straight or branched alkyl (for example methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, amyl group, isopentyl, hexyl etc.).Preferred especially C
1-4The straight or branched alkyl.
The substituent group of the alkyl of described replacement comprises for example C
6-10Aryl (for example phenyl, naphthyl etc.), amino, C
1-6Alkyl amino (for example methylamino, ethylamino, isopropylamino etc.), two-C
1-6Alkyl amino (for example dimethylamino, lignocaine etc.), N-aralkyl-N-cycloalkyl amino (for example N-benzyl-N-cyclohexyl amino etc.), N-aralkyl-N-alkyl amino [for example N-(1-naphthyl methyl)-N-ethylamino etc.], azido, nitro, halogen (for example fluorine, chlorine, bromine and iodine), hydroxyl, C
1-4Alkoxyl (for example methoxyl group, ethyoxyl, propoxyl group, butoxy etc.), C
6-10Aryloxy group (for example phenoxy group, naphthoxy etc.), C
1-6Alkylthio group (for example methyl mercapto, ethylmercapto group, rosickyite base etc.), C
6-10Arylthio (for example thiophenyl, naphthalene sulfenyl etc.), cyano group, carbamoyl, carboxyl, C
1-4Alkoxy carbonyl (for example methoxycarbonyl, ethoxy carbonyl etc.), C
7-11Aryloxycarbonyl (for example phenyloxycarbonyl, 1-naphthoxy carbonyl, 2-naphthoxy carbonyl etc.), carboxyl-C
1-4Alkoxyl (for example carboxyl methoxyl group, 2-carboxyl ethyoxyl etc.), C
1-6Alkanoyl (for example formoxyl, acetyl group, propiono, different propiono, bytyry, valeryl, caproyl etc.), C
7-11Aroyl (for example benzoyl, 1-naphthoyl, 2-naphthoyl etc.), C
6-10Aryl sulfonyl (for example benzenesulfonyl, 1-naphthalene sulfonyl base, 2-naphthalene sulfonyl base etc.), C
1-6Alkyl sulphinyl (for example methylsulfinyl, ethyl sulfinyl etc.), C
6-10Aryl sulfonyl kia (for example benzenesulfinyl, 1-naphthalene sulfinyl, 2-naphthalene sulfinyl etc.), C
1-6Alkyl sulphonyl (mesyl for example; ethylsulfonyl etc.); has 1 to 4 hetero atom (N for example; O; S etc.) 5-or 6-unit heterocyclic group (2-furyl for example; the 2-thienyl; the 4-thiazolyl; the 4-imidazole radicals; the 4-pyridine radicals; 1; 3; 4-thiadiazoles-2-base; 1-methyl-5-tetrazole radical etc.); has 1 to 4 hetero atom (N for example; O; S) 5-or 6-unit heterocycle phosphinylidyne (2-furoyl for example; the 2-thenoyl; nicotinoyl; different nicotinoyl etc.) and have 1 to 4 hetero atom (N for example; O; S etc.) 5-or 6-unit heterocycle sulfenyl (heterocyclic thio groups) (4-pyridine sulfenyl for example; 2-pyrimidine sulfenyl; 1; 3,4-thiadiazoles-2-sulfenyl; 1-methyl-5-tetrazolium sulfenyl etc.).Described heterocycle sulfenyl can form the bicyclic structure (for example 2-[4-morpholinodithio sulfenyl, 8-quinoline sulfenyl etc.) that condenses with phenyl ring separately.In described substituent group, preferred halogen (for example fluorine, chlorine, bromine and iodine), hydroxyl and C
1-4Alkoxyl (for example methoxyl group, ethyoxyl, propoxyl group, butoxy etc.).
Described substituent number can be in 1 to 5 scope, and preferred 1 to 3.
R
1Preferred hydrogen, alkyl or alkoxyl, more preferably C
1-6Alkyl or C
1-6Alkoxyl, preferred especially C
1-3Alkyl.
R
3Preferred hydrogen, alkyl or alkoxyl, more preferably hydrogen or C
1-6Alkyl, preferred especially hydrogen.
R
2Preferably can be randomly by 1) halogen, 2) hydroxyl or 3) C
1-4The C that alkoxyl replaces
1-6Alkyl more preferably can be randomly by (1) halogen or (2) C
1-4The C that alkoxyl replaces
1-4Alkyl.
