CN104840436A - Medicine composition - Google Patents

Medicine composition Download PDF

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Publication number
CN104840436A
CN104840436A CN201510320016.5A CN201510320016A CN104840436A CN 104840436 A CN104840436 A CN 104840436A CN 201510320016 A CN201510320016 A CN 201510320016A CN 104840436 A CN104840436 A CN 104840436A
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CN
China
Prior art keywords
terazosin
pharmaceutical composition
acid
excipient
injectable powder
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Granted
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CN201510320016.5A
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Chinese (zh)
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CN104840436B (en
Inventor
刘磊
官清华
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Beijing Ansai Biotechnology Co ltd
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Individual
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Priority to CN201510320016.5A priority Critical patent/CN104840436B/en
Publication of CN104840436A publication Critical patent/CN104840436A/en
Priority to PCT/CN2016/080459 priority patent/WO2016197738A1/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine

Abstract

The invention relates to a medicine composition. The medicine composition comprises terazosin and an excipient, wherein the excipient is selected from mannitol, lactose, sorbitol, xylitol, glucose, maltose, glycine, soluble dextrin, xanthan gum, gelatine, hydrolyzed gelatine, Arabic gum, pectin, guar gum, peach gum, tragacanth gum, acacia gum, sodium carboxymethylcellulose, polyvinylpyrrolidone, carbomer, hydroxy propyl cellulose, hydroxypropyl methyl cellulose, alginate or is a combination thereof, wherein the weight ratio of the terazosin to the excipient is 1: (10 to 1000). The invention further relates to a method for preparing the medicine composition. The medicine composition disclosed by the invention has the excellent properties shown in the description.

Description

Pharmaceutical composition
Technical field
The invention belongs to medical art, relate to a based composition, particularly relate to the compositions of a class injectable administration.
Background technology
Terazosin (Terazosin) is used for clinical with its hydrochlorate usually, and the specification of gone on the market tablet or capsule has 1mg, 2mg and 5mg etc.Terazosin hydrochloride can be used for treat benign prostate hyperplasia, also can be used for treat hypertension, can be used alone or with other antihypertensive drug as diuretic or Alpha 1 adrenergic blocking agent share.For existing clinical indication, terazosin is 1 ~ 10mg for the daily dose usual range of being grown up.Terazosin is used for the treatment of benign prostatic hyperplasia (BPH), and after medication, benign prostate hyperplasia shape alleviates that to improve the smooth muscle loosening caused by blocking with the alpha 1 adrenergic receptor in neck of bladder and prostate with urine flow velocity relevant.Because there is relatively few alpha 1 adrenergic receptor in body of bladder, therefore terazosin can alleviate the obstruction of bladder outlet and not affect the contraction of bladder.In addition, terazosin is by reducing Total peripheral vascular resistance thus making blood pressure reduce.Vasodilation, the blood pressure reducing effect of terazosin seem mainly caused by alpha 1 adrenergic receptor blocks.
Terazosin chemistry (4-(4-amido-6,7-dimethoxy quinazoline-2-base) piperazine-1-base) (oxolane-2-base) ketone by name, molecular formula is C 19h 25n 5o 4, chemical structural formula is with following formula I:
Existing terazosin or its pharmaceutical salts is main clinically presents with oral dosage form, such as tablet, capsule etc.But when treating for acute disease, these oral formulations can not meet clinical demand, typically ejection preparation is useful.
Therefore, this area is still expected to have and be can be used for terazosin that acute illness treatment uses and the pharmaceutical composition of analog thereof.
Summary of the invention
The object of the present invention is to provide a kind of acute illness that can be used for treat the terazosin of use or the pharmaceutical composition of its pharmaceutical salts, and expect that this pharmaceutical composition presents gratifying pharmaceutical characteristic.The present invention is beat all discovery, and the pharmaceutical composition with feature of the present invention uses as pharmaceutical preparation and can obtain technique effect as described in the present invention.The present invention is based on this find and be accomplished.
For this reason, first aspect present invention provides a kind of pharmaceutical composition, comprising: terazosin, excipient.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein said terazosin can also be its pharmaceutical salts or its solvate such as hydrate.
In the present invention, when mentioning terazosin, it not only comprises the compound shown in above structure, also comprises the acceptable salt of pharmacy (such as hydrochlorate) of said structure compound, and the solvate of said structure compound and salt thereof such as hydrate.In a preferred embodiment of the invention, described terazosin refers to terazosin hydrochloride dihydrate.The present invention is hereafter used as the terazosin of formula I typical case to carry out large quantity research to show the beat all effect of the present invention; In following experiments particularly biological test, as do not indicated in addition, reagent terazosin used refers to terazosin hydrochloride dihydrate.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein said terazosin is terazosin hydrochlorate.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein said terazosin is terazosin hydrochloride dihydrate.In following experiments, as do not indicated in addition, reagent terazosin used refers to terazosin hydrochloride dihydrate.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein said excipient is selected from: mannitol, lactose, sorbitol, xylitol, glucose, maltose, glycine, soluble dextrins, xanthan gum, gelatin, gelatin hydrolysate, arabic gum, pectin, guar gum, Resina persicae, tragacanth, acacin, sodium carboxymethyl cellulose, polyvinylpyrrolidone, carbomer, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, alginate or its combination.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the weight ratio of wherein said terazosin and excipient is 1:10 ~ 1000.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the weight ratio of wherein said terazosin and excipient is 1:20 ~ 750.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the weight ratio of wherein said terazosin and excipient is 1:25 ~ 500.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein said excipient is selected from: mannitol, lactose, sorbitol, xylitol, glucose, maltose, glycine.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein said excipient is selected from: mannitol, lactose, glycine.Have been surprisingly found that, when the particular excipient of terazosin and specified quantitative combines, the growth rate of impurity that can be effectively relevant with terazosin in composite inhibiting.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein said excipient does not comprise gelatin or gelatin hydrolysate.Have been surprisingly found that, it is disadvantageous for adding gelatin or gelatin hydrolysate for the preparation of compositions.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is cryodesiccated compositions.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is the cryodesiccated injectable powder that can be used for injecting.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is the cryodesiccated injectable powder that can be used for injecting, and this injectable powder is seal-packed with vial.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is the cryodesiccated injectable powder that can be used for injecting, this injectable powder is seal-packed with vial, and the amount of the terazosin in every bottle is 0.1mg ~ 5mg, and the amount of such as, terazosin in every bottle is 0.1mg ~ 2.5mg.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein this pharmaceutical composition is under air-proof condition, place in the time of 6 months 40 DEG C of lucifuges, and impurity A increment rate is less than 100%, is particularly less than 75%, is more especially less than 50%.
Term " impurity A " is N-(4-Amino-6,7-dimethoxy-2-quinazolinyl) piperazine or be called 6,7-dimethoxy-2-(piperazin-1-yl) quinazolin-4-amine, namely has the following formula: compound that R is H:
It is believed that this impurity A is that active component hydrolysis produces.Although pharmaceutical composition of the present invention is the freeze-dried preparation of a kind of substantially anhydrous (typically moisture is lower than 5%), but have been found that, even if under this substantially anhydrous drying regime, this impurity still has significantly along with the storage time prolongation of compositions and increases.This is also current edition American Pharmacopeia (USP35), all give the reason of strict monitoring in current edition British Pharmacopoeia (BP2013) and current edition European Pharmacopoeia (EP8.0).
