CN102872011B - Comprise the pharmaceutical composition of (S)-Esomeprazole - Google Patents
Comprise the pharmaceutical composition of (S)-Esomeprazole Download PDFInfo
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- CN102872011B CN102872011B CN201210363950.1A CN201210363950A CN102872011B CN 102872011 B CN102872011 B CN 102872011B CN 201210363950 A CN201210363950 A CN 201210363950A CN 102872011 B CN102872011 B CN 102872011B
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Abstract
The present invention relates to the pharmaceutical composition comprising (S)-Esomeprazole.Particularly, the present invention relates to the pharmaceutical composition of (the S)-Esomeprazole comprised in levorotatory form, wherein comprise active component, and the acceptable adjuvant of pharmacy.Pharmaceutical composition of the present invention has good character.
Description
Technical field
The invention belongs to medical art, relate to the pharmaceutical composition that one comprises (S)-Esomeprazole, the pharmaceutical preparation that this pharmaceutical composition can use as oral or injection.
Background technology
Oxiracetam (oxiracetam) is that a kind of promotion learns, the novel medicine for central nervous system of memory reinforcing.This active component is a kind of hydroxy-amino-butyric acid (BABOB) cyclic derivatives of synthesis; only act on central nervous system; mainly be distributed in cerebral cortex, Hippocampus; there are activation, protection or promote the functional rehabilitation of neurocyte; improve memory and the learning functionality of disturbance of intelligence patient; and medicine itself does not have direct vasoactive, also not having central excitation effect, is a kind of lasting facilitation on the impact of ability of learning and memory.Study mechanism result shows, oxiracetam can promote the synthesis of phosphatidylcholine and PHOSPHATIDYL ETHANOLAMINE, promotes brain metabolism, improves blood brain barrier to the stimulation of special nervus centralis road, improve the ratio of ATP/ADP in brain, the synthesis of protein and nucleic acid in brain is increased.
Oxiracetam is in 1987 in Italy's listing, and the dosage form of listing is tablet, 800mg; Capsule, 800mg; Injection, 1g/5ml.Domestic at present only have oxiracetam capsule and injection listing, and main active used is racemic modification.Research finds, compare with racemic modification, (S)-Esomeprazole (also can be described as S-oxiracetam or levo-oxiracetam in this article), has better curative effect and lower toxic and side effects.
Its molecular formula of S-oxiracetam configuration and molecular weight are respectively: C
6h
10n
2o
3, Mr.158.16; Its structural formula is:
Know, material medicine is when being mixed with preparation, and need effectively to give preparation and meet the character that marketing drugs requires, such as human body can accept, medicine is stable.
But levo-oxiracetam still can not be applied to clinical.Therefore those skilled in the art expect that having new technology to be applied to levo-oxiracetam is such as made into preparation to make its applicable clinical application.
Summary of the invention
The object of the invention is to provide a kind of pharmaceutical composition such as pharmaceutical preparation with the levo-oxiracetam of superperformance for clinical.The present inventor finds that the combination be mixed with under given conditions has good performance.The present invention is based on this find and be accomplished.
In first of the present invention, the invention provides a kind of pharmaceutical composition, wherein comprise the levo-oxiracetam as active component, and the acceptable adjuvant of pharmacy.
According to pharmaceutical composition of the present invention, its dissolve with distilled water or dilution to make activity component concentration be the solution of 1g:20ml time, the pH value of this solution is 3 ~ 8, such as, be 4 ~ 7, such as, be 5 ~ 6, such as, be 5.2 ~ 5.8.
According to pharmaceutical composition of the present invention, wherein containing the material for regulating said composition acid-base value.In one embodiment, this consumption that can be used for the material of adjustment present composition acid-base value is, be enough to make said composition acid-base value be adjusted to described compositions dissolve with distilled water or dilution to make activity component concentration be the solution of 1g:20ml time, the pH value of this solution is 3 ~ 8 (is such as 4 ~ 7, being such as 5 ~ 6, such as, is 5.2 ~ 5.8) scope.In one embodiment, this can be used for regulating the material of present composition acid-base value to be selected from acid-base modifier, buffer agent or its compositions.
According to pharmaceutical composition of the present invention, wherein said for regulating the material of said composition acid-base value to be selected from hydrochloric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, phosphoric acid, dibastic sodium phosphate, sodium dihydrogen phosphate, sodium phosphate, citric acid, sodium citrate, acetic acid, sodium acetate etc.
According to pharmaceutical composition of the present invention, the acceptable adjuvant of wherein said pharmacy comprises solvent.Described solvent is selected from water, alcohols solvent or its combination.In one embodiment, described alcohols solvent be selected from ethanol, glycerol, propylene glycol, molecular weight be 200 ~ 600 Polyethylene Glycol or its combination.In one embodiment, described solvent be selected from water, ethanol, glycerol, propylene glycol, molecular weight be 200 ~ 600 Polyethylene Glycol or its combination.
According to pharmaceutical composition of the present invention, the acceptable adjuvant of wherein said pharmacy comprises osmotic pressure regulator.Described osmotic pressure regulator is such as but not limited to: glucose, sucrose, mannitol, lactose, fructose, sodium chloride or its combination.When for injectable drug particularly directly intravenous administration, it is favourable that the present composition comprises osmotic pressure regulator.The consumption of osmotic pressure regulator can not be particularly limited, generally speaking can according to the osmotic pressure determination osmotic pressure regulator that produces of the compositions of this preparation amount of adding itself, to reach isotonic with blood of human body or slightly highly to ooze.
According to pharmaceutical composition of the present invention, the acceptable adjuvant of wherein said pharmacy comprises excipient, such as glucose, sucrose, mannitol, lactose, fructose, sodium chloride or its combination.These excipient especially can as in lyophilization injectable powder to give form that freeze-drying prods fixes substantially and there is good dissolubility.
According to pharmaceutical composition of the present invention, it is the medicament in liquid condition.In one embodiment, this liquid preparation is injection or oral liquid.In one embodiment, this liquid preparation is high-capacity injection or injection with small volume.In one embodiment, this liquid preparation is injection with small volume.In one embodiment, this liquid preparation is injection with small volume, in this injection, the concentration of active component is 1g:(2 ~ 50) ml, such as concentration is 1g:(2 ~ 25) ml, such as concentration is 1g:(2 ~ 20) ml, such as concentration is 1g:(2 ~ 10) ml.
