CN101152147B - Ligustrazine compound emulsion and method for preparing the same - Google Patents
Ligustrazine compound emulsion and method for preparing the same Download PDFInfo
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- CN101152147B CN101152147B CN2006100219781A CN200610021978A CN101152147B CN 101152147 B CN101152147 B CN 101152147B CN 2006100219781 A CN2006100219781 A CN 2006100219781A CN 200610021978 A CN200610021978 A CN 200610021978A CN 101152147 B CN101152147 B CN 101152147B
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Abstract
The present invention relates to a tetramethylpyrazine compound emulsion and a preparation method and belongs to the field of medical technology. Prescription composition of the emulsion is counted by weight percentage comprising 0.05 percent to 5 percent of tetramethylpyrazine compound, 10 percent to 30 percent of triglyceride compound, 0.5 percent to 5 percent of emulsifier and 0 percent to 10 percent of addition agent and injection water or pharmaceutical water. The preparing process of the present invention of the tetramethylpyrazine compound emulsion comprises colostrum preparation, high pressure homogenization and moist heat sterilization and other steps. The emulsion is used for curing occlusive vascular disease, coronary heart disease, angina and other cardio-cerebrovascular disease. The present invention of the tetramethylpyrazine compound emulsion is capable of significantly enhancing drug efficacy and has the advantages of sustained release, targeting, and low toxicity. The present invention of the tetramethylpyrazine compound emulsion is good in stability, qualified in security test and accord with clinical medicine requirements. The present invention is used for intravenous and oral administration.
Description
Technical field
The present invention relates to a kind of ligustrazine compound emulsion and preparation method thereof, belong to drug world.
Background technology
Cardiovascular and cerebrovascular disease is commonly encountered diseases, the frequently-occurring disease that human health in serious harm.Data shows that because of the death that cardiovascular and cerebrovascular disease caused has surpassed 50% of the total cause of the death of population, World Health Organization (WHO) classifies cardiovascular and cerebrovascular disease as " the sanitarian dead enemy in the world ".The research and development cardiovascular medicament has become one of grand strategy of global medicine and health work.
Ligustrazine (Ligustrazine, Lig; Tetramethylpyrazine is the effective ingredient that extracts from Chinese medicine samphire Rhizoma Chuanxiong (Ligusticum Chuanxiong) rhizome TMP), and chemical constitution is a 2, and structural formula is as follows:
It is reported, ligustrazine has the platelet aggregation of inhibition, causes that the negative inotropic acts on, suppresses multiple pharmacologically actives such as vasoconstriction, can be used as and expand blood vessel medicine, free radical scavenger, antithrombotic and antihypertensive drug, be widely used in treatment coronary atherosclerotic disease and ischemic cardio cerebrovascular diseases in China.Yet the pharmacokinetic of ligustrazine shows: the ligustrazine bioavailability is low, and metabolism is fast, the half-life short (seeing test example 9 for details), therefore need frequent drug administration guaranteeing blood drug level in effective range, and frequent drug administration easily causes savings to be poisoned.Therefore, it is significant to create a kind of new ligustrazine preparation efficient, low toxicity
[1]
The ligustrazine water solublity is relatively poor, therefore is made into salt usually, increases its water solublity.Ligustrazine preparation commonly used clinically at present has two kinds, and a kind of is ligustrazine microcosmic salt, and another kind is the ligustrazine salt hydrochlorate.And these two kinds of form of medication all fail effectively to solve the problem that its half-life is short, bioavailability is low.
Emulsion has the following advantages as pharmaceutical carrier: 1. as the soybean oil of oil phase and as the lecithin of emulsifying agent, the safety of body is identified.Soybean oil and lecithin are recorded by China and other multinational pharmacopeia of the world as injection supplementary material.2. the dispersion of drop is very big in the Emulsion, the bioavailability height.3. the drop in the Emulsion can play the effect of control diffusion, can make medicament slow releaseization, prolong half-life.4. can improve the targeting of medicine, reach effect efficient, low toxicity target tissue.At present existing multiple medicine is prepared to Emulsion for clinical use, as Alprostadil emulsions, Limethason Emulsion, emulsio olei jecoris piscis, fatsoluble vitamin Emulsion, neomycin Emulsion etc.
But, use Emulsion to have two key issues to need to solve: 1. medication preparation can be become Emulsion to depend on the physicochemical property and the clinical indication thereof of medicine itself as pharmaceutical carrier, be not that any crude drug all is fit to be prepared into Emulsion, also prescription and the preparation technology without any a drug loaded emulsion can directly apply mechanically prior art simply to obtain.2. can get a desired effect and simply to know by inference after medication preparation being become Emulsion, must test and be verified.Up to now, do not see the document and the patent report of any relevant ligustrazine Emulsion both at home and abroad as yet.
