聚L-乳酸电纺纤维和中空微球中药物的酶降解释放
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摘要
合成了聚酯高分子并进行干法静电纺丝试验：采用熔融开环聚合L-丙交酯制备得到分子量较高,多分散系数较小的聚乙二醇嵌段的聚L-乳酸,聚乙二醇嵌段的聚ε-己内酯和乙醇引发聚合的聚L-乳酸。采用改进的工艺合成得到α-羟基辛酸,产率较文献报道提高至77%,并通过脱水环合成辛交酯,采用熔融开环聚合辛交酯得到聚乙二醇嵌段的聚α-羟基辛酸。对聚乙二醇嵌段聚L-乳酸进行了纺丝试验,通过扫描电镜观察纤维形态确定了纺丝的条件,同时将聚乙二醇嵌段聚α-羟基辛酸和聚乙二醇嵌段聚ε-己内酯共混进聚乙二醇嵌段聚L-乳酸进行了纺丝试验。电子扫描显微镜观察发现复合高分子纺丝能够得到无相分离的纤维。
采用单一高分子PEG-PLLA溶液直接纺丝法制备了厚朴酚超细纤维：制备了相对于高分子材料质量的载药量为10%,20%和30%的纤维,经过电镜观察和广角X-射线衍射观察,发现药物能够完好包裹在纤维中,药物突释量较小,药物释放曲线在初期阶段符合α=kt1/2公式,发现随着载药量的逐渐增高,纤维在酶降解下的降解速率逐步变慢,相对于载药量为10%的纤维毡,载药量为20%和30%的纤维毡中药物的释放速率明显变慢。厚朴酚的亲脂的化学结构导致了随着厚朴酚的含量增高,释放介质对纤维表面及更深处的浸润程度变低,纤维降解变慢,药物释放变慢。
采用单一高分子PLLA和PEG-PLLA溶液直接纺丝法制备了布洛芬超细纤维：制备了相对于高分子材料质量的载药量为10%和20%的纤维,经过电镜观察和广角x-射线衍射观察,发现药物能够完好包裹在纤维中,实验结果显示PLLA纤维中的药物突释较小,而PEG-PLLA纤维中药物突释明显。两种高分子纤维中的药物均随着蛋白酶K浓度的增高而释放加快。除突释阶段外,对于不同高分子材料制备所得纤维和同种高分子材料而不同载药量的纤维,药物释放均分两个阶段符合α=kt1/2公式,PEG-PLLA纤维中包裹的布洛芬的释放速率比PLLA纤维中的要快,20%载药量的纤维中的药物释放速率比10%载药量的要快。由于布洛芬具有亲水的羧基,所以载药量多时,释放介质对纤维的浸润变得更容易,药物释放便加快了。
采用PEG-PLLA和PEG-PHO复合高分子溶液直接纺丝法制备了布洛芬超细纤维,并且采用该复合材料并用乳化-纺丝法制备了阿霉素超细纤维：发现当纤维中掺入质量百分比为5%的质均分子量为5000左右的PEG-PHO时,后者就会阻碍纤维对酶的降解,即阻碍蛋白酶K对纤维的降解,对于直接干法电纺的含有布洛芬的纤维和经过乳化-纺丝的包裹有盐酸阿霉素的纤维来说,使得药物的释放在末期受阻；1周后释放百分率较没有加入的低。主载体材料中加入小部分非降解的材料即对整个体系的降解性能产生影响,这种现象为首次报道。
分别用PEG-PLLA和PLLA两种材料,采用复乳化法制备了包载有水溶性药物盐酸吉西他滨的中空微球。采用PLLA制备得到的微球表面有孔洞缺陷存在,采用PEG-PLLA制备得到的微球表面仅有有规律的细小格状花纹出现,剖面显示,两种微球内部均成蜂窝状结构。所得微球粒径分别为270+109.7μm和279±127.2μm, PEG-PLLA微球中PEG嵌段的存在导致微球中药物的突释,PLLA微球无药物突释；PEG嵌段的存在使得微球中包裹的药物释放更为完全,尤其是在释放介质中有蛋白酶K存在的条件下,而PLLA微球。1个月后,在释放介质中无蛋白酶K存在的情况下,PLLA微球中的药物释放少于载药量的40%,而PEG-PLLA中释放的为载药量的70%。在含有蛋白酶K的释放介质中,PLLA微球的释放量在50%左右。而PEG-PLLA微球中药物的释放量在70%以上,尤其是在蛋白酶K为10μg/mL时,释放量为100%。
Synthetic method of a-hydroxyl octanoic acid and 3,6-dihexyl-1,4-dioxane-2,5-dione was improved and optimized by using heptaldehyde as the starting material via the process of nucleophilic substitution,displacement reaction,acid hydrolysis,deaminization by alkalinization and the process of dehydration of acid catalysis respectively. The improved method increased the yield of a-hydroxyl octanoic acid to 77%. The improved method ensured the material to react thoroughly at every step for synthesizing a-hydroxyl octanoic acid therefore increasing the utilance of material and decreasing the waste of reactant.
