CN103142515B - Asarone injection and preparation method thereof - Google Patents
Asarone injection and preparation method thereof Download PDFInfo
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- CN103142515B CN103142515B CN201310114184.XA CN201310114184A CN103142515B CN 103142515 B CN103142515 B CN 103142515B CN 201310114184 A CN201310114184 A CN 201310114184A CN 103142515 B CN103142515 B CN 103142515B
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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 injection relating to asarone and preparation method thereof.
Background technology
Alpha-ararin chemistry Alpha-Asaronum by name, be one of principle active component of Chinese medicine Rhizoma Acori Graminei, there is calmness, convulsion, spasmolytic, relieving asthma, eliminate the phlegm, cough-relieving, blood fat reducing, function of gallbladder promoting, the multiple pharmacological effect such as anticancer; Simultaneously there is inhibitory action in various degree for streptococcus pneumoniae, staphylococcus aureus and colibacillary growth.Clinically, asarone has been widely used in the disease such as treatment upper respiratory tract infection, bronchitis, bronchial asthma, acute and chronic cholecystitis, cholelithiasis, epilepsy grand mal, and the treatment especially for pneumonia, bronchial asthma and chronic obstructive pulmonary disease (such as chronic obstructive pulmonary disease, COPD) acute attack has remarkable result.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 is the extremely strong and compound of hydrophilic extreme difference as lipotropy, the Tablet and Capsula of the asarone of current listing, due to its water solublity extreme difference, not easily dispersion and stripping after oral, little with effective ratio area during bioresorbable, such as common oral preparation bioavailability is only 2-5%, cannot 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, such as CN1290495C discloses employing alpha-ararin, add oil, emulsifying agent, water for injection makes 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, and redissolution weak effect before lyophilized powder injection, produce muddy, impact uses.
In active medicinal matter, major part is insoluble in the fat-soluble medicine of water, brings a lot of inconvenience to formulation process and clinical practice, also brings many harmful effects to the performance of drug effect, is even difficult to be prepared into rational preparation.In order to solve problems, one of comparatively conventional method carries out solubilising with surfactants on drug.
In order to improve its curative effect, research worker, by adding certain surface activating agent, increases asarone dissolubility in water, has made Asarone Injectin.But some surfactant is used for injection may cause there is serious potential safety hazard, such as: CN1313086C discloses and adopts Tween 80 as solubilizing agent asarone, those skilled in the art answer heightened awareness to showing that Tween 80 has certain safety applications scope to the great mass of data of Tween 80 safety research both at home and abroad, as to dog, rabbit, cat and monkey intravenous injection Tween 80 all can cause transient blood pressure to reduce (the especially systolic pressure of dog, 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 pages), therefore be difficult to determine whether said preparation causes even more serious impact to human body, meanwhile, described product is due to containing more Tween 80, and cause product lyophilizing incomplete, outward appearance is not good, and more serious consequence redissolves weak effect after being lyophilizing, be unfavorable for practical clinical.
For solving the 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 make cosolvent.First, verified its of the literature research of prior art has the safety being much better than Tween 80; Experiment also proves that Pregnant Rabbits intravenous injection gives can cause obvious maternal toxicity containing Tween 80 187.5mg/kg, 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 the ejection preparation adopting HS15 as the asarone of emulsifying agent; such as, disclose the Emulsion of asarone in patent documentation C101088499A; adopt the emulsifying agent of the oil phase of soybean oil and median chain triglyceride oil mixture, soybean lecithin and HS15 to make Emulsion, and add freeze drying protectant further and make dry emulsion.But the complicated process of preparation of freeze-dried emulsion, the physical stability of manufactured goods is bad, to need below 10 DEG C even freezing state to preserve, even if at room temperature place a period of time, emulsion droplet all can be polymerized gradually and breaks, and does not reach the requirement of injection after redissolution.The Asarone injection adopting HS15 as solubilizing agent is disclosed again in such as patent documentation CN101647774B, find that this patent system exists major defect for the method for Asarone injection after preparing Asarone injection according to the preparation method of embodiment 1, embodiment 2 and embodiment 3, be mainly manifested in principal agent alpha-ararin in preparation process a large amount of losses (at least losing 10%) and loss fluctuation is large and after sterilizing clarity defective, namely cannot require make qualified medicine according to existing " Chinese Pharmacopoeia " version in 2010.Such as patent documentation CN102973499A(and this patent are same applicant again) in disclose and adopt HS15 as the Asarone injection of solubilizing agent, the method existing defects of this patent system for Asarone injection is found after preparing Asarone injection according to the preparation method of embodiment 1, embodiment 2 and embodiment 3, main manifestations obtains Asarone Injectin after the production, and to examine or check clarity after 5 months for a long time defective, and the effect duration of medicine can only be denoted as 5 months.
