CN102008713B - Ciclosporin A proliposome, pharmaceutical composition and preparation method thereof - Google Patents
Ciclosporin A proliposome, pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN102008713B CN102008713B CN201010570255A CN201010570255A CN102008713B CN 102008713 B CN102008713 B CN 102008713B CN 201010570255 A CN201010570255 A CN 201010570255A CN 201010570255 A CN201010570255 A CN 201010570255A CN 102008713 B CN102008713 B CN 102008713B
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Abstract
The invention discloses a ciclosporin A proliposome for oral administration, a pharmaceutical composition and a preparation method thereof. The ciclosporin A proliposome comprises the following pharmaceutical active ingredients and non-active ingredients by weight percent: 1-25% of ciclosporin A, 2-40% of lecithin, 0.5-12.5% of cholesterol, 21-96.45% of polyol and 0.05-1.50% of vitamin E. The proliposome is prepared from the ciclosporin A, a lipid membrane material, a hydrophilic matrix and the like through the ultrasonic dispersion method and the reverse phase evaporation method, and a liposome is formed spontaneously after the dispersion in water. The proliposome can improve the dispersity and the oral bioavailability of ciclosporin A which is an insoluble drug, lead the stability to be good and be more applicable to industrial production in comparison with the ordinary liposome.
Description
Technical field
The present invention relates to proliposome preparation of a kind of ciclosporin A and preparation method thereof.
Background technology
Ciclosporin A (C
62H
111N
11O
12) by the ring type polypeptide that 11 aminoacid are formed, be a kind of immunosuppressant of strong effect, can act on lymphocyte speciallyly and reversiblely, and not influence hemopoietic and cytophagous function.Be widely used in anti-rejection of organ transplantation patient and various autoimmune disease, be important medication clinically at present.Because the water solublity of ciclosporin A is very poor, oral administration biaavailability is low, for its dosage form reasonable in design significant.The ciclosporin A first-selection is an oral administration, and the listing product has oral solution, capsule and self-emulsifying soft capsule agent both at home and abroad at present.Wherein, oral solution is a non-aqueous solution, need mix clothes with beverage such as milk, and medication has inconvenience more.The stripping of conventional capsule agent medicine is relatively poor, and drug absorption is prone to influences such as drug solubility and feed, it is reported that its bioavailability is very unstable.And the self-emulsifying soft capsule agent, for example the ciclosporin A self-emulsification soft capsules (sandimmun neoral) of Switzerland Novartis Co.,Ltd is present staple product on the market, makes medicine in gastrointestinal tract, form the emulsion droplet of high degree of dispersion through the self emulsifying technology, promotes drug absorption.But should technology owing to introduced a large amount of surfactants, cause a series of toxic and side effects, for example GI irritation property, anaphylaxis, nephrotoxicity etc.In order to improve the deficiency of the existing preparation of ciclosporin A; Explore both at home and abroad in recent years always and study; For example, in Chinese patent (Granted publication CN1245212C) " ciclosporin A solid dispersion and preparation method thereof ", a kind of ciclosporin A solid dispersion formulations is provided, its external medicine dissolution rate is significantly increased than crude drug; (sandimmun neoral, Switzerland Novartis) is similar with the ciclosporin A self-emulsification soft capsules.A kind of ciclosporin A enteric nano particle preparations is provided in Chinese patent (Granted publication CN1233413C) " supplies oral nanoparticle drug-supplying system ", and oral administration biaavailability is similar with sandimmun neoral.A kind of fast release solid dosage forms is disclosed in one Chinese patent application (publication number CN101239048A) " cyclosporine A fast release solid dosage forms and preparation method thereof "; System is dissolved in ciclosporin A in the matrix material of heating and melting; Add porous materials such as micropowder silica gel again and fully absorb the pressed powder of system.This invention has increased the dissolution rate of ciclosporin A, helps drug absorption, and has good stable property.
The small vesicle that liposome is made up of phospholipid bilayer is one of the most potential novel pharmaceutical formulation in recent years.Have stronger medicine carrying and pass the medicine ability, and nontoxic nonirritant, biocompatibility is splendid.Remove intravenous administration, the application of liposome in oral administration system in recent years also shows application potential gradually.Research surface, liposome can significantly promote slightly solubility and the difficult oral absorption that absorbs the drug, and this has benefited from the unique film of liposome and merges pass through mechanism and solubilising power.But the liposome preparation complex process is difficult to suitability for industrialized production, has limited its practical application.
