CN101843588A - Biphenyl dimethylesterate nano lipid carrier and preparation method thereof - Google Patents
Biphenyl dimethylesterate nano lipid carrier and preparation method thereof Download PDFInfo
- Publication number
- CN101843588A CN101843588A CN201010195342A CN201010195342A CN101843588A CN 101843588 A CN101843588 A CN 101843588A CN 201010195342 A CN201010195342 A CN 201010195342A CN 201010195342 A CN201010195342 A CN 201010195342A CN 101843588 A CN101843588 A CN 101843588A
- Authority
- CN
- China
- Prior art keywords
- biphenyl
- dimethylesterate
- water
- lipid
- lipid carrier
- 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.)
- Granted
Links
Images
Abstract
The invention discloses a biphenyl dimethylesterate nano lipid carrier, mainly prepared by biphenyl dimethylesterate, solid lipid material, liquid lipid, water soluble emulsifier, lipid soluble emulsifier and water for injection. The preparation method thereof includes: (1) the biphenyl dimethylesterate, solid lipid material, liquid lipid and lipid soluble emulsifier are dissolved into organic solvent when being heated, so as to form an organic phase; (2) the water soluble emulsifier and additive are dissolved into the water for injection, heating is carried out, so as to form a water phase; (3) the organic phase is injected into the water phase while stirring, stirring is carried out until the organic solvent is completely volatilized, thus obtaining primary emulsion; (4) the primary emulsion is poured into iced water, and stirring is carried out, thus obtaining the biphenyl dimethylesterate nano lipid carrier. The biphenyl dimethylesterate nano lipid carrier of the invention has good biocompatibility, is easy to degrade, reduces toxic and side effect of biphenyl dimethylesterate and improves tolerance of organism.
Description
Technical field
The present invention relates to a kind of biphenyl dimethylesterate nano lipid carrier and preparation method thereof.
Background technology
Bifendate (Bifendate, be called for short DDB) is the intermediate of synthetic schisandrin C, is the hepatoprotective of efficient, the low toxicity with new structure of China's initiative.Its chemistry is called 4,4 '-dimethoxy-5,6, and 5 ', 6 '-secondary first dioxy-2,2 '-dioctyl phthalate methyl ester biphenyl, molecular formula is: C
20H
18O
10, molecular weight is: 418.36.This product is a kind of white crystalline powder, and odorless, tasteless is water-soluble hardly, is slightly soluble in methanol and ethanol, is soluble in chloroform, dimethyl formamide season pyridine, is certain fat-soluble.
Clinical research shows that the main pharmacological of bifendate has: (1) has significant function for protecting liver and reducing enzyme activity: can obviously reduce serum glutamic pyruvic transminase (glutamic pyrumic transaminase, GPT) and glutamic oxaloacetic transaminase, GOT (glutamic Oxalictransaminase, GOT); (2) strengthen the function of detoxification of liver: the content of hepatomicrosome such as P-450 is significantly increased, and then strengthen the detoxification ability of liver; (3) the liver protecting is avoided the poisonous substance damage: alleviate the hepatic injury that is caused by chemical substances such as carbon tetrachloride, anticarcinogen, antitubercular agents; The effect of (4) anti-cell sudden change, necrosis.This poison of drug is very low, and no teratogenesis tire, mutagenic action are a kind of relatively safe drugs, and cheap, easy for patients to accept, thereby have good research and application prospect.At present this medicine is clinical is used for the gpt activity rising person that chronic persistent hepatitis is followed, and also can be used for chemical toxicant, drug-induced gpt activity raises.
The almost water-fast character of bifendate makes the external stripping of its preparation poor, though be not destroyed in gastrointestinal tract, the serious liver first-pass effect in oral back causes this medicine oral administration biaavailability low, generally has only 25%～30%.Bifendate enter in the body back at liver rapidly by metabolic conversion, plasma half-life had only about 5 hours, 70% discharges from feces after 24 hours.Though only absorb about 25%, show the very strong GPT effect of falling, illustrate that its biological activity is very high, be one the researching value medicine to be arranged.The preparation that uses at present or study mainly contains Bifendate Tablet, Bifendate, bifendate drop pill, compound bifenox sheet, compound bifenox electuary, bifendate oral administration mixed suspension etc., CN 200410070669.4 (publication number CN1586472) discloses a kind of bifendate oral disintegration tablet, CN 03145971.4 (publication number CN1476831) discloses a kind of bifendate slow releasing preparation, because bifendate is water insoluble, so the low shortcoming of these preparation ubiquity bioavailability.CN 03146030.5 discloses a kind of biphenyl diester emulsion, and CN 100998561A discloses a kind of bifendate intravenous injection emulsion, and liquid preparation stores and the transportation inconvenience, also causes the medicine instability easily.CN 200610038662.3 (publication number CN1850071) discloses a kind of bifendate solid dispersion, and CN 200810234507.8 (publication number CN101401788) discloses a kind of self-emulsifying formulation of biphenyldicarboxylatand, to improve its bioavailability and stability.