The research of prior art shows, the micelle be made up of single surfactant no doubt has obvious effect, but it is high also to there is dosage of surfactant to some poorly water soluble drugs, preparation viscosity is large, dilution stability is bad, and corresponding preparation toxic and side effects, injection pain, the clinical application brought 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 describes the Micellar drug preparation that HS15 and one or more other surfactant, phospholipid etc. can be adopted to make asaricin.But wherein phospholipid is very easy to oxidation, all need with nitrogen protection in production, and production cost is high; The lysophosphatide produced has very strong toxic and side effects, is must the strict impurity controlled in injection.
Instant invention overcomes above technology prejudice, adopt the aqueous Asarone Injectin that safety and the higher surfactant HS15 of solubilization-aid effect are made by the aseptic filtration production technology (i.e. aseptic processing) of empirical tests as cosolvent and asarone as solubilizing agent, propylene glycol and ethanol, can not only effective degerming guarantee safety underproof phenomenon of clarity of injection that Yin Gaowen can also be avoided to cause.Obtained Asarone Injectin meets the requirement of existing " Chinese Pharmacopoeia " version in 2010 for injection completely, and stable content, final mean annual increment solution clarity is good.Simultaneously safety testing also the Asarone Injectin that obtains of proved patent system be same applicant according to patent documentation CN102973499A(with this patent) obtained Asarone Injectin safety is identical, namely in safety, this patent product and patent documentation CN102973499A(are same applicant 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 the multiple security risk and preparation defect that in prior art, Aarin preparation exists, there is provided a kind of HS15 (hereinafter referred to as HS15) that adopts 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---preoperative without the need to using hydryllin and corticoid;
Low haemolysis;
Higher human body safety in utilization, verified its of literature research of prior art has the safety being much better than Tween 80;
Higher physiological tolerance;
High solubilising power-make the injection of low capacity high dose become possibility;
Low viscosity, even if when high concentration, 30% strength solution also can painless administration;
Take in Deutscher Arzneibucs (being about to income to US and European pharmacopeia) in the near future;
The object of the present invention is to provide a kind of injection using asarone as active component and preparation method thereof.
Namely asarone of the present invention is interpreted as alpha-ararin, but is not limited thereto, and β-asarone is suitable for the present invention too.
Injection of the present invention, it is characterized in that comprising alpha-ararin, HS15, propylene glycol, ethanol and pH adjusting agent, described injection solvent refers to water for injection.
As preferred embodiment, Asarone injection of the present invention, mainly comprises the alpha-ararin 1 part based on parts by weight, HS15 8 ~ 12 parts, propylene glycol 50 parts, ethanol (density is in 0.8) 12 parts and appropriate injection solvent.
Preferred embodiment be choose 8 parts, 10 parts, 12 parts HS15 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.Pharmaceutically acceptable various freeze drying protectant can be added, preferably mannitol in described freeze-dry process.
