CN101422454A - Omega-3 polyunsaturated fatty acid tanshinone IIA sub-microemulsion and preparation method thereof - Google Patents
Omega-3 polyunsaturated fatty acid tanshinone IIA sub-microemulsion and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a stable Tanshinone IIA submicron emulsion and a preparation method thereof. The characteristic of Omega-3 polyunsaturated fatty acid for dissolving high-purity Tanshinone IIA is utilized and the pharmacological action of the Omega-3 polyunsaturated fatty acid is combined for preparing the stable Tanshinone IIA submicron emulsion. The stable Tanshinone IIA submicron emulsion of the Omega-3 polyunsaturated fatty acid obtained by the invention has better stability; animal test proves that the stable Tanshinone IIA submicron emulsion has no anaphylactic reaction, no hemolytic reaction and no agglutination reaction, and has no local thrill; and the stable Tanshinone IIA submicron emulsion not only can be prepared into an injection preparation, but also can be prepared into an oral dripping agent.
Description
Technical field
The present invention relates to Tanshinone I I
AThe preparation method of preparation submicron emulsion preparation belongs to the medicament art.
Background technology
Radix Salviae Miltiorrhizae is a labiate, has stasis-dispelling and pain-killing, promoting blood circulation to restore menstrual flow, and clearing away heart-fire the effect of the stasis of blood.Radix Salviae Miltiorrhizae is used as medicine and has a long history in China.Song Xiaomei, Tang Zhishu edit " chemical composition of Chinese materia medica extraction separation and preparation " (People's Health Publisher, 2004:4 136-138), people such as Zhou Liyun deliver [Radix Salviae Miltiorrhizae and chemical constituent Progress in Pharmacokinetics thereof] in 2005 the 3rd phases " Chinese experimental pharmacology of Chinese medical formulae magazine " and point out respectively: the Radix Salviae Miltiorrhizae main chemical compositions is divided into liposoluble constituent and water soluble ingredient, wherein Tanshinone I, Tanshinone I I
A, Tanshinone I I
B, cryptotanshinone is fat-soluble phenanthrenequione compounds.Salviol acid A, B, C, danshensu, and protocatechualdehyde be water soluble ingredient.Point out in Yang Xiuwei chief editor " Chinese medicine ingredients metabolic analysis ": Radix Salviae Miltiorrhizae extract biological metabolism in body shows that TANSHINONES has the strongest biological activity (Chinese Medicine science and technology publishing house, 2003:9 98).
At present to Tanshinone I I
AResearch mainly concentrate on study of pharmacy, clinical practice and contain Radix Salviae Miltiorrhizae ingredient Tanshinone I I
AAspects such as quality arbitration.Show Tanshinone I I from many documents
AHave at aspects such as cardiovascular prevention and treatment, antitumor, anticancer, antiinflammatories therapeutic effect (for example, Wang Xinxing, You Jiemei. Tanshinone I I
ALow density lipoprotein, LDL is caused the research of cattle blood vessel endothelial injury. Chinese J Pharmacol Toxicol, 1993; 7 (2): 157-158; Song Yi, Emperor Yao, Pan Xiaoou. TANSHINONES antitumor action progress. Chinese Hospitals pharmaceutical journal, 2004; 24 (10): 637-638; Chang Ming, Tanshinone I I
AProgress at cardiovascular effect. the Henan traditional Chinese medical science, 2006; 26 (1): 85-87; The 01130086.6th application for a patent for invention etc.).
At present, list 16 of China national drug standards in as ingredient, include 4 of version Chinese Pharmacopoeias in 2005 in Radix Salviae Miltiorrhizae, Radix Salviae Miltiorrhizae extract.Though Radix Salviae Miltiorrhizae Injection and FUFANG DANSHEN ZHUSHEYE are widely used in treatment cardiovascular and cerebrovascular disease, hepatorenal disease and have received satisfied effect, exist fatal untoward reaction phenomenon clinically and many-sided clinical report is arranged.For example 2004 3 phases " medicine evaluation " and 2005 9 phases " Chinese Hospitals pharmaceutical journal " are reported 164 examples respectively and 119 routine FUFANG DANSHEN ZHUSHEYE cause anaphylaxis and allergy causes shock.In order to address this problem, the medicine worker takes meticulous extraction Radix Salviae Miltiorrhizae active component Tanshinone I I
AAnd make further sulfonating reaction and prepare water soluble drug.
Application number is to show in 200310125178,2003101111509,200310121026,200510064376 patents of invention, because Tanshinone I I
ASodium sulfonate sees that light chance heat is very unstable, and particularly decomposing under solution state increases Tanshinone I I behind the high temperature sterilize
ASodium sulfonate content descends.The foregoing invention patent adopts various antioxidants, stabilizing agent, excipient to make Tanshinone I I
AThe sodium sulfonate lyophilized injectable powder is to solve Tanshinone I I
AThe stability problem of sodium sulfonate.Application number 200410002103,200510035691,200510040386,200510051478,200510090487 patents of invention are described, adopt stabilizing agent sodium sulfite or vitamin C, cysteine salt, disodium edetate etc., adopt way solution Tanshinone I I such as photophobic outer package
AThe stability of sodium sulfonate aqueous injection.
Tanshinone I I
AThe utmost point is insoluble in water, contains Tanshinone I I
AThe ordinary preparation bioavailability not high, directly influenced clinical efficacy, also the someone propose with tanshinone extract and oil for injection or oleate etc. again with the general sieve Nico of surfactant F
68Mixing such as (chemical name polyoxyethylene-polyoxypropylene copolymer also claim poloxamer) and with emulsifying agent phospholipid etc. produce emulsion (for example, Zhang Ning, model green grass or young crops, Lv Huiyi, in good, the peace ripple. the preparation of TANSHINONES microemulsion and quality evaluation. CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2003; 28 (11): 1081-1082; Li Honglei, Zhang Zhongyi, Ma Leilei, Chen Xiaoning. the preparation of TANSHINONES microemulsion and rat are in the body intestinal absorption. CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2007; 32 (11): 1024-1027).
