CN103142515A - Asarone injection and preparation method thereof - Google Patents
Asarone injection and preparation method thereof Download PDFInfo
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- CN103142515A CN103142515A CN201310114184XA CN201310114184A CN103142515A CN 103142515 A CN103142515 A CN 103142515A CN 201310114184X A CN201310114184X A CN 201310114184XA CN 201310114184 A CN201310114184 A CN 201310114184A CN 103142515 A CN103142515 A CN 103142515A
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Abstract
The invention provides an alpha-asarone injection. Alpha-asarone (the chemical name is 2, 4, 5-trimethoxy-1-propenyl benzene) is taken as an active ingredient, polyethylene glycol-12-hydroxystearate is adopted as a solubilizing agent, propylene glycol and ethanol are taken as cosolvents for preparing the injection, and the injection can not only effectively solve the problem that asarone is not water-soluble, but also greatly improve the safety and stability of the asarone injection. The prepared asarone injection provided by the invention has the advantages of good stability and simple preparation process.
Description
Technical field
The present invention relates to field of medicine preparations, especially relate to injection of asarone and preparation method thereof.
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; Simultaneously for streptococcus pneumoniae, staphylococcus aureus and colibacillary growth, in various degree inhibitory action is arranged.Clinically, asarone has been widely used in disease, the especially treatments for pneumonia, bronchial asthma and chronic obstructive pulmonary disease (for example chronic obstructive pulmonary disease, COPD) acute attack such as treatment upper respiratory tract infection, bronchitis, bronchial asthma, acute and chronic cholecystitis, cholelithiasis, epilepsy grand mal and has had remarkable result.Nineteen eighty-two, Liuzhou pharmaceutical factory manually successfully synthesized alpha-ararin first at home, and made the 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 that goes on the market at present, due to its water solublity extreme difference, oral rear difficult dispersion and stripping, when contacting with body fluid, effective ratio area is little, for example the common oral preparation bioavailability is only 2-5%, can't realize the therapeutic effect of expecting at all.Prior art adopts various ways to prepare the injection of asarone, but there is number of drawbacks, for example CN1290495C discloses the 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 the 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 for preparation preparation process and clinical practice, also the performance of drug effect is brought many harmful effects, even is difficult to be prepared into rational preparation.In order to solve problems, comparatively one of method commonly used is with surfactant, medicine to be carried out solubilising.
In order to improve its curative effect, research worker increases asarone dissolubility in water by adding the certain surface activating agent, has made Asarone injection liquid.but being used for injection, some surfactant may cause existing serious potential safety hazard, for example: CN1313086C discloses the employing Tween 80 and has dissolved asarone as solubilizing agent, those skilled in the art answer heightened awareness to show that to domestic and international great mass of data to the Tween 80 safety research Tween 80 has certain safety applications scope, as to dog, rabbit, cat and monkey intravenous injection Tween 80 all can cause a Blood pressure drop of the crossing property (systolic pressure of dog especially, diastolic pressure, average pulse pressure significantly reduces) (Wang Qingli, the safety research progress toxicology magazine 2006 of Peng Jian Tween 80, 20 (4): the 262-264 page), therefore be difficult to determine whether said preparation causes even more serious impact to human body, simultaneously, described product causes the product lyophilizing incomplete owing to containing more Tween 80, 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 and ethanol are made cosolvent.At first, verified its of the literature research of prior art has the safety that is much better than Tween 80; Experiment proves that also the 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 HS15 as the ejection preparation of 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 below 10 ℃ even freezing state preserve, even at room temperature place a period of time, emulsion droplet all gradually polymerization break, do not reach the requirement of injection after redissolution.For example in patent documentation CN101647774B, the Asarone injection of employing HS15 as solubilizing agent disclosed again, find that there is major defect in the method for the standby Asarone injection of this patent system after preparing Asarone injection according to the preparation method of embodiment 1, embodiment 2 and embodiment 3, be mainly manifested in a large amount of losses (losing at least 10%) of principal agent alpha-ararin in preparation process and loss fluctuation is large and sterilization after clarity defective, namely can't " Chinese pharmacopoeia version in 2010 requires to make qualified medicine according to existing.For example patent documentation CN102973499A(and this patent are same applicant again) in disclose and adopt HS15 as the Asarone injection of solubilizing agent, find that there is defective in the method for the standby Asarone injection of this patent system after preparing Asarone injection according to the preparation method of embodiment 1, embodiment 2 and embodiment 3, 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.
