CN1939316A - Microsphere containing adriamycin, its usage and preparation - Google Patents
Microsphere containing adriamycin, its usage and preparation Download PDFInfo
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- CN1939316A CN1939316A CNA2005101052540A CN200510105254A CN1939316A CN 1939316 A CN1939316 A CN 1939316A CN A2005101052540 A CNA2005101052540 A CN A2005101052540A CN 200510105254 A CN200510105254 A CN 200510105254A CN 1939316 A CN1939316 A CN 1939316A
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Abstract
A doxorubicin microball used for arterial embolism, intratumor injection, tumor-side injection, or lumbar injection is prepared from polylactic acid-hydroxyacetic acid copolymer. Its preparing process is also disclosed.
Description
Technical field
The present invention relates to a kind of amycin microsphere, its purposes and its preparation method.
Background technology
Amycin (Adriamycin) is current strong effect wide-spectrum anticarcinogen of generally acknowledging.This product directly intercalation of DNA nuclear alkali between, disturb transcription, stop the formation of mRNA, play antitumor action.It had not only suppressed the synthetic of DNA but also had suppressed the synthetic of RNA, so all there is effect in each stage of cell cycle, was a cell cycle nonspecific agent (CCNSA), the S phase was acted on the strongest, and M, G1 and G2 phase are also had effect.In addition, also can cause the generation of free radical, can combine, combine with cell membrane with metal ion.Anoxic cell also there is effect.Amycin can produce biochemical effect widely to body, has intensive cytotoxic effect.Be used for acute leukemia (lymphatic and granulocytic), Hodgkin and malignant lymphoma, breast carcinoma, lung bronchogenic carcinoma, ovarian cancer, soft tissue sarcoma, osteogenic sarcoma, rhabdomyosarcoma, Ewing sarcoma, nephroblastoma, neuroblastoma clinically, wing takes off cancer, thyroid carcinoma, carcinoma of prostate, incidence scale cancer, carcinoma of testis, gastric cancer, hepatocarcinoma etc.Amycin has the wide spectrum tumor-inhibiting action, and main have water miscible gentle brown sugar amine again because it had both contained fat-soluble anthracene nucleus aglucon, has acidic phenol hydroxyl and alkalescence amino, is easy to by cell membrane, works at many target spots, so curative effect is extensive.
After traditional antitumor drug is administration by all means, reaches certain blood drug level and be distributed in whole body and produce therapeutical effect.The defective of this Therapeutic Method maximum is to lack selectivity, and the drug disposition behavior is by its physicochemical property and the decision of anatomical physiology characteristics.Great majority antitumor drug molecular weight commonly used is low, and diffusion easily causes average relatively tissue distribution in vivo, often produces toxic and side effects in treatment, and the antineoplaston that has a strong impact on these medicines is worth.Equally, amycin be used for clinical after the severeest problem also be untoward reaction, at present the amycin main adverse reaction of using clinically is common alopecia, bone marrow depression (leukocyte after medication 10～14 drop to minimum point), the myocardial toxicity incidence rate and the order of severity are directly proportional with this product cumulant, tardy serious ejection heart failure mostly after medication later six months or accumulated dose take place when exceeding 700mg.Commonly feel sick, vomiting, stomatitis, esophagitis and leukopenia, alopecia.Accidental myocardial toxicity, and should watch out for the possibility of congestive heart failure, it is dead to quench sometimes.Stomachache, diarrhoea or full gastroenteritis, hyperuricemia and kidney damage etc. also can appear.Excessive pain, tissue necrosis even the peak nest cellulites of occurring of vein.The big clinical use that has limited amycin of the erious adverse reaction of amycin.
In order to reduce toxicity, improve curative effect, developed a series of amycin novel forms in recent years both at home and abroad: Evacet, amycin microsphere, amycin magnetic microsphere, amycin nanoparticle, amycin Emulsion.The biodegradable microsphere of storage storehouse formula with long-acting is for treatment of diseases provides new route of administration.The biodegradation sustained-release microspheres injection, can every month or the several months injection once, in vivo by the polymer biological Degradation, continue to discharge medicine, keep the required blood drug level that reaches of normal physiological activity, simultaneously through subcutaneous or administered intramuscular, avoided the liver first-pass effect of oral formulations, have bioavailability preferably, improved the compliance of preparation, have significant pharmacoeconomics benefit.