According to pharmaceutical composition of the present invention, it is the medicament in liquid condition, and wherein comprises and be selected from following solvent: water, ethanol, glycerol, propylene glycol, molecular weight are Polyethylene Glycol or its combination of 200 ~ 600.In one embodiment, this liquid preparation is injection with small volume, in this injection, the concentration of active component is 1g:(2 ~ 50) ml, such as concentration is 1g:(2 ~ 25) ml, such as concentration is 1g:(2 ~ 20) ml, such as concentration is 1g:(2 ~ 10) ml, and comprise and be selected from following solvent: water, ethanol, glycerol, propylene glycol, molecular weight are Polyethylene Glycol or its combination of 200 ~ 600.
According to pharmaceutical composition of the present invention, it is the medicament in solid state.In one embodiment, this solid chemicals is when dissolving with distilled water that to make activity component concentration be the solution of 1g:20ml, and the pH value of this solution is 3 ~ 8, such as, be 4 ~ 7, such as, be 5 ~ 6, such as, be 5.2 ~ 5.8.In one embodiment, this solid chemicals be first by solubilize active ingredients in solvent (particularly water), regulate the acid-base value of this medicinal liquid, and then water removing prepared.In one embodiment, this solid chemicals is injection preparation.In one embodiment, this solid chemicals is the lyophilization injectable powder of injection.
Although pharmaceutical composition of the present invention can because concrete form is different from likely there is diverse combination during different auxiliary material combinations, such as when being mixed with aqueous injectable, containing relatively large solvent particularly water in this pharmaceutical composition, the weight ratio of such as levo-oxiracetam and water can be 1:(2 ~ 50), such as 1:(2 ~ 25), such as concentration is 1g:(2 ~ 20) ml, such as concentration is 1g:(2 ~ 10) ml.And when being mixed with the lyophilization injectable powder of injection, relatively less freeze-dried excipient such as mannitol only can be comprised in this injectable powder, the weight ratio of such as levo-oxiracetam and mannitol can be 1:(0.1 ~ 2), such as 1:(0.1 ~ 1.5), such as 1:(0.1 ~ 1).
In pharmaceutical composition of the present invention, can also flavoring agent be contained, particularly when said composition as medicinal preparation for oral administration when.Flavoring agent is as sweeting agent, aromatic etc.The consumption of flavoring agent can be determined according to the experience of those skilled in the art.
In pharmaceutical composition of the present invention, can also antiseptic be contained, particularly when said composition as the medicinal preparation for oral administration of medicinal preparation for oral administration particularly as multiple-unit container when.The kind of antiseptic and consumption can be determined according to the experience of those skilled in the art.Surprisingly, the present composition is when combining with antiseptic alkyl paraben (such as methyl ester, ethyl ester, propyl ester), disadvantageous for the maintenance of enantiomeric purity in compositions, therefore in some embodiments of the present invention, alkyl paraben is not comprised in the present composition.
According to pharmaceutical composition of the present invention, it is injection.In one embodiment, this injection comprises active component levo-oxiracetam, water for injection and regulates the material of said composition acid-base value, wherein the concentration of levo-oxiracetam is 0.05g/ml ~ 0.5g/ml (such as 0.1g/ml ~ 0.5g/ml), and regulate the amount of substance of said composition acid-base value to be this injection distilled water can be made to dissolve when to make activity component concentration be the solution of 1g:20ml, the pH value of this solution is 3 ~ 8 (is such as 4 ~ 7, being such as 5 ~ 6, such as, is 5.2 ~ 5.8) scope.
According to pharmaceutical composition of the present invention, it is injection lyophilization injectable powder.In one embodiment, this injection lyophilization injectable powder comprises the levo-oxiracetam of 1 weight portion, excipient (the such as glucose of 0 ~ 1 weight portion (such as 0 ~ 0.5 weight portion), sucrose, mannitol, lactose, fructose, sodium chloride, or its combination), and regulate the material of said composition acid-base value, and regulate the amount of substance of said composition acid-base value to be this injection lyophilization injectable powder distilled water can be made to dissolve when to make activity component concentration be the solution of 1g:20ml, the pH value of this solution is 3 ~ 8 (is such as 4 ~ 7, be such as 5 ~ 6, be such as 5.2 ~ 5.8) scope.
According to pharmaceutical composition of the present invention, it is oral solution.In one embodiment, this oral solution comprises active component levo-oxiracetam, water, the material of adjustment said composition acid-base value and other optional pharmaceutic adjuvant, wherein the concentration of levo-oxiracetam is 0.05g/ml ~ 0.5g/ml (such as 0.1g/ml ~ 0.5g/ml), and regulate the amount of substance of said composition acid-base value to be this oral solution distilled water can be made to dissolve when to make activity component concentration be the solution of 1g:20ml, the pH value of this solution is 3 ~ 8 (is such as 4 ~ 7, being such as 5 ~ 6, such as, is 5.2 ~ 5.8) scope.
According to pharmaceutical composition of the present invention, wherein for levo-oxiracetam the percentage amounts of dextrorotation oxiracetam lower than 5%, such as, lower than 2%, such as, lower than 1%, such as, lower than 0.5%, such as, lower than 0.2%; Preferred lower than 1%, more preferably less than 0.5%.
According to pharmaceutical composition of the present invention, it is after 50 ° of C lower seals place 90 days, and in said composition, the changing value of the relative amount of dextrorotation oxiracetam is no more than 1%, such as, be no more than 0.5%.
According to pharmaceutical composition of the present invention, it is after 60 ° of C lower seals place 30 days, and in said composition, the changing value of the relative amount of dextrorotation oxiracetam is no more than 1%, such as, be no more than 0.5%.
In this article, phrase " relative amount of dextrorotation oxiracetam ", referred to as " d-isomer relative amount ", can refer to that the amount of dextrorotation oxiracetam in said composition is multiplied by 100% percent obtained again divided by the amount of levo-oxiracetam in said composition herein; That is, in compositions for levo-oxiracetam the percentage amounts of dextrorotation oxiracetam; Such as in a certain amount of compositions, the active component levo form containing 1000mg, and the dextrorotation oxiracetam as impurity also containing 5mg in this certain amount of compositions, then in said composition, " d-isomer relative amount " is 5/1000 × 100%=0.5%.
In this article, phrase " changing value of the relative amount of dextrorotation oxiracetam ", can referred to as " d-isomer relative amount changing value " at this paper, refer to compared with high-temperature process (such as 50 ° of C lower seals are placed and processed for 90 days) sample, the value of the relative amount of dextrorotation oxiracetam in said composition; That is the d-isomer relative amount through high-temperature process sample deducts the value (%) of the d-isomer relative amount gained without high-temperature process sample; Such as, if " d-isomer relative amount " is 0.13% in certain compositions, said composition is through measuring after high-temperature process, and wherein " d-isomer relative amount " is 1.05%, then said composition " d-isomer relative amount changing value " is 1.05%-0.13%=0.92%.Above-mentioned high-temperature process can be that 50 ° of C lower seals place process in 90 days or 60 ° of C lower seals place process in 30 days, or also can be other high-temperature process condition.
