CN101007868B - Preparation method of biodegradable nano micelle controlled release formulation - Google Patents
Preparation method of biodegradable nano micelle controlled release formulation Download PDFInfo
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- CN101007868B CN101007868B CN2007100368155A CN200710036815A CN101007868B CN 101007868 B CN101007868 B CN 101007868B CN 2007100368155 A CN2007100368155 A CN 2007100368155A CN 200710036815 A CN200710036815 A CN 200710036815A CN 101007868 B CN101007868 B CN 101007868B
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Abstract
The invention relates to a method for preparing biodegradable nanomicelle release controlling agent. It comprises following steps: taking metal zinc powder, zinc lactate or stannous octoic acid as catalyst, initiating laevo- lactide, racemic lactide and d-lactide by carbowax with its molecular weight being 1000-20000 for ring-opening polymerization reaction to produce polylactic acid- carbowax second or third segmented copolymer, and getting water- soluble copolymer; then dissolving polylactic acid- carbowax segmented copolymer into water, the concentration is between 0.1g/l to 10 g/l, and getting biodegradable PLA/PEC nanomicelle. The inner part of micelle is hydrophobic polylactic acid segment, which can dissolve insoluble medicine and thus it is a good medicine release controlling vector. The invention is characterized by simplified process, shortened time and effect removal of influence of organic solvent to product.
Description
Technical field
The invention belongs to the pharmaceutics field, the preparation method who relates to a kind of self-assembly biodegradable nano micelle control-released agent, or rather, the present invention relates to a kind of preparation method of polylactic acid-polyglycol segmented copolymer self-assembly biodegradable nano micelle control delivery.
Background technology
Recent two decades comes, and the medicine control release technic has obtained very extensive studies, and the medicine controlled releasing goods occupy the market ratio also in quick growth, and 2005 annual value of production have reached more than 50,000,000,000 dollars, account for 20 percent of whole pharmacy market.The improvement of medicine release method means that dose reduces, and side reaction alleviates, and effect of drugs increases.Along with development of biology, increasing product has been developed in pharmaceutical industry, needs sustained release system competence exertion effectiveness, particularly polymer drug (as protein, polypeptide, nucleic acid) and insoluble drugs (as anticarcinogen).In addition, in recent years, high amount of drug will lose the patent protection of main drugmaker, find new prescription will prolong the life of a medicine by new drug delivery system.
The medicament slow release system has many potential purposes, as treatment cancer, drug rehabilitation, contraception, immunity etc.From send mode, the medicament slow release system can be divided into two classes.One class is larger-size various graft, and its advantage is to discharge medicine long-term effectively, and shortcoming is to implant by surgical operation.Another kind of is injectable slow-releasing system, comprise micropartical, nanoparticle, micella, hydrogel and water miscible macromolecular drug, can send into (S.M.Li and M.Vert in the body to medicine by subcutaneous, intramuscular or intravenous injection, " Biodegradable polymers:polyesters ", in Encyclopedia of Controlled Drug Delivery, E.Mathiowitz ed., JohnWiley ﹠amp; Sons, 1999, pp.71-93).Along with the fast development of nanotechnology, the nano controlled release system more and more obtains people's attention.Wherein biodegradable nano micelle occupies the status of particularly important, because they can decompose in vivo, and is absorbed by body after mission is finished or excretes by metabolism, thereby can not assemble in vivo.Poly(lactic acid)/ethylene glycol copolymer (PLA/PEG) has good biocompatibility, biological degradability and bioresorbable, can prepare medicament slow release system (Liu, L. such as micropartical, nanoparticle, nano-micelle, hydrogel by different methods; Li, C.; Li, X.; Yuan, Z.; An, Y.; He, B.J.Appl.Polym.Sci.2001,80,1976-1982; Pierri, E.; Avgoustakis, K.J.Biomed.Mater.Res.2005,75A, 639-647.)
The common method of preparation nano-micelle is dialysis method and solvent evaporation method (Kwon, G.S.; Okano, T.Adv.Drug Deliv.Rev.1996,21,107-116; Liggins, R.T.; Burt, H.M.Adv.Drug Deliv.Rev.2002,54,191-202).Dialysis method is earlier polymkeric substance to be dissolved in organic solvent, exchanges with water and obtains nano-micelle.Solvent evaporation method is earlier polymkeric substance to be dissolved in organic solvent, again solution is dispersed in aqueous phase, forms nano-micelle after the solvent evaporates.Organic solvent has negative impact for some drugs (as pharmaceutical grade protein), and is difficult to remove fully, as the medicine controlled releasing goods human body is had certain hazardness.