Bifendate is as a kind of medicine of life-time service, and a kind of administration number of times of clinical needs is few, bioavailability is high, good stability, preparation simply help the preparation that the patient uses.
Nanoparticle (nanoparticles) is the medicine carrying microgranule that utilizes natural polymer or synthetic chemical substance to make for carrier, diameter 10～1000nm.Nanoparticle has targeting, and directly target structure conveying medicine in target organ, target cell or cell has advantages such as slow release, protection medicine, raising curative effect, reduction toxic and side effects simultaneously.Behind the intravascular injection nanoparticle, nanoparticle is mainly engulfed by reticuloendothelial system (RES), and RES comes from the very strong monocytic general designation of bone marrow phagocytic function.Numerous reticuloendothelial cell is arranged in the liver, and fixed-site, be known as the Kupffer cell, therefore medicine can be assembled in liver, progressively is released into blood circulation then, and liver drug concentration is increased, to other internal organs adverse reaction reduction, liver there is the passive target effect; When nanoparticle enough little (100～150nm) and the surface coated with special packet by after, just can escape from engulfing of Kupffer cell, be positioned hepatic parenchymal cells by the materials such as specific antibody of its connection and play a role, thereby have initiatively targeting.Therefore, nanoparticle acquires a special sense for the various hepatic disease of treatment.
(nanostructured lipid carriers is that (solid lipidnanoparticles SLN) develops and next a kind of new colloidal carrier system by solid lipid nanoparticle NLC) to nano-lipid carrier.The problem that solid lipid nanoparticle exists is that SLN is mixed and made into by single solid-state lipid or different types of solid-state lipid, and the lipid crystallization of its high-sequential, rule has not only limited the medicine carrying ability, and can cause effluxing of the medicine that is wrapped.And NLC joins the liquid lipid under the room temperature in the solid-state lipid, thereby causes crystalline randomness to increase, and makes carrier have higher crystal defect, thereby can hold more drug molecule.Mix by solid-state lipid with the inconsistent liquid lipid in its space just because of NLC and to form, make it have special nanostructured, it is advantageous that: the dissolubility of (1) insoluble drug in liquid fatty is big than solid lipid, introduces envelop rate and drug loading that liquid fatty can increase medicine; (2) adding of liquid lipid can delay solid-state lipid by the conversion of alpha crystalline form to crystal form β, can delay the leakage of medicine; (3) introducing of appropriate amount of fluid lipid can not change the character of nanoparticle solid kernel, so NLC still possesses the slow controlled release characteristics similar to SLN.
This shows; NLC has not only that SLN physical stability height, protection sensitive medicaments are not degraded, sustained release, excellent biological compatibility, be easy to advantage such as large-scale production, also improved the SLN medicine carrying limited in one's ability, reveal easily at the storage process Chinese medicine, problem such as envelop rate reduction.Therefore this effect characteristics of NLC have not only overcome the weak point of traditional SLN, and have enlarged its application.
In sum, bifendate is made nano-lipid carrier, expection can reach to change in the medicine body and distribute, prolong drug action time, improves purpose such as bioavailability.Though it is conventional technological means that medicine is made nano-lipid carrier, but develop a kind ofly have that good effect, release are controlled, the prescription and the preparation method of good biocompatibility, advantage such as stable be not easily, creative work be need pay, a large amount of tests and conditional filtering carried out.
Summary of the invention
At above-mentioned prior art, the invention provides a kind of novel form of bifendate, that is: biphenyl dimethylesterate nano lipid carrier, said preparation makes bifendate have higher chemical stability, is difficult for degraded; Good biocompatibility, stable, release is controlled, and can reach the hepatic tissue passive target by the particle diameter of control nanoparticle, improve bioavailability, improve the purpose of patient's compliance.And can overcome the phenomenon that solid lipid nanoparticle put procedure Chinese medicine effluxes, envelop rate reduces, make preparation can stablize storage.
