CN103877012A - Asarone injection and preparation process thereof - Google Patents
Asarone injection and preparation process thereof Download PDFInfo
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- CN103877012A CN103877012A CN201310114183.5A CN201310114183A CN103877012A CN 103877012 A CN103877012 A CN 103877012A CN 201310114183 A CN201310114183 A CN 201310114183A CN 103877012 A CN103877012 A CN 103877012A
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Abstract
The invention provides an alpha-Asarone injection, which takes alpha-Asarone (with a chemical name of 2, 4, 5-trimethoxy-1-allylbenzene) as the active component. Polyethylene glycol-12-hydroxystearate is taken as a solubilizing agent, propylene glycol is employed as a cosolvent, and benzyl alcohol is used as a preservative to prepare the injection. The problem that asarone is insoluble in water is effectively solved, and also the safety and stability of the asarone injection are greatly improved. The asarone injection prepared by the invention has good stability, and the preparation process is simple.
Description
Technical field
The present invention relates to field of medicine preparations, especially relate to injection and the preparation technology thereof of asarone.
Background technology
Alpha-ararin chemistry Alpha-Asaronum by name, is one of main effective ingredient of Chinese medicine Rhizoma Acori Graminei, has calmness, convulsion, spasmolytic, relievings asthma, eliminates the phlegm, cough-relieving, blood fat reducing, function of gallbladder promoting, the multiple pharmacological effect such as anticancer; There is inhibitory action in various degree for streptococcus pneumoniae, staphylococcus aureus and colibacillary growth simultaneously.Clinically, asarone has been widely used in the diseases such as treatment upper respiratory tract infection, bronchitis, bronchial asthma, acute and chronic cholecystitis, cholelithiasis, epilepsy grand mal, especially for example, has remarkable result for the treatment of pneumonia, bronchial asthma and chronic obstructive pulmonary disease (chronic obstructive pulmonary disease, COPD) acute attack.Nineteen eighty-two, Liuzhou pharmaceutical factory manually successfully synthesized alpha-ararin first at home, and made Tablet and Capsula agent and put on market.
Asarone and the compound of hydrophilic extreme difference extremely strong as lipotropy, the Tablet and Capsula of the asarone of listing at present, due to its water solublity extreme difference, oral rear difficult dispersion and stripping, while contact with body fluid, effective ratio area is little, for example common oral preparation bioavailability is only 2-5%, cannot realize the therapeutic effect of expection at all.Prior art adopts various ways to prepare the injection of asarone, but there is number of drawbacks, for example CN1290495C discloses employing alpha-ararin, add oil, emulsifying agent, water for injection make fat micro sphere preparation, complex process, cost is high, and the parcel of longer-term storage lipoid microsphere easily breaks to produce and leaks, and is unfavorable for injection; CN1657071A adopts water and organic solvent dissolution asarone, makes lyophilized formulations, redissolution weak effect before lyophilized powder injection, and generation is muddy, and impact is used.
In active medicinal matter, major part is insoluble in the fat-soluble medicine of water, brings a lot of inconvenience to preparation preparation process and clinical practice, also the performance of drug effect is brought to many harmful effects, is even difficult to be prepared into rational preparation.In order to solve problems, one of comparatively conventional method is, with surfactant, medicine is carried out to solubilising.
In order to improve its curative effect, research worker, by adding certain surface activating agent, increases asarone dissolubility in water, has made Asarone injection liquid.But some surfactant may cause existing serious potential safety hazard for injection, for example: CN1313086C discloses employing Tween 80 and dissolved asarone as solubilizing agent, those skilled in the art answer heightened awareness to the great mass of data of Tween 80 safety research being shown to Tween 80 has certain Secure Application scope both at home and abroad, as to dog, rabbit, cat and monkey intravenous injection Tween 80 all can cause Blood pressure drop (the especially systolic pressure of dog of a property crossed, diastolic pressure, average pulse pressure significantly reduces) (Wang Qingli, the safety research progress toxicology magazine 2006 of Peng Jian Tween 80, 20 (4): 262-264 page), therefore be difficult to determine whether said preparation causes even more serious impact to human body, meanwhile, described product, owing to containing more Tween 80, causes product lyophilizing incomplete, and outward appearance is not good, and more serious consequence is to redissolve weak effect after lyophilizing, is unfavorable for practical clinical.
For addressing the above problem, the invention provides a kind of Asarone injection, this injection adopts HS15 (also referred to as " HS15 ", polyoxyethylene-660-12-hydroxy stearate, trade name Solutol HS15) do solubilizing agent, propylene glycol makees cosolvent, and benzyl alcohol cooks antiseptic.First, the literature research of prior art has confirmed that Solutol HS15 has the safety that is much better than Tween 80; Experiment also proves that Pregnant Rabbits intravenous injection contains Tween 80 187.5mg/kg and can cause obvious maternal toxicity, and intravenous injection gives HS15 215mg/kg and has no significant effect.And experiment shows that HS15 can increase the dissolubility of alpha-ararin in water preferably.