In the present composition, the content of levo-oxiracetam and dextrorotation oxiracetam can make to measure in many ways, and along with technological progress, assay method can also improve further, therefore can not do special restriction to the content assaying method of levo form and d-isomer in the present invention.But in an example, the content of levo-oxiracetam of the present invention and dextrorotation oxiracetam can measure according to following HPLC condition: chromatographic column: chiral chromatographic column (ChiralpakAD-H, 4.6*250mm); Column temperature: 25 ° of C; Mobile phase: normal hexane-ethanol (4:1); Flow velocity: 1.0ml/min; Detector: UV detects (wavelength 215nm); System suitability: levo-oxiracetam must not be less than 4.0 with both d-isomers separating degree as impurity.Can use purity be greater than 99.5% levo-oxiracetam and dextrorotation oxiracetam in contrast product measure.In the present invention, if not otherwise specified, in compositions or crude drug, the amount of levo-oxiracetam and dextrorotation oxiracetam or relative quantity are measured by the method for above HPLC condition.
Because to the essence that prior art is contributed, the present invention is that the compositions made for levo-oxiracetam provides one acid or alkali environment uniquely, therefore regulate the consumption of the material of Acidity of Aikalinity, and the consumption of other material, special restriction can not be done.
In an embodiment of pharmaceutical composition of the present invention, the amount of other pharmaceutic adjuvant beyond wherein desolventizing for the amount of active component lower than 100%, such as, lower than 75%, lower than 50%, lower than 25%, lower than 20%, lower than 10%.
In an embodiment of pharmaceutical composition of the present invention, when said composition is the medicament in solution state, wherein the concentration of levo-oxiracetam is 0.05g/ml ~ 0.5g/ml (such as 0.1g/ml ~ 0.5g/ml), and the amount desolventizing other pharmaceutic adjuvant beyond particularly water for the amount of active component lower than 100%, such as lower than 75%, lower than 50%, lower than 25%, lower than 20%, lower than 10%.
In an embodiment of pharmaceutical composition of the present invention, when said composition is the medicament in solid state, wherein, the amount of other pharmaceutic adjuvant for the amount of active component lower than 100%, such as, lower than 75%, lower than 50%, lower than 25%, lower than 20%, lower than 10%.
Second aspect of the present invention provides the method for the pharmaceutical composition of preparation pharmaceutical composition of the present invention such as first aspect present invention, and the method comprises the steps:
I) by active component levo-oxiracetam dissolution with solvents;
Ii) material regulating acid-base value is added, its consumption is said composition distilled water is dissolved or dilution when to make activity component concentration be the solution of 1g:20ml, the pH value of this solution is 3 ~ 8 (is such as 4 ~ 7, be such as 5 ~ 6, be such as 5.2 ~ 5.8) scope, optionally adding (material except regulating acid-base value) other pharmacy acceptable adjuvant, obtaining compositions; And optionally further,
Iii) by step I i) the solvent removing of the compositions of gained, obtain compositions.
Inventive compound levo-oxiracetam can be used as cerebrovascular medication, particularly may be used for memory that the diseases such as light moderate vascular dementia, alzheimer disease and cerebral trauma cause and disturbance of intelligence.Therefore, the purposes of the pharmaceutical composition that 3rd aspect of the present invention provides pharmaceutical composition of the present invention such as first aspect present invention in the medicine for the preparation of prevention or treatment cerebrovascular, particularly can for the preparation of prevention or the purposes for the treatment of memory that the diseases such as light moderate vascular dementia, alzheimer disease and cerebral trauma cause and disturbance of intelligence.Such as can the higher concentration solution that provides of the application of the invention, dilute laggard row vein with 0.9% sodium chloride injection or 5% glucose injection during use and instil, or use the oral administration solution of higher concentration, in use it is taken with after beverage dilution.
Arbitrary embodiment of either side of the present invention, can combine with arbitrary embodiment of this aspect or other side, as long as this compositions there will not be contradiction.
In the present invention, phrase " its dissolve with distilled water or dilution to make activity component concentration be the solution of 1g:20ml time ", represent that present composition distilled water dissolves (when said composition is solid state) or dilution (when said composition is liquid condition), formed in every 20ml solution containing 1g active component levo-oxiracetam.In this article, term " distilled water " refers to and at least distills through 2 times the water obtained.The present invention uses the object of distilled water to be the sign that can not affect present composition acid-base value because its ions content is low; Therefore, for this purpose, distilled water of the present invention can also with low water such as water for injection, ultra-pure water (the such as MILLI-Q pure water of other ion concentration; MILLIPORE company produces).Therefore, in the present invention, term " distilled water " comprises the implication of distilling the water, water for injection (such as meeting the waters for injection of Chinese Pharmacopoeia version in 2010 two regulations), ultra-pure water etc. obtained through 2 times or more times, and they are all in the intended scope of this term of the present invention " distilled water ".In addition, for the Special Contributions of the present invention to prior art, the present composition also comprises such situation, and namely the present composition is liquid dosage form, and wherein activity component concentration is 1g:20ml or rarer, such as concentration is 1g:25ml or 1g:30ml, in the case, the present composition directly measures without dilution, and its pH value is 3 ~ 8 (is such as 4 ~ 7, being such as 5 ~ 6, such as, is 5.2 ~ 5.8) scope.Therefore in some embodiments of the present invention, compositions of the present invention is solution, and wherein activity component concentration is 1g:20ml or rarer, and the pH value of this solution is the scope of 3 ~ 8 (being such as 4 ~ 7, such as, is 5 ~ 6, such as, be 5.2 ~ 5.8)
The invention provides a kind of with the S-oxiracetam of more high bioactivity or its salt be active component, stable injection preparation.It is with S-oxiracetam or its salt for medicinal active ingredient, with pharmaceutically acceptable adjuvant make can the compositions of injection.
