CN101822839A - Preparation of nanometer structure lipid carrier by using seal oil as liquid-phase substrate and application - Google Patents
Preparation of nanometer structure lipid carrier by using seal oil as liquid-phase substrate and application Download PDFInfo
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Abstract
The invention relates to preparation of nanometer structure lipid carrier by using seal oil as a liquid-phase substrate and application, wherein the nanometer structure lipid carrier consist of the solid-phase substrate and a liquid-phase substrate, wherein the solid-phase substrate is phosphatidyl choline and saturated fatty acid, and the liquid-phase substrates is marine organism fat.
Description
Technical field
The present invention relates to the application of the nano structured lipid carrier system of seal oil preparation, relate generally to nano structured lipid carrier and strengthening medicine stability, slow release effect and change medicine body giving drugs into nose are for the application in the dynamic process.
Background technology
(Nanostructured lipid carriers is to be developed by solid lipid nanoparticle NLC) to nano structured lipid carrier.Solid lipid nanoparticle (Solid lipid nanoparticles, SLN), be to be carrier, pharmaceutical pack is wrapped in the lipoid nuclear, the nanometer drug delivery system of particle diameter between 50～1000nm of making through distinct methods with solid-state natural or synthetic lipoid such as lecithin, three fatty acyl glycerol etc.Compare with microemulsion with some traditional carrier system liposomees, medicine has been realized better controlled release and slow release effect owing to being encapsulated in the good solid skeletal of physiological compatibility, because it uses biocompatible lipoid as carrier matrix, therefore significantly reduced the acute and chronic toxic danger of generation simultaneously.However, SLN still has its limitation:, burst effect low as drug loading and physical stability are poor.Because single solid lipid substrate can form the lipid crystal, limited its medicine carrying ability, and can change to perfect cystal gradually, thereby cause the storage process Chinese medicine to be squeezed lattice, these shortcomings have caused nano structured lipid carrier (Nanostructured Lipid Carrier, appearance NLC).
The difference of NLC and SLN is that NLC is by several different structures, a kind of lipid infill system with special construction that the solid-liquid lipid mixture of immiscible (fusing point difference) is prepared from.The adding of liquid fatty can be upset the lattice structure of solid lipid rule, increases the ratio of irregular crystal formation in the nanoparticle structure, the spatial content of entrapped drug is increased, and then improve the medicine carrying ability of carrier, and prevent drug leakage.NLC has also inherited some advantages of SLN, and, protection medicine good as physiological compatibility is not subjected to chemical degradation (comprising as sunscreen) but mass preparation, with low cost, and can be made into tablet, pill, capsule and powder with dealing with various requirements.By controlling liquid lipid ratio, also can make NLC under body temperature, keep the solid skeletal structure, realize that the NLC controlled delivery of pharmaceutical agents discharges.
Seal oil is the animal oil that is rich in omega-3 unsaturated fatty acid that enjoyed people to pay close attention in the last few years, is used to body-care and immunomodulating.It is rich in a high proportion of omega-3 unsaturated fatty acid, EPA, DPA and DHA, the oxidation and the trans fatty acid of the vitamin K of low content and low ratio.Based on the above characteristics of seal oil, we consider to select for use the liquid-phase substrate of seal oil as the preparation nano structured lipid carrier, in the hope of obtaining having the nano structured lipid carrier of good result.
All-trans-retinoic acid (ATRA) is the vitamin A derivant of metabolism birth in vivo, is successfully synthesized external in nineteen forty-six by ArensJF and Van Dorp the earliest.Retinoic acid has the very strong differentiation tumor cytosis of inducing, and enjoys the concern of international and domestic the world of medicine, is the clinical choice drug for the treatment of acute promyelocytic leukemia, myelodysplastisches (preleukemia) at present.Retinoic acid has the growth of support, promotes the epithelium differentiation, suppresses effects such as cell proliferation, and can be a kind of more satisfactory cell proliferation medicine to the growth and the differentiation generation effect of kinds of tumor cells.Clinical acne, lichen planus, white macula, multiple verruca vulgaris and other keratinization dermatoses of being used for the treatment of also has significant curative effect simultaneously.Retinoic acid is yellow or light orange crystalline powder, and is almost insoluble in water, simultaneously very unstable under illumination, heat and some oxidizing conditions, influenced the clinical use of medicine.
