CN101829051B - 1'-acetoxychavicol acetate injection - Google Patents
1'-acetoxychavicol acetate injection Download PDFInfo
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- CN101829051B CN101829051B CN2010101874669A CN201010187466A CN101829051B CN 101829051 B CN101829051 B CN 101829051B CN 2010101874669 A CN2010101874669 A CN 2010101874669A CN 201010187466 A CN201010187466 A CN 201010187466A CN 101829051 B CN101829051 B CN 101829051B
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- injection
- aca
- acetoxychavicol acetate
- acid
- castor oil
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Abstract
The invention discloses a 1'-acetoxychavicol acetate injection which is prepared from 1'-acetoxy chavicol acetic ester, absolute ethyl alcohol, a polyoxyethylene castor oil derivative and acid and used for intravenous injection. The injection has stable quality and no obvious irritation, anaphylaxis and hemolytic reaction, and a physiological saline solution and a 5 percent glucose solution diluent of 100 times of the injection have stable quality after being placed for 8 hours at room temperature. Compared with 1'-acetoxychavicol acetate, the injection has no obvious changes in the aspects of HIV (Human Immunodeficiency Virus) resistant effect and acute toxicity test results.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, more particularly, relate to 1 '-acetoxychavicol acetate injection and preparation method thereof.
Background technology
The English 1 '-acetoxychavicol acetate (ACA) by name of 1 '-acetoxychavicol acetate, molecular formula is C
13H
14O
4, molecular weight is 234.25, structural formula does
Chinese patent ZL031308767 report has the duplicate effect of the HIV-1 NL43 of inhibition the MT-4 cell from 1 '-acetoxychavicol acetate of the dry rhizome Rhizoma Alpiniae Galangae extraction separation purification of Zingiberaceae Zingiberaceae Alpinia plants Fructus Galangae Alpinia galanga Willd.; And the MT-4 cell survival is not had influence; Show tight security and the characteristics that suppress the external migration of HIV Rev pyrenoids, have significant anti-HIV-1 infection activity as the Rev protein inhibitor.
Also have the research report to show that 1 '-acetoxychavicol acetate has antitumor (Moffatt J, A, etal. [J] .Carcinogenesis, 2000,21:2151-2157; Zheng Q et al. [J] .J Cancer ResClin Oncol, 2002,128:539～546), antibacterium (Janssen A M; [J] .plantaMed, 507～511), antifungal (Ficker C E, et al. [J] .JEthnophamacal 1985 (6):; 2003,85:589～593), antiulcer (Mitsuis, et al. [J] .Chem PhamBull; 1976,24:2377～2382), antioxidation (Kubota K, et al. [J] .Spec Publ R SocChem; 2001,274:601～607), antiinflammatory (Nakamura Y, [J] .Cancer Res; 1998,58:4832～4839) etc. biological activity discovers also that in recent years it has the tuberculosis activity.
The Another application of 1 '-acetoxychavicol acetate is to be used for food industry.Result of study shows that 1 '-acetoxychavicol acetate is a kind of antioxidant, and has good antioxygenic property, antioxidant effect even also better than the antioxidant of some synthetic.Because it is a kind of crude; Antioxidant than synthetic is safer, reliable, and therefore, 1 '-acetoxychavicol acetate can be applied in the preservation of food; Replace the existing manual synthetized oxidation preventive agent, as a kind of safe and reliable antioxidant of meat product.
1 '-acetoxychavicol acetate still is a kind of material with pungent characteristic, so it also has other a kind of purposes in food industry---as the additive of food (as: beverage, confectionery) and personal care articles (like toothpaste).Experimentation is found (Matsuda, et al.Biorganic & MedicinalChemistry Letters, 2003,13:3197～3202), in alcoholic beverage, adds a small amount of 1 '-acetoxychavicol acetate and can make drinking utensils that better mouthfeel is arranged.For example; Alcohol content is when containing 1 ' of 50mg/kg-acetoxychavicol acetate in 20% the alcoholic beverage; Happy equilibrated effect is made us in burning sensation formation after just obtaining just the drink burning sensation and drinking, and is that 30% beverage has better mouthfeel than alcohol content.And when 1 '-acetoxychavicol acetate content was 160mg/kg in the non-alcoholic drink, this beverage just had the mouthfeel characteristic of alcoholic beverage.It is thus clear that, in beverage, add 1 ' an amount of-acetoxychavicol acetate, can partly even replace the alcoholic content in the beverage fully.In addition; Because the pungent of 1 '-acetoxychavicol acetate is purer; And shorter in the intraoral persistent period than the pungent of Fructus Capsici, so can also be applied in other food (like hard sugar and chewing gum), personal care articles (like toothpaste), make it have the sensation of pungent stimulation.
