CN103142484B - Fenofibrate lipid cubic liquid crystal solid powder and preparation method thereof - Google Patents
Fenofibrate lipid cubic liquid crystal solid powder and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the technical field of pharmaceutic preparations, and provides fenofibrate lipid cubic liquid crystal solid powder and a preparation method thereof. The fenofibrate lipid cubic liquid crystal solid powder is prepared by adding an appropriate amount of maltodextrin in fenofibrate lipid cubic crystal and spraying and drying the fenofibrate lipid cubic crystal; or adding a freeze-drying excipient in fenofibrate lipid cubic crystal and spraying and drying the fenofibrate lipid cubic crystal. The fenofibrate lipid cubic liquid crystal solid powder has the advantages of convenience in transportation and storage, high stability and high drug loading capacity and bioavailability of medicine.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, more specifically, relate to a kind of fenofibrate lipid cubic liquid crystal solid powder and preparation method thereof.
Background technology
Lipid cubic liquid crystal microgranule (cubosomes) refers to that certain density amphipathic lipids can spontaneous formation thermodynamically stable double-layer of lipoid in water, and then formed by distortion can the space cubic liquid crystal system of filling.This cubic liquid crystal has co-continuous but Uncrossed water channel, and namely on three-dimensional, with minimal surface principle, pool and the arrangement of lipid district periodic cycle, form " cellular " structure.Because two channel structures of its uniqueness, make it have diversified parcel, it can coated water-soluble medicine as timolol maleate, tetracycline, cefazolin, amycin etc., also fat-soluble medicine can be wrapped up as vitamin E, aspirin etc., in addition, some medicines such as metronidazole, chlorphenamine maleate, propantheline bromide, propranolol hydrochloride also can wrap up wherein.
Be self-assembled into the amphiphilic lipid molecular report of cubic liquid crystal nanoparticle maximum be glycerin mono-fatty acid ester (GMO), glycerin mono-fatty acid ester-water system is the most conventional.But the simple lipid cubic liquid crystal aqueous dispersion formed by GMO and water is also unstable, because its hydrophobic chain can be exposed in aqueous medium, thus destroys the internal structure of crystal.
In prior art, lipid cubic liquid crystal has three kinds of classical microgranules: one is the precursor adopting spray drying method to prepare, with solid-state or liquid existence; Two is the large cubic gel microgranules adopting classical mechanical high-energy input method to prepare, and it has isotropism (clarifying in appearance), stiff solid-state shape; Three is the cubic liquid crystal nanoparticle dispersions adopting emulsion process to prepare, and is shown as homogeneous, Thermodynamically stable, in periodic arrangement crystal.
The concrete operations of high-energy input method are first by matrix material and the obtained large cubic gel particle of aqueous phase mixing, react 24 hours, by Mechanical Method or ultrasonic method, cubic gel particle dispersion are become nanometer and micron-sized granule.Dispersion processing process commonly uses high pressure homogenizer, and the homogenizing of circulation for several times could form homogeneous isometric particle.If make granule less, high pressure emulsifier can be used to reduce particle diameter.But the method has following shortcoming: 1. the intermediate product large cubic gel particle viscosity owing to being formed is very large, will by more difficult for its nanorize, need to input large energy, can reduce the self assembly ability of cube lipid-water system, and too much energy input can destroy the internal structure of cubic liquid crystal phase; 2. the response time is long, is unfavorable for a large amount of production.
The concrete operations of emulsion process are at ambient temperature, and by dilution glycerin mono-fatty acid ester-Ethanol System, spontaneous emulsification, forms cubic liquid crystal nanoparticle; In whole process, just simple mixing, avoids the input of the excessive power such as mechanical energy or ultrasonic energy.The key of the method adds to help aqueous solvent (as ethanol).But help aqueous solvent to be a kind of amphipathic molecule not having surfactant function, it can destroy liquid crystalline phase, namely promotes to form liquid crystal particle disperse system, itself does not participate in forming liquid crystal, when being mixed into a certain amount of, it can increase the dissolubility of water-insoluble lipid as glycerin mono-fatty acid ester.Under emulsion process can be applicable to room temperature condition, and its intermediate product is low viscosity, anisotropic L
αphase, without the need to the lipid-based cubic liquid crystalline nanoparticle that high-energy input can be made.Though emulsion process has above advantage, its product is liquid, and be unfavorable for transport, particle diameter should not control, unstable.
