聚乳酸载药微米球、纳米球的制备及其释药性能研究
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摘要
本文首先采用二步法合成(D，L)型聚乳酸(PLA)，将合成出来的聚乳酸进行了纯化、分子量测定、红外光谱分析、HNMR谱图分析及DSC谱图分析；讨论了辛酸亚锡的用量对聚乳酸的分子量的影响、重结晶次数对聚乳酸分子量的影响、分子量与Tg之间关系等。结果表明在丙交酯的开环聚合中，引发剂与单体的比例对聚乳酸的分子量的大小起决定性作用，辛酸亚锡与丙交酯的比例过高或过低，均只能得到较低分子量的聚乳酸。开环聚合反应属于逐步聚合反应，引发剂与单体的比例过高，活性点过多，不易得到较高分子量的聚乳酸。引发剂与单体的比例过低，活性点过少，单体难以完全发生聚合。重结晶次数越多，单体的旋光性能改善，纯度得以提高，在一定引发剂与单体配比条件下，PLA的分子量大小可以得到控制。
再以制得的PLA作为包裹材料，分别以利福平和盐酸土霉素作为囊心物质，以O／W和W／O溶媒挥发法制得了聚乳酸载药微球，讨论了不同条件对聚乳酸载药微球的影响，研究了聚乳酸分子量、药物含量、微球粒径、释放介质pH值等因素对微球释药性能的影响。结果表明PLA分子量大较难降解，其释药速率较慢；药含量较高，微球内外药物浓度梯度大，药物的释放较快；微球的粒径越小，释药越快；介质呈碱性时聚乳酸的降解较快，利福平的溶解度较大，释药亦快。
最后运用均匀设计实验以灰黄霉素为囊心物质用O／W溶剂挥发法制备了灰黄霉素／聚乳酸纳米球，并且分析比较了载药微米球和纳米球的释药性能。结果表明所获得的纳米球球形较好且较为分散，粒径分布较为均一，粒径在114nm左右。经线性回归和三次重复试验得综合评分S为95.59，误差为3.66％，载药量(DL／％)为13.55％。载药微米球的释药速率较慢，而纳米球在性能上有一个“突跃”，能起到“增溶”药物的作用。
In this paper, the D,L polylactic acid (PLA) was synthesized by the two-step polymerization.Then the PLA was purifized and the molecular weight was determined. The product was characteristized by using IR,HNMR and DSC spectrum .The influence of the amounts of octoate stannum on the molecular weight ,the recrystallization times on the molecular weight and the relationship between the molecular weight and Tg was discussed. The results showed that in the course of ring-opening polymerization of lactide the ratio of initiator to monomer was critical to the molecular weight of PLA. If the ratio of octoate stannum to lactide was too high or too low, the high molecular weight PLA would be unable to be got. When the ratio of the initator to the monomer was too high, the activate centers would be too many and it was hard to get a high molecular weight PLA,while the ratio of the initator to the monomer was too low and the activate centers were too few and then it would be hard to get a great monomer conversion. The more recrystallization times of raw lactide,the better its optical activity and then the higher its purity.Therefore it would be easier to controll the PLA molecular weight by varing the molar ratio of iniator to monomer.
The PLA microsphere containg RFP or Hydrochloride Oxytetracycline was prepared by an oil-in-water and water-in-oil solvent evaporation method and the different process conditions of preparing the drug-loading polylactic acid microsphere were investigated. Influence of some factors such as the molecular weight of PLA, the content of drug,the microsphere size and the pH value of release media on the drug-releasing performance of the microspheres was studied.The result showed that the greater the molecular weight of PLA , the less it degraded and the slower the drug released. Again, the greater the content of the drug and the bigger the difference of drug concentration between in and out of the microsphere, and the more quickly the drug released. The smaller the microsphere size , the more quickly the drug released. In the alkali medium, the PLA degraded more quickly and RFP became more stable, resulting in faster release of drug.