ACA is almost insoluble in water, and at dehydrated alcohol, methanol is prone in the acetone and other organic solvent dissolve, and therefore desires to be made into injection, and what at first should solve is the ACA solubility.
ACA has dissolubility preferably in dehydrated alcohol; In order to reduce the zest that dehydrated alcohol brings; We once attempted with the solvent of PEG400 instead of part ethanol as ACA, but after finding to add PEG400, solution becomes is muddy; There is ACA to separate out, explains that ACA is difficult for dissolving in PEG400.We attempt again with 1; 2-propylene glycol instead of part ethanol is as the solvent of ACA, but this solution has the ACA crystallization to separate out with 50 times of normal saline dilutions and 100 times diluent room temperature placement 24 hours; Explain 1, the adding of 2-propylene glycol can not improve the stability of ACA normal saline diluent.
ACA is responsive to heat, is prone to oxidized decomposition, and therefore normal saline diluent poor stability considers to add antioxidant, improves medicine stability.Antioxidant to being suitable for screens, and sodium sulfite and sodium pyrosulfite do not dissolve at dehydrated alcohol as a result; The solution that adds 0.1% cysteine hydrochloride heated 1 hour for 100 ℃; Solution colour is become buff and is occurred muddy by faint yellow; Sample is measured after with 0.45 μ m filtering with microporous membrane; It is about 3% that ACA content has descended, and analyzing reason is that the oxidized solution colour that makes of cysteine hydrochloride high temperature is deepened, and the solution muddiness possibly be due to cysteine hydrochloride is separated out; The solution that adds 0.1% ascorbic acid heated 1 hour for 100 ℃; Solution colour is by the faint yellow buff that becomes; Along with the prolongation solution colour of time is more and more darker, analyze reason and be ascorbic acid oxidized due to, the assay result shows that the stability of solution do not improve.
Summary of the invention
For dissolubility and the stability problem that solves ACA, adapt to the requirement of injection, under the situation that does not influence ACA drug effect and safety; The present invention is a crude drug with ACA, is solvent with the dehydrated alcohol, is solubilizing agent with the castor oil derivatives; With acid is stabilizing agent, processes ACA solution, high temperature sterilize; Under logical nitrogen situation, the sterile solution sealing by fusing in ampoule, is processed the ACA injection that injection for intravenous is used.
Technical scheme of the present invention is, gets ACA and is added in the dehydrated alcohol, makes the ACA dissolving; Add acid, mixing adds castor oil derivatives; Mixing; Process ACA solution, 15 minutes sterilization backs of 110 ℃ of 30 minutes or 115 ℃ under the situation of inflated with nitrogen with the sterile solution sealing by fusing in ampoule, process the ACA injection.During use, the ACA injection is injected with 0.9% sodium chloride injection or 5% glucose injection dilution posterior vein.
Can be used for acid of the present invention and include but not limited to lactic acid, glacial acetic acid, citric acid, tartaric acid, malic acid, phosphoric acid, the amount concentration of acid is 0.1mol/L.
The castor oil derivatives that the present invention is used and the volume ratio of dehydrated alcohol are 50: 50,40: 60,30: 70,20: 80,15: 85.
The specification of the ACA injection that the present invention processes is lmg/ml, 3mg/ml, 5mg/ml, 10mg/ml, 15mg/ml, 20mg/ml, 30mg/ml.
The effect that the present invention is useful
1, ACA injection content assaying method
Measure according to HPLC (two appendix VD of Chinese Pharmacopoeia version in 2005).
Chromatographic condition and system suitability test chromatographic column are Yi Lite Hypersil-BDS C
18(250mm * 4.6mm, 5 μ m); Mobile phase is acetonitrile-methanol-water (30: 20: 50); The detection wavelength is 218nm; Flow velocity is 1.0mLmin-1; Column temperature is a room temperature; Sample size is 20 μ L.Theoretical cam curve is calculated by the ACA peak should be lower than 2000.
The algoscopy precision takes by weighing ACA reference substance 10mg, puts in the 50ml measuring bottle, with mobile phase dissolving and be diluted to scale, shakes up, and is prepared into the reference substance stock solution that every lml contains ACA 200 μ g.Precision is measured reference substance stock solution 2.5mL, puts in the 10mL measuring bottle, is diluted to scale with mobile phase, shakes up, and processes the reference substance solution that every lml contains ACA 50 μ g approximately.