Studies show that of prior art, the micelle that is comprised of single surfactant no doubt has obvious effect, but it is high that some poorly water soluble drugs are also existed dosage of surfactant, the preparation viscosity is large, dilution stability is bad, and corresponding preparation toxic and side effects, injection pain, the clinical application that brings requires high problems.The mixed micelle system of the mutual composite formation of surfactant has the characteristic that characteristic of solubilizing is better than 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.Yet wherein phospholipid is very easy to oxidation, all needs with nitrogen protection in production, and production cost is high; The lysophosphatide that produces 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 the higher surfactant HS15 of safety and solubilization-aid effect to make by the aseptic filtration production technology (being aseptic processing) of empirical tests as cosolvent and asarone as solubilizing agent, propylene glycol and ethanol, effectively the degerming assurance safety underproof phenomenon of clarity of injection that can also avoid Yin Gaowen to cause.That the Asarone injection liquid that makes meets fully is existing " Chinese pharmacopoeia version in 2010 is for the requirement of injection, stable content, and the final mean annual increment solution clarity is good.Simultaneously safety testing also the Asarone injection liquid that gets of proved patent system be same applicant according to patent documentation CN102973499A(and this patent) the Asarone injection liquid safety that makes is identical, namely this patent product is same applicant with patent documentation CN102973499A(with this patent in safety) product identical all higher than existing with the commercially available Asarone injection liquid product of Tween 80 as solubilizing agent.
Summary of the invention
The present invention is in order to solve multiple security risk and the preparation defective that in prior art, Aarin preparation exists, provide a kind of employing HS15 (hereinafter to be referred as HS15) as solubilizing agent, propylene glycol and ethanol are as the ejection preparation of the asarone of cosolvent.
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---need not to use hydryllin and corticoid before art;
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 when high concentration, 30% concentration solution also can painless administration;
Take in the near future Deutscher Arzneibucs (being about to income to the US and European pharmacopeia);
The object of the present invention is to provide a kind of with asarone as injection of active component and preparation method thereof.
Asarone of the present invention namely 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, ethanol 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 based on 1 part of the alpha-ararin of weight portion meter, 8～12 parts of HS15s, 50 parts of propylene glycol, 12 parts of ethanol (density is in 0.8) 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.Can add pharmaceutically acceptable various freeze drying protectant in described freeze-dry process, preferably mannitol.
The method for preparing the alpha-ararin injection of the present invention comprises the steps:
A, the alpha-ararin that accurately takes recipe quantity, HS15, propylene glycol measure ethanol, and the preparation pH adjusting agent seals stand-by;
B, measure the water for injection of 50% recipe quantity volume, add HS15, stirring and dissolving under the condition of constant temperature to 60～70 ℃, continue to add alpha-ararin under 60～70 ℃ of conditions, be stirred to dissolve, let cool to room temperature, add successively propylene glycol, ethanol, stir;
C, inject water to 95% of recipe quantity volume, mix, regulate pH to 6.0～6.1, benefit adds to the full amount of water for injection, and mix homogeneously filters, and packing namely gets the alpha-ararin injection;
In d, above-mentioned steps b, after adding successively propylene glycol, ethanol, also can be in freeze drying protectant: full dose water for injection ratio be 10: 100 (g: ml) add freeze drying protectant mannitol, stirring and dissolving; Add to the full amount of water for injection, mix homogeneously filters, packing, and after 3 hours, evacuation adopts a sublimed method to obtain the alpha-ararin freeze-dried powder in-40 ℃ of pre-freezes.
