CN1813733A - Vitamin E nicotinate lipide microsphere injection and its preparing method - Google Patents
Vitamin E nicotinate lipide microsphere injection and its preparing method Download PDFInfo
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Abstract
The present invention provides a lipid microsphere injection containing vitamin E nicotinate and its preparation method. The invented preparation utilizes the interfacial membrane medicine-carrying principle to greatly raise medicine-carrying quantity and stability of water-insoluble medicine vitamin E nicotinate in the emulsion and reduce its toxicity, and raise its target property and patient's compliance. The distributed quantity of the invented vitamin E nicotinate in the interfacial membrane of oil-water two phases and oil phase can be up to 80-98%. Said preparation can be used as a new preparation for reducing blood-lipid.
Description
Technical field
The present invention relates to medical pharmaceutical field, particularly a kind of lipide microsphere injection (oil in water emulsion) that contains vitamin E Nicotinate and preparation method thereof.
Background technology
Vitamin E Nicotinate (Vitamin E nicotinate, Tocopheryl nicotinate) is the ester type compound that is formed by two kinds of necessary important vitamin-vitamin Es of human body and nicotinic acid condensation, is a kind of novel microcirculation activator.Vitamin E Nicotinate can directly act on blood vessel wall, the diastole peripheral vessels, promote the blood circulation of brain, skin, muscle, lasting and stable blood flow increasing, the capillary permeability that kininase is caused is hyperfunction specific inhibitory effect, and can suppress the synthetic of cholesterol, prevent that cholesterol deposits is in blood vessel wall, promote cholesterol to drain, it is widely used in the caused various diseases of coronary heart disease, hyperlipemia, cerebral arteriosclerosis, arteriosclerosis, cerebral concussion or brain injury sequela, central serous chorioretinopathy and disturbance of blood circulation clinically; Also be used for abnormalities of sugar/lipid metabolism, hypertension and coronary blood supply insufficiency etc.The clinical practice to vitamin E Nicotinate now is summarized as follows:
1, coronary heart disease.Vitamin E Nicotinate has the effect that beta-blocker reduces myocardial oxygen consumption, and can improve partial pressure of oxygen in the blood, and it is open to promote that CC circulates, and increases vessel wall elasticity, improves the fan and walks activity, and decreased heart rate alleviates heart front and back load; Promote microcirculation, regulate lipid metabolism, suppress platelet aggregation, promote the effect of fibrinolytic.From the arteria coronaria deposit that improves coronary heart disease and sympathetic and vagal balance angle of improving coronary heart disease, this medicine is having better effect aspect the treatment coronary heart disease.Clinical research observation the influence of vitamin E Nicotinate to the coronary heart disease heart rate variability, select patients with coronary heart disease and adopt single at random blind controlled trial, treatment group and matched group are all with nitrate preparations, aspirin, routine medication such as lowering myocardial oxygen consumption and/or calcium ion antagonist, the treatment group adds in addition uses vitamin E Nicotinate, detect the heart rate variability standard deviation before and after the treatment respectively respectively once, average according to the standard deviation increase, adopt statistical method that the two standard sets difference is compared, the result shows, the treatment group is compared with matched group, latent coronary heart disease, angina pectoris, all there is significant difference (P＜0.01) in the myocardial infarction standard deviation, illustrate that vitamin E Nicotinate can improve the patients with coronary heart disease heart rate variability, thereby reduce the sudden death rate of patients with coronary heart disease.Perspective epidemiologic data also shows, men and women no matter, and vitimin supplement E all can reduce the danger of coronary heart disease.
2, hyperlipemia.Vitamin E and esters thereof have inhibitory action to the biosynthesis of cholesterol and promote the drainage of cholesterol, reduce its deposition in blood vessel wall.Therefore, take vitamin E and esters thereof and can suppress diseases such as atherosclerosis to a certain extent.Treat hyperlipemia with vitamin E nicotinate capsule clinically, the treatment group is taken vitamin E nicotinate capsule, and 0.2g/ time, 3 times/day, be 3 months the course of treatment; Matched group is taken Evening Primrose Oil, and 1.5g/ time, 2 times/day.The result shows that the average rate of decrease before and after treatment group serum cholesterol (CH) treatment is 13.7%, and matched group is 7.8%, learn by statistics and handle, and P＜0.01, difference has significance; Average rate of decrease before and after treatment group serum triglycerides (TG) treatment is 11.2%, and matched group is 3.86%, learn by statistics and handle, and P＜0.01, difference has significance.Vitamin E Nicotinate is to fall CH, and the TG reducing effect is less, and effect for reducing fat is gentle lasting.
3, apoplexy sequela.Adopt vitamin E Nicotinate treatment apoplexy sequela clinically, at random the apoplexy sequela patient is divided into treatment group example and matched group, matched group adopts Piracetam Tablet, the treatment of troxerutin sheet, the treatment group adds the vitamin E nicotinate capsule of producing with the big pharmaceutical Co. Ltd in Tonghua side, Chinese Jilin, 2/time, 3 times/day, 6 weeks were 1 course of treatment, tested after 2 courses of treatment of taking medicine.The result shows that treatment group effective percentage is 89.06%, and the matched group effective percentage is 72.22%, and after handled by statistics, P＜0.01 had significant difference.Show that vitamin E Nicotinate treatment apoplexy sequela effect is remarkable.
4, cerebral blood supply insufficiency.Existing result of study shows, uses vitamin E Nicotinate treatment cerebral blood supply insufficiency patient, wherein shows as feeling of fullness in the head person, headache person, dizzy person, to showing as the feeling of fullness in the head patients whose symptoms were less severe, takes vitamin E Nicotinate, 0.1g/ time, and 3 times/day; Headache, the heavier person of dizzy symptom 0.2g/ time, 3 times/day, all took for 1 week.The result shows that the total effective rate of feeling of fullness in the head, headache, dizzy patient treatment is respectively 94.6%, 88.6%, 86.2%.Its reason is that vitamin E Nicotinate can be expanded blood capillary, and blood vessel dilating has blood circulation promoting and blood stasis dispelling, suppress the generation of lipid peroxide, blood fat reducing improves the oxygen availability, quicken blood flow rate, thereby improve a series of clinical symptoms of blood supply insufficiency of brain to cause.