Application number is 200510067836, denomination of invention is that to contain the patent of invention of the lipomul of tanshinone analog and application thereof described, in tanshinone analog (it is one kind of to comprise all extracts of Radix Salviae Miltiorrhizae) and vegetable oil soybean oil, Semen Maydis oil, sunflower oil, Oleum Arachidis hypogaeae semen, Oleum sesami, the Oleum Brassicae campestris one or more, and phospholipid comprises Ovum Gallus domesticus Flavus lecithin, soybean phospholipid, cephalin hydrogenated phospholipid one or more is prepared into Emulsion.Described preparation method is tanshinone analog, vegetable oil, phospholipid, adding tween 80, ethene polymers, non-ionic surface active agent, cholesterol, propylene glycol etc. to be mixed stir, and be heated to 60～70 ℃, add the recipe quantity water homogenisation and transfer pH4.65～pH7.5 scope, become Emulsion through high pressure homogenize again, 115 ℃ of sterilizations in 20 minutes.A undisputable fact has been run counter in last patent application, and a primary condition that contains medicine constituents fats Emulsion preparation is, participates in emulsive medicine and must be dissolved in the suitable oil or at the fluid camber and disperse (for example prostadil fatty emulsion injection).The described Tanshinone I I of this patent
AChemical constituent very indefinite.On the one hand, inventor's evidence refine yolk lecithin emulsifying capacity is very low, is unsuitable for Tanshinone I I
AThe preparation of emulsion; On the other hand, the described vegetable oil proportion of this patent working example is greater than 30%, and the shared ratio of lecithin is greater than 2.5%, exceed domestic and international approved vegetable oil and the ratio of lecithin in fats emulsion, relate to thus drug safety problems such as pharmacology, toxicity (Zhu Shengshan. new drug formulation. Chemical Industry Press, 2003:8510-512; The Sanitation Ministry medicine standard. two ones. fat emulsion injection C
14～24).
Application number is 200610005271, and denomination of invention is that the patent of invention of a kind of tanshinone emulsion and preparation method thereof is described, and the every 1000ml of tanshinone emulsion contains TANSHINONES 100mg～1500mg, injection or oral oil 100g～500g, emulsifying agent 5g～50g.Further described TANSHINONES is Tanshinone I I
AContent 90～100%, injection or oral oil are long-chain fat acid glycerol and composition thereof in soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Sesami, Oleum Camelliae, the long-chain, emulsifying agent is fabaceous lecithin, lecithin, general sieve Nico F
68, soil temperature 80, arabic gum or gelatin.The described method of preparing emulsion of this patent application is with TANSHINONES or Tanshinone I I
ABe dissolved in the oil, emulsifying agent is soluble in water, and oil-water emulsion becomes Emulsion.This application for patent is pointed out: Tanshinone I I
ADissolubility is subjected to its purity that material impact is arranged in vegetable oil, measures Tanshinone I I
ADissolubility at the injection soybean oil is 2mg/g.
People such as Yao Jianguo studies have shown that and " do solubilizing agent with ethanol and some medicinal non-ionic surface active agents, to Tanshinone I I
ACarried out the solubilising experiment.Found that Tanshinone I I
AInsoluble in water, dissolubility can reach 6mg/g in ethanol " (Yao Jianguo, Zhou Maoxing, Feng Yu, Jiang Yonghong. surfactant is to the research of TANSHINONES solubilization. daily chemical industry, 2003,33 (1): 12-14).
Threpsology expert points out that soybean oil long-chain fat Emulsion is inhibited to body's immunity both at home and abroad, especially uses in heavy dose of short-term.Clinical should limit use long-chain fat Emulsion (Li Qiang, Cao Xinwei. fat milk and to the influence of body's immunity. Chinese clinical nutrition magazine, 2004,14 (1): 51-53).Last 2 routine tanshinone emulsion patents of invention have all adopted general sieve Nico F
68Surfactants such as (polyoxyethylene-polyoxypropylene copolymer) and soil temperature 80 are to increase TANSHINONES dissolubility and prepared stability of emulsion in vegetable oil, but being limited in, surfactant strictnesses such as polyoxyethylene-polyoxypropylene copolymer, soil temperature 80 use in the intravenous fluid, particularly in the emulsion formulation, all do not ratify both at home and abroad at present to use.
The inventor is to Tanshinone I I
ADissolubility is tested in following solution, and the result is as shown in table 1.
Table 1 Tanshinone I I
ASolubility test data (mg/g)
Thus, the inventor finds that containing the fish oil that enriches omega-3 polyunsaturated fatty acids has good dissolubility to the high-purity TANSHINONES.And omega-3 polyunsaturated fatty acids itself also has the effect to the human body beneficial.
Be eicosapentaenoic acid (EPA), docosahexenoic acid (DHA) to the most important composition of human body in the omega-3 polyunsaturated fatty acids.Omega-3 polyunsaturated fatty acids can not be made by self, needs to rely on outside supply, is the indispensable fatty acid of human health, so be also referred to as essential fatty acid.Omega-3 polyunsaturated fatty acids can promote the high density cholesterol levels, suppresses arrhythmia, reduces the platelet stickiness, reduces the generation of diabetes and cardiovascular disease.FDA (Food and Drug Adminstration) (FDA) in 2004 authentication: " omega-3 polyunsaturated fatty acids is qualified health food, can reduce the cause of coronary heart disease risk ".
Edible vegetable oil soybean oil, Oleum Gossypii semen, rapeseed oil, Oleum Helianthi, Oleum Arachidis hypogaeae semen, Testa oryzae oil, Semen Sesami wet goods edible vegetable oil and fat contain more omega 6 polyunsaturated fatty acid, but contain EPA and DHA hardly.Contain abundant EPA and DHA in the bathypelagic fish oil.China SFDA ratified the omega-3 polyunsaturated fatty acids fish oil fat emulsion injection that Austrian Fresenius Kabi company produces and is used for clinical in 2005.
