CN101357119B - Medicine microemulsion injection composition and preparation method thereof - Google Patents
Medicine microemulsion injection composition and preparation method thereof Download PDFInfo
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- CN101357119B CN101357119B CN2007100295417A CN200710029541A CN101357119B CN 101357119 B CN101357119 B CN 101357119B CN 2007100295417 A CN2007100295417 A CN 2007100295417A CN 200710029541 A CN200710029541 A CN 200710029541A CN 101357119 B CN101357119 B CN 101357119B
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Abstract
The invention relates to a combination of medicine microemulsion injecta and the preparation method thereof. The technical problem to be resolved by the invention overcomes the defect that the current medicine microemulsion injecta is not stable. The medicine microemulsion injecta of the invention contains basic remedy, oil for injection, an emulsifier, an auxiliary emulsifier, a pH modifier, an antioxidant and water for injection. The emulsifier contains polyoxyethylene castor oil, poloxamer, phospholipid, and cholate or deoxidization cholate. The proportion by weight of four components of the emulsifier is 1:0.02-0.1:0.1-0.5:0.001-0.02. The combination and the preparation method of the invention have the advantages of convenient operation and stable product quality, and are widely suitable for the preparation process of various microemulsion preparations.
Description
Technical field
The present invention relates to a kind of medicine microemulsion injection composition and preparation method thereof.
Background technology
Single emulsifying agent, co-emulsifier, oil phase and the water of adopting promptly can be made into microemulsion more in the microemulsion commonly used at present, but all exist instability; Can not be by water or other solvent dilution; In sterilization process, because emulsifying agent point covered with clouds, cause the problems such as layering or muddiness of microemulsion.
Summary of the invention
The technical problem that the present invention will solve is the above-mentioned defective that how to overcome existing medicine microemulsion injection composition, a kind of good stability is provided, point covered with clouds can occur during diluted and sterilization easily, is difficult for layering, is difficult for muddy medicine microemulsion injection composition and preparation method thereof.
For solving the problems of the technologies described above; Medicine microemulsion injection composition of the present invention; Comprise principal agent, oil for injection, emulsifying agent, co-emulsifier, PH regulator, antioxidant and water for injection; Said emulsifying agent comprises polyoxyethylene castor oil, poloxamer, phospholipid, it is characterized in that: also comprise cholate or deoxycholate in the said emulsifying agent, four kinds of component weight ratios of this emulsifying agent are: 1:0.02～0.1:0.1～0.5:0.001～0.02.So design not only helps the stable of phospholipid, and has increased the dissolubility of nimodipine.Cholate, deoxycholate can be sodium salts, also can be potassium salt.
As optimization, said co-emulsifier is for mixing co-emulsifier, and this mixes co-emulsifier and is made up of ethanol and PEG400, and the weight ratio of ethanol and PEG400 is 1:0.3～10.
As optimization, said principal agent is a nimodipine, contains among every 100ml: nimodipine 0.01～0.2g, oil for injection 2～10g, emulsifying agent 5～30g, co-emulsifier 5～30g, isoosmotic adjusting agent, pH regulator agent, antioxidant are an amount of, and all the other are water for injection.Nimodipine is suitable for improving cerebral blood flow.According to the nimodipine microemulsion injection composition good stability of above-mentioned formulation, point covered with clouds, not stratified, haze-free can not appear when easily dilutable and sterilization.
The method for preparing of said medicine microemulsion injection composition comprises that the following step gathers:
1., the preparation of oil phase: in preparing tank, add oil phase under the room temperature, add nimodipine then, stirring and evenly mixing; Add polyoxyethylene castor oil, stirring and evenly mixing dissolves nimodipine fully; As solution A, under nitrogen, phospholipid is added in the ethanol; Make the phospholipid dissolving, alcoholic solution, PEG400 and the antioxidant with phospholipid joins in the above-mentioned solution A again, mixes.