The concrete operations of spray drying method are that cubic liquid crystal nanoparticle is made precursor powder form: 1. in water reclamation starch solution, and the dispersion that spraying dry is formed by starch-glycerin mono-fatty acid ester-water system makes the glycerin mono-fatty acid ester being enclosed with starch; 2. form Emulsion by ethanol-glucosan-glycerin mono-fatty acid ester-water system, after spraying dry, make the glycerin mono-fatty acid ester being enclosed with glucosan.Starch and glucosan, as the capsule material of parcel glycerin mono-fatty acid ester, not only in dry run, can reduce the cohesion of powder, and when powder forms lipid-based cubic liquid crystalline nanoparticle by hydration, have the effect of solubility deflocculant.After adding water, it is the colloidal of 0.6 μm, stable cubic liquid crystal nanoparticle that two kinds of powder can form mean diameter.What starch systems was formed is thick disperse system, and the formation of glucosan system is Emulsion, and Emulsion is easier than thick disperse system sprays and disperses, so the particle size distribution scope that glucosan system obtains is narrower.But the method is used for doing starch and the beta-dextran content very high (starch 75%, Dextran 60 %) of capsule, cause liposome content little, can the content also corresponding minimizing of packaging medicine.Be suitable for the medicine that drug effect value is higher in this approach, as enzyme, vitamin etc.And the particle diameter formed comparatively large (600nm), be unsuitable for making injection.
Fenofibrate is fibrate lipid regulating agent, it significantly can reduce the concentration of serum triglycerides and low density lipoprotein, LDL, cholesterol, very low density lipoprotein (VLDL) and apo-B, and the ratio of high density lipoprotein, apolipoprotein-A and Apolipoprotein A1 and apo-B can be made to raise, effect compared with clofibrate is stronger, it is applicable to various hyperlipemia, as: high TC mass formed by blood stasis, high TG mass formed by blood stasis and combined hyperlipidemia familial, TG reducing effect is remarkable, can be used as the choice drug of TG reducing.In addition, fenofibrate can also reduce plasma fibrinogen content, reduces hematoblastic viscosity, thus reduces the formation of thrombosis.After fenofibrate enters human body, can by the esterase hydrolyzed in tissue and blood plasma, the activated metabolite of tool---the fenofibrate of generation, thus play the effect reducing blood fat.
Fenofibrate belongs to lipophilic compound, and almost insoluble in water, Determination of oil-water partition coefficient is 5.3, and oral absorption is poor, and therefore bioavailability is low.Up to the present, the dosage form that fenofibrate has at home and abroad gone on the market mainly contains capsule and tablet, and modal is adopt crude drug micronization technology, to improve its bioavailability; In addition fenofibrate double layer osmotic pump preparation, slow-release micro-pill, nano suspension, micronization capsule etc., all existing bibliographical information.But the ability that these dosage forms improve fenofibrate bioavailability is still limited.
Summary of the invention
Technical problem to be solved by this invention is the technical deficiency overcoming existing fenofibrate dosage form, provides a kind of preparation method of fenofibrate lipid cubic liquid crystal solid powder.
Another technical problem that the present invention will solve is to provide the fenofibrate lipid cubic liquid crystal solid powder obtained based on described preparation method, described fenofibrate lipid cubic crystal pressed powder has good drug loading characteristic, can improve fenofibrate bioavailability well.
Object of the present invention is achieved by the following technical programs:
A kind of preparation method of fenofibrate lipid cubic liquid crystal solid powder is provided, comprises the following steps:
S1. fenofibrate lipid cubic liquid crystal is prepared;
S2. add maltodextrin in the fenofibrate lipid cubic liquid crystal prepared toward S1 and obtain mixture, through spraying dry and get final product after mixture described in dilute with water; Or through lyophilization and get final product add freeze-dried excipient in the fenofibrate lipid cubic liquid crystal that S1 prepares after;
Wherein, the preparation method of the fenofibrate cubic liquid crystal described in S1 is, according to mass ratio, get glycerin mono-fatty acid ester (GMO) and poloxamer188 (F-127) at 50 ~ 70 DEG C, to add fenofibrate after water-bath melting become oil phase, add in oil phase the ultrasonic mixing of a certain amount of water dissolve after mixture, mixture is inserted in autoclave, be heated to 90 ~ 110 DEG C, let cool gas 3 ~ 5min, then cover air vent, heat to 115 ~ 125 DEG C of process 10 ~ 20min;
The mass ratio of described glycerin mono-fatty acid ester (GMO), poloxamer188 (F-127), fenofibrate and water is 20:1.5 ~ 3.0:0.5 ~ 3.0:180;
The mass ratio of the maltodextrin described in S2, glycerin mono-fatty acid ester (GMO), poloxamer188 (F-127), fenofibrate and water is 60:20:1.5 ~ 3.0:0.5 ~ 3.0:400g.