Prior art also discloses and has adopted the ejection preparation of HS15 as the asarone of emulsifying agent; the Emulsion of asarone is for example disclosed in patent documentation C101088499A; adopt the emulsifying agent of oil phase, soybean lecithin and the HS15 of soybean oil and median chain triglyceride oil mixture to make Emulsion, and further add freeze drying protectant to make dry emulsion.But the complicated process of preparation of freeze-dried emulsion, the physical stability of manufactured goods is bad, need to 10 ℃ below even freezing state preserve, even if at room temperature place a period of time, emulsion droplet all gradually polymerization break, after redissolution, do not reach the requirement of injection.For example in patent documentation CN101647774B, the Asarone injection of employing HS15 as solubilizing agent disclosed again, after preparing Asarone injection according to the preparation method of embodiment 1, embodiment 2 and embodiment 3, find that this patent system exists major defect for the method for Asarone injection, after being mainly manifested in a large amount of losses (at least losing 10%) of principal agent alpha-ararin in preparation process and losing fluctuate large and sterilizing, clarity is defective, cannot require make qualified medicine according to existing " Chinese Pharmacopoeia " version in 2010.For example patent documentation CN102973499A(and this patent are same applicant again) in disclose and adopted the Asarone injection of HS15 as solubilizing agent, after preparing Asarone injection according to the preparation method of embodiment 1, embodiment 2 and embodiment 3, find that this patent system exists defect for the method for Asarone injection, be mainly manifested in obtain after preparation the long-term examination of Asarone injection liquid after 5 months clarity defective, the effect duration of medicine can only be denoted as 5 months.
The research of prior art shows, the micelle being made up of single surfactant no doubt has obvious effect, but it is high that some poorly water soluble drugs are also existed to dosage of surfactant, preparation viscosity is large, dilution stability is bad, and corresponding preparation toxic and side effects, injection pain, the clinical application bringing requires high problems.The mixed micelle system of the mutual composite formation of surfactant has characteristic of solubilizing and is better than the characteristic of single surfactant solution.Patent documentation CN101138550A has introduced the micelle pharmaceutical preparation that can adopt HS15 and one or more other surfactants, phospholipid etc. to make asaricin.But wherein phospholipid is very easy to oxidation, all need be with nitrogen protection in production, production cost is high; The lysophosphatide producing has very strong toxic and side effects, is must the strict impurity of controlling in injection.
The present invention has overcome above technology prejudice, the aqueous Asarone injection liquid that adopts safety and the higher surfactant HS15 of solubilization-aid effect to make by the aseptic filtration production technology (being aseptic processing) of empirical tests as antiseptic and asarone as cosolvent and benzyl alcohol as solubilizing agent, propylene glycol, the underproof phenomenon of clarity of injection that effectively degerming assurance safety can also avoid Yin Gaowen to cause.The Asarone injection liquid making meets the requirement of existing " Chinese Pharmacopoeia " version in 2010 for injection completely, stable content, and final mean annual increment solution clarity is good.Simultaneously the safety testing Asarone injection liquid that also proved patent system obtains be same applicant according to patent documentation CN102973499A(and this patent) the Asarone injection liquid safety that makes is identical, in safety, this patent product is same applicant with patent documentation CN102973499A(with this patent) product is identical all higher than the existing commercially available Asarone injection liquid product using Tween 80 as solubilizing agent.
Summary of the invention
The present invention is in order to solve multiple security risk and the preparation defect that in prior art, Aarin preparation exists, provide a kind of HS15 (hereinafter to be referred as HS15) that adopts as solubilizing agent, propylene glycol is as cosolvent, and benzyl alcohol is as the ejection preparation of the asarone of antiseptic.
HS15 is a kind of nonionic surfactant, has good biological tolerance and applied range, and is proved to be outstanding solubilizing agent, and the present invention adopts HS15 as solubilizing agent, has following advantages:
Low histamine release---preoperative without using hydryllin and corticoid;
Low haemolysis;
Higher human body safety in utilization, verified its of the literature research of prior art has the safety that is much better than Tween 80;
Higher physiological tolerance;
High solubilising power-make the injection of low capacity high dose become possibility;
Low viscosity, even in the time of high concentration, 30% concentration solution also can painless administration;
Take in the near future Deutscher Arzneibucs (being about to income to US and European pharmacopeia);
The object of the present invention is to provide a kind of injection using asarone as active component and preparation method thereof.
Asarone of the present invention is interpreted as alpha-ararin, but is not limited to this, and β-asarone is suitable for the present invention too.
Injection of the present invention, is characterized in that comprising alpha-ararin, HS15, propylene glycol, benzyl alcohol and pH adjusting agent, and described injection solvent refers to water for injection.
As preferred embodiment, Asarone injection of the present invention, is mainly to comprise 1 part of alpha-ararin based on weight portion meter, 8～12 parts of HS15s, 50 parts of propylene glycol, 2.5 parts of benzyl alcohol and appropriate injection solvent.
Preferred embodiment is to choose the HS15 of 8 parts, 10 parts, 12 parts as solubilizing agent.
Injection of the present invention, described injection solvent refers to water for injection, wherein, the water for injection of full dose: the ratio of alpha-ararin is 1～10: 10 (ml: mg).
Preferred embodiment is the water for injection of full dose: the ratio of alpha-ararin is 2: 8 (ml: mg).
Asarone injection of the present invention can also adopt pharmaceutically acceptable method lyophilizing, makes lyophilized formulations.In described freeze-dry process, can add pharmaceutically acceptable various freeze drying protectant, preferably mannitol.