2., the preparation of water: under the room temperature, poloxamer is added in the water of about 2 times of amounts, make the poloxamer dissolving; Sodium cholate or sodium deoxycholate are dissolved in an amount of water; Under stirring,, slowly join in the above-mentioned mixing oil phase the aqueous solution of poloxamer aqueous solution and sodium cholate or sodium deoxycholate; Add to the full amount of water for injection gradually 80%; Add isoosmotic adjusting agent, pH regulator agent as required, regulate pH to 5.0～7.5, stir.
3., in above-mentioned solution, add 0.05%～0.1% needle-use activated carbon, 40 ℃ of absorption 30 minutes filters through 0.22 μ m microporous filter membrane, adds to the full amount of water for injection, and promptly get the nimodipine microemulsion injection composition, sterilizes, and gets final product.
Said before the consumption of each component in gathering in the above-mentioned step.So design is easy to operate, constant product quality.
After adopting technique scheme; That medicine microemulsion injection composition of the present invention, particularly nimodipine microemulsion injection composition have is stable, when easily dilutable and sterilization, not stratified, point covered with clouds do not occur; Haze-free advantage; The method for preparing of medicine microemulsion injection composition of the present invention has easy to operate, and the advantage of constant product quality prepares in the process adaptable across various microemulsion medicaments.
Description of drawings
Fig. 1 is the nimodipine microemulsion injection freeze etching Electronic Speculum picture by the inventive method preparation;
Fig. 2 is the nimodipine microemulsion injection particle size distribution figure by the inventive method preparation.
The specific embodiment:
Be described further in the face of the present invention down:
Embodiment 1:
Prescription: nimodipine 0.1g
Polyoxyethylene castor oil 10.0g
Poloxamer 0.8g
Phosphatidase 13 .0g
Sodium cholate 0.05g
Dehydrated alcohol 3.0g
PEG400 1.0g
Middle chain triglyceride 1.6g
Tocopherol 0.1g
Glucose 5.0g
Water for injection adds to 100ml
Technology:
1, the preparation of oil phase: in preparing tank, add middle chain triglyceride under the room temperature, add nimodipine then, stirring and evenly mixing.Add polyoxyethylene castor oil, stirring and evenly mixing dissolves nimodipine, as solution A fully.Phospholipid is added in the ethanol, make the phospholipid dissolving.Alcoholic solution, PEG400 and tocopherol with phospholipid joins in the above-mentioned solution A again, mixes.
2, under the room temperature, poloxamer is added in about 2g water, make the poloxamer dissolving.Sodium cholate is dissolved in an amount of water.Under stirring, with the aqueous solution of poloxamer aqueous solution and sodium cholate, slowly join in the above-mentioned mixing oil phase, add the injection water gradually to 80ml, after the dissolving of adding glucose, using sodium hydroxide solution to regulate pH is 7.0, stirs.
3, the needle-use activated carbon of adding 0.05% in above-mentioned solution, 40 ℃ adsorbed 30 minutes, filtered through 0.22 μ m microporous filter membrane, added to the full amount of water for injection.115 ℃ of pressure sterilizings 30 minutes.Promptly get the nimodipine microemulsion injection composition, for having a little light blue opalescent clear liquid, mean diameter is 56.2nm.
Embodiment 2:
Prescription: nimodipine 0.2g
Polyoxyethylene castor oil 6.0g
Poloxamer 0.6g
Phosphatidase 11 .0g
Sodium deoxycholate 0.15g
Dehydrated alcohol 2.0g
PEG400 1.5g
Middle chain triglyceride 1.5g
Tocopherol 0.1g
Sodium chloride 0.9g
Water for injection adds to 100ml
Technology:
1, the preparation of oil phase: in preparing tank, add middle chain triglyceride under the room temperature, add nimodipine then, stirring and evenly mixing.Add polyoxyethylene castor oil, stirring and evenly mixing dissolves nimodipine, as solution A fully.Phospholipid is added in the ethanol, make the phospholipid dissolving.Alcoholic solution, PEG400 and tocopherol with phospholipid joins in the above-mentioned solution A again, mixes.