Finally the PLA nanospheres containing Griseofulvin were prepared by method of oil -in-water solvent evaporation and uniform designed experiment. The result shew that the nanospheres were good in spherical shape and narrow distribution of the particle sizes.The
particle diameter was about 114nm , the comprehensive score(S) of the nanosphere was 95.59, the error was 3.66% and the drug content (DL%) was 13.55% by the linearity regression and the three-time-repeated experiments. The drug-releasing rate of the microsphere was slower, while that of the nanosphere could have an abrupt increase, which indicated the latter could have the function of solubilizing the drug.
再以制得的PLA作为包裹材料，分别以利福平和盐酸土霉素作为囊心物质，以O／W和W／O溶媒挥发法制得了聚乳酸载药微球，讨论了不同条件对聚乳酸载药微球的影响，研究了聚乳酸分子量、药物含量、微球粒径、释放介质pH值等因素对微球释药性能的影响。结果表明PLA分子量大较难降解，其释药速率较慢；药含量较高，微球内外药物浓度梯度大，药物的释放较快；微球的粒径越小，释药越快；介质呈碱性时聚乳酸的降解较快，利福平的溶解度较大，释药亦快。
最后运用均匀设计实验以灰黄霉素为囊心物质用O／W溶剂挥发法制备了灰黄霉素／聚乳酸纳米球，并且分析比较了载药微米球和纳米球的释药性能。结果表明所获得的纳米球球形较好且较为分散，粒径分布较为均一，粒径在114nm左右。经线性回归和三次重复试验得综合评分S为95.59，误差为3.66％，载药量(DL／％)为13.55％。载药微米球的释药速率较慢，而纳米球在性能上有一个“突跃”，能起到“增溶”药物的作用。
In this paper, the D,L polylactic acid (PLA) was synthesized by the two-step polymerization.Then the PLA was purifized and the molecular weight was determined. The product was characteristized by using IR,HNMR and DSC spectrum .The influence of the amounts of octoate stannum on the molecular weight ,the recrystallization times on the molecular weight and the relationship between the molecular weight and Tg was discussed. The results showed that in the course of ring-opening polymerization of lactide the ratio of initiator to monomer was critical to the molecular weight of PLA. If the ratio of octoate stannum to lactide was too high or too low, the high molecular weight PLA would be unable to be got. When the ratio of the initator to the monomer was too high, the activate centers would be too many and it was hard to get a high molecular weight PLA,while the ratio of the initator to the monomer was too low and the activate centers were too few and then it would be hard to get a great monomer conversion. The more recrystallization times of raw lactide,the better its optical activity and then the higher its purity.Therefore it would be easier to controll the PLA molecular weight by varing the molar ratio of iniator to monomer.
The PLA microsphere containg RFP or Hydrochloride Oxytetracycline was prepared by an oil-in-water and water-in-oil solvent evaporation method and the different process conditions of preparing the drug-loading polylactic acid microsphere were investigated. Influence of some factors such as the molecular weight of PLA, the content of drug,the microsphere size and the pH value of release media on the drug-releasing performance of the microspheres was studied.The result showed that the greater the molecular weight of PLA , the less it degraded and the slower the drug released. Again, the greater the content of the drug and the bigger the difference of drug concentration between in and out of the microsphere, and the more quickly the drug released. The smaller the microsphere size , the more quickly the drug released. In the alkali medium, the PLA degraded more quickly and RFP became more stable, resulting in faster release of drug.
Finally the PLA nanospheres containing Griseofulvin were prepared by method of oil -in-water solvent evaporation and uniform designed experiment. The result shew that the nanospheres were good in spherical shape and narrow distribution of the particle sizes.The
particle diameter was about 114nm , the comprehensive score(S) of the nanosphere was 95.59, the error was 3.66% and the drug content (DL%) was 13.55% by the linearity regression and the three-time-repeated experiments. The drug-releasing rate of the microsphere was slower, while that of the nanosphere could have an abrupt increase, which indicated the latter could have the function of solubilizing the drug.