Polyester polymer was synthesized and electrospinned by dry method:poly L-lactide with high molecular weight and low poly dispersitu index was prepared by melting-polymerization method. a-hydroxyl octanoic was synthesized by dehydration modified process.and its was synthesized by ring opening polymerization at melting state. PEG blocked poly L-lactic acid was electrospun and condition for spinning was optimized by scanning electronic microscope observation. Meanwhile, PEG-PHO and PEG-PCL was respectively mixed with PEG-PLLA and electrospun. Fibers with no phase separation was obtained by mixture organic solution electrospinning.
Ultra-fine fibers with magnolol entrapped was prepared by solution from single polymer PEG-PLLA.Fibers with 10%,20% and 30% mass ratio of drug loading was prepared. By SEM onservation and WAXD detection, magnolol could be entrapped in fibers perfectly. Drug burst release amount was small. At prior period of drug release experiment, profiles fitted to a=kt1/2 equation. As the drug amount became bigger, degradation of fibers become slower. And compared to fibers with 10% magnolol loaded release, fibers with 20% and 30% drug loaded release drug slower. Lipophilicity of magnolol lead to weak moisturation of release media onto fiber surface and into fibers inner part. As degradation of fibers became slower, drug release speed became slower.
PLLA and PEG-PLLA was used to prepare ultra-fine fibers by solution direct electrospinning.10% and 20% drug to mass ratio of drug loading was prepared. By observation of SEM, ibuprofen was perfectly entrapped in the fibers. Drug release experiment indicated that drug burst release was obvious for that in PEG-PLLA fibers but not for that in PLLA fibers. As higher as concentration of proteinase K in release media became, drug release became faster and PEG blocked PLLA fibers was more easily be affected by proteinase K and release drug faster than that of PLLA fibers. The release profile could be fitted for a=kt1/2 at two stage except for burst release phase. Fibers with 20% drug loaded release drug more faster than that with 10% drug loaded irrespect of the fiber was spun from PLLA or PEG-PLLA.
Ultra-fine fibers with ibuprofen entrapped was spun from PEG-PLLA和PEG-PHO composite organic solution. And ultra-fine fibers was also spun from this kind of composite solution to entrap doxorubicin hydrochloride by emulsification-electrospinning process. It was found that as though as 5% mass ratio of PEG-PLLA was replaced by PEG-PHO with molecula weight of about 5000,the fibers would block the fibers from being degradated.For this kind of fibers,1 week cumulated drug release amount was lower than that of with no PEG-PHO added. Just a little addition of low molecula weight polymer into PLLA fibers could prohibit fibers from being degradated.