Summary of the invention
Purpose one of the present invention: a kind of nano structured lipid carrier with light stability is provided.
Purpose two of the present invention: the preparation method that the nano structured lipid carrier that is loaded with retinoic acid is provided.
Purpose three of the present invention: with the nano structured lipid carrier of seal oil as liquid-phase substrate.
Nano structured lipid carrier of the present invention is made up of solid-phase matrix and liquid-phase substrate, and wherein solid-phase matrix is lecithin and satisfied fatty acid, and liquid-phase substrate is a marine organisms fat.
Wherein said satisfied fatty acid is that the molecular formula of known structure is: CH
3(CH
2) nCH
2The material of COOH, wherein n is 5,7,9,11,13 or 15, preferred n-capric acid or lauric acid, wherein said marine organisms fat is seal oil.
Wherein solid-phase matrix accounts for 0.02-32% (w/V), and liquid-phase substrate accounts for 0.02-32% (w/V), stores within 30 days particle diameter at 100-500nm, and polydispersity index P.I. is at 0.15-0.30, and Zeta potential is at-25--50mV.
Preferably, contain solid-phase matrix 20-80% (W/W) in the described carrier material, contain liquid-phase substrate 20-80% (W/W).
Be more preferably: contain solid-phase matrix 40-60% (W/W) in the described carrier material, contain liquid-phase substrate 40-60% (W/W).
The preparation method of nano structured lipid carrier of the present invention: comprise the steps: weighing solid-phase matrix and liquid-phase substrate, mix homogeneously adds the PBS that contains Tween 80, is stirred to the formation pre-emulsion, and standardize solution is after the even nano structured lipid carrier that forms of high pressure breast.
Concrete steps are as follows: take by weighing a certain amount of solid-phase matrix and liquid-phase substrate in the eggplant bottle according to recipe quantity, and add appropriate amount of drug, constant temperature vibration mix homogeneously becomes oil phase.An amount of Tween 80 dispersed with stirring of weighing forms water in the PBS buffer, constantly stirs under the room temperature water is added oil phase, is stirred to and forms even pre-emulsion, and standardize solution is in 50ml.Adopt the even circulation of high pressure homogenization machine room temperature 900-1500bar pressure stimulating milk secretion 5 times, promptly form the aqueous dispersion of NLC.Its matrix material is made up of lecithin, fatty acid and liquid lipid seal oil,
The present invention also comprises the drug sustained release system with described nano structured lipid carrier preparation, it is characterized in that, the ratio of each component is: medicine 0.01-20% (W/V), nano structured lipid carrier is 0.1-40% (W/V), all the other ooze PBS for the grade of pH74, described slow-released system, its particle diameter are 100-500nm, and Zeta potential is between-25--50mV.
Wherein said medicine is selected from: fat-soluble medicine such as all-trans-retinoic acid, nimodipine, paclitaxel or Docetaxel.
Preferred medicine is selected from all-trans-retinoic acid.
The preferred drug sustained release system of the present invention the ratio of each component is: all-trans-retinoic acid 0.01-20% (W/V), nano structured lipid carrier are 0.1-40% (W/V), and all the other ooze PBS for the grade of pH7.4.
The preparation method of fat-soluble medicine slow-released system of the present invention: comprise the steps: weighing solid-phase matrix and liquid-phase substrate and fat-soluble medicine, use dissolve with ethanol, behind the mix homogeneously, add the PBS that contains Tween 80, be stirred to the formation pre-emulsion, standardize solution is after the high pressure breast is even.
Some fat-soluble medicines in the prior art have been improved because the application limitations that poorly soluble, photo-labile and pharmacokinetics process cause with nano structured lipid carrier of the present invention.
Nano structured lipid carrier of the present invention and dried frozen aquatic products thereof can strengthen the protective effect of photo-labile medicine and improve the purposes of fat-soluble medicine body giving drugs into nose for dynamic process.
The present invention also comprises, with novel nano structured lipid carrier of the present invention and dried frozen aquatic products thereof in medical science, the purposes in the fields such as biology, pesticide and cosmetics.