5, hypertension, cerebral arteriosclerosis, arteriosclerosis etc.Vitamin E Nicotinate has a significant effect to hemorheological property, just washes blood high viscosity syndrome effects such as hypertension, cerebral arteriosclerosis more outstanding.Someone studies the patient who has observed blood high viscosity syndromes such as hypertension, cerebral arteriosclerosis treats the front and back hemorheological property with vitamin E nicotinate capsule change.Use the vitamin E nicotinate capsule that the Harbin No.6 Pharmaceutical Factory produces, oral 200mg/ time, 3 times/day, be 3 months the course of treatment, observe the variation of treatment front and back hemorheological property, the result shows that there are highly significant difference (P＜0.01) blood viscosity (nb) and microcirculation holdup time (MST) before and after the treatment, and packed cell volume (HCT), plasma viscosity (np), there were significant differences for reduced viscosity (nr) (P＜0.05).Vitamin E Nicotinate is blood flow increasing sustainedly and stably, suppresses the blood capillary permeability of kininase specifically, discharges kassinin kinin, brings high blood pressure down.Other there are some researches show, with vitamin E nicotinate capsule 257 routine patients is carried out clinical observation, oral 200mg/ time of outbreak initial stage, 3 times/day; Behind doing well,improving, change 100mg/ time 3 times/day into.As a result, treatment cerebral arteriosclerosis, arteriosclerosis (comprise and follow the formation of brain bolt, hypertension, hyperlipidemia), effective percentage is 91.91%; Treatment cerebral trauma and cerebral trauma sequela, effective percentage is 88.00%; Treat other as coronary heart disease, hypertension, chronic nephritis, effective percentage is 85.71%.Stephens etc. reported once that oral vitamin E also can reduce the incidence rate of coronary atherosclerosis patient non-lethal myocardial infarction, and the toleration of vitamin E is fabulous.
In addition, vitamin E Nicotinate can improve an ear hemodynamics in treatment ophthalmic diseases (retinopathy, cornea ablation art etc.) and aspects such as ear disease such as senile tinnitus, usually as the medicine commonly used for the treatment of this type of disease and relevant disease thereof.
Vitamin E Nicotinate has own original advantage, and its metabolisable form has determined the safety of its height.Vitamin E Nicotinate is the chemical compound that vitamin E and nicotinic acid form through esterification under specific process conditions, it not only has the physiological action separately of vitamin E and nicotinic acid, and than both single with or have more stable, persistent pharmacological action when share, and low because of its toxicity, side effect is little, conscience kidney and hemopoietic function are all had no adverse effects, have tight security, be particularly useful for the gerontal patient.And when using nicotinic acid separately, untoward reaction has flush, pruritus, and other has the digestive tract irritation, but dosage hyperamization sugar raise, uric acid increases and abnormal liver function, this has limited its use to a certain extent.Compare with nicotinic acid, after vitamin E nicotinic acid extremely enters human body, under the effect of esterase, hydrolysis discharges vitamin E and nicotinic acid, more independent vitamin E stable in properties, more independent nicotinic acid side effect is little, and simultaneously nicotinic acid becomes fat-soluble strong behind the ester, easier of blood brain barrier, can reach therapeutic effect to brain diseases.Because the rate of release of vitamin E and nicotinic acid is slow, this has just alleviated nicotinic acid, and release is to the stimulation of the intestines and stomach suddenly in addition, and the concentration of nicotinic acid in blood can more persistently be kept on the other hand, makes it just bring into play effective function at less dosage.Clinical practice shows that the Liver and kidney toxicity of vitamin E nicotinic acid vinegar can be ignored.The safety of its height is the prerequisite as long-term pharmaceutical intervention.In blood, there are vitamin E, nicotinic acid and three kinds of materials of vitamin E nicotinic acid vinegar in addition after its hydrolysis simultaneously, not only they have given play to separately effect respectively, and also has synergism, strengthened curative effect, enlarged therapeutic domain, be comparatively ideal microcirculation activator and lipid regulating agent, thereby more and more cause the great attention of the world of medicine, its clinical practice is more extensive, and prospect is wide day by day.
And the dosage form of at present domestic relevant vitamin E Nicotinate is very single, almost is oral capsule entirely, and dosage is bigger, the digestive tract irritation appears after oral, the utilization and extention that is unfavorable for this medicine, but this medicine is water-soluble hardly again, is difficult to make the normal injection agent.
Lipomul is applied to clinical nearly half a century as the important supply mode of the outer energy of intestinal.Between 1920～nineteen thirty, Japanese scholar was that raw material, lecithin are emulsifying agent with Oleum Ricini once, and at first the synthetic lipomul is tried out in animal; The U.S. has released Lipomul based on cotton seed oil the fifties and has been applied to patient but all fails to promote because of serious toxicity.1964, the U.S. stopped to produce and using lipomul.But in Europe, with Wretling be a collection of scholar of representative to study untiringly and use based on soybean oil, with the lecithin be emulsifying agent, be the lipomul Introlipid of isotonic agent with glycerol.1962, Introlipid was used for clinical in Sweden by official approval.1967, article " lipomul the is applied to complete intravenous nutrition " comprehensive summing up of delivering by Hallberg etc. experiment and the clinical research of Introlipid, prove that it is applied to clinical is safe and reliable, and proposed the criterion of Introlipid clinical practice." obtaining growth, growth and positive nitrogen balance under the long-term complete parenteral nutrition " literary composition that this literary composition and nineteen sixty-eight Dudrick etc. deliver is acknowledged as parenteral nutrition is developed into two pieces of classical works that routine clinical is used significant impact.After this more than 20 year, Introlipid obtained extensive use all over the world, and developed countries such as moral, method, Japan and the United States have developed national lipomul in succession.1976, U.S. appropriate authorities have ratified lipomul again can be in routine clinical application.At present, kind of a lipomul appeared on the market surplus the whole world had 20 at least.China is also joint the end of the eighties and Sweden Kabi company, and mass production Introlipid is for clinical practice.1973, that Solassol etc. have at first introduced is three-in-one, and (Allin-one, the AIO) notion of solution proved that lipomul and all other nutritional solutions can be mixed in the bottle or in the bag, can keep stable and nutritional support effect at certain condition with in the time.After this promoted AIO transfusion plastic bag, the preparation and the infusion of parenteral nutrition liquid simplified in this simple but relevant improvement greatly, for the wide clinical application of lipomul has been widened road.Up to the present, it is oil-in-water type (oil in water, the o/w) submicronized emulsion of emulsifying agent as decentralized photo with the Ovum Gallus domesticus Flavus lecithin that common lipomul is meant with fatty glyceride.Because the Chylomicron that exists behind the composition of lipomul emulsion droplet and particle diameter and the oral fat group food is very similar, therefore it has been generally acknowledged that the emulsion droplet of lipomul is also similar with Chylomicron in the intravital behavior of people in blood.Along with the further investigation to lipomul, it is also just bringing into play more and more important effect at pharmaceutical field.
The special physicochemical property and the hypotoxicity of lipomul have determined it to can be used as fat-soluble medicine, particularly the good carrier of cancer therapy drug, blood lipid-lowering medicine and anti-inflammatory drug.The normal method that adopts is the lipid core part that pharmaceutical pack is wrapped in lipomul because this structure also is similar to microsphere, so lipid microsphere (Lipid Microsphere, title LM) is also arisen at the historic moment.It is generally acknowledged that lipid microsphere is by medicine is dissolved in the fatty oil, and after phospholipid emulsifying is scattered in water, make, be a kind of be soft substrate and the microparticulate system sealed by immobilized artificial membrane with fatty oil, mean diameter is seen Fig. 1 about 200nm.