The applicant finds unexpectedly in nearest research, and ciclosporin A and the suitable pharmaceutic adjuvant specific method for preparing of merga pass that matches can be obtained a kind of ciclosporin A pro-liposome, can realize the medicine carrying identical with liposome and pass drug effect really.Pro-liposome is based on the novel form of liposome technology, is phospholipid is adsorbed in a kind of solid dosage forms that solid state powder that solid carrier surface forms forms, and faces the time spent to add water and redissolve, and perhaps contact with gastro-intestinal Fluid, just can form liposome, brings into play the effect of liposome.Pro-liposome has series of advantages, the stability problem when for example having solved liposome and storing, be fit to oral administration, preparation technology simple, be fit to suitability for industrialized production etc.Research proof, pro-liposome can improve the oral administration biaavailability of insoluble drug, for example report (Hongtao Xu such as Hongtao Xu; Et al; J Control.Release, 2009,140:61-68); (vinpocetine) is prepared into pro-liposome with the insoluble drug vinpocetine, and its oral administration biaavailability is 3.5 times of common suspensoid.Report such as Lin Wei (Acta Pharmaceutica Sinica, 2009,44:192-196), Nobiletin is prepared into pro-liposome, to compare with suspensoid, relative bioavailability is 264.3%, and the mean residence time of medicine obtains prolonging.Deng Yingjie etc. are in Chinese patent (Granted publication CN1444948B) " breviscapine liposome and preparation method thereof "; A kind of breviscapine precursor lipidosome has been described; Improve breviscapine oral administration absorption difference, deficiency that bioavailability is low, and improved the stability of Liposomal formulation.
Summary of the invention
The object of the present invention is to provide a kind of oral ciclosporin A pro-liposome and preparation method thereof that supplies.Further purpose is to provide ciclosporin A pro-liposome pharmaceutical composition and preparation method thereof.Be characterized in to improve the dissolution and the oral administration biaavailability of ciclosporin A, have good stability, and be suitable for suitability for industrialized production.
The present invention realizes through following technical scheme:
A kind of ciclosporin A pro-liposome is characterized in that being made up of the pharmacy activity component and the non-active ingredient of following percentage by weight:
Ciclosporin A 1%-25%
Lecithin 2%-25%
Cholesterol 0.5%-12.5%
Polyhydric alcohol 36.00%-96.45%
Vitamin E 0.05%-1.50%.
Described ciclosporin A pro-liposome is characterized in that lecithin is meant one or more the mixture in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, hydrogenated soy phosphatidyl choline or the hydrogenated yolk lecithin.
Described ciclosporin A pro-liposome is characterized in that polyhydric alcohol is meant one or more the mixture in sorbitol, xylitol or the mannitol.
Described ciclosporin A pro-liposome is spontaneous formation liposome after adding aqueous medium.
A kind of ciclosporin A pro-liposome pharmaceutical composition promptly is further to be prepared into and is used for oral capsule, tablet, suspensoid or dry suspension.
A kind of method for preparing of ciclosporin A pro-liposome; May further comprise the steps: ciclosporin A, lecithin, cholesterol and vitamin E are dissolved in the solution that forms clear in the organic solvent; With gained solution and polyhydric alcohol powder uniform mixing, this mixture is through decompression and/or add the heat extraction organic solvent.
Further, the method for preparing of described ciclosporin A pro-liposome is characterized in that also comprising following steps: polyhydric alcohol is crushed to the uniform powder of particle diameter before use.
In the above-mentioned method for preparing, described organic solvent is meant a kind of or wherein multiple mixture in ethanol, propylene glycol, the tert-butyl alcohol, n-butyl alcohol or the methanol, is preferably a kind of in ethanol, propylene glycol or the tert-butyl alcohol.
Further, described method for preparing is to mix and remove the organic solvent step through fluid bed or Rotary Evaporators.
Beneficial effect of the present invention:
Ciclosporin A pro-liposome of the present invention has suitable suitability for industrialized production, has good stability, has advantages such as higher dissolution and oral administration biaavailability.
The method for preparing of ciclosporin A pro-liposome provided by the present invention has been simplified the required processing step of conventional liposome significantly, can realize the laboratory small lot to industrialized mass, and the stability and the repeatability of product are good.
3 lot sample article to adopting embodiment 2 said method preparations have carried out study on the stability; The result shows; Prepared ciclosporin A pro-liposome stores 6 months at 25 ℃, and its content, envelop rate all do not have remarkable reduction, and indexs such as related substance and oxidized phospholipids content meet the requirements.
3 lot sample article to adopting embodiment 2 said methods preparations have carried out the dissolution investigation, and the result shows, dissolution is greater than 85% in the time of 30 minutes for these article warp, and good dissolution is one of important prerequisite condition of assurance oral administration biaavailability.
