CN103330682B - Potassium dehydroandrographolide succinate injection and preparation method - Google Patents
Potassium dehydroandrographolide succinate injection and preparation method Download PDFInfo
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Abstract
The invention relates to potassium dehydroandrographolide succinate injection and a preparation method, in particular to a pharmaceutical composition which comprises potassium dehydroandrographolide succinate, alkali metal salt and water for injection. The preparation method of the pharmaceutical composition comprises steps as follows: auxiliary materials such as the alkali metal salt and the like are dissolved in an appropriate amount of the water for injection, the potassium dehydroandrographolide succinate is added to the solution and stirred to be dissolved, about 0.1%-0.5% of activated carbon is added to the solution and stirred for absorption for 30 minutes, and filtration is performed to remove carbon; the water for injection is refilled to a full dose, a pH value of the solution is checked, and if necessary, an acidifying or alkalizing agent is used for adjusting the pH value of the solution to be in the range from 6.5 to 8.0; 0.4 mu m and 0.22 mu m millipore filtering films are used for filtering a liquid medicine, the liquid medicine is split and filled in glass bottles, then sealed and autoclaved at the temperature of 115 DEG C for 30 minutes, and the potassium dehydroandrographolide succinate injection is obtained. The prepared potassium dehydroandrographolide succinate injection has a good pharmaceutical property.
Description
Technical field
The invention belongs to medical art, relate to a kind of medicament of disease being used for the treatment of viral pneumonia, viral upper respiratory tract infection, particularly relate to a kind of Chuanhuning preparation, be specifically related to the preparation method of a kind of stable potasium dehydroandrographolisuccinate succinate injection and this injection.
Background technology
Andrographolide, chemical name: 14-deshydroxy 11,12-bis-dehydrogenation andrographolide-3,19-disuccinic acid half ester monopotassium salt, English name: Potassium Dehydroandrograpolide Succinate; Molecular formula: C28H35KO10, molecular weight: 570.68, its molecular formula is as follows with following formula I (it also can be described as formula I in the present invention):
The existing Chuanhuning preparation applied clinically has lyophilization injectable powder, low capacity aqueous injection and large capacity transfusion agent, because the stability of Andrographolide has problems usually, therefore classical or be applied to clinical in the mode of injectable powder, such as China's coastal port and Chinese Pharmacopoeia version in 2010 have recorded raw material and the injectable powder of Andrographolide all, wherein Andrographolide lyophilized injectable powder is white or yellowish lyophilizing block or powder, specification is every bottle of 20mg, 40mg, 100mg or 200mg, and the stability of aqueous injection particularly attracts people's attention.
Pharmacological evaluation shows: (1) Andrographolide causes the rabbit of heating to have stronger refrigeration function to bacterial endotoxin, can promote disappearing of heating, and effect also can maintain more than 4 hours rapidly; (2) Andrographolide has good antiinflammatory action, can resist Permeability of Capillary Wall caused by dimethylbenzene or histamine and increase, and have obvious antagonism to epinephrine acute lung edema; (3) Andrographolide can shorten the white mouse Sleep latency that pentobarbital sodium causes, and extends its length of one's sleep, and the pentobarbital sodium effect of measuring under can also strengthening threshold, causes white mice to sleep, and this experimental result points out this product to have obvious sedation; (4) Andrographolide can promote Rat Adrenal cortex hormone function significantly, increases body to the emergency capability of pathogenic infection; (5) show Andrographolide infected by influenza first I type, first type III, pneumonia adenovirus (Adv) type III, IV type through clinical nosetiology diagnostic test and inactivated tissue culture test, intestinal syncytial virus and respiratory syncytial virus (RSV) all have deactivation.Andrographolide toxicity is little, nonirritant, and intravenous drip LD50 is 675 ± 30mg/kg.After Andrographolide intramuscular or intravenously administrable, absorb rapidly in vivo, distribute, it absorbs the phase half-life (t1/2Ka) is 18.90 ± 12.12min, and distribution phase half-life (t1/2 α) is only 1.3 ± 0.3min.Medication after 6 hours blood drug level obviously decline, its eliminate the phase half-life (t1/2 β) be 3.86 ± 1.06 hours, medication can discharge more than 85% of dosage after 2 days.The bioavailability of intramuscular injection reaches 94.2 ± 32.9%, absorbs more complete after showing intramuscular injection.
Andrographolide clinically for viral pneumonia, viral upper respiratory tract infection etc.The using method of injectable powder is normally: dissolve in right amount with sodium chloride injection before use.Intramuscular injection, a 100mg, 1 ~ 2 time on the one, children's is cut down according to the circumstance or is followed the doctor's advice.Intravenous drip, 400 ~ 800mg on the one, divide with sodium chloride injection and dilute rear instillation for 2 times, must not cross 400mg, children's is cut down according to the circumstance at every turn, or follows the doctor's advice.In addition, record according to product description, Andrographolide avoids with acid, alkalescent medicine or containing sodium sulfite, sodium pyrosulfite is the compatibility of drugs of antioxidant.
About the stability of Andrographolide in prior art, much more all the physical stability and the chemical stability problems that comprise it have report.Common physical stability is solubility, such as powder pin is occurring that the situation of dissolubility deficiency occurs in use, such as yellow precious elegant report (Huang Baoxiu, the research of Potassium DehydroandrograpolidSuccinate Succinate for Injection deposited phenomenon, Heilungkiang medicine, 2001,14 (5): 366) Andrographolide with the glucose injection compatibility of variable concentrations/pH value after have deposited phenomenon to occur.It is believed that in Andrographolide drug molecular structure to there is bridge shape conjugated structure, α and β-unsaturated lactone key, its aqueous solution is easily hydrolyzed, and causes product color to be deepened, and content declines.Common chemical stability shows as impurity to be increased and/or content decline, such as pay the spring (Fu Chunmei such as prunus mume (sieb.) sieb.et zucc., Liu Sankang, Li Zhangwan, Qian Guangsheng, the Related substances separation of Andrographolide crude drug and injection thereof and containing study on determination method, pharmaceutical analysis magazine, 2005, 25 (2): 157) report: " injection study on the stability finds, the peak area of related substance obviously increases, content reduces, commercially available many products content after placing half a year only has about 80% of labelled amount, and the increase of related substance reduces with content and does not mate, illustrate that Related substances separation does not reflect the catabolite of sample completely ... suggestion production unit improves process for preparing injection liquid or makes injectable powder, to improve its stability.”
Therefore, people are expected for and clinically provide a kind of Chuanhuning preparation in physical stability and/or chemical stability with superperformance, such as potasium dehydroandrographolisuccinate succinate injection.
Summary of the invention
The object of the invention is to provide a kind of Chuanhuning preparation in physical stability and/or chemical stability with superperformance, such as potasium dehydroandrographolisuccinate succinate injection for clinical.The present inventor finds that the potasium dehydroandrographolisuccinate succinate injection with formula of the present invention has good physical stability and/or chemical stability.The present invention is based on this find and be accomplished.