Because S-oxiracetam is a kind of levo form, expecting that it has enough stability when it makes pharmaceutical preparation, can not there is uncontrollable change in the amount of such as isomer.May racemization be there is in optical isomer under certain conditions (as soda acid, high temperature, light exposure).For obtaining stable S-oxiracetam pharmaceutical preparation, needing to take corresponding measure, suppressing S-oxiracetam racemization, thus maintain the stability of S-oxiracetam and corresponding high pharmacologically active.Have been surprisingly found that the pH of S-oxiracetam drug solution is one and the closely-related factor of racemization.When preparing S-oxiracetam oral administration solution, injection or injection freeze-dried powder, can by the pH regulator of medicinal liquid or lyophilizing prodrug solution to particular range (3 ~ 8, be such as 4 ~ 7, be such as 5 ~ 6, be such as 5.2 ~ 5.8), be prepared into preparation according to galenic pharmacy means subsequently, contribute to the oxiracetam pharmaceutical preparation obtaining there is stable S-configuration, and maintain the stability between its storage life.
All containing in the injection of active component S-oxiracetam described in the present invention, pharmaceutic adjuvant at least can comprise the material (such as pH adjusting agent), one or more in intercalating agent that regulate Acidity of Aikalinity.Wherein, described pH adjusting agent is water solublity regulator, can be one or more in hydrochloric acid, phosphoric acid, hydrobromic acid, acetic acid, potassium acetate, sodium acetate, boric acid, citric acid, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, phosphate, dihydric phosphate, hydrophosphate, tartaric acid, biatrate, aminoacid and salt thereof, acid regulator is preferably hydrochloric acid, and alkaline conditioner is preferably sodium hydroxide.For the metal-chelator used in ejection preparation, preferably use sodium ethylene diamine tetracetate calcium.
Particularly, when described S-oxiracetam injection is injection S-oxiracetam freeze-dried powder, wherein also can contain or not contain pharmaceutical carrier (filler), can be one or more in mannitol, glucose, sorbitol, sodium chloride, dextran, sucrose, lactose, glycine, cyclodextrin and derivant thereof, be preferably the one in mannitol, sorbitol and lactose or compositions.
But, the present inventor finds: the same with the left-handed of other or right-handed spiral configuration compound, as well do not controlled prescription and the processing parameter of S-oxiracetam injection preparation, easily there is racemization in S-oxiracetam, form raceme, thus cause the pharmacological activity advantage of S-oxiracetam to be lost.
Study by experiment, we find, when preparing the powder ampoule agent for injection of this active component, only have when the pH of S-oxiracetam drug solution is 3 ~ 8, being such as 4 ~ 7, such as, is 5 ~ 6, such as, be 5.2 ~ 5.8, may produce and obtain high-purity S-oxiracetam drug solution, and make final dried frozen aquatic products have acceptable long-time stability.
Detailed description of the invention
By following instance, the present invention is further described in detail, including but not limited to following instance.In example hereafter, the raw material levo-oxiracetam of use, if not otherwise specified, wherein oxiracetam " d-isomer relative amount " is 0.13%.
test example 1: Acidity of Aikalinity is on the impact of levo-oxiracetam drug solution
Containing levo-oxiracetam concentration with water for injection preparation is the solution of 1g/17ml, and as prefabricated solution, then the material of adjustment in use acid-base value regulates the pH value of solution to the pH value of regulation as follows:
(1) acid-base pair: use 1M hydrochloric acid solution and 1M sodium hydroxide solution, directly to prepared prefabricated solution adjust ph to desired value, then become levo-oxiracetam concentration to be the solution of 1g/20ml with water for injection standardize solution; Verifying pH value if desired whether to coincide with desired value, then can using, as misfitted then reprovision as coincideing.
(2) phosphoric acid buffer pair: add appropriate sodium dihydrogen phosphate or sodium dihydrogen phosphate (if desired phosphoric acid or sodium phosphate) in prefabricated solution, solution ph is made to be transferred to the pH value of regulation, and the concentration of phosphate radical controls in the scope of 0.02 ~ 0.025mol/L in whole solution, then levo-oxiracetam concentration is become to be the solution of 1g/20ml with water for injection standardize solution; Verifying pH value if desired whether to coincide with desired value, then can using, as misfitted then reprovision as coincideing.
(3) citric acid buffering is right: in prefabricated solution, add appropriate citric acid or sodium citrate, solution ph is made to be transferred to the pH value of regulation, and the concentration of citric acid radical controls in the scope of 0.02 ~ 0.025mol/L in whole solution, then levo-oxiracetam concentration is become to be the solution of 1g/20ml with water for injection standardize solution; Verifying pH value if desired whether to coincide with desired value, then can using, as misfitted then reprovision as coincideing.
(4) acetate buffer pair: add proper amount of acetic acid or sodium acetate in prefabricated solution, solution ph is made to be transferred to the pH value of regulation, and the concentration of acetate controls in the scope of 0.02 ~ 0.025mol/L in whole solution, then levo-oxiracetam concentration is become to be the solution of 1g/20ml with water for injection standardize solution; Verifying pH value if desired whether to coincide with desired value, then can using, as misfitted then reprovision as coincideing.
More than using during often kind of acid-base modifier, solution target ph is regulated to be respectively: 3.5,4.0,4.25,4.5,4.75,5.0,5.2,5.4,5.6,5.8,6.0,6.25,6.5,6.75,7.0,7.5, namely the solution of 16 kinds of pH value is made into respectively with often kind of acid-base modifier, totally 64 solution.
Get 64 kinds of medicinal liquids of above preparation respectively, sealing by fusing is in colourless ampoule bottle, and every bottle of 5ml, obtains 64 kinds of solution examples, carry out high-temperature process test as solution.
Get 64 kinds of medicinal liquids of above preparation respectively, be dispensed in cillin bottle, every bottle of 5ml, then carry out lyophilization to eliminate water (to moisture lower than 4%) wherein, sealing, obtains 64 kinds of dry powder samples, carries out high-temperature process test as dry powder.
Above 64 kinds of solution examples and 64 kinds of dry powder samples are placed under 60 ° of C hot conditionss and place 30 days, then measure each sample relative to for high-temperature process sample wherein " d-isomer relative amount changing value ", represent with %, result is as follows:
Result shows, the d-isomer impurity in levo-oxiracetam shows lower change under specific pH value condition.