Statistics shows, the incidence rate of Japanese's coronary heart disease and cerebral thrombosis is negative correlation with the EPA level in the patient blood.The Denmark researcher adopts contrast, double blind method, and the effect of the arrhythmia danger of research fish oil after to myocardial infarction finds that fish oil has β retardance or angiotensin converting enzyme (ACE) inhibitory action, thereby reduces the mortality rate of patient behind the myocardial infarction.Add omega-3 polyunsaturated fatty acids in the diet and not only help general crowd's prevents heart disease, and improve the patient's that heart disease has taken place prognosis.German scholar discovers that the danger that the fish oil additive of edible pufa-containing can make menopausal women suffer from a heart complaint reduces 27%.Chemical compound in the fish oil can suppress the generation of special fatty acid in the liver, reduces other fatty acids and is secreted into ratio in the blood.
Summary of the invention
The objective of the invention is to utilize omega-3 polyunsaturated fatty acids to have dissolving high-purity Tanshinone I I
ACharacteristics, prepare stable Tanshinone I I in conjunction with the omega-3 polyunsaturated fatty acids pharmacological action
AThe submicron emulsion preparation.
The present invention is as solvent, with high-purity Tanshinone I I with omega-3 polyunsaturated fatty acids
ADissolving also is prepared into submicron emulsion, wherein said high-purity Tanshinone I I
ARefer to that its content reaches 90% at least, preferably is higher than 98.5%.Preferred embodiment be, adopt and to be rich in omega-3 polyunsaturated fatty acids and to be not less than 60% that wherein EPA, DHA total amount are no less than 45% fish oil as solvent, dissolving purity is not less than 90% Tanshinone I I
AAlso can adopt with fish oil be higher than 45% EPA and DHA for the raw material dna purity ethyl polyenoate as solvent to dissolve highly purified Tanshinone I I
A
Can adopt any favourable emulsifying agent in the preparation of Emulsion of the present invention, preferred solvent adopts soybean phospholipid.Particularly, oral formulations adopts the pharmaceutical grade soybean phospholipid, and wherein phosphatidylcholine (PC) content is 40%～80%, injection adopt the injection soybean phospholipid wherein phosphatidylcholine (PC) content 65%～95%; LYSO-PHOSPHATIDYLCHOLINE LYSOPC (L-PS) must not be greater than 3.0%.
As required, can add antioxidant, stabilizing agent and chelating agen etc. in the Emulsion of the present invention.Specifically, can be with vitamin E as antioxidant; Ethyl oleate or enuatrol are as the stabilizing agent of submicron emulsion film system; Disodium edetate is as chelating agen.
In addition, the ω-6 that recommends according to international threpsology is of value to the balance human blood-pressure with ω-3 ratio 4:1～2:1, stops thrombosis and improves the theory of immunocompetence.Also can add Radix Oenotherae erythrosepalae oil and the olive oil that contains abundant omega 6 polyunsaturated fatty acid in the Emulsion of the present invention.And olive oil also plays natural fragrant agent effect.
In addition, as required, the present invention can also adopt any favourable alkali regulator to regulate pH value, specifically can adopt sodium hydroxide.
Also can add sweeting agent in the Emulsion of the present invention and wait the ginseng agent, for example add hydroxyl isomaltulose or xylitol, glycerol as sweeting agent and etc. the ginseng agent.
The omega-3 polyunsaturated fatty acids Tanshinone I I that the present invention is prepared
AEmulsion breast grain mean diameter is less than 200nm.According to novel Emulsion classification, breast grain mean diameter is not more than 200nm, belong to submicron emulsion Emulsion and also claim nano-emulsion, submicron emulsion have improve medicine stability, reduce toxic and side effects, improve in the body and percutaneous absorb, make medicament slow release, controlled release or have characteristics such as targeting (Zhu Shengshan. new drug formulation. Chemical Industry Press, 2003:8 506-507,526-527).
The preferred version that the present invention adopts is described below, and preparation method thereof:
Each component is pressed 1000ml and is calculated use in the Emulsion of the present invention: Tanshinone I I
A0.8g～1.5g, medicinal fish oil 50g～150g, Radix Oenotherae erythrosepalae oil 50g～150g, olive oil 50g～150g, soybean phospholipid 8g～15g, vitamin E 0.1mg～1mg, ethyl oleate or enuatrol 0.1mg～1mg, disodium edetate 0.005mg～0.05mg, hydroxyl isomaltulose or xylitol 10g～50g, glycerol 20g～25g, sodium hydroxide 25～35mg.
Fish oil in the such scheme can replace with containing the highly purified ethyl polyenoate of EPA and DHA, and use amount is identical.
The invention process method is: under the nitrogen protection state, get fish oil and place the emulsifying systems oil tank, add Tanshinone I I
A, add Radix Oenotherae erythrosepalae oil or olive oil, add vitamin E, add prescription 1/3rd amount soybean phospholipids, slowly under stirring be warming up to 70 ℃ and make Tanshinone I I
ADissolve fully with soybean phospholipid, constant temperature, nitrogen protection adds ethyl oleate or enuatrol and stirs.
For highly purified Tanshinone I I
A, can adopt medicinal alcohol recrystallization way to improve Tanshinone I I
APurity, preparation injection omega-3 polyunsaturated fatty acids Tanshinone I I
ASubmicron emulsion.Its method is: get purity and be not less than 90% Tanshinone I I
AIn medicinal alcohol, be heated to ethanol evaporation and backflow, make it to dissolve fully, add and be equivalent to Tanshinone I I
A0.1%～1% active carbon of inventory is kept and was refluxed 3～5 minutes, and filtered while hot is removed active carbon and impurity, and filtrate was put 4 ℃～8 ℃ crystallizations more than 4 hours.Also with freezing medicinal alcohol flushing crystal, 105 ℃ aseptic dry 2 hours for filtration under diminished pressure.Detect Tanshinone I I
APurity reaches more than 98.5%.Claim high-purity Tanshinone I I
AIn the vacuum decompression emulsion tank, add medicinal alcohol, add hot ethanol and make it dissolving, claim recipe quantity injection fish oil, olive oil, soybean phospholipid 1/3rd amounts to place the vacuum decompression emulsion tank, stir and make Tanshinone I I
A, phospholipid dissolves fully, decompression vacuum pumping is removed ethanol.Constant temperature to 70 ℃, nitrogen injection add vitamin E, ethyl oleate or enuatrol and stir to normal pressure.
