聚β-环糊精载药微球的制备及药物释放性能的研究
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摘要
本文以双氯芬酸钠(Diclofenac Sodium, DFS)为模型药物,以β-环糊精为原料,使用三种方法研究制备了载药微球,并对聚β-环糊精微球的溶胀能力和聚β-环糊精微球体外释药行为进行了深入的探讨。
在微球制备方法的研究中,本文首先采用反相乳液聚合技术制备聚β-环糊精微球(β-CDP微球),对β-CDP微球的合成工艺进行了单因素考察和正交实验设计,以微球形态、粒径、产率等作为评价指标,判断各种因素对实验结果的影响,最终优选处方并制备出性质优良的空白微球。实验结果表明,影响粒径的最大因素是搅拌速度,影响产率的最大因素是乳化剂。制备β-CDP微球的最佳工艺条件为:以煤油为油相,环氧氯丙烷(ECH)的用量是n(ECH):n(β-CD)=15:1、交联聚合时间为1.5h、交联温度为30℃、乳化剂用量比为Span80:Tween20=3:1、乳化时间为7h、乳化温度为50℃、搅拌速度为900r/min。优化后的处方工艺重现性良好,制得的微球表面光滑圆整,大小均一,平均粒径为40.45±3.8μm,跨距为1±0.15(n=5)。制成的微球β-CD的含量较高且保留了环糊精自身的结构特点,内部结构疏松成蜂窝状,具有交联三维网状结构;并具有良好的流动性和较高的吸水性。
在确定了空白微球的最佳制备工艺后,本文采用了三种方法制备载药微球。第一种是直接载药法,即在制备微球的过程中将药物直接加入到水相中参与微球的生成而最终载药。第二种是先包合后成球法,即先制成双氯芬酸钠的β-CD包合物,然后按照空白微球的最佳制备工艺将包合物制备成微球。第三种是浸泡载药法,即将制备好的空白微球浸泡到药物溶液中载药。实验结果表明,(1)浸泡法载药的载药率明显高于直接载药法和先包合后成球法; (2)直接载药法和先包合后成球法制备的载药微球表面有药物结晶,而浸泡载药法制备的微球表面没有药物结晶。
在聚合物微球的溶胀性能研究中,通过考察不同条件下的微球溶胀后粒径的变化,得出聚合物微球溶胀速率随着缓冲溶液pH及其浓度的增加而增加。载药率越高,释放速度越快,但在高浓度的缓冲液中,其离子依赖型溶胀机制控制的溶胀速率将受到限制。然后,以扩散定律为基础建立了刻画药物释放的数学模型。同时考虑溶剂渗透引起材料松驰膨胀,在模型中引入描述应力应变关系的弹性体方程并引入溶胀界面数和扩散德伯拉数,来描述聚合物微球吸水和药物释放的过程。
本文采用透析释药法研究微球的体外释药。在本实验中,首先考察了浸泡法制备的双氯芬酸钠-β-CDP微球的释药行为,然后以双氯芬酸钠-β-CDP微球为重点,考察了不同制备方法、释放介质的不同pH值、载药率、粒径、袋内释放介质体积等因素对微球释药的影响。实验结果表明:(1)β-CDP微球对双氯芬酸钠的缓释作用效果明显,可达到24h,说明β-CDP微球网状结构的空腔能够包结双氯芬酸钠药物分子,从而使药物达到缓释的效果。(2)对于双氯芬酸钠-β-CDP微球,不同的体外释放条件对药物释放有明显的影响,其中微球材料本身的性质——粒径,对释药速率的影响最大。
关于微球的体外释药情况,本文首先使用经验和半经验数学模型进行拟合,实验结果表明,对于双氯芬酸钠-β-CDP微球,一级释放方程和Korsmeyer-Peppas模型方程拟合较好,由n值推断,这种药物从β-CDP微球网状结构中的释放以骨架溶蚀和药物扩散为主。然后根据Crank提出的球形释放机理模型,计算出载药微球的有效扩散系数D值。
In this paper, Diclofenac Sodium was chosen as model drug andβ-CD was used as material to prepare drug-β-CDP microspheres(MS). Furthermore, the swelling properties of the polymer microsphere and drug release behavior in vitro and their release mechanism were deeply studied.
In the study of preparation method,β-CDP MS was first prepared by the technique of inverse emulsion polymerization. And the synthesis ofβ-CDP MS was optimized by using the single factor investigation and the orthogonal test to test the effect of various factors on results. The criteria to evaluate the MS included the appearance, particle’s size and yield. Optimal formulation was chosen and MS were formed with good quality. The results showed that the stirring rate and emulsifier mainly affect the particle’s size and yield separately. The test technological conditions were: kerosene as the oil phase, n(ECH):n(β-CD)=15:1, crosslinking time=1.5h, crosslinking temperature=30℃, Span80:Tween20=3:1, emulsion time is 7h, emulsion temperature=50℃, the stirring rate is 900r/min. The repeatability of the technology was precise.β-CDP MS were shape spherical, size equality, regular in morphology, surface smooth, with the mean diameter of 40.45±3.8μm and the span of 1±0.15(n=5). Prepared microsphere reserved the cavity structure ofβ-CD and with a high content of it. Theβ-CDP MS had a unconsolidated, honeycomb, cross-linking three dimensions, reticular internal structure. They also had a good liquidity and high water-absorbent.