Below by test data beneficial effect of the present invention is described:
1, the physical stability of all-trans-retinoic acid nano structured lipid carrier
The physical stability of preparation is meant that physical property changes, and as the medicine stripping in the preparation, caking, crystalline growth, profit layering etc. takes place to assemble.The task of research pharmaceutical preparation stability is to improve the inherent quality of product.For reaching this purpose, at first to investigate the influence of environmental factors to medicine stability.The physical stability of nano structured lipid carrier is by monitoring lucifuge condition among the present invention, and the envelop rate of particle diameter, Zeta potential and medicament-carried nano structured lipid plastid under 25 ℃ is evaluated.The result illustrate that the nano structured lipid carrier stability of preparation is better, and low tempertaure storage is more favourable referring to accompanying drawing 3,4.
2, the chemical stability of all-trans-retinoic acid in the nano structured lipid carrier
The chemical stability of pharmaceutical preparation is meant medicine because the reaction of chemical degradations such as hydrolysis, oxidation, make medicament contg or tire, color and luster etc. produces and changes, thereby influence drug effect.Because all-trans-retinoic acid is extremely unstable under illumination; therefore (changes of contents of 4500 ± 500lx, 2000 ± 500lx) times all-trans-retinoic acids is evaluated the nano structured lipid carrier made with the seal oil photoprotection for medicine by the different illumination of monitoring.
Under the room temperature respectively with the methanol solution of matched group all-trans-retinoic acid, n-capric acid-seal oil ATRA-NLC and lauric acid-seal oil ATRA-NLC places the clarity lighting box, 100ul per hour takes a sample, after adding 5ml methanol solution dilution destruction, vortex 15s is to dissolving fully, 0.45 μ m membrane filtration is measured ATRA content with HPLC.The results are shown in accompanying drawing 5, accompanying drawing 6.As seen from the figure, all-trans-retinoic acid is decayed very fast in methanol solution, and being prepared into the NLC dosage form has tangible photoprotection to ATRA.From quantitative result, with the first _ order kinetics equation match, its half-life is compared with the all-trans-retinoic acid methanol solution with the result under two illumination of 4500 ± 500lx and 2000 ± 500lx, all has P＜0.01 that utmost point significant difference is promptly arranged.During 4500 ± 500lx illumination, what the NLC half-life was matched group to the maximum is 2.2 times; The NLC half-life is 2.9 times of matched group to the maximum under 2000 ± 500lx illumination, proves that this kind nano structured lipid carrier has tangible photoprotection to all-trans-retinoic acid.
3, the release in vitro of all-trans-retinoic acid nano structured lipid carrier
Be loaded with the medicine release in vitro of the nano structured lipid carrier of all-trans-retinoic acid, realize in the following manner: preparation contains n-capric acid-seal oil NLC dosage form of ATRA 200mg/L, the accurate 3mL that draws is in the bag filter of handling well, step up with dialysis clamp at two ends, places the wide mouthed bottle that contains 50mL dialysis medium.Wide mouthed bottle is put into 37 ℃ of air isothermal vibration devices, 90 times/minute vibrations, in 1h, 3h, 5h, 8h, 16h, 24h, 32h, the 40h sampling is also changed the fresh dialysis medium of 50mL (PBS+40% alcoholic solution).The medium that takes out with 0.45 μ m filtering with microporous membrane after, get the filtrate sample introduction, the concentration of HPLC analysis ATRA.Release with free drug simultaneously contrasts.The result is referring to accompanying drawing 7.
4, the interior medicine dynamics of all-trans-retinoic acid nano structured lipid carrier
Pharmacokinetics is the importance that pharmaceutical preparation is estimated.Realize in the following manner: laboratory animal adopts male Wistar rat, body weight 280-330g, administering mode: tail intravenous injection, dosage: 6mg/kg.Get the blood mode: eye socket is got blood.Experiment grouping: this experiment employing own control with intersect the mode that administration combines.A group: free ATRA, the PBS suspension of the ATRA of a small amount of Tween 80 hydrotropy.B group: the ATRA-NLC of n-capric acid-seal oil.Experimental rat is divided into 2 groups at random, 3 every group.Tested for first week according to the administration of AB order, through an off-drug period in week, test two groups successively according to the administration of BA order for the second time after the experiment.After administration 0.0167,0.083,0.167,0.333,0.5,1,2,4,6,8,12h gets about blood 0.6ml in the test tube of handling through heparin of the sharp end, the centrifugal 10min of 3000rpm, and getting upper serum, to place-20 ℃ of refrigerator and cooled to hide to be measured.