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is packed by cillin bottle.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is packed by cillin bottle, and in round pie in cillin bottle.
The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein moisture is lower than 10%, preferably lower than 8%, preferably lower than 7%, more preferably less than 5%.
The pharmaceutical composition of arbitrary embodiment, wherein also comprises acid-base modifier according to a first aspect of the present invention.In one embodiment, described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.
As everyone knows, the lyophilization injectable powder (usually referred to as lyophilized injectable powder or freeze-dried powder) obtained through freezing-vacuum drying, it is first by each material dissolution with solvents (being typically with water dissolution), be mixed with a solution, then this solution is made to carry out freezing, carry out evacuation, distillation again, substantially anhydrous (typically water content is lower than 8% for drying and the one that obtains, particularly be usually less than 7%, be particularly usually less than 5%) Powdered thing or block.Therefore, the acid-base value of this solid lyophilized products regulates the pH value of solution to control by process for preparation usually; Or the pH value that the solid lyophilized products of acquisition can be made under the dissolve/dilute degree of regulation to control this dissolve/dilute liquid by prescription adjustment controls (this is called the acid-base value controlling solid lyophilized products); A rear mode more generally uses usually, such as, in pharmacopeia contained many lyophilized injectable powders control the acid-base value of goods all in this way, and the acid-base value that this mode controls product usually can not the recipe quantity of concrete regulation acid-base modifier, and only specify the acid-base value of finished product.Be equally applicable to of the present inventionly be, lyophilized injectable powder according to a first aspect of the present invention described in arbitrary embodiment, the amount of wherein said optional acid-base modifier is, the amount of pH value in 3.0 ~ 5.0 scopes of this solution during the solution making described lyophilized injectable powder water for injection be dissolved into containing terazosin 0.5mg/ml concentration, the amount of pH value in 3.5 ~ 4.5 scopes of such as this solution.
The pharmaceutical composition of arbitrary embodiment, wherein also comprises citric acid according to a first aspect of the present invention.In one embodiment, the weight ratio of terazosin and citric acid is 1:1 ~ 10.In one embodiment, the weight ratio of terazosin and citric acid is 1:2 ~ 5.Having been surprisingly found that, the injectable powder with excellent properties can be obtained valuably when being the citric acid of 1:2 ~ 5 amount to the weight ratio of adding appropriate citric acid particularly terazosin and citric acid in the compositions that lyophilization is made.
The lyophilization injectable powder of arbitrary embodiment according to a first aspect of the present invention, it is prepare by comprising following step substantially:
A () takes terazosin and the excipient (and optional citric acid) of recipe quantity, add appropriate water for injection, be stirred to dissolve,
B () adds active carbon in previous step gained medicinal liquid, stir, filtering decarbonization;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH3.0 ~ 5.0 with acid-base modifier, preferred pH3.5 ~ 4.5;
D (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
E () lyophilization removing moisture, tamponade, to obtain final product.
The lyophilization injectable powder of arbitrary embodiment according to a first aspect of the present invention, wherein appropriate water for injection described in step (a) is the water for injection of 60 ~ 70% amounts of prescription full dose.
The lyophilization injectable powder of arbitrary embodiment according to a first aspect of the present invention, wherein the addition of active carbon described in step (b) is that concentration of activated carbon reaches the amount of 0.05 ~ 0.15% in medicinal liquid.
The lyophilization injectable powder of arbitrary embodiment according to a first aspect of the present invention, wherein stirring described in step (b) is stirring and adsorbing 10 ~ 20min, such as stirring and adsorbing 15min.
The lyophilization injectable powder of arbitrary embodiment according to a first aspect of the present invention, wherein the mode of filtering decarbonization described in step (b) is: after filtering with the titanium rod decarburization that aperture is 1um, then use the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration.
The lyophilization injectable powder of arbitrary embodiment according to a first aspect of the present invention, wherein mends described in step (c) and injects water to prescription full dose and refer to and add water for injection until activity component concentration is the amount of 0.1 ~ 5mg/ml (such as 0.2 ~ 2mg/ml).
The lyophilization injectable powder of arbitrary embodiment according to a first aspect of the present invention, wherein aseptic filtration described in step (d) uses the polyether sulfone filter element of 0.22um to carry out aseptic filtration.
Further, second aspect present invention provides the method making terazosin stable, and the method comprises the step making terazosin and excipient make pharmaceutical composition, and in this pharmaceutical composition, terazosin and excipient form homogeneous mixture.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said pharmaceutical composition is cryodesiccated compositions.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said pharmaceutical composition is the cryodesiccated injectable powder that can be used for injecting.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said pharmaceutical composition is the cryodesiccated injectable powder that can be used for injecting, and this injectable powder is seal-packed with vial.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said pharmaceutical composition is the cryodesiccated injectable powder that can be used for injecting, this injectable powder is seal-packed with vial, the amount of the terazosin in every bottle is 0.1mg ~ 5mg, and the amount of such as, terazosin in every bottle is 0.1mg ~ 2.5mg.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said pharmaceutical composition comprises: terazosin, excipient.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said terazosin can also be its pharmaceutical salts or its solvate such as hydrate.
In the present invention, when mentioning terazosin, it not only comprises the compound shown in above structure, also comprises the acceptable salt of pharmacy (such as hydrochlorate) of said structure compound, and the solvate of said structure compound and salt thereof such as hydrate.In a preferred embodiment of the invention, described terazosin refers to terazosin hydrochloride dihydrate.The present invention is hereafter used as the terazosin of formula I typical case to carry out large quantity research to show the beat all effect of the present invention; In following experiments particularly biological test, as do not indicated in addition, reagent terazosin used refers to terazosin hydrochloride dihydrate.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said terazosin is terazosin hydrochlorate.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said terazosin is terazosin hydrochloride dihydrate.In following experiments, as do not indicated in addition, reagent terazosin used refers to terazosin hydrochloride dihydrate.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said excipient is selected from: mannitol, lactose, sorbitol, xylitol, glucose, maltose, glycine, soluble dextrins, xanthan gum, gelatin, gelatin hydrolysate, arabic gum, pectin, guar gum, Resina persicae, tragacanth, acacin, sodium carboxymethyl cellulose, polyvinylpyrrolidone, carbomer, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, alginate or its combination.
The method of arbitrary embodiment according to a second aspect of the present invention, the weight ratio of wherein said terazosin and excipient is 1:10 ~ 1000.
The method of arbitrary embodiment according to a second aspect of the present invention, the weight ratio of wherein said terazosin and excipient is 1:20 ~ 750.
The method of arbitrary embodiment according to a second aspect of the present invention, the weight ratio of wherein said terazosin and excipient is 1:25 ~ 500.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said excipient is selected from: mannitol, lactose, sorbitol, xylitol, glucose, maltose, glycine.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said excipient is selected from: mannitol, lactose, glycine.Have been surprisingly found that, when the particular excipient of terazosin and specified quantitative combines, the growth rate of impurity that can be effectively relevant with terazosin in composite inhibiting.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said excipient does not comprise gelatin or gelatin hydrolysate.Have been surprisingly found that, it is disadvantageous for adding gelatin or gelatin hydrolysate for the preparation of compositions.