PEG-PLLA and PLLA was used respectively to prepare hollow microspheres with Gemcitabine entrapped by double emulsification process.There were holes existing on microspheres prepared from PLLA. And there were only tiny grid-like patterns on microspheres. From microsphere's cross section by ESEM observation, honeycomb structure was found in both kind of mirospheres. Particle size of two kind of microspheres are almostly the same which were 270±109.7μm and 279±127.2μm respectively. PEG segment in spheres lead to burst release of drug at the beginning and thorough release in the end especially for that there was enzyme in releae media. There was no burst release in PLLA sphere and although under proteinase K degradation, there was unreleased drug remained in inner sphere in the end. After about one month, when there was no proteinase K in release media, less than 40% of loaded drug was released from PLLA sphere and about 70% from PEG-PLLA. When there was proteinase K in release media, about 50% of loaded drug was released from PLLA sphere and more than 70% release from PEG-PLLA and even 100% for that in release media with 10μg/mL proteinase K added.
采用单一高分子PEG-PLLA溶液直接纺丝法制备了厚朴酚超细纤维：制备了相对于高分子材料质量的载药量为10%,20%和30%的纤维,经过电镜观察和广角X-射线衍射观察,发现药物能够完好包裹在纤维中,药物突释量较小,药物释放曲线在初期阶段符合α=kt1/2公式,发现随着载药量的逐渐增高,纤维在酶降解下的降解速率逐步变慢,相对于载药量为10%的纤维毡,载药量为20%和30%的纤维毡中药物的释放速率明显变慢。厚朴酚的亲脂的化学结构导致了随着厚朴酚的含量增高,释放介质对纤维表面及更深处的浸润程度变低,纤维降解变慢,药物释放变慢。
采用单一高分子PLLA和PEG-PLLA溶液直接纺丝法制备了布洛芬超细纤维：制备了相对于高分子材料质量的载药量为10%和20%的纤维,经过电镜观察和广角x-射线衍射观察,发现药物能够完好包裹在纤维中,实验结果显示PLLA纤维中的药物突释较小,而PEG-PLLA纤维中药物突释明显。两种高分子纤维中的药物均随着蛋白酶K浓度的增高而释放加快。除突释阶段外,对于不同高分子材料制备所得纤维和同种高分子材料而不同载药量的纤维,药物释放均分两个阶段符合α=kt1/2公式,PEG-PLLA纤维中包裹的布洛芬的释放速率比PLLA纤维中的要快,20%载药量的纤维中的药物释放速率比10%载药量的要快。由于布洛芬具有亲水的羧基,所以载药量多时,释放介质对纤维的浸润变得更容易,药物释放便加快了。
采用PEG-PLLA和PEG-PHO复合高分子溶液直接纺丝法制备了布洛芬超细纤维,并且采用该复合材料并用乳化-纺丝法制备了阿霉素超细纤维：发现当纤维中掺入质量百分比为5%的质均分子量为5000左右的PEG-PHO时,后者就会阻碍纤维对酶的降解,即阻碍蛋白酶K对纤维的降解,对于直接干法电纺的含有布洛芬的纤维和经过乳化-纺丝的包裹有盐酸阿霉素的纤维来说,使得药物的释放在末期受阻；1周后释放百分率较没有加入的低。主载体材料中加入小部分非降解的材料即对整个体系的降解性能产生影响,这种现象为首次报道。
分别用PEG-PLLA和PLLA两种材料,采用复乳化法制备了包载有水溶性药物盐酸吉西他滨的中空微球。采用PLLA制备得到的微球表面有孔洞缺陷存在,采用PEG-PLLA制备得到的微球表面仅有有规律的细小格状花纹出现,剖面显示,两种微球内部均成蜂窝状结构。所得微球粒径分别为270+109.7μm和279±127.2μm, PEG-PLLA微球中PEG嵌段的存在导致微球中药物的突释,PLLA微球无药物突释；PEG嵌段的存在使得微球中包裹的药物释放更为完全,尤其是在释放介质中有蛋白酶K存在的条件下,而PLLA微球。1个月后,在释放介质中无蛋白酶K存在的情况下,PLLA微球中的药物释放少于载药量的40%,而PEG-PLLA中释放的为载药量的70%。在含有蛋白酶K的释放介质中,PLLA微球的释放量在50%左右。而PEG-PLLA微球中药物的释放量在70%以上,尤其是在蛋白酶K为10μg/mL时,释放量为100%。
Synthetic method of a-hydroxyl octanoic acid and 3,6-dihexyl-1,4-dioxane-2,5-dione was improved and optimized by using heptaldehyde as the starting material via the process of nucleophilic substitution,displacement reaction,acid hydrolysis,deaminization by alkalinization and the process of dehydration of acid catalysis respectively. The improved method increased the yield of a-hydroxyl octanoic acid to 77%. The improved method ensured the material to react thoroughly at every step for synthesizing a-hydroxyl octanoic acid therefore increasing the utilance of material and decreasing the waste of reactant.