The present invention also provides the preparation method of this biphenyl dimethylesterate nano lipid carrier, and this method can adopt conventional process equipment, is fit to the extensive high benefit production of industry.
The present invention is achieved by the following technical solutions:
A kind of biphenyl dimethylesterate nano lipid carrier mainly is made up of bifendate, solid-state matrix material, liquid lipid, water soluble emulsifier, fat-soluble emulsifier and water for injection, and in the 100ml nano lipid vector preparation, it is composed as follows:
Bifendate 0.002～0.5g
Solid-state matrix material 0.05～2g
Water soluble emulsifier 0.05～5g
Fat-soluble emulsifier 0.05～5g
The water for injection surplus.
Preferably, in the 100ml nano lipid vector preparation, it is composed as follows:
Bifendate 0.002～0.2g
Solid-state matrix material 0.05～1g
Liquid lipid 0.01～0.5g
Water soluble emulsifier 0.05～2g
Fat-soluble emulsifier 0.05～2g
Additives 0～2.5g
The water for injection surplus.
Described solid-state matrix material is any or the combination in any in triglyceride, partial glyceride, fatty acid, waxiness class or the steroid.
Described triglyceride comprises tripalmitin, glyceryl tristearate, trilaurin, glycerol trioleate etc.; Described partial glyceride comprises glyceryl monostearate, contains list, two, the synthetic glyceride of triglyceride and composition thereof; Described fatty acid comprises stearic acid, Palmic acid; Described waxiness class comprises cetyl palmitate, spermol cetylate; Described steroid is a cholesterol.
Described liquid lipid is that crude vegetal, chain length are at C
8～C
10Between medium chain fatty glyceride, oleic acid, linoleic acid, vitamin E or vitamin esters in any or combination in any.Preferred chain length is at C
8～C
10Between medium chain fatty glyceride or vitamin E.
Described water soluble emulsifier is any or the combination in any in polyoxyethylene-polyoxypropylene copolymer analog (as Poloxammer series), polyoxyethylene fatty acid ester class or the polyoxyethylene aliphatic alcohol ether class (as Brij series).
Described fat-soluble emulsifier is any or a combination in any of phospholipid, the smooth class of fatty acid Pyrusussuriensis or Polysorbate apoplexy due to endogenous wind.
Described phospholipid comprises soybean phospholipid, egg yolk lecithin, lecithin; Smooth Span60 and the Span80 of comprising of described fatty acid Pyrusussuriensis; Described Polysorbate comprises Tween60 and Tween80.
For being suitable for intravenous administration better, the combination of preferred soybean phospholipid of emulsifying agent and poloxamer 188.
Described additives are any or the combination in any in osmotic pressure regulator, complexing of metal ion agent, antioxidant or the antiseptic.Described additives can play increases preparation stability, regulate effects such as osmotic pressure, antioxidation.
Described osmotic pressure regulator comprises propylene glycol, glycerol, mannitol etc.
Described complexing of metal ion agent comprises EDTA, b diammonium disodium edta salt etc.
Described antioxidant comprises vitamin C, vitamin E etc.
Described antiseptic comprises benzalkonium bromide, parabens, sorbic acid etc.
The preparation method of biphenyl dimethylesterate nano lipid carrier may further comprise the steps:
(1) bifendate, solid-state matrix material, liquid lipid, fat-soluble emulsifier are dissolved in the organic solvent, are heated to 60～100 ℃ and make dissolving, to constitute organic facies;
(2) water soluble emulsifier, additives are dissolved in the water for injection, are heated to 60～100 ℃, to constitute water;
(3) under 60～100 ℃ temperature, be under 400～1200r/min stirs organic facies to be injected aqueous phase at rotating speed, stir 0.5h～6h, organic solvent is volatilized fully, obtain colostrum;
(4) in the frozen water with 0～2 ℃ of colostrum impouring, be to stir 0.5h～4h under 400～1200r/min, promptly make biphenyl dimethylesterate nano lipid carrier at rotating speed.