The method of arbitrary embodiment according to a second aspect of the present invention, it makes this pharmaceutical composition under air-proof condition, places in the time of 6 months 40 DEG C of lucifuges, and impurity A increment rate is less than 100%, is particularly less than 75%, is more especially less than 50%.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said pharmaceutical composition is packed by cillin bottle.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said pharmaceutical composition is packed by cillin bottle, and in round pie in cillin bottle.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said pharmaceutical composition moisture lower than 10%, preferably lower than 8%, preferably lower than 7%, more preferably less than 5%.
The method of arbitrary embodiment according to a second aspect of the present invention, also comprises acid-base modifier in wherein said pharmaceutical composition.In one embodiment, described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.
As everyone knows, the lyophilization injectable powder (usually referred to as lyophilized injectable powder or freeze-dried powder) obtained through freezing-vacuum drying, it is first by each material dissolution with solvents (being typically with water dissolution), be mixed with a solution, then this solution is made to carry out freezing, carry out evacuation, distillation again, substantially anhydrous (typically water content is lower than 8% for drying and the one that obtains, particularly be usually less than 7%, be particularly usually less than 5%) Powdered thing or block.Therefore, the acid-base value of this solid lyophilized products regulates the pH value of solution to control by process for preparation usually; Or the pH value that the solid lyophilized products of acquisition can be made under the dissolve/dilute degree of regulation to control this dissolve/dilute liquid by prescription adjustment controls (this is called the acid-base value controlling solid lyophilized products); A rear mode more generally uses usually, such as, in pharmacopeia contained many lyophilized injectable powders control the acid-base value of goods all in this way, and the acid-base value that this mode controls product usually can not the recipe quantity of concrete regulation acid-base modifier, and only specify the acid-base value of finished product.Be equally applicable to of the present inventionly be, lyophilized injectable powder according to a first aspect of the present invention described in arbitrary embodiment, the amount of wherein said optional acid-base modifier is, the amount of pH value in 3.0 ~ 5.0 scopes of this solution during the solution making described lyophilized injectable powder water for injection be dissolved into containing terazosin 0.5mg/ml concentration, the amount of pH value in 3.5 ~ 4.5 scopes of such as this solution.
The pharmaceutical composition of arbitrary embodiment, wherein also comprises citric acid according to a first aspect of the present invention.In one embodiment, the weight ratio of terazosin and citric acid is 1:1 ~ 10.In one embodiment, the weight ratio of terazosin and citric acid is 1:2 ~ 5.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein said pharmaceutical composition is prepare by comprising following step substantially:
A () takes terazosin and the excipient (and optional citric acid) of recipe quantity, add appropriate water for injection, be stirred to dissolve,
B () adds active carbon in previous step gained medicinal liquid, stir, filtering decarbonization;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH3.0 ~ 5.0 with acid-base modifier, preferred pH3.5 ~ 4.5;
D (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
E () lyophilization removing moisture, tamponade, to obtain final product.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein appropriate water for injection described in step (a) is the water for injection of 60 ~ 70% amounts of prescription full dose.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein the addition of active carbon described in step (b) is that concentration of activated carbon reaches the amount of 0.05 ~ 0.15% in medicinal liquid.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein stirring described in step (b) is stirring and adsorbing 10 ~ 20min, such as stirring and adsorbing 15min.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein the mode of filtering decarbonization described in step (b) is: after filtering with the titanium rod decarburization that aperture is 1um, then use the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration.
The method of arbitrary embodiment according to a second aspect of the present invention, wherein mends described in step (c) and injects water to prescription full dose and refer to and add water for injection until activity component concentration is the amount of 0.1 ~ 5mg/ml (such as 0.2 ~ 2mg/ml).
The method of arbitrary embodiment according to a second aspect of the present invention, wherein aseptic filtration described in step (d) uses the polyether sulfone filter element of 0.22um to carry out aseptic filtration.
The method of arbitrary embodiment according to a second aspect of the present invention, it also comprises the treatment step that the described pharmaceutical composition of reduction sprays bottle incidence rate in freezing dry process.In one embodiment, this step in compositions, adds citric acid together with excipient.In one embodiment, the weight ratio of terazosin and citric acid is 1:1 ~ 10.In one embodiment, the weight ratio of terazosin and citric acid is 1:2 ~ 5.
Further, third aspect present invention provides the method for pharmaceutical compositions, and this pharmaceutical composition comprises: terazosin, excipient, and this pharmaceutical composition is made by freeze drying process.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein said terazosin can also be its pharmaceutical salts or its solvate such as hydrate.
In the present invention, when mentioning terazosin, it not only comprises the compound shown in above structure, also comprises the acceptable salt of pharmacy (such as hydrochlorate) of said structure compound, and the solvate of said structure compound and salt thereof such as hydrate.In a preferred embodiment of the invention, described terazosin refers to terazosin hydrochloride dihydrate.The present invention is hereafter used as the terazosin of formula I typical case to carry out large quantity research to show the beat all effect of the present invention; In following experiments particularly biological test, as do not indicated in addition, reagent terazosin used refers to terazosin hydrochloride dihydrate.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein said terazosin is terazosin hydrochlorate.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein said terazosin is terazosin hydrochloride dihydrate.In following experiments, as do not indicated in addition, reagent terazosin used refers to terazosin hydrochloride dihydrate.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein said excipient is selected from: mannitol, lactose, sorbitol, xylitol, glucose, maltose, glycine, soluble dextrins, xanthan gum, gelatin, gelatin hydrolysate, arabic gum, pectin, guar gum, Resina persicae, tragacanth, acacin, sodium carboxymethyl cellulose, polyvinylpyrrolidone, carbomer, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, alginate or its combination.
The method of arbitrary embodiment according to a third aspect of the present invention, the weight ratio of wherein said terazosin and excipient is 1:10 ~ 1000.
The method of arbitrary embodiment according to a third aspect of the present invention, the weight ratio of wherein said terazosin and excipient is 1:20 ~ 750.
The method of arbitrary embodiment according to a third aspect of the present invention, the weight ratio of wherein said terazosin and excipient is 1:25 ~ 500.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein said excipient is selected from: mannitol, lactose, sorbitol, xylitol, glucose, maltose, glycine.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein said excipient is selected from: mannitol, lactose, glycine.Have been surprisingly found that, when the particular excipient of terazosin and specified quantitative combines, the growth rate of impurity that can be effectively relevant with terazosin in composite inhibiting.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein said excipient does not comprise gelatin or gelatin hydrolysate.Have been surprisingly found that, it is disadvantageous for adding gelatin or gelatin hydrolysate for the preparation of compositions.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein said pharmaceutical composition is the cryodesiccated injectable powder that can be used for injecting.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein said pharmaceutical composition is the cryodesiccated injectable powder that can be used for injecting, and this injectable powder is seal-packed with vial.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein said pharmaceutical composition is the cryodesiccated injectable powder that can be used for injecting, this injectable powder is seal-packed with vial, the amount of the terazosin in every bottle is 0.1mg ~ 5mg, and the amount of such as, terazosin in every bottle is 0.1mg ~ 2.5mg.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein said pharmaceutical composition is under air-proof condition, place in the time of 6 months 40 DEG C of lucifuges, and impurity A increment rate is less than 100%, is particularly less than 75%, is more especially less than 50%.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein said pharmaceutical composition is packed by cillin bottle.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein said pharmaceutical composition is packed by cillin bottle, and in round pie in cillin bottle.