The Asarone injection of above-mentioned technique preparation 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 a kind of 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(based on 1 part of the alpha-ararin of weight portion meter, HS15 is 8 parts, and propylene glycol is 50 parts, and 12 parts of ethanol are unsterilised)
Take 4g alpha-ararin, 32g HS15,200g propylene glycol, seal stand-by; Measure the sealing of 60ml ethanol stand-by; Hydrochloric acid solution with concentrated hydrochloric acid preparation 0.01mol/L seals stand-by; Measure 500ml water for injection, add 32g HS15, stirring and dissolving under 60 ℃ of water bath condition; Add the 4g alpha-ararin under 60 ℃ of water-baths, be stirred to dissolve, let cool to room temperature; Add successively 200g propylene glycol and 60ml ethanol, stir; Inject water to 950ml, mix; Regulate pH to 6.03 with the 0.01mol/L hydrochloric acid solution, 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 the 2ml ampoule, sealing by fusing, leak detection obtains the alpha-ararin injection.
Embodiment 2(based on 1 part of the alpha-ararin of weight portion meter, HS15 is 10 parts, and propylene glycol is 50 parts, and 12 parts of ethanol are unsterilised)
Take 4g alpha-ararin, 40g HS15,200g propylene glycol, seal stand-by; Measure the sealing of 60ml ethanol stand-by; Hydrochloric acid solution with concentrated hydrochloric acid preparation 0.01mol/L seals stand-by; Measure 500ml water for injection, add 40g HS15, stirring and dissolving under 60 ℃ of water bath condition; Add the 4g alpha-ararin under 60 ℃ of water-baths, be stirred to dissolve, let cool to room temperature; Add successively 200g propylene glycol and 60ml ethanol, stir; Inject water to 950ml, mix; Regulate pH to 6.08 with the 0.01mol/L hydrochloric acid solution, 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 the 2ml ampoule, sealing by fusing, leak detection obtains the alpha-ararin injection.
Embodiment 3(based on 1 part of the alpha-ararin of weight portion meter, HS15 is 12 parts, and propylene glycol is 50 parts, and 12 parts of ethanol are unsterilised)
Take 4g alpha-ararin, 48g HS15,200g propylene glycol, seal stand-by; Measure the sealing of 60ml ethanol stand-by; Hydrochloric acid solution with concentrated hydrochloric acid preparation 0.01mol/L seals stand-by; Measure 500ml water for injection, add 48g HS15, stirring and dissolving under 60 ℃ of water bath condition; Add the 4g alpha-ararin under 60 ℃ of water-baths, be stirred to dissolve, let cool to room temperature; Add successively 200g propylene glycol and 60ml ethanol, stir; Inject water to 950ml, mix; Regulate pH to 6.10 with the 0.01mol/L hydrochloric acid solution, 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 the 2ml ampoule, sealing by fusing, leak detection obtains the alpha-ararin injection.
Embodiment 4(based on 1 part of the alpha-ararin of weight portion meter, HS15 is 10 parts, and propylene glycol is 50 parts, 12 parts of ethanol, freeze-dried powder)
Take 4g alpha-ararin, 40g HS15,200g propylene glycol, seal stand-by; Measure the sealing of 60ml ethanol stand-by; Measure 500ml water for injection, add 40g HS15, stirring and dissolving under 60 ℃ of water bath condition; Add the 4g alpha-ararin under 60 ℃ of water-baths, be stirred to dissolve, let cool to room temperature; Add successively 200g propylene glycol, 60ml ethanol 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, packing, in-40 ℃ of pre-freezes after 3 hours, evacuation reaches below 13.33Pa the interior vacuum of drying baker, slowly is 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 redissolved in 7 months after clear still.
Reference examples 1(based on 1 part of the alpha-ararin of weight portion meter, HS15 is 8 parts, and propylene glycol is 50 parts, 12 parts of ethanol, 100 ℃ of sterilizations 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; Hydrochloric acid solution with concentrated hydrochloric acid preparation 0.01mol/L seals stand-by; Measure 500ml water for injection, add 32g HS15, stirring and dissolving under 60 ℃ of water bath condition; Add the 4g alpha-ararin under 60 ℃ of water-baths, be stirred to dissolve, let cool to room temperature; Add successively 200g propylene glycol and 60ml ethanol, stir; Inject water to 950ml, mix; Regulate pH to 6.03 with the 0.01mol/L hydrochloric acid solution, add water for injection 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 the 2ml ampoule, sealing by fusing through 100 ℃ of sterilizations in 30 minutes, obtains the alpha-ararin injection.