Summary of the invention
The invention provides a kind of ligustrazine compound emulsion and preparation method thereof, it is to be main active with a kind of in ligustrazine or the ligustrazine lipophilic derivatives, add triglyceride compounds, emulsifying agent, water for injection or water for pharmaceutical purposes pharmaceutically commonly used, obtain through the emulsifying technology preparation.
In vitro study finds that the macrophage that liplid emulsions can be activated, neutrophilic granulocyte, vascular endothelial cell absorb.Behind the intravenous injection emulsion, owing to have the mononuclear phagocyte that normal tissue is more accumulated in a large number at inflammation, atherosclerotic lesions blood vessel and thrombosis position, can absorb and remove the lipid in the blood circulation, thereby emulsion carrier is optionally accumulated at inflammation, vascular injury site, made it become the ideal carrier of antiinflammatory and part treating cardiovascular disease medicine.In common Drug therapy, the medicine that can reach diseased region only for dosage 1% in addition still less; In the lesion region of various ischemic diseasess, the dose that can reach diseased region is very little especially.And utilize the special affinity of Emulsion and lesion vessels, can make the diseased region medication amount be higher than tens of times to hundreds of times of normal position, thereby significantly improve the Drug therapy index
[2～5]
This shows whether medicine suits to make Emulsion, should consider the pharmacologically active of medicine itself.Studies show that: ligustrazine has antiplatelet aggregation, the expansion small artery, and the microcirculation improvement function of promoting blood circulation to disperse blood clots, and accumulative platelet had depolymerisation.In addition, also has significant antiinflammatory action
[6～7]Therefore, ligustrazine is made Emulsion, can be with the curative effect and the target administration technology desired combination of ligustrazine.That is to say that cardiovascular and cerebrovascular vessel curative effect and antiinflammatory action that ligustrazine itself has make it become the desirable feedstock medicine of this targeting vector of Emulsion.
After definite ligustrazine is fit to make Emulsion, and then should consider that can it make Emulsion.Generally speaking, can medicine make Emulsion, depend primarily on its in the triglyceride compounds and water in solubility behavior.Therefore, at first tackle the solubility behavior of ligustrazine in various medicinal solvents and study, and then optimizing prescriptions.The inventor is through experimental studies have found that: dissolubility and the dissolubility in water of ligustrazine in triglyceride compounds (as soybean oil) is equal substantially, but its profit is distributed studies show that of behavior, the content ratio of ligustrazine in isopyknic profit is biphase be about 5: 1～and 6: 1.This dissolution characteristics shows: the ligustrazine lipotropy can be prepared to Emulsion obviously greater than hydrophilic.
Based on above result of study, we study the prescription and the preparation technology of ligustrazine Emulsion.Adopt uniform design commonly used in the pharmacy respectively triglyceride mass, ligustrazine amount, emulsifying dosage among every 100ml to be investigated according to 3 factors, 7 levels, the investigation scope is triglyceride 5～50g, ligustrazine 0.05～5g, emulsifying agent 0.5～5g.Particle diameter and the stability under high temperature (45 ℃), low temperature (5 ℃) and room temperature (25 ℃) condition thereof with gained Emulsion serve as to investigate index, optimizing prescriptions.The result is unexpected to find during dissolubility, still to have good stable when ligustrazine content in the Emulsion for preparing in ligustrazine oil, illustrates that we preferably write out a prescription to have broken through the restriction of dissolubility in the ligustrazine soybean oil, can increase substantially the drug loading of Emulsion.The result shows: when containing ligustrazine 0.1～1g, triglyceride compounds 10～25g, emulsifying agent 1～1.5 gram among the every 100g of Emulsion of preparation, the particle size distribution range of gained Emulsion sample is at 0.1 micron～1 micron, and mean diameter is 0.2 micron～0.4 micron.Under high temperature (45 ℃), low temperature (5 ℃) and room temperature (25 ℃) condition, investigate 6 months, the physical appearance of sample, pH value, content, mean diameter and Zeta potential have no significant change, explanation is good according to the emulsion stability of this prescription preparation, particle size distribution meets the requirement of injectable emulsion, can be used for intravenously administrable or oral administration.
Based on above-mentioned result of study, technical scheme of the present invention provides a kind of ligustrazine Emulsion, and another technical scheme of the present invention has provided a kind of ligustrazine lipophilic derivatives Emulsion.
