CN103933546A - Method for preparing nano oral microemulsion of rapamycin and ciclosporin A - Google Patents
Method for preparing nano oral microemulsion of rapamycin and ciclosporin A Download PDFInfo
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- CN103933546A CN103933546A CN201410118664.8A CN201410118664A CN103933546A CN 103933546 A CN103933546 A CN 103933546A CN 201410118664 A CN201410118664 A CN 201410118664A CN 103933546 A CN103933546 A CN 103933546A
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- rapamycin
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Abstract
The invention discloses a method for preparing a nano oral microemulsion of rapamycin and ciclosporin A. The method concretely comprises the following steps: 1, evenly mixing a surfactant with a cosurfactant according to the mass ratio of (1-3):(1-2); mixing with biocompatible oil and deionized water according to the mass percent of (29-35):(24-29):(35-39) after evenly mixing; slightly shaking, so as to prepare an oil-in-water microemulsion system of which the diameter is 30nm; 2, dissolving the rapamycin or the ciclosporin A or rapamycin and ciclosporin A solid into the oil-in-water microemulsion system prepared in the step 1; mixing at room temperature or the temperature of 37 DEG C for 2-24 hours at a constant rotation speed of 200-800r/min. Immunosuppressors, namely rapamycin and ciclosporin A, and a composite nano oral solution of the rapamycin and the ciclosporin A are prepared by adopting a microemulsion method, and the preparation method is a novel nano drug system, and has the advantages of high solubilizing power and thermodynamic stability.
Description
Technical field
The invention belongs to immunosuppressant nano oral medicine preparation research field, particularly a kind of microemulsion method is prepared the method for rapamycin, ciclosporin A, rapamycin+ciclosporin A combined nano oral administration solution.
Background technology
Rapamycin (Rapamycin), the anti-rejection drugs of novel macrolide, main target proteins is in vivo mTOR, current up-to-date potent immunosuppressant in the world, clinically for the treatment of the autoimmune diseasees such as the anti-rejection of organ transplantation and treatment rheumatoid arthritis, lupus erythematosus.The T cell proliferation that may start by blocking-up IL-2 and selectivity suppressor T cell is reacted for resisting transplant rejection.By having a liking for plain RMBP with corresponding immunity, be combined inhibition cell cycle G0 phase and G1 phase, blocking-up G1 enters the S phase and plays a role, and its effect is: 1. suppress T and B cell proliferation; 2. the lymphopoiesis that suppresses IL-1, IL-2, IL-6 and IFN-γ induction; 3. suppressing IgG and donor specific antibodies (cytotoxic antibody) produces; 4. suppress mononuclear cell propagation.The ring type polypeptide that ciclosporin A is comprised of 11 aminoacid forms, and is that a kind of selectively acting is in the lymphocytic potent immunosuppressant of T.By having a liking for plain cyclophilin with intracellular immunity, be combined, suppress helper T lymphocyte activation and the reactivity to IL-2, be mainly used in preventing posttransplantation graft-versus-host (GVH) reaction, or treatment various autoimmune is sick.Be mainly used in clinically the immunologic rejection reaction of liver, kidney and heart transplantation, also can with the same use of adrenocortical hormone, treatment immune disease.Rapamycin also has antineoplastic action, it forms RAP-FKBP-12 complex and is combined with the FRB territory of its target protein mTOR by being combined with cell internal specific rabphilin Rab FKBP-12, the protein kinase catalytic activity that suppresses mTOR, make it the regulating action of the phosphorylations such as downstream effect molecule p70S6K, 4EBP1/eIF4E weaken or disappear, the signal biography effect down of the trophic factors such as blocked amino acid and the transduction of multiple somatomedin, thus the beginning of translating suppressed; Rapamycin can also make cell cycle arrest in the G1 phase by reducing the kinase whose activity of CDK-cyclin complex, thus performance antineoplastic action.We adopt microemulsion method to prepare human clinical's experiment that immunosuppressant nano oral solution system is research Rapamycin, ciclosporin A nano oral solution formula and rapamycin and ciclosporin A combined nano oral administration solution system theoretical and the actual foundation that instructs are provided.
Summary of the invention
The object of the present invention is to provide a kind of new method of utilizing microemulsion method to prepare Rapamycin, ciclosporin A nano oral solution and Rapamycin+ciclosporin A combined nano oral administration solution system, realize to increase dissolubility and the permeability of water-insoluble immunosuppressant and improve the stability of nano oral solution, for the oral drugs formula of immune suppressant drug and human clinical's experimentation of composition of medicine formula provide new method.The solutes such as water-insoluble cancer therapy drug or immunosuppressant are had the oil-in-water microemulsion nanometer solution system of biocompatibility by solubilising, improve the dissolubility of hydrophobicity immunosuppressant and reduce side effects of pharmaceutical drugs.