Polylactic acid-glycolic guanidine-acetic acid (PLGA) and polylactic acid (PLA) have excellent biodegradability and histocompatibility, have used for many years as surgical sutures and pharmaceutical carrier, as the long-acting controlled release carrier good prospect are arranged also.Medicine slowly discharges from polymer microballoon continuously, depends primarily on the speed limit effect that depolymerization produces drug release.The polylactic acid-glycolic guanidine-acetic acid is the copolymer that is polymerized by lactic acid and hydroxyacetic acid ammonium certain proportion, by adjusting hydrophilic that its molecular weight size, two monomeric ratios etc. are scalable polylactic acid-glycolic guanidine-acetic acid and degradation cycle etc.
Zhao Ruiling etc. disclose a kind of preparation method of amycin polylactic acid microsphere in 2004 the 24th volumes of Chinese Hospitals pharmaceutical journal the 2nd phase P74 " preparation of amycin polylactic acid microsphere and release behaviour in vitro research ".This method for preparing microsphere comprises the amycin powder is suspended in the dichloromethane solution of polylactic acid, suspensoid is added contain emulsifying in the PVA aqueous solution, obtains microsphere through solvent evaporates again.The drug prepared envelop rate is 73.2%, 12 hour extracorporeal accumulating released medicine 36%.Press and stipulate in 2005 editions second appendix XIX E of Pharmacopoeia of People's Republic of China microcapsule, microsphere and the Liposomal formulation guideline that entrapment efficiency must not be less than 80%, therefore the above disclosed polylactic acid microsphere envelop rate for preparing the method preparation of amycin polylactic acid microsphere does not reach officinal requirement, and the author has only reported that this microsphere is at external 12 hours cumulative release curve.
And polylactic acid is to be formed by lactic acid polymerizes, and its hydrophobicity is stronger, bigger medicine such as the amycin of difficult preparation water solublity, and release is slower in body fluid, embeds hydroxyacetic acid in the polylactic acid main chain, the main chain chemical bond is formed changed, cause depolymerization speed to be accelerated.The degraded of polymer is the bimolecular hydrolysis, and by water and unstable chemical bond fellowship, reaction rate is subjected to the influence of both concentration.For the stronger polylactic acid of hydrophobicity, owing to its picked-up to moisture is restricted, so degradation rate is slow; And after polylactic acid and the hydroxyacetic acid copolymerization, the main polymer chain hydrophilic strengthens, and ester bond quantity increases, and causes degradation rate to be accelerated.Especially in the later stage, autocatalysis significantly increases the lactic acid production of generation.
Further, because the hydrophobicity of polylactic acid is stronger, the difficult control of hydrophilic medicament microsphere release is in vivo carried in preparation, causes that easily drug release is irregular, cause blood drug level under valid density near or surpass toxic dose.
Carrying the amycin microsphere can adopt multiple route of administration to carry out the local sustained release administration, reach and reduce whole body blood drug level, improve blood drug level in the local tumor tissue, thereby the toxic and side effects that has reduced amycin is dysentery, bone marrow depression, Toxicity of Kidney etc. after one's own heart, and has improved the local curative effect of medicine.It is the arterial thrombosis administration that present bibliographical information carries the more route of administration of amycin microsphere use, and the carrier material that microsphere uses comprises gelatin, carboxymethyl dextran resin, ethyl cellulose, albumin etc.The carrier material hydrophilic of these microspheres is strong, and is relatively poor for the controlled-release function of water soluble drug such as amycin, in 12 hours drug release all greater than 80%, difficult in the part long-time sustained-release administration.
Summary of the invention
According to aforementioned, in order to reach above purpose, the present invention obtains a kind of amycin microsphere, this amycin microsphere can meet in the Pharmacopoeia of People's Republic of China about the pertinent regulations in microcapsule, microsphere and the Liposomal formulation guideline: entrapment efficiency must not be less than 80%, and the burst size that medicine began in 0.5 hour requires to be lower than 40%.This amycin microsphere is a micro-sphere material with the polylactic acid-glycolic guanidine-acetic acid.
Therefore, the present invention relates to a kind of microsphere that contains amycin, it comprises amycin and polylactic acid-glycolic guanidine-acetic acid.
According to amycin microsphere of the present invention, wherein polylactic acid-glycolic guanidine-acetic acid molecular weight is between 5000-100000, preferably between 10000-50000.