R
7Preferred hydrogen.
N preferred 1.
The instantiation that is used for benzimidazole compound of the present invention comprises 2-[2-[3-methyl-4-(2; 2; the 2-trifluoro ethoxy) pyridine radicals] methylsulfinyl] benzimidazole (lansoprazole); the 2-[(2-pyridine radicals) methylsulfinyl] benzimidazole (thimoprazole); 2-[2-(3; 5-dimethyl-4-methoxypyridine base) methylsulfinyl]-5-methoxyl group-1H-benzimidazole (omeprazole); 2-[2-[4-(3-methoxy propoxy)-3-picolyl] methylsulfinyl]-sodium salt of 1H-benzimidazole; 2-[2-(3; 4-dimethoxy-pyridine base) methylsulfinyl]-5-difluoro-methoxy-1H-benzimidazole (pantoprazole); 2-[2-(3-methyl-4-(2; 2; 3,3-tetrafluoro propoxyl group) pyridine radicals] methyl mercapto] benzimidazole etc.
Be used for benzimidazole compound of the present invention or its salt especially can adopt the document delivered as Japan and European publication and foregoing United States Patent (USP) for example method or any method similar described in USP4255431, USP4508905, USP4628098, USP4738975 and the USP5312824 with it prepare.
The salt of described benzimidazole compound is harmless salt aspect physiology preferably.Described salt harmless aspect physiology comprises the salt that forms with inorganic base, with the salt of organic base formation and the salt that forms with basic amino acid.Above-mentioned inorganic base comprises alkali metal (for example sodium, potassium etc.) and alkaline-earth metal (for example calcium, magnesium etc.).Described organic base can be trimethylamine, triethylamine, pyridine, picoline, N, N-dibenzyl-ethylenediamin, ethanolamine, diethanolamine, trihydroxy methyl aminomethane, hexanamine etc.Described basic amino acid can be arginine, lysine etc.
These salt can the known preparation method of employing itself for example method or any method similar described in EP-A-295603 and the USP4738974 with it prepare.
Being used for water-soluble amide of the present invention is the chemical compound that is at least about 0.1W/W% at the dissolubility of water, and preferably the dissolubility in water is at least about the chemical compound of 1W/W%.Better water-soluble amide is the chemical compound of following formula (II) representative:
R in the formula
4Be hydrogen, amino, can randomly substituted alkyl, can randomly substituted aryl or can randomly substituted nitrogen heterocyclic ring group, R
5And R
6Identical or different, be hydrogen or alkyl.
Described by R
4Representative can randomly substituted alkyl comprise substituent group on the described A of the being used for ring etc.
By R
4Representative can randomly substituted aromatic yl group in aryl comprise for example C
6-12Aryl, for example phenyl, naphthyl etc.
By R
4Representative can randomly substituted heterocyclic group in heterocyclic radical comprise 5-or the 6-unit heterocyclic group (for example 2-pyridine radicals, 3-pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, piperazinyl, furyl, thiazolyl, oxazolyl, thienyl, pyrrole radicals, pyranose etc.) that has 1 to 4 hetero atom (for example nitrogen, oxygen, sulfur etc.) on the ring.
The substituent group of the aryl of described replacement or the heterocyclic group of replacement comprises C
6-10Aryl (for example phenyl, naphthyl etc.), amino, nitro, halogen (for example fluorine, chlorine, bromine or iodine), hydroxyl, cyano group, carboxyl etc.
R
4Preferred hydrogen, amino, C
1-8Alkyl, phenyl, pyridine radicals etc.
By R
5Or R
6The alkyl of representative comprises the described R of being used for
1Or R
3Those.
R
5Or R
6Preferred hydrogen or C
1-3Alkyl.
What the instantiation of described water miscible amide can be mentioned is nicotiamide, dimethyl acetylamide, dimethyl formamide, Benzoylamide, urea etc.Preferred nicotiamide.Such amide can use separately or be used in combination.
Pharmaceutical composition of the present invention can be a liquid or solid, and described fluid composition can for example be to contain the benzimidazole compound with antiulcer activity and the aqueous solution of described water solublity organic amide.Described solid composite can for example be with above-mentioned aqueous solution lyophilization or solid preparation that spray drying obtained or have the benzimidazole compound of antiulcer activity and be the mixture of solid water-soluble amide at normal temperatures.Preferred solid preparation is a lyophilized products.Above-mentioned liquid preparation comprises the aqueous solution of such solid preparation.Above-mentioned solid composite can also be complete form, and wherein this solid preparation and transfusion are made into independently preparation.