Technical scheme of the present invention is:
rapamycin and ciclosporin A nano oral microemulsion preparation method, specifically comprise the following steps:
Step 1. is first prepared the oil-in-water nanometer solution system with biocompatibility:
Surfactant is mixed homogeneously according to mass ratio 1-3:1-2 with cosurfactant, after mix homogeneously, with oil, the deionized water of biocompatibility according to mass percent, be: 29-35:24-32:35-39 mixes, jiggle and can prepare the oil-in-water microemulsion system that diameter is 30 nanometers;
Step 2. is dissolved in a certain amount of gram of rapamycin or ciclosporin A or rapamycin+ciclosporin A solid in the oil-in-water microemulsion system that step 1 prepares, at room temperature or 37 degree temperature, at the uniform velocity to mix 2-24 hour under the rotating speed of 200-800 rev/min, cancer therapy drug combined nano oral administration solution system.
Get the water-in-oil-in-water compositions sample of 100 microlitres, by the concentration of chromatography-mass spectroscopy methods analyst rapamycin, ciclosporin A, obtain the maxima solubility of 1 milliliter of microemulsion system rapamycin, ciclosporin A.
further, can also be by anticancer class medicine Docetaxel hydrophobic anticancer drug and rapamycin and according to the ratio proportioning of mass ratio 1:2-3 in described step 2, add in the oil-in-water microemulsion system that step 1 prepares simultaneously, at room temperature or 37 degree temperature, at the uniform velocity to mix 2-24 hour under the rotating speed of 200-800 rev/min, obtain rapamycin or ciclosporin A or rapamycin+ciclosporin A nano oral system solution.
further, the oil of described biocompatibility is that food stage or pharmaceutical grade material comprise Oleum sesami, olive oil or Capryol 90;
further, described surfactant be mainly food stage ionic surfactant pack draw together polyoxyethylene groups sorbitan laurate (comprise polysorbate20, polysorbate40, polysorbate60 and polysorbate80
) or castor oil polyoxyethylene ether.
further, described cosurfactant comprises food grade materials polyoxyethylene and dioxy glycol list vinyl Ether.
Resulting rapamycin, ciclosporin A nano oral solution system or the centrifugalize under the rotating speed of 14500 revs/min of rapamycin+ciclosporin A nanometer solution system, do not have solid precipitation to separate out, prepared microemulsion system is thermodynamic stable system, the characteristic not only with biocompatibility, high solubilising power and increase drug osmotic ability can also (pH=1.2 buffer solution) be stablized and be diluted 1 to 5 times under simulation gastric acid environment.Rapamycin, ciclosporin A nano oral solution or rapamycin
+ciclosporin A combined nano oral administration solution system in room temperature to stable in 40 degree temperature ranges and can preserve and do not change for 2 years.
This microemulsion preparation method compared with the conventional method, have efficiently, directly, advantage fast and accurately, prepared nano oral solution system is thermodynamic stable system energy long-term storage, steady quality, concentration is accurately and can produce in batches.Adopt microemulsion method, by selecting oil, surfactant, the cosurfactant preparation of biocompatibility to there is immunosuppressant nano oral solution, the combined nano oral administration solution system of biocompatibility.First mate improves the dissolubility of hydrophobicity Rapamycin, ciclosporin A, and provides new method for studying the research and development of oil-in-water microemulsion system rapamycin, ciclosporin A nano oral formula and rapamycin and ciclosporin A combined nano oral administration solution formula.
Compared with the existing technology, the present invention has following useful result:
1, the present invention adopts microemulsion method to prepare Rapamycin, ciclosporin A and rapamycin and ciclosporin A combined nano oral administration solution, is novel nano drug system, has high solubilising power, thermodynamically stable advantage.
2, the microemulsion system that prepared by the present invention is two kinds of solubilisings or above hydrophobicity immunosuppressant, cancer therapy drug simultaneously, prepared Rapamycin and ciclosporin A composite Nano oral administration solution system, Docetaxel and rapamycin combined nano oral administration solution, there is synergism, for the research of immunosuppressant combination formula and multiple cancer therapy drug combination formula of oral provides new method, experiment and theoretical foundation.