The method preparing alpha-ararin injection of the present invention, comprises the steps:
A, the alpha-ararin accurately taking recipe quantity, HS15, propylene glycol, measure ethanol, 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 DEG C, add HS15, stirring and dissolving, continue to add alpha-ararin under 60 ~ 70 DEG C of conditions, be stirred to dissolve, let cool to room temperature, add propylene glycol, ethanol successively, 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, mix homogeneously, and filter, subpackage, obtains alpha-ararin injection;
In d, above-mentioned steps b, after adding propylene glycol, ethanol successively, also can in freeze drying protectant: full dose water for injection ratio is that 10: 100 (g: ml) add freeze drying protectant mannitol, stirring and dissolving; Add to the full amount of water for injection, mix homogeneously, filter, subpackage, in-40 DEG C 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 the advantages such as technique is simple, with low cost, steady quality, safety is high, Clinical practice is convenient.
Therefore, the present invention will provide one Asarone injection safely and effectively for upper respiratory tract infection, bronchitis, bronchial asthma, acute and disease, particularly pneumonia, bronchial asthma and the chronic obstructive pulmonary disease acute attack patient such as chronic cholecystitis, cholelithiasis, epilepsy grand mal.
Detailed description of the invention
embodiment 1(based on the alpha-ararin 1 part of parts by weight, HS15 is 8 parts, and propylene glycol is 50 parts, and ethanol 12 parts is unsterilised)
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 DEG C of water bath condition, add 32g HS15, stirring and dissolving; Under 60 DEG C of water-baths, add 4g alpha-ararin, be stirred to dissolve, let cool to room temperature; Add 200g propylene glycol and 60ml ethanol successively, stir; Inject water to 950ml, be uniformly mixed; Regulate pH to 6.03 with 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 μm of filtering with microporous membrane, then through 0.22 μm of filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, leak detection, obtains alpha-ararin injection.
embodiment 2(based on the alpha-ararin 1 part of parts by weight, HS15 is 10 parts, and propylene glycol is 50 parts, and ethanol 12 parts is unsterilised)
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 DEG C of water bath condition, add 40g HS15, stirring and dissolving; Under 60 DEG C of water-baths, add 4g alpha-ararin, be stirred to dissolve, let cool to room temperature; Add 200g propylene glycol and 60ml ethanol successively, stir; Inject water to 950ml, be uniformly mixed; Regulate pH to 6.08 with 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 μm of filtering with microporous membrane, then through 0.22 μm of filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, leak detection, obtains alpha-ararin injection.
embodiment 3(based on the alpha-ararin 1 part of parts by weight, HS15 is 12 parts, and propylene glycol is 50 parts, and ethanol 12 parts is unsterilised)
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 DEG C of water bath condition, add 48g HS15, stirring and dissolving; Under 60 DEG C of water-baths, add 4g alpha-ararin, be stirred to dissolve, let cool to room temperature; Add 200g propylene glycol and 60ml ethanol successively, stir; Inject water to 950ml, be uniformly mixed; Regulate pH to 6.10 with 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 μm of filtering with microporous membrane, then through 0.22 μm of filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, leak detection, obtains alpha-ararin injection.
embodiment 4(based on the alpha-ararin 1 part of parts by weight, HS15 is 10 parts, and propylene glycol is 50 parts, ethanol 12 parts, 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, under 60 DEG C of water bath condition, add 40g HS15, stirring and dissolving; Under 60 DEG C of water-baths, add 4g alpha-ararin, be stirred to dissolve, let cool to room temperature; Add 200g propylene glycol, 60ml ethanol and 10g mannitol successively, stir; Add to the full amount of water for injection 1000ml, mix homogeneously, first through 0.45 μm of filtering with microporous membrane, then through 0.22 μm of filtering with microporous membrane, subpackage, in-40 DEG C of pre-freezes after 3 hours, evacuation, makes vacuum in drying baker reach below 13.33Pa, is slowly warming up to-20 DEG C, moisture in medicinal liquid is evaporated, obtains freeze-dried powder.