In addition, in the test supplemented, according to above acid-base pair to testing, the sample of 2 parts of solution-types is prepared respectively under each pH condition, add the methyl parahydroxybenzoate with weight such as active component in each pH series of samples of a copy of it, in another part of each pH series of samples, add the ethylparaben with weight such as active component; Place 30 days according under above 60 ° of C hot conditionss, the d-isomer relative amount changing value (%) of result two pH series of samples is all high by more than 0.3% than the result in " acid-base pair " hurdle " solution " sub-hurdle in upper table.Method like this again, upwards show to add in " acid-base pair " hurdle " dry powder " sub-hurdle series of samples and the methyl parahydroxybenzoate of the weight such as active component or ethylparaben, the d-isomer relative amount changing value (%) of result display gained corresponding pH series of samples is all high by more than 0.3% than the result in " acid-base pair " hurdle " solution " sub-hurdle in upper table.In addition, with reference to the mode adding methyl parahydroxybenzoate or ethylparaben in " acid-base pair " hurdle in above upwards table, add methyl parahydroxybenzoate or ethylparaben in above table in " phosphoric acid buffer to " hurdle, the d-isomer relative amount changing value (%) that result also shows gained corresponding pH series of samples is all high by more than 0.3% than the result in " phosphoric acid buffer to " hurdle correspondence " solution " sub-hurdle in upper table or " dry powder " sub-hurdle.
The present inventor is in other test, use racemic oxiracetam as crude drug, method according to above test example 1 is tested, various solution example d-isomer relative amounts changing value (%) of result between pH=5.2 ~ 5.8 are all greater than 0.65, and various dry powder sample d-isomer relative amounts changing value (%) between pH=5.2 ~ 5.8 are all greater than 0.4.
test example 2: the impact of supplementary product kind
1, containing levo-oxiracetam concentration with water for injection preparation is the solution of 1g/10ml, as prefabricated solution; Respectively to wherein adding the ethanol, propylene glycol, glycerol, the PEG200 that are equivalent to active component 5 times of weight; Then the acid-base pair of hydrochloric acid and sodium hydroxide composition is used to regulate the pH value of solution to the pH value of regulation respectively as follows: to use 1M hydrochloric acid solution and 1M sodium hydroxide solution, to containing the solution adjust ph of alcohol to desired value, then become levo-oxiracetam concentration to be the solution of 1g/20ml with water for injection standardize solution; Verifying pH value if desired whether to coincide with desired value, then can using, as misfitted then reprovision as coincideing.
Above acid-base pair is used to regulate solution target ph to be respectively: 3.5,4.0,4.25,4.5,4.75,5.0,5.2,5.4,5.6,5.8,6.0,6.25,6.5,6.75,7.0,7.5, namely the solution respectively containing different alcohol is regulated with acid-base pair, make the solution of 16 kinds of pH value respectively, totally 64 solution.
Get 64 kinds of medicinal liquids of above preparation respectively, sealing by fusing is in colourless ampoule bottle, and every bottle of 5ml, obtains 64 kinds of solution examples, carry out high-temperature process test as solution.
2, containing levo-oxiracetam concentration with water for injection preparation is the solution of 1g/15ml, as prefabricated solution; Respectively to wherein adding mannitol, lactose, sorbitol, glucose four kinds of excipient of being equivalent to active component 1 times of weight; Then the acid-base pair of hydrochloric acid and sodium hydroxide composition is used to regulate the pH value of solution to the pH value of regulation respectively as follows: to use 1M hydrochloric acid solution and 1M sodium hydroxide solution, to containing the solution adjust ph of excipient to desired value, then become levo-oxiracetam concentration to be the solution of 1g/20ml with water for injection standardize solution; Verifying pH value if desired whether to coincide with desired value, then can using, as misfitted then reprovision as coincideing.
Above acid-base pair is used to regulate solution target ph to be respectively: 3.5,4.0,4.25,4.5,4.75,5.0,5.2,5.4,5.6,5.8,6.0,6.25,6.5,6.75,7.0,7.5, namely the solution respectively containing different excipient is regulated with acid-base pair, make the solution of 16 kinds of pH value respectively, totally 64 solution.
Get 64 kinds of medicinal liquids of above preparation respectively, be dispensed in cillin bottle, every bottle of 5ml, then carry out lyophilization to eliminate water (to moisture lower than 4%) wherein, sealing, obtains 64 kinds of dry powder samples, carries out high-temperature process test as dry powder.
3, above 64 kinds of solution examples and 64 kinds of dry powder samples are placed under 60 ° of C hot conditionss and place 30 days, then measure each sample relative to for high-temperature process sample wherein " d-isomer relative amount changing value ", represent with %.Result demonstrates the result consistent with test example.That is, the solution of pH value between 5.2 ~ 5.8, their d-isomer relative amount changing value is all below 0.4%; And pH value be less than or equal to 5.0 or pH value be more than or equal to 6.0 solution, their d-isomer relative amount changing value is all more than 0.65%; Particularly pH value be less than or equal to 4.75 or pH value be more than or equal to 6.25 solution, their d-isomer relative amount changing value is all more than 0.9%.In addition, the dry powder of pH value between 5.2 ~ 5.8, their d-isomer relative amount changing value is all below 0.3%; And pH value be less than or equal to 5.0 or pH value be more than or equal to 6.0 dry powder, their d-isomer relative amount changing value is all more than 0.4%; Particularly pH value be less than or equal to 4.75 or pH value be more than or equal to 6.25 dry powder, their d-isomer relative amount changing value is all more than 0.5%.
Above result shows, uses conventional injection or adjuvant for oral use for d-isomer change not impact in the present composition.
test example 3: the impact of supplementary product consumption
1, with the solution of water for injection preparation containing levo-oxiracetam, concentration is respectively 1g/2.5ml, 1g/5ml, 1g/10ml, 1g/15ml, 1g/20ml, 1g/25ml.Acid-base pair described in each concentration samples embodiment 1 regulates the pH value of solution to the different pH value of regulation, obtain the solution of different pH value series: 3.5,4.5,4.75,5.0,5.2,5.4,5.6,5.8,6.0,6.25,6.75,7.5, namely often kind of strength solution prepares the solution of 12 different pH value.Be the solution of 1g/20ml, 1g/25ml for concentration, it be directly adjusted to above 12 different pH value; But be the sample of 1g/2.5ml, 1g/5ml, 1g/10ml, 1g/15ml for concentration, not directly they are adjusted to target ph, but be adjusted to suitable pH value by trial test, making the pH value of this solution when being diluted to 1g/20ml with water for injection is by chance target ph.Such as concentration be 1g/5ml, target ph is the sample of 5.5, the pH value of its practical adjustments under 1g/5ml state is about 5.2, and the pH value of this solution when being diluted to 1g/20ml with water for injection is by chance target ph 5.5.6 concentration are obtained, the serial solution of each concentration 12 kinds of different pH value, totally 72 kinds of solution by preparing with upper type.