3, the present invention adopts prepared biocompatibility oil-in-water (O/W) the microemulsion nanometer system of microemulsion system, it is that 100 mcg/ml surpass 90% to HeLa, M28 cell through 24 hours cultured cells survival rates that blank Emulsions ties up to concentration, for studying nano oral formula, combination oral administration nanometer solution and the human clinical thereof of immunosuppressant, cancer therapy drug, provides scientific basis.
specific implementation method
below in conjunction with specific embodiment, technical scheme of the present invention is described further.
Embodiment 1
By polysorbate20 with
dioxy glycol list vinyl Etheraccording to mass ratio 2:1 mix homogeneously, after mix homogeneously with
capryol 90, deionized water according to mass percent is: 35:30:35 mixes, and jiggles and can prepare the oil-in-water microemulsion system that diameter is 30 nanometers;
10 milligrams of immunosuppressant agent ciclosporin A solid or 10 milligrams of rapamycin pressed powders are dissolved in 1 milliliter of microemulsion nanometer solution, at 37 degree temperature, at the uniform velocity to mix under the rotating speed of 200 revs/min 24 hours, obtaining diameter is 30 nano oral solution system immunosuppressant nano oral solution systems, by in vitro release experiment and cell survival, test, prove that prepared microemulsion system has biocompatibility, obtain hydrophobicity immune suppressive cyclosporin A nano oral solution system.
Embodiment 2
By polysorbate80 with
dioxy glycol list vinyl Etheraccording to mass ratio 2:1 mix homogeneously, after mix homogeneously with
capryol 90, deionized water according to mass percent is: 35:29:36 mixes, and jiggles and can prepare the oil-in-water microemulsion system that diameter is 30 nanometers; 5 milligrams of rapamycin+5 milligram ciclosporin A solid are dissolved in 1 milliliter of oil-in-water microemulsion system, at 37 degree temperature, at the uniform velocity to mix under the rotating speed of 600 revs/min 20 hours, obtain Rapamycin+ciclosporin A combined nano oral administration solution system, by the drug level in chromatography-mass spectroscopy methods analyst nanometer solution, by in vitro release experiment and cell survival, test, prove that prepared microemulsion system has biocompatibility, obtain hydrophobicity Rapamycin+ciclosporin A combined nano oral administration solution system.
Embodiment 3
Will
castor oil polyoxyethylene etherwith
dioxy glycol list vinyl Etheraccording to mass ratio 2:1 mix homogeneously, after mix homogeneously with
capryol 90, deionized water according to mass percent is: 37:24:39 mixes, and jiggles and can prepare the oil-in-water microemulsion system that diameter is 30 nanometers;
The oil-in-water microemulsion system of preparing biocompatibility, by anticancer class medicine (hydrophobic anticancer drug such as Docetaxel) and rapamycin
according to mass ratio 1:1 to 1:3 proportioningbe dissolved in 1 milliliter of microemulsion nanometer solution simultaneously, at room temperature or 37 degree, at the uniform velocity to mix 12-24 hour under the rotating speed of 800 revs/min, obtain cancer therapy drug+immunosuppressant combined nano oral administration solution system, by in vitro release experiment, pass through epithelial cell and cell survival experiment, prove that prepared microemulsion system can strengthen the penetrating power of medicine and have the easy property of biofacies, multi-medicament association cording has synergism, improve curative effect of medication and reduce side effects of pharmaceutical drugs, realization combines to various hydrophobic cancer therapy drug the dual purpose that chemical therapy system improves the penetrating power of cancer therapy drug and reduces glycoprotein function.
Claims (5)
1. rapamycin and ciclosporin A nano oral microemulsion preparation method, is characterized in that, specifically comprises the following steps:
Step 1. is first prepared the oil-in-water nanometer solution system with biocompatibility:
Surfactant is mixed homogeneously according to mass ratio 1-3:1-2 with cosurfactant, again, with oil, the deionized water of biocompatibility according to mass percent, be: 29-35:24-32:35-39 mixes, and jiggles and can prepare the oil-in-water microemulsion system that diameter is 30 nanometers;
Step 2. is dissolved in a certain amount of rapamycin or ciclosporin A or rapamycin+ciclosporin A solid in the oil-in-water microemulsion system that step 1 prepares, at room temperature or 37 degree temperature, at the uniform velocity to mix 2-24 hour under the rotating speed of 200-800 rev/min, obtain rapamycin or ciclosporin A or rapamycin+ciclosporin A nano oral system solution;
Get the water-in-oil-in-water compositions sample of 100 microlitres, by the concentration of chromatography-mass spectroscopy methods analyst rapamycin, ciclosporin A, obtain the maxima solubility of 1 milliliter of microemulsion system nano oral system solution.