Plasma sample is handled: the accurate plasma sample 0.2ml that draws adds methanol 0.8ml protein precipitation, vortex 15s, centrifugal 3000rpm 10min in plastic test tube at the bottom of the 1.5ml tool plug tip.Adding 200 μ l chromatograph methanol concentrate after getting the supernatant vacuum drying, and sample introduction HPLC analyzes behind the 0.45 μ m filtering with microporous membrane excessively.With peak area substitution standard curve, calculate each time point sample Chinese medicine concentration, the results are shown in accompanying drawing 8.
Experimental result with 3P87 pharmacokinetics software during to rat body giving drugs into nose data handle calculating, simulate with two-compartment model, obtain pharmacokinetic parameters in the rat body, see Table 1.Can see that all-trans-retinoic acid is from the first order rate constant (k of periphery compartment to central compartment's transhipment
21), the first order rate constant (k that transports to periphery compartment from the central compartment
12) and the first order rate constant (k that eliminates from the central compartment of medicine
10) compare with the blank group and significant difference all to be arranged (P＜0.05).This in vivo distribution of explanation medicine, transhipment and eliminate speed and increase help medicine and play a role quickly in vivo and eliminate.This may have higher affinity relevant with nano structured lipid carrier and tissue and organ.ATRA poor solubility in water is that its absorption is not good, the one of the main reasons of bioavailability difference, and medicine dissolves in nano structured lipid carrier well, absorbs soon, and AUC increases obviously, thereby has improved bioavailability.Area under the drug-time curve (AUC) is compared with blank group ATRA with clearance rate (CL) all has utmost point significant difference (P＜0.01).Therefore nano structured lipid carrier has not only improved the blood peak concentration of drug of ATRA, has also increased ATRA greatly in the intravital body storage of rat simultaneously, can keep the treatment valid density of long period.
Pharmacokinetic parameters in table 1.ATRA and the ATRA-NLC rat body
*The expression blank group of contrast (ATRA) has significant difference P＜0.05
*The expression blank group of contrast (ATRA) has utmost point significant difference P＜0.01
Description of drawings
Fig. 1 has described the transmission electron microscope picture of nano structured lipid carrier.
Fig. 2 has described the sem photograph of nano structured lipid carrier.
The particle diameter and the Zeta potential of the nano structured lipid carrier that has been prepared by n-capric acid-seal oil and lauric acid-seal oil when Fig. 3 has described room temperature 25 degree storages change.
Fig. 4 has described to be loaded with the n-capric acid-seal oil of all-trans-retinoic acid when storing and the envelop rate of the nano structured lipid carrier that lauric acid-seal oil prepares changes.
All-trans-retinoic acid changes of contents when Fig. 5 has described that intensity of illumination is 4500 ± 500lx in all-trans-retinoic acid methanol solution and the nano structured lipid carrier.
All-trans-retinoic acid changes of contents when Fig. 6 has described that intensity of illumination is 2000 ± 500lx in all-trans-retinoic acid methanol solution and the nano structured lipid carrier.
Fig. 7 has described the medicine release in vitro curve of all-trans-retinoic acid in all-trans-retinoic acid and the nano structured lipid carrier.
Fig. 8 has described blood drug level variation in ATRA and the ATRA-NLC rat body.
The specific embodiment
In order further to set forth the present invention, provide a series of embodiment below.These embodiment are illustrative fully, and they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.
Embodiment 1: the preparation (blank NLC preparation) that with the seal oil is the nano structured lipid carrier of liquid-phase substrate
Weighing 0.5g seal oil, 0.375g lecithin and 0.125g n-capric acid or lauric acid in the eggplant bottle, constant temperature vibration mix homogeneously.Add the 0.6g Tween 80 in 20ml PBS, in the oil phase before adding while stirring as water, be stirred to the formation pre-emulsion, standardize solution is in 50ml, and the even circulation of high pressure breast promptly forms medicament-carried nano structured lipid carrier 5 times under the 900-1500bar pressure.