2, with the solution of water for injection preparation containing levo-oxiracetam 1g/6ml, add mannitol, addition is 0,0.1,0.25,0.5 or 1 times of levo-oxiracetam weight, or adds mannitol lactose 1:1 mixture, and addition is 0.25 times of levo-oxiracetam weight; These 6 kinds of solution waters for injection are diluted to the solution containing active component 1g/10ml; Regulate the pH value of solution to Appropriate (making solution pH value when being diluted to 1g/20ml with water for injection be 4.0,4.5,5.2,5.5,5.8,6.5 or 7.0) acid-base pair described in these solution embodiments 1 again.Obtain 6 kinds of solution thus, often kind of solution has 7 kinds of pH value respectively, totally 42 kinds of solution.Get 42 kinds of medicinal liquids of above preparation respectively, be dispensed in cillin bottle, every bottle of 5ml, then carry out lyophilization to eliminate water (to moisture lower than 4%) wherein, sealing, obtains 42 kinds of dry powder samples.
3, above 72 kinds of solution examples and 42 kinds of dry powder samples are placed under 60 ° of C hot conditionss and place 30 days, then measure each sample relative to for high-temperature process sample wherein " d-isomer relative amount changing value ", represent with %.Result demonstrates the result consistent with test example.That is, the solution of pH value between 5.2 ~ 5.8, their d-isomer relative amount changing value is all below 0.4%; And pH value be less than or equal to 5.0 or pH value be more than or equal to 6.0 solution, their d-isomer relative amount changing value is all more than 0.65%; Particularly pH value be less than or equal to 4.75 or pH value be more than or equal to 6.25 solution, their d-isomer relative amount changing value is all more than 0.9%.In addition, the dry powder of pH value between 5.2 ~ 5.8, their d-isomer relative amount changing value is all below 0.3%; And pH value be less than or equal to 5.0 or pH value be more than or equal to 6.0 dry powder, their d-isomer relative amount changing value is all more than 0.4%; Particularly pH value be less than or equal to 4.75 or pH value be more than or equal to 6.25 dry powder, their d-isomer relative amount changing value is all more than 0.5%.
Above result shows, when mixing with not commensurability adjuvant, in solution state or in drying regime for d-isomer change not impact in the present composition.
the preparation of embodiment 1:S-oxiracetam freeze-dried powder
Prescription:
| Component | Consumption |
| S-oxiracetam | 1000g |
| Mannitol | 200g |
| Sodium ethylene diamine tetracetate calcium | 2g |
| Water for injection | Add to 5000ml |
| Make altogether | 1000 bottles |
Preparation method: get 80% recipe quantity water for injection, active component and other adjuvants of adding recipe quantity are stirred to dissolve, with 1M hydrochloric acid solution and/or 1M sodium hydroxide solution adjust pH to Appropriate (make it be diluted to pH value when activity component concentration is 1g/20ml with water for injection be 5.5), 0.1% needle-use activated carbon is added by amount of preparation, by medicine liquid heating to about 60 DEG C, stir 20min, after filtering decarbonization, inject water to total amount, intermediate detects.After intermediate detection is qualified, then adopt 0.22 μm of microporous filter membrane fine straining, cillin bottle, in cillin bottle, is placed in freezer dryer, lyophilization, obtains final product by fill.
the preparation of embodiment 2:S-oxiracetam freeze-dried powder
Prescription:
| Component | Consumption |
| S-oxiracetam | 1000g |
| Sodium ethylene diamine tetracetate calcium | 2g |
| Water for injection | Add to 2000ml |
| Make altogether | 1000 bottles |
In its Raw S-oxiracetam, d-isomer relative amount is 0.36%.
Preparation method: get 80% recipe quantity water for injection, active component and other adjuvants of adding recipe quantity are stirred to dissolve, with 1M hydrochloric acid solution and/or 1M sodium hydroxide solution adjust pH to Appropriate (make it be diluted to pH value when activity component concentration is 1g/20ml with water for injection be 5.2), 0.1% needle-use activated carbon is added by amount of preparation, by medicine liquid heating to about 60 DEG C, stir 20min, after filtering decarbonization, inject water to total amount, intermediate detects.After intermediate detection is qualified, then adopt 0.22 μm of microporous filter membrane fine straining, cillin bottle, in cillin bottle, is placed in freezer dryer, lyophilization, obtains final product by fill.
the preparation of embodiment 3:S-oxiracetam freeze-dried powder
Prescription:
| Component | Consumption |
| S-oxiracetam | 1000g |
| Lactose | 100g |
| Water for injection | Add to 10000ml |
| Make altogether | 1000 bottles |
In its Raw S-oxiracetam, d-isomer relative amount is 0.36%.
Preparation method: get 80% recipe quantity water for injection, active component and other adjuvants of adding recipe quantity are stirred to dissolve, with 1M hydrochloric acid solution and/or 1M sodium hydroxide solution adjust pH to Appropriate (make it be diluted to pH value when activity component concentration is 1g/20ml with water for injection be 5.8), 0.1% needle-use activated carbon is added by amount of preparation, by medicine liquid heating to about 60 DEG C, stir 20min, after filtering decarbonization, inject water to total amount, intermediate detects.After intermediate detection is qualified, then adopt 0.22 μm of microporous filter membrane fine straining, cillin bottle, in cillin bottle, is placed in freezer dryer, lyophilization, obtains final product by fill.
the preparation of embodiment 4:S-oxiracetam injection
Prescription:
| Component | Consumption |
| S-oxiracetam | 1000g |
| Water for injection | Add to 5000ml |
| Make altogether | 1000 bottles |
Preparation method: get 80% recipe quantity water for injection, active component and other adjuvants of adding recipe quantity are stirred to dissolve, with 1M hydrochloric acid solution and/or 1M sodium hydroxide solution adjust pH to Appropriate (make it be diluted to pH value when activity component concentration is 1g/20ml with water for injection be 5.5), 0.1% needle-use activated carbon is added by amount of preparation, by medicine liquid heating to about 60 DEG C, stir 20min, after filtering decarbonization, inject water to total amount, intermediate detects.After intermediate detection is qualified, then adopt 0.22 μm of microporous filter membrane fine straining, fill is in ampoule bottle, and every bottle of 5ml, seals, and rotates moist heat sterilization (121 DEG C, 15 minutes).