Summary of the invention
The purpose of this invention is to provide a kind of easy method and prepare nano micelle controlled release formulation, to remove the influence of organic solvent, for new approach is opened up in the widespread use of nano-micelle controlled release goods.
Another object of the present invention provides the application of above-mentioned controlled release preparation.
The invention provides a kind of easy method and prepare the nano-micelle control-released agent.This method is used monohydroxy or the two hydroxyl polyoxyethylene glycol (PEG) of molecular weight as 1000-20000, with hypotoxicity catalyzer such as metal zinc, zinc lactate, stannous octoates, cause rac-Lactide and carry out ring-opening polymerization, synthesizing polylactic acid-polyoxyethylene glycol diblock and triblock copolymer (PLA/PEG), wherein catalyst levels is the 0.05%-0.2% of monomer total mass.Be 1/2 to 1/11 by the repeating unit mol ratio of regulating feed ratio control poly(lactic acid) and polyoxyethylene glycol simultaneously, to obtain water miscible multipolymer, promptly described biodegradable nano micelle controlled release formulation.Be reflected under the vacuum condition and carry out, temperature of reaction is 120-160 ℃, and the reaction times is 3-8 days.
Among the present invention, described rac-Lactide can be a levorotatory lactide.Promptly be raw material with the levorotatory lactide, the synthetic product is left-handed one-tenth polylactic acid-polyglycol diblock and triblock copolymer.
Among the present invention, described rac-Lactide can be the dextrorotation rac-Lactide.Be raw material with the dextrorotation rac-Lactide promptly, the synthetic product is that dextrorotation becomes polylactic acid-polyglycol diblock and triblock copolymer.
Among the present invention, described rac-Lactide can be a rac-lactide.
The resulting polylactic acid-polyglycol multipolymer of the present invention is determined its chemical constitution by nucleus magnetic resonance (Nuclear magneticresonance), (size-exclusion chromatography) measures its molecular weight by Size Exclusion Chromatograph SEC, (X-ray diffraction) determined the crystal form structure by X-ray diffraction, and (Differential scanning calorimetry) tests its thermal characteristics by differential scanning.
On the other hand, the present invention also provides above-mentioned biodegradable nano micelle control-released agent preparation method's application.
After obtaining polylactic acid-polyglycol diblock or triblock copolymer according to the method described above, the polylactic acid-polyglycol segmented copolymer is water-soluble, and concentration between the 10g/l, obtains biological degradability PLA/PEG nano-micelle at 0.1g/l.
Also can be in preparation process, levorotatory lactide and dextrorotation rac-Lactide are reacted with polyoxyethylene glycol respectively, obtain polylactic acid-polyglycol diblock or triblock copolymer respectively, then, Poly-L-lactic acid-polyoxyethylene glycol and dextrorotation polylactic acid-polyglycol is water-soluble respectively, concentration at 0.1g/l between the 10g/l; Again two kinds of solution are mixed, prepare more stable biological degradability PLA/PEG nano-micelle.
The resulting two kinds of nano-micelles of the present invention are by dynamic light scattering (Dynamic light scattering) test micella size and distribution thereof, and (Transmission electron microscopy) observes its pattern by transmission electron microscope.The nano-micelle size of the present invention's preparation is between 5-300nm.
The nano-micelle that the resulting nano-micelle of the present invention can be used for preparing is applied to medicine controlled releasing.
The micella inside of the present invention's preparation is hydrophobic polylactic acid chain segment, can dissolve insoluble drugs.When insoluble drugs adds in the micellar solution of the present invention, can spontaneously combine, enter micella inside with hydrophobic polylactic acid chain segment; After reaching in patient's body by injection, medicine can discharge gradually along with micelle degradation again, thereby the micella of the present invention's preparation is the excellent drug controlled release carrier.