引文
1 Ogawa Y, Yamaoto M.,Okada H., et al. them Pharm Bull, 1988, 36(3):1095
2 Wada R, Tabata Y, Hyon S.Y., et al. Bull Inst Chem Res, 1988, 66(3):241
3 Wada R , Hyon S., Hyui Ike.O., et al. Poly Mater sci Eng, 1988, 59:803
4 Jalil R, Nixon J.R. J Microencapsulation, 1990, 7:.41
5 Conti B, Pavanetto F, Genta I.J Microencapsulation, 1992, 9(2):153
6 Inoue Y, Kamei S.J Micromol Sci Pure Appl Chem, 1995, A 322:787
7 胡培战，吴兰亭，杨士林．生物医学工程学杂志，1993，10：183
8 Sung Il Moon, Chan Wooiee, Ma Satoshi, et al..Journal of Polymer Science. 2000, 38:1673-1680
9 日本专利，5996123
10 日本专利，63289020
11 日本专利，418096
12 常青．高分子材料科学与工程，1994，1(1)：140
13 沈之荃，孙俊全，吴良江等．化学学报，1990，48：686
14 沈正荣，朱家蕙，马臻．功能高分子学报，1995，8：489
15 中国专利，1 060 851A
16 Das KG. Controlled Release Technology Bioengineering Aspects, New York:John Wiley and Sons, 1983
17 Yolles Segmour, LeafeThomas D., Woodland James H. R., et al. J Pharm Sci, 1975, 64(2):348
18 Yamakawa I .J Pharm Sci, 1990, 79;505
19 Zhang Xc, Mc Auley K B, Goosen M FA.J control Release, 1995, 34(2):175
20 Mariette B, coundane J, Vert M, et al.J control Release, 1993, 24(1-3):237
21 Eein M J. Advance in Drug Delivery Systems. Am Stardam:Elsevier Sci Pub, 1987:225
22 Deasy P B, Finan M.P.,Klatt P.R., et al. Int J Pharmcol , 1993, 89(3):251
23 朱家惠，洗正荣，王芳等．中国药学杂志，1997，32(10)：595
24 Sanders L M, Kent J.S., Mckae G.I, et al. J Pharm Sci, 1984, 73(9):1294
25 Ji zheng and Peter J. Biotechnol. Prog, 1999, 15:763
26 Kukarni RK Moone EG, Hegneli A F, et al.J Biomed Mater Res, 1971,5:169
27 Getter I, Cutright DE, Bhaskar S N, J Oral Surg, 1972,30:344
28 Christel P, Chabot F. lray JL. Biodegradable Composite for Internal Fixation. Biomaterials, 1980, New Yorks, Wiley, 1982:271
29 LE, Marpuis J C, Nob Fred ria A, et al. Biomed. Master. Res, 1993, 27(1):11
30 Kinoshita Y, Kirigakubo M, Kobayashi M, et al. Biomaterials, 1993, 4:729
31 Bostman O M.J Bone Joint Surg, 1991, 73-A:148
32 Suganuma J, Alexander H. J Appl Biomater, 1993, 4:13
33 卓仁禧等．应用化学，1997，14(4)：102
34 Pearce EM. Contemporary Topic in Plymer Science , 1977, 2:251
35 Kricheldorf H R. Macromol Symp, 1996, 103:85
36 姚康德，孙珊，彭涛．智能性药物释放体系[J]．高分子通报，1992，(2)：116
37 Tabata y., Langer R.,Polyanhydride microspheres that display near-constant release of water-soluble model drug compounds[J].Pharm. Res.,1993, 10(3):391
38 Ohya y.,Kobayshi H., Ouchi T., Design of Polyla-malic acid)-5Fu-saccharide conjugate exhibiting antitumor activity[J].Reactive Polym.,1991, 15:153
39 罗毅，范吕烈，卓仁禧．含乙烷雌酚的聚磷酸酯的合成及其抗肿瘤活性研究[J]．高等化学学报，1994，15(7)：1090