Ligustrazine is metabolised to 2-methylol-3,5 rapidly in human body, the 6-trimethylpyrazine, and to studies show that of this metabolite, 2-methylol-3,5, the 6-trimethylpyrazine has stronger physiologically active, is that ligustrazine is at the intravital active metabolite of people.Researcher is arranged with the positive contrast of ligustrazine, observe 2-methylol-3,5, the 6-trimethylpyrazine is to the influence of hemorheological property, find that the two all significantly reduces the high shear viscosity of whole blood, the low shear viscosity of whole blood, the high shear viscosity of blood plasma, reduce the platelet adhesion reaction rate, packed cell volume is not had obvious effect, there was no significant difference between the two.Further discover, 2-methylol-3,5, the 6-trimethylpyrazine can obviously prolong mice electrocardio extinction time and blood coagulation time, obviously reduce the rat aorta blood pressure, but the rat heart rate is not had obvious influence, and this illustrates that this chemical compound has effects such as the myocardial hypoxia tolerance of improvement, blood pressure lowering and anticoagulant.It is lower that this chemical compound and ligustrazine are compared toxicity, and 2-methylol-3,5 is described, the 6-trimethylpyrazine is a kind of medicine of good treatment cardiovascular disease
[8]This shows the also suitable Emulsion that is prepared into of 2-methylol-3,5,6-trimethylpyrazine.
The inventor is through discovering: 2-methylol-3,5, the dissolubility of 6-trimethylpyrazine in triglyceride compounds (as soybean oil) is little, therefore as it being prepared into Emulsion, must carry out the lipotropy chemical modification to it, in the hope of increasing its dissolubility in the triglyceride compounds.
Therefore, we adopt endogenous fatty acid (stearic acid, palmitic acid, lauric acid) and 2-methylol-3,5 first, and the 6-trimethylpyrazine becomes ester, significantly increased its dissolubility in the triglyceride compounds, and then the derivant after the lipotropy modification has been prepared into Emulsion.Based on above purpose, we have synthesized following chemical compound first.
2-methylol-3,5,6-trimethylpyrazine stearate, structural formula is as follows:
2-methylol-3,5,6-trimethylpyrazine palmitate, structural formula is as follows:
2-methylol-3,5,6-trimethylpyrazine laurate, structural formula is as follows:
To studies show that of above-mentioned three kinds of chemical compounds, therefore its oil-soluble is commonly referred to as the ligustrazine lipophilic derivatives with it much larger than water solublity, and its general structure is as follows:
Wherein R is---(CH
2)
16CH
3,---(CH
2)
14CH
3,---(CH
2)
10CH
3
Emulsion has slow release, targeting, therefore becomes Emulsion can further improve its therapeutic effect above-mentioned three kinds of compound.Prescription screening to ligustrazine lipophilic derivatives Emulsion adopts and ligustrazine Emulsion prescription screening similar approach, the optimizing prescriptions that obtains is: contain ligustrazine lipotropy derive 0.5g～4g, triglyceride compounds 10g～25g, emulsifying agent 1g～1.5g in every 100g Emulsion, all the other are water for injection or water for pharmaceutical purposes.
Based on above-mentioned result of study, it is the Emulsion of main active with the ligustrazine compound that technical scheme of the present invention provides a kind of, and another technical scheme of the present invention has provided the preparation method of this Emulsion.
Emulsion provided by the invention is to be main active with the ligustrazine compound, add that triglyceride compounds, emulsifying agent, water for injection/preparation water pharmaceutically commonly used are prepared from, it is formed by weight percentage, comprises ligustrazine compound 0.05～5%, triglyceride compounds 10～30%, emulsifying agent 0.5～5%, additives 0～10%, all the other are water for injection or water for pharmaceutical purposes.Its particle size distribution range is at 0.1 micron～1 micron, and mean diameter is 0.2 micron～0.4 micron, therefore can be used for intravenous injection or oral administration.
Wherein, described triglyceride compounds is to meet a kind of of the long chain triglyceride of Chinese Pharmacopoeia regulation and/or medium chain triglyceride or two kinds, and wherein long chain triglyceride is a kind of in the soybean oil that meets the Chinese Pharmacopoeia regulation, Semen Maydis oil, Oleum Sesami, Oleum Cocois, safflower oil, silk floss oil, the Oleum Camelliae; Described emulsifying agent is a kind of among the fabaceous lecithin that meets Chinese Pharmacopoeia regulation, lecithin, the Pa Luoshamu 188 (F-68) or two kinds.
Also can add additives in the Emulsion provided by the invention.Additives can be one or more in the pH regulator agent that meets Chinese Pharmacopoeia regulation, stabilizing agent, isoosmotic adjusting agent, the antioxidant, and its content is every 100ml Emulsion 0～10; Wherein the pH regulator agent is hydrochloric acid or sodium hydroxide; Stabilizing agent is oleic acid and/or enuatrol; Isoosmotic adjusting agent is glycerol or mannitol; Antioxidant is vitamin E and/or sodium L-ascorbate-2-phosphate.
Emulsion provided by the invention also can be prepared into the form of anhydrous emulsion.In Emulsion provided by the invention, add one or more pharmaceutically acceptable cryoprotective agents and/or one or more skeletons formation agent; carrying out lyophilization handles; can obtain the anhydrous lactitol fluid composition, it is redispersible again and form the liquid emulsion with corresponding size and distribution that said composition adds water.