Preparation method's of the present invention positively effect is: by the multipolymer of synthesizing water-solubility, preparation biological degradation absorptivity nano-micelle under the condition that does not have organic solvent fully is for new approach has been opened up in the widespread use of nano-micelle controlled release goods.Preparation method of the present invention has simplified the preparation method of nano-micelle, has shortened preparation time, has removed the influence of organic solvent.
Embodiment
Embodiment 1
Adding 8.8g molecular weight is two hydroxyl polyoxyethylene glycol of 20000 in the 100ml reaction flask, 2.4g levorotatory lactide (or dextrorotation rac-Lactide) and 11.2mg zinc lactate, vacuumize the back tube sealing, put into reaction box, 160 ℃ of reaction taking-ups after 5 days down, dissolve with methylene dichloride, the anhydrous diethyl ether precipitation, vacuum-drying is to constant weight, the sample that obtains determines that with the nuclear magnetic resonance method test poly(lactic acid) and polyoxyethylene glycol repeating unit mol ratio are 1/11.0 and 1/10.5, measure its fusing point with the differential scanning calorimetry and be respectively 60.7 ℃ and 59.9 ℃, second-order transition temperature is respectively-61.4 ℃ and-62.2 ℃, and Tc is respectively-50.6 ℃ and-50.3 ℃.The 50mg polymkeric substance is dissolved in the micellar solution that makes 1g/l in the 50ml deionized water, and recording Poly-L-lactic acid-polyoxyethylene glycol micella particle diameter with dynamic light scattering method is 228nm.Get the mixed micelle solution that two kinds of solution mixing systems of 25ml get 1g/l respectively, recording the micella particle diameter with dynamic light scattering method is 202nm.
Embodiment 2
Adding 4.4g molecular weight is 5000 monohydroxy polyoxyethylene glycol in the 100ml reaction flask, 2.4g levorotatory lactide (or dextrorotation rac-Lactide) and 6.8mg zinc lactate, vacuumize the back tube sealing, put into reaction box, 140 ℃ of reaction taking-ups after 7 days down, dissolve with methylene dichloride, the anhydrous diethyl ether precipitation, vacuum-drying is to constant weight, the sample that obtains determines that with the nuclear magnetic resonance method test poly(lactic acid) and polyoxyethylene glycol repeating unit mol ratio are 1/4.5 and 1/4.3, measure its fusing point with the differential scanning calorimetry and be respectively 61.2 ℃ and 62.6 ℃, second-order transition temperature is respectively-47.8 ℃ and-46.9 ℃, and Tc is respectively-37.1 ℃ and-35.2 ℃.The 50mg polymkeric substance is dissolved in the micellar solution that makes 1g/l in the 50ml deionized water, and recording Poly-L-lactic acid-polyoxyethylene glycol micella particle diameter with dynamic light scattering method is 120nm.Get the mixed micelle solution that two kinds of solution mixing systems of 25ml get 1g/l respectively, recording the micella particle diameter with dynamic light scattering method is 116nm.
Embodiment 3
Adding 4.4g molecular weight is 2000 monohydroxy polyoxyethylene glycol in the 100ml reaction flask, 3.6g levorotatory lactide (or dextrorotation rac-Lactide) and 8mg zinc lactate, vacuumize the back tube sealing, put into reaction box, 120 ℃ of reaction taking-ups after 8 days down, dissolve with methylene dichloride, the anhydrous diethyl ether precipitation, vacuum-drying is to constant weight, the sample that obtains determines that with the nuclear magnetic resonance method test poly(lactic acid) and polyoxyethylene glycol repeating unit mol ratio are 1/2.3 and 1/2.6, measure its fusing point with the differential scanning calorimetry and be respectively 49.2 ℃ and 47.2 ℃, second-order transition temperature is respectively-36.3 ℃ and-34.9 ℃, and Tc is respectively-20.2 ℃ and-18.7 ℃.The 50mg polymkeric substance is dissolved in the micellar solution that makes 1g/l in the 50ml deionized water, and recording Poly-L-lactic acid-polyoxyethylene glycol micella particle diameter with dynamic light scattering method is 135nm.Get the mixed micelle solution of the mixed 1g/l of getting of two kinds of micellar solutions of 25ml respectively, recording the micella particle diameter with dynamic light scattering method is 113nm.