After establishment of optimal formulation of synthesizingβ-CDP MS, we prepared drug-β-CDP MS with three methods. One was direct method, and the other one was inclusion compound, the third was infusion method. The experimental results indicate that: first, drug content percent of the infusion method was higher than the direct method and inclusion compound method. Second, drug crystals were seen on the surface of drug-β-CDP MS by the direct method and inclusion compound method.
In the study of the swelling properties of the polymer microsphere, the swelling rate of the polymer microsphere increased with the increasing of the buffer solution pH and its concentration in different conditions. The higher the drug loaded, the faster the drug released, but the swelling speed controlled by ion-dependent swelling mechanism was limited in the high concentration buffer solution. Then, a mathematical model of drug release was established, based on the diffusion law. We applied elastomer equations about stress-strain relationship, De and Sw to describe the water-absorbed of polymer and the drug release process, taking into account the material expansion caused by solvent infiltration.
In the study of drug release from MS in vitro, commonly used dialysis method was studied comprehensively. In this experiment, DFS-β-CDP MS was the key point, and studied the effect of various factors (preparation method, pH of media, solution volume inside the dialytic-bags, drug content percent and particle’s size) on drug release behavior. The experimental results indicate that: first,β-CDP MS had a sustained release effect on DFS, achieving 24h. This indicated that cavity structure ofβ-CDP MS intercalated with drug to make it release slowly; second, for DFS-β-CDP MS, all the factors, especially the particle’s size, had an effect on drug release behavior.
The article also valuated the results of drug release from MS in vitro with two mathematical models. Firstly, empirical and half-empirical mathematical model were used to prove that release of DFS-β-CDP MS according with first-order release and Korsmeyer-Peppas model. The mechanism of drug release was bone solution and diffusion mainly. Secondly, diffusivity (D) was calculated by model of“radial diffusion in a sphere”(Crank).
在微球制备方法的研究中,本文首先采用反相乳液聚合技术制备聚β-环糊精微球(β-CDP微球),对β-CDP微球的合成工艺进行了单因素考察和正交实验设计,以微球形态、粒径、产率等作为评价指标,判断各种因素对实验结果的影响,最终优选处方并制备出性质优良的空白微球。实验结果表明,影响粒径的最大因素是搅拌速度,影响产率的最大因素是乳化剂。制备β-CDP微球的最佳工艺条件为:以煤油为油相,环氧氯丙烷(ECH)的用量是n(ECH):n(β-CD)=15:1、交联聚合时间为1.5h、交联温度为30℃、乳化剂用量比为Span80:Tween20=3:1、乳化时间为7h、乳化温度为50℃、搅拌速度为900r/min。优化后的处方工艺重现性良好,制得的微球表面光滑圆整,大小均一,平均粒径为40.45±3.8μm,跨距为1±0.15(n=5)。制成的微球β-CD的含量较高且保留了环糊精自身的结构特点,内部结构疏松成蜂窝状,具有交联三维网状结构;并具有良好的流动性和较高的吸水性。
在确定了空白微球的最佳制备工艺后,本文采用了三种方法制备载药微球。第一种是直接载药法,即在制备微球的过程中将药物直接加入到水相中参与微球的生成而最终载药。第二种是先包合后成球法,即先制成双氯芬酸钠的β-CD包合物,然后按照空白微球的最佳制备工艺将包合物制备成微球。第三种是浸泡载药法,即将制备好的空白微球浸泡到药物溶液中载药。实验结果表明,(1)浸泡法载药的载药率明显高于直接载药法和先包合后成球法; (2)直接载药法和先包合后成球法制备的载药微球表面有药物结晶,而浸泡载药法制备的微球表面没有药物结晶。
在聚合物微球的溶胀性能研究中,通过考察不同条件下的微球溶胀后粒径的变化,得出聚合物微球溶胀速率随着缓冲溶液pH及其浓度的增加而增加。载药率越高,释放速度越快,但在高浓度的缓冲液中,其离子依赖型溶胀机制控制的溶胀速率将受到限制。然后,以扩散定律为基础建立了刻画药物释放的数学模型。同时考虑溶剂渗透引起材料松驰膨胀,在模型中引入描述应力应变关系的弹性体方程并引入溶胀界面数和扩散德伯拉数,来描述聚合物微球吸水和药物释放的过程。
本文采用透析释药法研究微球的体外释药。在本实验中,首先考察了浸泡法制备的双氯芬酸钠-β-CDP微球的释药行为,然后以双氯芬酸钠-β-CDP微球为重点,考察了不同制备方法、释放介质的不同pH值、载药率、粒径、袋内释放介质体积等因素对微球释药的影响。实验结果表明:(1)β-CDP微球对双氯芬酸钠的缓释作用效果明显,可达到24h,说明β-CDP微球网状结构的空腔能够包结双氯芬酸钠药物分子,从而使药物达到缓释的效果。(2)对于双氯芬酸钠-β-CDP微球,不同的体外释放条件对药物释放有明显的影响,其中微球材料本身的性质——粒径,对释药速率的影响最大。
关于微球的体外释药情况,本文首先使用经验和半经验数学模型进行拟合,实验结果表明,对于双氯芬酸钠-β-CDP微球,一级释放方程和Korsmeyer-Peppas模型方程拟合较好,由n值推断,这种药物从β-CDP微球网状结构中的释放以骨架溶蚀和药物扩散为主。然后根据Crank提出的球形释放机理模型,计算出载药微球的有效扩散系数D值。
In this paper, Diclofenac Sodium was chosen as model drug andβ-CD was used as material to prepare drug-β-CDP microspheres(MS). Furthermore, the swelling properties of the polymer microsphere and drug release behavior in vitro and their release mechanism were deeply studied.