According to amycin microsphere of the present invention, wherein the ratio of lactic acid and hydroxyacetic acid is 10: 90 to 90: 10 in the polylactic acid-glycolic guanidine-acetic acid, and preferably both ratios are 25: 75 to 75: 25.
According to amycin microsphere of the present invention, the molecular weight of preferred polylactic acid-glycolic guanidine-acetic acid is between 10000-50000, and the ratio of lactic acid and hydroxyacetic acid is 50: 50.
According to the present invention, amycin content is 1-20mg in the unit dose microsphere of the present invention, preferred 5mg.
The preparation method that relates in one aspect to this microsphere more of the present invention, it may further comprise the steps:
A. amycin is soluble in water, this aqueous solution is added in the organic solvent solution of polylactic acid-glycolic guanidine-acetic acid;
B. make colostrum, this colostrum be added in the aqueous solution that contains emulsifying agent, stir emulsion (W/O/W);
C. add distilled water again, continue to stir, make the organic solvent volatilization fully, get microsphere;
D. dry, obtain exsiccant microsphere powder.
In the preparation method of described amycin microsphere, organic solvent is preferably dichloromethane, ethyl acetate or both pro rata mixed solvents for can dissolve the organic solvent of polylactic acid-glycolic guanidine-acetic acid or the mixed solvent of two or more these organic solvents.
In the preparation method of described amycin microsphere, the method for making colostrum is preferably high-speed homogenization or ultra-sonic dispersion is even.
In the preparation method of described amycin microsphere, this emulsifying agent can be polyvinyl alcohol, gelatin, Polyethylene Glycol or analog, is preferably polyvinyl alcohol, more preferably 6% polyvinyl alcohol water solution.
Another aspect of the present invention relates to the purposes of this microsphere.Can prepare the microsphere with different-grain diameter distribution and different drug release rates with preparation technology by adjusting prescription with this method, these microspheres can have different purposes.These purposes comprise intratumor injection, tumor-side injection, lumbar injection, arterial thrombosis etc.For example can prepare the microsphere of 80% above particle diameter between 40-120 μ m in this way, after screening out less than 40 μ m with greater than the microsphere of 120 μ m, get final product the arterial thrombosis microsphere.
Description of drawings
Fig. 1 contains the release in vitro curve of amycin microsphere for embodiment 1 gained.
Fig. 2 contains the release in vitro curve of amycin microsphere for embodiment 2 gained.
Fig. 3 contains the release in vitro curve of amycin microsphere for embodiment 3 gained.
Fig. 4 contains the release in vitro curve of amycin microsphere for embodiment 4 gained.
Fig. 5 contains the release in vitro curve of amycin microsphere for embodiment 5 gained.
Fig. 6 is the dense distiller line of blood medicine that doxorubicin injection and embodiment 5 gained amycin thromboembolisms are used microsphere.
The specific embodiment
Embodiment 1. contains the amycin microsphere of 5mg
Amycin 5mg is dissolved in the 0.1ml water, this aqueous solution is added polylactic acid-glycolic guanidine-acetic acid (molecular weight 10000, lactic acid, hydroxyacetic acid ratio are 50: 50) dichloromethane solution (200mg/ml) in, high-speed homogenization is made colostrum, and this colostrum is added in 4% polyvinyl alcohol (PVA) aqueous solution, stir emulsion (W/O/W), add distilled water again, continue to stir 4 hours, make the organic solvent volatilization fully, get microsphere.Lyophilization obtains exsiccant microsphere powder.This microsphere envelop rate is 81%, and the release in vitro curve is seen Fig. 1.
Embodiment 2. contains 5mg amycin microsphere
Amycin 5mg is dissolved in the 0.1ml water, this aqueous solution is added polylactic acid-glycolic guanidine-acetic acid (molecular weight 10000, lactic acid, hydroxyacetic acid ratio are 50: 50) dichloromethane solution (400mg/ml) in, high-speed homogenization is made colostrum, and this colostrum is added in 6% polyvinyl alcohol (PVA) aqueous solution, stir emulsion (W/O/W), add distilled water again, continue to stir 4 hours, make the organic solvent volatilization fully, get microsphere.Lyophilization obtains exsiccant microsphere powder.This microsphere envelop rate is 87%, and the release in vitro curve is seen Fig. 2.