Narrate the technology of preparing of Pharmaceutical composition of the present invention below.
Aqueous solution for example can be by conventional method itself, and benzimidazole compound by will having antiulcer activity and water miscible organic amide dissolve and prepare.Described aqueous solution preferably alkalescence.The pH of described aqueous solution is preferably about 9-12, more preferably about 9.5-11.Can be used for providing the preferred highly basic of alkali of alkalescence for described aqueous solution, for example alkali metal hydroxide such as sodium hydroxide, potassium hydroxide etc., alkali carbonate such as sodium carbonate, potassium carbonate etc. and arginine are only enumerated several examples.Alkali metal hydroxide preferably.
If use highly basic, in this solution is slow, can add acid.Spendable acid comprises glycine, sodium dihydrogen phosphate, sodium citrate etc.
The concentration of described benzimidazole compound in aqueous solution can for example be about 2-30mg/ml, preferably about 5-30mg/ml.Described concentration makes is enough to successfully carry out lyophilization just in program subsequently.
About the preparation of solid pharmaceutical composition, for example the aqueous solution that lyophilized products can be by will comprising benzimidazole compound with antiulcer activity and water-soluble amide preferably alkaline aqueous solution prepare by conventional method lyophilization itself.Typical method comprise with described aqueous solution approximately-25 ℃ freezing, simultaneously the internal negative pressure of this freeze dryer is maintained about 0.1 holder or below 0.1 holder, increasing plate temperature to final temperature with about 5-20 ℃/hour speed is about 25-40 ℃.
If carry out lyophilization, the form regulator can be added in the aqueous solution of benzimidazole compound to improve the form of described lyophilized products with antiulcer activity.Described form regulator comprises various sugar (sugar alcohol for example, as mannitol, xylitol, inositol, sorbitol etc., disaccharide based on hexose, as maltose, sucrose, lactose etc. and monosaccharide, as glucose), the alkali metal salt of natural amino acid (for example glycine, alanine, proline, valine, methionine etc.) and succinic acid (for example sodium succinate etc.).Preferred sugar, more preferably sugar alcohol in these form regulators.
If spray dried formulations is a target product, then above-mentioned aqueous solution is carried out spray drying with techniques known in themselves.Typical method comprises described aqueous solution to spurt into (for example the entrance and exit temperature of hothouse is respectively about 80-120 ℃ and about 30-50 ℃, and air velocity was for about 70-100kg/ hour) in its hothouse with about 5-20ml/ minute flow velocity vaporific nozzle from spray dryer (for example twin-jet nozzle, drive nozzle etc.) or the rotating disk.
Can be the ball piece or the powder of white by the lyophilization or the spray drying product of above-mentioned acquisition, its outward appearance changes hardly in time, thereby gives described benzimidazole compound with long storage period.
If being used for water-soluble amide of the present invention is solid at normal temperatures, then it directly can be mixed with the benzimidazole compound with antiulcer activity and prepare compositions.Blended method is unimportant, can use any known method.
If such solid pharmaceutical composition is made aqueous solution, preferably with its interim dissolving or dilution.
If Pharmaceutical composition of the present invention is an aqueous solution, then the concentration of the benzimidazole compound with antiulcer activity in this solution is about 0.03-20mg/ml, preferably about 0.1-15mg/ml, more preferably from about 2-10mg/ml.
The content of described water-soluble amide is every mole of about 1-300 mole of described benzimidazole compound, preferably about 2-200 mole, more preferably from about 5-85 mole.
For dissolubility and/or stability that strengthens described benzimidazole compound or the absorption of guaranteeing further to increase medicine, can use surfactant simultaneously in the present invention.