For this reason, in first of the present invention, provide a kind of pharmaceutical composition in liquid, wherein comprise: Andrographolide, alkali metal salt and water for injection.
Pharmaceutical composition according to a first aspect of the present invention, wherein also comprises cysteine or its pharmaceutical salts.
Pharmaceutical composition according to a first aspect of the present invention, wherein said cysteine or its pharmaceutical salts are selected from: L-cysteine hydrochloride, Cys, DL-cysteine, D-Cys, DL-cysteine hydrochloride.
Pharmaceutical composition according to a first aspect of the present invention, wherein also comprises and is selected from following cyclodextrin: alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, TM-β-CD, DM-β-CD, hydroxyethyl-β-cyclodextrin, HP-β-CD, sulphur methyl ether-beta-schardinger dextrin-, sulfobutyl ether-beta-cyclodextrin, malt sugar group-beta-cyclodextrin.The present inventor finds in test, the derivant of above-mentioned beta-schardinger dextrin-all has water solublity in various degree, and such as, dissolubility (25 ° of C) in water is respectively: TM-β-CD 31g/100ml water, DM-β-CD 55g/100ml water, hydroxyethyl-β-cyclodextrin 54g/100ml water, HP-β-CD 51g/100ml water, sulphur methyl ether-beta-schardinger dextrin-74g/100ml water, sulfobutyl ether-beta-cyclodextrin 78g/100ml water, malt sugar group-beta-cyclodextrin 95g/100ml water.
The HP-β-CD used in the present invention such as easily can be buied from market, such as, be the pharmaceutic adjuvant of the accurate word F20090001 of traditional Chinese medicines.Other adjuvant also easily obtains from market.Although the dissolubility of HP-β-CD in these cyclodextrin is not best, its chemical stability unexpectedly shown for formula I has good improvement result.
Pharmaceutical composition according to a first aspect of the present invention, wherein said alkali metal salt is selected from alkali carbonate, alkali metal hydrogencarbonate or its combination.
Pharmaceutical composition according to a first aspect of the present invention, wherein said alkali metal salt is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or its combination.
Pharmaceutical composition according to a first aspect of the present invention, wherein said alkali metal salt is sodium bicarbonate.
Pharmaceutical composition according to a first aspect of the present invention, wherein comprises: Andrographolide, alkali metal salt, cysteine or its pharmaceutical salts, cyclodextrin and water for injection.
Pharmaceutical composition according to a first aspect of the present invention, wherein the two mol ratio of Andrographolide and alkali metal salt (it is in alkali metal ion, lower with) is 1:(0.2 ~ 2.0).Pharmaceutical composition according to a first aspect of the present invention, wherein Andrographolide and the mol ratio both alkali metal salt are 1:(0.5 ~ 1.5).Pharmaceutical composition according to a first aspect of the present invention, wherein Andrographolide and the mol ratio both alkali metal salt are 1:(0.8 ~ 1.2) (if wherein alkali metal salt uses sodium bicarbonate, then now Andrographolide and the weight ratio both sodium bicarbonate are about 100:(10 ~ 20), such as be about 100:(11.7 ~ 17.7), be such as about 100:(12 ~ 17)).
Pharmaceutical composition according to a first aspect of the present invention, wherein the weight ratio of Andrographolide and cysteine or its pharmaceutical salts is 100:(1 ~ 10).Pharmaceutical composition according to a first aspect of the present invention, wherein the weight ratio of Andrographolide and cysteine or its pharmaceutical salts is 100:(2 ~ 8).Pharmaceutical composition according to a first aspect of the present invention, wherein the weight ratio of Andrographolide and cysteine or its pharmaceutical salts is 100:(3 ~ 7).Pharmaceutical composition according to a first aspect of the present invention, wherein the weight ratio of Andrographolide and cysteine or its pharmaceutical salts is 100:(4 ~ 6).Pharmaceutical composition according to a first aspect of the present invention, wherein the weight ratio of Andrographolide and cysteine or its pharmaceutical salts is about 100:5.
Pharmaceutical composition according to a first aspect of the present invention, wherein the weight ratio of Andrographolide and cyclodextrin is 100:(100 ~ 500).Pharmaceutical composition according to a first aspect of the present invention, wherein the weight ratio of Andrographolide and cyclodextrin is 100:(200 ~ 400).Pharmaceutical composition according to a first aspect of the present invention, wherein the weight ratio of Andrographolide and cyclodextrin is 100:(250 ~ 350).Pharmaceutical composition according to a first aspect of the present invention, wherein the weight ratio of Andrographolide and cyclodextrin is 100:(280 ~ 320).Pharmaceutical composition according to a first aspect of the present invention, wherein the weight ratio of Andrographolide and cyclodextrin is about 100:300.
Pharmaceutical composition according to a first aspect of the present invention, it is solution-type pharmaceutical composition, and wherein Andrographolide concentration is in the solution 0.1 ~ 10% (w/v).Pharmaceutical composition according to a first aspect of the present invention, it is solution-type pharmaceutical composition, and wherein Andrographolide concentration is in the solution 0.5 ~ 5% (w/v).Pharmaceutical composition according to a first aspect of the present invention, it is solution-type pharmaceutical composition, and wherein Andrographolide concentration is in the solution 1 ~ 3% (w/v).Pharmaceutical composition according to a first aspect of the present invention, it is solution-type pharmaceutical composition, and wherein Andrographolide concentration is in the solution 1.5 ~ 2.5% (w/v).Pharmaceutical composition according to a first aspect of the present invention, it is solution-type pharmaceutical composition, and wherein Andrographolide concentration is in the solution about 2% (w/v).
Pharmaceutical composition according to a first aspect of the present invention, wherein comprises: Andrographolide, alkali metal salt, cysteine or its pharmaceutical salts, cyclodextrin and water for injection; Wherein in the Andrographolide of every 100 weight portions, the amount of alkali metal salt is that 10 ~ 20 weight portions (are such as about 11.7 ~ 17.7 weight portions, such as be about 12 ~ 17 weight portions), the amount of cysteine or its pharmaceutical salts is 1 ~ 10 weight portion (such as 2 ~ 8 weight portions, such as be about 3 ~ 7 weight portions, such as be about 4 ~ 6 weight portions, such as be about 5 weight portions), the amount of cyclodextrin is that 100 ~ 500 weight portions (are such as about 200 ~ 400 weight portions, such as be about 250 ~ 350 weight portions, such as be about 280 ~ 320 weight portions, such as, be about 300 weight portions); This pharmaceutical composition is solution-type pharmaceutical composition, wherein Andrographolide concentration is in the solution 0.1 ~ 10% (w/v) (is such as 0.5 ~ 5% (w/v), be such as 1 ~ 3% (w/v), being such as 1.5 ~ 2.5% (w/v), such as, is about 2% (w/v).
Pharmaceutical composition according to a first aspect of the present invention, wherein comprises: Andrographolide, alkali metal salt, cysteine or its pharmaceutical salts, cyclodextrin and water for injection; Wherein in the Andrographolide of every 100 weight portions, the amount of alkali metal salt is 12 ~ 17 weight portions, and the amount of cysteine or its pharmaceutical salts is 3 ~ 7 weight portions, and the amount of cyclodextrin is 200 ~ 400 weight portions; This pharmaceutical composition is solution-type pharmaceutical composition, and wherein Andrographolide concentration is in the solution 1 ~ 3% (w/v).