The preparation method of Emulsion provided by the invention is as follows:
A, the ligustrazine compound that takes by weighing recipe quantity, triglyceride compounds, emulsifying agent, additives, water for injection or water for pharmaceutical purposes are standby;
B, ligustrazine compound, oil-soluble additives and triglyceride compound are formed oil phase, pre-stand-by heat;
C, emulsifying agent, water solublity additives are mixed with water for injection or water for pharmaceutical purposes form water, pre-stand-by heat;
D, under the high-speed stirred condition, drip oil phase and go into water, be dispersed in aqueous phase to oil phase, the milky colostrum;
D, get above-mentioned colostrum and be transferred in the high pressure dispersing emulsification machine, homogenize to mean diameter reaches below 0.5 micron, fills the nitrogen fill, pressure sterilizing, and Emulsion gets product.
Adopt the Emulsion of preparation method preparation provided by the present invention, particle size distribution range is at 0.1 micron～1 micron, and mean diameter is 0.2 micron～0.4 micron, meets the requirement of injectable emulsion, can be used for intravenously administrable or oral administration.(high temperature, low temperature, room temperature) carries out 6 months investigation under different condition, and the physical appearance of sample, pH value and content have no significant change, and illustrates that the emulsion stability for preparing according to this preparation method is good, can be applied to industrialized great production.
Emulsion with the present invention's preparation is trial drug, and itself and commercially available ligustrazine phosphate injection, Ligustrazine Hydrochloride Injection are compared research, and the result shows: the Emulsion of the present invention's preparation has improved 2 times than commercial preparation bioavailability, and the half-life has prolonged 3 times; Pharmacodynamic study shows: the Emulsion dosage of the present invention's preparation is can reach the curative effect identical with the commercial preparation under half the situation of commercial preparation, illustrate that the Emulsion of the present invention's preparation has reached the effect that lowers dosage, raising drug effect.
In sum, broken through the restriction of ligustrazine dissolubility in oil by the ligustrazine compound emulsion of technical solution of the present invention preparation, even in greater than ligustrazine oil under the situation of dissolubility, still can beat allly maintain a long-term stability, significantly increased the drug loading and the drug level of Emulsion, helped reducing production costs and making things convenient for clinical application.Simultaneously, the Emulsion of the present invention's preparation is compared with existing commercially available ligustrazine phosphate injection, Ligustrazine Hydrochloride Injection, has significantly improved bioavailability of medicament and half-life; And significantly strengthened curative effect of medication.
Obviously, according to foregoing of the present invention,,, can also make modification, replacement or the change of other various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill knowledge and the customary means of this area.
The specific embodiment of form is described in further detail foregoing of the present invention again by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
List of references
[1] Cheng Xianchao, Liu Xinyong, Xu Wenfang. ligustrazine cardiovascular and cerebrovascular vessel pharmaceutical research progress. Chinese Hospitals pharmaceutical journal .2005,25 (7): 661～663
[2]Igarashi，R.，Takenaga，M.，Matsuda，T.Distribution?of?lipid?microspherepreparations.Adv.Drug?Deliv.Rev.1996，20：147～154
[3]Yukihiro.C.，Toshiya?M.，Yoshiro.K.，et?al. Uptake?by?vascular?smooth?muscle?cellsplays?an?important?role?in?targeting?of?lipid?microspheres?inc
[4]Mizushima，Y.，Hamano，T.，Haramoto，S.，et?al.Distribution?of?lipid?microspheresincorporating?prostaglandin?E
1?to?vascular?lesions.Prostagl.Leukotr.Essent.FattyAcids?1990，41：269～272
[5]Kiyokawa，S.，Igarashi，R.，Iwayama，T.，et?al.
99mTc-labeled?lipid?microspheres(LM)would?be?useful?for?an?imaging?study?of?those?diseases.Jpn.J.Inflamm.1987，7：551～557
[6] Fan Zhiyun, Liu Yulan. ligustrazine is to acutely inflamed antiinflammatory action. Pharmacology and Clinics of Chinese Materia Medica .1999,15 (6): 13～14
[7] Wu Haiyun, Wang Shiwen etc. the research of ligustrazine antiinflammatory action in acute coronary syndrome. Chinese combination of Chinese and Western medicine first aid magazine .2004,11 (4): 196～198
[8] Chen Xuemin .2-methylols-3,5 such as Cao Yongxiao, the 6-trimethylpyrazine is to the pharmacological action of cardiovascular system. Chinese Journal of Pharmaceuticals .1998,29 (6): 258～260
Description of drawings
The particle diameter and the distribution thereof of accompanying drawing 1 ligustrazine vein emulsion
The Zeta potential measurement result of accompanying drawing 2 ligustrazine vein emulsions
The specific embodiment
Embodiment 1: 12g injection lecithin and 22g glycerol for injection are put in the high-speed tissue mashing machine, added the water for injection of 700ml preheating, stirring makes phospholipid be dispersed in aqueous phase; Other gets in the injection soybean oil of 2 gram ligustrazine adding 200g preheatings, gets oil phase after the dissolving fully.The aqueous phase that oil phase is slowly added high-speed stirred, insulated and stirred 5 minutes (10000 rev/mins), get the milky colostrum, colostrum is added injection water to 1000 milliliter, put in the high pressure dispersing emulsification machine homogenize repeatedly 3 times, reach below 0.5 micron to mean diameter, fill the nitrogen fill, pressure sterilizing, Emulsion gets product.But this Emulsion injection for intravenous.