The example of the described surfactant that can mention comprises non-ionic surface active agent, fatty acid esters of sorbitan (anhydro sorbitol monopalmitate for example for example, anhydro sorbitol sesquistearate etc.), fatty acid glyceride (monostearin (self-emulsifying type) for example, Deng], methyl glycol fatty acid ester (for example propylene glycol monostearate), polyoxyethylene fatty acid glyceride [polyoxyethylene (15) monostearin for example, Deng], cithrol [polyoxyethylene (10) monostearate for example, PEG distearate etc.], polyoxyethylene alkyl ether [polyoxyethylene (21) lauryl ether for example, polyoxyethylene (20) octadecyl ether etc.], polyoxyethylene hydrogenated Oleum Ricini [polyoxyethylene (80) castor oil hydrogenated for example, HCO 60 and HCO 50 (trade names, Nikko Chemicals Co.) etc.], polyoxyethylene sorbitol Cera Flava derivant [for example polyoxyethylene (20) sorbitol Cera Flava etc.], polyoxyethylene lanolin alcohol [for example polyoxyethylene (20) lanolin alcohol etc.], Polyoxyethylene Sorbitol Fatty Acid Esters [for example polyoxyethylene (6) sorbitol six stearates etc.], general youth Buddhist nun restrains series of surfactants [for example general youth Buddhist nun restrains F68 (polyoxyethylene [160] polyoxypropylene [30] glycol), and general youth Buddhist nun restrains F127 (polyoxyethylene [196] polyoxypropylene [67] glycol)] etc.; Anion surfactant, lauryl sulphate acid alkali metal salt [for example sodium lauryl sulphate etc.] for example, stearic acid alkali metal salt [for example sodium stearate], Palmic acid alkali metal salt [for example sodium palmitate], and liquid surfactant, for example polysorbas20 and Tween 80 (AstlaPowder Co., the U.S.) etc.Wherein, preferred nonionic surfactants, especially more preferably general youth Buddhist nun restrains series of surfactants.These surfactants can be used alone or be used in combination in suitable ratio.
By the described benzimidazole compound of every mg, the consumption of described surfactant is about 0.01-10mg, preferably about 0.05-5mg, more preferably from about 0.1-1mg.
In addition, be dissolubility or the stability of improving described benzimidazole compound, multiple salt (for example acylate such as sodium citrate, sodium tartrate, sodium benzoate etc.) and/or stabilizing agent (for example alkaline, inorganic salts such as magnesium carbonate, calcium carbonate, magnesium bicarbonate, calcium bicarbonate etc.) can be mixed or adds in the present composition.If be necessary, can also use the isoosmotic adjusting agent (for example sodium chloride) that is used to regulate osmotic pressure and/or ease the pain or local anesthetic (for example glucose, sorbitol, mannitol, benzyl alcohol, Mepivacaine Hydrochloride, lidocaine hydrochloride etc.).
In addition, can also add a small amount of antiseptic and pH controlling agent as required.
Described antiseptic comprises parabens, for example methyl parahydroxybenzoate, propyl p-hydroxybenzoate etc., alcohols, methaform for example, quaternary ammonium salt, for example geramine, hyamine 1622, cetrimonium bromide etc., sorbic acid, chlohexidine, thimerosal etc., wherein preferred parabens.
Described pH controlling agent comprises various acid, for example mineral acid example hydrochloric acid, boric acid, phosphoric acid, carbonic acid, bicarbonate radical (hydrogen carbonic acid) etc., organic acid, as list or polycarboxylic acid, aminoacid etc., and various alkali, alkali metal hydroxide for example is as sodium hydroxide, potassium hydroxide etc. and alkali metal carbonic acid (hydrogen) salt, as sodium bicarbonate, sodium carbonate etc.
These additives can use separately or share, can be in every milligram of about 0.001-10mg of described benzimidazole compound, the preferably ratio interpolation of about 0.01-5mg.For strengthening described dissolubility, can also add suitable salt, for example sodium chloride, magnesium chloride, potassium chloride etc. with benzimidazole compound of antiulcer activity.The consumption of these salt can be about 0.1-30mg, preferably about 1-20mg, more preferably from about 1-10mg.
Pharmaceutical composition of the present invention is generally with oral by the dosage form that described active component and pharmaceutically acceptable carrier or excipient prescription are made or use through the parenteral route approach.
Pharmaceutical composition of the present invention can use in the following manner.With the solid composite is example, it can be dissolved in temporarily in sterile purified water or the transfusion (for example normal saline, glucose infusion liquid etc.), and as for example intravenous fluid, subcutaneous injection liquid, intramuscular injection or intravenous drip liquid, or as ophthalmic solution.The preparation of such injection is best to be carried out according to known sterile procedure own.