2, under the room temperature, poloxamer is added in about 1.5g water, make the poloxamer dissolving.Sodium deoxycholate is dissolved in an amount of water.Under stirring, with the aqueous solution of poloxamer aqueous solution and sodium deoxycholate, slowly join in the above-mentioned mixing oil phase, add the injection water gradually to 80ml, after the dissolving of adding sodium chloride, using sodium hydroxide solution to regulate pH is 6.5, stirs.
3, the needle-use activated carbon of adding 0.05% in above-mentioned solution, 40 ℃ adsorbed 30 minutes, filtered through 0.22 μ m microporous filter membrane, added to the full amount of water for injection.115 ℃ of pressure sterilizings 30 minutes.Promptly get the nimodipine microemulsion injection composition, for having a little light blue opalescent clear liquid, mean diameter is 43.6nm.
Poloxamer changes respectively gets 0.12g, 0.36g, 0.6g, and all the other components and consumption are constant, repeat above-mentioned method for preparing, and gained nimodipine microemulsion injection composition has similar advantage at aspects such as stability, dilution property, so slightly.
Phospholipid changes respectively gets 0.6g, 1.8g, 3.0g, and all the other components and consumption are constant, repeat above-mentioned method for preparing, and gained nimodipine microemulsion injection composition has similar advantage at aspects such as stability, dilution property, so slightly.
Sodium deoxycholate changes respectively gets 0.006g, 0.063g, 0.12g, and all the other components and consumption are constant, repeat above-mentioned method for preparing, and gained nimodipine microemulsion injection composition has similar advantage at aspects such as stability, dilution property, so slightly.
PEG400 changes respectively gets 0.12g, 6.0g, 6.0g, and all the other components and consumption are constant, repeat above-mentioned method for preparing, and gained nimodipine microemulsion injection composition has similar advantage at aspects such as stability, dilution property, so slightly.
Replace sodium deoxycholate with sodium cholate, cholic acid potassium, deoxycholic acid potassio respectively, gained nimodipine microemulsion injection composition has similar advantage at aspects such as stability, dilution property, so slightly.
Embodiment 3:
Prescription: nimodipine 0.15g
Polyoxyethylene castor oil 6.5g
Poloxamer 0.8g
Phosphatidase 11 .2g
Sodium deoxycholate 0.04g
Dehydrated alcohol 2.5g
PEG400 1.5g
Injection soybean oil 1.0g
Water for injection adds to 100ml
Technology:
1, the preparation of oil phase: in preparing tank, add the injection soybean oil under the room temperature, add nimodipine then, stirring and evenly mixing.Add polyoxyethylene castor oil, stirring and evenly mixing dissolves nimodipine, as solution A fully.Phospholipid is added in the ethanol, make the phospholipid dissolving.Alcoholic solution and PEG400 with phospholipid joins in the above-mentioned solution A again, mixes.
2, under the room temperature, poloxamer is added in about 2g water, make the poloxamer dissolving.Sodium deoxycholate is dissolved in an amount of water.Under stirring, with the aqueous solution of poloxamer aqueous solution and sodium deoxycholate, slowly join in the above-mentioned mixing oil phase, add the injection water gradually to 80ml, using sodium hydroxide solution to regulate pH is 7.0, stirs.
3, the needle-use activated carbon of adding 0.1% in above-mentioned solution, 40 ℃ adsorbed 30 minutes, filtered through 0.22 μ m microporous filter membrane, added to the full amount of water for injection.115 ℃ of pressure sterilizings 30 minutes.Promptly get the nimodipine microemulsion injection composition, for having a little light blue opalescent clear liquid, mean diameter is 51.8nm.