As a kind of preferred version, S1 gets glycerin mono-fatty acid ester and poloxamer188 (F-127), water-bath melting at 60 DEG C respectively; Put into autoclave after adding distilled water ultrasonic dissolution, heating-up temperature, to 100 DEG C, lets cool gas 4min, covers air vent, after heating to 121 DEG C, continues heat treated 15min and obtains described fenofibrate lipid cubic liquid crystal.
Because the simple lipid cubic liquid crystal aqueous dispersion formed by GMO and water is also unstable, hydrophobic chain can be exposed in aqueous medium, thus destroys the internal structure of crystal.The present invention, when S1 prepares fenofibrate lipid cubic liquid crystal, adds the reaction that amphiphilic disperse medium avoids water delivery chain and aqueous medium in hydrophobic chain and aqueous medium, thus protection crystals is not destroyed.The present invention is directed to GMO, the characteristic of fenofibrate, constantly analysis and research are summed up in conjunction with great many of experiments, the poloxamer188 (F127) of Optimum is a kind of desirable stabilizing agent and disperse medium.Poloxamer188 (F127) forms PEO by polyoxyethylene (PEO), polyoxypropylene (PPO)
98-PPO
67-PEO
98nonionic triblock copolymer, hydrophobicity PPO is combined with particle surface, and hydrophilic PEO then covers surface, is formed " shield " spatially, and then plays stable effect.The content adding F127 can affect structure and the granular size of the last lipid liquid crystal nanoparticle formed.When F127 content is 3%, form spiral-shaped structure (C
d) be main, along with the increase of F127 content, spiral-shaped structure changes body-centered cubic structure (C gradually into
p), when F127 content reaches 15%, the lipid-based cubic liquid crystalline nanoparticle of formation is based on body-centered cubic structure, and the nanoparticle now formed is temperature influence (25 ~ 65 DEG C) not.This is because when F127 concentration is lower, F127 is mainly wrapped on the surface of granule, after the raising of F127 concentration covers particle surface completely, unnecessary F127 will enter glycerin mono-fatty acid ester inside.Compare with glycerin mono-fatty acid ester, the hydrophilic of F127 is stronger, so add the hydration level that F127 can increase Emission in Cubic.
As a kind of preferred version, described in S2, spray-dired condition is: inlet temperature is 120 ~ 140 DEG C, and actual outlet temperature is 85 ~ 100 DEG C, and wind speed is 80 ~ 100L/min, and charging rate is 30 ~ 40mL/min.
As one most preferably scheme, described in S2, spray-dired condition is: inlet temperature is 130 DEG C, and actual outlet temperature is 97 ~ 90 DEG C, and wind speed is 90L/min, and charging rate is 35mL/min.
Application spray drying technology is prepared in the process of fenofibrate lipid prismatic crystal pressed powder, needs to overcome the technical barrier such as thermal sensitivity, degeneration that liquid material produces in drying.Usually, when spraying dry suspension, under the inlet temperature conditions of some scope, spraying dry can only carry out original granule in dry suspension as the dry means of one, can not change the pattern of original granule; And under the inlet temperature of some scope, spraying dry can become the effective means of preparation desirable particle size product; Simultaneously, influencing each other between the factor such as performance and inlet temperature, outlet temperature, sample introduction flow velocity, pressure and wind speed such as thermal sensitivity and degeneration that also must consider liquid material itself, influencing each other between these factors is not simple man-to-man relation, needs to pay experiments a large amount of for a long time and gropes just can sum up solution targetedly with creationary analysis and summary.Fenofibrate lipid prismatic crystal and maltodextrin are obtained suspension according to the preparation that adds water after the mixing of suitable ratio by the present invention, dried powder is obtained after the spraying dry of refined condition setting, experimental result is known, again the lipid cubic liquid crystal after being disperseed by gained dried powder of the present invention is spherical in shape under the microscope, without obvious particles agglomerate phenomenon, effect is fine.