the preparation of embodiment 5:S-oxiracetam injection
Prescription:
| Component | Consumption |
| S-oxiracetam | 1000g |
| Sodium ethylene diamine tetracetate calcium | 2g |
| Sodium chloride | 45g |
| Water for injection | Add to 10000ml |
| Make altogether | 1000 bottles |
Preparation method: get 80% recipe quantity water for injection, active component and other adjuvants of adding recipe quantity are stirred to dissolve, with 1M hydrochloric acid solution and/or 1M sodium hydroxide solution adjust pH to Appropriate (make it be diluted to pH value when activity component concentration is 1g/20ml with water for injection be 5.2), 0.1% needle-use activated carbon is added by amount of preparation, by medicine liquid heating to about 60 DEG C, stir 20min, after filtering decarbonization, inject water to total amount, intermediate detects.After intermediate detection is qualified, then adopt 0.22 μm of microporous filter membrane fine straining, fill is in ampoule bottle, and every bottle of 10ml, seals, and rotates moist heat sterilization (121 DEG C, 15 minutes).
the preparation of embodiment 6:S-oxiracetam injection
Prescription:
| Component | Consumption |
| S-oxiracetam | 1000g |
| Water for injection | Add to 2000ml |
| Make altogether | 1000 bottles |
Preparation method: get 80% recipe quantity water for injection, active component and other adjuvants of adding recipe quantity are stirred to dissolve, with 1M hydrochloric acid solution and/or 1M sodium hydroxide solution adjust pH to Appropriate (make it be diluted to pH value when activity component concentration is 1g/20ml with water for injection be 5.8), 0.1% needle-use activated carbon is added by amount of preparation, by medicine liquid heating to about 60 DEG C, stir 20min, after filtering decarbonization, inject water to total amount, intermediate detects.After intermediate detection is qualified, then adopt 0.22 μm of microporous filter membrane fine straining, fill is in ampoule bottle, and every bottle of 2ml, seals, and rotates moist heat sterilization (121 DEG C, 15 minutes).
the preparation of embodiment 7:S-oxiracetam injection
Prescription:
| Component | Consumption |
| S-oxiracetam | 100g |
| Glucose | 400g |
| Water for injection | Add to 10000ml |
| Make altogether | 100 bottles |
Preparation method: get 80% recipe quantity water for injection, active component and other adjuvants of adding recipe quantity are stirred to dissolve, with 1M hydrochloric acid solution and/or 1M sodium hydroxide solution adjust pH to 5.5,0.1% needle-use activated carbon is added by amount of preparation, by medicine liquid heating to about 60 DEG C, stir 20min, after filtering decarbonization, inject water to total amount, intermediate detects.After intermediate detection is qualified, then adopt 0.22 μm of microporous filter membrane fine straining, be distributed into 100 bottles, sealing, rotate moist heat sterilization (121 DEG C, 15 minutes).
the preparation of embodiment 8:S-oxiracetam injection
Prescription:
| Component | Consumption |
| S-oxiracetam | 100g |
| Sodium chloride | 180g |
| Water for injection | Add to 20000ml |
| Make altogether | 100 bottles |
Preparation method: get 80% recipe quantity water for injection, active component and other adjuvants of adding recipe quantity are stirred to dissolve, with 1M hydrochloric acid solution and/or 1M sodium hydroxide solution adjust pH to 5.5,0.1% needle-use activated carbon is added by amount of preparation, by medicine liquid heating to about 60 DEG C, stir 20min, after filtering decarbonization, inject water to total amount, intermediate detects.After intermediate detection is qualified, then adopt 0.22 μm of microporous filter membrane fine straining, be distributed into 100 bottles, sealing, rotate moist heat sterilization (121 DEG C, 15 minutes).
the preparation of embodiment 9:S-oxiracetam oral administration solution
Prescription:
| Component | Consumption |
| S-oxiracetam | 200g |
| Sorbitol | 700g |
| Propylene glycol | 60g |
| Lemon flavouring | 3g |
| Purified water | Add to 2500ml |
| Make altogether | 1000 bottles |
Preparation method: active component and sorbitol are dissolved in suitable quantity of water, add propylene glycol and spice Fructus Citri Limoniae makes dissolving, add purified water to full dose, stir, with 1M hydrochloric acid solution and/or 1M sodium hydroxide solution adjust pH to Appropriate (make it be diluted to pH value when activity component concentration is 1g/20ml with water for injection be 5.5), with 0.45 μm of filtering with microporous membrane, use 0.22 μm of microporous filter membrane fine straining again, be distributed into 250 bottles, sealing.
In addition, with reference to the method for above embodiment 12, difference just adds methyl parahydroxybenzoate, ethylparaben or propyl p-hydroxybenzoate wherein, obtains comparative example 1, comparative example 2, comparative example 3 three kinds of samples respectively.
The each sample of each embodiment and comparative example above, reference test example 1 method above, places 30 days under 60 ° of C hot conditionss, test each sample d-isomer relative amount changing value.As a result, in three comparative sample, d-isomer relative amount changing value is all in the scope of 0.75% ~ 1.30%, and in each embodiment sample, d-isomer relative amount changing value is all in the scope of 0.1% ~ 0.35%.
Claims (30)
1. a pharmaceutical composition, wherein comprises the levo-oxiracetam as active component, and the acceptable adjuvant of pharmacy; This pharmaceutical composition is when dissolving with water for injection that to make activity component concentration be the solution of 1g:20ml, and the pH value of this solution is 5.4.
2. pharmaceutical composition according to claim 1, wherein containing the material for regulating said composition acid-base value.
3. pharmaceutical composition according to claim 2, wherein for regulating the consumption of the material of compositions acid-base value to be, be enough to make said composition acid-base value to be adjusted to described compositions when dissolving with water for injection that to make activity component concentration be the solution of 1g:20ml, the pH value of this solution is 5.4.
4. pharmaceutical composition according to claim 2, wherein said for regulating the material of said composition acid-base value to be selected from hydrochloric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, phosphoric acid, dibastic sodium phosphate, sodium dihydrogen phosphate, sodium phosphate, citric acid, sodium citrate, acetic acid, sodium acetate.
5. pharmaceutical composition according to claim 1, the acceptable adjuvant of wherein said pharmacy comprises solvent.
6. pharmaceutical composition according to claim 5, wherein said solvent is selected from water, alcohols solvent or its combination.
7. pharmaceutical composition according to claim 6, wherein said alcohols solvent is selected from ethanol, glycerol, propylene glycol, molecular weight are 200 ~ 600 Polyethylene Glycol or its combination.
8. pharmaceutical composition according to claim 1, the acceptable adjuvant of wherein said pharmacy comprises osmotic pressure regulator.
9. pharmaceutical composition according to claim 8, wherein said osmotic pressure regulator is selected from: glucose, sucrose, mannitol, lactose, fructose, sodium chloride or its combination.
10. pharmaceutical composition according to claim 1, the acceptable adjuvant of wherein said pharmacy comprises excipient.