Bioavailability study shows that ciclosporin A pro-liposome of the present invention can promote the oral absorption of medicine in the rat body, obtains good oral bioavailability.
In addition, ciclosporin A pro-liposome provided by the present invention because ciclosporin A is wrapped in the small vesicle of liposome, has avoided gastrointestinal tract directly to contact the medicine of high concentration in vivo, can alleviate medicine to the gastrointestinal zest.
The specific embodiment
Below through embodiment the present invention is done further elaboration, but these embodiment are not limitations of the present invention.
Embodiment 1, the ciclosporin A pro-liposome and suspension preparation
Take by weighing ciclosporin A 500mg, hydrogenated soy phosphatidyl choline 4000mg, cholesterol 1500mg and vitamin E 100mg, add 50mL ethanol ultrasonic dissolution, get solution (1).Take by weighing sorbitol 18.0g, put in the Universalpulverizer and pulverize, sieve, sorbitol powder is placed round-bottomed flask; Adding solution (1), the volatilization of decompression rotary evaporation to ethanol is complete down in 54 ℃, gets exsiccant white powder, takes out; Sieve, 40 ℃ of oven drying 1h promptly get the ciclosporin A pro-liposome.
These article of getting are scattered in the water in right amount, and jolting promptly gets translucent ciclosporin A liposome turbid liquor.Through its envelop rate of microtrabeculae centrifugal determination, the result is greater than 85%.
Embodiment 2, the capsular preparation of ciclosporin A pro-liposome
Take by weighing ciclosporin A pro-liposome powder 18.9g, microcrystalline Cellulose 2.5g, polyvinylpolypyrrolidone 1.2g and the silica sol 0.25g of embodiment 1 preparation, mix homogeneously is filled in No. 0 hard capsule case, promptly gets.
Embodiment 3, ciclosporin A pro-liposome preparation technology
Get sorbitol 1.8kg, grinding, sieving for standby.Get ciclosporin A 50.0g, hydrogenated soy phosphatidyl choline 400.0g, cholesterol 150.0g and vitamin E 10.0g, be dissolved in the propylene glycol, gained solution with fluid bed at the bottom of the spray mode be sprayed on above-mentioned sorbitol powder, drying is sieved, and promptly gets.
Embodiment 4, ciclosporin A pro-liposome preparation technology
Take by weighing sorbitol 10.0g, pulverizing, sieving for standby.Take by weighing ciclosporin A 500mg, soybean lecithin 2500mg, cholesterol 1000mg and vitamin E 50mg, be dissolved in the tert-butyl alcohol, get solution (1).Sorbitol powder is placed round-bottomed flask, adding solution (1), the volatilization of decompression rotary evaporation to the tert-butyl alcohols is complete down in 54 ℃, gets exsiccant white powder, takes out, and sieves, and 40 ℃ of oven drying 1h promptly get.
Embodiment 5, ciclosporin A pro-liposome preparation technology
Take by weighing xylitol 10.0g, pulverizing, sieving for standby.Take by weighing ciclosporin A 500mg, soybean lecithin 2000mg, cholesterol 500mg and vitamin E 50mg, be dissolved in n-butyl alcohol, get solution (1).Xylitol powder is placed round-bottomed flask, adding solution (1), the volatilization of decompression rotary evaporation to n-butyl alcohol is complete down in 54 ℃, gets exsiccant white powder, takes out, and sieves, and 40 ℃ of oven drying 1h promptly get.
Embodiment 6, the test of ciclosporin A pro-liposome rat oral administration biaavailability
14 of male West rats, body weight 200 ± 20g is equally divided into two groups, makes ciclosporin A pro-liposome powder (embodiment 1) and commercially available reference preparation self-emulsification soft capsules (sandimmun neoral) content by oneself by 15mg/kg dosage respectively behind the fasting 12h.Eye socket is got blood at the different time interval, handles by certain method, and precision is measured whole blood 1mL, puts in the 10mL tool plug centrifuge tube; Mark liquid 100 μ L and 0.1mol/L sodium hydroxide 0.5mL in adding behind the water-bath hatching 5min, add petroleum ether-ether 3mL; Vortex 5min, centrifugal, get the water-bath of ether layer and volatilize; Residue adds 70% methanol, 300 μ L and normal heptane 2mL respectively, and vortex 5min is centrifugal; Under 50 ℃ of water-bath nitrogen current, volatilize after removing upper strata liquid, with analyzing ciclosporin A concentration with HPLC sample introduction 20 μ L behind the 50 μ L dissolve with methanol, chromatographic condition is: chromatographic column: Diamasil C
18(4.6 * 200mm, 5 μ m); Mobile phase: acetonitrile-methanol-water-phosphoric acid (70: 12: 18: 0.03); Detect wavelength 210nm; 70 ℃ of column temperatures; Flow velocity 1.0mL/min.Mensuration result is as shown in the table.