Reference examples 2(based on 1 part of the alpha-ararin of weight portion meter, HS15 is 10 parts, and propylene glycol is 50 parts, 12 parts of ethanol, 100 ℃ of sterilizations 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; Hydrochloric acid solution with concentrated hydrochloric acid preparation 0.01mol/L seals stand-by; Measure 500ml water for injection, add 40g HS15, stirring and dissolving under 60 ℃ of water bath condition; Add the 4g alpha-ararin under 60 ℃ of water-baths, be stirred to dissolve, let cool to room temperature; Add successively 200g propylene glycol and 60ml ethanol, stir; Inject water to 950ml, mix; Regulate pH to 6.08 with the 0.01mol/L hydrochloric acid solution, add water for injection 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 the 2ml ampoule, sealing by fusing through 100 ℃ of sterilizations in 30 minutes, obtains the alpha-ararin injection.
Reference examples 3(based on 1 part of the alpha-ararin of weight portion meter, HS15 is 12 parts, and propylene glycol is 50 parts, 12 parts of ethanol, 100 ℃ of sterilizations 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; Hydrochloric acid solution with concentrated hydrochloric acid preparation 0.01mol/L seals stand-by; Measure 500ml water for injection, add 48g HS15, stirring and dissolving under 60 ℃ of water bath condition; Add the 4g alpha-ararin under 60 ℃ of water-baths, be stirred to dissolve, let cool to room temperature; Add successively 200g propylene glycol and 60ml ethanol, stir; Inject water to 950ml, mix; Regulate pH to 6.10 with the 0.01mol/L hydrochloric acid solution, add water for injection 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 the 2ml ampoule, sealing by fusing through 100 ℃ of sterilizations in 30 minutes, obtains the 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) (based on 1 part of the alpha-ararin of 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, add 4g alpha-ararin and 40g HS15 under 60 ℃ of water bath condition, stirring and dissolving; Add the 2g active carbon, stir decarburization filtration after 20 minutes under room temperature; Filtrate mends again through 0.22 μ m filtering with microporous membrane 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 the 2ml ampoule, sealing by fusing through 115 ℃ of 30 minutes pressure sterilizings, obtains the alpha-ararin injection again.
Reference examples 8(according to patent CN101647774B[0032]-[0035] described method make) (based on 1 part of the alpha-ararin of 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, add 4g alpha-ararin and 60g HS15 under 60 ℃ of water bath condition, stirring and dissolving; Add the 2g active carbon, stir decarburization filtration after 20 minutes under room temperature; Filtrate mends again through 0.22 μ m filtering with microporous membrane 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 the 2ml ampoule, sealing by fusing through 115 ℃ of 30 minutes pressure sterilizings, obtains the alpha-ararin injection again.
Reference examples 9(according to patent CN101647774B[0032]-[0035] described method make) (based on 1 part of the alpha-ararin of 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, add 4g alpha-ararin and 100g HS15 under 60 ℃ of water bath condition, stirring and dissolving; Add the 2g active carbon, stir decarburization filtration after 20 minutes under room temperature; Filtrate mends again through 0.22 μ m filtering with microporous membrane 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 the 2ml ampoule, sealing by fusing through 115 ℃ of 30 minutes pressure sterilizings, obtains the 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) that exists in medicinal liquid gently, respectively under the black and white background, hand-held test sample cervical region overturns medicinal liquid gently, surveys (illumination: 1000～1500lx) with visual inspection.
Standard code: must not detect smoke-like microparticle column, metal fillings, chips of glass, length or maximum particle diameter and surpass the obvious external foreign bodies such as the fiber of 2mm and block.Fine visible foreign matters is if any detecting only 1, then gets 20 with the 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 sterilization, 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%) small crystallization is arranged.