Embodiment 4 redissolves effect: embodiment 4 sample still clear after placing for a long time and redissolving for 7 months.
reference examples 1(based on the alpha-ararin 1 part of parts by weight, HS15 is 8 parts, and propylene glycol is 50 parts, ethanol 12 parts, 100 DEG C 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 DEG C of water bath condition, add 32g HS15, stirring and dissolving; Under 60 DEG C of water-baths, add 4g alpha-ararin, be stirred to dissolve, let cool to room temperature; Add 200g propylene glycol and 60ml ethanol successively, stir; Inject water to 950ml, be uniformly mixed; Regulate pH to 6.03 with 0.01mol/L hydrochloric acid solution, mend and inject water to full 1000ml, mix homogeneously, first through 0.45 μm of filtering with microporous membrane, then through 0.22 μm of filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, through 100 DEG C of sterilizings in 30 minutes, obtains alpha-ararin injection.
reference examples 2(based on the alpha-ararin 1 part of parts by weight, HS15 is 10 parts, and propylene glycol is 50 parts, ethanol 12 parts, 100 DEG C 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 DEG C of water bath condition, add 40g HS15, stirring and dissolving; Under 60 DEG C of water-baths, add 4g alpha-ararin, be stirred to dissolve, let cool to room temperature; Add 200g propylene glycol and 60ml ethanol successively, stir; Inject water to 950ml, be uniformly mixed; Regulate pH to 6.08 with 0.01mol/L hydrochloric acid solution, mend and inject water to full 1000ml, mix homogeneously, first through 0.45 μm of filtering with microporous membrane, then through 0.22 μm of filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, through 100 DEG C of sterilizings in 30 minutes, obtains alpha-ararin injection.
reference examples 3(based on the alpha-ararin 1 part of parts by weight, HS15 is 12 parts, and propylene glycol is 50 parts, ethanol 12 parts, 100 DEG C 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 DEG C of water bath condition, add 48g HS15, stirring and dissolving; Under 60 DEG C of water-baths, add 4g alpha-ararin, be stirred to dissolve, let cool to room temperature; Add 200g propylene glycol and 60ml ethanol successively, stir; Inject water to 950ml, be uniformly mixed; Regulate pH to 6.10 with 0.01mol/L hydrochloric acid solution, mend and inject water to full 1000ml, mix homogeneously, first through 0.45 μm of filtering with microporous membrane, then through 0.22 μm of filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, through 100 DEG C of sterilizings in 30 minutes, obtains alpha-ararin injection.
reference examples 4:obtained by CN101647774B embodiment 1, (specification is 2ml:10mg);
reference examples 5:obtained by CN101647774B embodiment 2, (specification is 2ml:10mg);
reference examples 6:obtained by CN101647774B embodiment 3, (specification is 2ml:10mg);
reference examples 7(obtaining according to patent CN101647774B [0032]-[0035] described method) (based on the alpha-ararin 1 part of parts by weight, HS15 is 10 parts, 115 DEG C 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 DEG C of water bath condition, stirring and dissolving; Add 2g active carbon, stirred at ambient temperature is decarburization filtration after 20 minutes; Filtrate, again through 0.22 μm of filtering with microporous membrane, mends the 1000ml that adds to the full amount of water for injection; Again through 0.22 μm of filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, through 115 DEG C of 30 minutes pressure sterilizings, obtain alpha-ararin injection.
reference examples 8(obtaining according to patent CN101647774B [0032]-[0035] described method) (based on the alpha-ararin 1 part of parts by weight, HS15 is 15 parts, 115 DEG C 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 DEG C of water bath condition, stirring and dissolving; Add 2g active carbon, stirred at ambient temperature is decarburization filtration after 20 minutes; Filtrate, again through 0.22 μm of filtering with microporous membrane, mends the 1000ml that adds to the full amount of water for injection; Again through 0.22 μm of filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, through 115 DEG C of 30 minutes pressure sterilizings, obtain alpha-ararin injection.
reference examples 9(obtaining according to patent CN101647774B [0032]-[0035] described method) (based on the alpha-ararin 1 part of parts by weight, HS15 is 25 parts, 115 DEG C 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 DEG C of water bath condition, stirring and dissolving; Add 2g active carbon, stirred at ambient temperature is decarburization filtration after 20 minutes; Filtrate, again through 0.22 μm of filtering with microporous membrane, mends the 1000ml that adds to the full amount of water for injection; Again through 0.22 μm of filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, through 115 DEG C of 30 minutes pressure sterilizings, obtain alpha-ararin injection.