Embodiment 2: 15g injection fabaceous lecithin, 10g Pa Luoshamu 188 (F-68) are scattered in the water for injection of 650ml preheating with the dissolving of 20g injection mannitol, are prepared into homodisperse water; Other gets in the oil for injection of 4g ligustrazine adding 250g preheating, gets oil phase after the dissolving fully.Oil phase is slowly added the aqueous phase of high-speed stirred, and insulated and stirred 10 minutes (10000 rev/mins) is prepared into the milky colostrum.Colostrum is added injection water to 1000 milliliter, put in the high pressure dispersing emulsification machine homogenize 3 times, reach below 0.5 micron to mean diameter, fill the nitrogen fill, sterilization, the Emulsion that gets product, but this Emulsion injection for intravenous.
Embodiment 3: 15g injection fabaceous lecithin and the dissolving of 25g glycerol for injection are scattered in the water for injection of an amount of preheating, prepare homodisperse water; Other gets in the oil for injection of 2 gram ligustrazine adding 150g preheatings, gets oil phase after the dissolving fully.Oil phase is slowly added the aqueous phase of high-speed stirred, and insulated and stirred 10 minutes is prepared into the milky colostrum.Colostrum is added injection water to 1000 milliliter, put in the high pressure dispersing emulsification machine repeatedly that homogenize to mean diameter reaches below 0.5 micron, fill the nitrogen fill, sterilization, the Emulsion that gets product, but this Emulsion injection for intravenous.
Embodiment 4: the dissolving of 5g fabaceous lecithin is scattered in the water for pharmaceutical purposes of 800ml preheating, prepares homodisperse water; Other gets 0.5 gram ligustrazine and 0.5g oleic acid adds in the silk floss oil of 100g preheating, gets oil phase after the dissolving fully.Oil phase is slowly added the aqueous phase of high-speed stirred, and insulated and stirred 10 minutes (10000 rev/mins) is prepared into the milky colostrum.Colostrum is added water for pharmaceutical purposes to 1000 milliliter,, put in the high pressure dispersing emulsification machine homogenize repeatedly 3 times, fill the nitrogen fill with sodium hydroxide test solution adjust pH to 7.5, sterilization, the Emulsion that gets product, this Emulsion can be for oral administration.
Embodiment 5: 30g fabaceous lecithin and 20g Pa Luoshamu 188 (F-68) dissolving are scattered in the water for pharmaceutical purposes of 600ml preheating, prepare homodisperse water; Other gets 150g Oleum Sesami and 150g Oleum Camelliae mixing preheating, drops into 15g ligustrazine and 1g vitamin E, gets oil phase after the dissolving fully.Oil phase is slowly added the aqueous phase of high-speed stirred, and insulated and stirred 10 minutes (10000 rev/mins) is prepared into the milky colostrum.Colostrum is added water for pharmaceutical purposes to 1000 milliliter, put in the high pressure dispersing emulsification machine homogenize repeatedly 3 times, fill the nitrogen fill, sterilization, the Emulsion that gets product, this Emulsion can be for oral administration.
Embodiment 6: 15g injection lecithin and 25g glycerol for injection are dissolved the water for injection that is scattered in the 650ml preheating, prepare homodisperse water; Other gets 50 gram 2-methylols-3,5, and 6-trimethylpyrazine stearate adds in the injection soybean oil of 250g preheating, gets oil phase after the dissolving fully.Oil phase is slowly added the aqueous phase of high-speed stirred, insulated and stirred 10 minutes (10000 rev/mins), the milky colostrum, colostrum is added injection water to 1000 milliliter, put in the high pressure dispersing emulsification machine repeatedly that homogenize to mean diameter reaches below 0.5 micron, fill the nitrogen fill, pressure sterilizing, Emulsion gets product.But this Emulsion injection for intravenous.
