CN101439018A - Silybin compound emulsion for intravenous injection and preparation method thereof - Google Patents
Silybin compound emulsion for intravenous injection and preparation method thereof Download PDFInfo
- Publication number
- CN101439018A CN101439018A CNA2008100465291A CN200810046529A CN101439018A CN 101439018 A CN101439018 A CN 101439018A CN A2008100465291 A CNA2008100465291 A CN A2008100465291A CN 200810046529 A CN200810046529 A CN 200810046529A CN 101439018 A CN101439018 A CN 101439018A
- Authority
- CN
- China
- Prior art keywords
- silibinin
- water
- injection
- oil
- emulsion
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Abstract
The invention relates to a silibinin compound emulsion used for intravenous injection and a preparation method. Components for preparing raw material of 1000 ml comprise 0.08 percent to 8 percent silibinin compound, 10 percent to 48 percent triglyceride compound, 0.08 percent to 18 percent emulsifier, 1 percent to 15 percent water-soluble or oil-soluble addition agent and the reminder which is injection water. The distribution range of particle size of the emulsion is ranged from 0.1 micron to 1 micron, and the average particle size is ranged from 0.2 micron to 0.4 micron. The preparation method comprises steps which are colostrum preparation, high pressure homogenization, sterilization, and the like; the emulsion has the advantages of dramatic efficacy, high bioavailability, high drug loading, sustained release, passive liver targeting, low toxic side effect, and the like.
Description
Technical field
The present invention relates to a kind of used for intravenous injection Emulsion, particularly a kind of silibinin compound emulsion and preparation method thereof belongs to the pharmaceutical drug substance field.
Background technology
China is hepatopathy country occurred frequently, chronic hepatitis B patient 3,000 ten thousand people of existing disease is arranged approximately, 1.2 hundred million hepatitis B virus carrierss at present.The hepatopath is mostly with gallbladder disease, and the medication cycle is longer, is difficult to thorough healing, and Fa Zuo situation is more repeatedly.
Silibinin (Silibinin; SL) be to extract refining from feverfew Herba Silybi mariani seed and flavonoids that obtain, its chemical structural formula is as follows:
It is reported that silibinin and isomers thereof have Stabilization to liver plasma membrane, it can stop or avoid dissolved cell component (for example transaminase) to run off.Silibinin can limit some Hepatoxic substance (as: α-amanitin) and penetrate into cell interior, strengthen protein synthesis capacity, the repair ability of enhance hepatocyte and regeneration capacity are widely used in the acute and chronic hepatitis of treatment clinically, initial stage hepatitis interstitialis chronica, diseases such as liver poisoning.Yet, the poorly water-soluble of silibinin and isomers thereof, lower (the standard extract that contains 70%～80% silymarin of its oral administration biaavailability, only can absorb 20%～30% from animal and human gastrointestinal tract), metabolism is very fast, therefore need frequent drug administration could guarantee blood drug level in effective range, and frequent drug administration easily cause savings to be poisoned.
Simultaneously, for the injection of silibinin compounds, do not see on market at present to occur that because of its common injection need add adjuvants such as a large amount of cosolvents or solubilizing agent, this will inevitably increase its toxicity and zest yet, increase the risk of clinical application.
And 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, have stronger liver passive targeting especially, can reach effect efficient, low toxicity target tissue.
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 silibinin lipomul both at home and abroad as yet.
Summary of the invention
The object of the present invention is to provide a kind of silybin compound emulsion for intravenous injection and preparation method thereof, it is to be main active with a kind of of silibinin or its isomers, 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, because the existence of inflammation, make the mononuclear phagocyte that has normal tissue more to accumulate in a large number can absorb and remove the lipid in the blood circulation, thereby emulsion carrier is optionally accumulated at inflammation part, make it become the ideal carrier of anti-inflammatory drug.In common Drug therapy, the medicine that can reach diseased region only for dosage 1% in addition still less, and utilize the special affinity at Emulsion and inflammatory disorders position, 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.
This shows whether medicine suits to make Emulsion, should consider the pharmacologically active of medicine itself.Studies show that: silibinin and isomers thereof have Stabilization to liver plasma membrane, and it stops or avoids dissolved cell component (for example transaminase) to run off.Silibinin can limit some Hepatoxic substance (as: α-amanitin) and penetrate into cell interior, strengthens protein synthesis capacity, the repair ability of enhance hepatocyte and regeneration capacity.Therefore, silibinin is made Emulsion, can be with the curative effect and the target administration technology desired combination of silibinin.