embodiment 1-embodiment 3, reference examples 1-reference examples 9 study on the stability contrasts
(A) clarity
Detection method foundation: National Drug Administration drug standard Asarone Injectin WS-10001-(HD-0437)-2002 and " Chinese Pharmacopoeia " version annex Ⅸ H visible foreign matters inspection technique in 2010
Instrument and equipment: YB-3 type clarity detecting apparatus
Detection method: get this product 20, clean container outer wall, rotation and inverting container make the visible foreign matters existed in medicinal liquid suspend (noting not making medicinal liquid produce bubble) gently, respectively under black and white background, hand-held test sample cervical region makes medicinal liquid overturn gently, surveys (illumination: 1000 ~ 1500lx) with visual inspection.
Standard specifies: must not detect smoke-like microparticle column, metal fillings, chips of glass, length or maximum particle diameter more than the obviously alien material such as the fiber of 2mm and block.Fine visible foreign matters if any detecting only 1, then gets 20 with method retrial, all must not detect.
Placement condition: long-term stable experiment condition, temperature 25 DEG C ± 2 DEG C, humidity 60% ± 10%
Result:
Reference examples 1, reference examples 2, reference examples 3 are placed for a long time the defective phenomenon of clarity and are described: after sterilizing, clarity is qualified, and long-term to place clarity after 4 months still qualified, and after being placed into 5 months for a long time, a small amount of sample (accounting for 10%-30%) has microscopic grains to separate out.
Reference examples 4, reference examples 5, reference examples 6, reference examples 7, reference examples 8, the defective phenomenon of reference examples 9 clarity describe: after sterilizing, most finished product all has bulk oil droplet to separate out, and floats on liquid level or sticks at ampoule interior wall.The grease placing rear section sample can not disappear, and even produces white granular material floats in solution.
clarity study on the stability conclusion:1, the regulation requirement of existing " Chinese Pharmacopoeia " version in 2010 cannot be reached according to the Asarone Injectin clarity that patent documentation CN101647774B preparation method is obtained, cannot use as clinical medicine.2, the regulation requirement of existing " Chinese Pharmacopoeia " version in 2010 can be reached according to the Asarone Injectin clarity that patent documentation CN102973499A preparation method is obtained, but the effect duration of medicine can only be denoted as 5 months.
(B) drug content
Detection method foundation: National Drug Administration drug standard Asarone Injectin WS-10001-(HD-0437)-2002
Detection method: get this product 5, mixing, 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 annex 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 specifies: this product is the sterile water solution that asarone adds appropriate cosolvent and makes.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 not to be suitable for actual production and the use of Asarone Injectin by the Asarone injection liquid and preparation method thereof existing defects that patent documentation CN101647774B and CN102973499A proposes.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 States Pharmacopoeia specifications and the Asarone Injectin of clear.It is undesirable that the defect of patent documentation CN102973499A is mainly that finished product places rear clarity for a long time, and the effect duration of the Asarone Injectin medicine causing this explained hereafter to go out is too short, inconvenient actual storage and using.And the present invention overcomes this two technical barriers just, the stable content, the clear and have the Asarone Injectin of longer effect duration that meet existing States Pharmacopoeia specifications can be produced.
embodiment 2 and reference examples 2 safety contrast
The relatively safety of the Asarone Injectin of the embodiment of the present invention 2 and reference examples 2.
one, product preparation
embodiment 2(based on the alpha-ararin 1 part of parts by weight, HS15 is 10 parts, and propylene glycol is 50 parts, and ethanol 12 parts is unsterilised)
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 DEG C of water bath condition, add 40g HS15, stirring and dissolving; Under 60 DEG C of water-baths, add 4g alpha-ararin, be stirred to dissolve, let cool to room temperature; Add 200g propylene glycol and 60ml ethanol successively, stir; Inject water to 950ml, be uniformly mixed; Regulate pH to 6.08 with 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 μm of filtering with microporous membrane, then through 0.22 μm of filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, leak detection, obtains alpha-ararin injection.