Pharmaceutical composition according to a first aspect of the present invention, wherein comprises: Andrographolide, sodium bicarbonate, Cys, HP-β-CD and water for injection; Wherein in the Andrographolide of every 100 weight portions, the amount of sodium bicarbonate is that 10 ~ 20 weight portions (are such as about 11.7 ~ 17.7 weight portions, such as be about 12 ~ 17 weight portions), the amount of Cys is 1 ~ 10 weight portion (such as 2 ~ 8 weight portions, such as be about 3 ~ 7 weight portions, such as be about 4 ~ 6 weight portions, such as be about 5 weight portions), the amount of HP-β-CD is that 100 ~ 500 weight portions (are such as about 200 ~ 400 weight portions, such as be about 250 ~ 350 weight portions, such as be about 280 ~ 320 weight portions, such as, be about 300 weight portions); This pharmaceutical composition is solution-type pharmaceutical composition, wherein Andrographolide concentration is in the solution 0.1 ~ 10% (w/v) (is such as 0.5 ~ 5% (w/v), be such as 1 ~ 3% (w/v), being such as 1.5 ~ 2.5% (w/v), such as, is about 2% (w/v).
Pharmaceutical composition according to a first aspect of the present invention, wherein also comprises acid-base modifier (being also called pH value regulator).Pharmaceutical composition according to a first aspect of the present invention, it is solution-type pharmaceutical composition, and its pH value is 6.5 ~ 8.0.
Pharmaceutical composition according to a first aspect of the present invention, wherein said 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.
Pharmaceutical composition according to a first aspect of the present invention, it is solution type injection agent.
Pharmaceutical composition according to a first aspect of the present invention, it is that the method for shining following steps prepares substantially:
(a) by alkali metal salt, cysteine or its pharmaceutical salts, cyclodextrin in appropriate water for injection;
B Andrographolide adds in above-mentioned solution by (), be stirred to dissolve;
C () adds about 0.1 ~ 0.5% active carbon in solution, stirring and adsorbing 30 minutes, filtering decarbonization;
D () is mended and is added to the full amount of water for injection, check the pH value of solution, regulates in pH value to 6.5 ~ 8.0 scope of solution if desired (be such as adjusted in 7.0 ~ 7.5 scopes) with acid-base modifier; Make medicinal liquid 0.4 μm and 0.22 μm of filtering with microporous membrane, be dispensed into by medicinal liquid in vial, sealing, 115 ° of C pressure sterilizing 30min, to obtain final product.
Pharmaceutical composition according to a first aspect of the present invention, wherein in step (a), appropriate water for injection can be the water for injection of 50 ~ 95% of prescription full dose, can be such as the water for injection of 70 ~ 95% of prescription full dose, such as, can be the water for injection of 80 ~ 90% of prescription full dose.
Further, second aspect present invention provides the method preparing pharmaceutical composition described in first aspect present invention, and it comprises the following steps:
(a) by alkali metal salt, cysteine or its pharmaceutical salts, cyclodextrin in appropriate water for injection;
B Andrographolide adds in above-mentioned solution by (), be stirred to dissolve;
C () adds about 0.1 ~ 0.5% active carbon in solution, stirring and adsorbing 30 minutes, filtering decarbonization;
D () is mended and is added to the full amount of water for injection, check the pH value of solution, regulates in pH value to 6.5 ~ 8.0 scope of solution if desired (be such as adjusted in 7.0 ~ 7.5 scopes) with acid-base modifier; Make medicinal liquid 0.4 μm and 0.22 μm of filtering with microporous membrane, be dispensed into by medicinal liquid in vial, sealing, 115 ° of C pressure sterilizing 30min, to obtain final product.
Method according to a second aspect of the present invention, wherein in step (a), appropriate water for injection can be the water for injection of 50 ~ 95% of prescription full dose, can be such as the water for injection of 70 ~ 95% of prescription full dose, such as, can be the water for injection of 80 ~ 90% of prescription full dose.
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.
Formula I any one individual isomer of also will comprising compound shown in formula I and may exist in the present invention, or the isomer of any more than 2 that compound shown in formula I may exist is with the mixture of arbitrary proportion.
" the acceptable adjuvant of pharmacy " used herein refers to the adjuvant that can be used for the special injectable drug of compounding pharmaceutical, it there is no harmful effect to organism, and normally organism can tolerate.
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 vial, 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 pharmaceutical composition of the present invention, it is injection and the injection of solution-type.In one embodiment, this injection is single-dose preparations (injection of such as glass bottle), and the amount of per unit dosage compounds of formula I can such as but not limited to about 5mg, about 10mg, about 20mg, about 40mg, about 50mg, about 75mg, about 100mg, about 150mg, about 200mg, about 250mg or about 500mg.
Herba Andrographis is the dry aerial parts of acanthaceous plant Herba Andrographis (Andrographispaniculata (Burm.F.) Nees), taps, dry when stem and leaf is luxuriant at the beginning of the autumn.Herba Andrographis has another name called Chun Lianqiuliu, Herba Andrographitis, Lan Helian, Radix Gentianae, golden Rhizoma et radix valerianae, Tremella aurantialba Bandoni et Zang hook, India's grass, Herba vallisneriae Spiralis etc.There are heat-clearing and toxic substances removing, antiinflammatory, reducing swelling and alleviating pain effect.Cure mainly bacillary dysentery, urinary tract infection, acute tonsillitis, enteritis, pharyngolaryngitis, pneumonia and influenza etc., external can treat furuncle toxic swelling, trauma infection contamination etc.Main product is in the province such as Guangdong, Fujian, and the ground such as Central China, North China, northwest are also introduced a fine variety.This kind oneself record in the People's Republic of China's 2010 editions pharmacopeia one.
Following chemical composition is comprised: andrographolide (has another name called andrographolide in known Herba Andrographis, Andrographolide), desoxyandrographolide (has another name called dexyandrographolide, deoxyandrographolide), neoandrographolide (has another name called Neoandrographolide, Neoandrographolide), dehydrorographolide (having another name called 14-Deoxy-11,12-didehydro-andrographolide, deoxydidehydroandrographolide).In addition these compounds are also prepared into their derivant by people through structure of modification, such as:
Andrographolide-(deshydroxy, dehydrogenation)-> dehydrorographolide-(two succinic acid esterification, one-tenth alkali metal salt)-> Andrographolide (half K salt) or andrographolide (K-Na salt), their chemical constitution difference is as follows:
For representing medicine, there is the function such as heat-clearing and toxic substances removing, removing heat from blood detumescence with andrographolide (Andrographolide) and derivant such as Andrographolide or andrographolide.It is the principle active component of the conventional creat formulations such as treatment upper respiratory tract infection, acute bacillary dysentery, viral influenza.Early 1970s, domestic beginning, by after the stem and leaf of Herba Andrographis or herb extraction, has made the common oral preparation such as andrographis tablet.Although ordinary preparation has certain inhibitory action to antibacterial, virus county, because its principle active component is water insoluble, power is not enough.