Embodiment 2: the preparation of all-trans-retinoic acid nano structured lipid carrier
Weighing 0.5g seal oil, 0.375g lecithin and 0.125g n-capric acid or lauric acid and a certain amount of all-trans-retinoic acid in the eggplant bottle, constant temperature vibration mix homogeneously.Add the 0.6g Tween 80 in 20ml PBS, in the oil phase before adding while stirring as water, be stirred to the formation pre-emulsion, standardize solution is in 50ml, and the even circulation of high pressure breast promptly forms medicament-carried nano structured lipid carrier 5 times under the 900-1500bar pressure.
Embodiment 3: the microscopic pattern of nano structured lipid carrier is observed
Get the NLC sample solution, use distilled water diluting respectively, get 10ul and place the copper mesh surface, following lining filter paper after volatilizing naturally, is prepared transmission electron microscope observing.Fixedly the Electronic Speculum electron-beam voltage is 80kV, and moving coordinate is regulated amplification, and searching is observed particle and taken pictures.See accompanying drawing 1.Simultaneously with the dilution sample drop 20ul on coverslip, after volatilizing naturally, metal spraying carries out scanning electron microscopic observation.See accompanying drawing 2.
The present invention passes through transmission electron microscope as can be seen, and single nano structured lipid carrier is a spheroidal particle, and size is homogeneous relatively, and it is more even to distribute; Also confirmed The above results in the scanning electron microscope visual field, can see after the amplification that nano structured lipid carrier is that the surface has fold and depression, is similar to the structure of vesicle.
Embodiment 4: the preparation of Nimodipime nanometer structured lipid carrier
Weighing 0.5g seal oil, 0.375g lecithin and 0.125g n-capric acid or lauric acid and a certain amount of nimodipine in the eggplant bottle, constant temperature vibration mix homogeneously.Add the 0.6g Tween 80 in 20ml PBS, in the oil phase before adding while stirring as water, be stirred to the formation pre-emulsion, standardize solution is in 50ml, and the even circulation of high pressure breast promptly forms medicament-carried nano structured lipid carrier 5 times under the 900-1500bar pressure.
Embodiment 5: the preparation of Docetaxel nano structured lipid carrier
Weighing 0.5g seal oil, 0.375g lecithin and 0.125g n-capric acid or lauric acid and a certain amount of Docetaxel in the eggplant bottle, constant temperature vibration mix homogeneously.Add the 0.6g Tween 80 in 20ml PBS, in the oil phase before adding while stirring as water, be stirred to the formation pre-emulsion, standardize solution is in 50ml, and the even circulation of high pressure breast promptly forms medicament-carried nano structured lipid carrier 5 times under the 900-1500bar pressure.
Embodiment 6: the preparation of paclitaxel nano structured lipid carrier
Weighing 0.5g seal oil, 0.375g lecithin and 0.125g n-capric acid or lauric acid and a certain amount of paclitaxel in the eggplant bottle, constant temperature vibration mix homogeneously.Add the 0.6g Tween 80 in 20ml PBS, in the oil phase before adding while stirring as water, be stirred to the formation pre-emulsion, standardize solution is in 50ml, and the even circulation of high pressure breast promptly forms medicament-carried nano structured lipid carrier 5 times under the 900-1500bar pressure.
Claims (10)
1. a nano structured lipid carrier is characterized in that, is made up of solid-phase matrix and liquid-phase substrate, and wherein solid-phase matrix is lecithin and satisfied fatty acid, and liquid-phase substrate is a seal oil; Wherein said satisfied fatty acid molecular formula is: CH
3(CH
2) nCH
2COOH, n are 5,7,9,11,13 or 15.
2. the nano structured lipid carrier of claim 1 is characterized in that, contains solid-phase matrix 20-80% (W/W) in the described carrier material, contains liquid-phase substrate 20-80% (W/W).
3. the nano structured lipid carrier of claim 1 is characterized in that, contains solid-phase matrix 40-60% (W/W) in the described carrier material, contains liquid-phase substrate 40-60% (W/W).