Reference examples 4, reference examples 5, reference examples 6, reference examples 7, reference examples 8, the reference examples 9 defective phenomenons of clarity are described: after sterilization, most finished products all have the bulk oil droplet to separate out, and float on liquid level or stick at the ampoule inwall.The grease of placing the rear section sample can not disappear, and even produces the white granular material floats in solution.
Clarity study on the stability conclusion:1, the Asarone injection liquid clarity that makes according to patent documentation CN101647774B preparation method can't reach that existing " the regulation requirement of Chinese pharmacopoeia version in 2010 can't be used as clinical medicine.2, that the Asarone injection liquid clarity that makes according to patent documentation CN102973499A preparation method can reach is existing " the regulation requirement of 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, mixing, precision measures 2ml, puts in the 50ml measuring bottle, add ethanol dilution to scale, shake up, precision measures 5ml, puts in the 50ml measuring bottle, add ethanol dilution to scale, according to spectrophotography (" 2010 editions two appendix IV A of Chinese pharmacopoeia), measure trap at the wavelength place of 313nm, press asarone C
12H
16O
3Absorptance (E
) be 380.8 calculating, and get final product.
Standard code: this product is the sterile water solution that asarone adds appropriate cosolvent to make.Contain 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 there is defective in the Asarone injection liquid and preparation method thereof that patent documentation CN101647774B and CN102973499A propose, is not suitable for actual production and the use of Asarone injection liquid.The defective of patent documentation CN101647774B is that mainly the drug content loss fluctuation in its preparation process is large and the 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 defective 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 longer effect duration is arranged.
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(based on 1 part of the alpha-ararin of weight portion meter, HS15 is 10 parts, and propylene glycol is 50 parts, and 12 parts of ethanol are unsterilised)
Take 4g alpha-ararin, 40g HS15,200g propylene glycol, seal stand-by; Measure the sealing of 60ml ethanol stand-by; Hydrochloric acid solution with concentrated hydrochloric acid preparation 0.01mol/L seals stand-by; Measure 500ml water for injection, add 40g HS15, stirring and dissolving under 60 ℃ of water bath condition; Add the 4g alpha-ararin under 60 ℃ of water-baths, be stirred to dissolve, let cool to room temperature; Add successively 200g propylene glycol and 60ml ethanol, stir; Inject water to 950ml, mix; Regulate pH to 6.08 with the 0.01mol/L hydrochloric acid solution, 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 the 2ml ampoule, sealing by fusing, leak detection obtains the alpha-ararin injection.
Reference examples 2(based on 1 part of the alpha-ararin of weight portion meter, HS15 is 10 parts, and propylene glycol is 50 parts, 12 parts of ethanol, 100 ℃ of sterilizations 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; Hydrochloric acid solution with concentrated hydrochloric acid preparation 0.01mol/L seals stand-by; Measure 500ml water for injection, add 40g HS15, stirring and dissolving under 60 ℃ of water bath condition; Add the 4g alpha-ararin under 60 ℃ of water-baths, be stirred to dissolve, let cool to room temperature; Add successively 200g propylene glycol and 60ml ethanol, stir; Inject water to 950ml, mix; Regulate pH to 6.08 with the 0.01mol/L hydrochloric acid solution, add water for injection 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 the 2ml ampoule, sealing by fusing through 100 ℃ of sterilizations in 30 minutes, obtains the alpha-ararin injection.
Two, safety testing
Safety judgment basis: the Cavia porcellus generation hypersensitive difference of active and degree are come 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 slow 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 with 5% or 10% glucose injection, intravenous drip, 2 times on the one.
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 subjected 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, and the animal production licence number is provided by Sichuan Province plant of laboratory animal special commission: the SCXK(river) No. 2008-14.Adopt the Cavia porcellus full-valence pellet feed, provided by Sichuan Province plant of laboratory animal special commission.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, the BS600L type, range 600g, precision 0.1g, Shanghai Yousheng Balance Co., Ltd. produces.