Polyester polymer was synthesized and electrospinned by dry method:poly L-lactide with high molecular weight and low poly dispersitu index was prepared by melting-polymerization method. a-hydroxyl octanoic was synthesized by dehydration modified process.and its was synthesized by ring opening polymerization at melting state. PEG blocked poly L-lactic acid was electrospun and condition for spinning was optimized by scanning electronic microscope observation. Meanwhile, PEG-PHO and PEG-PCL was respectively mixed with PEG-PLLA and electrospun. Fibers with no phase separation was obtained by mixture organic solution electrospinning.
Ultra-fine fibers with magnolol entrapped was prepared by solution from single polymer PEG-PLLA.Fibers with 10%,20% and 30% mass ratio of drug loading was prepared. By SEM onservation and WAXD detection, magnolol could be entrapped in fibers perfectly. Drug burst release amount was small. At prior period of drug release experiment, profiles fitted to a=kt1/2 equation. As the drug amount became bigger, degradation of fibers become slower. And compared to fibers with 10% magnolol loaded release, fibers with 20% and 30% drug loaded release drug slower. Lipophilicity of magnolol lead to weak moisturation of release media onto fiber surface and into fibers inner part. As degradation of fibers became slower, drug release speed became slower.
PLLA and PEG-PLLA was used to prepare ultra-fine fibers by solution direct electrospinning.10% and 20% drug to mass ratio of drug loading was prepared. By observation of SEM, ibuprofen was perfectly entrapped in the fibers. Drug release experiment indicated that drug burst release was obvious for that in PEG-PLLA fibers but not for that in PLLA fibers. As higher as concentration of proteinase K in release media became, drug release became faster and PEG blocked PLLA fibers was more easily be affected by proteinase K and release drug faster than that of PLLA fibers. The release profile could be fitted for a=kt1/2 at two stage except for burst release phase. Fibers with 20% drug loaded release drug more faster than that with 10% drug loaded irrespect of the fiber was spun from PLLA or PEG-PLLA.
Ultra-fine fibers with ibuprofen entrapped was spun from PEG-PLLA和PEG-PHO composite organic solution. And ultra-fine fibers was also spun from this kind of composite solution to entrap doxorubicin hydrochloride by emulsification-electrospinning process. It was found that as though as 5% mass ratio of PEG-PLLA was replaced by PEG-PHO with molecula weight of about 5000,the fibers would block the fibers from being degradated.For this kind of fibers,1 week cumulated drug release amount was lower than that of with no PEG-PHO added. Just a little addition of low molecula weight polymer into PLLA fibers could prohibit fibers from being degradated.
PEG-PLLA and PLLA was used respectively to prepare hollow microspheres with Gemcitabine entrapped by double emulsification process.There were holes existing on microspheres prepared from PLLA. And there were only tiny grid-like patterns on microspheres. From microsphere's cross section by ESEM observation, honeycomb structure was found in both kind of mirospheres. Particle size of two kind of microspheres are almostly the same which were 270±109.7μm and 279±127.2μm respectively. PEG segment in spheres lead to burst release of drug at the beginning and thorough release in the end especially for that there was enzyme in releae media. There was no burst release in PLLA sphere and although under proteinase K degradation, there was unreleased drug remained in inner sphere in the end. After about one month, when there was no proteinase K in release media, less than 40% of loaded drug was released from PLLA sphere and about 70% from PEG-PLLA. When there was proteinase K in release media, about 50% of loaded drug was released from PLLA sphere and more than 70% release from PEG-PLLA and even 100% for that in release media with 10μg/mL proteinase K added.
引文
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