reference examples 2(based on the alpha-ararin 1 part of parts by weight, HS15 is 10 parts, and propylene glycol is 50 parts, ethanol 12 parts, 100 DEG C 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 DEG C of water bath condition, add 40g HS15, stirring and dissolving; Under 60 DEG C of water-baths, add 4g alpha-ararin, be stirred to dissolve, let cool to room temperature; Add 200g propylene glycol and 60ml ethanol successively, stir; Inject water to 950ml, be uniformly mixed; Regulate pH to 6.08 with 0.01mol/L hydrochloric acid solution, mend and inject water to full 1000ml, mix homogeneously, first through 0.45 μm of filtering with microporous membrane, then through 0.22 μm of filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, through 100 DEG C of sterilizings in 30 minutes, obtains alpha-ararin injection.
two, safety testing
Safety judgment basis: according to different prescription products, initiatively hypersensitive difference and degree are produced to Cavia porcellus and compare its safety.
Animal experiment unit: Chengdu qi xanthate thing non-clinical study company limited
1, experiment material:
medicine
The name of an article: Asarone Injectin
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: be grown up a 16 ~ 24mg, and child 0.5mg/kg, is diluted to the solution of 0.01% ~ 0.02%, intravenous drip with 5% or 10% glucose injection, 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 in test product Cmax: 24mg/40ml=0.6mg/ml.
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
Cavia porcellus 36, body weight 251.7 ~ 335.2g, 18 is female 18 male, meets primary animal standard, provided, animal productiong credit 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, temperature 16 ~ 26 DEG C, 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, upper current chart level instruments and meters 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
Observe and test in Chengdu Animal House Cavia porcellus observation ward of qi xanthate thing non-clinical study company limited during test, animal occupancy permit number: SYXK(river) 2010-096.
Select reason: according to " Chemical induced irritation, anaphylaxis and hemolytic investigative technique guideline " hypersensitive test choice for use Cavia porcellus, be Primary Assay animal, therefore raise in open systems and observe.
3, test grouping
Get Cavia porcellus 36, 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 Injectin reference examples 2);
Low dose group 1(Asarone Injectin reference examples 2);
High dose group 2(Asarone Injectin embodiment 2);
Low dose group 2(Asarone Injectin embodiment 2);
4, test method
Dosage and cycle design: in hypersensitive test, for fully exposing the immunogenicity of medicinal liquid, should select concentration is maximum, dosage is maximum clinical administration as a reference.Therefore consider with clinical daily maximal dose 1.2mg/kg for dosage reference, with the clinical test product Cmax 0.6mg/ml that is subject to for concentration reference.
Dosage period 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 controls prepares: get 10% glucose injection for subsequent use.
Before sensitization, positive reference substance prepares: take appropriate egg protein powder, be dissolved in 10% glucose injection and be made into the solution for standby that concentration is 2mg/ml.
Prepare by test product before sensitization: high dose group 1: get Asarone Injectin 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 Injectin 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 Injectin 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 Injectin embodiment 2 and add the solution for standby that 10% glucose injection is diluted to concentration 0.6mg/ml.
Method of sensitization: each group is carried out sensitization by 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 Injectin reference examples 2 to prepare; High dose group 2 and low dose group 2 adopt Asarone Injectin embodiment 2 to prepare.
Front negative controls is excited 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.
Prepare by test product before exciting: high dose group 1: get Asarone Injectin 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 Injectin 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 Injectin 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 Injectin 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 excite by 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 Injectin reference examples 2 to prepare; High dose group 2 and low dose group 2 adopt Asarone Injectin embodiment 2 to prepare.
For the first time, last sensitization and excited measured the body weight often organizing every animal the same day.
After each sensitization and excite at once to 30 minute after intravenous injection, according to the form below 5 observes 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 normal, and situation without exception occurs.
Excite rear allergic conditions 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 Injectin reference examples 2 to prepare; High dose group 2 and low dose group 2 adopt Asarone Injectin embodiment 2 to prepare.