Embodiment 4:
Prescription: hexestrol 0.50g
Polyoxyethylene castor oil 8.0g
Poloxamer 0.8g
Phosphatidase 11 .5g
Sodium cholate 1.6g
Dehydrated alcohol 4.0g
PEG400 2.4g
Middle chain triglyceride 2.0g
Water for injection adds to 100ml
1, the preparation of oil phase: in preparing tank, add middle chain triglyceride under the room temperature, add hexestrol then, stirring and evenly mixing.Add polyoxyethylene castor oil, stirring and evenly mixing is as solution A.Phospholipid is added in the ethanol, make the phospholipid dissolving.Alcoholic solution and PEG400 with phospholipid joins in the above-mentioned solution A again, mixes.
2, under the room temperature, poloxamer is added in about 2g water, make the poloxamer dissolving.Sodium cholate is dissolved in an amount of water.Under stirring, with the aqueous solution of poloxamer aqueous solution and sodium cholate, slowly join in the above-mentioned mixing oil phase, add the injection water gradually to 80ml, stir, regulate pH to 6.5, stir.
3, the needle-use activated carbon of adding 0.08% in above-mentioned solution, 40 ℃ adsorbed 30 minutes, filtered through 0.22 μ m microporous filter membrane, added to the full amount of water for injection.115 ℃ of pressure sterilizings 30 minutes.Promptly get the hexestrol microemulsion injection composition, for having a little light blue opalescent clear liquid, mean diameter is 68.2nm.
The same as hexestrol; Substitute nimodipine with other principal agents that need prepare microemulsion injection; Have good stability equally, point covered with clouds can not occur during diluted and sterilization easily, be difficult for layering, be difficult for muddy advantage, slightly by the microemulsion injection medicament of said ratio, method preparation.
Observe form, granularity, measure of spread, study on the stability, bioavailability, zest, anaphylaxis, hemolytic test.
(1) morphology research
Pumping high vacuum to 3 * 10
-7Mbar is cooled to-120 ℃, with the rapid freezing microemulsion sample of liquid nitrogen, with sample transfer to freeze etching appearance, 3 * 10
-7Mbar gets under fine vacuum and-120 ℃ of states, and etched sample after one minute, in 45 ℃ of spray Pt, 90 ℃ of spray C, is taken out sample, in water, drags for film with copper mesh, dries last sem observation and photograph.Observe the nimodipine microemulsion under the Electronic Speculum and be the evenly spheroidal particle of rule of size.See Fig. 1.
(2) particle diameter and measure of spread thereof
The microemulsion sample of getting preparation is an amount of, measures particle diameter and distribution thereof with the laser particle size scatterometer.
The nimodipine microemulsion particle size distribution that the laser particle size scatterometer records is even, and mean diameter is 43.6nm, and polydispersity coefficient 0.277 is Gauss and distributes.Meet the particle diameter requirement of microemulsion.See Fig. 2.
(3) study on the stability
Influence factor's experiment: place 60 ℃ in baking oven, refrigerator to place 10 days for 4 ℃ the nimodipine microemulsion of preparation, in 0,5,10 day last sampling and measuring; Thermal cycle experiment three times (sample is placed-20 ℃ to place at every turn 2 days, be heated to 40 ℃ of placements then and measured in two days).Investigate items such as index appearance character, pH value, particle diameter, envelop rate, content, related substance.Microemulsion is under 60 ℃ of experimental conditions as a result, and pH value slightly descends, and related substance slightly increases; Under the illumination condition, solution colour becomes buff, and content is extremely low, shows that nimodipine sees that auroral poles be prone to decompose, and other indexs have no significant change.These article of prompting answer room temperature to keep in Dark Place.
Accelerated tests: place 40 ℃ of water isolation type electro-heating standing-temperature cultivators to place 6 months the nimodipine microemulsion of preparation, respectively at 0,1,2,3,6 the end of month sampling and measuring.The investigation index is the same, simultaneously aseptic the and pyrogen of inspection at 6 the end of month.The nimodipine microemulsion all is clears or has a little light blue opalescent thermodynamically stable weak yellow liquid as a result, does not see layering, flocculation, merges, breaks.Particle diameter, envelop rate, content, related substance all do not have the generation obvious variation.
