CN101810560B - Cyclosporine A polymeric micelles composition - Google Patents
Cyclosporine A polymeric micelles composition Download PDFInfo
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- CN101810560B CN101810560B CN2009100781804A CN200910078180A CN101810560B CN 101810560 B CN101810560 B CN 101810560B CN 2009100781804 A CN2009100781804 A CN 2009100781804A CN 200910078180 A CN200910078180 A CN 200910078180A CN 101810560 B CN101810560 B CN 101810560B
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Abstract
The invention relates to a cyclosporine A polymeric micelles composition. The composition contains cyclosporine A and polymeric micelles formed by an amphiphilic block copolymer. The composition has simple preparation method and can improve the bioavailability of the cyclosporine A for orally taking and prolong the circulation time of the cyclosporine A in blood during injection. The composition can ensure that the cyclosporine A is used for drug administration by orally taking and used for drug administration by injection.
Description
Technical field
The present invention relates to a kind ofly for oral cyclosporine A polymeric micelles composition, said composition also can be used for drug administration by injection.
Background technology
Along with the development of modern medicine, organ transplantation has also obtained very fast development, yet the organ transplantation meeting produces strong immunosuppressant reaction, and this has just promoted the development of immunosuppressant.Deepening continuously of basic research played positive impetus to the organ transplantation clinical development.Human Genome Project result of study will provide more complete information to the understanding of immunne response, and chance and the method for intervention are provided.The development of protein groups plan is improved the clinical transplantation level from the molecular biology angle, might provide the adjusting of immunne response more fully to understand.By the polymorphism research to cytokine and other genes, might determine high or low immunoreation person's genotype, for the rational Application immunosuppressant provides foundation.
Ciclosporin A (Cyclospor ine A, CyA) be to contain 11 amino acid whose lipotropy ring type polypeptides, molecular weight is 1203D, is a kind of potent immunosuppressant, is mainly used in the control of rejection after organ transplantation or the tissue transplantation and the treatment of autoimmune disease.Because the ciclosporin A molecular weight is bigger, be insoluble in water, easily by intestinal mucosa and the degraded of liver P4503A4 enzyme system, and CyA is the substrate of small intestinal mucosa P-glycoprotein, above-mentioned factor causes CyA oral administration biaavailability lower (10%-60%), and oral absorption is irregular.The oral back of the CyA microemulsion formulation sandimmun neoral (Sandimmune Neoral) of Sandoz company development is met pipe intestinal digesting liquid and can self emulsifying be formed microemulsion about particle diameter 30nm, can significantly increase the oral absorption (average bioavailability is high by 29% than cyclosporin A) of CyA, reduce the individual variation between the patient, reduce the influence of gastrointestinal tract physiologic factor CyA oral absorption.But contain the surfactant CremophorRH40 of higher dosage in its prescription, report that Cremophor RH40 has Toxicity of Kidney, and cause allergic reaction easily.
(Zhang Qiang such as Zhang Qiang, leaf National Day etc. the experimentation of ciclosporin A stearic acid nanometer ball. Acta Pharmaceutica Sinica, 1999,34 (4): 308-312) use fusing-homogenize method, adopted stearic acid, lecithin, poloxamer to prepare the ciclosporin A sodium stearate grain of rice, particle diameter is 316.1nm, envelop rate is 88.36%, drug loading is 8.98%, is contrast with commercially available sandimmun neoral, and the oral relative bioavailability of rat is 79.77%.But the particle diameter of this nanoparticle is big, and particle size distribution is inhomogeneous, complicated process of preparation, and relative bioavailability is lower.
(Dai Jundong such as Dai Jundong, Wang Xueqing, Deng. the preparation of ciclosporin A pH sensitivity nanoparticle and the oral pharmacokinetics of rat. Acta Pharmaceutica Sinica, 2004,39 (12): 1023-1027) using modified emulsifying-solvent diffuse technology has prepared CyA pH sensitivity nanoparticle, and having adopted Pluronic F68, Eudragit, dehydrated alcohol in the preparation process is material.Prepared nanoparticle particle diameter is about 100nm, envelop rate＞90%, and drug loading is about 20%, is contrast with commercially available sandimmun neoral, after the prepared nanoparticle rat oral gavage administration of four kinds of different Eudragit carrier materials, all with the sandimmun neoral bioequivalence.But the complicated process of preparation that this document adopts, and the Eudragit of higher concentration has cytotoxicity.