It is above to the emulsifying systems water pot to get sterilized water or water for injection prescription half amount, inflated with nitrogen deoxygenation in the water, be warming up to 70 ℃, the residue soybean phospholipid that adds prescription 2/3rds amounts, adding disodium edetate, hydroxyl isomaltulose or xylitol or glycerol, sodium hydroxide are stirred to dissolving fully, constant temperature.Under the nitrogen protection state, with the Tanshinone I I of above-mentioned acquisition
AThe slow water pot that injects of fish oil liquid starts the emulsify at a high speed cutter simultaneously, makes it Tanshinone I I
AFish oil becomes emulsion with water, adds the sterilized water or the water for injection of prescription surplus, stirs emulsion to evenly becoming colostrum.
As required, measure the pH value of colostrum, wherein should be pH6.5～pH7.0 for oral liquid pH, injection should be pH7.5～pH8.5 and is advisable.
Further, with the Tanshinone I I of above-mentioned acquisition
AThe fish oil colostric fluid injects the high-pressure emulsification homogenizer, and the circulation homogenizing obtains submicron emulsion, and this also is an optimal way of the present invention.Wherein, Tanshinone I I
AThe mean diameter of emulsion breast grain is not more than 200nm, and 90% particle diameter accumulated value is not more than 400nm, does not preferably have the granule greater than 5 μ m.
In addition, can adopt method well known in the art to measure Tanshinone I I
AContent.Provide a concrete grammar below.
Chromatographic condition and system suitability test (two ones of appendix VD high performance liquid chromatography .2005 version Chinese Pharmacopoeias, Chemical Industry Press, 2005: appendix 28-30): with octadecylsilane chemically bonded silica is filler, with methanol: water: acetic acid (80:19:1) is mobile phase, the detection wavelength is 270nm, suitably adjust the ratio of methanol and water, make Tanshinone I I
AThe retention time of main peak is about 18 minutes, and theoretical cam curve is pressed Tanshinone I I
AThe peak calculates, and should be not less than 2000.
It is an amount of that precision is measured this product, makes with isopropanol to contain Tanshinone I I among every 1ml approximately
AThe solution of 100 μ g shakes up, and it is an amount of that precision is measured this solution, adds methanol dilution and makes every 1ml and contain Tanshinone I I approximately
A40 μ g shake up, as need testing solution; Precision takes by weighing Tanshinone I I
AThe about 2.5mg of reference substance puts in the 25ml volumetric flask, adds dissolve with methanol and is diluted to scale, shakes up, and precision is measured this solution 1ml and put in the 2.5ml volumetric flask, adds methanol and is diluted to scale, shakes up, in contrast product solution; Precision is measured each 10 μ l of above-mentioned two kinds of solution, injects chromatograph of liquid respectively, and the record chromatogram is pressed external standard method with calculated by peak area, promptly.
In addition, can adopt method well known in the art measure omega-3 polyunsaturated fatty acids tanshinone breast grain particle diameter (alprostadil injection. national drug standards WS
1-(X-041)-2202Z).Get Tanshinone I I
AEmulsion 0.1ml is diluted to 5000 times with purified water (being the membrane filtration of 0.22 μ m in advance with the aperture) with emulsion, and mixing is with dynamic laser subparticle analysis-e/or determining.
The present invention has obtained following technique effect by taking such scheme, is in particular in:
1) omega-3 polyunsaturated fatty acids Tanshinone I I
AEmulsion drug loading height, on average can reach 1mg/ml, be up to 1.5mg/ml, relatively Tanshinone I I
ASodium sulfonate injection medicine operation instructions (national drug standards WS-10001-(HD-1014)-2002) quiet notes or quiet: every day 1 40～80mg.This product can be made 20～100ml intravenous injection.
2) according to similar compatibility mechanism biology, the film fusion takes place when the microemulsion membrane phospholipid combines with vascular endothelial cell and smooth muscle cell, the ingredient of microemulsion film parcel discharges and deposition.The medicine submicron emulsion also is referred to as the agent of lipoid microsphere passive target.The omega-3 polyunsaturated fatty acids Tanshinone I I that the present invention produces
AThe emulsion mean diameter in 160～180nm scope, have the characteristics of above-mentioned passive targeted preparation.Help Tanshinone I I
AIngredient deposition vascular lesion place (Xue Meiyan, Wang Dongkai, note mark. the progress of lipomul and the application in dosing eyes thereof. Chinese journal of Practical Pharmacy, 2007,5 (3): 126-131).
3) the present invention is with high-load EPA and DHA fish oil dissolving Tanshinone I I
AAnd the curative drug emulsion produced of an amount of olive oil of admixture or Radix Oenotherae erythrosepalae oil and vitamin E.Multinomial studies show that, the reduction that at present clinical soybean oil long chain fat emulsion (LCT) commonly used or middle long chain fat emulsion (LCT/MCT) can cause immune cell function, cause the risk (Sun Yongliang that merges complication and hepatic insufficiency takes place easily, Liu Yuewu, Jiang Zhuming. compound olive oil lipomul is to the influence of immunologic function and clinical final result. Chinese clinical nutrition magazine .2007,15 (3): 171-175) epidemic research shows that fish oil is in treatment coronary heart disease, hypertension, diabetes, arthritis, diseases associated with inflammation, and play an important role in autoimmune disease and the cancer.Olive oil has the effect of tangible reduction HDL-C.Radix Oenotherae erythrosepalae oil has effects such as tangible antiinflammatory, antioxidation, antithrombotic, blood fat reducing, blood sugar lowering, fat-reducing.Not only be of value to the balance human blood-pressure with the olive oil that is rich in ω-6 or its ratio of Radix Oenotherae erythrosepalae oil 1:4～1:2, stop thrombosis and raising immunocompetence more to help Tanshinone I I with the fish oil that is rich in omega-3 polyunsaturated fatty acids
AUse as the medicine long term injections.