Because andrographolide is the effective ingredient extracted from Herba Andrographis, monomer purity is high, and product quality and pharmacological action comparatively Herba Andrographis have more advantage.The peroral dosage forms such as current SFDA oneself approval production andrographolide tablet, capsule, soft capsule, drop pill.Its shortcoming is andrographolide is diterpenes diterpenoids lactones compound, is insoluble in water, usually only can oral administration.For the demand of viral infection emergency case clinically, introduce different hydrophilic groups by its structure, strengthen its water solublity and be prepared into injection, improve curative effect.In China, start to study andrographolide soluble derivative from the seventies, develop a series of injection, wherein main product is Andrographolide and andrographolide.
Andrographolide is andrographolide through esterification, dehydration, salify and the POTASSIUM DEHYDRO-OGRAPHOLIDE SUCCINATE made; Andrographolide is then by the reaction of Andrographolide and sodium hydroxide or carbonic acid (hydrogen) sodium and the dehydroandrograpolide succinate natrium potassium salt obtained; Be widely used in the viral diseases such as treatment high heat, respiratory tract infection, child's rotavirus enteritis, mumps clinically, be one of Emergency department in hospital of TCM (room) indispensable pure Chinese medicinal preparation, broken traditional saying that Chinese medicine can only be used for treating chronic disease.Current Andrographolide oneself record in Pharmacopoeia of People's Republic of China (two).In recent years, along with the extensive use of this medicine, its untoward reaction happens occasionally.Circulated a notice of in recent years according to national drug adverse reaction monitoring center, about the main adverse reaction of Andrographolide or potassium sodium dehydroandroan drographolide succinate injection is anaphylactic reaction and thrombocytopenia.The main reason that concrete analysis untoward reaction produces has (1) individual variation (allergic constitution) to cause; (2) andrographolide poor stability, the oxidation of ester hydrolysis in easily occurring, open loop, isomerization and unsaturated bond.(3) purity of initial feed (andrographolide) is not high, major impurity is macromolecule plant albumen, andrographolide hydrolysis, oxidation product and pigment etc., bibliographical information activated carbon decolorizing, carry out ultrafiltration with the ultrafilter membrane of molecular interception amount 5000 after the LD50 of mice single intravenous injection can be brought up to 910mg/kg from 757mg/kg; (4) andrographolide causes unstable product quality because production technology is unstable in the process of esterification, dehydration.In sum, although it is inevitable that this characteristic of Chinese medicine determines the untoward reaction more or less of the kind such as Andrographolide or andrographolide, it is also a undisputable fact that purity of improving the quality of products can increase substantially product clinical safety.
In the present invention, the content of injection compounds of formula I of the present invention and related substance, and the content of crude drug and related substance, High Performance Liquid Chromatographv (for example, see Chinese Pharmacopoeia version in 2010 two annex V D) all can be adopted to measure, or adopt spectrophotometry.In the assay method of an exemplary-amounts and related substance, concrete as follows [HPLC method A] all can be adopted to carry out (in the context of the present invention, if not otherwise indicated, measuring content and/or the related substance of Andrographolide in various goods).
[HPLC method A]:
Measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D);
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; With 0.05% potassium dihydrogen phosphate (with phosphoric acid adjust ph to 2.5 ± 0.05)-methanol (3:7) for mobile phase; Determined wavelength is 251nm.Number of theoretical plate calculates by dehydroandrograpolide succinate peak and is not less than 3000;
Determination: get this product and be about 10mg, accurately weighed, put in 100ml measuring bottle, add mobile phase and dissolve and be diluted to scale, shake up, precision measures 10 μ l, note people chromatograph of liquid, record chromatogram; Separately get dehydroandrograpolide succinate reference substance, be measured in the same method.By external standard method with the content of dehydroandrograpolide succinate (C28H36O10) in calculated by peak area test sample, be multiplied with 1.072, obtain final product;
Relate to the determination of related substances method of Andrographolide raw material: get this product in right amount, add mobile phase and dissolve and dilute the solution made containing 0.4mg in every 1ml, as need testing solution; Precision measures in right amount, makes the solution in contrast solution of every 1ml containing 8 μ g with mobile phase dilution.According to above-mentioned chromatographic condition, get contrast solution 10 μ l, injection liquid chromatography, regulate detection sensitivity, make the peak height of main constituent chromatographic peak be about 10% of full scale; Precision measures need testing solution and each 10 μ l of contrast solution, respectively injection liquid chromatography, and record chromatogram is to 4 times of main constituent peak retention time; In the chromatogram of need testing solution, if any impurity peaks, each impurity peak area and contrast solution main peak area (2.0%) must not be greater than;
Relate to the determination of related substances method of Chuanhuning preparation such as Andrographolide powder pin: the content got under content uniformity item is appropriate, add mobile phase and dissolve and dilute the solution made containing Andrographolide 0.4mg in every 1ml, as need testing solution; Precision measures in right amount, quantitatively dilutes the solution solution in contrast made containing Andrographolide 8 μ g in every 1ml with mobile phase.According to above-mentioned chromatographic condition, get contrast solution 10 μ l, injection liquid chromatography, regulate detection sensitivity, make the peak height of main constituent chromatographic peak be about 10% of full scale; Precision measures need testing solution and each 10 μ l of contrast solution, respectively injection liquid chromatography, and record chromatogram is to 4 times of main constituent peak retention time; If any impurity peaks in the chromatogram of need testing solution, each impurity peak area and 2 times (4.0%) of contrast solution main peak area must not be greater than.
In addition, the specific impurity in the literature method of following Yang Lei etc. (the method can be described as in the present invention [HPLC method B]) the mensuration present composition can also be adopted, i.e. impurity 1 and impurity 2: Yang Lei, Kong Yao, Yuan Jun, HPLC measure the related substance in potasium dehydroandrographolisuccinate succinate injection, West China pharmaceutical journal, 2012,27 (4): 445 ~ 446.Wherein impurity 1 and impurity 2 can position with reference to the relative retention time recorded in above-mentioned document (qualitative).
In the context of the present invention, as do not illustrated especially in addition, when the Andrographolide content measured in various compositions or crude drug and related substance total amount, use [HPLC method A]; And when the specific impurity measured in various compositions or crude drug and impurity 1 and impurity 2 content, use [HPLC method B].
In the present invention, formula I, and their standard substance, all can buy from market, or adopt method preparation disclosed in prior art.
Compositions provided by the invention can be used for the treatment of the disease of viral pneumonia, viral upper respiratory tract infection effectively.
Detailed description of the invention
Following examples further illustrate the present invention, instead of restriction the present invention.In example below.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 compositions completely according to existing knowledge.