2. preparation method as claimed in claim 1, it is characterized in that, can also be by anticancer class medicine Docetaxel hydrophobic anticancer drug and rapamycin and according to the ratio proportioning of mass ratio 1:2-3 in described step 2, add in the oil-in-water microemulsion system that step 1 prepares simultaneously, at room temperature or 37 degree temperature, at the uniform velocity to mix 2-24 hour under the rotating speed of 200-800 rev/min, obtain rapamycin or ciclosporin A or rapamycin+ciclosporin A cancer therapy drug combined nano oral administration solution system solution.
3. preparation method as claimed in claim 1 or 2, is characterized in that, the oil of described biocompatibility is that food stage or medical utmost point material comprise Oleum sesami, olive oil and Capryol 90.
4. preparation method as claimed in claim 1 or 2, is characterized in that, described surfactant is that nonionic is that food grade surfactant comprises polyoxyethylene groups sorbitan laurate or castor oil polyoxyethylene ether.
5. preparation method as claimed in claim 1 or 2, is characterized in that, described cosurfactant comprises polyoxyethylene and dioxy glycol list vinyl Ether.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107365138A (en) * | 2017-09-06 | 2017-11-21 | 建研科技股份有限公司 | Method for preparing silicon dioxide aerogel/vitrified microsphere/water glass composite thermal insulation material and thermal insulation material prepared by method |
| CN107998399A (en) * | 2017-12-22 | 2018-05-08 | 北京诺康达医药科技有限公司 | A kind of cyclosporine compound eye drops and preparation method thereof |
| CN113069530A (en) * | 2021-03-31 | 2021-07-06 | 河南大学 | Application of naphthalimide-polyamine derivative and cyclosporine A in preparation of antitumor drugs |
Citations (3)
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| CN1161652A (en) * | 1994-10-26 | 1997-10-08 | 诺瓦蒂斯有限公司 | Pharmaceutical compositions |
| CN100998864A (en) * | 2006-12-26 | 2007-07-18 | 沈阳药科大学 | Cyclosporin A semisolid skeleton capsule and its preparation method |
| CN102008437B (en) * | 2010-11-23 | 2012-11-14 | 赵晨 | Rapamycin microemulsion injection for eyes and preparation method and application thereof |
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2014
- 2014-03-27 CN CN201410118664.8A patent/CN103933546A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1161652A (en) * | 1994-10-26 | 1997-10-08 | 诺瓦蒂斯有限公司 | Pharmaceutical compositions |
| CN100998864A (en) * | 2006-12-26 | 2007-07-18 | 沈阳药科大学 | Cyclosporin A semisolid skeleton capsule and its preparation method |
| CN102008437B (en) * | 2010-11-23 | 2012-11-14 | 赵晨 | Rapamycin microemulsion injection for eyes and preparation method and application thereof |
Non-Patent Citations (2)
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| ZHONG-GAO GAO, ET AL.: "Physicochemical characterization and evaluation of a microemulsion system for oral delivery of cyclosporin A", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
| 牛慧彦 等: "雷帕霉素联合多西紫杉醇对肺癌细胞增殖和凋亡的影响", 《新乡医学院学报》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107365138A (en) * | 2017-09-06 | 2017-11-21 | 建研科技股份有限公司 | Method for preparing silicon dioxide aerogel/vitrified microsphere/water glass composite thermal insulation material and thermal insulation material prepared by method |
| CN107365138B (en) * | 2017-09-06 | 2020-04-07 | 建研科技股份有限公司 | Method for preparing silicon dioxide aerogel/vitrified microsphere/water glass composite thermal insulation material and thermal insulation material prepared by method |
| CN107998399A (en) * | 2017-12-22 | 2018-05-08 | 北京诺康达医药科技有限公司 | A kind of cyclosporine compound eye drops and preparation method thereof |
| CN107998399B (en) * | 2017-12-22 | 2021-01-12 | 北京诺康达医药科技股份有限公司 | Cyclosporine compound eye drops and preparation method thereof |
| CN113069530A (en) * | 2021-03-31 | 2021-07-06 | 河南大学 | Application of naphthalimide-polyamine derivative and cyclosporine A in preparation of antitumor drugs |
| CN113069530B (en) * | 2021-03-31 | 2022-01-25 | 河南大学 | Application of naphthalimide-polyamine derivative and cyclosporine A in preparation of antitumor drugs |
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Application publication date: 20140723 |