Embodiment 7: 10g injection fabaceous lecithin, 5g Pa Luoshamu 188 (F-68) and 20g injection mannitol are dissolved the water for injection that is scattered in the 700ml preheating, prepare homodisperse water; Other gets 20 gram 2-methylols-3,5, and 6-trimethylpyrazine palmitate adds in the injection soybean oil of 200g preheating, gets oil phase after the dissolving fully.Oil phase is slowly added the aqueous phase of high-speed stirred, insulated and stirred 5 minutes (10000 rev/mins), the milky colostrum, colostrum is added injection water to 1000 milliliter, put in the high pressure dispersing emulsification machine repeatedly that homogenize to mean diameter reaches below 0.5 micron, fill the nitrogen fill, pressure sterilizing, Emulsion gets product.But this Emulsion injection for intravenous.
Embodiment 8: 4g lecithin and 1g Pa Luoshamu 188 (F-68) are dissolved the water for pharmaceutical purposes that is scattered in the 800ml preheating, prepare homodisperse water; Other gets 1.5 gram 2-methylols-3,5, and 6-trimethylpyrazine laurate adds in the safflower oil of 100g preheating, gets oil phase after the dissolving fully.Oil phase is slowly added the aqueous phase of high-speed stirred, insulated and stirred 5 minutes (10000 rev/mins), the milky colostrum, colostrum is added water for pharmaceutical purposes to 1000 milliliter, put in the high pressure dispersing emulsification machine homogenize repeatedly 3 times, fill the nitrogen fill, pressure sterilizing, Emulsion gets product.This Emulsion can be for oral administration.
Embodiment 9: 15g injection lecithin and 50g injection mannitol are dissolved the water for injection that is scattered in the 700ml preheating, prepare homodisperse water; Other gets in the injection soybean oil of 3 gram ligustrazine adding 200g preheatings, gets oil phase after the dissolving fully.The aqueous phase that oil phase is slowly added high-speed stirred, insulated and stirred 10 minutes (10000 rev/mins), get the milky colostrum, colostrum is added injection water to 1000 milliliter, put in the high pressure dispersing emulsification machine repeatedly that homogenize to mean diameter reaches below 0.5 micron, fill, low temperature is pre-freeze rapidly, lyophilization, freeze-dried emulsion gets product.This Emulsion can be dispersed into the aqueous emulsions with corresponding particle size distribution after adding water once more, but injection for intravenous.
Test example 1 diameter of aspirin particle of the present invention distributes and the Zeta potential inspection
We measure the particle size distribution and the Zeta potential of the Emulsion of the embodiment of the invention 1 preparation, and particle size distribution measuring the results are shown in accompanying drawing 1, and the Zeta potential measurement result is seen accompanying drawing 2 (instrument: Malvern-3000 type particle size distribution and Zeta potential analyzer).
By accompanying drawing 1 as can be known, the Emulsion particle size distribution of the embodiment of the invention 1 preparation is even, and PDI is 0.089, is normal distribution, mean diameter 283.5nm; By accompanying drawing 2 as can be known, the Emulsion Zeta potential of the embodiment of the invention 1 preparation is-25.97mV.Particle size distribution and Zeta potential measurement result show: this Emulsion particle size distribution is even, has good stability, and meets the intravenous injection emulsion requirement.
Test example 2 medicine stabilities of the present invention are checked
We have carried out 6 months study on the stability by a definite date to the Emulsion of the embodiment of the invention 1 preparation, place respectively under room temperature (25 ℃), low temperature (5 ℃), high temperature (45 ℃) condition, in 0,1,2,3, the sampling in June investigates character, pH value, content, mean diameter and Zeta potential, the results are shown in Table 1.
The emulsion stability of table 1 embodiment of the invention 1 preparation is investigated the result
As shown in Table 1, the Emulsion of the embodiment of the invention 1 preparation was preserved 6 months in room temperature (25 ℃), low temperature (5 ℃), high temperature (45 ℃) condition, every index does not have significant change, estimates that its effect duration can reach 2 years, shows that the emulsion stability of the embodiment of the invention 1 preparation is good.
Test example 3 asepsis test in medication of the present invention
Get the Emulsion of the embodiment of the invention 1 preparation, according to the regulation in the Chinese Pharmacopoeia version in 2005, adopt direct inoculation to carry out sterility test, with staphylococcus aureus, clostridium sporogenes, the positive contrast of Candida albicans, the result shows that the Emulsion sterility test of the embodiment of the invention 1 preparation is qualified, can be used for intravenously administrable or oral administration.
Test example 4 medicine bacterial endotoxins of the present invention are checked
Get the Emulsion of the embodiment of the invention 1 preparation, according to the regulation in the Chinese Pharmacopoeia version in 2005, carry out the bacterial endotoxin inspection with tachypleus amebocyte lysate, the positive contrast of bacterial endotoxin working standard that provides with Nat'l Pharmaceutical ﹠ Biological Products Control Institute, the result shows the Emulsion bacterial endotoxin passed examination of the embodiment of the invention 1 preparation, can be used for intravenously administrable or oral administration.