After definite silibinin 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 silibinin in various medicinal solvents and study, and then optimizing prescriptions.Through experimental studies have found that: the dissolubility of silibinin in triglyceride compounds (as soybean oil) is all relatively poor with the dissolubility in water, but its profit is distributed studies show that of behavior, the content ratio of silibinin in isopyknic profit is biphase is about 22:1～24:1, by the amount of special method increase emulsifying agent, its profit partition coefficient can reach 30:1～33:1.This dissolution characteristics shows: the silibinin lipotropy can be prepared to Emulsion obviously greater than hydrophilic.
For achieving the above object, the technical solution used in the present invention is as follows:
A kind of silybin compound emulsion for intravenous injection, it is to be main active with the silibinin compounds, add triglyceride compounds pharmaceutically commonly used, emulsifying agent, water for injection is prepared from, it is characterized in that: by weight/percent by volume, the raw material of preparation 1000ml is formed and is comprised: silibinin compounds 0.08～8%, triglyceride compounds 10～48%, emulsifying agent 0.08～18%, water solublity or oil-soluble additives 1～15%, all the other are water for injection, the distribution of this Emulsion particle diameter is at 0.1～1 micron, and mean diameter is 0.2～0.4 micron.
Wherein, described triglyceride compounds is the long chain triglyceride that meets Chinese Pharmacopoeia regulation, or medium chain triglyceride a kind of or two kinds, also or the mixture of long chain triglyceride and medium chain triglyceride a kind of or two kinds.Wherein long chain triglyceride is soybean oil, Oleum Ricini, olive oil, Semen Maydis oil, Oleum Sesami, Oleum Cocois, safflower oil, Oleum Gossypii semen, Oleum Camelliae or oleum theobromatis; Medium chain triglyceride is a kind of in fatty glyceride, olein, glyceryl linoleate, Polyethylene Glycol glyceryl laurate ester, ethyl oleate, Ethyl linoleate, Trivent OCG or the tricaprin or more than one mixture.
Described emulsifying agent is one or more the mixture that meets among fabaceous lecithin, lecithin, soybean lecithin, Pa Luoshamu 188 (F-68), poloxamer 188, Tween80, Tween20 or the Span20 of Chinese Pharmacopoeia regulation.
Described water solublity additives are selected from the pH regulator agent that meets Chinese Pharmacopoeia regulation or one or more the material in the isoosmotic adjusting agent.Wherein the pH regulator agent is the hydrochloric acid of 0.1mol/L or the sodium hydroxide of 0.1mol/L; Isoosmotic adjusting agent is one or more the mixture in sodium chloride and glucose, sorbitol, xylitol, mannitol or the glycerol.
Described oil-soluble additives are selected from the stabilizing agent that meets Chinese Pharmacopoeia regulation or one or more the material in the antioxidant.Wherein stabilizing agent is one or more the mixture in oleic acid, enuatrol or the sodium caprylate; Antioxidant is one or more the mixture in vitamin A, vitamin E or the vitamin C.
In Emulsion of the present invention, add one or more pharmaceutically acceptable cryoprotective agents and/or skeleton formation agent; handle through lyophilization; 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 used for intravenous injection Emulsion of the present invention is as follows:
A, to take by weighing silibinin compounds, triglyceride compounds, emulsifying agent, additives and water for injection by above-mentioned weight/volume percent standby;
B, with the silibinin compounds or after wherein adding the oil-soluble additives, add again in the triglyceride compounds be preheated to 60 ℃, mix forming oil phase;
C, the dissolving of emulsifying agent and water solublity additives is scattered in the water for injection that is preheated to 60 ℃, mixes forming water;
D, under 10000 rev/mins high-speed stirred condition, the oil phase that the b step is made slowly adds the aqueous phase that people c step makes, and is dispersed in aqueous phase to oil phase and promptly makes colostrum;
E, the colostrum that the d step is made are transferred in the high pressure dispersing emulsification machine, and homogenize to the mean diameter of colostrum reaches below 0.4 micron repeatedly, fills the nitrogen fill, sterilization, and Emulsion gets product.
The invention has the advantages that:
1, the present invention passes through to increase the dissolubility and the stability of silibinin, thereby has effectively improved its bioavailability, has improved the targeting of silibinin at liver organization, has increased the action time and the action effect of medicine, has reduced toxic and side effects.