LM is as the DDS of pharmaceutical carrier, tremendous development had also been arranged in recent years, and injection liposome microball (lipomul) is to make oil phase with soybean oil or Flos Carthami wet goods oil for injection, makes emulsifying agent with natural phospholipid, ooze O/W type Emulsion with the grade that glycerol is made, it has following characteristics:
1, is the good carrier of fat-soluble medicine.Clinical many medicine poorly water-solubles must rely on the effect of organic solvent competence exertion, and organic solvent not only itself have certain toxicity, also may the interference medicament effect.
2, as the soybean oil of oil phase and as the lecithin of emulsifying agent, be identified in the intravital safety of machine.
3, the particle diameter of particle and surface electrical behavior can freely be controlled.
4, can effectively increase stability of drug.In the pastille lipid microsphere, quite a few drug distribution is arranged in oil phase or oil-water interfacial film, avoided directly contacting with water.Change responsive medicine for facile hydrolysis or to pH, this " isolation " played the effect that increases stability.
5, the LM Chinese medicine partly is wrapped in oil phase or the interfacial film, avoided with body fluid until contacting, thereby reduced issuable part of medicine self and blood vessel irritation.In addition, medicine is by slowly discharge the untoward reaction that can avoid medicine to cause owing to the initial stage excessive concentration in the oil phase when injection in vivo.
6, the small particle of particle diameter about 200nm can be engulfed by the phagocyte of the reticular tissue system of body and be trapped in the reticular tissue system (as liver, lung etc.), has targeting, and this characteristics are particularly important for raising drug effect, reduction toxic and side effects.
People's such as Takahashi relevant bibliographical information: manufacture experimently into LM with bleomycin, and compare, test with tumor-bearing rat with water preparation.Carry out administration in vein or the tumor, measure tumor size and tumor Chinese medicine concentration then respectively, the result shows: the tumor of LM group is dwindled more than 50%, still can detect medicine in 10 hours after the administration; And the tumor of water preparation group do not have and obviously dwindles, and can not detect medicine after 30 minutes to 1 hour.The dosage form difference of medicine more than is described, effect is also different, has shown that LM has the characteristics of selectivity distribution and slow release.
In recent years, be subject to people's attention gradually as the targeting transferance of pharmaceutical carrier with LM.The medicine lipomul is once exploitation, and good benefit has been received in just extensive use clinically.A series of medicine carrying lipomul Products Development listings such as the Lipo PGE1 of the Yutaka Mizushima development of Japan and Lipo PGI2 have indicated this type of preparation wide prospect.Especially the application of sophisticated Emulsion production technology and synthetic or natural surfactant and the raising of Emulsion production technology have been attained, promoted to have the development (stable phase is approximately 2 years) of the Emulsion product of commercial value, stable topography, for the Development and Production of pastille fat milk has been created better condition.As rely on a meter ester, propofol, dexamethasone palmitate lipomul, flurbiprofen ethyoxyl α-ethyl ester liplid emulsions, PGE1 lipid breast etc.
Summary of the invention
The invention provides a kind of composition and method of making the same of lipid microsphere (oil-in-water emulsion) injection of vitamin E Nicotinate.
Compositions of the present invention comprises vitamin E Nicotinate, oil (fat-soluble medium), water and surfactant.
The acceptable material of " oil " indication one big class physiology among the present invention, no matter be mineral oil, vegetable oil, animal oil, quintessence oil or artificial oil, or its mixture.Therefore, use term " oil " in order to refer to the very material of different chemical character that has of a wide region herein.With type or functional classification oil the time, as mineral oil source from oil and comprise fat or the cerul hydrocarbon, aromatic hydrocarbon or blended fat and aromatic radical hydrocarbon.The oil such as the refined paraffin wax wet goods that in the mineral oil classification, also comprise petroleum derivation.In the vegetable oil classification, oil is mainly derived from seed or nut, and comprises drying oil such as Semen Lini and Oleum Verniciae fordii; Semi-drying oil such as safflower oil and soybean oil; Non-drying oil such as Oleum Ricini, Oleum Gossypii semen and Oleum Cocois and the soap stock that can be used as such as Petiolus Trachycarpi oil and Oleum Cocois.In the animal oil classification, oil is usually from as sebum, Adeps Sus domestica and stearic fat.Aqueous animal oil comprises fish oil, oleic acid, spermaceti wet goods.They contain abundant fatty acid usually.Comprise some vegetable oil, as olive oil, Oleum Gossypii semen, corn oil and Oleum Arachidis hypogaeae semen also comprise some special fish oil, and they are used as medicine widely owing to be rich in vitamin, as the morrhua liver, shark liver oil etc.Aqueous fatty oil such as single, double, triglyceride, or its mixture is preferred oil.According to the present invention, the triglyceride of medium chain also are useful oil.Be preferably long-chain fat acid glyceride, medium chain length fatty acid triglyceride, and composition thereof.
Used surfactant can be any surfactant, is generally phospholipid, tween (Tween), pluronic (poloxamer), enuatrol, oleic acid, cholic acid, deoxycholic acid and composition thereof.Described phospholipid is selected from lecithin, fabaceous lecithin, and composition thereof.Described tween is selected from polysorbas20, polysorbate40, and polysorbate60, Tween 80, polysorbate85, and composition thereof.Be preferably lecithin, fabaceous lecithin, enuatrol, oleic acid, Tween 80, pluronic F68, and composition thereof.Selected osmotic pressure regulator is the salt that glycerol, ethylene glycol, isopropyl alcohol and sodium chloride etc. pharmaceutically allow.
If desired, also can add multiple additives in the compositions.As containing metal-chelator, the common metal chelating agen is disodium edetate (disodium EDTA), sodium calcium edetate (calcium disodium edathamil salt), and composition thereof.Metal-chelator is no more than 1% in the preparation consumption.Also can contain antioxidant, general antioxidant is vitamin C, sodium sulfite, sodium pyrosulfite, cysteine, the antioxidant that one or more Mixtards are commonly used.Antioxidant is 0.01% to 1% in the preparation consumption.The pH regulator agent is a hydrochloric acid, sodium hydroxide, commonly used buffer salt etc.
Also can comprise osmotic pressure regulator in this preparation, be generally glycerol, sorbitol, mannitol, glucose, and composition thereof, be 0.005% to 2% in the preparation consumption.
The concrete technical scheme of the present invention is:
A kind of vitamin E nicotinate lipide microsphere injection, the percentage by weight of its composition is: oil phase 5%～30%, vitamin E Nicotinate 0.1%～15%, surfactant 0.5%～5%, all the other are water for injection.
Wherein said oil is mineral oil, vegetable oil, animal oil, quintessence oil or artificial oil, and wherein appoints several mixture; Surfactant is phospholipid, tween, pluronic, span, enuatrol, oleic acid, cholic acid, deoxycholic acid and wherein appoints several mixture.
Preferred version is that wherein said oil is the oil in oil, seed or the nut of oil, petroleum derivation, and comprises drying oil, semi-drying oil; Non-drying oil and the oil that can be used as soap stock; Sebum, Adeps Sus domestica, stearic fat; Fish oil, oleic acid, sperm oil, aqueous fatty oil and wherein appoint several mixture; Described surfactant is a lecithin, fabaceous lecithin, enuatrol, oleic acid, polysorbas20, polysorbate40, polysorbate60, Tween 80, polysorbate85, pluronic F68; Described span is selected from span 20, span 40, and sorbester p18, sorbester p38, sorbester p17, sorbester p37, and wherein appoint several mixture.
