CN1823740A - Taxadol slow release nano-particle, its preparation method and application - Google Patents
Taxadol slow release nano-particle, its preparation method and application Download PDFInfo
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- CN1823740A CN1823740A CNA2005101336928A CN200510133692A CN1823740A CN 1823740 A CN1823740 A CN 1823740A CN A2005101336928 A CNA2005101336928 A CN A2005101336928A CN 200510133692 A CN200510133692 A CN 200510133692A CN 1823740 A CN1823740 A CN 1823740A
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Abstract
A slow-releasing taxusol nanoparticle used for anticancer medicine is prepared through dissolving biodegradable high-molecular polyester, poloxamer 188 (or 407) or polyethylene glycol and taxusol in acetone, adding it to the aqueous solution of polyvinyl alcohol or poloxamer 188, removing acetone, centrifugal separation, washing with distilled water and freeze drying.
Description
Technical field
The present invention relates to a kind of slow releasing pharmaceutical nanoparticle, preparation method and application thereof.
Background technology
Paclitaxel (paclitaxel) is to separate the PTS that obtains from taxaceae Taxus (Taxus) plant, has unique mechanism of action, can induce and promote tubulin polymerization, microtubule assembling and microtubule Stabilization, thereby stop the growth of tumor cell, breast carcinoma, ovarian cancer, incidence cancer, carcinoma of prostate etc. are all had the good anticancer effect.1992 the year end U.S. FDA ratify the transitivity ovarian cancer that paclitaxel is used for other chemotherapeutics refractory first, after ratify the metastatic breast cancer that it is used for the platinum medicine refractory again.
Paclitaxel is a diterpene-kind compound, water-soluble hardly (＜0.003mg/ml).Now be used for clinical formulation for paclitaxel and be mostly that be the injection that solvent is made with Cremophor EL (polyoxy ethyl Oleum Ricini) 50% (v/v) for solubilizing agent and 50% (v/v) dehydrated alcohol, this pharmaceutical carrier can cause some side effect, comprising severe anaphylactic reaction.Although these side effect can be prevented by methods such as pre-medications, whole medication process is inconvenience very, and need careful monitoring medication process, has therefore limited clinical application of taxol.For the bioavailability of improving paclitaxel reduces the side effect of dosage form simultaneously, the research of paclitaxel novel form becomes problem demanding prompt solution.
Generally the size of nanoparticle is defined in 1-1000nm in the pharmaceutics field, the nanoparticle in the pharmaceutics can be divided into two classes: nano-carrier and Nano medication.Nano-carrier is meant dissolving or is dispersed with the various nanoparticles of medicine, as nanometer liposome, polymer nanocomposite capsule, nanosphere, polymer micelle etc.Nano medication then is meant the nanoparticle that directly material medicine is processed into, and is actually the development of micronization technology, micropowder technology.Nano-carrier and cancer therapy drug are formed the nano controlled release system, its outstanding advantage is that nanoparticle is also little more many than erythrocyte, can free-running operation in blood, has the ability of passing the target tissue endotheliocyte, can be entered in the cell by the tumor cell picked-up, the chemotherapeutics that is comprised is discharged at cell and/or subcellsular level, improve curative effect of medication greatly.Medicine in the nano controlled release system can discharge by diffusion into the surface, also can by substrate itself gradually corrosion degraded drug release is wherein come out.The slow release of the polymer matrix may command medicine of nanoparticle, thus reach the permanently effective purpose of a drug.Compare with conventional medicine, Nano medication has characteristics such as granule is little, specific surface area is big, surface reaction activity is high, the active center is many, catalytic efficiency is high, high adsorption capacity, so its advantage of having many conventional medicines not have: thus promote medicine dissolution, improve and absorb, improve targeting and improve effectiveness etc.