Further comprising the steps of: as the biphenyl dimethylesterate nano lipid carrier that makes further to be added freeze drying protectant, to make lyophilized formulations.Wherein, the technology of prepared biphenyl dimethylesterate nano lipid carrier being carried out the lyophilizing processing can be: the freeze drying protectant of 1～10wt% (weight ratio) is dissolved in the aqueous dispersion of biphenyl dimethylesterate nano lipid carrier; be sub-packed in the cillin bottle then; put pre-freeze 24h in-80 ℃ the ultra cold storage freezer; take out; move into rapidly in the freezer dryer, lyophilizing 48h, the sealing of jumping a queue gets final product.
Described organic solvent is any or the combination in any in chloroform, acetone, ethanol, ethyl acetate or the isopropyl alcohol.
Described freeze drying protectant is any or the combination in any in lactose, glucose, mannitol, sucrose, trehalose, dextran or the sorbitol.
The present invention has the following advantages:
(1) biphenyl dimethylesterate nano lipid carrier good biocompatibility of the present invention is easily degraded, and has reduced the toxic and side effects of bifendate, has improved the toleration of body.
(2) biphenyl dimethylesterate nano lipid carrier particle diameter of the present invention is about 200nm, and the energy passive target improves curative effect in hepatic tissue, reduces toxic and side effects greatly, can improve the bioavailability of bifendate.And possess slow-release function in vivo, but the body-internal-circulation time of prolong drug.Adopt dialysis to measure the release in vitro degree of medicine, the result shows that nano-lipid carrier shows tangible slow release characteristics (referring to Fig. 4).
(3) the present invention adopts and mixes the medicine carrying material of lipid as bifendate, by in the solid lipid material, adding a certain proportion of liquid lipid, destroyed the crystal formation of material to a certain extent, improve drug loading and envelop rate, and avoided the phenomenon that medicine effluxes, envelop rate reduces in put procedure, made preparation can stablize storage.
(4) microemulsion technology-emulsifying evaporation-low-temperature setting method of technology of the present invention for transforming, it is simple to have preparation technology, and cost is low, and technological parameter is easy to characteristics such as control, is fit to the extensive high benefit production of industry.
Description of drawings
Fig. 1 is the biphenyl dimethylesterate nano lipid carrier transmission electron microscope picture;
Fig. 2 is the biphenyl dimethylesterate nano lipid carrier transmission electron microscope picture;
Fig. 3 is biphenyl dimethylesterate nano lipid carrier particle size distribution figure; Wherein, title: particle size distribution (Size distribution (s), abscissa: particle diameter (Diameter), vertical coordinate: percentage rate (%in class);
Fig. 4 is the release percentage rate-time graph of biphenyl dimethylesterate nano lipid carrier release in vitro.
The specific embodiment
The present invention is further elaborated below in conjunction with specific embodiment, but the present invention is not limited to these embodiment.
Embodiment 1 preparation bifendate lipid carrier
Step is as follows:
(1) get bifendate 10mg, cholesterol 160mg, oleic acid 40mg, Tween80450mg are dissolved in 10ml acetone-ethanol (volume ratio 1: 1), heating for dissolving in 75 ℃ of water-baths constitutes organic facies.
(2) poloxamer 188150mg is dissolved in 15ml water for injection, heating in water bath constitutes water to the temperature identical with organic facies.
(3) be under 700r/min stirs, organic facies streams shape slowly to be injected aqueous phase at rotating speed, 75 ℃ of constant temperature stir 4h, and organic solvent is volatilized fully, the preparation colostrum.
(4) in the frozen water with 0～2 ℃ of gained colostrum impouring 45ml, 1000r/min stirs 2h under the ice bath, thereby makes biphenyl dimethylesterate nano lipid carrier, 4 ℃ of airtight preservations.
Embodiment 2 preparation bifendate lipid carriers
Step is as follows:
(1) get bifendate 50mg, glyceryl monostearate 240mg, MCT 60mg, soybean phospholipid 200mg are dissolved in the 10ml chloroform, heating for dissolving in 75 ℃ of water-baths constitutes organic facies.
(2) poloxamer 188450mg is dissolved in the 15ml water for injection, heating in water bath constitutes water to the temperature identical with organic facies.
(3) be under 700r/min stirs, organic facies streams shape slowly to be injected aqueous phase at rotating speed, 75 ℃ of constant temperature stir 4h, and organic solvent is volatilized fully, the preparation colostrum;
(4) in the frozen water with 0～2 ℃ of gained colostrum impouring 45ml, 1000r/min stirs 2h under the ice bath, thereby makes biphenyl dimethylesterate nano lipid carrier, 4 ℃ of airtight preservations.