Preferred version is that wherein said oil is fat, cerul hydrocarbon, aromatic hydrocarbon again; Refined paraffin wax oil, Semen Lini, Oleum Verniciae fordii, safflower oil, soybean oil, Oleum Ricini, Oleum Gossypii semen, Oleum Cocois, Petiolus Trachycarpi oil, olive oil, Oleum Gossypii semen, corn oil, Oleum Arachidis hypogaeae semen, morrhua liver, shark liver oil; Single, double, triglyceride; The triglyceride of medium chain; Long-chain fat acid glyceride, medium chain length fatty acid triglyceride; And wherein appoint several mixture; Described surfactant is a lecithin, fabaceous lecithin, enuatrol, oleic acid, polysorbas20, polysorbate40, polysorbate60, Tween 80, polysorbate85, pluronic F68; Described span is a span 20, span 40, sorbester p18, sorbester p38, sorbester p17, sorbester p37; And wherein appoint several mixture.
More preferably scheme is that wherein said oil is safflower oil, soybean oil, Semen Maydis oil, MCT Oil, Semen Coicis oil, Oleum Fructus Bruceae; And wherein appoint several mixture; Described surfactant is lecithin, fabaceous lecithin, oleic acid, enuatrol, pluronic F68, Tween 80, span 20; And wherein appoint several mixture.
Be better realization the present invention, also can contain the osmotic pressure regulator of 0.5%～5% percentage by weight in the vitamin E nicotinate lipide microsphere injection.
The metal-chelator that also can contain 0.001%-1%.
Also can contain 0.01% to 0.2% antioxidant.
Described osmotic pressure regulator can be salt or its mixture that glycerol, ethylene glycol, isopropyl alcohol, sorbitol, mannitol, glucose, sodium chloride etc. pharmaceutically allow; Described metal-chelator is disodium EDTA or calcium disodium edathamil salt and composition thereof; Described antioxidant can be vitamin C, sodium sulfite, and sodium pyrosulfite, cysteine, and composition thereof.
The most preferably scheme that injection of the present invention is formed is: the injection soybean oil is 10g, vitamin E Nicotinate is 5g, lecithin is 1.5g, and glycerol is 2.5g, and oleic acid is 0.06g, vitamin C is 0.2g, sodium sulfite is 0.2g, and EDTA is 0.05g, and span 20 is 0.02g, water for injection adds to 100mL, and the pH value of injection is between 4-8.
The distributive law of vitamin E Nicotinate of the present invention in biphase interfacial film of profit and oil phase is 80～98%.
A kind of preparation method that contains the lipide microsphere injection of vitamin E Nicotinate provided by the invention comprises following steps:
Vitamin E Nicotinate solution or powder be added to the blank Emulsion that do not contain vitamin E Nicotinate through mixed vitamin E nicotinate lipide microsphere injection; Perhaps vitamin E Nicotinate solution or powder are added in the Emulsion that contains the part vitamin E Nicotinate through the mixed vitamin E nicotinate lipide microsphere injection that gets;
Perhaps vitamin E Nicotinate is added in the water-soluble medium that contains surfactant, mixes with oil phase then, prepare colostrum through high-speed stirred; Perhaps vitamin E Nicotinate solution or powder are added in the oil-soluble medium that contains surfactant, mixed with water then, prepare colostrum through high-speed stirred;
Preparation process should be controlled aqueous pH values and remain between the 4-8; The available hydrochloric acid of pH regulator agent, sodium hydroxide, acetic acid, sodium acetate, citric acid, sodium citrate, sodium hydrogen phosphate, sodium dihydrogen phosphate, and composition thereof; The most handy hydrochloric acid, sodium hydroxide;
The preparation process of preparation mainly comprises high-speed stirred process and high pressure homogenize process or ultra-sonic dispersion and emulsion process;
Steam rotation sterilization is adopted in the sterilization of preparation.
The preferred version of preparation method is: the preparation of (1) water: with surfactant, osmotic pressure regulator, metal-chelator, the stabilizing agent of recipe quantity and be preheated to 40-100 ℃ an amount of water for injection and mix, change in the tissue mashing machine, stirring gets water until each composition dissolving; (2) preparation of oil phase: simultaneously recipe quantity phospholipid, vitamin E Nicotinate are added to 40-100 ℃ of heating for dissolving in the soybean oil, get oil phase; (3) preparation of colostrum: oil phase slowly is added dropwise to aqueous phase, changes over to then in the tissue mashing machine, high-speed stirred until the oil phase homodisperse, gets colostrum, and adjust pH is to 4-8; (4) preparation of lipide microsphere injection: colostrum is added in the high pressure homogenizer homogenizing 1-10 time, the sampling microscopy, to emulsion droplet below 0.5 micron, get this submicronized emulsion embedding in infusion bottle, fill nitrogen, place steam rotation steriliser, sterilization.
The principle of preparation application interface film medicine carrying of the present invention is wrapped in vitamin E Nicotinate in oil phase and the interfacial film, reduces its toxic and side effects and toxicity, strengthens its curative effect.Because vitamin E Nicotinate dissolubility in oil is bigger, and almost insoluble in water, through high pressure homogenize, the high speed airflow bump forms a kind of supersonic speed and stirs, and makes medicine dissolving and be penetrated in the oil-water interfacial film with molecular forms rapidly.Wherein, vitamin E Nicotinate has certain distribution (reaching 80～98%) in biphase interfacial film of profit and oil phase.
This preparation is a kind of preparation of blood lipid-lowering medicine, and in vivo feature mainly shows as higher chemical physical stability, hypotoxicity, targeting and long-lasting behind the administrated by injection.
The lipid microsphere that the present invention makes is used for intravenous injection, compares the rapider and permanent release of onset with oral capsule.Medicine in the injection of the present invention has a process that discharges in vivo from preparation, also having medicine metabolism under the esterase hydrolyzed effect is the process of nicotinic acid and vitamin E, the scalable drug release rate, prolong medicine mean residence time (MRT) and the elimination half-life in vivo, widened its clinical treatment dosage range.And easy to use, can intravenous injection, be suitable for and out-patient treatment, convenient drug administration, moreover this preparation process thereof is simple, make preparation after the medicine dispersibility increase entrapment efficiency height, good stability greatly.The present invention researches and develops the vitamin E Nicotinate novel form, advantage with efficient, the low toxicity of novel form, give full play to the vitamin E Nicotinate blood fat reducing and reduce toxic and side effects, significant to further promotion and the application of popularization vitamin E Nicotinate in clinical.
The vitamin E nicotinate lipide microsphere injection (oil in water emulsion) of the present invention's preparation, improve pharmaceutical chemistry stability and curative effect and reduced toxic and side effects, improved the targeting of medicine, because the hydrolysis of medicine is one to continue process slowly, can suitably improve the slow release of dosage during injection, thereby reach slow release effect, and the brain volume of going into of medicine can correspondingly increase also behind the one-tenth ester, is undoubtedly a Gospel for Cerebral Infarction Patients.To sum up, said preparation has certain innovation and stronger practicality.