The adjuvant that is used to prepare Nanoparticulate formulations mostly is high molecular polymer.Polyesters is to study up to now at most, most widely used biodegradable synthesized polymer material, commonly used have polyglycolic acid (PGA), polylactic acid (PLA), polylactic acid-polyglycolic acid copolymer (PLGA), poly-epsilon-caprolactone (PCL) and a poly-β-hydroxy butyl ester (PHB) etc.Poloxamer (Poloxamer) 188, poloxamer 407 and cetomacrogol 1000, Macrogol 2000, Macrogol 4000, polyethylene glycol 6000 are the surfactant of nonionic, and be main as emulsifying agent and solubilizing agent in pharmaceutical preparation.
Malignant tumor serious harm people's health according to the WHO statistics, is died from malignant tumor person every year on average and is reached 6,900,000 people in the whole world more than 50 hundred million populations, new cases are 8,700,000 examples, and numeral is also increasing year by year.Therefore, national governments, research institution and drugmaker are paid much attention to tumor research and antitumor drug for a long time always.Malignant ascite is the common symptoms of some late tumors, can cause patient's abdominal distention, stomachache, dyspnea, and quality of life is low.Multipotency finds the malignant cell that comes off in ascites, account for 10% of all ascites.Simple drawing liquid can relief of symptoms, but the normal intractable of transudate ground exists, and is carrying out property and increases, and ascites will rise to the preceding level of drawing liquid in a few days.Cancer ascites can be lost to sb.'s illness took a turn for the worse because of body fluid in a large number through repeated localised puncture.The common method of control malignant ascite is an intraperitoneal perfusion cancer therapy drug at present.
Summary of the invention
The objective of the invention is to overcome deficiency of the prior art, a kind of taxadol slow release nano-particle of slow release of may command medicine is provided.
Second purpose of the present invention provides a kind of preparation method of taxadol slow release nano-particle.
The 3rd purpose of the present invention provides the application of taxadol slow release nano-particle at preparation treatment malignant tumor medicine.
Technical scheme of the present invention is summarized as follows:
A kind of taxadol slow release nano-particle, make with following method:
(1) with 50～95 polyester biodegradable macromolecular material that restrain, the paclitaxel of the poloxamer 188 of 2～10 grams or poloxamer 407 or cetomacrogol 1000 or Macrogol 2000 or Macrogol 4000 or polyethylene glycol 6000 and 5～30 grams is dissolved in 3000～9500 milliliters of acetone, preferably: with the polyester biodegradable macromolecular material of 63～90.25 grams, 3.5 the paclitaxel of the poloxamer 188 of～9.5 grams or poloxamer 407 or cetomacrogol 1000 or Macrogol 2000 or Macrogol 4000 or polyethylene glycol 6000 and 5～30 grams is dissolved in 3150～9025 milliliters of acetone, the molecular weight of described polyester biodegradable macromolecular material is 20,000～30,000, and described polyester biodegradable macromolecular material is poly-epsilon-caprolactone or polylactic acid or polylactic acid-polyglycolic acid copolymer;
(2) it is that 0.5～2.5% molecular weight is 30,000～70,000 polyvinyl alcohol water solution or poloxamer 188 aqueous solutions that 1: 1 by volume～4 ratio, the solution that step (1) is made join mass percent concentration, and adding speed is 0.5～5ml/min;
(3) 10 ℃～30 ℃, acetone is removed in decompression;
(4) 0 ℃～10 ℃, 15000～25000rpm, centrifugal 20～40min collects solidified nanoparticle, with distilled water wash, centrifugal polyvinyl alcohol or the poloxamer of removing in the nanoparticle suspension for 1～3 time 188;
(5) lyophilization promptly obtains a kind of taxadol slow release nano-particle.