Prepare in the example of various compositions such as injection below, the preparative-scale of every batch sample is 1000ml, and the amount of the formula I comprised in every bottle is 100mg (in each example, listed formula is the amount of 1 bottle of content); Although there is the product of multiple packing specification in existing product, such as there are 20mg/ bottle, 40mg/ bottle, 200mg/ bottle, those skilled in the art easily obtain the product of above-mentioned multiple loading amount specification by the formula of above-mentioned 100mg/ bottle, such as when medicinal liquid is dispensed in vial, every bottle doubles subpackage medicinal liquid, easily can obtain the product of the loading amount specification of 200mg/ bottle.Prepare in the example of various compositions below, in dosing process, use pH adjusting agent (1M sodium hydroxide solution or 1M hydrochloric acid solution) to regulate medicinal liquid to pH value in the scope of 7.0-7.5 if desired.
a, test method example part
test example 1: measure the remaining rate after the placement of each injection liquor high-temperature sample
In this test example, the injection measuring each test gained is placed after 6 months under 40 ° of C, content [40 ° of C of its compounds of formula I, June, can be described as high temperature average content, mg/ml, measure the meansigma methods of 10 bottles] under 20 ° of C, content [20 ° of C of corresponding time up-to-date style I are processed relative to this sample, June, can be described as room temperature average content, mg/ml, measure the meansigma methods of 10 bottles] percent, it can be regarded as remaining percent (%), and namely available following formula calculates:
Wherein, high temperature average content (mg/ml) and room temperature average content (mg/ml) are that sample measures and the content (averages of 10 bottles) of the formula I calculated through [HPLC method A], the situation of change of active component in the size reflection injection of this remaining percent (%), remaining percent (%) larger (more leveling off to 100%) then injection after high-temperature process, wherein active component maintenance is more, stability is better.
test example 2: measure the related substance changing value after the placement of each injection liquid samples high temperature
In this test example method, after the injection measuring each test gained with [HPLC method A] places 6 months under 40 ° of C, wherein amount [40 ° of C of total related substance, June, can be described as high temperature related substance, represent with %, measure the meansigma methods of 10 bottles] amount [20 ° of C of total related substance when processing the corresponding time relative to this sample under 20 ° of C, June, can be described as room temperature related substance, represent with %, measure the meansigma methods of 10 bottles] difference, it can be regarded as total related substance changing value (%), or can be described as total related substance changing value (%), namely available following formula calculates:
Total related substance changing value (%)=high temperature related substance (%)-room temperature related substance (%)
For the product being similar to the present composition, the Andrographolide raw material that version two in 2010 is recorded and Potassium DehydroandrograpolidSuccinate Succinate for Injection (powder pin) related substance limit are respectively 2% and 4%, injection of the present invention can refer to the restriction of injectable powder, such as, specify that the restriction of total related substance should lower than 4%.
The situation of change of total impurities in the size reflection injection of above-mentioned related substance changing value (%), the larger then injection of related substance changing value (%) after high-temperature process in injection total impurities amount more, stability is poorer.Because related substance changing value (%) is by above-mentioned formulae discovery, when therefore this value is 1%, it also shows there is larger change; Such as injection total related substance after 20 ° of C place June is 3%, and when after 40 ° of C placement process in June, injection related substance changing value (%) is 1% after measured, these 40 ° of C high-temperature process sample impurity contents just close on the limit of substandard product (>4%).
test example 3: the changing value measuring the specific impurities after the placement of each injection liquid samples high temperature and impurity 1 and impurity 2
In this test example method, after the injection measuring each test gained with [HPLC method B] places 6 months under 40 ° of C, wherein amount [40 ° of C, the June of impurity 1 and impurity 2, can be described as high temperature impurity level, represent with %, measure the meansigma methods of 10 bottles] amount [20 ° of C, the June of impurity 1 and impurity 2 when processing the corresponding time relative to this sample under 20 ° of C, can be described as room temperature impurity level, represent with %, measure the meansigma methods of 10 bottles] percent change, its available following formula calculates:
And following formula:
The situation of change of specific impurities and impurity 1 or impurity 2 in the size reflection injection of above-mentioned impurity percent change (%), the larger then injection of impurity percent change (%) after high-temperature process in injection this impurity level increase more, stability is poorer.
b, preparation example part: the injecta composition of the present invention preparing contained I
preparation example 1, preparation contain the injection of Andrographolide
Formula:
| formula I | 100mg, |
| sodium bicarbonate | 15mg, |
| cys | 5mg, |
| hP-β-CD | 300mg, |
| water for injection | in right amount, 5ml is added to. |
Preparation method:
(a) by alkali metal salt, cysteine or its pharmaceutical salts, cyclodextrin in about 85% water for injection of recipe quantity;
B Andrographolide adds in above-mentioned solution by (), be stirred to dissolve;
C () adds about 0.3% active carbon in solution, stirring and adsorbing 30 minutes, filtering decarbonization;
D () is mended and is added to the full amount of water for injection, check the pH value of solution, regulates the pH value to 7.3 of solution if desired with acid-base modifier; Make medicinal liquid 0.4 μm and 0.22 μm of filtering with microporous membrane, be dispensed into by medicinal liquid in vial, sealing, 115 ° of C pressure sterilizing 30min, to obtain final product.
The sample of this preparation example 1 can referred to as Ex1-01 in the present invention.
In this preparation example, supplement following preparation process, as a supplement preparation example:
supplement preparation example 1:in different formula, except sodium bicarbonate consumption changes into except the listed consumption of following table the 2nd row (mg is capable), other key element in prescription and preparation technology are all with above-mentioned preparation example 1.In table, the 1st row (No. is capable) is gained injection liquid samples numbering, and the complete of numbering 01 is numbered Eb1-01, and represent and supplement preparation example 1 gained No. 01 injection, the complete of numbering 02 is numbered Eb1-02, also has similar meaning.
| No. | 01 | 02 | 03 | 04 | 05 | 06 |
| mg | 5 | 9 | 12 | 17 | 20 | 25 |
Investigate each sample of above Ex1-01 and Eb1-01 to Eb1-06:
Outward appearance: colourless clear liquid.
According to above, " A, test method example part " method is carried out the stability test of high-temperature treatment and tests, result:
The remaining percent (%) of content: the remaining percent (%) of each sample of Ex1-01, Eb1-03, Eb1-04 is all between 95% ~ 99%, and the remaining percent of such as Ex1-01 is 98.8%; And the remaining percent (%) of each sample of Eb1-01, Eb1-02, Eb1-05, Eb1-06 is all between 75% ~ 88%, the remaining percent of such as both Eb1-01, Eb1-02 is respectively 77.5%, 86.4%;
Total related substance changing value (%): total related substance changing value (%) of each sample of Ex1-01, Eb1-03, Eb1-04 is all between 0.07% ~ 0.21%, and total related substance changing value (%) of such as Ex1-01 is 0.18%; And total related substance changing value (%) of each sample of Eb1-01, Eb1-02, Eb1-05, Eb1-06 is all between 0.86% ~ 1.74%, total related substance changing value (%) of such as both Eb1-01, Eb1-02 is respectively 1.13%, 0.96%.