Experimental data contrast table (the nimodipine microemulsion that the inventive method and conventional method prepare respectively)
Explain: the inventive method: added sodium cholate or sodium deoxycholate; Used the mixing co-emulsifier of ethanol and Polyethylene Glycol.
Conventional method: do not use sodium cholate or sodium deoxycholate; List uses ethanol or but uses Polyethylene Glycol to be co-emulsifier.
(4) bioavailability and the test of targeting property
This test adopts the HPLC method to measure the blood drug level of the nimodipine in the mice plasma, estimates the bioavailability and the targeting property of the quiet notes of nimodipine microemulsion with this.The contrast medicine is commercially available nimotop vial.
Chromatographic condition: with the octadecylsilane chemically bonded silica is filler, and the detection wavelength is 237nm, is mobile phase with acetonitrile-water (65:35), and flow velocity is 1.0ml/min.
Administration and sampling: mice administration fasting in preceding 12 hours, freely drink water, 10 groups of tail vein injection nimodipine microemulsions (content 0.4mg/ml) wherein, (0.25mg/kg, 0.25ml/20g) administration is as experimental group by the mice body weight.Other 10 groups of tail vein injection nimotop vials (same dose) are as matched group.Experimental group and matched group 0.08 (5min), 0.33 (20min), 0.5 (30min), 45min, 1.0h, 1.5,2,3,4,6h after administration pluck eyeball respectively and get blood; Put to death a treated animal immediately after getting blood; Get each time point blood plasma, brain, liver, spleen, heart sample immediately, measure after the sample treatment.The peak area that records is calculated the concentration of nimodipine in blood plasma, brain, the liver with external standard method.
The result shows: (1) nimodipine microemulsion has higher concentration in cerebral tissue, but concentration and PC there was no significant difference in the brain (P>0.05), each tissue concentration distribution order is a brain in the body>and blood plasma>liver.(2) the nimodipine microemulsion injection is higher than commercially available nimotop vial bioavailability; But there was no significant difference (P>0.05); Content is very little in the commercially available nimotop vial cerebral tissue liquid, has significant difference (P < 0.05) with nimodipine microemulsion injection ratio.
(5) zest, anaphylaxis, hemolytic test
Animal: albino guinea-pig body weight 250-300g, male and female dual-purpose; White big ear rabbit: body weight 2.8kg, male; Provide by Tsing-Hua University's medical college Experimental Animal Center.
Sensitivity test: 18 of extracting waste Cavia porcelluss, male and female dual-purpose, body weight 250-300g; Be divided into the confession reagent at random, three groups of negative control medicine and positive control drugs, every group of 6 Cavia porcelluss; Abdominal cavity nimodipine microemulsion injection solution 0.5ml/ only next day of supplying the reagent group respectively then; Lumbar injection is 0.9% sodium chloride solution 0.5ml/ the next day of negative control medicine group difference, and lumbar injection is 5% egg protein solution 0.5ml/ the next day of the positive controls difference, continuous three times; And then will supply reagent group, negative control group and positive controls to be divided into two groups respectively at random; 3 Cavia porcelluss of every group, first group the 14th day in the injection back, second group are in injecting the back the 21st day, by auricular vein injection original liquid 1ml/ only; And observe behind each medicine of injection in 15 minutes that Cavia porcellus has or not perpendicular hair, dyspnea, sneeze, dry cough or phenomenon such as cough 3 in two or more persons or one of rale, tic, collapse or phenomena of mortality person is arranged, be judged to allergic phenomena.The result shows: nimodipine microemulsion injection group Cavia porcellus is 14d after injection first; Again by auricular vein injection nimodipine microemulsion 1ml/ only, hair, cough, dyspnea, spasm, tic and even death all appear obviously trembling, erecting in 3 Cavia porcelluss in 15 minutes.Show that this batch preparation does not have anaphylaxis to take place.