Test example 5 drug sensitivities of the present invention are checked
Method: Cavia porcellus is divided into 3 groups at random by body weight, 6 every group.The 1st group of each Cavia porcellus every other day once, an Emulsion 0.5ml/ sensitization of continuous four lumbar injection embodiment of the invention, 1 preparation, the 10th day after last sensitization then, the Emulsion 1.0ml/ of the Cavia porcellus digital veins of the foot injection embodiment of the invention 1 preparation only excites; The 2nd group of each Cavia porcellus every other day once, continuous four intraperitoneal injection of saline 0.5ml/ sensitization, the 10th day after last sensitization then, Cavia porcellus digital veins of the foot injecting normal saline 1.0ml/ only excites; The 3rd group of each Cavia porcellus every other day once, 0.5ml/ sensitization of continuous four lumbar injections, 15% egg clear liquid, the 10th day after last sensitization then, the Cavia porcellus digital veins of the foot is injected 15% egg clear liquid 1.0ml/ and is only excited.Three groups of reactions of all after booster injection, observing every animal at once to 30 minutes.
The result: 1st, after 2 groups of Cavia porcellus booster injection in 30 minutes, none perpendicular hair, dyspnea, sneeze only occur, scratches nose, cough, jump, spasm, rotation and death; After the 3rd group of Cavia porcellus booster injection in 2 minutes, dyspnea jump, spasm and death take place all.
Conclusion: the Emulsion of the embodiment of the invention 1 preparation does not have sensitization, can be used for intravenous injection.
Test example 6 medicine hemolytics of the present invention are checked
Method: get 21 and clean and through the dry test-tube that normal saline solution dropped down, be divided into parallel three groups, every group of 7 test tubes are numbered 1～7.Be responsible for test by a people and the result observes for every group.Every group of each test tube adds 2% red cell suspension 2.5ml respectively, and wherein 1～No. 5 test tube adds Emulsion 0.5ml, 0.4ml, 0.3ml, 0.2ml, 0.1ml and normal saline solution 2.0ml, 2.1ml, 2.2ml, 2.3ml, the 2.4ml that the embodiment of the invention 1 prepares respectively; No. 6 test tube adds normal saline solution 2.5ml; No. 7 test tubes add distilled water 2.5ml, after all shaking up, put in 37 ℃ of thermostatic water tanks temperature and incubate, and observe once in per 15 minutes during beginning, observe once every 1 hour after 1 hour, observe continuously 4 hours.
The result: each is organized 1～No. 6 test tube and there is no haemolysis in 4 hours, and erythrocyte sinks to the pipe end, the supernatant liquid achromatism and clarity, and the jolting erythrocyte can disperse; Haemolysis in No. 7 test tubes 15 minutes, it is red that supernatant liquid shows.
Conclusion: the Emulsion of the embodiment of the invention 1 preparation does not have haemolysis, can be used for intravenous injection.
Test example 7 medicine irritations of the present invention are checked
Method: get 3 of healthy new zealand rabbits, all in the Emulsion 25ml/kg of the left ear auricular vein instillation embodiment of the invention 1 preparation, auris dextra auricular vein instillation normal saline 25ml/kg, once a day, continuously quiet three days, in quiet beginning in first day, before administration every day, administration 3 hours, 24 hours observes the injection site and has or not edema, erythema, last was injected back 24 hours, and animal is put to death in the carotid artery blood-letting, cutting ear from the basal part of the ear puts 10% formalin fixing, specimens paraffin embedding slices, the histopathology microscopy is made in H.E dyeing.
The result: rabbit ear edge intravenous site is not seen edema and erythema; Epidermis and dermal tissue structure are intact near the pathological study rabbit ear edge vein, do not see degeneration, necrosis, disappearance and hyperkeratosis, and the auricular vein blood vessel structure is normal, does not see thrombosis, and blood vessel does not have degeneration, necrosis.
Conclusion: the Emulsion nonirritant of the embodiment of the invention 1 preparation can be used for intravenous injection.
Test example 8 compatibility of drugs stability of the present invention are checked
Get the Emulsion of the embodiment of the invention 1 preparation, dilute 10 times with 5% glucose injection and 0.9% sodium chloride injection respectively, placed 12 hours down, investigate character, pH value and content, the results are shown in Table 2 in room temperature (25 ℃).
The Emulsion compatibility stability of table 2 embodiment of the invention 1 preparation is investigated the result
As shown in Table 2, the Emulsion of the embodiment of the invention 1 preparation and 5% glucose injection and 0.9% sodium chloride injection compatibility stability are good.