In the study of preparation method,β-CDP MS was first prepared by the technique of inverse emulsion polymerization. And the synthesis ofβ-CDP MS was optimized by using the single factor investigation and the orthogonal test to test the effect of various factors on results. The criteria to evaluate the MS included the appearance, particle’s size and yield. Optimal formulation was chosen and MS were formed with good quality. The results showed that the stirring rate and emulsifier mainly affect the particle’s size and yield separately. The test technological conditions were: kerosene as the oil phase, n(ECH):n(β-CD)=15:1, crosslinking time=1.5h, crosslinking temperature=30℃, Span80:Tween20=3:1, emulsion time is 7h, emulsion temperature=50℃, the stirring rate is 900r/min. The repeatability of the technology was precise.β-CDP MS were shape spherical, size equality, regular in morphology, surface smooth, with the mean diameter of 40.45±3.8μm and the span of 1±0.15(n=5). Prepared microsphere reserved the cavity structure ofβ-CD and with a high content of it. Theβ-CDP MS had a unconsolidated, honeycomb, cross-linking three dimensions, reticular internal structure. They also had a good liquidity and high water-absorbent.
After establishment of optimal formulation of synthesizingβ-CDP MS, we prepared drug-β-CDP MS with three methods. One was direct method, and the other one was inclusion compound, the third was infusion method. The experimental results indicate that: first, drug content percent of the infusion method was higher than the direct method and inclusion compound method. Second, drug crystals were seen on the surface of drug-β-CDP MS by the direct method and inclusion compound method.
In the study of the swelling properties of the polymer microsphere, the swelling rate of the polymer microsphere increased with the increasing of the buffer solution pH and its concentration in different conditions. The higher the drug loaded, the faster the drug released, but the swelling speed controlled by ion-dependent swelling mechanism was limited in the high concentration buffer solution. Then, a mathematical model of drug release was established, based on the diffusion law. We applied elastomer equations about stress-strain relationship, De and Sw to describe the water-absorbed of polymer and the drug release process, taking into account the material expansion caused by solvent infiltration.
In the study of drug release from MS in vitro, commonly used dialysis method was studied comprehensively. In this experiment, DFS-β-CDP MS was the key point, and studied the effect of various factors (preparation method, pH of media, solution volume inside the dialytic-bags, drug content percent and particle’s size) on drug release behavior. The experimental results indicate that: first,β-CDP MS had a sustained release effect on DFS, achieving 24h. This indicated that cavity structure ofβ-CDP MS intercalated with drug to make it release slowly; second, for DFS-β-CDP MS, all the factors, especially the particle’s size, had an effect on drug release behavior.
The article also valuated the results of drug release from MS in vitro with two mathematical models. Firstly, empirical and half-empirical mathematical model were used to prove that release of DFS-β-CDP MS according with first-order release and Korsmeyer-Peppas model. The mechanism of drug release was bone solution and diffusion mainly. Secondly, diffusivity (D) was calculated by model of“radial diffusion in a sphere”(Crank).
引文
[1]崔福德药剂学.人民卫生出版,第五版,制剂新技术.
[2]张强,武鳯兰主编.药剂学.北京大学医学出版社,最新版,385.
[3]陆冬梅,罗志刚,杨连生,高群玉.环糊精模拟酶的研究进展.粮油食品科技,2005,13(4):27～28.
[4] Mark E. Davis,Marcus E. Brewster. Cyclodextrin-baesd pharmaceutics:past,present ,future. Nature,Drug discovery, 2004.12,(3):1023~1035.
[5]肖学文,廖双泉,廖建和,杨晓红.环糊精聚合物的结构与应用.热带农业科学,2004,24(2):73～77.
[6]童林荟.环糊精化学——基础与应用.科学出版社,2001年3月,第一版,20.
[7] Harada A , Li J , Kamachi M. Preparation of tubular polymers from cyclodextrin.Pure & Appl Chem,1995,32:813~819.
[8] Frank, S G:J Pharm Sci,64(10):1585～1975.
[9]李文德,周俊侠,张力田,Harold Corke.环糊精的发展与改性研究.山西食品工业,1996,第一期,10~15.
[10]李明时,裘利言.β-环糊精的化学修饰及其应用.金陵石油化工,1996,46
[11] S. Kobayashi, K. Kainuma, J. Jpn. Soc. Starch Sci.,1981, 28(2),132.
[12]程池.歧化环糊精的研究进展[J].食品与发酵工业,1992,18(3)L:77～80.
[13]李文德,周俊侠,张力田,环糊精的发展与改性研究山西食品工业1996,第一期,10～15.
[14]吴剑峰.环糊精及其衍生物在药学领域的应用[J].时珍国医国药,2004,15(3):181~182.
[15]冯波,高红旺,许英爱等.地尔硫卓-乙基化β-环糊精包合物的释放度测定.第四军医大学吉林军医学院学报,2003,25(2):76～78.
[16]高申.现代药物新剂型新技术[M].北京:人民军医出版社, 2002,90.
[17] Loftsson T, Masson M, Brewster ME. Self2association of cyclodextrins and cyclodextrin complexes [J]. J Pharm Sci ,2004 ,93 (5)∶1091~1099.