Precision is measured ACA injection 0.5mL, puts in the 10mL measuring bottle, is diluted to scale with mobile phase, shakes up, and precision is measured 0.5mL and put in the 5mL measuring bottle, is diluted to scale with mobile phase, shakes up, and processes the need testing solution that every 1ml contains ACA 50 μ g approximately.
Accurate respectively reference substance solution and each 20 μ l of need testing solution of drawing, injecting chromatograph, the record chromatogram, external standard method is calculated content.
2, ACA injection determination of related substances method
The accurate ACA injection 0.5mL that draws puts in the 10mL measuring bottle, is diluted to scale with mobile phase, shakes up, and processes the solution that every 1ml contains ACA 500 μ g approximately, as test liquid.The accurate test liquid 0.5ml that draws puts in the 5ml measuring bottle, is diluted to scale with mobile phase, shakes up, and the accurate 1ml that draws puts in the 10ml measuring bottle, is diluted to scale with mobile phase, shakes up, as contrast liquid.Get contrast liquid 20 μ l injecting chromatographs, the record chromatogram is got test liquid 20 μ l injecting chromatographs again, and 3 times of record chromatogram to main peak retention time desolventize outside the peak, calculate the impurity peaks gross area.
3, ACA injection normal saline, 100 times of diluent room temperatures of 5% glucose solution shelf-stability
Investigate the stability that room temperature is placed behind ACA injection and clinical normal saline commonly used, the 5% glucose compatibility, adopt HPLC to measure medicament contg variation behind the injection compatibility, direct clinical medication.
The result shows that ACA injection normal saline, 100 times of diluent room temperatures of 5% glucose solution are placed 8 hours steady qualities.
4, ACA injection influence factor tests stability
Get same batch of ACA injection, with appearance character, content and related substance are index, investigate it at illumination 4500LX ± 500LX, the stability under 40 ℃ of high temperature and the freeze-thaw cycle condition.
1. high temperature and exposure experiments to light: respectively 40 ℃ and 4500LX ± 500LX illumination condition held 10 days, detect in the 5th day and sampling in the 10th day, the result shows ACA injection steady quality.
2. freezing-thawing test: under-10～-20 ℃ of conditions 2 days, under 40 ℃ of conditions, investigate 2 days then, 3 sub-samplings that circulate detect, and the result shows ACA injection steady quality.
5, ACA injection room temperature long term test stability
3 batches of ACA injection liquid samples of simulation listing packing are placed under (25 ± 2) ℃ condition,, investigate its content and related substance etc. respectively at 3,6,9,12,18,24 months sampling and measuring, and with 0 month relatively.The result shows ACA injection steady quality.
6, the classical constant temperature method of ACA injection is predicted effect duration
By prescription preparation sample solution, measure an amount of dress and be encapsulated in the 1mL ampoule, be divided into 4 groups, place different temperatures held (70,80,90 and 100 ℃).Detect respectively at the different time sampling, prepare by need testing solution compound method under the assay item, sample introduction 20 μ L measure content.
ACA injection content decline basic symbols unification level kinetic model; Get logarithmic formula according to the Arrhenius law: 1gK=-E/2.303RT+1gA; With 1gK 1/T is carried out linear regression; Regression equation 1gK=10.003-4471.14/T, r=0.9999, thus derive ACA injection room temperature (25 ℃) decomposition rate constant K and effect duration is K
25 ℃=1.016 * 10
-5h
-1, t
0.9 25 ℃=1.2y.
Regression equation and the decomposition rate constant of table .ACA injection under different temperatures
7, anti-HIV effect of ACA injection and safety
Results of pharmacodynamic test shows, with ACA relatively, ACA injection of the present invention to the C8166 cytotoxicity, induce the C8166 cell to form the inhibitory action that syncytium and p24 antigen produces to HIV-1 not have significant change.
The acute toxicity tests shows, compares with ACA, and safety of the present invention does not have significant change.
Zest, anaphylaxis, hemolytic result of the test show that ACA injection of the present invention does not have obvious irritation, anaphylaxis and hemolytic reaction.