The technique of preparing alpha-ararin injection of the present invention, comprises the steps:
A, the alpha-ararin that accurately takes recipe quantity, HS15, propylene glycol, measure benzyl alcohol, and preparation pH adjusting agent, seals stand-by;
B, measure the water for injection of 50% recipe quantity volume, under the condition of constant temperature to 60～70 ℃, add HS15, stirring and dissolving; Under 60～70 ℃ of conditions, continue to add alpha-ararin, be stirred to dissolve, let cool to room temperature; Add successively propylene glycol, benzyl alcohol, stir;
C, inject water to 95% of recipe quantity volume, be uniformly mixed; Regulate pH to 6.0～6.1, benefit adds to the full amount of water for injection, and mix homogeneously filters, and subpackage, obtains alpha-ararin injection.
In d, above-mentioned steps b, add successively after propylene glycol, benzyl alcohol, also can be in freeze drying protectant: full dose water for injection ratio is that 10: 100 (g: ml) adds freeze drying protectant mannitol, stirring and dissolving; Add to the full amount of water for injection, mix homogeneously, filters, subpackage, and in-40 ℃ of pre-freezes, after 3 hours, evacuation, adopts a sublimed method to obtain alpha-ararin freeze-dried powder.
Asarone injection prepared by above-mentioned technique, has that technique is simple, with low cost, a steady quality, safe, the clinical advantage such as easy to use.
Therefore, the present invention will provide one Asarone injection safely and effectively for disease, particularly pneumonia, bronchial asthma and chronic obstructive pulmonary disease acute attack patients such as upper respiratory tract infection, bronchitis, bronchial asthma, acute and chronic cholecystitis, cholelithiasis, epilepsy grand mal.
The specific embodiment
embodiment 1(1 part of the alpha-ararin based on weight portion meter, HS15 is 8 parts, propylene glycol is 50 parts, 2.5 parts of benzyl alcohol are unsterilised)
Take 4g alpha-ararin, 32g HS15,200g propylene glycol, seal stand-by; Measure the sealing of 10ml benzyl alcohol stand-by; With the hydrochloric acid solution of concentrated hydrochloric acid preparation 0.01mol/L, seal stand-by; Measure 500ml water for injection, under 60 ℃ of water bath condition, add 32g HS15, stirring and dissolving; Under 60 ℃ of water-baths, add 4g alpha-ararin, be stirred to dissolve, let cool to room temperature; Add successively 200g propylene glycol and 10ml benzyl alcohol, stir; Inject water to 950ml, be uniformly mixed; With 0.01mol/L hydrochloric acid solution adjusting pH to 6.05, mend the 1000ml that adds to the full amount of water for injection, mix homogeneously, first through 0.45 μ m filtering with microporous membrane, then through 0.22 μ m filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, leak detection, obtains alpha-ararin injection.
embodiment 2(1 part of the alpha-ararin based on weight portion meter, HS15 is 10 parts, propylene glycol is 50 parts, 2.5 parts of benzyl alcohol are unsterilised)
Take 4g alpha-ararin, 40g HS15,200g propylene glycol, seal stand-by; Measure the sealing of 10ml benzyl alcohol stand-by; With the hydrochloric acid solution of concentrated hydrochloric acid preparation 0.01mol/L, seal stand-by; Measure 500ml water for injection, under 60 ℃ of water bath condition, add 40g HS15, stirring and dissolving; Under 60 ℃ of water-baths, add 4g alpha-ararin, be stirred to dissolve, let cool to room temperature; Add successively 200g propylene glycol and 10ml benzyl alcohol, stir; Inject water to 950ml, be uniformly mixed; With 0.01mol/L hydrochloric acid solution adjusting pH to 6.06, mend the 1000ml that adds to the full amount of water for injection, mix homogeneously, first through 0.45 μ m filtering with microporous membrane, then through 0.22 μ m filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, leak detection, obtains alpha-ararin injection.
embodiment 3(1 part of the alpha-ararin based on weight portion meter, HS15 is 12 parts, propylene glycol is 50 parts, 2.5 parts of benzyl alcohol are unsterilised)
Take 4g alpha-ararin, 48g HS15,200g propylene glycol, seal stand-by; Measure the sealing of 10ml benzyl alcohol stand-by; With the hydrochloric acid solution of concentrated hydrochloric acid preparation 0.01mol/L, seal stand-by; Measure 500ml water for injection, under 60 ℃ of water bath condition, add 48g HS15, stirring and dissolving; Under 60 ℃ of water-baths, add 4g alpha-ararin, be stirred to dissolve, let cool to room temperature; Add successively 200g propylene glycol and 10ml benzyl alcohol, stir; Inject water to 950ml, be uniformly mixed; With 0.01mol/L hydrochloric acid solution adjusting pH to 6.04, mend the 1000ml that adds to the full amount of water for injection, mix homogeneously, first through 0.45 μ m filtering with microporous membrane, then through 0.22 μ m filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, leak detection, obtains alpha-ararin injection.
embodiment 4(1 part of the alpha-ararin based on weight portion meter, HS15 is 10 parts, propylene glycol is 50 parts, 2.5 parts of benzyl alcohol, 2.5 parts, mannitol, freeze-dried powder)
Take 4g alpha-ararin, 40g HS15,200g propylene glycol, seal stand-by; Measure the sealing of 10ml benzyl alcohol stand-by; Measure 500ml water for injection, under 60 ℃ of water bath condition, add 40g HS15, stirring and dissolving; Under 60 ℃ of water-baths, add 4g alpha-ararin, be stirred to dissolve, let cool to room temperature; Add successively 200g propylene glycol, 10ml benzyl alcohol and 10g mannitol, stir; 1000ml adds to the full amount of water for injection, mix homogeneously, first through 0.45 μ m filtering with microporous membrane, then through 0.22 μ m filtering with microporous membrane, subpackage, in-40 ℃ of pre-freezes after 3 hours, evacuation, reaches below 13.33Pa vacuum in drying baker, is slowly warming up to-20 ℃, make the moisture evaporation in medicinal liquid, obtain freeze-dried powder.