[18] Kopecky F, Kopecka B, Kaclik P. Dissolution of mimodipine in an aqueous solution of hydroxyethyl-beta-cyclodextrin and a review of solubility of nimodipine with cyclodextrins[J]. Ceska Slov Farm, 2003, 52 (1) : 33~38.
[19] Linares MS, Longhi MR. Effects of hydroxyp ropylbetacyclodextrin on the chemical stability of a naphthoquinone in aqueous solutions [J]. Pharmazie, 2003, 58 (l) :32~37.
[20] Mohsen AB, Khalid AA. Effect of inclusion comp lexation with cyclodextrins on photostability of nifedip in einsolid state [J]. International Journal of Pharmaceutics,2002, 243 (1) : 107~117.
[21] Kim JH, Lee SK, KiMH, et al.Development of parenteral formulation for a novel angiogenesis inhibitor, CKD - 732 throughcomp lexation with hydroxyp ropyl - beta - cyclodextrin1 Int J Pharm, 2004, 272 (1-2) : 79~89.
[22] Puglisi G, Venture C A, Spadaro A, et al.Difierential efiects of modinedβ-CD on pharmacological activity and bioavailability of 4 - biphenylacetic acid in rats after oral administration.J Pharm Pharmacol, 1995, 47: 120.
[23]黎洪珊,王培玉.β-环糊精衍生物的研究进展及在药剂学上的应用[J].中国药学杂志, 1999, 34 (4) : 220 ~ 223.
[24] Zuo Z, Tam YK. Hydroxyp ropyl-beta-cyclodextrin-flutamide inclusion comp lex [J]. J Pharm Pharm Sci. , 2002, 5 (3) : 292 ~ 298.
[25] Fathy M, Sheha M. In vitro and in vivo evaluation of anamy lobarbitone /hydroxyp ropyl-beta-cyclodextrin com.p lex p repared by a freeze-drying method [J]. Pharmaz2ie, 2000, 55 (7) : 513 ~517.
[26] Matsubara K, Abe K, Irie T, et al.Imp rovement of nasal biovailabilny of buserelin by cycoldextrin derivatives in rats.J PharmSci, 1995, 84 (11) : 1295
[27]黎洪珊,王培玉.β-环糊精衍生物的研究进展及在药剂学上的应用[J].中国药学杂志, 1999, 34 (4) : 220 ~223.
[28] Piel G, Evrard B , Van Hees T, et al . Comparison of the IV pharmacokinetics in sheep of miconazole2cyclodextrin solutions and amicellar solution [J] . Int J Pharm ,1999 ,180 (1)∶41~45.
[29] Stella VJ ,Rao VM, Zannou EA , et al . Mechanisms of drug release from cyclodextrin complexes [J] . Adv Drug Deliv Rev ,1999 ,36 (1)∶3~16.
[30] Nagase Y,Arima H , Wada K, et al . Inhibitory effect of sulfobutyl ether beta-cyclodextrin on DY29760e-induced cellular damage : In vitro and in vivo studies [J] . J Pharm Sci ,2003 ,92 (12)∶2466 ~2474.
[31] Partyka M, Au BH , Evans CH. Cyclodextrins as phototoxicity inhibitors in drug formulations : studies on model systems involving naproxen and beta-cyclodextrin [J] . J Photoch Photobio A ,2001 ,140(1)∶67 ~74.
[32]陆彬.药物新剂型与新技术[M].北京:人民卫生出版社,1998.36~38
[33]何伟,丛竹凤,李勇.胃舒颗粒中莪术挥发油的提取及β-环糊精包合物的制备研究.中药新药与临床药理, 2004, 15(1) : 56.
[34]王守愚,徐淑卿,史公良,王丹.β-环糊精包合连翘挥发油的工艺研究.中成药, 2006, 28 (6) : 908.
[35]庞承新,梁艳,杨枰.樟树子油β-环糊精包合物的制备工艺研究,广西师范学院学报(自然科学版) , 2007, 24 (1) .
[36]易延逵,陈志良.环糊精包合中药复方中挥发性成分研究,南方医科大学学报.2006, 9: 1337.
[37] SkibaM, Puisieux F,Duchene D, et al1Direct imaging of modifiedβ- CD nanospheres by photon scanning tuneling and scanning forcemicroscopy. [J] Pharm, 1995, 120 (1): 11
[38] SkibaM,Morvan C,DucheneD, et al.Evaluation of gastrointestinal behavior in the rat of amphiphilicβ-CD nanocap sules,loaded with indomethacin. Int J Pharm, 1995, 126: 275.
[39] Freville J C,Dollo G Corre P L, et al.Controlled systemic absordtion and increased anesthetic effect of bup ivacaine followingep idural administration of bup ivacaine HP -β- CD comp lex.Pharm Res, 1996, 13 (10) : 1576.
[40] Cheng JJ , Khin KT, Davis ME. Antitumor activity of beta-cyclodextrin polymer-camptothecin conjugates [J]. Mol Pharm ,2004 ,1 (3):183~193.
[41] Kamada M,Hirayama F,Udo K, et al . Cyclodextrin conjugate-based controlled release system: repeatedand prolonged releases of ketoprofen after oral administration in rats [J]. J Controlled Release ,2002 ,82 (223):407~ 416.