A kind of preparation method of taxadol slow release nano-particle comprises the steps:
(1) with 50～95 polyester biodegradable macromolecular material that restrain, the paclitaxel of the poloxamer 188 of 2～10 grams or poloxamer 407 or cetomacrogol 1000 or Macrogol 2000 or Macrogol 4000 or polyethylene glycol 6000 and 5～30 grams is dissolved in 3000～9500 milliliters of acetone, preferably: with the polyester biodegradable macromolecular material of 63～90.25 grams, 3.5 the paclitaxel of the poloxamer 188 of～9.5 grams or poloxamer 407 or cetomacrogol 1000 or Macrogol 2000 or Macrogol 4000 or polyethylene glycol 6000 and 5～30 grams is dissolved in 3150～9025 milliliters of acetone, the molecular weight of described polyester biodegradable macromolecular material is 20,000～30,000, and described polyester biodegradable macromolecular material is poly-epsilon-caprolactone or polylactic acid or polylactic acid-polyglycolic acid copolymer;
(2) it is that 0.5～2.5% molecular weight is 30,000～70,000 polyvinyl alcohol water solution or poloxamer 188 aqueous solutions that 1: 1 by volume～4 ratio, the solution that step (1) is made join mass percent concentration, and adding speed is 0.5～5ml/min;
(3) 10 ℃～30 ℃, acetone is removed in decompression;
(4) 0 ℃～10 ℃, 15000～25000rpm, centrifugal 20～40min collects solidified nanoparticle, with distilled water wash, centrifugal polyvinyl alcohol or the poloxamer of removing in the nanoparticle suspension for 1～3 time 188;
(5) lyophilization promptly obtains a kind of taxadol slow release nano-particle.
Taxadol slow release nano-particle is in the application of preparation treatment malignant tumor medicine.
Advantage of the present invention is: the present invention utilizes polyester biodegradable macromolecular material and poloxamer 188 or poloxamer 407 polyethylene glycols blends to form the nano controlled release system as nano-carrier and anti-cancer medicine paclitaxel, poloxamer 188 or poloxamer 407 or polyethylene glycols have concurrently fat-soluble and water solublity, its fat-soluble characteristics have determined it and polyester biodegradable macromolecular material to have intermiscibility, can form uniform blend; Its water solublity characteristic has determined it can form microcellular structure at the polyester biodegradable polymer surface in aqueous solution, and then has reached the purpose that increases drug release.After the administration of paclitaxel nano grain, the nanoscale paclitaxel contacts with tumor tissues and to its internal penetration, tumor tissues is produced powerful lethal effect; The slow release of nano-carrier polyester biodegradable macromolecular material and poloxamer 188 or poloxamer 407 or polyethylene glycols blend may command medicine in the nano controlled release system simultaneously, thereby reach the purpose of slow release long-acting, in addition because the existence of body fluid, poloxamer 188 or poloxamer 407 or polyethylene glycols form microcellular structure on the surface of nano-carrier, increase the release of paclitaxel in the nano-carrier, keep effective treatment concentration of paclitaxel in the tumor tissues.
Description of drawings
Fig. 1 is the inhibition effect of paclitaxel nano grain to mice H22 ascites tumor;
Fig. 2 is dispersed in the tumor tissues after to the mouse entity locally injected into tumor for the paclitaxel nano grain.
The specific embodiment
The present invention is further illustrated below in conjunction with specific embodiment.
Embodiment 1:
Poly-epsilon-caprolactone can use the commercial goods also can adopt to control oneself preparation.
The preparation method of poly-epsilon-caprolactone:
Under nitrogen protection with caprolactone and stannous octoate (1-12: 0.001-0.1) drop in the there-necked flask, mix vacuumize degassing after airtight: room temperature, vacuum＜80Pa, time 5-15 minute, and then charge into high pure nitrogen in proportion;
2. raw materials mixed is transferred in the polymeric kettle under nitrogen protection, repeats above-mentioned vacuum outgas and nitrogen replacement process, charges into nitrogen rear enclosed gas valve for the last time, polymeric kettle is put into 100-300 ℃ constant temperature oven polymerization 24-96 hour.
After polymerization is finished, polymer is extruded by the discharging valve of polymeric kettle bottom, in the room temperature cooling curing.