The hemolytic test; Prepare 2% red cell suspension: get tame Sanguis Leporis seu oryctolagi 10ml, remove Fibrinogen after, put into the conical beaker jolting 10min that cleaning fills glass bead; After removing Fibrinogen, add about 10 times of amount 0.9% sodium chloride solutions, shake up; Centrifugal with 3000r/min, abandoning supernatant, deposition erythrocyte; Till reuse 0.9% sodium chloride solution cyclic washing to the redfree, measure blood cell, be configured to 2% red cell suspension with 0.9% sodium chloride solution.Method of testing: get 7 of clean tube, once add 2% red cell suspension and 0.9% sodium chloride solution by the table proportional quantity, behind the mixing; Place 30min in 37 degrees centigrade of waters bath with thermostatic control, add not commensurability nimodipine microemulsion injection then respectively, the 6th pipe does not add medicinal liquid and does the negative control pipe; The 7th pipe does not also add medicinal liquid, and 0.9% sodium chloride solution changes adding distil water, does the positive control pipe; After each test tube all shakes up, put in 37 degrees centigrade of waters bath with thermostatic control, begin to observe and put into back 15min, 30min, 45min, 1h, 2h, 3h, 4h and have or not haemolysis and RCA to occur; In the time of in the result of the test application of sample time, do not see erythrocytolysis and hemagglutination to occur.
The blood vessel irritation test: get 6 of rabbit, male, body weight 2.5-2.8kg is divided into two groups, three every group.The medication group only slowly injects nimodipine microemulsion injection solution 5.0ml/ for the rabbit auricular vein with asepsis injector every day, matched group injection equivalent 0.9% sodium chloride solution, all once a day; Continuous three days, 30 fens execution rabbit behind the last medicine, clip injection site ear; It is fixing to put into 10% formalin behind the labelling; FFPE, section, HE dyeing, light microscopic is observed blood vessel down and is had or not degeneration and tissue necrosis.Light microscopic is observed down, and the rabbit blood vessel does not have degeneration and necrosis, and this batch nimodipine microemulsion injection does not have obvious irritation to blood vessel.
Claims (1)
1. medicine microemulsion injection composition,
Prescription:
Technology:
1., the preparation of oil phase: in preparing tank, add middle chain triglyceride under the room temperature, add nimodipine then, stirring and evenly mixing; Add polyoxyethylene castor oil, stirring and evenly mixing dissolves nimodipine fully; As solution A, phospholipid is added in the dehydrated alcohol, make the phospholipid dissolving; Ethanol solution, PEG400 and tocopherol with phospholipid joins in the above-mentioned solution A again, mixes;
2., under the room temperature, poloxamer is added in the 1.5g water, make the poloxamer dissolving; Sodium deoxycholate is dissolved in an amount of water, under stirring, the aqueous solution of poloxamer aqueous solution and sodium deoxycholate; Slowly join in the above-mentioned mixing oil phase, add the injection water gradually, after the dissolving of adding sodium chloride to 80ml; Using sodium hydroxide solution to regulate pH is 6.5, stirs;
3., 2. add 0.05% needle-use activated carbon in the gained solution in step; 40 ℃ adsorbed 30 minutes, filtered through 0.22 μ m microporous filter membrane, added to the full amount of water for injection; 115 ℃ of pressure sterilizings 30 minutes; Promptly get the nimodipine microemulsion injection composition, for having a little light blue opalescent clear liquid, mean diameter is 43.6nm.
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| CN102525917B (en) * | 2012-01-04 | 2014-06-18 | 四川百利药业有限责任公司 | Nimodipine micelle injection and preparation method thereof |
| CN104415336B (en) * | 2013-08-28 | 2019-05-03 | 沈阳药科大学 | The composition and its application in pharmaceutical preparation that poloxamer plays phenomenon covered with clouds can be eliminated |
| CN114224829A (en) | 2014-06-27 | 2022-03-25 | 玫帝托克斯股份有限公司 | Preparation of cholic acid and salt for reducing fat and application thereof |
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