[42]唐晓荞,刘宏,杨祥良.双亲性环糊精纳米粒的制备和应用[J] .中国医药工业杂志,2003 ,34 (11) :586
[43] Duchene D , Ponchel G, Boudad H , et al. Use of cyclodextrins in the formulation of polyalkylcyanoacrylate nanoparticles charged with different active ingredients [J] . Ann Phar Fr , 2001 , 59 (6) : 384
[44]谢伯泰,杨国武,谢薇梅.羟丙基-β-环糊精特性及其在医药领域中的应用与安全性[J] .国外医药合成药、生化药、制剂分册,2002 ,23 (5) :302
[45] Brewter ME , Estes K, Loftsson T , et a1. Improved delivery through biological membrances XXXI : solubilization and stabillzation of an estadiol chemical delivery system by modified cyclodextrins [J] . J Pharm Sci , 1988 , 77 : 981
[46] Shinoda T , Maeda A , Kagatani S , et al. Specific interaction between galactose branched - cyclodextrins and hepatocytes in vitro [J] .Int J Pharm ,1998 ,167:147
[47]仇毓东,陈汉,沈锋,等.β-环糊精14硫酸酯选择性抑制微血管内皮细胞增殖的研究[J] .中华实验外科杂志,2000 ,17 (2) :165
[48] Masson M , Loftsson T , Masson G, et al. Cyclodextrins as permeation enhancers : some theoretical evaluations and in vit ro testing [J] . J Control Release , 1999 , 59 (1) :107
[49]方世平,杨宝玉.药剂学促进透皮吸收技术的机制[J] .中国医院药学杂志,2000 ,20 (12) :750
[50]夏金兰,蒋海明,聂珍媛.透皮给药制剂研究[J] .中南工业大学学报自然科学版,2003 ,34 (5) :494
[51] Babu R J , Pandit J K. Effect of cyclodextrins on the complexation and transdermal delivery of bupranolol through ratskin [J] . J Pharm. , 2004 , 271 (1 - 2) : 155
[52]张建宝.环糊精在医药领域中的新应用[J] .国外医药合成药、生化药、制剂分册,1992 ,13 (6) :350
[53] Lric T , Abe K, Uekama K. Enhanced nasal delivery of luteinizing hormone releasing hormone agonist buserelin by oleic acid solubilized and stabilized in hydroxypropyl -βcyclodextrin [J] . Chem Pharm Bull , 1995 , 43 ( 12 ) :2232
[54]赵晓斌(Zhao X B) ,何炳林(He B L ) ,离子交换与吸附( Ion Exchange and Adsorption) , 1994, 10 (5) ,472~ 478.
[55] Solms J, Egli R H, H elv. Chim. Acta, 1965, 48, 1225~1228.
[56]黄乃聚(Huang N J ) ,尤晨(You C) ,章道道(Zhang D D) ,有机化学(Chinese Journal of Organic Chemistry ) , 1987, (6) , 482~488.
[57] RuebnerA, et al.Synthesis of a linear polymer with pendent gammacyclodextrins. Macromol Chem Phys, 2000, 201: 1185.
[58] Chen SP, et al. Study onβ-cyclodextrin grafting with chitosan and slow release of its inclusion complex with radioactive iodine. J App. Polym Sci, 2001, 82:2414.
[59]刘琼,范晓东.功能高分子学报,2001,14:279~282.
[60]赵晓斌,何炳林.离子交换与吸附,1994,4:472 ~478
[61]李英杰,韩家军.以β-环糊精树脂为载体提纯肌醇的研究.吉林大学自然科学学报,2001(2):99～102
[62] Chino M, Kasama T, Noguchi Y, et a1. Sustmned-release of drugs from cyclodextrin-containing hydrogels. Proceedings of the International Symposium on Controlled Release of Bioactive Materials 19,Orlan do,1992,98~99.
[63] Watanabe J,Ooya T,Yui N.Chem Lett,1998,1031~1032.
[64]刘琼,范晓东.高分子通报,2002,5:41~48.
[65]李英杰,张文治,韩家军.分子科学学报,2001,17(2):105~108.
[66]董方言.现代实用中药新剂型新技术.北京:人民卫生出版社,2001.
[67] Longo W, Iwata H , Lindheimer T ,et al. Preparation of hydrophilicalbumin using polymeric dispersing agents. J Pharm Sci ,1982 ,71 :1323.
[68]陆彬,张景.肺靶向卡铂明胶微球的药物动力学和体内分布研究.中国医药工业杂志,2001 ,32 :251~253.
[69] Wang YM ,Sato H ,Adachi I ,et al. Preparationand characterizationof poly(lactic -glycolic acid) microspheres for targeted delivery of a novel anticancer agent ,taxol,Chem Pharm Bull ,1996 ,44(10) :1935.
[70] Hayashi Y, Yoshioka S ,Aso Y1Entrapment of protein in poly (L- lactide) microspheres using reversed micelle solvent evaporation ,Pharm Res ,1994 ,11 (2) :337~340.
[71] Park TG,Lee HY,Nam YS1A new preparation method for protein loaded poly (D - L - lactic - co - glycolic acid) microspheres and protein release mechanism study.[J] Controlled Release ,1998 ,55 (23) :181-191.
[72] TAN Zai-You, LIAO Qing-Jiang, Robin Y Xiao, Deniel Q. G. So.Characteristics of Epristeride Microspheres with TwoEmulsifying Preparation Methods.Journal of China Pharmaceutical University,2003,34 (4):309～312.
[73] McGee J P ,Davi SSS ,O′Hagan DT1Zero order release of protein from poly (D ,L - lactic - co - glycolide) microparticles preparedusing a modified phase separation technique[J] Controlled Release ,1995 ,34 (2) :77~86.