Embodiment 2
The preparation method of taxadol slow release nano-particle:
The method for preparing the nano controlled release system has polyreaction method and polymeric material dispersion method, emulsion polymerisation and interfacial polymerization technology that the former is prepared by polyreaction as the use different monomers; The method of the latter as utilizing high molecular polymer to adopt emulsifying-solvent evaporation method to be prepared.Among the present invention, adopt the solvent substitution method to prepare nanoparticle.With emulsifying commonly used-solvent evaporation method relatively, solvent substitution method operational approach is easy, does not need high-speed stirred emulsifying or ultrasonic, and required energy consumption is low.
(1) molecular weight with 63 grams is that 20,000～30,000 poly-epsilon-caprolactone, the poloxamer 188 of 6 grams and the paclitaxel of 25 grams are dissolved in 4000 milliliters of acetone;
(2) it is that 2% molecular weight is 30,000～70,000 polyvinyl alcohol water solution that 1: 1 by volume ratio, the solution that step (1) is made join mass percent concentration, and adding speed is 0.5ml/min;
(3) 15 ℃, acetone is removed in decompression;
(4) 0 ℃, 15000rpm, centrifugal 30min collects solidified nanoparticle, with distilled water wash, the centrifugal polyvinyl alcohol of removing in the nanoparticle suspension for 2 times;
(5) lyophilization promptly obtains a kind of taxadol slow release nano-particle.
Embodiment 3
The preparation method of taxadol slow release nano-particle:
(1) molecular weight with 90.25 grams is that 20,000～30,000 polylactic acid, the poloxamer 407 of 2 grams and the paclitaxel of 5 grams are dissolved in 3000 milliliters of acetone;
(2) it is that 0.5% molecular weight is 110,000 poloxamer 188 aqueous solutions that 1: 4 by volume ratio, the solution that step (1) is made join mass percent concentration, and adding speed is 5ml/min;
(3) 10 ℃, acetone is removed in decompression;
(4) 0 ℃, 20000rpm, centrifugal 20min collects solidified nanoparticle, with distilled water wash, the centrifugal poloxamer of removing in the nanoparticle suspension for 1 time 188;
(5) lyophilization promptly obtains a kind of taxadol slow release nano-particle.
Embodiment 4
The preparation method of taxadol slow release nano-particle:
(1) molecular weight with 50 grams is that polylactic acid-polyglycolic acid copolymer of 20,000～30,000, the cetomacrogol 1000 of 10 grams and the paclitaxel of 30 grams are dissolved in 9500 milliliters of acetone;
(2) it is that 2.5% molecular weight is 30,000～70,000 polyvinyl alcohol water solution that 1: 3 by volume ratio, the solution that step (1) is made join mass percent concentration, and adding speed is 0.5ml/min;
(3) 30 ℃, acetone is removed in decompression;
(4) 10 ℃, 25000rpm, centrifugal 40min collects solidified nanoparticle, with distilled water wash, the centrifugal polyvinyl alcohol of removing in the nanoparticle suspension for 3 times;
(5) lyophilization promptly obtains a kind of taxadol slow release nano-particle.
Embodiment 5
The preparation method of taxadol slow release nano-particle:
(1) molecular weight with 95 grams is that 20,000～30,000 poly-epsilon-caprolactone, the Macrogol 2000 of 3.5 grams and the paclitaxel of 25 grams are dissolved in 3150 milliliters of acetone;
(2) it is that 2% molecular weight is 30,000～70,000 polyvinyl alcohol water solution that 1: 2 by volume ratio, the solution that step (1) is made join mass percent concentration, and adding speed is 3ml/min;
(3) 20 ℃, acetone is removed in decompression;
(4) 10 ℃, 20000rpm, centrifugal 30min collects solidified nanoparticle, with distilled water wash, the centrifugal polyvinyl alcohol of removing in the nanoparticle suspension for 2 times;
(5) lyophilization promptly obtains a kind of taxadol slow release nano-particle.