40 由英才，鲁才，申玉晖等．聚乳酸的合成及降解的研究[J]．中国生物医学工程学报，1985，4(4)：244
41 敬松．一种新型医用高分子—聚乳酸[J]．四川化工，1994，2：38
42 Masao Matsui(杨革生译，沉新元校)．由聚乳酸制备的可生物降解纤维[J]．产业用纺织品，1997，15：38
43 范吕烈，李兵，刘振华等．D，L—丙交酯与2—氢—2—氧—1，3，2—二氧磷杂环己烷的开环的开环及聚合研究[J]．高等学校化学学报，1995，6(16)：971
44 Baglay E, Song FA. Two Stage Sorption and Desorption of Organic Vapor in Cellulose Acetate [J]. J Am them Soc, 1955,77:2172
45 Thomas N L, Windle Ah, The Modeling of Case Ⅱ Diffusion [J].Polymer ,1980,21:613
46 Thomas NL, Windle AH. A, Theory of Case Ⅱ Diffusion in Polymers [J].Polymer, 1982,23:529
47 Whiteski T P. Traveling wave Solution for Case Ⅱ Diffusion in Polymers [J].J polymer Sci ,Part B, 1996,34:141
48 Carbonel R G, Sarti G C. Continum Merchanics Model of Penetrant Diffusion [J]. Ind Eng Chem Res, 1990,29:1194
49 Tabard Y, Langer R. Polyanhydride Microspheres that Display Near-constant Release of Water-soluable Model Drug Compounds Drug Compounds[J] .Pharm Res, 1993,10(3):391
50 Wood worth J R, DennisS R T, Hinsvark O N, et al.,Bioavailability Evaluation of a Controlled Release Dextromethrophan Liquid [J].J clin Pharmacol, 1987,27:133
51 Iwata M, Mc Ginity Jw, Dissolution ,Stability and Morphological Properties and Multiphase Poly(d,l-lactic-co-glycolic acid)Microspheres Containing Water-soluble Compounds[J].Pharm Res, 1993,10(8):1219
2 Wada R, Tabata Y, Hyon S.Y., et al. Bull Inst Chem Res, 1988, 66(3):241
3 Wada R , Hyon S., Hyui Ike.O., et al. Poly Mater sci Eng, 1988, 59:803
4 Jalil R, Nixon J.R. J Microencapsulation, 1990, 7:.41
5 Conti B, Pavanetto F, Genta I.J Microencapsulation, 1992, 9(2):153
6 Inoue Y, Kamei S.J Micromol Sci Pure Appl Chem, 1995, A 322:787
7 胡培战，吴兰亭，杨士林．生物医学工程学杂志，1993，10：183
8 Sung Il Moon, Chan Wooiee, Ma Satoshi, et al..Journal of Polymer Science. 2000, 38:1673-1680
9 日本专利，5996123
10 日本专利，63289020
11 日本专利，418096
12 常青．高分子材料科学与工程，1994，1(1)：140
13 沈之荃，孙俊全，吴良江等．化学学报，1990，48：686
14 沈正荣，朱家蕙，马臻．功能高分子学报，1995，8：489
15 中国专利，1 060 851A
16 Das KG. Controlled Release Technology Bioengineering Aspects, New York:John Wiley and Sons, 1983
17 Yolles Segmour, LeafeThomas D., Woodland James H. R., et al. J Pharm Sci, 1975, 64(2):348
18 Yamakawa I .J Pharm Sci, 1990, 79;505
19 Zhang Xc, Mc Auley K B, Goosen M FA.J control Release, 1995, 34(2):175
20 Mariette B, coundane J, Vert M, et al.J control Release, 1993, 24(1-3):237
21 Eein M J. Advance in Drug Delivery Systems. Am Stardam:Elsevier Sci Pub, 1987:225
22 Deasy P B, Finan M.P.,Klatt P.R., et al. Int J Pharmcol , 1993, 89(3):251
23 朱家惠，洗正荣，王芳等．中国药学杂志，1997，32(10)：595