[74] Wang N , Wu XS. A novel approach to stabilization of protein drugs in poly (lactide2co2glycolic acid) microspheres using agarose hydrogel.[J] Pharm ,1998 ,166 (1) :1~14.
[75]尤国庆,邢春方.谈肝癌的介入疗法[J].中国医药导报。2006,3(17):55.56.
[76] Yamamoto K,TanakaY.Rlldio flequeney capacitive hyperthermia for unsechepatic cancers[J].J Gastroenerol,1997,32(3):361～366.
[77]马光辉,苏志国.高分子微球材料[M].北京:化学工业出版社,2OO5,267.
[78]马秀玲,黄丽梅,郑思宁等.磁性微球的制备及研究进展[J].广州化学,2003,28(3):58～64.
[79]马骚骚,封兴华.微球制剂的给药途径及在医学康复的应用进展[J].中国临床康复,2OO3,7(1):110～115.
[80]周友中,李锐,林佳洁.恩诺沙星肺靶向微球的研究[J].中国兽医杂志,2OO6,42(4):60～62.
[81]钟延强,任常顺,王春燕,等.关节腔内注射用氟比洛芬明胶微球[J].药学学报,1999,34(7):543～546.
[82] Ugwoke M I,AgI R U,Verbeke N,et a1.Nasal mucoadhesivearug delivery:background, application ,trends and future perspectives[J].Adv DrugDelive Rev,2OO5,57(11):1640～1665.
[83] Gavini E,Hegge A B,Rassu G,et a1.Nasal administration of carbsmazepine using chitosan microspheres:in vitro/in vivo studies[J]. J Pharm,2006,307(1):9～15.
[84] Yildiz A,Oi,yar A,Baktir G,et a1.Nasal administration of heparin-loaded microspheres based on poly(1actic acid)[J].Farmaco(erat),2005,60(11～l2):919～924.
[85] Genta I,Conti B,Perugini P,et a1.Bioadhesive microspheres for ophthalmic administration of acydovir[J].J Pharm Pharmacol,1997,49(8):737～742.
[86] Vyas S P,Jain C P.Bioadhesive poly-grafted starch microspheres bearing isosorbide dinitrate for buccal administration [J].J Microencapsul,1992,9(4):457～464.
[87]高萍,丁平田,陈大为.注射用长效微球体外释放特性的研究进展[J].中南药学,2OO4,3(2):105～108.
[88]田成华,司天梅,舒良.第一个长效非典型抗精神病药:注射用利培酮微球[J].中国新药与临床杂志,2OO4,23(1O):723.725.
[89] Le Guevello P,Le Cone P,Chevanne F,et a1.High-performance liquid ehramatolgaphic determination of bupivaeaine in plasma samples for biopharmaceutical studies in application to seven other local anaes thetics[J].J Chromatogr,1993,622(2):284～90.
[90]王亚敏,石庭.微球制剂药物控释研究进展.中国药学,1996,31(3):131～134
[91]王伟,杨永新,李岩.微球的释药特性研究[J].西北药学杂志,2OO4,19(3):138～139.
[92]王襄平,梅兴国.多肽及蛋白类药物微球包封率和释放的研究进展[J].国外医学药学分册,2OO6,33(3):219～223.
[93]何应,魏树礼.破伤风类毒素聚乳酸微球的制备工艺研究[J].北京医科大学学报,2OOO,31(3):239～243
[94]张洪涛,黄锦霞.乳液聚合新技术及应用.化学工业出版社,2007年1月,第一版,102.
[95]曹同玉,刘庆普,胡金生.聚合物乳液合成原理性能及应用[M]北京:化学工业出版社,1999:15~25.
[96]杜定准,汪月生,徐文英.1H NMR研究β-环糊精与环氧氯丙烷共聚物的反应机理和分子链结构.波谱学杂质,1992,9(2):121~129.
[97]吴文娟,郑敦胜,蔡诗填,黄远铿β-环糊精聚合物微球的合成及药物控释行为的研究中药材2007,30(3), 329~331
[98] Baille W E, Huang W Q, Nichifor M, Zhu X X. [J]. J. Macromol. Sci. Pure Appl.Chem, 2000, A37 (7):677～690.
[99]严春美,刘郁杨,范晓东.β-环糊精球的制备及其药物控释行为研究.化工新型材料,2004,32(6):39~42.
[100]Mark E. Davis, Marcus E. Brewster.Cyclodextrin-baesd pharmaceutics:past, present, future.Nature,Drug discovery, 2004.12,(3):1023~1035.
[101]黄一平,贾晓斌.藏药学域抗风湿胶囊成型工艺的研究.第四届全国药用辅料与中药制剂新技术应用研讨会(资料汇编),2007.
[102]曹春林.中药药剂学[M].上海:上海科学技术出版社,1986:291.
[103]刘郁杨.用于新型抗癌药物定向控制释放的高分子载体的合成与表征.西北工业大学博士学位论文,2003年.
[104]杜定准,汪月生,徐文英.1H NMR研究β-环糊精与环氧氯丙烷共聚物的反应机理和分子链结构.波谱学杂质,1992,9(2):121~129.
[105] Anderson JM,Shiver MS.Biodegradation and biocompatibility of PLA and PLGA microsphere[J].A dv Drug Deliv Rev,1997,28(11):5~24
[106]谷福根,柳翠敬.双氯芬酸钠-β-环糊精包合物的研制.中国药学杂志,1998,33(3):153.