2, the intravenous injection emulsion that makes of the present invention, broken through silibinin in oil to the restriction of its dissolubility, significantly increased the drug loading and the drug level of Emulsion, thereby reduced production cost, be more convenient for clinical application.
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 in inflammation, can absorb and remove the lipid in the blood circulation, thereby emulsion carrier is optionally accumulated at inflammation part, make it become the ideal carrier of anti-inflammatory drug.In common Drug therapy, the medicine that can reach diseased region only for dosage 1% in addition still less, and utilize the special affinity at Emulsion and inflammatory disorders position, 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.
Description of drawings
Fig. 1 is the particle size distribution of silibinin vein emulsion of the present invention figure as a result
Fig. 2 is the Zeta potential measurement result figure of silibinin vein emulsion of the present invention
The specific embodiment
Embodiment 1
The dissolving of 10g lecithin and 30g glycerol is scattered in the water for injection that 700ml is preheated to 60 ℃, stirs and make phospholipid be dispersed in aqueous phase; Other gets the 3g silibinin and adds 200g and be preheated in 60 ℃ the soybean oil, after the dissolving fully oil phase.Slowly adding is with the aqueous phase of 10000 rev/mins of stirrings with the injection soybean oil, and stirring is 5 minutes under 60 ℃ temperature, gets 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 0.4 micron, fill the nitrogen fill, sterilization, used for intravenous injection Emulsion gets product.
Embodiment 2
10g fabaceous lecithin, 4g Pa Luoshamu 188 (F-68) and the dissolving of 20g mannitol are scattered in the water for injection that 650ml is preheated to 60 ℃, are prepared into homodisperse water; Other gets the 4g silibinin and adds 250g and be preheated in 60 ℃ the injection Oleum Ricini, after the dissolving fully oil phase.Slowly adding is with the aqueous phase of 10000 rev/mins of stirrings with oil phase, and stirring is 10 minutes under 60 ℃ temperature, is prepared into colostrum; Colostrum is added injection water to 1000 milliliter, put in the high pressure dispersing emulsification machine homogenize 3 times, reach below 0.4 micron to mean diameter, fill the nitrogen fill, sterilization, used for intravenous injection Emulsion gets product.
The dissolving of 20g fabaceous lecithin and 25g glycerol is scattered in the water for injection that 600ml is preheated to 60 ℃, prepares homodisperse water; Other gets the 2g silibinin and adds 150g and be preheated in 60 ℃ the soybean oil, after the dissolving fully oil phase.Slowly adding is with the aqueous phase of 10000 rev/mins of stirrings with oil phase, and stirring is 10 minutes under 60 ℃ temperature, is prepared into colostrum; Colostrum is added injection water to 1000 milliliter, put the high pressure dispersing emulsification machine repeatedly in homogenize to mean diameter reach below 0.4 micron, fill the nitrogen fill, sterilization, used for intravenous injection Emulsion gets product.
Embodiment 4
The dissolving of 20g lecithin and 50g mannitol is scattered in the water for injection that 700ml is preheated to 60 ℃, prepares homodisperse water; Other gets the 3g silibinin and adds 200g and be preheated in 60 ℃ the soybean oil, after the dissolving fully oil phase.Slowly adding is with the aqueous phase of 10000 rev/mins of stirrings with oil phase, and stirring is 10 minutes under 60 ℃ temperature, gets 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 0.4 micron, fill the nitrogen fill, sterilization, used for intravenous injection Emulsion gets product.
Embodiment 5
15g fabaceous lecithin, 3g tween 80 and the dissolving of 30g mannitol are scattered in the water for injection that 600ml is preheated to 60 ℃, are prepared into homodisperse water; Other gets the 3g silibinin and adds 200g and be preheated in 60 ℃ the Semen Maydis oil, after the dissolving fully oil phase.Slowly adding is with the aqueous phase of 10000 rev/mins of stirrings with oil phase, and stirring is 10 minutes under 60 ℃ temperature, is prepared into 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 0.4 micron, fill the nitrogen fill, sterilization, used for intravenous injection Emulsion gets product.
Embodiment 6
The dissolving of 10g fabaceous lecithin and 20g glycerol is scattered in the water for injection that 500ml is preheated to 60 ℃, prepares homodisperse water; Other gets the 2g silibinin and adds 150g and be preheated in 60 ℃ the soybean oil, after the dissolving fully oil phase.Slowly adding is with the aqueous phase of 10000 rev/mins of stirrings with oil phase, and stirring is 10 minutes under 60 ℃ temperature, is prepared into 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 0.4 micron, fill the nitrogen fill, sterilization promptly gets used for intravenous injection finished product Emulsion.