Wang Xue waits (Wang Xueqing clearly, Dai Jundong, Deng. the rat relative bioavailability of ciclosporin A-hypromellose phenolphthalein ester nanoparticles. Acta Pharmaceutica Sinica, 2004,39 (6): 463-466) the solvent-applied diffusion method has prepared ring spore A hypromellose phenolphthalein (HPMCP) nanoparticle, and particle diameter is 50nm, envelop rate is 97%, be contrast with commercially available sandimmun neoral, the oral relative bioavailability of rat is 82.3%, 119.6%.But this nanoparticle is the thermodynamic unstable system of high degree of dispersion, and aggregation of particles and sedimentation easily take place in storage process.
Wang Xue waits (Wang Xueqing clearly, Zhang Tao, Deng. the preparation of ciclosporin A polylactic acid nano particle colloid and the mensuration of rat bioavailability. Acta Pharmaceutica Sinica, 2004,39 (1): 68-71) and (5 Li Hong corals such as Li Hongshan, Zhao Jingling. the preparation of cyclosporin A polylactic acid nano particle colloid and the oral absorption of rat. Chinese Pharmaceutical Journal, 1999,34 (8): 532-536) solvent-applied-non-solvent method has prepared ring spore A polylactic acid nano particle respectively, be contrast with commercially available sandimmun neoral, the oral relative bioavailability of rat is respectively 101.6% and 112.39%.But the complicated process of preparation of this nanoparticle is the thermodynamic unstable system of high degree of dispersion, aggregation of particles and sedimentation easily take place in storage process, and particle diameter is very inhomogeneous, can cause to absorb instability.
CN1239432A discloses the solid composite medicament that comprises cyclosporin and anionic surfactant, adopt the solid hybrid technology to prepare the solid composite medicament that comprises cyclosporin and anionic surfactant, reached and the bioequivalent effect of sandimmun neoral.But the consumption of surfactant sodium laurylsulfate is up to encircling 80% of spore A, toxicity and big to the gastrointestinal zest.
CN1418703A discloses for oral nanoparticle drug-supplying system, adopts the solvent-nonsolvent method to prepare the oral enteric nanoparticle of ciclosporin A, is contrast with commercially available sandimmun neoral, and relative bioavailability is 82.4%, 119.6%.But prescription and complex process are unsuitable for suitability for industrialized production.
CN1128671A discloses the capsule composition that contains cyclosporin, has prepared the soft capsule of the microemulsion concentrated solution that contains ciclosporin A, with commercially available sandimmun neoral bioequivalence, has solved the volatile problem of ethanol in the sandimmun neoral.But prescription is complicated and contain a large amount of surfactants, and gastrointestinal tract is had zest.
Therefore, still need to develop a kind of prescription and preparation technology simple, be suitable for suitability for industrialized production, good stability, safety is good, bioavailability is high is suitable for ring spore A compositions oral and that inject.
Block copolymer micelle has excellent biological compatibility, can carry out intermolecular complexation by polymer unit independently, can be dissociated into independently block chain again under certain condition, and the copolymer that adopts in the research at present, have biocompatibility and biodegradability mostly, be convenient in body, remove; Hydrophobic region solubilising poorly water soluble drugs by kernel increases its dissolubility; Be in the medicine in the micelle kernel owing to isolated well, thus not can with body in biotic environment interact, thereby delayed the degraded of medicine, and reduced the chance that bad side reaction takes place; As the carrier of oral drugs, can reduce medicine at gastrointestinal tract by metabolism, increase the absorption of medicine; The micelle particle diameter can be as small as tens nanometers, can increase medicine in the action time of sticking prolong drug of small intestine epithelium, improves to absorb; Amphipathic high molecular polymer has low-down critical micelle concentration, and is very stable in vivo.