Behind the dilute with water, with its form of H-7000 type transmission electron microscopy observation, as shown in Figure 1.As shown in Figure 1, gained biphenyl dimethylesterate nano lipid carrier size homogeneous, form rounding, particle diameter are about 200nm.
Embodiment 3 preparation bifendate lipid carriers
Step is as follows:
(1) get bifendate 20mg, tripalmitin 120mg, stearic acid 60mg, soybean oil 30mg, Span60250mg are dissolved in 10ml acetone-chloroform (volume ratio 1: 1), heating for dissolving in 80 ℃ of water-baths constitutes organic facies.
(2) poloxamer 188450mg is dissolved in the 15ml water for injection, heating in water bath constitutes water to the temperature identical with organic facies.
(3) be under 700r/min stirs, organic facies streams shape slowly to be injected aqueous phase at rotating speed, 80 ℃ of constant temperature stir 4h, and organic solvent is volatilized fully, the preparation colostrum.
(4) in the frozen water with 0～2 ℃ of gained colostrum impouring 45ml, 700r/min stirs 2h under the ice bath, thereby makes biphenyl dimethylesterate nano lipid carrier, lyophilizing.
Wherein, freeze-dry process is: mannitol and the dextran (mass ratio is 1: 1) of getting 10wt%, be dissolved in the biphenyl dimethylesterate nano lipid carrier aqueous dispersion, be sub-packed in the cillin bottle then, put pre-freeze 24h in-80 ℃ the ultra cold storage freezer, take out, move in the freezer dryer rapidly,-40 ℃, 0.10mbar lyophilizing 48h, the sealing of jumping a queue gets final product.
Embodiment 4 preparation bifendate lipid carriers
Step is as follows:
(1) get bifendate 10mg, glyceryl monostearate 160mg, MCT 40mg, soybean phospholipid 200mg are dissolved in 10ml acetone-ethanol (volume ratio 1: 1), heating for dissolving in 75 ℃ of water-baths constitutes organic facies.
(2) poloxamer 188300mg is dissolved in the 15ml water for injection, heating in water bath constitutes water to the temperature identical with organic facies.
(3) be under 700r/min stirs, organic facies streams shape slowly to be injected aqueous phase at rotating speed, 75 ℃ of constant temperature stir 4h, and organic solvent is volatilized fully, the preparation colostrum.
(4) in the frozen water with 0～2 ℃ of gained colostrum impouring 45ml, 1000r/min stirs 2h under the ice bath, thereby makes biphenyl dimethylesterate nano lipid carrier, lyophilizing.
Wherein, freeze-dry process is: get the mannitol of 5wt%, be dissolved in the biphenyl dimethylesterate nano lipid carrier aqueous dispersion, be sub-packed in then in the cillin bottle, put pre-freeze 24h in-80 ℃ the ultra cold storage freezer, take out, move into rapidly in the freezer dryer ,-40 ℃, 0.10mbar lyophilizing 48h, the sealing of jumping a queue gets final product.
After getting an amount of lyophilized powder dilute with water, with its form of H-7000 type transmission electron microscopy observation, as shown in Figure 2.Gained biphenyl dimethylesterate nano lipid carrier size homogeneous, form rounding, good moldability, particle diameter are about 200nm as shown in Figure 2.
Step is as follows:
(1) get bifendate 30mg, glyceryl monostearate 75mg, stearic acid 100mg, MCT 20mg, soybean phospholipid 200mg is dissolved in 10ml acetone-ethanol (volume ratio 1: 1), heating for dissolving in 70 ℃ of water-baths constitutes organic facies.
(2) poloxamer 188600mg is dissolved in the 15ml water for injection, heating in water bath constitutes water to the temperature identical with organic facies.
(3) be under 600r/min stirs, organic facies streams shape slowly to be injected aqueous phase at rotating speed, 70 ℃ of constant temperature stir 4h, and organic solvent is volatilized fully, the preparation colostrum.
(4) in the frozen water with 0～2 ℃ of gained colostrum impouring 45ml, 1000r/min stirs 2h under the ice bath, thereby makes biphenyl dimethylesterate nano lipid carrier, 4 ℃ of airtight preservations.