In addition, after measured, the pH value of each sample of Ex1-01 and Eb1-01 to Eb1-06 before high-temperature process and after high-temperature process is all between 6.8 ~ 7.6, and such as both Ex1-01, Eb1-03 pH value after high-temperature process is respectively 7.13,7.04.
Above result shows, formula of the present invention is when sodium bicarbonate consumption is in 12 ~ 17 weight portions (relative to every 100 weight portion Andrographolide meters) scope, injection of the present invention has good stability, but when sodium bicarbonate consumption departs from above-mentioned scope, even if be all adjusted in the scope of 6.5 ~ 8.0 by the pH value of medicinal liquid, also demonstrate unsafty stability.
supplement preparation example 2:in different formula, except cysteine consumption changes into except the listed consumption of following table the 2nd row (mg is capable), other key element in prescription and preparation technology are all with above-mentioned preparation example 1.In table, the 1st row (No. is capable) is gained injection liquid samples numbering, and the complete of numbering 01 is numbered Eb2-01, and represent and supplement preparation example 2 gained No. 01 injection, the complete of numbering 02 is numbered Eb2-02, also has similar meaning.
| No. | 01 | 02 | 03 | 04 | 05 | 06 |
| mg | 0 | 1 | 3 | 7 | 10 | 15 |
Investigate each sample of above Eb2-01 to Eb2-06:
Outward appearance: colourless clear liquid.
According to above, " A, test method example part " method is carried out the stability test of high-temperature treatment and tests, result:
The remaining percent (%) of content: the remaining percent (%) of each sample of Eb2-03, Eb2-04 is all between 97% ~ 99%, and the remaining percent of such as Eb2-03 is 98.6%; And the remaining percent (%) of each sample of Eb2-01, Eb2-02, Eb2-05, Eb2-06 is all between 71% ~ 89%, the remaining percent of such as both Eb2-01, Eb1-02 is respectively 71.3%, 84.6%;
Total related substance changing value (%): total related substance changing value (%) of each sample of Eb2-03, Eb2-04 is all between 0.11% ~ 0.20%, and total related substance changing value (%) of such as Eb2-03 is 0.17%; And total related substance changing value (%) of each sample of Eb2-01, Eb2-02, Eb2-05, Eb2-06 is all between 0.7% ~ 2.7%, total related substance changing value (%) of such as both Eb2-01, Eb2-02 is respectively 2.64%, 1.26%.
In addition, after measured, the pH value of each sample of Eb2-01 to Eb2-06 before high-temperature process and after high-temperature process is all between 6.8 ~ 7.6, and such as both Eb2-01, Eb2-02 pH value after high-temperature process is respectively 7.06,6.94.
Above result shows, formula of the present invention is when Cys consumption is in 3 ~ 7 weight portions (relative to every 100 weight portion Andrographolide meters) scope, injection of the present invention has good stability, but when Cys consumption departs from above-mentioned scope, even if be all adjusted in the scope of 6.5 ~ 8.0 by the pH value of medicinal liquid, also demonstrate unsafty stability.
supplement preparation example 3:carry out according to preparation example 1, unlike the L-cysteine hydrochloride, DL-cysteine, D-Cys, the DL-cysteine hydrochloride that Cys are wherein replaced with respectively equivalent, obtain four samples and be designated as Eb3-01 to Eb3-04 respectively; Carry out according to preparation example 1, unlike the L-cysteine hydrochloride, DL-cysteine, D-Cys, the DL-cysteine hydrochloride that Cys are wherein replaced with respectively 3 weight portions (relative to every 100 weight portion Andrographolide meters), obtain four samples and be designated as Eb3-05 to Eb3-08 respectively; Carry out according to preparation example 1, unlike the L-cysteine hydrochloride, DL-cysteine, D-Cys, the DL-cysteine hydrochloride that Cys are wherein replaced with respectively 7 weight portions (relative to every 100 weight portion Andrographolide meters), obtain four samples and be designated as Eb3-09 to Eb3-12 respectively.
Investigate each sample of above Eb3-01 to Eb3-12:
Outward appearance: colourless clear liquid.
According to above, " A, test method example part " method is carried out the stability test of high-temperature treatment and tests, result:
The remaining percent (%) of content: the remaining percent (%) of each sample of Eb3-01 to Eb3-12 is all between 76% ~ 87%, and the remaining percent of such as Eb3-01, Eb3-05 is respectively 86.6% and 82.3%;
Total related substance changing value (%): total related substance changing value (%) of each sample of Eb3-01 to Eb3-12 is all between 0.81% ~ 2.25%, and total related substance changing value (%) of such as Eb3-03 is 1.57%.
In addition, after measured, the pH value of each sample of Eb3-01 to Eb3-12 before high-temperature process and after high-temperature process is all between 6.8 ~ 7.6.
Above result shows, formula of the present invention is when Cys consumption is within the scope of 3 ~ 7 relative weight parts, injection of the present invention has good stability, but when using the cysteine of other form of a great deal of instead, even if the pH value of medicinal liquid is all adjusted in the scope of 6.5 ~ 8.0, also demonstrate unsafty stability, such as active medicine content when high-temperature process obviously reduces, and total impurities increases obviously.
supplement preparation example 4:in different formula, except cyclodextrin consumption changes into except the listed consumption of following table the 2nd row (mg is capable), other key element in prescription and preparation technology are all with above-mentioned preparation example 1.In table, the 1st row (No. is capable) is gained injection liquid samples numbering, and the complete of numbering 01 is numbered Eb4-01, and represent and supplement preparation example 4 gained No. 01 injection, the complete of numbering 02 is numbered Eb4-02, also has similar meaning.
| No. | 01 | 02 | 03 | 04 | 05 | 06 |
| mg | 0 | 100 | 200 | 400 | 500 | 600 |
Investigate each sample of above Eb4-01 to Eb4-06:
The each sample colourless clear liquid of outward appearance: Eb4-03 to Eb4-06, Eb4-01 and Eb4-02 has obvious muddiness, shows there is the phenomenon of not exclusively dissolving without active component during cyclodextrin.
The each sample of Ex1-01, Eb4-03 to Eb4-06 is after experience " 0 ° of C × 24hr->25 ° C × 24hr " is disposed for 10 times repeatedly, Ex1-01, Eb4-03 and Eb4-04 show original colourless clear liquid, but Eb4-05 and Eb4-06 that surprisingly Cyclodextrin consumption is excessive obviously has precipitation.When the amount of display cyclodextrin is 200 ~ 400 weight portions (relative to every 100 weight portion Andrographolide meters), the molding of medicine and physical stability are highly profitable.
According to above, " A, test method example part " method is carried out the stability test of high-temperature treatment and tests, result:
The remaining percent (%) of content: the remaining percent (%) of each sample of Eb4-03 to Eb4-06 is all between 97% ~ 99%, and the remaining percent of such as Eb4-04 is 98.2%; And the remaining percent (%) of each sample of Eb4-01, Eb4-02 is all between 78% ~ 86%, the remaining percent of such as Eb4-01 is respectively 79.6%;
Total related substance changing value (%): total related substance changing value (%) of each sample of Eb4-03 to Eb4-06 is all between 0.04% ~ 0.25%, and total related substance changing value (%) of such as Eb4-05 is 0.22%; And total related substance changing value (%) of each sample of Eb4-01, Eb4-02 is all between 0.6% ~ 1.3%, total related substance changing value (%) of such as Eb4-01 is 1.24%.