Test example 9 drug bioavailabilities of the present invention and pharmacokinetics test
With the embodiment of the invention 1 medicine is trial drug, commercially available ligustrazine phosphate injection (manufacturer: be control drug A, commercially available Ligustrazine Hydrochloride Injection (manufacturer: be control drug B Nanning Fengye Pharmaceutical Industry Co. Ltd.) Gansu Lanyao Pharmaceutical Industry Group Co., Ltd.), dosage is 12mg/kg, relatively three kinds of preparations the results are shown in Table 3 in the intravital pharmacokinetics index of normal dogs.
Three kinds of preparations of table 3 are in the intravital pharmacokinetics result of the test of normal dogs (n=6)
| Group | The trial drug group | Control drug A group | Control drug B group |
| t 1/2(min) | 64.41±4.39 | 24.67±3.59 | 17.62±3.21 |
| AUC(μg/ml·min) | 841.72±69.63 | 390.39±44.55 | 402.48±39.22 |
The result shows that under identical dosage the Emulsion of the embodiment of the invention 1 preparation is compared with Ligustrazine Hydrochloride Injection with commercially available ligustrazine phosphate injection, and bioavailability is significantly improved, and the half-life prolongs (P＜0.01).
Test example 10 medicine pharmacological testings of the present invention
Emulsion with the embodiment of the invention 1 preparation is trial drug; commercially available Ligustrazine Hydrochloride Injection (manufacturer: be control drug Nanning Fengye Pharmaceutical Industry Co. Ltd.); with the pretreated whole animal model of rat heart muscle ischemia is test model; with arrhythmia incidence rate and persistent period, myocardial infarction area, lactic acid dehydrogenase (LDH) and creatine phosphokinase (CPK) activity serves as to investigate index; relatively the two the results are shown in Table 4 to the protective effect of rat myocardial ischemia and reperfusion damage.
Two kinds of preparations of table 4 are to the protective effect result of the test (n=8) of rat myocardial ischemia and reperfusion damage
The result shows that the Emulsion of the embodiment of the invention 1 preparation under the Isodose obviously is better than commercially available Ligustrazine Hydrochloride Injection to the protective effect that rat myocardial ischemia and reperfusion damages; has significant difference (P＜0.05) between the two; and the Emulsion median dose group (20mg/kg) of the embodiment of the invention 1 preparation is suitable to the action effect of the protective effect of rat myocardial ischemia and reperfusion damage and commercially available Ligustrazine Hydrochloride Injection high dose group (40mg/kg); there was no significant difference between the two (P＞0.05) illustrates that the Emulsion of the embodiment of the invention 1 preparation has reached attenuating dosage; improve the effect of drug effect.
Claims (6)
1. ligustrazine Emulsion, it is formed by weight percentage, comprise ligustrazine 0.05～5%, triglyceride compounds 10～30%, emulsifying agent 0.5～5%, additives 0～10%, all the other are water for pharmaceutical purposes, wherein said ligustrazine has following general structure:
2. Emulsion according to claim 1 is characterized in that: it is formed by weight percentage, contains ligustrazine 0.05～5%, triglyceride compounds 10～25%, emulsifying agent 0.5～2%, additives 0～5%, and all the other are water for pharmaceutical purposes.
3. Emulsion according to claim 2 is characterized in that: emulsifying agent is selected from a kind of in fabaceous lecithin, lecithin, the poloxamer 188 or two kinds; The triglyceride compounds is selected from a kind of of long chain triglyceride and/or medium chain triglyceride or two kinds.
4. Emulsion according to claim 3 is characterized in that: described long chain triglyceride is selected from a kind of in soybean oil, Semen Maydis oil, Oleum Sesami, Oleum Cocois, safflower oil, silk floss oil, the Oleum Camelliae.
5. Emulsion according to claim 4 is characterized in that: described additives are one or more in pH regulator agent, stabilizing agent, isoosmotic adjusting agent, the antioxidant, and wherein said pH regulator agent is hydrochloric acid or sodium hydroxide; Described stabilizing agent is oleic acid and/or enuatrol; Described isoosmotic adjusting agent is glycerol or mannitol; Described antioxidant is vitamin E and/or sodium L-ascorbate-2-phosphate.
6. the preparation method of Emulsion according to claim 1 comprises the steps:
A, the ligustrazine that takes by weighing recipe quantity, triglyceride compounds, emulsifying agent, additives, water for pharmaceutical purposes are standby;
B, the oil-soluble additives in ligustrazine, the above-mentioned additives and triglyceride compound are formed oil phase, pre-stand-by heat;
C, the water solublity additives in emulsifying agent, the above-mentioned additives are mixed with water for pharmaceutical purposes form water, pre-stand-by heat;
D, under the high-speed stirred condition, drip oil phase and go into water, be dispersed in aqueous phase to oil phase, the milky colostrum;
E, get above-mentioned colostrum and be transferred in the high pressure dispersing emulsification machine, homogenize to mean diameter reaches below 0.5 micron, fills the nitrogen fill, pressure sterilizing, and Emulsion gets product.
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