Embodiment 7
The dissolving of 10g soybean lecithin for injection and 50g injection mannitol is scattered in the water for injection that 500ml is preheated to 60 ℃, prepares homodisperse water; Other gets the 3g silibinin and adds 300g and be preheated in 60 ℃ the Fructus Canarii albi, after the dissolving fully oil phase.With the slow aqueous phase that adds with 10000 rev/mins of stirrings of oil phase, under 60 ℃ temperature, stirred 10 minutes, get colostrum, colostrum is added injection water to 1000 milliliter, putting in the high pressure dispersing emulsification machine repeatedly, homogenize to mean diameter reaches below 0.4 micron, fill the nitrogen fill, sterilization promptly gets used for intravenous injection finished product Emulsion.
Embodiment 8
15g Ovum Gallus domesticus Flavus lecithin, 20g poloxamer 188 and the dissolving of 35g glycerol are scattered in the water for injection that 700ml is preheated to 60 ℃, prepare homodisperse water; Other gets 3g silibinin, 10g enuatrol, add 100g and be preheated in 60 ℃ the soybean oil, after the dissolving fully oil phase.Slowly adding is with the aqueous phase of 10000 rev/mins of stirrings with oil phase, and stirring is 10 minutes under 60 ℃ temperature, is prepared into colostrum.Colostrum is added injection water to 1000 milliliter, put homogenize repeatedly in the high pressure dispersing emulsification machine, reach below 0.4 micron to mean diameter, fill the nitrogen fill, sterilization promptly gets used for intravenous injection finished product Emulsion.
Embodiment 9
10g soybean lecithin and the dissolving of 30g glycerol are scattered in the water for injection of 600ml preheating in 60 ℃ of water-baths, prepare homodisperse water; Other gets 10g silibinin, 10g vitamin E, adds in the Oleum Ricini of 100g preheating in 60 ℃ of water-baths, gets oil phase after the dissolving fully.Slowly pour oil phase into water, disperseed 5 minutes with the high speed shear dispersion emulsifying machine, 10000 rev/mins of rotating speeds stirred 10 minutes under 60 ℃ temperature, were prepared into colostrum.Colostrum is added injection water to 1000 milliliter, and homogenize repeatedly on high pressure homogenizer reaches below 0.4 micron to mean diameter, fills the nitrogen fill, and sterilization promptly gets used for intravenous injection finished product Emulsion.
Be described further below by pharmacology, drug effect and the beneficial effect of related experiment data result Emulsion of the present invention:
Test example 1 diameter of aspirin particle distributes and the Zeta potential inspection
We measure Emulsion particle size distribution and Zeta potential prepared in the embodiment of the invention, and particle size distribution measuring the results are shown in Figure 1, and the Zeta potential measurement result is seen Fig. 2 (instrument: Malvern-3000 type particle size distribution and Zeta potential analyzer).As shown in Figure 1, the Emulsion particle size distribution of the present invention's preparation is even, and PDI is 0.086, is normal distribution, mean diameter 279.3nm; As shown in Figure 2, the Emulsion Zeta potential of the present invention's preparation is-24.72mV.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.
The 2 drug sensitivity inspections of test example
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 the present invention preparation, the 10th day after last sensitization then, the Emulsion 1.0ml/ of Cavia porcellus digital veins of the foot injection the present invention 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: Emulsion of the present invention does not have sensitization, can be used for intravenous injection.
Test example 3 medicine hemolytics 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 present invention 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: Emulsion of the present invention does not have haemolysis, can be used for intravenous injection.
The 4 medicine irritation inspections of test example
Method: get 3 of healthy new zealand rabbits, all in the Emulsion 25ml/kg of left ear auricular vein instillation the present invention 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: Emulsion nonirritant of the present invention can be used for intravenous injection.
Test example 5 drug bioavailabilities and pharmacokinetics test
With drug prepared in the embodiment of the invention is the test medication, and homemade silibinin injection is a control drug, and dosage is 10mg/kg, and relatively two kinds of preparations the results are shown in following table in the intravital pharmacokinetics index of normal dogs.
| Group | The test medicine | Control drug |
| AUC (0-∞)(ug/L*min) | 3.165±0.019 | 1.825±0.013 |
| T 1/2(min) | 128.67±7.42 | 68.56±5.66 |
The result shows that under identical dosage the Emulsion of the present invention's preparation is compared with injection, and bioavailability is significantly improved, and the half-life prolongs (P＜0.01).