The method of arbitrary embodiment according to a third aspect of the present invention, in wherein said pharmaceutical composition, moisture is lower than 10%, preferably lower than 8%, preferably lower than 7%, more preferably less than 5%.
The method of arbitrary embodiment according to a third aspect of the present invention, also comprises acid-base modifier in wherein said pharmaceutical composition.In one embodiment, described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.
As everyone knows, the lyophilization injectable powder (usually referred to as lyophilized injectable powder or freeze-dried powder) obtained through freezing-vacuum drying, it is first by each material dissolution with solvents (being typically with water dissolution), be mixed with a solution, then this solution is made to carry out freezing, carry out evacuation, distillation again, substantially anhydrous (typically water content is lower than 8% for drying and the one that obtains, particularly be usually less than 7%, be particularly usually less than 5%) Powdered thing or block.Therefore, the acid-base value of this solid lyophilized products regulates the pH value of solution to control by process for preparation usually; Or the pH value that the solid lyophilized products of acquisition can be made under the dissolve/dilute degree of regulation to control this dissolve/dilute liquid by prescription adjustment controls (this is called the acid-base value controlling solid lyophilized products); A rear mode more generally uses usually, such as, in pharmacopeia contained many lyophilized injectable powders control the acid-base value of goods all in this way, and the acid-base value that this mode controls product usually can not the recipe quantity of concrete regulation acid-base modifier, and only specify the acid-base value of finished product.Be equally applicable to of the present inventionly be, lyophilized injectable powder according to a first aspect of the present invention described in arbitrary embodiment, the amount of wherein said optional acid-base modifier is, the amount of pH value in 3.0 ~ 5.0 scopes of this solution during the solution making described lyophilized injectable powder water for injection be dissolved into containing terazosin 0.5mg/ml concentration, the amount of pH value in 3.5 ~ 4.5 scopes of such as this solution.
The pharmaceutical composition of arbitrary embodiment, wherein also comprises citric acid according to a first aspect of the present invention.In one embodiment, the weight ratio of terazosin and citric acid is 1:1 ~ 10.In one embodiment, the weight ratio of terazosin and citric acid is 1:2 ~ 5.
The method of arbitrary embodiment according to a third aspect of the present invention, it consists essentially of following steps:
A () takes terazosin and the excipient (and optional citric acid) of recipe quantity, add appropriate water for injection, be stirred to dissolve,
B () adds active carbon in previous step gained medicinal liquid, stir, filtering decarbonization;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH3.0 ~ 5.0 with acid-base modifier, preferred pH3.5 ~ 4.5;
D (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
E () lyophilization removing moisture, tamponade, to obtain final product.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein appropriate water for injection described in step (a) is the water for injection of 60 ~ 70% amounts of prescription full dose.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein the addition of active carbon described in step (b) is that concentration of activated carbon reaches the amount of 0.05 ~ 0.15% in medicinal liquid.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein stirring described in step (b) is stirring and adsorbing 10 ~ 20min, such as stirring and adsorbing 15min.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein the mode of filtering decarbonization described in step (b) is: after filtering with the titanium rod decarburization that aperture is 1um, then use the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration.
The method of arbitrary embodiment according to a third aspect of the present invention, wherein mends described in step (c) and injects water to prescription full dose and refer to and add water for injection until activity component concentration is the amount of 0.1 ~ 5mg/ml (such as 0.2 ~ 2mg/ml).
The method of arbitrary embodiment according to a third aspect of the present invention, wherein aseptic filtration described in step (d) uses the polyether sulfone filter element of 0.22um to carry out aseptic filtration.
State on the invention in the step of preparation method, although its concrete steps described in some details or the language step described in preparation example that describes up and down literary composition detailed description of the invention part distinguish to some extent, but those skilled in the art can summarize the above method step completely according to the open in detail of the present invention's full text.
Arbitrary embodiment of either side of the present invention, can combine with other embodiment, as long as they there will not be contradiction.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characteristic goes for this technical characteristic in other embodiment, as long as they there will not be contradiction.
The invention will be further described below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.
Have been found that the pharmaceutical composition in lyophilization injectable powder form that the inventive method prepares has beat all advantage.Such as embody stability test in the following areas, redissolution time, spray bottle rate etc.:
Stability test: whole compositionss that Examples below 1 to embodiment 12 prepares, is placed in 40 DEG C of places and places June to carry out high-temperature treatment test; For each compositions, use the method in American Pharmacopeia USP35 version the 4787th page of terazosin sheet (http://www.drugfuture.com/Pharmacopoeia/usp35/data/v35300/usp35 nf30s0m80842.html) it [impurity] detection, related substance when measuring said composition 0 month time and in June and impurity A (relative to main constituent) content, the content being calculated as follows impurity A increases percent (%, can referred to as " impurity A increment "):
The above-mentioned compositions all in powder form uses and prepares with a collection of crude drug, the Impurity A content of whole injectable powder 0 month time is substantially suitable, all in 0.08 ~ 0.11% scope, but after being through above-mentioned high-temperature treatment, different sample presents visibly different impurity A situation of change.Specifically: embodiment 10 and the whole compositions of embodiment 12 gained and embodiment 11 gained #111 to #114 four impurity A increment (%) all in 114 ~ 235% scopes, the impurity A increment (%) of such as #121 and #122 is respectively 207% and 234%; The impurity A increment (%) of the whole compositions of embodiment 1-9 gained and embodiment 11 gained #115 to #119 five is all in 17 ~ 32% scopes, and the impurity A increment (%) of such as embodiment 1 compositions is 22%.Visible, compared with the mannitol that use is in shortage, or compared with using the conventional freeze-dried excipient of other kind, using amount mannitol of the present invention, lactose, glycine to give, the stability, particularly impurity A of compositions excellence is this is inhibited believed as hydrolysis impurity growth rate in compositions Long-term Storage process.Even and mannitol in shortage or similar conventional freeze-dried excipient, but unexpectedly show this effect that they can not give compositions.
Redissolution timing: take off the composition powder injection that civilian each embodiment prepares, add appropriate water for injection and make solid concentration all reach the degree of 5% in every bottle, leaves standstill, calculates and dissolve the required time completely from adding water to.Result: the redissolution time of the whole injectable powder of embodiment 1-9 gained and embodiment 11 gained #111 to #117 seven is all less than 20 seconds, all within the scope of 9 ~ 18 seconds; But the redissolution time of both embodiment 11 gained #118 to #119 reaches 132 seconds and 184 seconds respectively, crossing a large amount of mannitol makes the injectable powder time of redissolving extend significantly, therefore from the consumption of mannitol, be useful lower than equaling 500 parts (relative to 1 part of terazosin).In other supplementary test, with reference to the formula/method for making of embodiment 11, unlike using lactose or glycine instead, result similarly shows, the injectable powder time of redissolving that lactose or glycine consumption are more than or equal to 1000 parts (relative to 1 part of terazosin) is all greater than 110 seconds, and the injectable powder time of redissolving being less than or equal to 500 parts (relative to 1 part of terazosin) is all less than 30 seconds; In addition, the powder pin of lactose or glycine is used instead with reference to embodiment 11, when carrying out 40 DEG C of places and placing June, similar to embodiment 11 acquired results, amount of excipient is more than or equal to impurity A increment (%) increment in the powder pin of 25 parts (relative to 1 part of terazosin) and is all less than 40%, and amount of excipient is less than or equal to impurity A increment (%) increment in the powder pin of 15 parts (relative to 1 part of terazosin) is all greater than 95%.