In addition, after measured, the pH value of each sample of Eb4-01 to Eb4-06 before high-temperature process and after high-temperature process is all between 6.9 ~ 7.7.
supplement preparation example 5:carry out according to preparation example 1, following 6 kinds of cyclodextrin unlike HP-β-CD wherein being replaced with respectively equivalent: TM-β-CD, DM-β-CD, hydroxyethyl-β-cyclodextrin, sulphur methyl ether-beta-schardinger dextrin-, sulfobutyl ether-beta-cyclodextrin, malt sugar group-beta-cyclodextrin, obtain 6 samples and are designated as Eb5-01 to Eb5-06 respectively; Carry out according to preparation example 1, following 6 kinds of cyclodextrin unlike HP-β-CD wherein being replaced with respectively 200 weight portions (relative to every 100 weight portion Andrographolide meters): TM-β-CD, DM-β-CD, hydroxyethyl-β-cyclodextrin, sulphur methyl ether-beta-schardinger dextrin-, sulfobutyl ether-beta-cyclodextrin, malt sugar group-beta-cyclodextrin, obtain 6 samples and be designated as Eb5-07 to Eb5-12 respectively;
Carry out according to preparation example 1, following 6 kinds of cyclodextrin unlike HP-β-CD wherein being replaced with respectively 400 weight portions (relative to every 100 weight portion Andrographolide meters): TM-β-CD, DM-β-CD, hydroxyethyl-β-cyclodextrin, sulphur methyl ether-beta-schardinger dextrin-, sulfobutyl ether-beta-cyclodextrin, malt sugar group-beta-cyclodextrin, obtain 6 samples and be designated as Eb5-13 to Eb5-18 respectively.
Investigate each sample of above Eb5-01 to Eb5-18:
Outward appearance: colourless clear liquid; Each sample, after experience " 0 ° of C × 24hr->25 ° C × 24hr " is disposed for 10 times repeatedly, all shows original colourless clear liquid state.
According to above, " A, test method example part " method is carried out the stability test of high-temperature treatment and tests, result:
The remaining percent (%) of content: the remaining percent (%) of each sample of Eb5-01 to Eb5-18 is all between 96% ~ 99%, and the remaining percent of such as Eb5-01, Eb5-05 is respectively 98.6% and 97.3%;
Total related substance changing value (%): total related substance changing value (%) of each sample of Eb5-01 to Eb5-18 is all between 0.11% ~ 0.35%, and total related substance changing value (%) of such as Eb5-03 and Eb5-12 is respectively 0.27% and 0.21%.
In addition, after measured, the pH value of each sample of Eb5-01 to Eb5-18 before high-temperature process and after high-temperature process is all between 6.8 ~ 7.6.
According to above, " A, test method example part " method carries out the stability test of high-temperature treatment, and measures the changing value of the specific impurities after the placement of each injection liquid samples high temperature and impurity 1 and impurity 2 with [HPLC method B], result:
Impurity 1 percent change (%): impurity 1 percent change (%) of each sample of Eb5-01 to Eb5-18 all reaches 183% ~ 266%, impurity 1 percent change (%) of each sample of such as Eb5-04, Eb5-13 is respectively 183.7% and ~ 238%.But sample Ex1-01, Eb1-03, Eb1-04, Eb2-03, Eb2-04, Eb4-03 and the Eb4-04 with feature of the present invention of preparing above, their impurity 1 percent change (%) is all 23% ~ 56%, and impurity 1 percent change (%) of each sample of such as Ex1-01, Eb2-04 is respectively 33.2% and 28.4%.
Impurity 2 percent change (%): impurity 2 percent change (%) of each sample of Eb5-01 to Eb5-18 all reaches 168% ~ 251%, impurity 2 percent change (%) of each sample of such as Eb5-03, Eb5-11 is respectively 193% and ~ 214%.But sample Ex1-01, Eb1-03, Eb1-04, Eb2-03, Eb2-04, Eb4-03 and the Eb4-04 with feature of the present invention of preparing above, their impurity 2 percent change (%) is all 21% ~ 63%, and impurity 2 percent change (%) of each sample of such as Ex1-01, Eb2-03 is respectively 47.4% and 34.1%.Visible, the generation of specific impurities in injection effectively can be suppressed when using specific cyclodextrin.
cyclodextrin investigates test to the lyotropy of Andrographolide:
In 100ml water, add Andrographolide while stirring makes it dissolve, and records meltage (W0) based on the Andrographolide amount can dissolving maximum in this 100ml water time extremely insoluble;
To in above-mentioned solution, add the TM-β-CD of 10g, DM-β-CD, hydroxyethyl-β-cyclodextrin, HP-β-CD, sulphur methyl ether-beta-schardinger dextrin-, sulfobutyl ether-beta-cyclodextrin or malt sugar group-beta-cyclodextrin, stirring makes cyclodextrin, obtains 7 kinds of solution;
Go up respectively in above-mentioned 7 kinds of solution and add Andrographolide while stirring and make it dissolve, record the meltage of the Andrographolide that second time is added time insoluble to Andrographolide, this meltage characterizes cyclodextrin to the solubilizing amount (W1) of Andrographolide;
Andrographolide solubilising percent is calculated: Andrographolide solubilising percent (%)=W1/W0 × 100% with following formula.
Result, the Andrographolide solubilising percent of hydroxyethyl-β-cyclodextrin, sulphur methyl ether-beta-schardinger dextrin-, sulfobutyl ether-beta-cyclodextrin, malt sugar group-beta-cyclodextrin is all 213% ~ 293%, and the Andrographolide solubilising percent of such as malt sugar group-beta-cyclodextrin is 243%; DM-β-CD, TM-β-CD, HP-β-CD, Andrographolide solubilising percent all 83% ~ 146%, the Andrographolide solubilising percent of such as HP-β-CD is 115%.Although as well known to those skilled in the art, cyclodextrin to micromolecular compound have to be played solubilising by clathration and and then improve medicine stability may, but the above results display HP-β-CD is not special ideal for the solubilizing effect of Andrographolide relative to other cyclodextrin, but from the context of the invention, when use HP-β-CD but not other cyclodextrin time significantly effectively can suppress the amount of specific impurities in injection, this is that any theory is all unaccountable.
supplement preparation example 6:control sample preparation and the investigation with commercially available sample thereof
Control sample 1: the injection that formula and method for making according to CN101380302A (Chinese Patent Application No. 2008102305850, Nanyang Pu Kang) description embodiment 1 prepare.
Control sample 2: the injection prepared according to CN101721359A (Chinese Patent Application No. 2009101727544, auxiliary Renhuai Qing Tang) formula described in description [0059] to [0060] section and method for making.
Control sample 3: commercially available product potasium dehydroandrographolisuccinate succinate injection (the accurate word H20046670 of traditional Chinese medicines).