4) prove by following result of the test, the omega-3 polyunsaturated fatty acids Tanshinone I I that produces
AEmulsion was at first being placed 4 hours under 4 ℃ of environment and then after 10 tests of 40 ℃ of placements repeated stock in 4 hours, is being placed shaking table again and detect particle size of emulsion and Tanshinone I I after 10 hours with eccentric throw 10mm rotating speed 50rpm vibration
AContent.Then sample is placed under the room temperature state, detected particle size of emulsion and Tanshinone I I after 1 year
AContent with do not have obvious variation (to see Fig. 1 for details, Fig. 2) the year before.The omega-3 polyunsaturated fatty acids Tanshinone I I that proof the present invention obtains
AEmulsion has good stability.
5) the omega-3 polyunsaturated fatty acids Tanshinone I I of the present invention's acquisition
AEmulsion does not have irritated reaction, no haemolysis and agglutination, no local irritation through the animal experiment proof.
6) the omega-3 polyunsaturated fatty acids Tanshinone I I of the present invention's acquisition
AEmulsion can be made into 20～100ml and supplies with the arteries and veins ejection preparation; Can be made into the oral drop of 1～5ml.
Description of drawings
Fig. 1: embodiment 2 Tanshinone I I
AThe changes of contents liquid chromatogram of emulsion the 0th month and December, wherein, Fig. 1 a is the 0th month Tanshinone I I
AReference substance liquid chromatogram, Fig. 1 b are the 0th month Tanshinone I I
AEmulsion liquid chromatogram, Fig. 1 c are December Tanshinone I I
AReference substance liquid chromatogram, Fig. 1 d are December Tanshinone I I
AThe emulsion liquid chromatogram.
Fig. 2: embodiment 2 Tanshinone I I
AThe 0th month breast grain of emulsion detects figure.
Fig. 3: embodiment 2 Tanshinone I I
AEmulsion December breast grain detects figure.
Fig. 4: embodiment 10 Tanshinone I I
AEmulsion rabbit ear pathology picture, wherein Fig. 4 a is Tanshinone I I
AEmulsion rabbit ear blood vessel irritation pathology picture, the positive 0.9% sodium chloride injection matched group rabbit ear blood vessel irritation pathology picture of Fig. 4 b.
The specific embodiment
Detailed description below by the specific embodiment is further illustrated the present invention, but is not limitation of the present invention, only does the example explanation.
The embodiment of the invention is selected emulsifying device and detecting instrument for use:
Emulsifying systems is that Shanghai Ritai Medical Equipment Engineering Co., Ltd. makes, it is that BMS402 type 0.75KW, oil-water emulsion jar are BMS802 type 1.75KW high-speed shearing machine that special electromechanical equipment Science and Technology Ltd. of Shanghai Bell makes oil tank, Italian Niro Soavi NS3006E type high pressure homogenizer.Agilent 1100 systems are selected in the content calibrating for use, and Beckman N5 type dynamic laser subparticle analyser is selected in the calibrating of microemulsion particle diameter for use.
The supplementary material that the embodiment of the invention is selected for use:
Tanshinone I I
A(content 90%): Xi'an Honson Biotechnology Co., Ltd.'s lot number: 050809
Injection fish oil: German Lipoid company lot number: 796003
Medicinal ethyl polyenoate: Yuwang Pharmaceutical Co., Ltd., Shandong Prov.'s lot number: 20051001
Injection olive oil: German Lipoid company lot number: 799358
Medicinal Radix Oenotherae erythrosepalae oil: Jilin Pharmaceutical Factory, Bethune Medical Univ. lot number: YD-050501
Injection soybean phospholipid S100: German Lipoid company lot number: 790539-1
Injection soybean phospholipid S75: German Lipoid company lot number: 776099-3
Medicinal soybean phospholipid S45: German Lipoid company lot number: 755033-3
Vitamin E: Shanghai D SM company lot number: UT05090183
Enuatrol: German Lipoid company lot number: 202219
Ethyl oleate: Shanghai chemical reagents corporation lot number: 20050301
Glycerol for injection: Suichang, Zhejiang pharmaceutical Co. Ltd lot number: 20060201
Disodium edetate; Beijing Chemical Plant's lot number: 20050201
Sodium hydroxide: Beijing Chemical Plant's lot number: 20030307
Xylitol: Shanghai chemical reagents corporation import lot number of the repackaged products: CN No:11183
Hydroxyl isomaltulose: Guangxi Nanning Chemical Pharmaceutical Ltd.'s lot number: 20050501
Medicinal alcohol: Anhui An Te Bioisystech Co., Ltd import lot number of the repackaged products: CN No:32061
Embodiment 1
Tanshinone I I
A5g
Medicinal ethyl polyenoate 500g
Medicinal soybean phospholipid (S45) 60g
Vitamin E 0.5mg
Ethyl oleate 0.5mg
Disodium edetate 0.025mg
Xylitol 50g
Sodium hydroxide 150mg
Sterilized water adds to 5000ml
Emulsifying systems oil tank inflated with nitrogen takes by weighing the recipe quantity ethyl polyenoate and puts in the oil tank, takes by weighing recipe quantity Tanshinone I I
A, take by weighing soybean phospholipid 20g and put in the oil tank, open blender and stir, open oil tank interlayer hot water valve, oily temperature rise to 70 ℃, and constant temperature, visor is observed Tanshinone I I
ADissolve fully with soybean phospholipid, keep the nitrogen pressure atmospheric pressure state, take by weighing in recipe quantity vitamin E, the ethyl oleate adding oil tank, stir.
The emulsifying systems water pot injects sterilized water 4000ml, inflated with nitrogen deoxygenation in the water, claim soybean phospholipid 40g, claim recipe quantity sodium hydroxide, disodium edetate, xylitol to add in the water, open blender and stir, open water pot interlayer hot water valve, water temperature rises to 70 ℃, and constant temperature, inflated with nitrogen, visor is observed soybean phospholipid and is dissolved fully, opens high-speed shearing machine.