4. the preparation method of the nano structured lipid carrier of claim 1: it is characterized in that, comprise the steps: weighing solid-phase matrix and liquid-phase substrate, mix homogeneously adds the PBS that contains Tween 80, be stirred to the formation pre-emulsion, standardize solution is after the even nano structured lipid carrier that forms of high pressure breast.
5. the preparation method of claim 4: it is characterized in that, comprise the steps: weighing 0.5g seal oil, 0.375g lecithin and 0.125g n-capric acid or lauric acid in the eggplant bottle, constant temperature vibration mix homogeneously.Add the 0.6g Tween 80 in 20mlPBS, in the oil phase before adding while stirring as water, be stirred to the formation pre-emulsion, standardize solution is in 50ml, and the even circulation of high pressure breast promptly forms medicament-carried nano structured lipid carrier 5 times under the 900-1500bar pressure.
6. use the drug sustained release system of the described nano structured lipid carrier preparation of claim 1, it is characterized in that, the ratio of each component is: medicine 0.01-20% (W/V), nano structured lipid carrier is 0.1-40% (W/V), all the other ooze PBS for the grade of pH7.4, described slow-released system, its particle diameter are 100-500nm, and Zeta potential is between-25--50mV.
7. the drug sustained release system of claim 6 is characterized in that, described medicine is selected from: all-trans-retinoic acid, nimodipine, paclitaxel or Docetaxel.
8. the fat-soluble medicine slow-released system of claim 7 is characterized in that, its Chinese medicine is selected from all-trans-retinoic acid, described system, the ratio of each component is: all-trans-retinoic acid 0.01-20% (W/V), nano structured lipid carrier are 0.1-40% (W/V), and all the other ooze PBS for the grade of pH7.4.
9. the preparation method of the fat-soluble medicine slow-released system of claim 6: it is characterized in that, comprise the steps: weighing solid-phase matrix and liquid-phase substrate and fat-soluble medicine, behind the mix homogeneously, add the PBS that contains Tween 80, be stirred to the formation pre-emulsion, standardize solution is after the high pressure breast is even.
10. the preparation method of claim 9: it is characterized in that, comprise the steps: weighing 0.5g seal oil, 0.375g lecithin and 0.125g n-capric acid or lauric acid and a certain amount of all-trans-retinoic acid in the eggplant bottle, constant temperature vibration mix homogeneously.Add the 0.6g Tween 80 in 20ml PBS, in the oil phase before adding while stirring as water, be stirred to the formation pre-emulsion, standardize solution is in 50ml, and the even circulation of high pressure breast promptly forms medicament-carried nano structured lipid carrier 5 times under the 900-1500bar pressure.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102579338A (en) * | 2012-03-02 | 2012-07-18 | 首都医科大学 | Preparation method and application of paclitaxel intravenous fat emulsion |
| WO2013057144A3 (en) * | 2011-10-18 | 2013-11-14 | Dr. Rimpler Gmbh | Aqueous dispersion having a content of lipid nanoparticles, process for production thereof and use thereof |
| CN111568880A (en) * | 2015-09-17 | 2020-08-25 | 阿赖耶识（上海）生物技术有限公司 | High-stability non-vesicular nanoparticles and application thereof in treating propionibacterium acnes infection |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1620253A (en) * | 2001-12-27 | 2005-05-25 | 创世纪集团公司 | Seal oil based lipid emulsions and uses thereof |
| CN1166368C (en) * | 2003-02-26 | 2004-09-15 | 刘威 | Seal oil cream and its prepn process and appplication in preparing intravenous injection |
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2010
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013057144A3 (en) * | 2011-10-18 | 2013-11-14 | Dr. Rimpler Gmbh | Aqueous dispersion having a content of lipid nanoparticles, process for production thereof and use thereof |
| CN102579338A (en) * | 2012-03-02 | 2012-07-18 | 首都医科大学 | Preparation method and application of paclitaxel intravenous fat emulsion |
| CN111568880A (en) * | 2015-09-17 | 2020-08-25 | 阿赖耶识（上海）生物技术有限公司 | High-stability non-vesicular nanoparticles and application thereof in treating propionibacterium acnes infection |
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