Electronic balance, the FA1004 type, range 100g, precision 0.0001g, the flat instrument and meter company limited of upper current chart is produced.
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
Observe and test animal occupancy permit number during test in Chengdu qi xanthate thing non-clinical study company limited Animal House Cavia porcellus observation ward: the SYXK(river) 2010-096.
Select reason: according to " chemicals zest, anaphylaxis and hemolytic investigative technique guideline " hypersensitive test choice for use Cavia porcellus, be the one-level experimental animal, therefore raise and observe in open systems.
3, test grouping
Get 36 of Cavia porcelluss, by the 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, be fully to expose the immunogenicity of medicinal liquid, should select concentration is maximum, dosage is maximum clinical administration mode as a reference.Therefore consider take clinical daily maximal dose 1.2mg/kg as the dosage reference, take the clinical test product Cmax 0.6mg/ml that is subjected to as the 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 standby.
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 Asarone injection liquid reference examples 2 and add the solution for standby that 10% glucose injection is diluted to concentration 2.4mg/ml; Low dose group 1: get Asarone injection liquid reference examples 2 and add the solution for standby that 10% glucose injection is diluted to concentration 0.6mg/ml; High dose group 2: get Asarone injection liquid embodiment 2 and add the solution for standby that 10% glucose injection is diluted to concentration 2.4mg/ml; Low dose group 2: get Asarone injection liquid embodiment 2 and add the solution for standby that 10% glucose injection is diluted to concentration 0.6mg/ml.
The sensitization method: each the group carry out sensitization by each solution of group lumbar injection, the next day 1 time, totally 3 times.Dosage regimen sees Table 3.
Annotate: high dose group 1 and low dose group 1 adopt 2 preparations of Asarone injection liquid reference examples; High dose group 2 and low dose group 2 adopt Asarone injection liquid embodiment 2 preparations.
Excite front negative reference substance to prepare: to get 10% glucose injection standby.
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 Asarone injection liquid reference examples 2 and add the solution for standby that 10% glucose injection is diluted to concentration 2.4mg/ml; Low dose group 1: get Asarone injection liquid reference examples 2 and add the solution for standby that 10% glucose injection is diluted to concentration 0.6mg/ml; High dose group 2: get Asarone injection liquid embodiment 2 and add the solution for standby that 10% glucose injection is diluted to concentration 2.4mg/ml; Low dose group 2: get Asarone injection liquid embodiment 2 and add the solution for standby that 10% glucose injection is diluted to concentration 0.6mg/ml.
Exciting method: after last sensitization, the 14th day each group excites by each solution of group instep intravenous injection.Dosage regimen sees Table 4.
Annotate: high dose group 1 and low dose group 1 adopt 2 preparations of Asarone injection liquid reference examples; High dose group 2 and low dose group 2 adopt Asarone injection liquid embodiment 2 preparations.
Last sensitization and excite and measured the body weight of every group every animal the same day for the first time.
After each sensitization and excite after intravenous injection at once to 30 minute, according to the form below 5 is observed reaction symptom and the death time of every animal in detail.The longest observation 3 hours.Estimate by table 6 evaluation criterion.
5, result of the test and analysis
During sensitization, the Cavia porcellus ordinary circumstance is observed normally, occurs without abnormal conditions.
Excite rear irritated situation statistics to see Table 7, test result analysis sees Table 8.
Annotate: high dose group 1 and low dose group 1 adopt 2 preparations of Asarone injection liquid reference examples; High dose group 2 and low dose group 2 adopt Asarone injection liquid embodiment 2 preparations.
Annotate: high dose group 1 and low dose group 1 adopt 2 preparations of Asarone injection liquid reference examples; High dose group 2 and low dose group 2 adopt Asarone injection liquid embodiment 2 preparations.