Behind the dilute with water, measure particle size distribution with Zetasizer 3000HS type laser particle size distribution instrument, recording mean diameter is 217.0nm, and polydispersity coefficient is 0.149, as shown in Figure 3.
Embodiment 6 preparation bifendate lipid carriers
Step is as follows:
(1) get bifendate 20mg, glyceryl monostearate 240mg, MCT 40mg, soybean phospholipid 250mg are dissolved in 10ml acetone-ethanol (volume ratio 1: 1), heating for dissolving in 75 ℃ of water-baths constitutes organic facies.
(2) poloxamer 188300mg is dissolved in the 15ml water for injection, heating in water bath constitutes water to the temperature identical with organic facies.
(3) be under 700r/min stirs, organic facies streams shape slowly to be injected aqueous phase at rotating speed, 75 ℃ of constant temperature stir 4h, and organic solvent is volatilized fully, the preparation colostrum.
(4) in the frozen water with 0～2 ℃ of gained colostrum impouring 45ml, 1000r/min stirs 2h under the ice bath, thereby makes biphenyl dimethylesterate nano lipid carrier, 4 ℃ of airtight preservations.
Adopt reverse dynamic dialysis method to measure the release of medicine: to contain 30% alcoholic acid PH is that 7.4 phosphate buffer (PBS) 200ml is a release medium, and mixing speed is 100r/min, and temperature is 37 ± 0.5 ℃.Sampling back sample introduction 20 μ l carry out HPLC and measure, and calculate the cumulative release percentage rate, as shown in Figure 4.
Embodiment 7 preparation bifendate lipid carriers
Step is as follows:
(1) get bifendate 10mg, glyceryl monostearate 80mg, stearic acid 80mg, MCT 60mg, soybean phospholipid 200mg is dissolved in 10ml acetone-ethanol (volume ratio 1: 1), heating for dissolving in 75 ℃ of water-baths constitutes organic facies.
(2) poloxamer 188450mg is dissolved in the 15ml water for injection, heating in water bath constitutes water to the temperature identical with organic facies.
(3) be under 800r/min stirs, organic facies streams shape slowly to be injected aqueous phase at rotating speed, 75 ℃ of constant temperature stir 4h, and organic solvent is volatilized fully, the preparation colostrum.
(4) in the frozen water with 0～2 ℃ of gained colostrum impouring 45ml, 1000r/min stirs 2h under the ice bath, thereby makes biphenyl dimethylesterate nano lipid carrier, 4 ℃ of airtight preservations.
Adopt reverse dynamic dialysis method to measure the release of medicine: to contain 30% alcoholic acid PH is that 7.4 phosphate buffer (PBS) 200ml is a release medium, and mixing speed is 100r/min, and temperature is 37 ± 0.5 ℃.Sampling back sample introduction 20 μ l carry out HPLC and measure, and calculate the cumulative release percentage rate, as shown in Figure 4.The biphenyl dimethylesterate nano lipid carrier release in vitro is two-phase kinetics as seen from the figure, promptly is initially the prominent back of releasing and is slow release; It is big more that liquid lipid accounts for TL proportion, and release is fast more.
Claims (10)
1. biphenyl dimethylesterate nano lipid carrier, it is characterized in that: mainly form by bifendate, solid-state matrix material, liquid lipid, water soluble emulsifier, fat-soluble emulsifier and water for injection, in the 100ml nano lipid vector preparation, it is composed as follows:
Bifendate 0.002～0.5g
Solid-state matrix material 0.05～2g
Liquid lipid 0～1g
Water soluble emulsifier 0.05～5g
Fat-soluble emulsifier 0.05～5g
Additives 0～5g
The water for injection surplus.
2. biphenyl dimethylesterate nano lipid carrier according to claim 1 is characterized in that: in the 100ml nano lipid vector preparation, it is composed as follows:
Bifendate 0.002～0.2g
Solid-state matrix material 0.05～1g
Liquid lipid 0.01～0.5g
Water soluble emulsifier 0.05～2g
Fat-soluble emulsifier 0.1～2g
Additives 0～2.5g
The water for injection surplus.
3. biphenyl dimethylesterate nano lipid carrier according to claim 1 and 2 is characterized in that: described solid-state matrix material is any or the combination in any in triglyceride, partial glyceride, fatty acid, waxiness class or the steroid.