Description of drawings
Fig. 1 is the LM structural representation.Wherein 1 is medicine, and 2 is immobilized artificial membrane, and 3 is lipid core.
The specific embodiment
The prescription preparation technology of vitamin E Nicotinate preparation
| Vitamin E Nicotinate | 0.1-10g |
| Soybean oil, safflower oil, Semen Coicis oil, Oleum Fructus Bruceae, medium chain length fatty acid triglyceride | 5-30g |
| Lecithin, fabaceous lecithin | 0-3g |
| Oleic acid, enuatrol | 0-0.5g |
| Glycerol | 0-5g |
| EDTA | 0-0.5g |
| Poloxamer F68 | 0-1g |
| Tween 80 | 0-0.4g |
| Water for injection | In right amount |
(embodiment 1)
Prescription 1: injection safflower oil 5g, vitamin E Nicotinate 1g, lecithin 1.2g, glycerol 2.5g, water for injection adds to 100mL.
Preparation method: mix the glycerol of recipe quantity (1) with an amount of water for injection that is preheated to 40 ℃, changes in the tissue mashing machine, stirs, and until each composition dissolving, gets water; Simultaneously lecithin is added in the recipe quantity safflower oil,, get oil phase 40 ℃ of heating for dissolving; (2) oil phase is added aqueous phase, change in the tissue mashing machine, stir,, get colostrum, adjust pH to 4 until the oil phase homodisperse; (3) the vitamin E Nicotinate drug powder is added this Ruzhong just, stirred 10 minutes, adding is preheated to 40 ℃ water for injection to full dose; (4) be transferred in the high pressure homogenizer, high pressure homogenize 1 time, the sampling microscopy, to oil droplet below 0.5 micron; (5) embedding is filled nitrogen in infusion bottle, places steam rotation steriliser to sterilize.
(embodiment 2)
Prescription 2: the injection soybean oil is 30g, and vitamin E Nicotinate is 10g, and fabaceous lecithin is 1.2g, and glycerol is 2.5g, and Tween-80 is 0.02g, and enuatrol is 0.05g, and water for injection adds to 100mL.
Preparation method: (1) is with Tween-80, enuatrol, the glycerol of recipe quantity and be preheated to 100 ℃ an amount of water for injection and mix, and changes in the tissue mashing machine, stir, until each composition dissolving, water; Simultaneously fabaceous lecithin is added in the recipe quantity soybean oil,, get oil phase 100 ℃ of heating for dissolving; (2) oil phase is added aqueous phase, change in the tissue mashing machine, stir,, get colostrum, adjust pH to 8 until the oil phase homodisperse; (3) the vitamin E Nicotinate drug powder is added this Ruzhong just, stirred 10 minutes, adding is preheated to 100 ℃ water for injection to full dose; (4) be transferred in the high pressure homogenizer, high pressure homogenize 10 times, the sampling microscopy, to oil droplet below 0.5 micron; (5) embedding is filled nitrogen in infusion bottle, places steam rotation steriliser to sterilize.
(embodiment 3)
Prescription 3: (soybean oil/MCT) is 20g to oil phase, and vitamin E Nicotinate is 15g, and lecithin is 1.2g, and glycerol 2.5g, oleic acid are 0.03g, and Tween-80 is 0.02g, and EDTA is 0.05g, and water for injection adds to 100mL.
Preparation method: (1) is with Tween-80, EDTA, the glycerol of recipe quantity and be preheated to 80 ℃ an amount of water for injection and mix, and changes in the tissue mashing machine, stir, until each composition dissolving, water; Simultaneously lecithin, oleic acid, vitamin E Nicotinate are added in the recipe quantity soybean oil,, get oil phase 80 ℃ of following heating for dissolving; (2) oil phase is added aqueous phase, change in the tissue mashing machine, stir,, get colostrum, adjust pH to 6 until the oil phase homodisperse; (4) colostrum is added in the high pressure homogenizer homogenizing 5 times, the sampling microscopy, to oil droplet below 0.5 micron; (6) get the embedding of vitamin E Nicotinate submicronized emulsion in infusion bottle, fill nitrogen, place steam rotation steriliser, sterilization.
(embodiment 4)
Prescription 4: (soybean oil/MCT) is 15g to oil phase, and vitamin E Nicotinate is 5g, and lecithin is 1.2g, and glycerol is 2.5g, and oleic acid is 0.06g, and EDTA is 0.05g, and water for injection adds to 100mL.
Preparation method: (1) is with EDTA, the glycerol of recipe quantity and be preheated to 90 ℃ an amount of water for injection and mix, and changes in the tissue mashing machine, stir, until each composition dissolving, water; Simultaneously lecithin, oleic acid, vitamin E Nicotinate are added in the recipe quantity soybean oil,, get oil phase 90 ℃ of following heating for dissolving; (2) oil phase is added aqueous phase, change in the tissue mashing machine, stirred 5 minutes,, get colostrum, adjust pH to 7 until the oil phase homodisperse; (4) colostrum is added in the high pressure homogenizer homogenizing 8 times, the sampling microscopy, to oil droplet below 0.5 micron; (6) get the embedding of vitamin E Nicotinate submicronized emulsion in infusion bottle, fill nitrogen, place steam rotation steriliser, sterilization.
(embodiment 5)
Prescription 5: (soybean oil/MCT) is 25g to oil phase, and vitamin E Nicotinate is 15g, and lecithin is 1.5g, and glycerol is 2.5g, and oleic acid is 0.06g, and EDTA is 0.05g, and span 20 is 0.02g, and water for injection adds to 100mL.
Preparation method: (1) is with EDTA, the glycerol of recipe quantity and be preheated to 40-100 ℃ an amount of water for injection and mix, and changes in the tissue mashing machine, stirred 2 minutes, 5 times, until each composition dissolving, water; Simultaneously lecithin, oleic acid, span 20, vitamin E Nicotinate are added to 40-100 ℃ of heating for dissolving in the recipe quantity soybean oil, get oil phase; (2) oil phase is added aqueous phase, change in the tissue mashing machine, stirred 2 minutes, 5 times, until the oil phase homodisperse, get colostrum, adjust pH is to 4-8; (4) colostrum is added in the high pressure homogenizer homogenizing 5 times, the sampling microscopy, to oil droplet below 0.5 micron; (6) get the embedding of vitamin E Nicotinate submicronized emulsion in infusion bottle, fill nitrogen, place the high-pressure rotary steriliser, sterilization.
(embodiment 6)
Prescription 6: (soybean oil/MCT) is 10g to oil phase, and vitamin E Nicotinate is 5g, and lecithin is 4g, and glycerol is 4g, and oleic acid is 0.06g, and EDTA is 0.05g, and span 20 is 0.02g, and water for injection adds to 100mL.