Control sample 4: commercially available product potasium dehydroandrographolisuccinate succinate injection (the accurate word H42023017 of traditional Chinese medicines).
Above control sample 1,2,3,4 respectively according to above " A, test method example part " method carry out the stability test of high-temperature treatment and test, result:
The remaining percent (%) of content: the remaining percent (%) of each sample of control sample 1,2,3,4 is all between 93% ~ 97%, and the remaining percent of such as control sample 1 is 93.4%;
Total related substance changing value (%): total related substance changing value (%) of each sample of control sample 1,2,3,4 is all between 0.83% ~ 1.45%, and total related substance changing value (%) of such as control sample 2 is 1.23.
In addition, after measured, the pH value of control sample 1,2,3,4 each samples before high-temperature process and after high-temperature process is all between 6.8 ~ 7.6.
Above control sample 1,2,3,4 respectively according to above " A, test method example part " method carry out the stability test of high-temperature treatment, and measure the changing value of the specific impurities after the placement of each injection liquid samples high temperature and impurity 1 and impurity 2 with [HPLC method B], result:
Impurity 1 percent change (%): impurity 1 percent change (%) of each sample of control sample 1,2,3,4 all reaches 175% ~ 250%, and impurity 1 percent change (%) of such as control sample 1 is 197%;
Impurity 2 percent change (%): impurity 2 percent change (%) of each sample of control sample 1,2,3,4 all reaches 190% ~ 267%, and impurity 2 percent change (%) of such as control sample 2 is 241%;
preparation example 2, preparation contain the injection of Andrographolide
Formula:
| formula I | 100mg, |
| sodium bicarbonate | 12mg, |
| cys | 7mg, |
| hP-β-CD | 200mg, |
| acid-base modifier, in right amount | adjust ph 7.0, |
| water for injection | in right amount, 5ml is added to. |
Preparation method: the method with reference to preparation example 1 is carried out.
preparation example 3, preparation contain the injection of Andrographolide
Formula:
| formula I | 100mg, |
| sodium bicarbonate | 17mg, |
| cys | 3mg, |
| hP-β-CD | 400mg, |
| acid-base modifier, in right amount | adjust ph 7.5, |
| water for injection | in right amount, 5ml is added to. |
Preparation method: the method with reference to preparation example 1 is carried out.
preparation example 4, preparation contain the injection of Andrographolide
Formula:
| formula I | 100mg, |
| sodium bicarbonate | 15mg, |
| cys | 5mg, |
| hP-β-CD | 300mg, |
| acid-base modifier, in right amount | adjust ph 7.2, |
| water for injection | in right amount, 10ml is added to. |
Preparation method: the method with reference to preparation example 1 is carried out.
preparation example 5, preparation contain the injection of Andrographolide
Formula:
| formula I | 100mg, |
| sodium bicarbonate | 15mg, |
| cys | 5mg, |
| hP-β-CD | 300mg, |
| acid-base modifier, in right amount | adjust ph 7.2, |
| water for injection | in right amount, 3.33ml is added to. |
Preparation method: the method with reference to preparation example 1 is carried out.
Inventor has the injection of feature of the present invention to preparation above, comprise Ex1-01, Eb1-03, Eb1-04, Eb2-03, Eb2-04, Eb4-03, Eb4-06, preparation example 2, preparation example 3, preparation example 4, preparation example 5 each sample, measure according to reference to the method under Chinese Pharmacopoeia version in 2010 two " Potassium DehydroandrograpolidSuccinate Succinate for Injection " items, result indices all meets standards of pharmacopoeia prescribed limit.Particularly, these samples seal preservation after 24 months at shady and cool dry place, measure related substance according to [HPLC method A] and be all less than 0.43%, and content is all in 96% ~ 105% scope of labelled amount, impurity 1 and impurity 2 are when 0 month and 24 months all lower than 0.11%, and the pharmaceutical composition showing these injection forms of the present invention has good property thing such as physical stability and chemical stability.
Claims (13)
1. a pharmaceutical composition for solution-type, wherein comprises: Andrographolide, sodium bicarbonate, Cys, HP-β-CD and water for injection; Wherein the weight ratio of Andrographolide and sodium bicarbonate is 100:(12 ~ 17), the weight ratio of Andrographolide and Cys is 100:(3 ~ 7); The weight ratio of Andrographolide and HP-β-CD is 100:(200 ~ 400); Andrographolide concentration is in the solution 0.1 ~ 10%.
2. pharmaceutical composition according to claim 1, wherein the weight ratio of Andrographolide and Cys is 100:(4 ~ 6).
3. pharmaceutical composition according to claim 1, wherein the weight ratio of Andrographolide and Cys is 100:5.
4. pharmaceutical composition according to claim 1, wherein Andrographolide concentration is in the solution 0.5 ~ 5%.
5. pharmaceutical composition according to claim 1, wherein Andrographolide concentration is in the solution 1 ~ 3%.
6. pharmaceutical composition according to claim 1, wherein in the Andrographolide of every 100 weight portions, the amount of HP-β-CD is 250 ~ 350 weight portions.
7. pharmaceutical composition according to claim 1, wherein in the Andrographolide of every 100 weight portions, the amount of HP-β-CD is 280 ~ 320 weight portions.
8. pharmaceutical composition according to claim 1, wherein in the Andrographolide of every 100 weight portions, the amount of HP-β-CD is 300 weight portions.
9. pharmaceutical composition according to claim 1, wherein Andrographolide concentration is in the solution 1.5 ~ 2.5%.
10. pharmaceutical composition according to claim 1, wherein Andrographolide concentration is in the solution 2%.
11. pharmaceutical compositions according to claim 1, wherein also comprise acid-base modifier.
12. pharmaceutical compositions according to claim 1, this pharmaceutical composition is solution-type pharmaceutical composition, and its pH value is 6.5 ~ 8.0.
13. methods preparing pharmaceutical composition described in any one of claim 1-12, it comprises the following steps:
A sodium bicarbonate, Cys, HP-β-CD are dissolved in appropriate water for injection by ();
B Andrographolide adds in above-mentioned solution by (), be stirred to dissolve;
C () adds 0.1 ~ 0.5% active carbon in solution, stirring and adsorbing 30 minutes, filtering decarbonization;
D () is mended and is added to the full amount of water for injection, check the pH value of solution, regulates in pH value to 6.5 ~ 8.0 scope of solution with acid-base modifier; Make medicinal liquid 0.4 μm and 0.22 μm of filtering with microporous membrane, be dispensed into by medicinal liquid in vial, sealing, 115 DEG C of pressure sterilizing 30min, to obtain final product.
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| CN101697959A (en) * | 2009-11-06 | 2010-04-28 | 山西大学 | Potassium sodium dehydroandrographolide succinate and sodium chloride injection and preparation method thereof |
| CN101721359A (en) * | 2009-11-27 | 2010-06-09 | 河南辅仁怀庆堂制药有限公司 | Potassium dehydroandrogrpholide succinate injection and preparation method thereof |
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| CN103330682A (en) | 2013-10-02 |
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