Table: behind the rat oral administration the average blood drug level of ciclosporin A over time, reference preparation is a sandimmun neoral, receiving test preparation is self-control ciclosporin A pro-liposome.
Can know through calculating, receive the average area under the drug-time curve AUC of test preparation
0-TBe 10.12 * 10
3NgmL
-1H, the average area under the drug-time curve AUC of reference preparation
0-TBe 11.16 * 10
3NgmL
-1H; Relative bioavailability is 90.7%; Show that ciclosporin A pro-liposome of the present invention is the same with the self-emulsification soft capsules sandimmun neoral, can obtain good oral bioavailability, but avoided the toxic and side effects that surfactant caused in the self-emulsification soft capsules.
Claims (10)
1. ciclosporin A pro-liposome is characterized in that being processed by the pharmacy activity component and the non-active ingredient of following percentage by weight:
Ciclosporin A 1%-25%,
Lecithin 2%-40%,
Cholesterol 0.5%-12.5%,
Polyhydric alcohol 21.00%-96.45%,
Vitamin E 0.05%-1.50%.
2. ciclosporin A pro-liposome according to claim 1 is characterized in that lecithin is meant a kind of or wherein multiple mixture in soybean lecithin or Ovum Gallus domesticus Flavus lecithin or hydrogenated soy phosphatidyl choline or the hydrogenated yolk lecithin.
3. ciclosporin A pro-liposome according to claim 1 and 2 is characterized in that polyhydric alcohol is meant a kind of or wherein multiple mixture in sorbitol or xylitol or the mannitol.
4. adopt the liposome of the described ciclosporin A pro-liposome of claim 1, it is characterized in that adding spontaneous formation liposome behind the aqueous medium.
5. the pharmaceutical composition of ciclosporin A pro-liposome according to claim 1 is characterized in that being prepared into and is used for oral capsule, tablet, suspensoid or dry suspension.
6. the method for preparing of ciclosporin A pro-liposome according to claim 1; May further comprise the steps: ciclosporin A, lecithin, cholesterol and vitamin E are dissolved in the solution that forms clear in the organic solvent; With gained solution and polyhydric alcohol powder uniform mixing, this mixture is through decompression and/or add the heat extraction organic solvent.
7. the method for preparing of ciclosporin A pro-liposome according to claim 6 is characterized in that also comprising following steps: polyhydric alcohol is crushed to the uniform powder of particle diameter before use.
8. the method for preparing of ciclosporin A pro-liposome according to claim 6 is characterized in that organic solvent is meant a kind of or wherein multiple mixture in ethanol or propylene glycol or the tert-butyl alcohol or n-butyl alcohol or the methanol.
9. the method for preparing of ciclosporin A pro-liposome according to claim 8 is characterized in that organic solvent is a kind of in ethanol or the propylene glycol or the tert-butyl alcohol.
10. the method for preparing of ciclosporin A pro-liposome according to claim 6 is characterized in that comprising through fluid bed or Rotary Evaporators and mixes and remove the organic solvent step.
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| CN102274175A (en) * | 2011-07-01 | 2011-12-14 | 中国人民解放军第二军医大学 | Nano lipid cubic crystal preparation, its preparation method and application |
| CN111759807B (en) * | 2019-04-01 | 2021-06-01 | 上海谷森医药有限公司 | Cyclosporine liposome and preparation method thereof |
| CN114773629B (en) * | 2022-05-20 | 2024-04-12 | 昆明理工大学 | Preparation method of injectable photo-curing hemostatic hydrogel for traumatic brain injury |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1224347A (en) * | 1996-07-03 | 1999-07-28 | 研究发展基金会 | High dose liposomal aerosol formulations |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1224347A (en) * | 1996-07-03 | 1999-07-28 | 研究发展基金会 | High dose liposomal aerosol formulations |
Non-Patent Citations (4)
| Title |
|---|
| 环孢素A制剂的研究进展;蒋正立;《海峡药学》;20051231;第17卷(第4期);8-10 * |
| 环孢素A脂质体制备及其体外释药方法学考察;许洁 等.,;《抗感染药学》;20081231;第5卷(第4期);222-227 * |
| 蒋正立.环孢素A制剂的研究进展.《海峡药学》.2005,第17卷(第4期),8-10. |
| 许洁 等.,.环孢素A脂质体制备及其体外释药方法学考察.《抗感染药学》.2008,第5卷(第4期),222-227. |
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