Each group compares * * * P1＜0.001 * * P1＜0.01 * P1＜0.05 with 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 high dose group 1 be 000 P3＜0.001,00 P3＜0.01 zero P3＜0.05 relatively
Low dose group 2 compares P4＜0.001 P4＜0.01 P4＜0.05 with low dose group 1
1., negative control group, positive controls and two batches batches of Asarone injection liquid duration of test are respectively organized the 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., the negative control group Cavia porcellus excites rear anaphylaxis negative, the 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 the test data accuracy is high; 3., low dose group 1, with the 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 the 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
Experimental study shows according to Asarone injection liquid systemic anaphylaxis, safety and the reference examples 2 Asarone injection liquid of the embodiment of the present invention 2 Asarone injection liquid [adopting HS15 to make by the aseptic filtration production technology (being aseptic processing) of empirical tests as cosolvent and asarone as solubilizing agent, propylene glycol and ethanol]
[(patent documentation CN102973499A embodiment 2), adopt HS15 to make by 100 ℃ of sterilizations 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) the safety experiment data, show this patent product in safety higher than existing with the commercially available Asarone injection liquid product of Tween 80 as solubilizing agent.
Claims (6)
1. Asarone injection liquid, it is characterized in that comprising the principal agent alpha-ararin, solubilizer polyethylene glycol-12-hydroxy stearic acid ester, cosolvent propylene glycol and ethanol, wherein comprise based on 1 part of the alpha-ararin of weight portion meter, 8～12 parts of HS15s, 50 parts of propylene glycol, density is in 12 parts of 0.8 ethanol; Its preparation method is:
A, the alpha-ararin that accurately takes recipe quantity, HS15, propylene glycol measure ethanol, seal stand-by;
B, measure the water for injection of 50% recipe quantity volume, add HS15, stirring and dissolving under the condition of constant temperature to 60～70 ℃; Continue to add alpha-ararin under 60～70 ℃ of conditions, be stirred to dissolve, let cool to room temperature; Add successively propylene glycol, ethanol, stir; Inject water to 95% of recipe quantity volume, mix; Regulate pH to 6.0～6.1, benefit adds to the full amount of water for injection, and mix homogeneously filters, and is aseptic subpackaged, namely gets the alpha-ararin injection.
2. alpha-ararin injection according to claim 1, be characterised in that and adopt 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 the 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310114184.XA CN103142515B (en) | 2012-12-21 | 2013-04-03 | Asarone injection and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201210561393.4 | 2012-12-21 | ||
| CN 201210561393 CN102973499A (en) | 2012-12-21 | 2012-12-21 | Asarone injection and preparation method thereof |
| CN201310114184.XA CN103142515B (en) | 2012-12-21 | 2013-04-03 | Asarone injection and preparation method thereof |
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| CN 201210561393 Pending CN102973499A (en) | 2012-12-21 | 2012-12-21 | Asarone injection and preparation method thereof |
| CN201310114182.0A Withdrawn CN103877011A (en) | 2012-12-21 | 2013-04-03 | Asarone injection and preparation process thereof |
| CN201310114183.5A Withdrawn CN103877012A (en) | 2012-12-21 | 2013-04-03 | Asarone injection and preparation process thereof |
| CN201310114184.XA Active CN103142515B (en) | 2012-12-21 | 2013-04-03 | Asarone injection and preparation method thereof |
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| CN201310114182.0A Withdrawn CN103877011A (en) | 2012-12-21 | 2013-04-03 | Asarone injection and preparation process thereof |
| CN201310114183.5A Withdrawn CN103877012A (en) | 2012-12-21 | 2013-04-03 | Asarone injection and preparation process thereof |
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| 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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| 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 |
Citations (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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- 2012-12-21 CN CN 201210561393 patent/CN102973499A/en active Pending
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2013
- 2013-04-03 CN CN201310114182.0A patent/CN103877011A/en not_active Withdrawn
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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 |
Non-Patent Citations (1)
| Title |
|---|
| 廖娟娟: "细辛脑氯化钠注射液的研究", 《中国优秀硕士学位论文全文数据库医药卫生科技辑》 * |
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 |
|---|---|
| CN102973499A (en) | 2013-03-20 |
| CN103877012A (en) | 2014-06-25 |
| CN103877011A (en) | 2014-06-25 |
| CN103142515B (en) | 2015-02-18 |
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