As a kind of preferred version, described in S2, cryodesiccated condition is :-45 DEG C of pre-freezes start the drying that heats up in 6 hours afterwards, and program is :-35 DEG C of 1h;-30 DEG C of 8h;-25 DEG C of 8h;-20 DEG C of 5h;-10 DEG C of 2h; 0 DEG C of 2h; 10 DEG C of 1h; 20 DEG C of 3h.
As a kind of preferred version, freeze-dried excipient described in S2 is one in mannitol, maltose, lactose and glucose or its mixing.
As one most preferably scheme, freeze-dried excipient described in S2 is the mixture of manna alcohol and glucose, or is the mixture of mannitol and lactose.
As one most preferably scheme, the mixing quality ratio of described manna alcohol and glucose is 1:1; The described mixing quality ratio for mannitol and lactose is 1:1.
As a kind of preferred version, it accounts for 9.09% of fenofibrate lipid cubic liquid crystal and freeze-dried excipient mixture gross mass and determines according to after adding for the addition of freeze-dried excipient described in S2.
The present invention provides a kind of fenofibrate lipid prismatic crystal pressed powder prepared by above-mentioned preparation method simultaneously.
The present invention has following beneficial effect:
The present invention is directed to the preparation method that fenofibrate provides its lipid cubic liquid crystal pressed powder, through creatively analyzing and great many of experiments, sum up prescription compatibility of medicines and preparation technology parameter, the fenofibrate solid powder obtained is convenient to transport, storage, drug loading is high, significantly improve the bioavailability of fenofibrate, after described lipid cubic liquid crystal pressed powder medicine carrying, uniform particle sizes, after redissolving, particle diameter is at about 500nm, and stability is high.
Accompanying drawing explanation
Fig. 1 fenofibrate physical mixed polarisation photo.
Fig. 2 fenofibrate lipid cubic liquid crystal Emission in Cubic polarisation photo.
Fig. 3 fenofibrate lipid cubic liquid crystal microgranule transmission electron microscope.
Polarizing microscope after Fig. 4 fenofibrate lipid cubic liquid crystal spray-dried powders redissolves.
Transmission electron microscope after Fig. 5 fenofibrate lipid cubic liquid crystal spray-dried powders redissolves.
Fig. 6 fenofibrate lipid cubic liquid crystal spray-dried powders and crude drug cumulative release amount.
Blood concentration-time curve (n=6) in Fig. 7 fenofibrate lipid cubic liquid crystal spray-dried powders and its crude drug suspensoid rat body.
Detailed description of the invention
Explain the present invention further below in conjunction with specific embodiment, but embodiment itself does not limit in any form to invention.
The preparation of embodiment 1 fenofibrate lipid cubic liquid crystal
Get glycerin mono-fatty acid ester 20g, emulsifying agent poloxamer188 (F-127) 2.0 g, water-bath melting at 60 DEG C, adding fenofibrate 1g becomes oil phase, adds deionized water 177ml in oil phase, autoclave is put into after ultrasonic dissolution, be heated to 100 DEG C, let cool gas 3 ~ 5min, then cover air vent, after heating to 121 DEG C, continue heat treated 15min.Obtain fenofibrate lipid cubic liquid crystal.
The preparation of embodiment 2 fenofibrate lipid cubic liquid crystal spray-dried powders
S1. glycerin mono-fatty acid ester (GMO) and poloxamer188 (F-127) and fenofibrate is got respectively, water-bath melting at 60 DEG C; Put into autoclave after adding deionized water 45mL ultrasonic dissolution, be added to 100 DEG C, let cool gas 4min, then cover air vent, after heating to 121 DEG C, continue heat treated 15min;
S2. add maltodextrin, be diluted to finite concentration with deionized water 55mL, carry out spraying dry with spray dryer; Spray condition is: inlet temperature is 130 DEG C, and actual outlet temperature is 97 ~ 90 DEG C, and wind speed is 90L/min, and charging rate is 35mL/min.Result obtains fenofibrate lipid cubic liquid crystal spray-dried powders.
The preparation of embodiment 3 fenofibrate lipid cubic liquid crystal lyophilization powder
S1. glycerin mono-fatty acid ester 20g is got, emulsifying agent poloxamer188 (F-127) 2.0g, water-bath melting at 60 DEG C, adds fenofibrate 1.0g, by oil phase: add distilled water 177ml, autoclave is put into after ultrasonic dissolution, heating-up temperature, to 100 DEG C, lets cool gas 3 ~ 5min, air vent on bonnet, after heating to 121 DEG C, continue heat treated 15min and obtain fenofibrate lipid cubic liquid crystal;
S2. cold by carrying out after adding 20g freeze-dried excipient respectively in S1 gained fenofibrate lipid cubic liquid crystal
Dry; The condition that lyophilizing is dry: pre-freeze 6h in the freeze dryer of-45 DEG C, start the drying that heats up afterwards, program is :-35 DEG C of 1h;-30 DEG C of 8h;-25 DEG C of 8h;-20 DEG C of 5h;-10 DEG C of 2h; 0 DEG C of 2h; 10 DEG C of 1h; 20 DEG C of 3h.