Embodiment 4 redissolve effect: embodiment 4 samples long-term place within 7 months, redissolve after clear still.
reference examples 1(1 part of the alpha-ararin based on weight portion meter, HS15 is 8 parts, propylene glycol is 50 parts, 12 parts of ethanol, 100 ℃ of sterilizings in 30 minutes) (patent documentation CN102973499A embodiment 1)
Take 4g alpha-ararin, 32g HS15,200g propylene glycol, seal stand-by; Measure the sealing of 60ml ethanol stand-by; With the hydrochloric acid solution of concentrated hydrochloric acid preparation 0.01mol/L, seal stand-by; Measure 500ml water for injection, under 60 ℃ of water bath condition, add 32g HS15, stirring and dissolving; Under 60 ℃ of water-baths, add 4g alpha-ararin, be stirred to dissolve, let cool to room temperature; Add successively 200g propylene glycol and 60ml ethanol, stir; Inject water to 950ml, be uniformly mixed; With 0.01mol/L hydrochloric acid solution adjusting pH to 6.03, mend and inject water to full 1000ml, mix homogeneously, first through 0.45 μ m filtering with microporous membrane, then through 0.22 μ m filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, through 100 ℃ of sterilizings in 30 minutes, obtains alpha-ararin injection.
reference examples 2(1 part of the alpha-ararin based on weight portion meter, HS15 is 10 parts, propylene glycol is 50 parts, 12 parts of ethanol, 100 ℃ of sterilizings in 30 minutes) (patent documentation CN102973499A embodiment 2)
Take 4g alpha-ararin, 40g HS15,200g propylene glycol, seal stand-by; Measure the sealing of 60ml ethanol stand-by; With the hydrochloric acid solution of concentrated hydrochloric acid preparation 0.01mol/L, seal stand-by; Measure 500ml water for injection, under 60 ℃ of water bath condition, add 40g HS15, stirring and dissolving; Under 60 ℃ of water-baths, add 4g alpha-ararin, be stirred to dissolve, let cool to room temperature; Add successively 200g propylene glycol and 60ml ethanol, stir; Inject water to 950ml, be uniformly mixed; With 0.01mol/L hydrochloric acid solution adjusting pH to 6.08, mend and inject water to full 1000ml, mix homogeneously, first through 0.45 μ m filtering with microporous membrane, then through 0.22 μ m filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, through 100 ℃ of sterilizings in 30 minutes, obtains alpha-ararin injection.
reference examples 3(1 part of the alpha-ararin based on weight portion meter, HS15 is 12 parts, propylene glycol is 50 parts, 12 parts of ethanol, 100 ℃ of sterilizings in 30 minutes) (patent documentation CN102973499A embodiment 3)
Take 4g alpha-ararin, 48g HS15,200g propylene glycol, seal stand-by; Measure the sealing of 60ml ethanol stand-by; With the hydrochloric acid solution of concentrated hydrochloric acid preparation 0.01mol/L, seal stand-by; Measure 500ml water for injection, under 60 ℃ of water bath condition, add 48g HS15, stirring and dissolving; Under 60 ℃ of water-baths, add 4g alpha-ararin, be stirred to dissolve, let cool to room temperature; Add successively 200g propylene glycol and 60ml ethanol, stir; Inject water to 950ml, be uniformly mixed; With 0.01mol/L hydrochloric acid solution adjusting pH to 6.10, mend and inject water to full 1000ml, mix homogeneously, first through 0.45 μ m filtering with microporous membrane, then through 0.22 μ m filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, through 100 ℃ of sterilizings in 30 minutes, obtains alpha-ararin injection.
reference examples 4:made (specification is 2ml:10mg) by CN101647774B embodiment 1;
reference examples 5:made (specification is 2ml:10mg) by CN101647774B embodiment 2;
reference examples 6:made (specification is 2ml:10mg) by CN101647774B embodiment 3;
reference examples 7(according to patent CN101647774B[0032]-[0035] described method make) (1 part of alpha-ararin based on weight portion meter, HS15 is 10 parts, 115 ℃ of 30 minutes pressure sterilizings)
Take 4g alpha-ararin, 40g HS15,2g active carbon, seal stand-by; Measure 500ml water for injection, under 60 ℃ of water bath condition, add 4g alpha-ararin and 40g HS15, stirring and dissolving; Add 2g active carbon, under room temperature, stir decarburization after 20 minutes and filter; Filtrate, again through 0.22 μ m filtering with microporous membrane, is mended the 1000ml that adds to the full amount of water for injection; Through 0.22 μ m filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, through 115 ℃ of 30 minutes pressure sterilizings, obtains alpha-ararin injection again.
