CN1939316B - Microsphere containing adriamycin, its usage and preparation - Google Patents
Microsphere containing adriamycin, its usage and preparation Download PDFInfo
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- CN1939316B CN1939316B CN2005101052540A CN200510105254A CN1939316B CN 1939316 B CN1939316 B CN 1939316B CN 2005101052540 A CN2005101052540 A CN 2005101052540A CN 200510105254 A CN200510105254 A CN 200510105254A CN 1939316 B CN1939316 B CN 1939316B
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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.These article 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 also there are effect M, G1 and G2 phase.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 through cell membrane, works at many target spots, so curative effect is extensive.
After traditional antitumor drug is administered by various routes, reaches certain blood drug level and be distributed in whole body and produce therapeutical effect.The maximum defective of this Therapeutic Method 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 in treatment, produces toxic and side effects, 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; The amycin main adverse reaction of using clinically at present 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 these article 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 erious adverse reaction limitations of amycin the clinical use 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 through 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, through 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 method for preparing 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 disclosed polylactic acid microsphere envelop rate for preparing the method preparation of amycin polylactic acid microsphere does not reach officinal requirement more than, 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, in the polylactic acid main chain, embeds hydroxyacetic acid; The main chain chemical bond is formed changed, cause the depolymerization faster.The degraded of polymer is the bimolecular hydrolysis, and by water and unstable chemical bond fellowship, reaction rate receives 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.
Say that further because the hydrophobicity of polylactic acid is stronger, the difficult control of hydrophilic medicament microsphere release is in vivo carried in preparation, is prone to cause that 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 property, 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-hydroxyacetic 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 UD microsphere of the present invention, preferred 5mg.
The method for preparing 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. process 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 method for preparing 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 method for preparing of described amycin microsphere, the method for processing colostrum is preferably high-speed homogenization or ultra-sonic dispersion is even.
In the method for preparing 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 through the adjustment 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,, get final product to such an extent that arterial thrombosis is used microsphere after screening out less than 40 μ m with greater than the microsphere of 120 μ m.
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 doxorubicin injection and the embodiment 5 gained amycin thromboembolisms dense distiller line of blood medicine with 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 in the dichloromethane solution (200mg/ml) of polylactic acid-glycolic guanidine-acetic acid (molecular weight 10000, lactic acid, hydroxyacetic acid ratio are 50: 50); High-speed homogenization is processed 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 in the dichloromethane solution (400mg/ml) of polylactic acid-glycolic guanidine-acetic acid (molecular weight 10000, lactic acid, hydroxyacetic acid ratio are 50: 50); High-speed homogenization is processed 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 in the dichloromethane solution (300mg/ml) of polylactic acid-glycolic guanidine-acetic acid (molecular weight 10000, lactic acid, hydroxyacetic acid ratio are 75: 25); High-speed homogenization is processed 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 in the dichloromethane solution (400mg/ml) of polylactic acid-glycolic guanidine-acetic acid (molecular weight 10000, lactic acid, hydroxyacetic acid ratio are 75: 25); High-speed homogenization is processed 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 of 5mg amycin and uses microsphere
Amycin 5mg is dissolved in the 0.1ml water, this aqueous solution is added in the dichloromethane solution (500mg/ml) of polylactic acid-glycolic guanidine-acetic acid (molecular weight 10000, lactic acid, hydroxyacetic acid ratio are 50: 50); High-speed homogenization is processed 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 (5)
1. amycin microsphere, it contains amycin and polylactic acid-glycolic guanidine-acetic acid polymer, and entrapment efficiency is not less than 80%, and said amycin microsphere is through the following steps preparation:
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 processes 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;
D is dry, obtains exsiccant microsphere powder.
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 UD microsphere contains the 1-20mg amycin.
4. each 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 the amycin of UD microsphere is 5mg.
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Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| AU2010303552B2 (en) | 2009-10-06 | 2013-11-14 | Regents Of The University Of Minnesota | Bioresorbable embolization microspheres |
| CN102885785B (en) * | 2012-09-26 | 2014-01-15 | 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 |
| CN108403644B (en) * | 2018-03-16 | 2020-08-14 | 安徽工程大学 | Anticancer medicine nano microsphere and its preparation method |
| 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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| CN1330921A (en) * | 2000-06-28 | 2002-01-16 | 东国制药株式会社 | Method of mfg. slowly-released microball by combined milk process |
| CN1507357A (en) * | 2000-10-31 | 2004-06-23 | PRҩƷ����˾ | Method and compositions for enhanced delivery of bioactive molecules |
| CN1546006A (en) * | 2003-12-11 | 2004-11-17 | 同济大学 | Preparation method of biodegradable polymer pharmaceutical microsphere |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1330921A (en) * | 2000-06-28 | 2002-01-16 | 东国制药株式会社 | Method of mfg. slowly-released microball by combined milk process |
| CN1507357A (en) * | 2000-10-31 | 2004-06-23 | PRҩƷ����˾ | Method and compositions for enhanced delivery of bioactive molecules |
| CN1546006A (en) * | 2003-12-11 | 2004-11-17 | 同济大学 | Preparation method of biodegradable polymer pharmaceutical microsphere |
Non-Patent Citations (2)
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| 冉海涛等.包裹阿霉素的高分子材料微泡声学造影剂制备及显影效果实验研究.临床超声医学杂志7 4.2005,7(4),217-220. |
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