Embodiment 6
The preparation method of taxadol slow release nano-particle:
(1) molecular weight with 95.25 grams is that 20,000～30,000 poly-epsilon-caprolactone, the Macrogol 4000 of 9.5 grams and the paclitaxel of 15 grams are dissolved in 9025 milliliters of acetone;
(2) it is that 2% molecular weight is poloxamer 188 aqueous solutions that 1: 2 by volume ratio, the solution that step (1) is made join mass percent concentration, and adding speed is 3ml/min;
(3) 20 ℃, acetone is removed in decompression;
(4) 10 ℃, 20000rpm, centrifugal 30min collects solidified nanoparticle, with distilled water wash, the centrifugal poloxamer of removing in the nanoparticle suspension for 2 times 188;
(5) lyophilization promptly obtains a kind of taxadol slow release nano-particle.
Embodiment 7
The preparation method of taxadol slow release nano-particle:
(1) molecular weight with 63 grams is that 20,000～30,000 polylactic acid, the polyethylene glycol 6000 of 6.5 grams and the paclitaxel of 25 grams are dissolved in 5000 milliliters of acetone;
(2) it is that 2% molecular weight is 30,000～70,000 polyvinyl alcohol water solution that 1: 2 by volume ratio, the solution that step (1) is made join mass percent concentration, and adding speed is 3ml/min;
(3) 20 ℃, acetone is removed in decompression;
(4) 10 ℃, 20000rpm, centrifugal 30min collects solidified nanoparticle, with distilled water wash, the centrifugal polyvinyl alcohol of removing in the nanoparticle suspension for 2 times;
(5) lyophilization promptly obtains a kind of taxadol slow release nano-particle.
Embodiment 8
The preparation method of taxadol slow release nano-particle:
(1) be that 20,000～30,000 polylactic acid, 6.5 kilograms polyethylene glycol 6000 and 25 kilograms paclitaxel are dissolved in 5000 liters of acetone with 63 kilograms molecular weight;
(2) it is that 2% molecular weight is 30,000～70,000 polyvinyl alcohol water solutions that 1: 2 by volume ratio, the solution that step (1) is made join mass percent concentration, and adding speed is 3ml/min;
(3) 20 ℃, acetone is removed in decompression;
(4) 10 ℃, 20000rpm, centrifugal 30min collects solidified nanoparticle, with distilled water wash, the centrifugal polyvinyl alcohol of removing in the nanoparticle suspension for 2 times;
(5) lyophilization promptly obtains a kind of taxadol slow release nano-particle.
Embodiment 9
Taxadol slow release nano-particle is in the application of preparation treatment malignant tumor medicine.
In order to understand essence of the present invention better, below with test and the result thereof of the paclitaxel injection of using in now clinical in rat liver cancer cell H22 cell line ascites tumor model the effectiveness of paclitaxel nano grain in the treatment malignant ascite is described relatively with taxadol slow release nano-particle (the taxadol slow release nano-particle preparation injection with embodiment 2 uses).
Experimental result shows: paclitaxel nano granule type has better tumor-inhibiting action to hepatoma carcinoma cell H22 cell line ascites tumor model.Taxadol slow release nano-particle dosage form (dose of paclitaxel is 60mg/kg) is compared with paclitaxel injection dosage form (dose of paclitaxel is 30mg/kg), and toxicity is less, and curative effect is lasting, does not need frequent intermittent administration.When the treatment malignant ascite, can adopt the intraperitoneal injection administration; During the treatment entity tumor, but the local injection administration.
Claims (7)
1. taxadol slow release nano-particle is characterized in that making with following method:
(1) the polyester biodegradable macromolecular material of 50～95 grams, the poloxamer 188 of 2～10 grams or the paclitaxel of poloxamer 407 or cetomacrogol 1000 or Macrogol 2000 or Macrogol 4000 or polyethylene glycol 6000 and 5～30 grams are dissolved in 3000～9500 milliliters of acetone;
(2) it is that 0.5～2.5% molecular weight is 30,000～70,000 polyvinyl alcohol water solution or poloxamer 188 aqueous solutions that 1: 1 by volume～4 ratio, the solution that step (1) is made join mass percent concentration, and adding speed is 0.5～5ml/min;
(3) 10 ℃～30 ℃, acetone is removed in decompression;
(4) 0 ℃～10 ℃, 15000～25000rpm, centrifugal 20～40min collects solidified nanoparticle, with distilled water wash, centrifugal polyvinyl alcohol or the poloxamer of removing in the nanoparticle suspension for 1～3 time 188;
(5) lyophilization promptly obtains a kind of taxadol slow release nano-particle.