Preparation method: (1) is with EDTA, the glycerol of recipe quantity and be preheated to 40-100 ℃ an amount of water for injection and mix, and changes in the tissue mashing machine, stirred 5 minutes, 2 times, until each composition dissolving, water; Simultaneously lecithin, oleic acid, span 20, vitamin E Nicotinate are added to 40-100 ℃ of heating for dissolving in the recipe quantity soybean oil, get oil phase; (2) oil phase is added aqueous phase, change in the tissue mashing machine, stirred 5 minutes, 2 times, until the oil phase homodisperse, get colostrum, adjust pH is to 4-8; (4) colostrum is added in the high pressure homogenizer homogenizing 6 times, the sampling microscopy, to oil droplet below 0.5 micron; (6) get the embedding of vitamin E Nicotinate submicronized emulsion in infusion bottle, fill nitrogen, place the high-pressure rotary steriliser, sterilization.
(embodiment 7)
Prescription 7: the injection soybean oil is 30g, and vitamin E Nicotinate is 10g, and fabaceous lecithin is 1.2g, and glycerol is 2.5g, and pluronic F68 is 2g, and enuatrol is 0.05g, and water for injection adds to 100mL.
Preparation method: (1) is with Tween-80, enuatrol, the glycerol of recipe quantity and be preheated to 100 ℃ an amount of water for injection and mix, and changes in the tissue mashing machine, stir, until each composition dissolving, water; Simultaneously fabaceous lecithin is added in the recipe quantity soybean oil,, get oil phase 100 ℃ of following heating for dissolving; (2) oil phase is added aqueous phase, change in the tissue mashing machine, stirred 5 minutes, 5 times, until the oil phase homodisperse, get colostrum, adjust pH is to 7-8; (3) the vitamin E Nicotinate drug powder is added this Ruzhong just, stirred 10 minutes, adding is preheated to 100 ℃ water for injection to full dose; (4) be transferred in the high pressure homogenizer, high pressure homogenize 10 times, the sampling microscopy, to oil droplet below 0.5 micron; (5) embedding is filled nitrogen in infusion bottle, places steam rotation steriliser to sterilize.
(embodiment 8)
Prescription 8: (soybean oil/MCT) is 10g to oil phase, and vitamin E Nicotinate is 5g, and lecithin is 1.2g, and glycerol is 2.5g, and oleic acid is 0.03g, and pluronic F68 is 1g, and EDTA is 0.05g, and water for injection adds to 100mL.
Preparation method: (1) is with Tween-80, EDTA, the glycerol of recipe quantity and be preheated to 40-100 ℃ an amount of water for injection and mix, and changes in the tissue mashing machine, stirred 2 minutes, 5 times, until each composition dissolving, water; Simultaneously lecithin, oleic acid, vitamin E Nicotinate are added to 40-100 ℃ of heating for dissolving in the recipe quantity soybean oil, get oil phase; (2) oil phase is added aqueous phase, change in the tissue mashing machine, stirred 2 minutes, 5 times, until the oil phase homodisperse, get colostrum, adjust pH is to 5-6; (4) colostrum is added in the high pressure homogenizer homogenizing 2 times, the sampling microscopy, to oil droplet below 0.5 micron; (6) get the embedding of vitamin E Nicotinate submicronized emulsion in infusion bottle, fill nitrogen, place steam rotation steriliser, sterilization.
(embodiment 9)
Prescription 9: (soybean oil/MCT) is 10g to oil phase, and vitamin E Nicotinate is 5g, and lecithin is 1.2g, and glycerol is 2.25g, and enuatrol is 0.5g, and EDTA is 0.05g, and water for injection adds to 100mL.
Preparation method: (1) is with EDTA, the glycerol of recipe quantity and be preheated to 60 ℃ an amount of water for injection and mix, and changes in the tissue mashing machine, stir, until each composition dissolving, water; Simultaneously lecithin, enuatrol, vitamin E Nicotinate are added in the recipe quantity soybean oil, 60 ℃ of heating for dissolving get oil phase; (2) oil phase is added aqueous phase, changes in the tissue mashing machine, stirred for several minute, 1-5 time, until the oil phase homodisperse, colostrum, adjust pH is to 6-7; (4) colostrum is added in the high pressure homogenizer homogenizing 5 times, the sampling microscopy, to oil droplet below 0.5 micron; (6) get the embedding of vitamin E Nicotinate submicronized emulsion in infusion bottle, fill nitrogen, place steam rotation steriliser, sterilization.
(embodiment 10)
Prescription 10: the injection soybean oil is 10g, and vitamin E Nicotinate is 10g, and fabaceous lecithin is 1.2g, and glycerol is 2.25g, and pluronic F68 is 0.8g, and enuatrol is 0.1g, and water for injection adds to 100mL.
Preparation method: (1) is with Tween-80, enuatrol, the glycerol of recipe quantity and be preheated to 50 ℃ an amount of water for injection and mix, and changes in the tissue mashing machine, stirred 5 minutes, 3 times, until each composition dissolving, water; Simultaneously fabaceous lecithin is added in the recipe quantity soybean oil, 50 ℃ of heating for dissolving get oil phase; (2) oil phase is added aqueous phase, change in the tissue mashing machine, stirred 5 minutes, 3 times, until the oil phase homodisperse, get colostrum, adjust pH is to 4-5; (3) the vitamin E Nicotinate drug powder is added this Ruzhong just, stirred 10 minutes, adding is preheated to 50 ℃ water for injection to full dose; (4) be transferred in the high pressure homogenizer, high pressure homogenize 8 times, the sampling microscopy, to oil droplet below 0.5 micron; (5) embedding is filled nitrogen in infusion bottle, places steam rotation steriliser to sterilize.
(embodiment 11)
Prescription 11: (soybean oil/MCT) is 10g to oil phase, and vitamin E Nicotinate is 5g, and lecithin is 1.2g, and glycerol is 2.5g, and oleic acid is 0.06g, and vitamin C is 0.2g, and EDTA is 0.05g, and water for injection adds to 100mL.
Preparation method: (1) is with EDTA, the glycerol of recipe quantity and be preheated to 90 ℃ an amount of water for injection and mix, and changes in the tissue mashing machine, stirred 5 minutes, 5 times, until each composition dissolving, water; Simultaneously lecithin, oleic acid, vitamin E Nicotinate are added in the recipe quantity soybean oil, 90 ℃ of heating for dissolving get oil phase; (2) oil phase is added aqueous phase, change in the tissue mashing machine, stirred 5 minutes, 5 times,, get colostrum, adjust pH to 7 until the oil phase homodisperse; (4) colostrum is added in the high pressure homogenizer homogenizing 5 times, the sampling microscopy, to oil droplet below 0.5 micron; (6) get the embedding of vitamin E Nicotinate submicronized emulsion in infusion bottle, fill nitrogen, place steam rotation steriliser, sterilization.
(embodiment 12)
Prescription 12: oil phase (Oleum Fructus Bruceae) is 10g, and vitamin E Nicotinate is 5g, and lecithin is 1.5g, and glycerol is 2.5g, and oleic acid is 0.06g, and vitamin C is 0.2g, and sodium sulfite is 0.2g, and EDTA is 0.05g, and span 20 is 0.02g, and water for injection adds to 100mL.