Hereafter in the whole embodiments preparing injectable powder, have at least 500 bottles to carry out lyophilization during every batch of lyophilizing, after the medicinal liquid lyophilization of partly jumping a queue, whether the powder pin observing at least 250 bottles has the problem of spray bottle to occur, and statistics spray bottle incidence rate.Have been found that in the injectable powder of embodiment 1-8 whole batches, all have the spray bottle incidence rate that 2-5% does not wait, although middle kind of incidence rate is not high and be only affect powder pin outward appearance, generally this phenomenon is that those skilled in the art expect to overcome; But the spray bottle of embodiment 9 gained 9 batches of injectable powder composition incidence rate is but 0, and in view of freeze drying process and the embodiment 1-3 of embodiment 9 are identical, therefore the spray bottle phenomenon of embodiment 1-8 is relevant with prescription, and adding of micro-citric acid can overcome this phenomenon.
In the present invention, preferred lyophilized injectable powder compositions of the present invention after make the solution containing active component 0.5mg in every 1ml with water, then measures the acid-base value of this freeze-dried powder according to the method under Chinese Pharmacopoeia version in 2010 two annex VI H items and pH value algoscopy.
The preparation process of lyophilization injectable powder well known to a person skilled in the art pharmaceutical technology, such as following kind of the schematic freeze-drying curve of two shown in freeze-drying curve A and freeze-drying curve B:
Hereafter preparing in the instantiation in lyophilization injectable powder, if not otherwise specified, freeze-drying curve used is freeze-drying curve A.
Water content in lyophilization injectable powder is general below 8%, preferably lower than 7%, more preferably less than 5%.Moisture Control is by suitably adjusting lyophilization program to control.Moisture in this lyophilization injectable powder can measure according to many known methods, such as dry weight-loss method.
In the present invention, in order to regulate the pH value of medicinal liquid where necessary, suitable pH adjusting agent can be added in compositions.Although the present inventor only regulates with not having the strong acid of buffer capacity or strong base solution such as a sodium hydrate aqueous solution and aqueous hydrochloric acid solution, but, those skilled in the art understand, if the pH requirement of system can be met with this pH adjusting agent process of not having buffer capacity, the pH adjusting agent then with buffer capacity will can realize the object of the invention more, therefore these buffer agents not only can adjust ph, and can stablize pH value.Therefore arbitrary pH adjusting agent listed by the present invention or its combination include in spirit and scope of the invention.
When preparing lyophilized injectable powder of the present invention, in the medicinal liquid prepared, solid content is 1 ~ 20% (w/v), preferably 1 ~ 15% (w/v), more more preferably 1 ~ 10%.Obtain because lyophilized injectable powder normally carries out lyophilization in tubulose cillin bottle, those skilled in the art understand this product at acquisition finished product even before for doctor, usually a round pie is all presented, although in the volume theory of this cake, lecture is fewer than the volume of original aqueous solution (slightly reducing), but this reducing can not narrow down to former aqueous solution volume 50% usually usually, usual meeting is between the 80-120% of former aqueous solution volume, between the 90-100% being more typically in former aqueous solution volume, and can be observed in finished product cillin bottle former aqueous solution liquid level vestige (main body cake because of lyophilizing reduce after remain in liquid level vestige bottle wall, even if the dried frozen aquatic products in cillin bottle is Powdered because of reasons such as a variety of causes such as collide, usually original liquid level vestige can still be retained), vestige also can estimate the aqueous solution volume of this freeze-dried composition before lyophilization accordingly.Therefore, although the present invention is to provide a kind of substantially anhydrous lyophilization injectable powder, but still roughly can estimate it when preparing according to this injectable powder, medicine liquid volume at least before lyophilization starts, the weight of the dry end-product in the volume estimated according to this and cillin bottle, also can calculate when preparing lyophilized injectable powder of the present invention, the content of the solid content in the medicinal liquid prepared.Therefore, lyophilized injectable powder according to a first aspect of the present invention, its solid content of medicinal liquid when preparing is 1 ~ 20% (w/v), preferably 1 ~ 15% (w/v), more more preferably 1 ~ 10%.
In the present invention, symbol %, according to the linguistic context that it uses, can have the implication of those skilled in the art's easy understand.Such as when mentioning solid content, this symbol represents the percent (w/v, such as g/100ml) of weight/volume; Again such as when mentioning " water content " in lyophilization injectable powder, such as water content is below 8%, and now this symbol % represents the percent (w/w, g/100g) of w/w.Generally speaking, solid dispersal in a liquid time, % represents weight/volume percent; Solid dispersal in solids or liquid dispersion in solids (such as the water content of powder pin) time, % represents w/w percent.In other cases, unless otherwise noted, symbol % represents w/w percent.
When preparing medicinal liquid of the present invention, as well known to those skilled in the art, the microporous filter membrane of example 0.45um according to appointment can carry out coarse filtration filtration, by before in liquid medicine filling to cillin bottle, the microporous filter membrane of example 0.22um according to appointment can carry out fine straining and filter with degerming, can filter repeatedly if desired.
According to lyophilized injectable powder of the present invention, it redissolves with water for injection, and typically the redissolution time is in 30 seconds, preferably in 20 seconds, more preferably in 15 seconds.
According to the compositions in lyophilized injectable powder form of the present invention, it to be made in every 1ml containing the solution of reactive compound 0.5mg with water and measures according to the method under Chinese Pharmacopoeia version in 2010 two annex VI H items, and the pH value of this solution is 3.0 ~ 5.0.In one embodiment, pH value is 3.5 ~ 4.5.
Lyophilized injectable powder provided by the invention can be preserved at least 24 months at dry place below 25 DEG C, can meet the Storage Requirement of general lyophilization injectable powder.
Clinically, terazosin hydrochloride can be used for treating benign prostate hyperplasia.Terazosin hydrochloride also can be used for treat hypertension, can be used alone or with other antihypertensive drug as diuretic or beta-adrenergic blocking agent share.
Pharmacodynamics aspect, benign prostatic hyperplasia (BPH): the symptom relevant with BPH relates to Bladder outlet obstruction, it comprises two elements: static part and dynamic part.Static part is the result that prostate increases.In a period of time, prostate can constantly expand.But clinical research shows, the seriousness of prostatic size and BPH symptom or the degree of urethral obstruction have nothing to do.Dynamic part is the function that prostate and bladder neck smooth muscle anxiety increase, and causes the narrow of bladder outlet.Smooth muscle tone is mediated by the sympathetic stimulation effect of alpha 1 adrenergic receptor, and this receptor is abundant in prostate, prostatic utriculus and neck of bladder.After giving terazosin, symptom alleviates that to improve the smooth muscle loosening caused by blocking with the alpha 1 adrenergic receptor in neck of bladder and prostate with urine flow velocity relevant.Because there is relatively few alpha 1 adrenergic receptor in body of bladder, therefore terazosin can alleviate the obstruction of bladder outlet and not affect the contraction of bladder.Overall merit has been carried out to the general function of urinating and symptom, compared with the patient treated with blank, the overall improvement having obviously (p≤0.001) large with the patient of terazosin treatment.In long term test, terazosin makes symptom and urine flow velocity maximum mark all have clear improvement, and prompting terazosin makes smooth muscle cell relaxation.Although block the blood pressure that alpha 1 adrenergic receptor also reduces the hypertensive patient caused because peripheral vascular resistance increases, during normotensive BPH male patient terazosin treatment, do not cause clinically significantly blood pressure reducing effect.