reference examples 8(according to patent CN101647774B[0032]-[0035] described method make) (1 part of alpha-ararin based on weight portion meter, HS15 is 15 parts, 115 ℃ of 30 minutes pressure sterilizings)
Take 4g alpha-ararin, 60g HS15,2g active carbon, seal stand-by; Measure 500ml water for injection, under 60 ℃ of water bath condition, add 4g alpha-ararin and 60g HS15, stirring and dissolving; Add 2g active carbon, under room temperature, stir decarburization after 20 minutes and filter; Filtrate, again through 0.22 μ m filtering with microporous membrane, is mended the 1000ml that adds to the full amount of water for injection; Through 0.22 μ m filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, through 115 ℃ of 30 minutes pressure sterilizings, obtains alpha-ararin injection again.
reference examples 9(according to patent CN101647774B[0032]-[0035] described method make) (1 part of alpha-ararin based on weight portion meter, HS15 is 25 parts, 115 ℃ of 30 minutes pressure sterilizings)
Take 4g alpha-ararin, 100g HS15,2g active carbon, seal stand-by; Measure 500ml water for injection, under 60 ℃ of water bath condition, add 4g alpha-ararin and 100g HS15, stirring and dissolving; Add 2g active carbon, under room temperature, stir decarburization after 20 minutes and filter; Filtrate, again through 0.22 μ m filtering with microporous membrane, is mended the 1000ml that adds to the full amount of water for injection; Through 0.22 μ m filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, through 115 ℃ of 30 minutes pressure sterilizings, obtains alpha-ararin injection again.
embodiment 1-embodiment 3, the 9 study on the stability contrasts of reference examples 1-reference examples
(A) clarity
Detection method foundation: the drug standard Asarone injection liquid WS-10001-(HD-0437 of National Drug Administration)-2002 and " Chinese Pharmacopoeia " version appendix IX H visible foreign matters inspection technique in 2010
Instrument and equipment: YB-3 type clarity detecting apparatus
Detection method: get 20 of this product, clean container outer wall, rotation and inverting container make the visible foreign matters suspension (noting not making medicinal liquid to produce bubble) existing in medicinal liquid gently, respectively under black and white background, hand-held test sample cervical region overturns medicinal liquid gently, with visual inspection survey (illumination: 1000～1500lx).
Standard regulation: must not detect the obvious external foreign body such as fiber and block that smoke-like microparticle column, metal fillings, chips of glass, length or maximum particle diameter exceed 2mm.Fine visible foreign matters is if any detecting only 1, then gets 20 with method retrial, all must not detect.
Placement condition: long-term stable experiment condition, 25 ℃ ± 2 ℃ of temperature, humidity 60% ± 10%
Result:
The long-term defective phenomenon of clarity of placing of reference examples 1, reference examples 2, reference examples 3 is described: after sterilizing, clarity is qualified, places for a long time after 4 months clarity still qualified, be placed into for a long time 5 months after a small amount of sample (accounting for 10%-30%) have small crystallization.
Reference examples 4, reference examples 5, reference examples 6, reference examples 7, reference examples 8, the defective phenomenon of reference examples 9 clarity are described: after sterilizing, most finished products all have bulk oil droplet to separate out, and float on liquid level or stick at ampoule inwall.The grease of placing rear section sample can not disappear, and even produces white granular material floats in solution.
clarity study on the stability conclusion:1, the Asarone injection liquid clarity making according to patent documentation CN101647774B preparation method cannot reach the regulation requirement of existing " Chinese Pharmacopoeia " version in 2010, cannot use as clinical medicine.2, the Asarone injection liquid clarity making according to patent documentation CN102973499A preparation method can reach the regulation requirement of existing " Chinese Pharmacopoeia " version in 2010, but the effect duration of medicine can only be denoted as 5 months.
(B) drug content
Detection method foundation: the drug standard Asarone injection liquid WS-10001-(HD-0437 of National Drug Administration)-2002
Detection method: get 5 of this product, mix, precision measures 2ml, puts in 50ml measuring bottle, add ethanol dilution to scale, shake up, precision measures 5ml, puts in 50ml measuring bottle, add ethanol dilution to scale, according to spectrophotography (" Chinese Pharmacopoeia " 2010 editions two appendix IV A), measure trap at the wavelength place of 313nm, by asarone C
12h
16o
3absorptance (E
) be 380.8 calculating, to obtain final product.
Standard regulation: this product is the sterile water solution that asarone adds appropriate cosolvent to make.Containing asarone (C
12h
16o
3) should be 93.0%～107.0% of labelled amount.(labelled amount is drug specifications herein)
Result:
Above-mentioned experimental result shows that the Asarone injection liquid and preparation method thereof that patent documentation CN101647774B and CN102973499A propose exists defect, is not suitable for actual production and the use of Asarone injection liquid.The defect of patent documentation CN101647774B is mainly that the drug content loss fluctuation in its preparation process is large and finished product clarity is undesirable, causes this technique to produce and meets the stable content of existing pharmacopeia regulation and the Asarone injection liquid of clear.The defect of patent documentation CN102973499A is mainly that finished product is long-term place after clarity undesirable, cause the effect duration of the Asarone injection liquid medicine that this explained hereafter goes out too short, inconvenient actual storage and using.And the present invention has overcome this two technical barriers just, can produce stable content, the clear that meets existing pharmacopeia regulation and the Asarone injection liquid that has longer effect duration.
embodiment 2 and reference examples 2 safety contrasts
The relatively safety of the Asarone injection liquid of the embodiment of the present invention 2 and reference examples 2.