Preparation method: (1) is with EDTA, the glycerol of recipe quantity and be preheated to 100 ℃ an amount of water for injection and mix, and changes in the tissue mashing machine, stirred 5 minutes, 3 times, until each composition dissolving, water; Simultaneously lecithin, oleic acid, span 20, vitamin E Nicotinate are added in the recipe quantity soybean oil, heating 100 ℃ of dissolvings down, gets oil phase; (2) oil phase is added aqueous phase, change in the tissue mashing machine, stirred 5 minutes, 3 times,, get colostrum, adjust pH to 7 until the oil phase homodisperse; (4) colostrum is added in the high pressure homogenizer homogenizing 8 times, the sampling microscopy, to oil droplet below 0.5 micron; (6) get the embedding of vitamin E Nicotinate submicronized emulsion in infusion bottle, fill nitrogen, place the high-pressure rotary steriliser, sterilization.
(embodiment 13)
Prescription 13: oil phase (medium chain length fatty acid triglyceride) is 10g, and vitamin E Nicotinate is 5g, and lecithin is 4g, and sorbitol is 4g, and oleic acid 0.06g, EDTA are 0.05g, and span 20 is 0.02g, and water for injection adds to 100mL.
Preparation method: (1) is with EDTA, the glycerol of recipe quantity and be preheated to 90 ℃ an amount of water for injection and mix, and changes in the tissue mashing machine, stirred 2 minutes, 5 times, until each composition dissolving, water; Simultaneously lecithin, oleic acid, span 20, vitamin E Nicotinate are added in the recipe quantity soybean oil, heating 90 ℃ of dissolvings down, gets oil phase; (2) oil phase is added aqueous phase, change in the tissue mashing machine, stirred 2 minutes, 5 times, until the oil phase homodisperse, get colostrum, adjust pH is to 7-8; (4) colostrum is added in the high pressure homogenizer homogenizing 5 times, the sampling microscopy, to oil droplet below 0.5 micron; (6) get the embedding of vitamin E Nicotinate submicronized emulsion in infusion bottle, fill nitrogen, place the high-pressure rotary steriliser, sterilization.
Sample 0 constantly every index of above-mentioned 13 prescription preparations is investigated as follows:
| Sample | Outward appearance | Mean diameter | Zeta potential | Encapsulation ratio |
| Prescription 1 | Even emulsion | 175nm | -25.76 | 90.5％ |
| Prescription 2 | Even emulsion | 256nm | -27.85 | 91.3％ |
| Prescription 3 | Even emulsion | 212nm | -17.58 | 94.5％ |
| Prescription 4 | Even emulsion | 182nm | -19.56 | 91.3％ |
| Prescription 5 | Even emulsion | 259nm | -20.64 | 89.5％ |
| Prescription 6 | Even emulsion | 216nm | -22.13 | 91.6％ |
| Prescription 7 | Even emulsion | 267nm | -24.10 | 88.1％ |
| Prescription 8 | Even emulsion | 206nm | -19.86 | 86.9％ |
| Prescription 9 | Even emulsion | 285nm | -25.54 | 92.1％ |
| Prescription 10 | Even emulsion | 197nm | -21.03 | 95.3％ |
| Prescription 11 | Even emulsion | 224nm | -23.10 | 91.3％ |
| Prescription 12 | Even emulsion | 236nm | -25.6 | 89.3％ |
| Prescription 13 | Even emulsion | 209nm | -20.9 | 91.9％ |
The investigation of vitamin E nicotinate lipide microsphere stability
According to the bibliographical information experimental technique: with the vitamin E nicotinate lipide microsphere sample respectively with redistilled water, buffer salt (Na
2HPO
4, 0.017M; KH
2PO
4, 0.0014M; NaCl, 0.1370M pH7.4) and glycerol (2.21%w/w) dilution, measures dilution back 1h, 2h, 4h, the particle diameter behind 24h and the 48h, Zeta-potential and medicine encapsulation ratio.Vitamin E nicotinate lipide microsphere was preserved 6 months respectively at 4-8 ℃ and 25 ℃, the particle diameter of different time points working sample and encapsulation ratio, result of the test shows that the particle diameter of vitamin E nicotinate lipide microsphere is not subjected to the influence of redistilled water, buffer salt (pH7.4) and glycerol (2.21%w/w) dilution.Behind the 48h, the particle diameter in redistilled water and the glycerol does not almost change, and particle diameter has increased 50nm in buffer salt (pH7.4).4-8 ℃ and 25 ℃ six months experimental result that keep sample shows that the particle diameter of vitamin E nicotinate lipide microsphere of the present invention and entrapment efficiency significantly do not change.
Claims (13)
1, a kind of vitamin E nicotinate lipide microsphere injection is characterized in that: the percentage by weight of its composition is: oil phase 5%～30%, and vitamin E Nicotinate 0.1%～15%, surfactant 0.5%～5%, all the other are water for injection.
2, vitamin E nicotinate lipide microsphere injection according to claim 1 is characterized in that: wherein said oil is mineral oil, vegetable oil, animal oil, quintessence oil or artificial oil, and wherein appoints several mixture; Surfactant is phospholipid, tween, pluronic, span, enuatrol, oleic acid, cholic acid, deoxycholic acid and wherein appoints several mixture.
3, vitamin E nicotinate lipide microsphere injection according to claim 2 is characterized in that: wherein said oil is the oil in oil, seed or the nut of oil, petroleum derivation, and comprises drying oil, semi-drying oil; Non-drying oil and the oil that can be used as soap stock; Sebum, Adeps Sus domestica, stearic fat; Fish oil, oleic acid, sperm oil, aqueous fatty oil and wherein appoint several mixture; Described surfactant is a lecithin, fabaceous lecithin, enuatrol, oleic acid, polysorbas20, polysorbate40, polysorbate60, Tween 80, polysorbate85, pluronic F68; Described span is selected from span 20, span 40, and sorbester p18, sorbester p38, sorbester p17, sorbester p37, and wherein appoint several mixture.
4, vitamin E nicotinate lipide microsphere injection according to claim 3 is characterized in that: wherein said oil is fat, cerul hydrocarbon, aromatic hydrocarbon; Refined paraffin wax oil, Semen Lini, Oleum Verniciae fordii, safflower oil, soybean oil, Oleum Ricini, Oleum Gossypii semen, Oleum Cocois, Petiolus Trachycarpi oil, olive oil, Oleum Gossypii semen, corn oil, Oleum Arachidis hypogaeae semen, morrhua liver, shark liver oil; Single, double, triglyceride; The triglyceride of medium chain; Long-chain fat acid glyceride, medium chain length fatty acid triglyceride; And wherein appoint several mixture; Described surfactant is a lecithin, fabaceous lecithin, enuatrol, oleic acid, polysorbas20, polysorbate40, polysorbate60, Tween 80, polysorbate85, pluronic F68; Described span is a span 20, span 40, sorbester p18, sorbester p38, sorbester p17, sorbester p37; And wherein appoint several mixture.