[107]杨瑞芹,陈尔凡,杨春艳等. MMA-AA共聚物的合成及其玻璃化温度(Tg)的测定.沈阳化工学院学报.1998,12(4):282~6.
[108]王晓明.聚β-环糊精缓释微球的制备、结构表征及其释药性能的研究.广东药学院硕士学位论文.2007年.
[109] tella V J, et al. J Pharm Res, 1997, 14:556. ibby D C, et al. Int J Pharm,2000,197:1.
[110] ee Y B, et al. Pharm Res, 1991,8:531.
[111] Bae YH,et a1“.On-of”thermocontrol of solute transport.I.Temperature dependence of swelling of N-isopro phylaerylamide networks modified with hydrophobic com-ponents in water.Pharm Res,1991,8:531.
[112] Unsal E,Camli S T,Tuncel A.[J].Journal of Applied Polymer Science,2004,92:607~618.
[113]徐晖,丁平田,郑俊民.聚合物系统中药物的非扩散控制释放.药学学报.2000,35(9):710～740.
[114]李希明,刘成杰,陈文明,高分子学报,1989,5:519
[115] Ritger PL ,Peppas NA.A simple equation for description of solute release.Ⅱ.Fickian and anamalous release from swellable devices.J Controlled Release,1987.5(1):37～42
[116] Peppas NA.Relea.~ of bioative agents from swellable polymers.Anderson JM,Kim SW.Recent advances in drug delivery system.New York and London:Plenum Press.1984.279～290
[117] Hariharan D,Peppas NA.Modeling of water transport and solute release in physiologically sensitive gels.J Controlled Release.1993.23(2):123～136
[118]李凌冰,徐明瑜.溶剂在玻璃状高分子材料中非Fick扩散机理的研究.中国生物医学工程学报.1999.4:441～450.
[119] Cohen DS,Erneux T.Free boundary problems in controlled release pharmaceuticals.SIAM Appl Math,1988.48(6)1466～1469
[120]潘吉铮.聚乳酸微球载体的结构与控释性能关系及模型.华南理工大学博士论文,2004年.
[121]中国药典,2005版,附录XI XD缓释、控释制剂指导原则
[122] Mulye, N. V., Turco, S. J., A simple model based on first order kinetics to explain release of highly water soluble drugs from porous dicalcium phosphate dehydrate matrices, Drug Dev. Ind. Pharm., 21, 943~953.
[123] Higuchi, T., Rate of release of medicaments from ointment bases containing drugs in suspensions, J. Pharm. Sci., 1961,50,874~75.
[124] Chandrasekaran SK, Paul DR. Dissolution-controlled transport from dispersed matrixes[J]J Pharm Sci, 1982, 71(12):1339~402.
[125] Zheng JM, Yang L, He YQ. A simplified expression for a diffusion-dissolution controlled release of drug from matrix in TDDS[J].J Chin Pharm Sci (in Chinese), 1995, 4(3):125~9.
[126] John W. Skoug, Martin V. Mikelsons, Cynthia N,et al. Qualitative evaluation of the mechanism of release of matrix sustained release dosage forms by measurement ofpolymer release. Journal of Controlled Release, 1993(27):227~245.
[127] Peppas NA. Release of bioactive agents from swellable polymers[A].Anderson JM, Kim SW. Recent Advances in Drug Delivery Systems[M]. New York and London: Plenum Press, 1984.279~90.
[128] Jean-maurice vergnaud. Controlled drug release of oral dosageforms.Ellis Horwood Limited, 1993:59~69.
[129] Crank, J The mathematics of diffusion, ED.Carendon.Carendon press,1975 Oxford, U.K.
[2]张强,武鳯兰主编.药剂学.北京大学医学出版社,最新版,385.
[3]陆冬梅,罗志刚,杨连生,高群玉.环糊精模拟酶的研究进展.粮油食品科技,2005,13(4):27～28.
[4] Mark E. Davis,Marcus E. Brewster. Cyclodextrin-baesd pharmaceutics:past,present ,future. Nature,Drug discovery, 2004.12,(3):1023~1035.
[5]肖学文,廖双泉,廖建和,杨晓红.环糊精聚合物的结构与应用.热带农业科学,2004,24(2):73～77.
[6]童林荟.环糊精化学——基础与应用.科学出版社,2001年3月,第一版,20.
[7] Harada A , Li J , Kamachi M. Preparation of tubular polymers from cyclodextrin.Pure & Appl Chem,1995,32:813~819.
[8] Frank, S G:J Pharm Sci,64(10):1585～1975.
[9]李文德,周俊侠,张力田,Harold Corke.环糊精的发展与改性研究.山西食品工业,1996,第一期,10~15.
[10]李明时,裘利言.β-环糊精的化学修饰及其应用.金陵石油化工,1996,46
[11] S. Kobayashi, K. Kainuma, J. Jpn. Soc. Starch Sci.,1981, 28(2),132.
[12]程池.歧化环糊精的研究进展[J].食品与发酵工业,1992,18(3)L:77～80.
[13]李文德,周俊侠,张力田,环糊精的发展与改性研究山西食品工业1996,第一期,10～15.
[14]吴剑峰.环糊精及其衍生物在药学领域的应用[J].时珍国医国药,2004,15(3):181~182.
[15]冯波,高红旺,许英爱等.地尔硫卓-乙基化β-环糊精包合物的释放度测定.第四军医大学吉林军医学院学报,2003,25(2):76～78.