one, product preparation
embodiment 2(1 part of the alpha-ararin based on weight portion meter, HS15 is 10 parts, propylene glycol is 50 parts, 2.5 parts of benzyl alcohol are unsterilised)
Take 4g alpha-ararin, 40g HS15,200g propylene glycol, seal stand-by; Measure the sealing of 10ml benzyl alcohol stand-by; With the hydrochloric acid solution of concentrated hydrochloric acid preparation 0.01mol/L, seal stand-by; Measure 500ml water for injection, under 60 ℃ of water bath condition, add 40g HS15, stirring and dissolving; Under 60 ℃ of water-baths, add 4g alpha-ararin, be stirred to dissolve, let cool to room temperature; Add successively 200g propylene glycol and 10ml benzyl alcohol, stir; Inject water to 950ml, be uniformly mixed; With 0.01mol/L hydrochloric acid solution adjusting pH to 6.06, mend the 1000ml that adds to the full amount of water for injection, mix homogeneously, first through 0.45 μ m filtering with microporous membrane, then through 0.22 μ m filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, leak detection, obtains alpha-ararin injection.
reference examples 2(1 part of the alpha-ararin based on weight portion meter, HS15 is 10 parts, propylene glycol is 50 parts, 12 parts of ethanol, 100 ℃ of sterilizings in 30 minutes) (patent documentation CN102973499A embodiment 2)
Take 4g alpha-ararin, 40g HS15,200g propylene glycol, seal stand-by; Measure the sealing of 60ml ethanol stand-by; With the hydrochloric acid solution of concentrated hydrochloric acid preparation 0.01mol/L, seal stand-by; Measure 500ml water for injection, under 60 ℃ of water bath condition, add 40g HS15, stirring and dissolving; Under 60 ℃ of water-baths, add 4g alpha-ararin, be stirred to dissolve, let cool to room temperature; Add successively 200g propylene glycol and 60ml ethanol, stir; Inject water to 950ml, be uniformly mixed; With 0.01mol/L hydrochloric acid solution adjusting pH to 6.08, mend and inject water to full 1000ml, mix homogeneously, first through 0.45 μ m filtering with microporous membrane, then through 0.22 μ m filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, through 100 ℃ of sterilizings in 30 minutes, obtains alpha-ararin injection.
two, safety testing
Safety judgment basis: the Cavia porcellus generation hypersensitive difference of active and degree are carried out to its safety of comparison according to different prescription products.
Animal experiment unit: Chengdu qi xanthate thing non-clinical study company limited
1, experiment material:
medicine
The name of an article: Asarone injection liquid
Lot number: embodiment 2, reference examples 2
Specification: 2ml:8mg
Production unit: Chengdu Lisite Pharmaceutical Co., Ltd.
Usage and dosage: intravenous injection.1. intravenous injection: a 16～24mg, is diluted in 20% glucose injection 40ml slowly intravenous injection, 2～3 times on the one.Child dose cuts down according to the circumstance.2. intravenous drip: the 16～24mg that is grown up a time, 0.5mg/kg of child, is diluted to 0.01%～0.02% solution, intravenous drip, 2 times on the one with 5% or 10% glucose injection.
Storage: keep in Dark Place.
Rapid Dose Calculation: according to description:
Clinical daily maximal dose: 24mg × 3 time/60kg=1.2mg/kg;
Clinical test product Cmax: the 24mg/40ml=0.6mg/ml that is subject to.
reference substance
10% glucose injection, specification: 250ml:25g, lot number: C110618B1, Kelun Pharm Ind Co., Ltd., Sichuan produces.
Egg protein powder: specification: 100g, lot number: F20100819, Chemical Reagent Co., Ltd., Sinopharm Group produces.
animal
36 of Cavia porcelluss, body weight 251.7～335.2g, 18 female 18 heros, meet one-level animal standard, are provided animal production licence number: SCXK(river by plant of laboratory animal special commission of Sichuan Province) No. 2008-14.Adopt Cavia porcellus full-valence pellet feed, provided by plant of laboratory animal special commission of Sichuan Province.Freely drink urban life drinking-water.Feeding environment is conventional system, 16～26 ℃ of temperature, relative humidity 40～70%, gravity-flow ventilation, ventilation, natural lighting.
instrument
Electronic balance, BS600L type, range 600g, precision 0.1g, Shanghai Yousheng Balance Co., Ltd. produces.
Electronic balance, FA1004 type, range 100g, precision 0.0001g, the flat instrument and meter of upper current chart company limited produces.
material
Disposable sterilized syringe, specification: 1ml, lot number: 20120122, expiration date: 201412, Jiangxi Hongda Medical Equipment Group Corp., Ltd. produces.
Disposable sterilized syringe, specification: 2.5ml, lot number: 20101212, expiration date: 201311, Jiangxi Hongda Medical Equipment Group Corp., Ltd. produces.
Disposable sterilized syringe, specification: 5ml, lot number: 20101009, expiration date: 201309, Chengdu Xinjin Shifeng Medical Device Co., Ltd. produces.
2, experimental system and selection reason
When test, observe and test animal occupancy permit number: SYXK(river in Chengdu Animal House Cavia porcellus observation ward of qi xanthate thing non-clinical study company limited) 2010-096.
Select reason: according to " chemicals zest, anaphylaxis and hemolytic investigative technique guideline " hypersensitive test choice for use Cavia porcellus, be one-level experimental animal, therefore raise and observe in open systems.