The specific embodiment
Embodiment 1
ACA 1g
Dehydrated alcohol 700ml
Lactic acid 5ml
Castor oil derivatives 295ml
Process 1000ml
Embodiment 2
ACA 3g
Dehydrated alcohol 700ml
Lactic acid 5ml
Castor oil derivatives 295ml
Process 1000ml
Embodiment 3
ACA 5g
Dehydrated alcohol 700ml
Lactic acid 5ml
Castor oil derivatives 295ml
Process 1000ml
Embodiment 4
ACA 10g
Dehydrated alcohol 700ml
Lactic acid 5ml
Castor oil derivatives 295ml
Process 1000ml
Embodiment 5
ACA 15g
Dehydrated alcohol 700ml
Lactic acid 5ml
Castor oil derivatives 295ml
Process 1000ml
Embodiment 6
ACA 20g
Dehydrated alcohol 700ml
Lactic acid 5ml
Castor oil derivatives 295ml
Process 1000ml
Embodiment 7
ACA 30g
Dehydrated alcohol 700ml
Lactic acid 5ml
Castor oil derivatives 295ml
Process 1000ml
Embodiment 8
ACA 10g
Dehydrated alcohol 800ml
Lactic acid 5ml
Castor oil derivatives 195ml
Process 1000ml
Embodiment 9
ACA 10g
Dehydrated alcohol 600ml
Lactic acid 5ml
Castor oil derivatives 395ml
Process 1000ml
Embodiment 10
ACA 10g
Dehydrated alcohol 500ml
Lactic acid 5ml
Castor oil derivatives 495ml
Process 1000ml
Embodiment 11
ACA 10g
Dehydrated alcohol 850ml
Lactic acid 5ml
Castor oil derivatives 145ml
Process 1000ml
Embodiment 12
ACA 10g
Dehydrated alcohol 700ml
Glacial acetic acid 7ml
Castor oil derivatives 293ml
Process 1000ml
Embodiment 13
ACA 10g
Dehydrated alcohol 700ml
Citric acid 25g
Castor oil derivatives 300ml
Process 1000ml
Embodiment 14
ACA 10g
Dehydrated alcohol 700ml
Tartaric acid 18g
Castor oil derivatives 300ml
Process 1000ml
Embodiment 15
ACA 10g
Dehydrated alcohol 700ml
Malic acid 16g
Castor oil derivatives 300ml
Process 1000ml
Embodiment 16
ACA 10g
Dehydrated alcohol 700ml
Phosphoric acid 5ml
Castor oil derivatives 295ml
Process 1000ml
Claims (1)
1.1 '-acetoxychavicol acetate injection is characterized in that it is by 1 '-acetoxychavicol acetate, dehydrated alcohol, castor oil derivatives and sour the composition; The English of described 1 '-acetoxychavicol acetate is called 1 '-acetoxychavicolacetate, and molecular formula is C
13H
14O
4,
Molecular weight is 234.25, and structural formula is 50: 50,40: 60,30: 70,20: 80 or 15: 85 for the volume ratio of castor oil derivatives in
described injection and dehydrated alcohol consumption; The acid that adds in the said injection is lactic acid, glacial acetic acid, citric acid, tartaric acid, malic acid or phosphoric acid, and the amount concentration of acid is 0.1mol/L; The amount that contains 1 '-acetoxychavicol acetate in every 1ml 1 '-acetoxychavicol acetate injection is 1mg, 3mg, 5mg, 10mg, 15mg, 20mg or 30mg; Described 1 '-acetoxychavicol acetate injection preparation is to get 1 '-acetoxychavicol acetate to be added in the dehydrated alcohol; Make the dissolving of 1 '-acetoxychavicol acetate; Add acid; Mixing adds castor oil derivatives, mixing; 1 '-acetoxychavicol acetate solution of processing under the 15 minutes situation of sterilization back of 110 ℃ of 30 minutes or 115 ℃ at inflated with nitrogen with the sterile solution sealing by fusing in ampoule, process 1 '-acetoxychavicol acetate injection that injection for intravenous is used.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101874669A CN101829051B (en) | 2010-05-31 | 2010-05-31 | 1'-acetoxychavicol acetate injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101874669A CN101829051B (en) | 2010-05-31 | 2010-05-31 | 1'-acetoxychavicol acetate injection |
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| Publication Number | Publication Date |
|---|---|
| CN101829051A CN101829051A (en) | 2010-09-15 |
| CN101829051B true CN101829051B (en) | 2012-09-12 |
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|---|---|---|---|
| CN2010101874669A Expired - Fee Related CN101829051B (en) | 2010-05-31 | 2010-05-31 | 1'-acetoxychavicol acetate injection |
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Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102198096B (en) * | 2011-05-27 | 2012-12-12 | 河南省医药科学研究院 | ACA (acetoxychavicol acetate) submicron emulsion for intravenous injection, and preparation method and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ258044A (en) * | 1992-11-27 | 1995-12-21 | Faulding F H & Co Ltd | Pharmaceutical composition comprising taxol, solubilising agent, an acid and an organic solvent |
| CZ294371B6 (en) * | 2002-06-10 | 2004-12-15 | Pliva - Lachema, A. S. | Stabilized pharmaceutical composition based on polyoxyethylated castor oil and process for preparing thereof |
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