Pharmaceutical composition of the present invention can effectively prevent very much and treat mammal (for example mice, rat, exempt from, cat, Canis familiaris L., cattle, horse, goat, sheep, monkey and people) peptic ulcer (for example gastric ulcer, duodenal ulcer, anastomotic ulcer, Zollinger-Ellison syndrome etc.), gastritis, reflux esophagitis, and can treat described mammiferous operation back gastrointestinal hemorrhage very effectively.
Therefore Pharmaceutical composition hypotoxicity of the present invention can be given the people safely and domestic animal is oral or use through the parenteral route approach.
The dosage of Pharmaceutical composition of the present invention depends on kind and other factor of dosage form, therapeutic modality, reactive compound.Yet with the waterborne compositions is example, and the benzimidazole compound with antiulcer activity is for the preferably about 5-300mg of man's daily dose, and about 10-180mg is better.Under this daily dose, but this benzimidazole compound uses once or is divided into 2 or 3 times use every day.
According to the present invention, can make water-insoluble benzimidazole compound solubilising, and stable Pharmaceutical composition can be provided with antiulcer activity.Solid pharmaceutical composition of the present invention can be dissolved in sterile purified water or the transfusion (for example normal saline, glucose infusion liquid etc.) temporarily, can be used as injection easily.
To the present invention be described in detail in detail with following experiment embodiment and embodiment below.
Experiment embodiment 1
The lyophilized products that will obtain in following embodiment 1 is dissolved in the 5ml water for injection.In just dissolving, reach after this 4,8 and 24 hours, detect the outward appearance of this solution and the content of lansoprazole (in table 1, being called content).The results are shown in Table 1.
Table 1
The molten colourless transparent transparent content of liquid appearance transparent of the present invention (%) 100 98.4 97.0 99.0 after 24 hours after 8 hours after 4 hours during dissolving just
Pharmaceutical composition of the present invention all kept its outward appearance and content in back 24 hours well until dissolving, had confirmed the stability that it is splendid.
Experiment embodiment 2
The lyophilized products that will obtain in following embodiment 4,5 and 6 is that 6mglansoprazole/ml is dissolved in respectively and prepares preparation in the distilled water by final concentration, and they are called preparation A, B and C.On the other hand, 3g lansoprazole is dissolved in the 115ml 1N sodium hydrate aqueous solution, adds enough distilled water then and make into 200ml.This solution is filtered by biofilter, pack into filtrate in the bottle and use the conventional method lyophilizing.With this lyophilized products by final concentration for 6mg lansoprazole/ml is dissolved in the distilled water, make preparation, be referred to as preparation D.
The color of comparative formulations A, B, C and D and clarity the results are shown in Table 2.
Table 2
Molten back 4 hours molten back 8 hours molten back 24 hours preparation A of the present invention are colourless during dissolving just
Transparent preparation B is colourless
Transparent formulation C is colourless
Precipitation is found in the fine discovery of the colourless discovery of transparent control formulation D less
Transparent insoluble matter amount precipitation and muddy
At the content of dissolving detection in back 24 hours preparation A, B and C lansoprazole separately, the content during by firm dissolving is 100%, and content separately is at least 96%.
Until at least 24 hours, its outward appearance and content were still complete acceptable after dissolving for preparation A of the present invention, B and C, and this shows that the active agent stability in each preparation is quite gratifying.Embodiment 1
375mg glycine, 12.5g nicotiamide and 300mg sodium hydroxide are dissolved in the water for injection, add then and dissolve 1000mg lansoprazole to make into cumulative volume with the 1.5g mannitol be 50ml.This solution is sterilized after filtration, filtrate is divided by every part of 1.5ml be filled to 9cm
3Bottle in and lyophilization according to a conventional method, obtain containing the lyophilized products of lansoprazole.
Embodiment 2
1000mg lansoprazole, 300mg methylglucosamine and 15g nicotiamide are mixed and be dissolved in the water for injection.This solution is transferred to 10.5 with the 1N sodium hydrate aqueous solution with pH make into 50ml.This solution is sterilized after filtration,, obtain containing the spray dried formulations of lansoprazole the filtrate spray drying.
Embodiment 3
3000mg lansoprazole is mixed with the 60g dimethyl acetylamide and this mixture is dissolved in the water for injection.This solution is transferred to pH10.7 and makes into 500ml with the 1N sodium hydrate aqueous solution.This solution is sterilized after filtration, and filtrate is filled to 10cm by every part of 5ml branch
3Bottle in, obtain containing the aqueous formulation of lansoprazole.