3, test grouping
Get 36 of Cavia porcelluss, by body weight hierarchical grouping, be divided into 6 groups, 6/group, male and female half and half:
Negative control group (10% glucose injection);
Positive controls (egg protein powder);
High dose group 1(Asarone injection liquid reference examples 2);
Low dose group 1(Asarone injection liquid reference examples 2);
High dose group 2(Asarone injection liquid embodiment 2);
Low dose group 2(Asarone injection liquid embodiment 2);
4, test method
Dosage and cycle design: in hypersensitive test, for fully exposing the immunogenicity of medicinal liquid, should select the clinical administration mode of concentration maximum, dosage maximum as a reference.Therefore consider take clinical daily maximal dose 1.2mg/kg as dosage reference, take the clinical test product Cmax 0.6mg/ml that is subject to as concentration reference.
Administration cycle and route of administration: the next day lumbar injection 1 sensitization, totally 3 times, after last sensitization, instep intravenous injection in the 14th day excites.
Before sensitization, negative reference substance is prepared: get 10% glucose injection for subsequent use.
Before sensitization, positive reference substance is prepared: take appropriate egg protein powder, be dissolved in 10% glucose injection and be made into the solution for standby that concentration is 2mg/ml.
Prepared by test product: high dose group 1: to get the solution for standby that Asarone injection liquid reference examples 2 adds 10% glucose injection and be diluted to concentration 2.4mg/ml; Low dose group 1: get the solution for standby that Asarone injection liquid reference examples 2 adds 10% glucose injection and be diluted to concentration 0.6mg/ml; High dose group 2: get the solution for standby that Asarone injection liquid embodiment 2 adds 10% glucose injection and be diluted to concentration 2.4mg/ml; Low dose group 2: get the solution for standby that Asarone injection liquid embodiment 2 adds 10% glucose injection and be diluted to concentration 0.6mg/ml.
Sensitization method: each group is carried out sensitization by the each solution of group lumbar injection, the next day 1 time, totally 3 times.Dosage regimen is in table 3
Note: high dose group 1 and low dose group 1 adopt Asarone injection liquid reference examples 2 to prepare; High dose group 2 and low dose group 2 adopt Asarone injection liquid embodiment 2 to prepare.
Excite front negative reference substance to prepare: to get 10% glucose injection for subsequent use.
Excite front positive reference substance to prepare: to take appropriate egg protein powder, be dissolved in 10% glucose injection and be made into the solution for standby that concentration is 2mg/ml.
Prepared by test product: high dose group 1: to get the solution for standby that Asarone injection liquid reference examples 2 adds 10% glucose injection and be diluted to concentration 2.4mg/ml; Low dose group 1: get the solution for standby that Asarone injection liquid reference examples 2 adds 10% glucose injection and be diluted to concentration 0.6mg/ml; High dose group 2: get the solution for standby that Asarone injection liquid embodiment 2 adds 10% glucose injection and be diluted to concentration 2.4mg/ml; Low dose group 2: get the solution for standby that Asarone injection liquid embodiment 2 adds 10% glucose injection and be diluted to concentration 0.6mg/ml.
Exciting method: after last sensitization the 14th day each group excite by the each solution of group instep intravenous injection.Dosage regimen is in table 4.
Note: high dose group 1 and low dose group 1 adopt Asarone injection liquid reference examples 2 to prepare; High dose group 2 and low dose group 2 adopt Asarone injection liquid embodiment 2 to prepare.
Last sensitization and excite the body weight of measuring every group every animal the same day for the first time.
After each sensitization and excite at once to 30 minute after intravenous injection, according to the form below 5 is observed reaction symptom and the death time of every animal in detail.The longest observation 3 hours.Evaluate by table 6 evaluation criterion.
5, result of the test and analysis
During sensitization, Cavia porcellus ordinary circumstance is observed normally, occurs without abnormal conditions.
Excite rear irritated situation to add up in table 7, test result analysis is in table 8
Note: high dose group 1 and low dose group 1 adopt Asarone injection liquid reference examples 2 to prepare; High dose group 2 and low dose group 2 adopt Asarone injection liquid embodiment 2 to prepare.
Note: high dose group 1 and low dose group 1 adopt Asarone injection liquid reference examples 2 to prepare; High dose group 2 and low dose group 2 adopt Asarone injection liquid embodiment 2 to prepare.
Each group and relatively * * * P1<0.001 * * P1<0.01 * P1<0.05 of negative control group
Each tested group is compared △ △ △ P2<0.001 △ △ P2<0.01 △ P2<0.05 with positive controls
High dose group 2 and relatively 000 P3<0.001 00 P3<0.01 zero P3<0.05 of high dose group 1
Low dose group 2 and relatively P4<0.001 P4<0.01 P4<0.05 of low dose group 1
1., negative control group, positive controls and two batches batches of Asarone injection liquid duration of test are respectively organized Cavia porcellus body weight all increases to some extent, body weight zero difference between each group table 7,8 results show: Asarone injection liquid whole body is initiatively in sensitivity test.2., negative control group Cavia porcellus excites rear anaphylaxis feminine gender, positive controls Cavia porcellus excites the extremely strong positive of rear anaphylaxis, positive controls and negative control group have utmost point significant difference (P<0.001), show that test data accuracy is high; 3., low dose group 1, with negative control group anaphylaxis all negative, zero difference, has utmost point significant difference (P<0.001) with positive controls; Low dose group 2 is all negative with negative control group anaphylaxis, and zero difference, has utmost point significant difference (P2<0.001) with positive controls; 4., high dose group 2 and high dose group 1 anaphylaxis zero difference (P > 0.05); Low dose group 2 and low dose group 1 anaphylaxis zero difference (P > 0.05).