Embodiment 3. contains 5mg amycin microsphere
Amycin 5mg is dissolved in the 0.1ml water, this aqueous solution is added polylactic acid-glycolic guanidine-acetic acid (molecular weight 10000, lactic acid, hydroxyacetic acid ratio are 75: 25) dichloromethane solution (300mg/ml) in, high-speed homogenization is made colostrum, and this colostrum is added in 6% polyvinyl alcohol (PVA) aqueous solution, stir emulsion (W/O/W), add distilled water again, continue to stir 4 hours, make the organic solvent volatilization fully, get microsphere.Lyophilization obtains exsiccant microsphere powder.This microsphere envelop rate is 92%, and the release in vitro curve is seen Fig. 3.
Embodiment 4. contains 5mg amycin microsphere
Amycin 5mg is dissolved in the 0.1ml water, this aqueous solution is added polylactic acid-glycolic guanidine-acetic acid (molecular weight 10000, lactic acid, hydroxyacetic acid ratio are 75: 25) dichloromethane solution (400mg/ml) in, high-speed homogenization is made colostrum, and this colostrum is added in 6% polyvinyl alcohol (PVA) aqueous solution, stir emulsion (W/O/W), add distilled water again, continue to stir 4 hours, make the organic solvent volatilization fully, get microsphere.Lyophilization obtains exsiccant microsphere powder.This microsphere envelop rate is 92%, and the release in vitro curve is seen Fig. 4.
Embodiment 5. contains the thromboembolism microsphere of 5mg amycin
Amycin 5mg is dissolved in the 0.1ml water, this aqueous solution is added polylactic acid-glycolic guanidine-acetic acid (molecular weight 10000, lactic acid, hydroxyacetic acid ratio are 50: 50) dichloromethane solution (500mg/ml) in, high-speed homogenization is made colostrum, and this colostrum is added in 8% polyvinyl alcohol (PVA) aqueous solution, stir emulsion (W/O/W), add distilled water again, continue to stir 4 hours, make the organic solvent volatilization fully, get microsphere.Lyophilization obtains exsiccant microsphere powder.Sieve and remove less than 40 μ m with greater than the microsphere of 120 μ m.This microsphere envelop rate is 97%, and the release in vitro curve is seen Fig. 5.
The pharmacokinetics test of embodiment 6. dog hepatic artery embolisms
12 test dogs are divided into two groups of A, B at random, and 6 every group, the A group is amycin solution group, and the B group is amycin embolism microball group.Animal is anaesthetized with pentobarbital sodium, lie on the back and be fixed on the operating-table, a side inguinal region cropping, sterilization, drape.It is long to cut the about 3cm of skin of groin, separates subcutaneous tissue and muscle, exposes and separation femoral artery, vein and nerve, with venous detaining needle puncture femoral artery antetheca, introduces seal wire and conduit.Under radioscopy, intubate is to left branch of proper hepatic artery.Under fluoroscopic monitoring, slowly pour into amycin solution or amycin embolism microball.Carry out femoral vein after the administration in required time and get blood, measure blood drug level.The plasma concentration curve that records is seen Fig. 6.
The release in vitro method:
Precision takes by weighing carries an amycin microsphere 5mg, places the 50ml release medium, is placed in 37 ℃, the constant temperature shaking table of 100rpm velocity fluctuation timing sampling 1ml, and additional 1ml release medium.With the centrifugal 10min of release medium 3000rpm, with FLUO star OPTIMA fluorescence analyser, select the 460-12 optical filter as the excitation wavelength optical filter, the 545-10 optical filter is as the emission wavelength optical filter, measure amycin content, and calculate the cumulative release percentage rate of microsphere.
Claims (6)
1. amycin microsphere, it contains amycin and polylactic acid-glycolic guanidine-acetic acid polymer.
2. amycin microsphere as claimed in claim 1, this microsphere are the microsphere that is used for arterial thrombosis, intratumor injection, tumor-side injection, lumbar injection.
3. claim 1 or 2 microsphere, wherein the unit dose microsphere contains the 1-20mg amycin.
4. the arbitrary microsphere of claim 1-3, wherein the molecular weight of polylactic acid-glycolic guanidine-acetic acid polymer is 5000-100000, lactic acid and hydroxyacetic acid ratio are 10: 90 to 90: 10 in the polylactic acid-glycolic guanidine-acetic acid.