Embodiment 4
3000mg lansoprazole, 18g nicotiamide and the general youth Buddhist nun of 1g are restrained F68 mix, be dissolved in then in the 115ml 0.1N sodium hydrate aqueous solution and make into 200ml with powder-form.This solution is filtered with biofilter, filtrate is divided by every part of 2ml be filled to 17cm
3Bottle in, and lyophilization according to a conventional method obtains containing the pharmaceutical preparation of lansoprazole.
Embodiment 5
3000mg lansoprazole and 9g nicotiamide are mixed with powder-form, be dissolved in then in the 115ml 0.1N sodium hydrate aqueous solution and make into 200ml.This solution is filtered with biofilter, filtrate is divided by every part of 2ml be filled to 17cm
3Bottle in, and lyophilization according to a conventional method obtains containing the pharmaceutical preparation of lansoprazole.
Embodiment 6
3000mg lansoprazole is dissolved in the 40ml 1N sodium hydrate aqueous solution, and adding 9g nicotiamide, the general youth Buddhist nun of 0.5g restrain F68,1.1g citric acid, 5g sodium hydrogen phosphate, 1.2g sodium bicarbonate and 7g mannitol in this solution.With this mixture with enough distilled water dilutings to 300ml.This solution is filtered with biofilter, filtrate is divided by every part of 3ml be filled to 17cm
3Bottle in, and lyophilization according to a conventional method obtains containing the pharmaceutical preparation of lansoprazole.
Claims (13)
1. Pharmaceutical composition, it comprises benzimidazole compound and the water miscible amide with antiulcer activity.
2. according to the compositions of claim 1, wherein said benzimidazole compound is the compound or its salt of following formula representative:
The A ring can randomly be substituted R in the formula
1, R
3And R
7Identical or different, be hydrogen, alkyl or alkoxyl, R
2Be can randomly substituted alkyl, and n be 0 or 1.
3. according to the compositions of claim 2, R wherein
1And R
3Identical or different, be hydrogen, alkyl or alkoxyl, R
2Be C
1-4Alkyl, it can be randomly by (1) halogen or (2) C
1-4Alkoxyl replaces, and R
7It is hydrogen atom.
4. according to the compositions of claim 1, wherein said benzimidazole compound is 2-[2-[3-methyl-4-(2,2, the 2-trifluoro ethoxy) pyridine radicals] methylsulfinyl] benzimidazole.
5. according to the compositions of claim 1, wherein said water-soluble amide is the chemical compound of following formula representative:
R in the formula
4Be hydrogen, amino, can randomly substituted alkyl, can randomly substituted aryl or can randomly substituted nitrogen heterocyclic ring group, R
5And R
6Identical or different, be hydrogen or alkyl.
6. according to the compositions of claim 5, R wherein
4Be can randomly substituted nitrogen heterocyclic ring group, R
5And R
6Identical or different, be hydrogen or alkyl.
7. according to the compositions of claim 5, wherein said water-soluble amide is a nicotiamide.
8. according to the compositions of claim 1, it also comprises at least a sugar.
9. according to the compositions of claim 8, wherein said sugar is sugar alcohol.
10. according to the compositions of claim 1, it is a lyophilized products.
11. according to the compositions of claim 1, it is an aqueous solution.
12. according to the compositions of claim 11, wherein said aqueous solution is an injection.
13. according to the compositions of claim 10, it prepares by comprising the benzimidazole compound with antiulcer activity and the alkaline aqueous solution lyophilization of water-soluble amide.
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| CN 94116369 CN1116092A (en) | 1994-10-14 | 1994-10-14 | Pharmaceutical composition |
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| CN 94116369 CN1116092A (en) | 1994-10-14 | 1994-10-14 | Pharmaceutical composition |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102772409A (en) * | 2012-08-20 | 2012-11-14 | 长春海悦药业有限公司 | Pharmaceutical composition |
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1994
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102772409A (en) * | 2012-08-20 | 2012-11-14 | 长春海悦药业有限公司 | Pharmaceutical composition |
| CN102772409B (en) * | 2012-08-20 | 2014-04-02 | 长春海悦药业有限公司 | Pharmaceutical composition |
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