Hypertension: in animal, terazosin is by reducing Total peripheral vascular resistance thus making blood pressure reduce.Vasodilation, the blood pressure reducing effect of terazosin seem mainly caused by alpha 1 adrenergic receptor blocks.Upon administration in 15 minutes, terazosin makes blood pressure reduce gradually.Suffer from slight (about 77%, diastolic pressure 95-105mmHg) or moderate (about 23%, diastolic pressure 105-115mmHg) hypertensive patient, according to the accumulated dose of 5-20mg/ days, once a day or twice gives terazosin carried out clinical trial.The same with all antagonisies, because terazosin can make blood pressure decline rapidly first or after front administration several times, therefore initial dose is 1mg, then adjusts to a certain fixed dosage or adjusts to a certain specific blood pressure terminal (diastolic pressure of usual dorsal position is 90mmHg).The end of term (usual 24 hours) Measure blood pressure between administration, result shows, and hypotensive effect continues whole interval, and usually, the systolic pressure of dorsal position reduces than blank large 5-10mmHg, the large 3.5-8mmHg of reduction of diastolic pressure.Within after administration 24 hours, measure, heart rate does not change.Cause the amount of blood pressure response and prazosin similar, but lower than hydrochlorothiazide.Terazosin small dose group reduces the T-CHOL of patient, low-density and very low density lipoprotein (VLDL) statistically significantly, but does not obviously change high density lipoprotein and triglyceride.
Toxicity is carcinogenic, mutagenesis and genotoxicity aspect, and terazosin does not have mutagenic action.Also no evidence supports that terazosin has carcinogenesis.Treatment does not have an impact to the weight of testis and form.With 30 and 120mg/kg/ days dosed administrations, smear sperm content compared with contrast smear in uterus reduces and the quantity of sperm and becoming pregnant subsequently have reasonable dependency.When giving rat 1 year or 2 years with the oral dose of 40 and 250mg/kg/ days (recommending maximal dose to people for 29 and 175 times), the incidence rate of atrophy of testis obviously increases, but does not increase when 8mg/kg/ days (> people recommends 6 of maximal dose times) dosage.In the experiment of Canis familiaris L., also been observed atrophy of testis during (> people recommends 500 of maximal dose times) administration in 300mg/kg/ days 3 months, but not observed atrophy of testis when dosage is 20mg/kg/ days (> people recommends 38 of maximal dose times).Period of pregnancy teratogenesis not yet carry out in pregnant woman enough with good Comparative study and terazosin not yet determine in the safety of period of pregnancy.Be not recommended in and use terazosin period of pregnancy, unless proved that helpfulness is higher than the danger to puerpera and fetus.
Pharmacokinetics aspect, absorbs after male patient takes medicine substantially completely.Immediately after meals is taken medicine minimum on the impact of degree of absorption, but makes plasma concentration peak time postpone about 40 minutes.The liver first pass metabolism of terazosin is very little.Within after taking medicine about 1 hour, reach peak value, the half-life is about 12 hours.The age to the research of terazosin Pharmacokinetic effect in find, 70 years old and 20-39 year the age patient, its plasma half-life is respectively 14.0 and 11.4 hours.Plasma protein binding rate is 90-94%.About 40% through homaluria, and about 60% discharges with feces.
Detailed description of the invention
Can be conducted further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite not deviating from the spirit and scope of the present invention, can carry out various change and modification to the present invention.The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and operational approach is well known in the art, the present invention still describes in detail as far as possible at this.Following examples further illustrate the present invention, instead of restriction the present invention.Any conceive according to the present invention done be only pro forma but not substantial equivalent transformation and all should be considered as technical scheme category of the present invention.
In example below, if not otherwise indicated, be use the terazosin crude drug of same batch (to be terazosin hydrochloride dihydrate, all to refer to free base when the present invention measures it when preparing injectable powder; After testing, it meets the quality standard of American Pharmacopeia USP35 version the 4785th page of terazosin hydrochloride recorded (dihydrate)).
In example below, the pH adjusting agent (in the present invention that is acid-base modifier) used, unless otherwise noted, 1M sodium hydroxide solution or 1M hydrochloric acid solution, its consumption is when making to prepare injectable powder, the pH value of the solution prepared before making lyophilization is adjusted to a certain setting or scope, this setting or scope be lyophilization gained dry powder water for injection be diluted to containing active component 0.5mg/ml (as in dosing lower than this concentration, then do not regulate, the context of the invention processes all similarly) the value of pH value that measures of solution or scope.The hereafter object of preparation process in order to illustrate, and based on each citing comparability and make some specific description, those skilled in the art therefrom can summarize the method obtaining the present invention and prepare lyophilized injectable powder completely according to existing knowledge.Dosing is prepared in various compositions below, and if not otherwise indicated, the total dosing amount often criticized is the amount of 1000 bottles, but when listing formula, the amount all containing terazosin 1mg in every bottle is illustrated.
embodiment 1: prepare terazosin lyophilization injectable powder
formula:
Terazosin: 1mg,
Mannitol: 50mg,
Acid-base modifier: use appropriate if desired, regulate the setting in pH to following method for making,
Water for injection: to 1ml.
method for making:
A () takes active component and the solid adjuvant material of recipe quantity, add appropriate (65% of prescription full dose) water for injection, be stirred to dissolve,
B () adds active carbon (0.1%) in previous step gained medicinal liquid, stir (making absorption 15min), filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then using the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, measure solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH4.0 (the present embodiment and the whole embodiment of the present invention with acid-base modifier, step (c) directly adjust ph so far setting herein, the pH value of this solution when the injectable powder water for injection that lyophilizing obtains is dissolved into the solution containing terazosin 0.5mg/ml concentration, directly adjust ph is identical for this value and step (c));
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 3%), tamponade, to obtain final product.
In addition, by the adjustment of every bottle of gun propellant separated loading charge liquid measure, the amount of the terazosin in can making every bottle is the injectable powder of 0.1mg ~ 2.5mg amount.
embodiment 2: prepare terazosin lyophilization injectable powder
formula:
Terazosin: 1mg,
Mannitol: 25mg,
Acid-base modifier: use appropriate if desired, regulate the setting in pH to following method for making,
Water for injection: to 2.5ml.
method for making:
A () takes active component and the solid adjuvant material of recipe quantity, add appropriate (70% of prescription full dose) water for injection, be stirred to dissolve,
B () adds active carbon (0.15%) in previous step gained medicinal liquid, stir (making absorption 10min), filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then using the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH4.5 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 4%), tamponade, to obtain final product.
embodiment 3: prepare terazosin lyophilization injectable powder
formula:
Terazosin: 1mg,
Mannitol: 500mg,
Acid-base modifier: use appropriate if desired, regulate the setting in pH to following method for making,
Water for injection: to 5ml.
method for making:
A () takes active component and the solid adjuvant material of recipe quantity, add appropriate (60% of prescription full dose) water for injection, be stirred to dissolve,
B () adds active carbon (0.05%) in previous step gained medicinal liquid, stir (making absorption 20min), filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then using the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH3.5 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 5%), tamponade, to obtain final product.