6, conclusion
According to Asarone injection liquid systemic anaphylaxis, experimental study shows,
the embodiment of the present invention 2the safety of Asarone injection liquid [adopt HS15 make by the aseptic filtration production technology (being aseptic processing) of empirical tests as antiseptic and asarone as cosolvent and benzyl alcohol as solubilizing agent, propylene glycol] and
reference examples 2asarone injection liquid
[(patent documentation CN102973499A embodiment 2), adopt HS15 to make by 100 ℃ of sterilizings in 30 minutes as cosolvent and asarone as solubilizing agent, propylene glycol and ethanol] identical, be same applicant in conjunction with patent documentation CN102973499A(and this patent) safety experiment data, show this patent product in safety higher than the existing commercially available Asarone injection liquid product using Tween 80 as solubilizing agent.
Claims (6)
1. an Asarone injection liquid, it is characterized in that comprising principal agent alpha-ararin, solubilizer polyethylene glycol-12-hydroxy stearic acid ester, cosolvent propylene glycol and antiseptic benzyl alcohol, wherein comprise 1 part of alpha-ararin based on weight portion meter, 8～12 parts of HS15s, 50 parts of propylene glycol, 2.5 parts of benzyl alcohol; Its preparation method is:
A, the alpha-ararin that accurately takes recipe quantity, HS15, propylene glycol, measure benzyl alcohol, seals stand-by;
B, measure the water for injection of 50% recipe quantity volume, under the condition of constant temperature to 60～70 ℃, add HS15, stirring and dissolving, under 60～70 ℃ of conditions, continue to add alpha-ararin, be stirred to dissolve, let cool to room temperature, add successively propylene glycol, benzyl alcohol, stir, inject water to again 95% of recipe quantity volume, be uniformly mixed, regulate pH to 6.0～6.1, benefit adds to the full amount of water for injection, mix homogeneously, filter, aseptic subpackaged, obtain alpha-ararin injection.
2. alpha-ararin injection according to claim 1, is characterised in that and adopts hydrochloric acid solution as pH adjusting agent.
3. alpha-ararin injection according to claim 1 and 2, is characterized in that making according to a conventional method alpha-ararin freeze-dried powder, and wherein freeze drying protectant is selected from mannitol.
4. alpha-ararin injection according to claim 1, is characterised in that the HS15 of choosing 8 parts, 10 parts or 12 parts is as solubilizing agent.
5. the application of alpha-ararin injection according to claim 1 in the medicine of preparation treatment upper respiratory tract infection, bronchitis, bronchial asthma, acute and chronic cholecystitis, cholelithiasis, epilepsy grand mal.
6. the application of alpha-ararin injection according to claim 1 in the medicine of preparation treatment pneumonia and chronic obstructive pulmonary disease acute attack.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310114183.5A CN103877012A (en) | 2012-12-21 | 2013-04-03 | Asarone injection and preparation process thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210561393.4 | 2012-12-21 | ||
| CN 201210561393 CN102973499A (en) | 2012-12-21 | 2012-12-21 | Asarone injection and preparation method thereof |
| CN201310114183.5A CN103877012A (en) | 2012-12-21 | 2013-04-03 | Asarone injection and preparation process thereof |
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| CN 201210561393 Pending CN102973499A (en) | 2012-12-21 | 2012-12-21 | Asarone injection and preparation method thereof |
| CN201310114184.XA Active CN103142515B (en) | 2012-12-21 | 2013-04-03 | Asarone injection and preparation method thereof |
| CN201310114183.5A Withdrawn CN103877012A (en) | 2012-12-21 | 2013-04-03 | Asarone injection and preparation process thereof |
| CN201310114182.0A Withdrawn CN103877011A (en) | 2012-12-21 | 2013-04-03 | Asarone injection and preparation process thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104857516A (en) * | 2015-05-12 | 2015-08-26 | 张蕊 | Asarone injection and preparation process thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102973499A (en) * | 2012-12-21 | 2013-03-20 | 张蕊 | Asarone injection and preparation method thereof |
| CN104873460B (en) * | 2015-05-12 | 2017-10-31 | 张蕊 | A kind of Asarone Injectin and preparation method thereof |
| CN106619498B (en) * | 2016-12-19 | 2019-08-06 | 宜昌三峡制药有限公司 | A kind of production method of asarone sodium chloride injection |
| US20230404945A1 (en) * | 2021-07-22 | 2023-12-21 | Sichuan University | Application of alpha-asarone in preparation of medicine for preventing or treating hemorrhagic stroke |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102973499A (en) * | 2012-12-21 | 2013-03-20 | 张蕊 | Asarone injection and preparation method thereof |
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2012
- 2012-12-21 CN CN 201210561393 patent/CN102973499A/en active Pending
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2013
- 2013-04-03 CN CN201310114184.XA patent/CN103142515B/en active Active
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104857516A (en) * | 2015-05-12 | 2015-08-26 | 张蕊 | Asarone injection and preparation process thereof |
| CN104857516B (en) * | 2015-05-12 | 2017-11-10 | 张蕊 | A kind of Asarone Injectin and its preparation technology |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103142515A (en) | 2013-06-12 |
| CN103877011A (en) | 2014-06-25 |
| CN103142515B (en) | 2015-02-18 |
| CN102973499A (en) | 2013-03-20 |
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Application publication date: 20140625 |