Open emulsifying systems oil phase pump with Tanshinone I I
AEthyl polyenoate solution injects water pot, and about 10 minutes of high speed shear is injected sterilized water to full dose, and sampling detects ph value of emulsion in pH6.5～pH7.0 scope.Open homogenizer colostrum topping-up pump, open homogenizer, set homogenizer outlet pressure (secondary pressure) 80bar, set first class pressure 100bar, with circulate homogenizing 2 times of colostrum, set first class pressure 400bar, emulsion is circulated homogenizing once, set first class pressure 600bar, emulsion is circulated homogenizing once, set first class pressure 800bar, with the emulsion homogenizing secondary that circulates, sampling detects the mean diameter of emulsion and should not keep 800bar 1～2 circulation of homogenizing again in this scope less than 200nm, until the mean diameter of emulsion less than the 200nm requirement.Open emulsion filtration lobe pump and cross 5 μ m and 0.45 μ m film respectively, filtrate is to storage tank.Fill 1～5ml; Oral drop adopts 80～82 ℃ of sterilizations of online microwave.
Embodiment 2
Tanshinone I I
A5g
Injection fish oil 500g
Injection soybean phospholipid (S75) 60g
Vitamin E 0.5mg
Ethyl oleate 0.5mg
Disodium edetate 0.025mg
Xylitol 50g
Sodium hydroxide 150mg
Sterilized water adds to 5000ml
Be prepared by the preparation process identical with embodiment 1.
Embodiment 2 samples carry out the study on the stability experimental study.At first with the omega-3 polyunsaturated fatty acids Tanshinone I I that produces
AEmulsion is put in the cold closet, and 4 ℃ of temperature are set, and places 4 hours, takes out and places in the ageing oven, and 40 ℃ of temperature are set, and places taking-up in 4 hours; Repeat to amount to 10 times.To place on the medicine shaking table testing machine through sample behind the temperature shock test again, eccentric throw 10mm, rotating speed 50rpm will be set, and vibrate and detect particle size of emulsion and Tanshinone I I after 10 hours
AContent.The detection method that provides by this patent detects content of drug and breast grain particle diameter.
Precision takes by weighing Tanshinone I I
AThe about 2.5mg of reference substance puts in the 25ml volumetric flask, adds dissolve with methanol and is diluted to scale, shakes up, and precision is measured this solution 1ml and put in the 2.5ml volumetric flask, adds methanol and is diluted to scale, shakes up, in contrast product solution; Other gets test specimen 1ml and puts in the 10ml volumetric flask, adds isopropanol to scale, shakes up, and precision is measured this solution 1ml and put in the 2.5ml volumetric flask, adds methanol and is diluted to scale, shakes up, as need testing solution.Precision is measured each 10 μ l of above-mentioned two kinds of solution, injects chromatograph of liquid respectively, and the record chromatogram with calculated by peak area, promptly gets this product Tanshinone I I by external standard method
AContent (seeing shown in Fig. 1 a to Fig. 1 b).
Measure test specimen 0.1ml and put in the 500ml volumetric flask, add through 0.22 μ m filtering with microporous membrane purified water and be diluted to scale, shake up; Measure this solution 1ml again and put in the 100ml volumetric flask, add through 0.22 μ m filtering with microporous membrane purified water and be diluted to scale, shake up, detect as sample breast grain particle diameter and use.The breast grain is detected liquid pour the detection ware into, 20 ℃ of dynamic laser granularity subparticle analyser sample bin temperature are set, record detects collection of illustrative plates (seeing shown in Figure 2).
The study on the stability test specimen is placed under the room temperature state, the content of test sample and breast grain particle diameter after 1 year, and detection method is the same.Testing result shows, the content of reserved sample observing sample tanshinone and emulsion particle diameter and do not have obvious variation (seeing Fig. 1 c to Fig. 1 d and Fig. 3) the year before after 1 year.The study on the stability of this product is still continuing.
Embodiment 3
Tanshinone I I
A5g
Injection fish oil 350g
Radix Oenotherae erythrosepalae oil 650g
Injection soybean phospholipid (S100) 60mg
Vitamin E 0.5mg
Ethyl oleate 0.5mg
Disodium edetate 0.025mg
Hydroxyl isomaltulose 50g
Sodium hydroxide 150mg
Sterilized water adds to 5000ml
Emulsifying systems oil tank inflated with nitrogen takes by weighing recipe quantity fish oil and puts in the oil tank, takes by weighing recipe quantity Tanshinone I I
A, claim the recipe quantity Radix Oenotherae erythrosepalae oil, take by weighing soybean phospholipid 20g and put in the oil tank, open blender and stir, open oil tank interlayer hot water valve, oily temperature rise to 70 ℃, and constant temperature, visor is observed Tanshinone I I
ADissolve fully with soybean phospholipid, keep the nitrogen pressure atmospheric pressure state, take by weighing in recipe quantity vitamin E, the ethyl oleate adding oil tank, stir.
The emulsifying systems water pot injects sterilized water 4000ml, inflated with nitrogen deoxygenation in the water, claim soybean phospholipid 40g, claim recipe quantity sodium hydroxide, disodium edetate, hydroxyl isomaltulose to add in the water, open blender and stir, open water pot interlayer hot water valve, water temperature rises to 70 ℃, and constant temperature, inflated with nitrogen, visor is observed soybean phospholipid and is dissolved fully, opens high-speed shearing machine.
Emulsifying, fill, sterilization process and embodiment 1 identical preparation process are prepared.
Embodiment 4
Tanshinone I I
A5g
Injection fish oil 350g
Injection olive oil 650g
Medicinal soybean phospholipid (S45) 60mg
Vitamin E 0.5mg
Ethyl oleate 0.5mg
Disodium edetate 0.025mg
Hydroxyl isomaltulose 50g
Sodium hydroxide 150mg
Sterilized water adds to 5000ml
Be prepared by the preparation process identical with embodiment 3.
Tanshinone I I
A(high-purity is more than 98%) 5g
Injection fish oil 500g
Injection soybean phospholipid (S75) 60g
Vitamin E 0.5mg
Glycerol for injection 110g
Sodium hydroxide 175mg
Enuatrol 0.5mg
Disodium edetate 0.025mg
Water for injection adds to 5000ml
High-purity Tanshinone I I
APreparation:
Get the Tanshinone I I of purity 90%
A200g is heated to ethanol evaporation and backflow in the 20L dehydrated alcohol, make Tanshinone I I
ADissolving is fully kept and was refluxed 10 minutes, adds the 0.5g active carbon and keeps backflow 5 minutes, and filtered while hot is removed active carbon and impurity, and filtrate was put 4 ℃～8 ℃ crystallizations more than 4 hours.Also with freezing medicinal alcohol flushing crystal, 105 ℃ aseptic dry 2 hours for filtration under diminished pressure.Detect Tanshinone I I
APurity reaches more than 98.5%.