4. biphenyl dimethylesterate nano lipid carrier according to claim 3 is characterized in that: described triglyceride is tripalmitin, glyceryl tristearate, trilaurin, glycerol trioleate etc.; Described partial glyceride is glyceryl monostearate, contain synthetic glyceride of list, two, triglyceride and composition thereof; Described fatty acid is stearic acid, Palmic acid; Described waxiness class is cetyl palmitate, spermol cetylate; Described steroid is a cholesterol.
5. biphenyl dimethylesterate nano lipid carrier according to claim 1 and 2 is characterized in that: described liquid lipid is that crude vegetal, chain length are at C
8～C
10Between medium chain fatty glyceride, oleic acid, linoleic acid, vitamin E or vitamin esters in any or combination in any.
6. biphenyl dimethylesterate nano lipid carrier according to claim 1 and 2 is characterized in that: described water soluble emulsifier is any or a combination in any of polyoxyethylene-polyoxypropylene copolymer analog, polyoxyethylene fatty acid ester class or polyoxyethylene aliphatic alcohol ether apoplexy due to endogenous wind;
Described fat-soluble emulsifier is any or a combination in any of phospholipid, the smooth class of fatty acid Pyrusussuriensis or Polysorbate apoplexy due to endogenous wind;
Described additives are any or the combination in any in osmotic pressure regulator, complexing of metal ion agent, antioxidant or the antiseptic.
7. method for preparing claim 1 or 2 described biphenyl dimethylesterate nano lipid carriers is characterized in that: may further comprise the steps:
(1) bifendate, solid-state matrix material, liquid lipid, fat-soluble emulsifier are dissolved in the organic solvent, are heated to 60～100 ℃ and make dissolving, to constitute organic facies;
(2) water soluble emulsifier, additives are dissolved in the water for injection, are heated to 60～100 ℃, to constitute water;
(3) under 60～100 ℃ temperature, be under 400～1200r/min stirs organic facies to be injected aqueous phase at rotating speed, stir 0.5h～6h, organic solvent is volatilized fully, obtain colostrum;
(4) in the frozen water with 0～2 ℃ of colostrum impouring, be to stir 0.5h～4h under 400～1200r/min, promptly make biphenyl dimethylesterate nano lipid carrier at rotating speed.
8. the preparation method of biphenyl dimethylesterate nano lipid carrier according to claim 7 is characterized in that: further comprising the steps of:
The biphenyl dimethylesterate nano lipid carrier that makes is further added freeze drying protectant, to make lyophilized formulations.
9. biphenyl dimethylesterate nano lipid carrier according to claim 8 is characterized in that: described freeze drying protectant is any or the combination in any in lactose, glucose, mannitol, sucrose, trehalose, dextran, the sorbitol.
10. biphenyl dimethylesterate nano lipid carrier according to claim 7 is characterized in that: described organic solvent is any or the combination in any in chloroform, acetone, ethanol, ethyl acetate or the isopropyl alcohol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101953425A CN101843588B (en) | 2010-06-09 | 2010-06-09 | Biphenyl dimethylesterate nano lipid carrier and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101953425A CN101843588B (en) | 2010-06-09 | 2010-06-09 | Biphenyl dimethylesterate nano lipid carrier and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101843588A true CN101843588A (en) | 2010-09-29 |
| CN101843588B CN101843588B (en) | 2011-11-30 |
Family
ID=42768535
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010101953425A Expired - Fee Related CN101843588B (en) | 2010-06-09 | 2010-06-09 | Biphenyl dimethylesterate nano lipid carrier and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101843588B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103784421A (en) * | 2014-02-27 | 2014-05-14 | 哈尔滨医科大学 | Curcumin and piperine carried solid lipid nanoparticles and preparation method thereof |
| CN105030680A (en) * | 2015-08-19 | 2015-11-11 | 合肥华方医药科技有限公司 | Total bufogenin nano lipid carrier drug delivery system for injection and preparation method thereof |
| CN111110587A (en) * | 2019-12-12 | 2020-05-08 | 江南大学 | Preparation method of nanocapsule for carrying fat-soluble active substances |
| CN112999351A (en) * | 2021-03-11 | 2021-06-22 | 华中农业大学 | Preparation method and application of artificial lipid drops and freeze-dried preparation thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1478465A (en) * | 2003-07-14 | 2004-03-03 | 丽 佟 | Biphenyl diester liquid medicinal composition containing fat |