embodiment 4: prepare terazosin lyophilization injectable powder
formula:
Terazosin: 1mg,
Mannitol: 100mg,
Acid-base modifier: use appropriate if desired, regulate the setting in pH to following method for making,
Water for injection: to 2ml.
method for making:
A () takes active component and the solid adjuvant material of recipe quantity, add appropriate (65% of prescription full dose) water for injection, be stirred to dissolve,
B () adds active carbon (0.1%) in previous step gained medicinal liquid, stir (making absorption 15min), filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then using the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH3.0 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 3%), tamponade, to obtain final product.The present embodiment uses lyophilization curve B to carry out lyophilizing.
embodiment 5: prepare terazosin lyophilization injectable powder
formula:
Terazosin: 1mg,
Mannitol: 250mg,
Acid-base modifier: use appropriate if desired, regulate the setting in pH to following method for making,
Water for injection: to 5ml.
method for making:
A () takes active component and the solid adjuvant material of recipe quantity, add appropriate (65% of prescription full dose) water for injection, be stirred to dissolve,
B () adds active carbon (0.1%) in previous step gained medicinal liquid, stir (making absorption 15min), filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then using the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH5.0 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 3%), tamponade, to obtain final product.
embodiment 6: prepare terazosin lyophilization injectable powder
formula:
Terazosin: 1mg,
Mannitol: 25mg,
Acid-base modifier: use appropriate if desired, regulate the setting in pH to following method for making,
Water for injection: to 0.5ml.
method for making:
A () takes active component and the solid adjuvant material of recipe quantity, add appropriate (65% of prescription full dose) water for injection, be stirred to dissolve,
B () adds active carbon (0.1%) in previous step gained medicinal liquid, stir (making absorption 15min), filtering decarbonization (after filtering with the titanium rod decarburization that aperture is 1um, then using the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration);
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH4.0 with acid-base modifier;
D (), by medicinal liquid aseptic filtration (carrying out aseptic filtration with the polyether sulfone filter element of 0.22um), fill is in cillin bottle;
E () lyophilization removing moisture (moisture is lower than 3%), tamponade, to obtain final product.
embodiment 7: prepare terazosin lyophilization injectable powder
Respectively with reference to formula and the method for making of embodiment 1-3, different is only lactose mannitol wherein being replaced with equivalent, obtains three batches of injectable powder and is designated as #71, #72, #73 respectively.
embodiment 8: prepare terazosin lyophilization injectable powder
Respectively with reference to formula and the method for making of embodiment 1-3, different is only glycine mannitol wherein being replaced with equivalent, obtains three batches of injectable powder and is designated as #81, #82, #83 respectively.
embodiment 9: prepare terazosin lyophilization injectable powder
Respectively with reference to formula and the method for making of embodiment 1-3, different is only add citric acid (its amount is 3.5 times of terazosin) wherein together with mannitol again, obtains three batches of injectable powder and is designated as #91, #92, #93 respectively; Respectively with reference to formula and the method for making of embodiment 1-3, different is only add citric acid (its amount is 2 times of terazosin) wherein again, obtains three batches of injectable powder and is designated as #94, #95, #96 respectively; Respectively with reference to formula and the method for making of embodiment 1-3, different is only add citric acid (its amount is 5 times of terazosin) wherein again, obtains three batches of injectable powder and is designated as #97, #98, #99 respectively.
embodiment 10: prepare terazosin lyophilization injectable powder
Respectively with reference to the formula of embodiment 1 and method for making, different is only replaces with the sorbitol of equivalent, xylitol, glucose or maltose by mannitol wherein, obtain four batches of injectable powder and be designated as #101, #102, #103, #104 respectively.
embodiment 11: prepare terazosin lyophilization injectable powder
Respectively with reference to formula and the method for making of embodiment 1, different is only the amount of mannitol wherein changed into: 0mg, 5mg, 10mg, 15mg, 25mg, 100mg, 500mg, 1000mg or 2000mg (rear four amount of water suitably adjust and make solid concentration in medicinal liquid be 10%), obtain four batches of injectable powder and be designated as #111, #112, #113, #114, #115, #116, #117, #118, #119 respectively.
embodiment 12: prepare terazosin freeze-dried composition
By 2g terazosin hydrochloride, 7.5g gelatin, 0.5g gelatin hydrolysate, 14g mannitol 350ml water dissolution, gained medicinal liquid is sub-packed in cillin bottle, every bottle of 2ml, then puts into freezer dryer and carries out lyophilization by freeze-drying curve A of the present invention, obtain compositions #121.
2g terazosin hydrochloride is added 200ml water dissolution, forms solution A; Sweet to 7.5g gelatin, 0.5g gelatin hydrolysate, 14g mannitol, 1.5g A Siba, 1.4g menthol, 0.1g NHDC are dissolved in 100ml water, form solution B; By solution A and solution B mixing, and add suitable quantity of water and be diluted to 350ml, fully stir.Gained medicinal liquid is sub-packed in cillin bottle, every bottle of 2ml, then puts into freezer dryer and carry out lyophilization by freeze-drying curve A of the present invention, obtain compositions #122.
industrial applicability
The invention provides a kind of terazosin lyophilization injectable powder with the injectable of excellent properties, and the preparation method of this terazosin lyophilization injectable powder.The terazosin lyophilization injectable powder of the injectable that the present invention prepares has excellent physicochemical property.

Claims (10)

1. a pharmaceutical composition, comprising: terazosin, excipient.
2. pharmaceutical composition according to claim 1, is characterized in that:
Described terazosin can also be its pharmaceutical salts or its solvate such as hydrate;
Described terazosin is terazosin hydrochlorate;
Described terazosin is terazosin hydrochloride dihydrate;
Wherein said excipient is selected from: mannitol, lactose, sorbitol, xylitol, glucose, maltose, glycine, soluble dextrins, xanthan gum, gelatin, gelatin hydrolysate, arabic gum, pectin, guar gum, Resina persicae, tragacanth, acacin, sodium carboxymethyl cellulose, polyvinylpyrrolidone, carbomer, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, alginate or its combination;
The weight ratio of described terazosin and excipient is 1:10 ~ 1000, such as 1:20 ~ 750, such as 1:25 ~ 500;
Described excipient is selected from: mannitol, lactose, sorbitol, xylitol, glucose, maltose, glycine;
Described excipient is selected from: mannitol, lactose, glycine; And/or
Described excipient does not comprise gelatin or gelatin hydrolysate.
3. pharmaceutical composition according to claim 1, is characterized in that:
It is cryodesiccated compositions;
It is the cryodesiccated injectable powder that can be used for injecting;
It is the cryodesiccated injectable powder that can be used for injecting, and this injectable powder is seal-packed with vial;
It is the cryodesiccated injectable powder that can be used for injecting, and this injectable powder is seal-packed with vial, and the amount of the terazosin in every bottle is 0.1mg ~ 5mg, and the amount of such as, terazosin in every bottle is 0.1mg ~ 2.5mg;
This pharmaceutical composition is under air-proof condition, place in the time of 6 months 40 DEG C of lucifuges, and impurity A increment rate is less than 100%, is particularly less than 75%, is more especially less than 50%; And/or
Wherein moisture is lower than 10%, preferably lower than 8%, preferably lower than 7%, more preferably less than 5%.