Summary of the invention
On the one hand, the invention provides a kind of polymer micelle composition that encircles spore A.
On the other hand, the polymer micelle composition that the invention provides ring spore A is used for the purposes of oral administration, also can be used for drug administration by injection.
According to an aspect of the present invention, it provides a kind of for polymer micelle composition oral and the ring spore A that injects, and it comprises the micelle of ring spore A and amphipathic block formation.
The invention still further relates to the method for preparing polymer micelle composition, this method is selected from dialysis, film dispersion method, emulsion process, solvent evaporation method, lyophilization, cosolvent volatility process, injection method etc.The mean diameter of micelle is below 200nm.
The present composition can be mixed with various preparations according to any conventional method, for example oral liquid, tablet, capsule, injection etc.
The present composition can be used for preparing the medicine of relevant disease such as rejection and treatment autoimmune disease after control organ transplantation or the tissue transplantation.
The present composition can pass through oral and injection administration for the preparation of the medicine of the above-mentioned disease for the treatment of.The preferred oral administration.
The present composition comprises the ring spore A as active component, also comprises the micelle that is made of amphipathic nature block polymer.Compositions of the present invention improves the oral administration biaavailability of ring spore A greatly, and the circulation time of ring spore A injection back in blood prolonged.The representative example of ring spore A in the present composition is ring spore A and its variant.Ring spore A in the present composition is wherein a kind of at least, and the weight ratio of present composition medium ring spore A and block copolymer is 1: 100-1: 1, preferred 1: 10-1: 4.
Amphipathic nature block polymer is the main component that constitutes micelle in the present composition.The amphipathic nature block polymer that can use in the present invention comprises and is selected from following hydrophilic segment: Polyethylene Glycol (PEG), polyoxyethylene (PEO), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyethers are (as Pluronic, Poloxamer) etc.Preferred Polyethylene Glycol.Polyethylene Glycol is Polyethylene Glycol or poly glycol monomethyl ether, has the molecular weight of 1000-20000Da, preferred 2000Da-6000Da.The amphipathic nature block polymer of Shi Yonging comprises and is selected from following hydrophobic segment in the present invention: polyoxypropylene, phospholipid, phospholipid derivative, polyester, polyamino acid etc., and as polylysine, poly-Aspartic Acid, poly-(N-maltose acyl-L-lysine), poly arginine, polylactic acid (PLA), poly-(the stearic acid benzyl ester of N--L-lysine), poly-oleic acid vinyl acetate, poly-Acetic acid, hydroxy-, bimol. cyclic ester, polycaprolactone, poly (glycolide-co-lactide) (PLGA) etc.Nondegradable polystyrene, PNIPAM hydrophobic segments such as (PIPAA) are also arranged in addition.Preferred polyester.Preferred PLA and PLGA, more preferably PLA.Amphipathic nature block polymer is diblock copolymer and triblock copolymer and/or their mixture.
In addition, compositions of the present invention also comprises optional pharmaceutically acceptable additive.
In order to reach purpose of the present invention, the present invention has carried out the pharmacokinetics test through the oral present composition of rat.
Description of drawings
With reference to the accompanying drawings 1 and 2, by the following description of the present invention, above-mentioned and other purpose of the present invention and feature will be apparent.Accompanying drawing 1 has shown the particle size distribution of the embodiment of the invention 1.Curve when accompanying drawing 2 has shown the medicine of the embodiment of the invention 1 and the administration of commercially available sandimmun neoral soft capsule oral.
As mentioned above, compositions of the present invention significantly improves the bioavailability of ring spore A oral administration administration, and a little more than commercially available sandimmun neoral soft capsule.
Following examples are used for further describing the present invention, but limit the scope of the present invention anything but.
The specific embodiment
Embodiment 1: the preparation of oral liquid
The PEG5000-PLA2500 of 25.00mg and the ciclosporin A of 5.00mg fully are dissolved in the amount of methanol, behind the rotation evaporate to dryness methanol, add water and carry out aquation, get micelle composition through the filtering with microporous membrane of 0.45 μ m.