Take by weighing recipe quantity Tanshinone I I
A, claim recipe quantity fish oil, take by weighing soybean phospholipid 20g and put in the emulsifying systems oil tank, open blender and stir, open oil tank interlayer hot water valve, oily temperature rise to 70 ℃, and constant temperature, visor is observed Tanshinone I I
ADissolve fully with soybean phospholipid, keep the nitrogen pressure atmospheric pressure state, take by weighing in recipe quantity vitamin E, the enuatrol adding oil tank, stir.
Inject water for injection 4000ml in the emulsifying systems water pot, inflated with nitrogen deoxygenation in the water, claim soybean phospholipid 40g, claim recipe quantity glycerol, sodium hydroxide, disodium edetate to add in the water, open blender and stir, open water pot interlayer hot water valve, water temperature rises to 70 ℃, and constant temperature, inflated with nitrogen, visor is observed soybean phospholipid and is dissolved fully, opens high-speed shearing machine.
Emulsification process is prepared by the preparation process identical with embodiment 4.Sampling detects ph value of emulsion in pH7.5～pH8.5 scope, and detecting emulsion particle diameter should be less than 200nm.
Fill high pure nitrogen fill 20～100ml; Sterilized 15～20 minutes for 120～122 ℃.
Embodiment 6
Tanshinone I I
A(high-purity is more than 98%) 5g
Injection fish oil 500g
Injection soybean phospholipid (S100) 60g
Vitamin E 0.5mg
Glycerol for injection 110g
Sodium hydroxide 175mg
Enuatrol 0.5g
Disodium edetate 0.025mg
Water for injection adds to 5000ml
Claim recipe quantity high-purity Tanshinone I I
AIn the vacuum decompression emulsion tank, add medicinal alcohol 2L, open a jar interlayer hot water valve, add hot ethanol to Tanshinone I I
ADissolving claims recipe quantity injection fish oil, places the vacuum decompression emulsion tank for injection soybean phospholipid 20g, stirs and makes Tanshinone I I
A, phospholipid dissolves fully, decompression vacuum pumping is removed ethanol.Constant temperature to 65 ℃, nitrogen injection claim the recipe quantity enuatrol to add and stir to normal pressure.
Inject water for injection 4000ml in the emulsifying systems water pot, inflated with nitrogen deoxygenation in the water, claim soybean phospholipid 40g, claim recipe quantity glycerol, sodium hydroxide, disodium edetate to add in the water, open blender and stir, open water pot interlayer hot water valve, water temperature rises to 70 ℃, and constant temperature, inflated with nitrogen, visor is observed soybean phospholipid and is dissolved fully, opens high-speed shearing machine.
Emulsification process is prepared by the preparation process identical with embodiment 5.Sampling detects ph value of emulsion in pH7.5～pH8.5 scope, detects emulsion particle diameter less than 200nm.
Fill high pure nitrogen fill 20～100ml; Sterilized 15～20 minutes for 120～122 ℃.
Embodiment 7
Tanshinone I I
A(high-purity is more than 98%) 5g
Injection fish oil 350g
Injection olive oil 650g
Injection soybean phospholipid (S75) 60g
Vitamin E 0.5mg
Glycerol for injection 110g
Sodium hydroxide 175mg
Enuatrol 0.5mg
Disodium edetate 0.025mg
Water for injection adds to 5000ml
Take by weighing recipe quantity Tanshinone I I
A, claim recipe quantity fish oil, olive oil takes by weighing soybean phospholipid 20g and puts in the emulsifying systems oil tank, opens blender and stirs, and opens oil tank interlayer hot water valve, oily temperature rise to 70 ℃, and constant temperature, visor is observed Tanshinone I I
ADissolve fully with soybean phospholipid, keep the nitrogen pressure atmospheric pressure state, take by weighing in recipe quantity vitamin E, the enuatrol adding oil tank, stir.
Inject water for injection 4000ml in the emulsifying systems water pot, inflated with nitrogen deoxygenation in the water, claim soybean phospholipid 40g, claim recipe quantity glycerol, sodium hydroxide, disodium edetate to add in the water, open blender and stir, open water pot interlayer hot water valve, water temperature rises to 70 ℃, and constant temperature, inflated with nitrogen, visor is observed soybean phospholipid and is dissolved fully, opens high-speed shearing machine.
Emulsification process is prepared by the preparation process identical with embodiment 6.Sampling detects ph value of emulsion in pH7.5～pH8.5 scope, and detecting emulsion particle diameter should be less than 200nm.
Fill high pure nitrogen fill 20～100ml; Sterilized 15～20 minutes for 120～122 ℃.
Embodiment 8: Tanshinone I I
AThe emulsion sensitivity test:
Tanshinone I I with embodiment 7 preparations
AEmulsion is example (gets emulsion 2ml and be diluted to the 10ml0.9% sodium chloride injection)
Get 18 of healthy guinea pigs, body weight 280～293g, male and female half and half are divided into 3 groups at random, i.e. negative control group 0.9% sodium chloride injection group, positive controls 1% Ovum Gallus domesticus album group and Tanshinone I I
AThe emulsion group, 6 every group, difference every other day lumbar injection 0.9% sodium chloride injection, 1% Ovum Gallus domesticus album and Tanshinone I I
AEmulsion test solution 0.5ml, inject 3 times after, more every group of 6 Cavia porcelluss are divided into 2 groups, 3 every group, respectively at injecting for the first time back 14 days and 21 days by vena femoralis injection 0.9% sodium chloride injection, 1% Ovum Gallus domesticus album and Tanshinone I I
AEmulsion test solution 1ml, the observation injection has or not allergic phenomena in back 30 minutes.As a result, behind the 14th day and the 21 days vena femoralis injections, allergic symptom does not all appear in negative control group and administration group.