The screening of freeze-dried excipient: add glucosan, mannitol, lactose, maltose, glucose, glucosan according to the compatibility of table 3 and ratio respectively in obtained fenofibrate lipid cubic liquid crystal: mannitol (mass ratio is 1:1), glucosan: lactose (mass ratio is 1:1), glucosan: glucose (mass ratio is 1:1), mannitol: lactose (mass ratio is 1:1), mannitol: glucose (mass ratio is 1:1) is freeze-dried excipient, gets 2ml and respectively puts in 10ml cillin bottle and carry out follow-up lyophilization experiment;
In general, after adding freeze-dried excipient, solids content is preferably 4% ~ 25%, and therefore solids content is 19.54% herein, and amount of water is 80.46%, as shown in table 3.
Examine record fenofibrate lipid cubic liquid crystal lyophilization powder outward appearance; And add appropriate distilled water, under room temperature, jolting is even, regains fenofibrate lipid cubic liquid crystal suspension, observes and record its state.If adding without freeze-dried excipient, in lyophilization, former dosage form can be destroyed; Therefore freeze-dried excipient is added very necessary.As shown in Table 4, mannitol, maltose, lactose are as freeze-dried excipient, more effective than glucosan, glucose; In addition, two kinds of freeze-dried excipient mixing are more effective than single kind freeze-dried excipient.Wherein mannitol+glucose, mannitol+lactose effect are best, therefore, select these two kinds of adjuvants as freeze-dried excipient herein.
The granularity research of embodiment 4 fenofibrate lipid cubic liquid crystal solid powder
By dried fenofibrate lipid cubic liquid crystal spray-dried powders, add in appropriate distilled water, under room temperature, jolting is even, regains fenofibrate lipid cubic liquid crystal microgranule.Attached Figure 4 and 5 show: fenofibrate Drug presents polarisation color under polarizing microscope, and after forming lipid cubic liquid crystal, the polarized light of drug crystallization disappears.Spraying dry and cryodesiccated inborn nature thing are all water solublity, and by polarizing microscope and electron-microscopic analysis after redissolution, lipid hexagonal structure still exists, and just granularity increases.
Before getting fenofibrate lipid cubic liquid crystal, spraying dry respectively (adding maltodextrin) and spraying dry redissolve after liquid, before lyophilizing, redissolve after lyophilizing, carry out granulometry with particle size analyzer.As shown in Table 5, after adding maltodextrin, the particle diameter of cubic liquid crystal is increased to 276.5 ± 38.18nm by 235.2 ± 25.32nm.And after redissolving, cubic liquid crystal particle diameter is comparatively increased to 567.8 ± 150.5, than adding one times before spraying dry.
Embodiment 5 vitro release is tested
Paddle method is adopted to investigate the extracorporeal releasing characteristic of fenofibrate lipid cubic liquid crystal spray-dried powders, raw material medicated powder.The results are shown in shown in accompanying drawing 6.
The preparation of release medium: take 40g sodium lauryl sulphate, soluble in water with 1:100 mass ratio, be mixed with 4000ml1%SDS solution for standby.
The pharmacokinetic study of embodiment 6 lipid cubic liquid crystal microgranule in rat body
Dosing Regimens: 12 SD rats, weighs successively, is divided into 2 groups by body weight homeostatic principle, male and female half and half, every 6 one group; Equal fasting 12h before experiment, drinking-water freely.One group as a control group, gives fenofibrate suspensoid, and another group is sample sets, gives the sample after the redissolution of fenofibrate lipid cubic liquid crystal spray-dried powders.According to the dosage containing FT20mg/kg to rat oral gavage administration;
Sample sets administration: the sample after fenofibrate lipid cubic liquid crystal spray-dried powders (embodiment 2 prepares) redissolves.Rat Fast 12h, takes corresponding fenofibrate lipid cubic liquid crystal dried powder according to the Determination of Fenofibrate of 20mg/kg appropriate, adds 3ml distilled water and dissolves, to rat oral gavage administration.