| CN101401788A (en) * | 2008-11-20 | 2009-04-08 | 中国药科大学 | Self-emulsifying formulation of biphenyldicarboxylate and preparation method thereof |
| CN101632638A (en) * | 2009-08-21 | 2010-01-27 | 山东大学 | Silybin nanostructured lipid carrier and preparation method thereof |
-
2010
- 2010-06-09 CN CN2010101953425A patent/CN101843588B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1478465A (en) * | 2003-07-14 | 2004-03-03 | 丽 佟 | Biphenyl diester liquid medicinal composition containing fat |
| CN101401788A (en) * | 2008-11-20 | 2009-04-08 | 中国药科大学 | Self-emulsifying formulation of biphenyldicarboxylate and preparation method thereof |
| CN101632638A (en) * | 2009-08-21 | 2010-01-27 | 山东大学 | Silybin nanostructured lipid carrier and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 20071231 张洪,等 联苯双酯固体脂质纳米粒的制备 37-50 第23卷, 第6期 2 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103784421A (en) * | 2014-02-27 | 2014-05-14 | 哈尔滨医科大学 | Curcumin and piperine carried solid lipid nanoparticles and preparation method thereof |
| CN105030680A (en) * | 2015-08-19 | 2015-11-11 | 合肥华方医药科技有限公司 | Total bufogenin nano lipid carrier drug delivery system for injection and preparation method thereof |
| CN111110587A (en) * | 2019-12-12 | 2020-05-08 | 江南大学 | Preparation method of nanocapsule for carrying fat-soluble active substances |
| CN112999351A (en) * | 2021-03-11 | 2021-06-22 | 华中农业大学 | Preparation method and application of artificial lipid drops and freeze-dried preparation thereof |
| CN112999351B (en) * | 2021-03-11 | 2022-06-10 | 华中农业大学 | Preparation method and application of artificial lipid drops and freeze-dried preparation thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101843588B (en) | 2011-11-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101862306B (en) | New type slightly soluble oral medicine self-emulsification preparation and preparation method thereof | |
| CN101909614B (en) | Nanodispersion | |
| CN102579341A (en) | Docetaxel solid lipid nanoparticle and preparation method thereof | |
| CN102228430B (en) | Nano suspension of silybin-phospholipid complex and preparation method thereof | |
| CN101569607B (en) | Di-demethoxycurcumin precursor liposome and preparation method thereof | |
| CN104337851A (en) | Preparation method of oleum fructus bruceae nano structure lipid carrier and freeze-dried powder thereof | |
| Li et al. | Preparation and properties of mixed micelles made of Pluronic polymer and PEG-PE | |
| CN101953792B (en) | Irinotecan nano circulating liposome and preparation method thereof | |
| CN104163915B (en) | Cholesterol-poloxamer-cholesterol triblock copolymer and its preparation method and application | |
| CN101843588B (en) | Biphenyl dimethylesterate nano lipid carrier and preparation method thereof | |
| Dasgupta et al. | Solid lipid nanoparticles (SLNs) gels for topical delivery of aceclofenac in vitro and in vivo evaluation | |
| CN101632638B (en) | Silybin nanostructured lipid carrier and preparation method thereof | |
| CN1850070A (en) | Quercetin solid liposome nano particle preparation and its preparing method | |
| CN101322690A (en) | Stable medicament lipid complexes | |
| CN102366411B (en) | Dexamethasone palmitate acid liposome injection | |
| CN1980671B (en) | Liposome preparation containing slightly water-soluble camptothecin | |
| CN101099733B (en) | Taxol freezing-dried emulsion for injection and preparation method thereof | |
| CN104997759B (en) | A kind of total toadpoison lactone solid lipid nano granule drug delivery system of injection and preparation method thereof | |
| CN101439020A (en) | Polyenic taxusol nano lipid carrier and preparation method thereof | |
| CN104013600A (en) | Psoralen-enveloped nanostructure lipid carrier preparation and preparation method thereof | |
| CN102048702B (en) | Bifendate nano crystal preparation and preparation method thereof | |
| CN101439019A (en) | Paclitaxel nano lipid carrier and preparation method thereof | |
| CN102961346A (en) | Tamibarotene nano-liposome carrier and preparation method thereof | |
| CN1875944B (en) | A carbowax modified stealthy liposome nanosphere of hydroxycamtothecine and preparation method thereof | |
| CN112121028B (en) | Simvastatin solid nanoparticle preparation and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20111130 Termination date: 20120609 |