5. the microsphere of claim 4, wherein the molecular weight of polylactic acid-glycolic guanidine-acetic acid polymer is 1000-50000, and lactic acid and hydroxyacetic acid ratio are 50: 50 in the polylactic acid-glycolic guanidine-acetic acid, and the amount of amycin is 5mg.
6. the preparation method of amycin microsphere according to claim 1, it comprises:
A is soluble in water with amycin, this aqueous solution is added in the organic solvent solution of polylactic acid-glycolic guanidine-acetic acid;
B makes colostrum, and this colostrum is added in the aqueous solution that contains emulsifying agent, stir emulsion (W/O/W);
C adds distilled water again, continues to stir, and makes the organic solvent volatilization fully, gets microsphere;
The d drying obtains exsiccant microsphere powder.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102885785A (en) * | 2012-09-26 | 2013-01-23 | 复旦大学附属金山医院 | Adriamycin-containing nanometer medicament microspheres and preparation method thereof |
| CN102905733A (en) * | 2009-10-06 | 2013-01-30 | 明尼苏达大学董事会 | Bioresorbable embolization microspheres |
| CN105193735A (en) * | 2014-06-23 | 2015-12-30 | 李茂全 | Application of polylactic acid microspheres in malignant tumors |
| CN108403644A (en) * | 2018-03-16 | 2018-08-17 | 安徽工程大学 | Anticancer drug nanoparticle and preparation method thereof |
| US10182979B2 (en) | 2016-03-22 | 2019-01-22 | Regents Of The University Of Minnesota | Biodegradable microspheres |
| CN112791228A (en) * | 2019-11-13 | 2021-05-14 | 太阳雨林（厦门）生物医药有限公司 | Slow-release embolism microsphere for pulmonary tuberculosis hemoptysis |
| CN112972753A (en) * | 2019-12-02 | 2021-06-18 | 太阳雨林（厦门）生物医药有限公司 | Sustained-release embolism microsphere for treating bronchiectasis hemoptysis caused by chronic inflammation |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100392501B1 (en) * | 2000-06-28 | 2003-07-22 | 동국제약 주식회사 | Preparation Method for Sustained Release Microparticles by Multiple Emulsion Method and Micropartic les Thereof |
| JP2004534721A (en) * | 2000-10-31 | 2004-11-18 | ピーアール ファーマシューティカルズ，インク． | Methods and compositions for enhanced delivery of bioactive molecules |
| CN100444828C (en) * | 2003-12-11 | 2008-12-24 | 同济大学 | Preparation method of biodegradable polymer pharmaceutical microsphere |
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2005
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102905733A (en) * | 2009-10-06 | 2013-01-30 | 明尼苏达大学董事会 | Bioresorbable embolization microspheres |
| CN102905733B (en) * | 2009-10-06 | 2014-10-15 | 明尼苏达大学董事会 | Bioresorbable embolization microspheres |
| US10179187B2 (en) | 2009-10-06 | 2019-01-15 | Regents Of The University Of Minnesota | Bioresorbable embolization microspheres |
| US11439725B2 (en) | 2009-10-06 | 2022-09-13 | Regents Of The University Of Minnesota | Bioresorbable embolization microspheres |
| CN102885785A (en) * | 2012-09-26 | 2013-01-23 | 复旦大学附属金山医院 | Adriamycin-containing nanometer medicament microspheres and preparation method thereof |
| CN105193735A (en) * | 2014-06-23 | 2015-12-30 | 李茂全 | Application of polylactic acid microspheres in malignant tumors |
| US10182979B2 (en) | 2016-03-22 | 2019-01-22 | Regents Of The University Of Minnesota | Biodegradable microspheres |
| CN108403644A (en) * | 2018-03-16 | 2018-08-17 | 安徽工程大学 | Anticancer drug nanoparticle and preparation method thereof |
| CN112791228A (en) * | 2019-11-13 | 2021-05-14 | 太阳雨林（厦门）生物医药有限公司 | Slow-release embolism microsphere for pulmonary tuberculosis hemoptysis |
| CN112972753A (en) * | 2019-12-02 | 2021-06-18 | 太阳雨林（厦门）生物医药有限公司 | Sustained-release embolism microsphere for treating bronchiectasis hemoptysis caused by chronic inflammation |
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