Embodiment 4
Poly-L-lactic acid-the polyoxyethylene glycol of embodiment 1 preparation, its micelle-forming concentration is 0.11g/l.Preparation 20ml concentration is 0,0.2,0.5,1.0, the polymers soln of 3.0g/l, adding 20mg Rimonophenazine (antileprotic, redness, water insoluble), stirred 2 hours, filter.As a result, the solution that does not contain polymer micelle is water white transparency, shows Rimonophenazine not dissolving fully.On the contrary, several polymer micelle solution are pale red to scarlet, show that Rimonophenazine is dissolved in the micellar solution.And micellar concentration is high more, and the Rimonophenazine solvability is good more.
Claims (7)
1. the preparation method of a biodegradable nano micelle controlled release formulation, it is characterized in that: with metal zinc, zinc lactate or stannous octoate is catalyzer, use monohydroxy or the two hydroxyl polyoxyethylene glycol of molecular weight as 1000-20000, cause rac-Lactide and carry out ring-opening polymerization, synthesizing polylactic acid-polyoxyethylene glycol diblock or triblock copolymer is to obtain water miscible multipolymer; Wherein catalyst levels is the 0.05%-0.2% of monomer total mass, and rac-Lactide is 1/2 to 1/11 with the ratio of the molar weight of polyoxyethylene glycol repeating unit; Temperature of reaction is 120-160 ℃, reaction times is 3-8 days, be reflected under the vacuum condition and carry out, after obtaining polylactic acid-polyglycol diblock or triblock copolymer, the polylactic acid-polyglycol segmented copolymer is water-soluble, concentration between the 10g/l, obtains biological degradability PLA/PEG nano-micelle at 0.1g/l.
2. preparation method as claimed in claim 1 is characterized in that, rac-Lactide is a levorotatory lactide.
3. preparation method as claimed in claim 1 is characterized in that, rac-Lactide is the dextrorotation rac-Lactide.
4. preparation method as claimed in claim 1 is characterized in that, rac-Lactide is a rac-lactide.
5. preparation method as claimed in claim 1, it is characterized in that, levorotatory lactide or dextrorotation rac-Lactide react with polyoxyethylene glycol respectively, obtain polylactic acid-polyglycol diblock or triblock copolymer respectively, then, Poly-L-lactic acid-polyoxyethylene glycol or dextrorotation polylactic acid-polyglycol is water-soluble respectively, concentration at 0.1g/l between the 10g/l; Again two kinds of solution are mixed preparation biological degradability PLA/PEG nano-micelle.
6. preparation method as claimed in claim 1 is characterized in that, the nano-micelle size of preparation is at 5-300nm.
7. the micella that is obtained as claim 1 preparation method is applied to medicine controlled releasing.
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| CN108434456A (en) * | 2018-05-03 | 2018-08-24 | 中山大学附属第六医院 | A kind of nano-medicament carrier and the preparation method and application thereof |
| CN110078901A (en) * | 2019-05-24 | 2019-08-02 | 上海典范医疗科技有限公司 | A kind of poly-dl-lactide preparation method |
| CN111821221B (en) * | 2020-07-09 | 2023-05-12 | 广州美茵生物科技有限公司 | Micelle of hydrophilic-hydrophobic structure polymer self-assembled encapsulated essence and preparation method thereof |
| CN111888523A (en) * | 2020-09-08 | 2020-11-06 | 尹振宇 | Preparation method of polylactic acid gel for improving skin |
| CN115969969A (en) * | 2023-02-13 | 2023-04-18 | 中国科学院长春应用化学研究所 | Virus-like structure nanoparticle vaccine and preparation method and application thereof |
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| CN1412220A (en) * | 2002-07-12 | 2003-04-23 | 天津大学 | Preparation method of polyethylene-b-polylactic acid amphiphilic diblock copolymer |
| CN1517384A (en) * | 2003-01-16 | 2004-08-04 | 北京天润兴生物技术开发有限公司 | Preparation method of polylactic acid-polyethylene glycol block copolymer |
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| CN1412220A (en) * | 2002-07-12 | 2003-04-23 | 天津大学 | Preparation method of polyethylene-b-polylactic acid amphiphilic diblock copolymer |
| CN1517384A (en) * | 2003-01-16 | 2004-08-04 | 北京天润兴生物技术开发有限公司 | Preparation method of polylactic acid-polyethylene glycol block copolymer |
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