4. pharmaceutical composition according to claim 1, is characterized in that:
Wherein also comprise acid-base modifier;
Described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination;
Described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution;
The amount of described optional acid-base modifier is, the amount of pH value in 3.0 ~ 5.0 scopes of this solution during the solution making described lyophilized injectable powder water for injection be dissolved into containing terazosin 0.5mg/ml concentration, the amount of pH value in 3.5 ~ 4.5 scopes of such as this solution;
Wherein also comprise citric acid; And/or
The weight ratio of terazosin and citric acid is 1:1 ~ 10, such as 1:2 ~ 5.
5. pharmaceutical composition according to claim 1, is characterized in that:
It is prepare by comprising following step substantially:
A () takes terazosin and the excipient of recipe quantity, add appropriate water for injection, be stirred to dissolve,
B () adds active carbon in previous step gained medicinal liquid, stir, filtering decarbonization;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH3.0 ~ 5.0 with acid-base modifier, preferred pH3.5 ~ 4.5;
D (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
(e) lyophilization removing moisture, tamponade, to obtain final product;
Wherein appropriate water for injection described in step (a) is the water for injection of 60 ~ 70% amounts of prescription full dose;
Wherein the addition of active carbon described in step (b) is that concentration of activated carbon reaches the amount of 0.05 ~ 0.15% in medicinal liquid;
Wherein stirring described in step (b) is stirring and adsorbing 10 ~ 20min, such as stirring and adsorbing 15min;
Wherein the mode of filtering decarbonization described in step (b) is: after filtering with the titanium rod decarburization that aperture is 1um, then use the polyether sulfone filter element of 0.45um by medicinal liquid coarse filtration;
Wherein mend described in step (c) and inject water to prescription full dose and refer to and add water for injection until activity component concentration is the amount of 0.1 ~ 5mg/ml (such as 0.2 ~ 2mg/ml); And/or
Wherein aseptic filtration described in step (d) uses the polyether sulfone filter element of 0.22um to carry out aseptic filtration.
6. make the method that terazosin is stable, the method comprises the step making terazosin and excipient make pharmaceutical composition, and in this pharmaceutical composition, terazosin and excipient form homogeneous mixture.
7. method according to claim 6, is characterized in that:
Described pharmaceutical composition is cryodesiccated compositions;
Described pharmaceutical composition is the cryodesiccated injectable powder that can be used for injecting;
Described pharmaceutical composition is the cryodesiccated injectable powder that can be used for injecting, and this injectable powder is seal-packed with vial;
Described pharmaceutical composition is the cryodesiccated injectable powder that can be used for injecting, and this injectable powder is seal-packed with vial, and the amount of the terazosin in every bottle is 0.1mg ~ 5mg, and the amount of such as, terazosin in every bottle is 0.1mg ~ 2.5mg;
Described pharmaceutical composition comprises: terazosin, excipient;
Described terazosin can also be its pharmaceutical salts or its solvate such as hydrate;
Described terazosin is terazosin hydrochlorate;
Described terazosin is terazosin hydrochloride dihydrate;
Described excipient is selected from: mannitol, lactose, sorbitol, xylitol, glucose, maltose, glycine, soluble dextrins, xanthan gum, gelatin, gelatin hydrolysate, arabic gum, pectin, guar gum, Resina persicae, tragacanth, acacin, sodium carboxymethyl cellulose, polyvinylpyrrolidone, carbomer, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, alginate or its combination;
The weight ratio of described terazosin and excipient is 1:10 ~ 1000, such as 1:20 ~ 750, such as 1:25 ~ 500;
Described excipient does not comprise gelatin or gelatin hydrolysate.
8. method according to claim 6, is characterized in that:
The method its make this pharmaceutical composition under air-proof condition, place in the time of 6 months 40 DEG C of lucifuges, impurity A increment rate is less than 100%, is particularly less than 75%, is more especially less than 50%;
Described pharmaceutical composition is packed by cillin bottle;
Described pharmaceutical composition is packed by cillin bottle, and in round pie in cillin bottle;
Described pharmaceutical composition moisture lower than 10%, preferably lower than 8%, preferably lower than 7%, more preferably less than 5%;
Also acid-base modifier is comprised in described pharmaceutical composition;
Described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination;
Described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution;
The amount of described optional acid-base modifier is, the amount of pH value in 3.0 ~ 5.0 scopes of this solution during the solution making described lyophilized injectable powder water for injection be dissolved into containing terazosin 0.5mg/ml concentration, the amount of pH value in 3.5 ~ 4.5 scopes of such as this solution;
Wherein also comprise citric acid;
The weight ratio of terazosin and citric acid is 1:1 ~ 10, such as 1:2 ~ 5; And/or
Described pharmaceutical composition is prepare by comprising following step substantially:
A () takes terazosin and the excipient (and optional citric acid) of recipe quantity, add appropriate water for injection, be stirred to dissolve,
B () adds active carbon in previous step gained medicinal liquid, stir, filtering decarbonization;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH3.0 ~ 5.0 with acid-base modifier, preferred pH3.5 ~ 4.5;
D (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
E () lyophilization removing moisture, tamponade, to obtain final product.
9. the method for the pharmaceutical compositions such as pharmaceutical composition of any one of claim 1-5, it consists essentially of following steps:
A () takes terazosin and the excipient of recipe quantity, add appropriate water for injection, be stirred to dissolve,
B () adds active carbon in previous step gained medicinal liquid, stir, filtering decarbonization;
C () is mended and is injected water to prescription full dose, stir, and measures solution ph and optional mensuration active component content, if desired (or optionally) be adjusted to pH3.0 ~ 5.0 with acid-base modifier, preferred pH3.5 ~ 4.5;
D (), by medicinal liquid aseptic filtration, fill is in cillin bottle;
E () lyophilization removing moisture, tamponade, to obtain final product.
10. method according to claim 9, is characterized in that:
Described terazosin is terazosin hydrochloride dihydrate;
Described excipient is selected from: mannitol, lactose, sorbitol, xylitol, glucose, maltose, glycine, soluble dextrins, xanthan gum, gelatin, gelatin hydrolysate, arabic gum, pectin, guar gum, Resina persicae, tragacanth, acacin, sodium carboxymethyl cellulose, polyvinylpyrrolidone, carbomer, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, alginate or its combination;
The weight ratio of terazosin and excipient is 1:10 ~ 1000, such as 1:20 ~ 750, such as 1:25 ~ 500;
Described excipient does not comprise gelatin or gelatin hydrolysate;
Described pharmaceutical composition is the cryodesiccated injectable powder that can be used for injecting, and this injectable powder is seal-packed with vial, and the amount of the terazosin in every bottle is 0.1mg ~ 5mg, and the amount of such as, terazosin in every bottle is 0.1mg ~ 2.5mg;
Described pharmaceutical composition is under air-proof condition, place in the time of 6 months 40 DEG C of lucifuges, and impurity A increment rate is less than 100%, is particularly less than 75%, is more especially less than 50%;
In described pharmaceutical composition, moisture is lower than 10%, preferably lower than 8%, preferably lower than 7%, more preferably less than 5%; And/or
The method is further as described in embodiment as arbitrary in the description third aspect.
CN201510320016.5A 2015-06-11 2015-06-11 Pharmaceutical composition Active CN104840436B (en)

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