5, vitamin E nicotinate lipide microsphere injection according to claim 4 is characterized in that: the described oil of wherein said oil is safflower oil, soybean oil, Semen Maydis oil, MCT Oil, Semen Coicis oil, Oleum Fructus Bruceae; And wherein appoint several mixture; Described surfactant is lecithin, fabaceous lecithin, oleic acid, enuatrol, pluronic F68, Tween 80, span 20; And wherein appoint several mixture.
6, according to claim 1,2,3,4 and/or 5 described vitamin E nicotinate lipide microsphere injections, it is characterized in that: wherein also contain percentage by weight and be 0.5%～5% osmotic pressure regulator.
7, vitamin E nicotinate lipide microsphere injection according to claim 6 is characterized in that: wherein also contain the metal-chelator that percentage by weight is 0.001%--1%.
8, vitamin E nicotinate lipide microsphere injection according to claim 7 is characterized in that: wherein also containing percentage by weight is 0.01% to 0.2% antioxidant.
9, want 8 described vitamin E nicotinate lipide microsphere injections according to right, it is characterized in that: wherein said osmotic pressure regulator is salt or its mixture that glycerol, ethylene glycol, isopropyl alcohol, sorbitol, mannitol, glucose, sodium chloride etc. pharmaceutically allow; Described metal-chelator is disodium EDTA or calcium disodium edathamil salt and composition thereof; Described antioxidant is vitamin C, sodium sulfite, and sodium pyrosulfite, cysteine, and composition thereof.
10, vitamin E nicotinate lipide microsphere injection according to claim 9, it is characterized in that: its composition is: the injection soybean oil is 10g, vitamin E Nicotinate is 5g, and lecithin is 1.5g, and glycerol is 2.5g, oleic acid is 0.06g, vitamin C is 0.2g, and sodium sulfite is 0.2g, and EDTA is 0.05g, span 20 is 0.02g, and water for injection adds to 100mL; And the pH value of injection is between 4-8.
11, vitamin E nicotinate lipide microsphere injection according to claim 10 is characterized in that: wherein the distributive law of vitamin E Nicotinate in biphase interfacial film of profit and oil phase is 80～98%.
12, according to the described a kind of preparation method that contains the lipide microsphere injection of vitamin E Nicotinate of above-mentioned arbitrary claim, it is characterized in that: comprise following steps:
Vitamin E Nicotinate solution or powder be added to the blank Emulsion that do not contain vitamin E Nicotinate through mixed vitamin E nicotinate lipide microsphere injection; Perhaps vitamin E Nicotinate solution or powder are added in the Emulsion that contains the part vitamin E Nicotinate through the mixed vitamin E nicotinate lipide microsphere injection that gets;
Perhaps vitamin E Nicotinate is added in the water-soluble medium that contains surfactant, mixes with oil phase then, prepare colostrum through high-speed stirred; Perhaps vitamin E Nicotinate solution or powder are added in the oil-soluble medium that contains surfactant, mixed with water then, prepare colostrum through high-speed stirred;
Preparation process should be controlled aqueous pH values and remain between the 4-8;
The preparation process of preparation mainly comprises high-speed stirred process and high pressure homogenize process or ultra-sonic dispersion and emulsion process;
Steam rotation sterilization is adopted in the sterilization of preparation.
13, a kind of preparation method that contains the lipide microsphere injection of vitamin E Nicotinate according to claim 12, it is characterized in that: comprise following steps: the preparation of (1) water: with surfactant, osmotic pressure regulator, metal-chelator, the stabilizing agent of recipe quantity and be preheated to 40-100 ℃ an amount of water for injection and mix, change in the tissue mashing machine, stirring gets water until each composition dissolving; (2) preparation of oil phase: simultaneously recipe quantity phospholipid, vitamin E Nicotinate are added to 40-100 ℃ of heating for dissolving in the soybean oil, get oil phase; (3) preparation of colostrum: oil phase slowly is added dropwise to aqueous phase, changes over to then in the tissue mashing machine, high-speed stirred until the oil phase homodisperse, gets colostrum, and adjust pH is to 4-8; (4) preparation of lipide microsphere injection: colostrum is added in the high pressure homogenizer homogenizing 1-10 time, the sampling microscopy, to emulsion droplet below 0.5 micron, get this submicronized emulsion embedding in infusion bottle, fill nitrogen, place steam rotation steriliser, sterilization.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1927202B (en) * | 2006-08-25 | 2010-10-13 | 西南合成制药股份有限公司 | Vitamin E nicotinate microcapsule and its preparing process |
| CN103127129A (en) * | 2013-03-08 | 2013-06-05 | 海南卫康制药(潜山)有限公司 | Cefuroxime sodium pharmaceutical composition and preparation method thereof |
| CN110123749A (en) * | 2019-06-03 | 2019-08-16 | 北京普瑞博思投资有限公司 | Nicorandil fat micro sphere preparation and preparation method thereof |
| WO2020221052A1 (en) * | 2019-04-28 | 2020-11-05 | 中国科学院上海药物研究所 | Alpha-tocopherol microsphere and preparation method therefor |
| CN112807248A (en) * | 2020-12-31 | 2021-05-18 | 海南大学 | Coconut oil nanosphere and preparation method thereof |
| CN114788524A (en) * | 2022-01-25 | 2022-07-26 | 中国农业科学院烟草研究所(中国烟草总公司青州烟草研究所) | Bacteriostatic microemulsion preparation and preparation method and application thereof |
| CN114788524B (en) * | 2022-01-25 | 2024-05-31 | 中国农业科学院烟草研究所(中国烟草总公司青州烟草研究所) | Antibacterial microemulsion preparation and preparation method and application thereof |
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- 2005-12-09 CN CN 200510127995 patent/CN1813733A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1927202B (en) * | 2006-08-25 | 2010-10-13 | 西南合成制药股份有限公司 | Vitamin E nicotinate microcapsule and its preparing process |
| CN103127129A (en) * | 2013-03-08 | 2013-06-05 | 海南卫康制药(潜山)有限公司 | Cefuroxime sodium pharmaceutical composition and preparation method thereof |
| WO2020221052A1 (en) * | 2019-04-28 | 2020-11-05 | 中国科学院上海药物研究所 | Alpha-tocopherol microsphere and preparation method therefor |
| CN110123749A (en) * | 2019-06-03 | 2019-08-16 | 北京普瑞博思投资有限公司 | Nicorandil fat micro sphere preparation and preparation method thereof |
| CN110123749B (en) * | 2019-06-03 | 2022-01-25 | 太阳升(亳州)生物医药科技有限公司 | Nicorandil lipid microsphere preparation and preparation method thereof |
| CN112807248A (en) * | 2020-12-31 | 2021-05-18 | 海南大学 | Coconut oil nanosphere and preparation method thereof |
| CN114788524A (en) * | 2022-01-25 | 2022-07-26 | 中国农业科学院烟草研究所(中国烟草总公司青州烟草研究所) | Bacteriostatic microemulsion preparation and preparation method and application thereof |
| CN114788524B (en) * | 2022-01-25 | 2024-05-31 | 中国农业科学院烟草研究所(中国烟草总公司青州烟草研究所) | Antibacterial microemulsion preparation and preparation method and application thereof |
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