Claims (10)
1, a kind of silybin compound emulsion for intravenous injection, it is to be main active with the silibinin compounds, add triglyceride compounds pharmaceutically commonly used, emulsifying agent, water for injection is prepared from, it is characterized in that: by weight/percent by volume, the raw material of preparation 1000ml is formed and is comprised: silibinin compounds 0.08～8%, triglyceride compounds 10～48%, emulsifying agent 0.08～18%, water solublity or oil-soluble additives 1～15%, all the other are water for injection, the distribution of this Emulsion particle diameter is at 0.1～1 micron, and mean diameter is 0.2～0.4 micron.
2, silibinin compound emulsion according to claim 1 is characterized in that: described triglyceride compounds is soybean oil, Oleum Ricini, olive oil, Semen Maydis oil, Oleum Sesami, Oleum Cocois, safflower oil, Oleum Gossypii semen, Oleum Camelliae or oleum theobromatis.
3, silibinin compound emulsion according to claim 1 is characterized in that: described triglyceride compounds is a kind of in fatty glyceride, olein, glyceryl linoleate, Polyethylene Glycol glyceryl laurate ester, ethyl oleate, Ethyl linoleate, Trivent OCG or the tricaprin or more than one mixture.
4, silibinin compound emulsion according to claim 1 is characterized in that: described emulsifying agent is one or more the mixture among fabaceous lecithin, lecithin, soybean lecithin, Pa Luoshamu 188, poloxamer 188, Tween80, Tween20 or the Span20.
5, silibinin compound emulsion according to claim 1 is characterized in that: described water solublity additives are selected from one or more the mixture in 0.1mol/L hydrochloric acid, 0.1mol/L sodium hydroxide, sodium chloride and glucose, sorbitol, xylitol, mannitol or the glycerol.
6, silibinin compound emulsion according to claim 1 is characterized in that: described oil-soluble additives are selected from one or more the mixture in oleic acid, enuatrol or the sodium caprylate.
7, silibinin compound emulsion according to claim 1 is characterized in that: described oil-soluble additives are one or more the mixture in vitamin A, vitamin E or the vitamin C.
8, the preparation method of silibinin compound emulsion according to claim 1 is characterized in that:
A, by weight/that percent by volume takes by weighing silibinin compounds, triglyceride compounds, emulsifying agent, additives and water for injection is standby;
B, with the silibinin compounds or after wherein adding the oil-soluble additives, add again in the triglyceride compounds be preheated to 60 ℃, mix forming oil phase;
C, the dissolving of emulsifying agent and water solublity additives is scattered in the water for injection that is preheated to 60 ℃, mixes forming water;
D, under 10000 rev/mins high-speed stirred condition, the oil phase that the b step is made slowly adds the aqueous phase that people c step makes, and is dispersed in aqueous phase to oil phase and promptly makes colostrum;
E, the colostrum that the d step is made are transferred in the high pressure dispersing emulsification machine, and homogenize to the mean diameter of colostrum reaches below 0.4 micron repeatedly, fills the nitrogen fill, sterilization, and Emulsion gets product.
9, the preparation method of silibinin compound emulsion according to claim 8 is characterized in that: the dissolving of 10g lecithin and 30g glycerol is scattered in the water for injection that 700ml is preheated to 60 ℃, stirs and make phospholipid be dispersed in aqueous phase; Other gets the 3g silibinin and adds 200g and be preheated in 60 ℃ the soybean oil, after the dissolving fully oil phase; Slowly adding is with the aqueous phase of 10000 rev/mins of stirrings with oil phase, and stirring is 5 minutes under 60 ℃ temperature, gets 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 0.4 micron, fill the nitrogen fill, sterilization, used for intravenous injection Emulsion gets product.