Note: high dose group 1 and low dose group 1 adopt Asarone Injectin reference examples 2 to prepare; High dose group 2 and low dose group 2 adopt Asarone Injectin embodiment 2 to prepare.
Each group is compared * * * 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 compares 000 P3<0.001 00 P3<0.01 zero P3<0.05 with high dose group 1
Low dose group 2 compares P4<0.001 P4<0.01 P4<0.05 with low dose group 1
Table 7,8 results displays: Asarone Injectin whole body is initiatively in sensitivity test, 1., negative control group, positive controls and two batches batches of Asarone Injectin duration of test respectively organize Cavia porcellus body weight increases all to some extent, body weight zero difference between each group.2., negative control group Cavia porcellus excites rear anaphylaxis negative, and positive controls Cavia porcellus excites the extremely strong positive of rear anaphylaxis, and positive controls and negative control group have pole significant difference (P<0.001), shows that test data accuracy is high; 3., low dose group 1, with negative control group anaphylaxis be feminine gender, zero difference, have pole significant difference (P<0.001) with positive controls; Low dose group 2 and negative control group anaphylaxis are feminine gender, zero difference, have pole 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
Show according to the experimental study of Asarone Injectin systemic anaphylaxis, the safety of the embodiment of the present invention 2 Asarone Injectin [adopting HS15 to be made by the aseptic filtration production technology (i.e. aseptic processing) of empirical tests as cosolvent and asarone as solubilizing agent, propylene glycol and ethanol] and reference examples 2 Asarone Injectin
[(patent documentation CN102973499A embodiment 2), HS15 is adopted to be made by 100 DEG C of sterilizings in 30 minutes with asarone as cosolvent 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 (1)
1. a preparation method for Asarone Injectin, is characterized in that: 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 DEG C of water bath condition, add 40g HS15, stirring and dissolving; Under 60 DEG C of water-baths, add 4g alpha-ararin, be stirred to dissolve, let cool to room temperature; Add 200g propylene glycol and 60ml ethanol successively, stir; Inject water to 950ml, be uniformly mixed; Regulate pH to 6.08 with 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 μm of filtering with microporous membrane, then through 0.22 μm of filtering with microporous membrane, be sub-packed in 2ml ampoule, sealing by fusing, leak detection, obtains alpha-ararin injection.
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| CN201310114184.XA CN103142515B (en) | 2012-12-21 | 2013-04-03 | Asarone injection and preparation method thereof |
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| CN 201210561393 CN102973499A (en) | 2012-12-21 | 2012-12-21 | Asarone injection and preparation method thereof |
| CN201210561393.4 | 2012-12-21 | ||
| CN201310114184.XA CN103142515B (en) | 2012-12-21 | 2013-04-03 | Asarone injection and preparation method thereof |
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| 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 |
| CN201310114184.XA Active CN103142515B (en) | 2012-12-21 | 2013-04-03 | Asarone injection and preparation method thereof |
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| 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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| 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 |
| CN104857516B (en) * | 2015-05-12 | 2017-11-10 | 张蕊 | A kind of Asarone Injectin and its preparation technology |
| 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 |
| EP4205734A4 (en) * | 2021-07-22 | 2024-05-01 | Univ Sichuan | Application of alpha-asarone in preparation of medicine for preventing or treating hemorrhagic stroke |
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| CN102973499A (en) * | 2012-12-21 | 2013-03-20 | 张蕊 | Asarone injection and preparation method thereof |
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- 2013-04-03 CN CN201310114183.5A patent/CN103877012A/en not_active Withdrawn
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| CN102973499A (en) * | 2012-12-21 | 2013-03-20 | 张蕊 | Asarone injection and preparation method thereof |
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| Title |
|---|
| 细辛脑氯化钠注射液的研究;廖娟娟;《中国优秀硕士学位论文全文数据库医药卫生科技辑》;20120715(第7期);第14-15页 * |
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| CN103142515A (en) | 2013-06-12 |
| CN103877011A (en) | 2014-06-25 |
| CN103877012A (en) | 2014-06-25 |
| CN102973499A (en) | 2013-03-20 |
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