2. a kind of taxadol slow release nano-particle according to claim 1, it is characterized in that described polyester biodegradable macromolecular material is 63～90.25 grams, described poloxamer 188 or poloxamer 407 or cetomacrogol 1000 or Macrogol 2000 or Macrogol 4000 or polyethylene glycol 6000 are 3.5～9.5 grams, and described acetone is 3150～9025 milliliters.
3. a kind of taxadol slow release nano-particle according to claim 1 and 2, the molecular weight that it is characterized in that described polyester biodegradable macromolecular material is 20,000～30,000, and described polyester biodegradable macromolecular material is poly-epsilon-caprolactone or polylactic acid or polylactic acid-polyglycolic acid copolymer.
4. the preparation method of a taxadol slow release nano-particle is characterized in that comprising the steps:
(1) the polyester biodegradable macromolecular material of 50～95 grams, the poloxamer 188 of 2～10 grams or the paclitaxel of poloxamer 407 or cetomacrogol 1000 or Macrogol 2000 or Macrogol 4000 or polyethylene glycol 6000 and 5～30 grams are dissolved in 3000～9500 milliliters of acetone;
(2) it is that 0.5～2.5% molecular weight is 30,000～70,000 polyvinyl alcohol water solution or poloxamer 188 aqueous solutions that 1: 1 by volume～4 ratio, the solution that step (1) is made join mass percent concentration, and adding speed is 0.5～5ml/min;
(3) 10 ℃～30 ℃, acetone is removed in decompression;
(4) 0 ℃～10 ℃, 15000～25000rpm, centrifugal 20～40min collects solidified nanoparticle, with distilled water wash, centrifugal polyvinyl alcohol or the poloxamer of removing in the nanoparticle suspension for 1～3 time 188;
(5) lyophilization promptly obtains a kind of taxadol slow release nano-particle.
5. the preparation method of a kind of taxadol slow release nano-particle according to claim 4, it is characterized in that described polyester biodegradable macromolecular material is 63～90.25 grams, described poloxamer 188 or poloxamer 407 or cetomacrogol 1000 or Macrogol 2000 or Macrogol 4000 or polyethylene glycol 6000 are 3.5～9.5 grams, and described acetone is 3150～9025 milliliters.
6. according to the preparation method of claim 4 or 5 described a kind of taxadol slow release nano-particles, the molecular weight that it is characterized in that described polyester biodegradable macromolecular material is 20,000～30,000, and described polyester biodegradable macromolecular material is poly-epsilon-caprolactone or polylactic acid or polylactic acid-polyglycolic acid copolymer.
7. taxadol slow release nano-particle is in the application of preparation treatment malignant tumor medicine.
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| CN101843582A (en) * | 2010-05-18 | 2010-09-29 | 南京工业大学 | Taxol nanosuspension and preparation method thereof |
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| CN104434807A (en) * | 2014-11-10 | 2015-03-25 | 上海交通大学 | Solid dispersion nanoparticles of taxol and taxol homologue and preparation method of solid dispersion nanoparticles |
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| CN110772496A (en) * | 2018-10-11 | 2020-02-11 | 西电集团医院 | Paclitaxel nanoparticles applied to liver cancer interventional therapy |
| CN112083081A (en) * | 2019-06-12 | 2020-12-15 | 中国科学院大连化学物理研究所 | In-situ analysis method for intracellular protein complex and application thereof |
| CN112083081B (en) * | 2019-06-12 | 2022-02-08 | 中国科学院大连化学物理研究所 | In-situ analysis method for intracellular protein complex and application thereof |
| CN110638963A (en) * | 2019-11-01 | 2020-01-03 | 慧生医学科技(徐州)有限公司 | Degradable sustained-release pharmaceutical composition and preparation method thereof |
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