Then with its fill in cillin bottle, add a cover, the sealing, radiation sterilization is namely.
Embodiment 2: the preparation of tablet
The PEG5000-PLA5000 of 20.00mg and the ciclosporin A of 5.00mg fully are dissolved among an amount of DMSO, are transferred to molecular cut off then and are in 3500 the bag filter, the 24h that dialyses in the 1L distilled water changes a water recently distilled every 4h.After dialysis is finished the solution in the bag filter is taken out, centrifugal 30min gets supernatant under 3000rpm, gets micelle composition through the filtering with microporous membrane of 0.45 μ m.
In the micelle composition of gained, add an amount of PEG4000, mix homogeneously, lyophilizing.Then lyophilized powder is crossed 80 mesh sieves, with the microcrystalline Cellulose mixing, the adding starch slurry is made soft material, after granulating with 14 mesh sieves, places 40 ℃ of dry backs to cross 12 mesh sieve granulate, and tabletting namely gets ring spore A tablet behind adding dried starch and the magnesium stearate mixing.
Embodiment 3: the preparation of hard capsule
The PEG5000-PLA2500 of 18.00mg and the ciclosporin A of 5.00mg fully are dissolved in the amount of methanol, behind the rotation evaporate to dryness methanol, add water and carry out aquation, get micelle composition through the filtering with microporous membrane of 0.45 μ m.
In the micelle composition of gained, add an amount of PEG4000, mix homogeneously, lyophilizing.Then lyophilized powder is filled in the capsule, obtains a capsules.
Embodiment 4: the preparation of freeze-dried powder
The PEG5000-PLA15000 of 10.00mg and the ciclosporin A of 5.00mg fully are dissolved among an amount of DMSO, are transferred to molecular cut off then and are in 3500 the bag filter, the 24h that dialyses in the 1L distilled water changes a water recently distilled every 4h.After dialysis is finished the solution in the bag filter is taken out, centrifugal 30min gets supernatant under 3000rpm, gets micelle composition through the filtering with microporous membrane of 0.45 μ m.
In the micelle composition of gained, add an amount of PEG4000, mix homogeneously, lyophilizing, sealing, radiation sterilization is namely.
Test example 1: the pharmacokinetics test of oral administration
In order to investigate the oral pharmacokinetics feature of ring spore A that is included in the present composition, following preparation of the present invention among the embodiment 1, commercially available soft capsule are carried out pharmacokinetic respectively.Content with high effective liquid chromatography for measuring blood medium ring spore A.
The SD rat that 10 body weight is about 200g is divided into two groups at random.Test fasting in preceding 12 hours, can freely drink water.Weigh the back by 10mg/kg dosage, irritate the commercially available sandimmun neoral soft capsule of stomach liquid for one group, another group is irritated the preparation of the present invention of stomach embodiment 1.Get blood 0.5mL (getting the prior heparinization of blood container) respectively at different time points eye socket venous plexus after the administration, add 50 μ l ring spore D inner mark solution (60 μ g/ml), add 1ml hydrochloric acid solution (180mmol/ml) vortex 1min then and destroy hemocyte, add 5ml and heavily steam vortex 10min behind the absolute ether, centrifugal 10min under 3000rpm.Draw the supernatant and place another tool plug teat glass, add 1mlNaOH solution (100mmol/ml) back vortex 5min, centrifugal 10min under 3000rpm.Draw the supernatant to another tool plug teat glass, nitrogen dries up ether under 40 ℃ of water-baths.Add 120 μ l mobile phases (acetonitrile: water=80: 20) redissolve, add the 1ml normal hexane then, vortex 2min, centrifugal 10min under 3000rpm discards the upper strata normal hexane, repeats aforesaid operations more once.Get 20 μ l sample introductions.Calculate blood drug level according to standard curve.
Chromatographic condition is as follows: DiamonsilTM C18 chromatographic column, 250 * 4.6mm, 5 μ m; Mobile phase: acetonitrile water=80: 20; Flow velocity: 1ml/min; Column temperature: 70 ℃; Detect wavelength: 210nm; Sample size: 20 μ l.