11. pharmaceutical compositions according to claim 10, wherein said excipient is selected from: glucose, sucrose, mannitol, lactose, fructose, sodium chloride or its combination.
12. pharmaceutical compositions according to claim 1, it is the medicament in liquid condition, and wherein comprises and be selected from following solvent: water, ethanol, glycerol, propylene glycol, molecular weight are Polyethylene Glycol or its combination of 200 ~ 600.
13. pharmaceutical compositions according to claim 12, wherein said liquid preparation is injection with small volume, and in this injection, the concentration of active component is 1g:(2 ~ 50) ml.
14. pharmaceutical compositions according to claim 1, it is the medicament in solid state.
15. pharmaceutical compositions according to claim 14, wherein said solid chemicals is when dissolving with water for injection that to make activity component concentration be the solution of 1g:20ml, and the pH value of this solution is 5.4.
16. pharmaceutical compositions according to claim 14, wherein said solid chemicals be first by solubilize active ingredients in solvent, regulate the acid-base value of this medicinal liquid, and then water removing prepared.
17. pharmaceutical compositions according to claim 14, wherein said solid chemicals is injection preparation.
18. pharmaceutical compositions according to claim 14, wherein said solid chemicals is the lyophilization injectable powder of injection.
19. pharmaceutical compositions according to claim 1, it is injection.
20. pharmaceutical compositions according to claim 19, wherein said injection comprises active component levo-oxiracetam, water for injection and regulates the material of said composition acid-base value, wherein the concentration of levo-oxiracetam is 0.05g/ml ~ 0.5g/ml, and regulate the amount of substance of said composition acid-base value to be this injection water for injection can be made to dissolve when to make activity component concentration be the solution of 1g:20ml, the pH value of this solution is 5.4.
21. pharmaceutical compositions according to claim 1, it is injection lyophilization injectable powder.
22. pharmaceutical compositions according to claim 21, wherein said injection lyophilization injectable powder comprises the levo-oxiracetam of 1 weight portion, the excipient of 0 ~ 1 weight portion and regulates the material of said composition acid-base value, and regulate the amount of substance of said composition acid-base value to be this injection lyophilization injectable powder water for injection can be made to dissolve when to make activity component concentration be the solution of 1g:20ml, the pH value of this solution is 5.4.
23. pharmaceutical compositions according to claim 1, it is oral solution.
24. pharmaceutical compositions according to claim 23, wherein said oral solution comprises active component levo-oxiracetam, water, the material of adjustment said composition acid-base value and other optional pharmaceutic adjuvant, wherein the concentration of levo-oxiracetam is 0.05g/ml ~ 0.5g/ml, and regulate the amount of substance of said composition acid-base value to be this oral solution water for injection can be made to dissolve when to make activity component concentration be the solution of 1g:20ml, the pH value of this solution is 5.4.
25. pharmaceutical compositions according to claim 1, the amount of other pharmaceutic adjuvant beyond wherein desolventizing for the amount of active component lower than 100%.
26. pharmaceutical compositions according to claim 1, when said composition is the medicament in solution state, wherein the concentration of levo-oxiracetam is 0.05g/ml ~ 0.5g/ml, and the amount desolventizing other pharmaceutic adjuvant beyond particularly water for the amount of active component lower than 100%.
27. pharmaceutical compositions according to claim 1, when said composition is in the medicament of solid state, wherein, the amount of other pharmaceutic adjuvant for the amount of active component lower than 100%.
28. pharmaceutical compositions according to claim 1, wherein for levo-oxiracetam the percentage amounts of dextrorotation oxiracetam lower than 5%.
29. pharmaceutical compositions according to claim 1, it is after 60 DEG C of lower seals place 30 days, and in said composition, the changing value of the relative amount of dextrorotation oxiracetam is no more than 1%.
The method of the pharmaceutical composition of 30. any one of preparation claim 1 to 29, the method comprises the steps:
I) by active component levo-oxiracetam dissolution with solvents;
Ii) material regulating acid-base value is added, its consumption is said composition water for injection is dissolved when to make activity component concentration be the solution of 1g:20ml, the pH value of this solution is the scope of 5.4, optionally add the acceptable adjuvant of other pharmacy except the material regulating acid-base value, obtain compositions; And optionally further,
Iii) by step I i) the solvent removing of the compositions of gained, obtain compositions.
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| CN201210363950.1A CN102872011B (en) | 2012-05-31 | 2012-09-26 | Comprise the pharmaceutical composition of (S)-Esomeprazole |
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| CN201210363950.1A Active CN102872011B (en) | 2012-05-31 | 2012-09-26 | Comprise the pharmaceutical composition of (S)-Esomeprazole |
| CN2012103639728A Pending CN102871959A (en) | 2012-05-31 | 2012-09-26 | Stable (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide pharmaceutical composition |
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| CN102670497A (en) * | 2012-05-31 | 2012-09-19 | 北京阜康仁生物制药科技有限公司 | Stable S-oxiracetam preparation for injection and preparation method of same |
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| CN107468641A (en) * | 2016-06-08 | 2017-12-15 | 重庆润泽医药有限公司 | A kind of preparation method of levo-oxiracetam injection |
| CN107753481B (en) * | 2016-08-17 | 2021-01-15 | 沈阳药科大学 | A pharmaceutical composition containing buffer for treating cancer |
| CN107913247A (en) * | 2016-10-10 | 2018-04-17 | 北京阜康仁生物制药科技有限公司 | A kind of Levetiracetam injection preparation and preparation method thereof |
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- 2012-09-26 CN CN201210363950.1A patent/CN102872011B/en active Active
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| CN101396358A (en) * | 2007-09-25 | 2009-04-01 | 广东世信药业有限公司 | Oxiracetam injection |
| CN101766597A (en) * | 2008-12-31 | 2010-07-07 | 北京利乐生制药科技有限公司 | Injection preparation with levo-oxiracetam as active component |
| CN102274195A (en) * | 2011-07-18 | 2011-12-14 | 石药集团欧意药业有限公司 | Oxiracetam freeze-dried powder preparation and preparation method thereof |
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| CN102871959A (en) | 2013-01-16 |
| CN102872011A (en) | 2013-01-16 |
| CN102670497A (en) | 2012-09-19 |
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Denomination of invention: Pharmaceutical composition comprising (S) -4- hydroxy -2- oxo -1- pyrrolidine acetamide Effective date of registration: 20171023 Granted publication date: 20151202 Pledgee: Zhongguancun Beijing technology financing Company limited by guarantee Pledgor: Beijing Fu Kang Ren Bio-pharm Tech Co., Ltd. Registration number: 2017990000975 |
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