24 Sanders L M, Kent J.S., Mckae G.I, et al. J Pharm Sci, 1984, 73(9):1294
25 Ji zheng and Peter J. Biotechnol. Prog, 1999, 15:763
26 Kukarni RK Moone EG, Hegneli A F, et al.J Biomed Mater Res, 1971,5:169
27 Getter I, Cutright DE, Bhaskar S N, J Oral Surg, 1972,30:344
28 Christel P, Chabot F. lray JL. Biodegradable Composite for Internal Fixation. Biomaterials, 1980, New Yorks, Wiley, 1982:271
29 LE, Marpuis J C, Nob Fred ria A, et al. Biomed. Master. Res, 1993, 27(1):11
30 Kinoshita Y, Kirigakubo M, Kobayashi M, et al. Biomaterials, 1993, 4:729
31 Bostman O M.J Bone Joint Surg, 1991, 73-A:148
32 Suganuma J, Alexander H. J Appl Biomater, 1993, 4:13
33 卓仁禧等．应用化学，1997，14(4)：102
34 Pearce EM. Contemporary Topic in Plymer Science , 1977, 2:251
35 Kricheldorf H R. Macromol Symp, 1996, 103:85
36 姚康德，孙珊，彭涛．智能性药物释放体系[J]．高分子通报，1992，(2)：116
37 Tabata y., Langer R.,Polyanhydride microspheres that display near-constant release of water-soluble model drug compounds[J].Pharm. Res.,1993, 10(3):391
38 Ohya y.,Kobayshi H., Ouchi T., Design of Polyla-malic acid)-5Fu-saccharide conjugate exhibiting antitumor activity[J].Reactive Polym.,1991, 15:153
39 罗毅，范吕烈，卓仁禧．含乙烷雌酚的聚磷酸酯的合成及其抗肿瘤活性研究[J]．高等化学学报，1994，15(7)：1090
40 由英才，鲁才，申玉晖等．聚乳酸的合成及降解的研究[J]．中国生物医学工程学报，1985，4(4)：244
41 敬松．一种新型医用高分子—聚乳酸[J]．四川化工，1994，2：38
42 Masao Matsui(杨革生译，沉新元校)．由聚乳酸制备的可生物降解纤维[J]．产业用纺织品，1997，15：38
43 范吕烈，李兵，刘振华等．D，L—丙交酯与2—氢—2—氧—1，3，2—二氧磷杂环己烷的开环的开环及聚合研究[J]．高等学校化学学报，1995，6(16)：971
44 Baglay E, Song FA. Two Stage Sorption and Desorption of Organic Vapor in Cellulose Acetate [J]. J Am them Soc, 1955,77:2172
45 Thomas N L, Windle Ah, The Modeling of Case Ⅱ Diffusion [J].Polymer ,1980,21:613
46 Thomas NL, Windle AH. A, Theory of Case Ⅱ Diffusion in Polymers [J].Polymer, 1982,23:529
47 Whiteski T P. Traveling wave Solution for Case Ⅱ Diffusion in Polymers [J].J polymer Sci ,Part B, 1996,34:141
48 Carbonel R G, Sarti G C. Continum Merchanics Model of Penetrant Diffusion [J]. Ind Eng Chem Res, 1990,29:1194
49 Tabard Y, Langer R. Polyanhydride Microspheres that Display Near-constant Release of Water-soluable Model Drug Compounds Drug Compounds[J] .Pharm Res, 1993,10(3):391
50 Wood worth J R, DennisS R T, Hinsvark O N, et al.,Bioavailability Evaluation of a Controlled Release Dextromethrophan Liquid [J].J clin Pharmacol, 1987,27:133
51 Iwata M, Mc Ginity Jw, Dissolution ,Stability and Morphological Properties and Multiphase Poly(d,l-lactic-co-glycolic acid)Microspheres Containing Water-soluble Compounds[J].Pharm Res, 1993,10(8):1219