Matched group administration: fenofibrate suspensoid.Rat Fast 12h, take corresponding fenofibrate crude drug according to the dosage of 20mg/kg appropriate, join in the 3ml aqueous solution containing appropriate amount of maltodextrin, mix homogeneously, to rat oral gavage administration.
The preparation of heparin centrifuge tube and capillary tube: be put in vitro by the 1% heparin sodium solution of 0.1ml, evenly soak tube wall, is put in the oven dry of 80 DEG C, baking oven, for subsequent use; Be the 1% heparin sodium solution impregnation of the effective 0.1mL of capillary glass of 1mm by diameter, rear filter paper blots, and be cut into edge with emery wheel even, about 2cm gets blood capillary tube.
Matched group and sample sets sampling: after administration respectively at 0.5,1.5,2.5,4.5,7,10,13,16,24,30,36,48, the arrogant Mus orbital venous plexus of 60h gets whole blood and is about 0.4ml in heparin centrifuge tube, 4000r/min, centrifugal 10min, gets supernatant and is blood plasma, save backup.
6 groups of rats gastric infusion respectively, measure the blood drug level of each time point, and draw each group of Drug-time curve according to blood drug level, the results are shown in accompanying drawing 7, in rat body, in 4.5h time, Cmax is reached after the fenofibrate lipid cubic liquid crystal spray-dried powders administration that embodiment 2 prepares, and up to 89.92 μ g/ml, and fenofibrate suspensoid reaches peak when 7h, concentration is 6.44 μ g/ml.From result, after fenofibrate being made lipid cubic liquid crystal dosage form, serum level obviously raises, and illustrates that fenofibrate lipid cubic liquid crystal spray-dried powders of the present invention can significantly improve the absorption of rat to fenofibrate, improves bioavailability.
Claims (2)
1. a preparation method for fenofibrate lipid cubic liquid crystal solid powder, is characterized in that, comprises the following steps:
S1. fenofibrate lipid cubic liquid crystal is prepared;
S2. add maltodextrin in the fenofibrate lipid cubic liquid crystal prepared toward S1 and obtain mixture, through spraying dry and get final product after mixture described in dilute with water; Or through lyophilization and get final product add freeze-dried excipient in the fenofibrate lipid cubic liquid crystal that S1 prepares after;
Wherein, the preparation method of the fenofibrate cubic liquid crystal described in S1 is, according to mass ratio, get glycerin mono-fatty acid ester and poloxamer188 at 60 DEG C, to add fenofibrate after water-bath melting become oil phase, in oil phase, to add water and mix after dissolving to obtain mixture, mixture is inserted in autoclave, be heated to 100 DEG C, let cool gas 4min, then cover air vent, heat to 121 DEG C of process 15min;
The mass ratio of described glycerin mono-fatty acid ester, poloxamer188, fenofibrate and water is 20:1.5 ~ 3.0:0.5 ~ 3.0:180;
The mass ratio of the maltodextrin described in S2, glycerin mono-fatty acid ester, poloxamer188, fenofibrate and water is 60:20:1.5 ~ 3.0:0.5 ~ 3.0:400;
Described in S2, spray-dired condition is: inlet temperature is 130 DEG C, and actual outlet temperature is 97 ~ 90 DEG C, and wind speed is 90L/min, and charging rate is 35mL/min;
Described in S2, cryodesiccated condition is :-45 DEG C of pre-freezes start the drying that heats up in 6 hours afterwards, and program is :-35 DEG C of 1h;-30 DEG C of 8h;-25 DEG C of 8h;-20 DEG C of 5h;-10 DEG C of 2h; 0 DEG C of 2h; 10 DEG C of 1h; 20 DEG C of 3h;
Freeze-dried excipient described in S2 is the mixture of manna alcohol and glucose, or is the mixture of mannitol and lactose;
The mixing quality ratio of described manna alcohol and glucose is 1:1; The described mixing quality ratio for mannitol and lactose is 1:1; It accounts for 9.09% of fenofibrate lipid cubic liquid crystal and freeze-dried excipient mixture gross mass and determines according to after adding for the addition of freeze-dried excipient described in S2.
2. the fenofibrate lipid cubic liquid crystal solid powder for preparing of preparation method described in claim 1.
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| CN101502485A (en) * | 2009-03-20 | 2009-08-12 | 中国药科大学 | Nano cubic liquid crystal dexamethasone preparation for eye and preparation method thereof |
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