Unpeaceful, continuous dry cough then appears in 1% Ovum Gallus domesticus album positive controls, grab with pawl that nose, perpendicular hair, extremity feel like jelly, dyspnea, and after attacking by the femoral vein administration in 14 days after the first administration, spasm death appears in 3 Cavia porcelluss, after being attacked by the femoral vein administration in 21 days, spasm death appears in 2 Cavia porcelluss again.
Tanshinone I I
AEmulsion components is not attacked in half an hour by the femoral vein administration to quick back 14 days, 21 days in for the first time and was not met quick phenomenon, continues to observe 7, and animal activity is as usual, and none death shows Tanshinone I I
AEmulsion anaphylaxis feminine gender.
Embodiment 9: Tanshinone I I
AThe test of emulsion hemolytic:
Tanshinone I I with embodiment 7 preparations
AEmulsion (get emulsion 2ml and be diluted to the 10ml0.9% sodium chloride injection)
Get the about 2.5kg rabbit of healthy weight back of the body position and be fixed in the rabbit platform, separate the common carotid artery intubate and get blood in centrifuge tube, defibrinate, add normal saline and shake up, the centrifugal supernatant that goes is measured erythrocyte and is diluted to 2% red blood cell suspension and is for experiment.Get 7 numberings of test tube and add various test solutions, put in 37 ℃ of water-baths, write down 0.5,1,2,3,4 hour result, have or not haemolysis and hemagglutination, and after room temperature is placed 24 hours, observe above-mentioned phenomenon by table 2.See Table 2 Tanshinone I I
AEmulsion hemolytic test operation order and observed result.
Proof Tanshinone I I
AEmulsion is put in 37 ℃ of water-baths, observes 4 hours no haemolysis, does not see haemolysis and agglutination in 24 hours.
Table 2: Tanshinone I I
AEmulsion hemolytic test operation order
Embodiment 10: Tanshinone I I
AThe test of emulsion blood vessel irritation:
Tanshinone I I with embodiment 7 preparations
AEmulsion is example (gets emulsion 2ml and be diluted to the 10ml0.9% sodium chloride injection)
Get 4 of healthy rabbits, body weight about 2.5kg, male and female half and half.Be divided into 0.9% sodium chloride injection matched group and Tanshinone I I by body weight and sex
AEmulsion is for examination group, 2 every group.Tanshinone I I
AEmulsion is pressed the 2ml/kg administration in the quiet notes of rabbit left side ear ear edge, once a day, and continuous 7 days.Matched group is with quiet notes 0.9% sodium chloride injection of method.Observe the administration topical manifestations during each administration and after the administration, cut the medicine exterior feature of picking up the ears behind the quiet notes of last,, cut the wide sample of 0.5cm, get 3 specimen altogether, section statining, observation every 1cm apart from quiet notes pin proximal end to heart 1cm place.Its result is shown in Fig. 4 a and Fig. 4 b.The wide vasodilation of the visible rabbit ear of naked eyes does not have redness, and pathologic finding administration group blood vessel has expansion slightly under the mirror, and matched group and administration group are not seen cell infiltration.Proof Tanshinone I I
AThe quiet notes of emulsion do not have local irritation.
Claims (9)
1, a kind of stable Tanshinone I I
ASubmicron emulsion is characterized in that, it is to be not less than 60% edible oil or medicinal oil as solvent, with Tanshinone I I with omega-3 polyunsaturated fatty acids content
ABe prepared into submicron emulsion.
2, submicron emulsion according to claim 1 is characterized in that, described solvent is the fish oil that contains omega-3 polyunsaturated fatty acids, or is the ethyl polyenoate that raw material extracts with fish oil.
3, submicron emulsion according to claim 2 is characterized in that, the omega-3 polyunsaturated fatty acids of described fish oil is not less than 60%, and perhaps the purity of described ethyl polyenoate is higher than 45%.
4, submicron emulsion according to claim 1 is characterized in that, described Tanshinone I I
APurity be higher than 90%, preferred more than 98.5%.
5, a kind ofly prepare stable Tanshinone I I
AThe method of submicron emulsion, it comprises the steps:
1) in emulsifying systems, will be not less than 60% edible oil or medicinal oil and Tanshinone I I with omega-3 polyunsaturated fatty acids content
AAnd partial emulsifier mixing, and dissolving fully;
2) remaining emulsifying agent is added in the entry mix, and dissolving fully;
3) with the 1st) lysate that obtains of step is slow injects the 2nd) lysate and the high speed shear that obtain of step, carry out emulsifying, obtain colostric fluid;
4) colostric fluid is carried out high-pressure emulsification, obtain submicron emulsion.
6, method according to claim 5 is characterized in that: further mix Radix Oenotherae erythrosepalae oil and/or olive oil the 1st), further go back mixed stabilizer and antioxidant.
7, method according to claim 6 is characterized in that: described stabilizing agent is ethyl oleate or enuatrol, and described antioxidant is a vitamin E.
8, method according to claim 5 is characterized in that: the 2nd) in further mix chelating agen, be preferably disodium edetate, also further mixing sweetener and isotonic agent are preferably hydroxyl isomaltulose or xylitol, glycerol respectively.
9, according to each described method in the claim 5-8, it is characterized in that: described emulsifying agent is a soybean phospholipid.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101797059A (en) * | 2010-04-17 | 2010-08-11 | 上海交通大学 | Food-grade fish oil microemulsion carrier and preparation method thereof |
| WO2021143751A1 (en) * | 2020-01-14 | 2021-07-22 | 中国科学院上海药物研究所 | Injectable long-acting analgesic pharmaceutical composition, preparation method therefor, and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100362993C (en) * | 2005-01-07 | 2008-01-23 | 四川思达康药业有限公司 | Tanshinone emulsion and its making method |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101797059A (en) * | 2010-04-17 | 2010-08-11 | 上海交通大学 | Food-grade fish oil microemulsion carrier and preparation method thereof |
| CN101797059B (en) * | 2010-04-17 | 2012-09-05 | 上海交通大学 | Food-grade fish oil microemulsion carrier and preparation method thereof |
| WO2021143751A1 (en) * | 2020-01-14 | 2021-07-22 | 中国科学院上海药物研究所 | Injectable long-acting analgesic pharmaceutical composition, preparation method therefor, and application thereof |
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