Result such as Fig. 2 and table 1.
The concentration (ng/ml) of table 1 different time blood medium ring spore A
According to the result of table 1 and Fig. 2, both t checks there was no significant difference on 0.05 level illustrates preparation of the present invention and commercially available soft capsule bioequivalence.
Invention has been described though utilized above-mentioned specific embodiment, it should be understood that those skilled in the art also can carry out various improvement and change, and within their scopes of the present invention that also should limit as claims.
Claims (5)
1. oral administration polymer micelle composition, it comprises ring spore A, amphipathic block and other optional pharmaceutically acceptable auxiliaries; Described block copolymer is PEG-PLA.
2. polymer micelle composition as claimed in claim 1, the weight ratio of its medium ring spore A and block copolymer is 1: 100-1: 1.
3. polymer micelle composition as claimed in claim 2, the weight ratio of its medium ring spore A and block copolymer is 1: 10-1: 4.
4. as each compositions of claim 1-3, described compositions is mixed with tablet, capsule according to any conventional method.
As each compositions of claim 1-4 for the preparation of control organ transplantation or tissue transplantation after the purposes of medicine of rejection or treatment autoimmune disease.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2009100781804A CN101810560B (en) | 2009-02-20 | 2009-02-20 | Cyclosporine A polymeric micelles composition |
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| CN2009100781804A CN101810560B (en) | 2009-02-20 | 2009-02-20 | Cyclosporine A polymeric micelles composition |
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| CN101810560B true CN101810560B (en) | 2013-07-10 |
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| WO2014001905A1 (en) * | 2012-06-27 | 2014-01-03 | Medincell | Biodegradable drug delivery for hydrophobic compositions |
| HUP1300647A2 (en) | 2013-11-12 | 2015-05-28 | Druggability Technologies Ip Holdco Jersey Ltd | Complexes of cyclosporine a and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
| CN103976978A (en) * | 2014-04-30 | 2014-08-13 | 成都市绿科华通科技有限公司 | Polypyrrole-type polymer drug carrier micelle |
| CN111053737A (en) * | 2018-10-15 | 2020-04-24 | 北京大学 | Polymer micelle composition of targeting small intestine transporter for improving oral absorption of insoluble drug |
| CN111700876A (en) * | 2020-03-12 | 2020-09-25 | 上海市肿瘤研究所 | Drug-loading delivery drug delivery system for treating systemic lupus erythematosus and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1197396A (en) * | 1995-09-21 | 1998-10-28 | 株式会社三养社 | Copolymeric micelle drug compsn. and method for the prepn. thereof |
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| CA2580305A1 (en) * | 2004-06-02 | 2005-12-15 | The Governors Of The University Of Alberta | Polymer based nano-carriers for the solubilization and delivery of hydrophobic drugs |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1197396A (en) * | 1995-09-21 | 1998-10-28 | 株式会社三养社 | Copolymeric micelle drug compsn. and method for the prepn. thereof |
Non-Patent Citations (4)
| Title |
|---|
| Hamidreza Montazeri Aliabadi et al.Micelles of methoxy poly(ethylene oxide)-b-poly(ε-caprolactone) as vehicles for the solubilization and controlled delivery of cyclosporine A.《Journal of Controlled Release》.2005,第104卷301–311页. |
| Hamidreza Montazeri Aliabadi et al.Polymeric micelles for the solubilization and delivery of cyclosporine A: pharmacokinetics and biodistribution.《Biomaterials》.2005,第26卷摘要、7215页右栏、7252页右栏及7254页. |
| Micelles of methoxy poly(ethylene oxide)-b-poly(ε-caprolactone) as vehicles for the solubilization and controlled delivery of cyclosporine A;Hamidreza Montazeri Aliabadi et al;《Journal of Controlled Release》;20050408;第104卷;301–311页 * |
| Polymeric micelles for the solubilization and delivery of cyclosporine A: pharmacokinetics and biodistribution;Hamidreza Montazeri Aliabadi et al;《Biomaterials》;20050706;第26卷;摘要、7251页右栏、7252页右栏及7254页 * |
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