10, the preparation method of silibinin compound emulsion according to claim 8 is characterized in that: the dissolving of 20g lecithin and 50g mannitol is scattered in the water for injection that 700ml is preheated to 60 ℃, prepares homodisperse water; Other gets the 3g silibinin and adds 200g and be preheated in 60 ℃ the soybean oil, after the dissolving fully oil phase; Slowly adding is with the aqueous phase of 10000 rev/mins of stirrings with oil phase, and stirring is 10 minutes under 60 ℃ temperature, gets 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 0.4 micron, fill the nitrogen fill, sterilization, finished product used for intravenous injection Emulsion.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100465291A CN101439018A (en) | 2008-11-11 | 2008-11-11 | Silybin compound emulsion for intravenous injection and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100465291A CN101439018A (en) | 2008-11-11 | 2008-11-11 | Silybin compound emulsion for intravenous injection and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101439018A true CN101439018A (en) | 2009-05-27 |
Family
ID=40723719
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008100465291A Pending CN101439018A (en) | 2008-11-11 | 2008-11-11 | Silybin compound emulsion for intravenous injection and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101439018A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102614121A (en) * | 2011-11-10 | 2012-08-01 | 上海天氏利医药科技有限公司 | Silibinin injection composition and preparation process |
| US9248115B2 (en) | 2007-11-15 | 2016-02-02 | Madaus Gmbh | Silibinin component for the treatment of hepatitis |
| CN110507549A (en) * | 2019-08-12 | 2019-11-29 | 西安现代生物科技有限公司 | A kind of non-toxic, environmental friendly mosquito repellent emulsion and preparation method thereof |
| CN111714454A (en) * | 2020-07-22 | 2020-09-29 | 宿迁医美科技有限公司 | Perilla seed oil and silybum marianum seed oil compounded fat emulsion and preparation method thereof |
-
2008
- 2008-11-11 CN CNA2008100465291A patent/CN101439018A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9248115B2 (en) | 2007-11-15 | 2016-02-02 | Madaus Gmbh | Silibinin component for the treatment of hepatitis |
| CN102614121A (en) * | 2011-11-10 | 2012-08-01 | 上海天氏利医药科技有限公司 | Silibinin injection composition and preparation process |
| CN102614121B (en) * | 2011-11-10 | 2013-12-11 | 上海天氏利医药科技有限公司 | Silibinin injection composition and preparation process |
| CN110507549A (en) * | 2019-08-12 | 2019-11-29 | 西安现代生物科技有限公司 | A kind of non-toxic, environmental friendly mosquito repellent emulsion and preparation method thereof |
| CN111714454A (en) * | 2020-07-22 | 2020-09-29 | 宿迁医美科技有限公司 | Perilla seed oil and silybum marianum seed oil compounded fat emulsion and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2678319C2 (en) | Hormone-containing emulsion | |
| US9265724B2 (en) | Oral dosage form of tetrahydrocannabinol and a method of avoiding and/or suppressing hepatic first pass metabolism via targeted chylomicron/lipoprotein delivery | |
| CN101909614B (en) | Nanodispersion | |
| EP0315079A1 (en) | Drug carriers | |
| CN107397718A (en) | Externally-applied medicinal composition based on semifluorinated alkane class | |
| CN101926757A (en) | Liquid composition of indissolvable medicines and preparation method thereof | |
| US20120045489A1 (en) | Nano-Emulsion Injection of Vinca Alkaloids and the Preparation Method Thereof | |
| US20190015346A1 (en) | Self-emulsifying drug delivery system | |
| US20210299062A1 (en) | Cannabinoid compositions and methods of treatment | |
| CN101496787A (en) | Prostaglandin E1 lipid microsphere injection with charge effect and preparation method thereof | |
| JP5860468B2 (en) | Cyclosporine emulsion | |
| KR20180006902A (en) | Cavacetaxel liposome emulsion injection and method of making same and use thereof | |
| Su et al. | Evaluation of the efficacy, toxicity and safety of vinorelbine incorporated in a lipid emulsion | |
| CN101439018A (en) | Silybin compound emulsion for intravenous injection and preparation method thereof | |
| CN102552137B (en) | Triptolide fat emulsion injection and preparation method thereof | |
| JPS61291520A (en) | Fat emulsion of erythromycin | |
| CN100457089C (en) | Solid liposome nanoparticles of arenobufagin and preparation method thereof | |
| CN101797228B (en) | Method for preparing oryzanol microemulsion | |
| CN101322688B (en) | Flumazenil oil-in-water emulsion for vein and preparation thereof | |
| CN101416942A (en) | Nimodipine sub micro-emulsion injection and preparation method thereof | |
| CN100515389C (en) | Medicinal emulsion adapted for difficultly soluble medicine and method for preparing the same | |
| CN114010597B (en) | Propyl gallate fat emulsion injection with special grease proportion and preparation method thereof | |
| CN101716147A (en) | Alprostadil liposome microsphere preparation | |
| CN100362993C (en) | Tanshinone emulsion and its making method | |
| CN101152147B (en) | Ligustrazine compound emulsion and method for preparing the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20090527 |