[16]高申.现代药物新剂型新技术[M].北京:人民军医出版社, 2002,90.
[17] Loftsson T, Masson M, Brewster ME. Self2association of cyclodextrins and cyclodextrin complexes [J]. J Pharm Sci ,2004 ,93 (5)∶1091~1099.
[18] Kopecky F, Kopecka B, Kaclik P. Dissolution of mimodipine in an aqueous solution of hydroxyethyl-beta-cyclodextrin and a review of solubility of nimodipine with cyclodextrins[J]. Ceska Slov Farm, 2003, 52 (1) : 33~38.
[19] Linares MS, Longhi MR. Effects of hydroxyp ropylbetacyclodextrin on the chemical stability of a naphthoquinone in aqueous solutions [J]. Pharmazie, 2003, 58 (l) :32~37.
[20] Mohsen AB, Khalid AA. Effect of inclusion comp lexation with cyclodextrins on photostability of nifedip in einsolid state [J]. International Journal of Pharmaceutics,2002, 243 (1) : 107~117.
[21] Kim JH, Lee SK, KiMH, et al.Development of parenteral formulation for a novel angiogenesis inhibitor, CKD - 732 throughcomp lexation with hydroxyp ropyl - beta - cyclodextrin1 Int J Pharm, 2004, 272 (1-2) : 79~89.
[22] Puglisi G, Venture C A, Spadaro A, et al.Difierential efiects of modinedβ-CD on pharmacological activity and bioavailability of 4 - biphenylacetic acid in rats after oral administration.J Pharm Pharmacol, 1995, 47: 120.
[23]黎洪珊,王培玉.β-环糊精衍生物的研究进展及在药剂学上的应用[J].中国药学杂志, 1999, 34 (4) : 220 ~ 223.
[24] Zuo Z, Tam YK. Hydroxyp ropyl-beta-cyclodextrin-flutamide inclusion comp lex [J]. J Pharm Pharm Sci. , 2002, 5 (3) : 292 ~ 298.
[25] Fathy M, Sheha M. In vitro and in vivo evaluation of anamy lobarbitone /hydroxyp ropyl-beta-cyclodextrin com.p lex p repared by a freeze-drying method [J]. Pharmaz2ie, 2000, 55 (7) : 513 ~517.
[26] Matsubara K, Abe K, Irie T, et al.Imp rovement of nasal biovailabilny of buserelin by cycoldextrin derivatives in rats.J PharmSci, 1995, 84 (11) : 1295
[27]黎洪珊,王培玉.β-环糊精衍生物的研究进展及在药剂学上的应用[J].中国药学杂志, 1999, 34 (4) : 220 ~223.
[28] Piel G, Evrard B , Van Hees T, et al . Comparison of the IV pharmacokinetics in sheep of miconazole2cyclodextrin solutions and amicellar solution [J] . Int J Pharm ,1999 ,180 (1)∶41~45.
[29] Stella VJ ,Rao VM, Zannou EA , et al . Mechanisms of drug release from cyclodextrin complexes [J] . Adv Drug Deliv Rev ,1999 ,36 (1)∶3~16.
[30] Nagase Y,Arima H , Wada K, et al . Inhibitory effect of sulfobutyl ether beta-cyclodextrin on DY29760e-induced cellular damage : In vitro and in vivo studies [J] . J Pharm Sci ,2003 ,92 (12)∶2466 ~2474.
[31] Partyka M, Au BH , Evans CH. Cyclodextrins as phototoxicity inhibitors in drug formulations : studies on model systems involving naproxen and beta-cyclodextrin [J] . J Photoch Photobio A ,2001 ,140(1)∶67 ~74.
[32]陆彬.药物新剂型与新技术[M].北京:人民卫生出版社,1998.36~38
[33]何伟,丛竹凤,李勇.胃舒颗粒中莪术挥发油的提取及β-环糊精包合物的制备研究.中药新药与临床药理, 2004, 15(1) : 56.
[34]王守愚,徐淑卿,史公良,王丹.β-环糊精包合连翘挥发油的工艺研究.中成药, 2006, 28 (6) : 908.
[35]庞承新,梁艳,杨枰.樟树子油β-环糊精包合物的制备工艺研究,广西师范学院学报(自然科学版) , 2007, 24 (1) .
[36]易延逵,陈志良.环糊精包合中药复方中挥发性成分研究,南方医科大学学报.2006, 9: 1337.
[37] SkibaM, Puisieux F,Duchene D, et al1Direct imaging of modifiedβ- CD nanospheres by photon scanning tuneling and scanning forcemicroscopy. [J] Pharm, 1995, 120 (1): 11
[38] SkibaM,Morvan C,DucheneD, et al.Evaluation of gastrointestinal behavior in the rat of amphiphilicβ-CD nanocap sules,loaded with indomethacin. Int J Pharm, 1995, 126: 275.
[39] Freville J C,Dollo G Corre P L, et al.Controlled systemic absordtion and increased anesthetic effect of bup ivacaine followingep idural administration of bup ivacaine HP -β- CD comp lex.Pharm Res, 1996, 13 (10) : 1576.
[40] Cheng JJ , Khin KT, Davis ME. Antitumor activity of beta-cyclodextrin polymer-camptothecin conjugates [J]. Mol Pharm ,2004 ,1 (3):183~193.
[41] Kamada M,Hirayama F,Udo K, et al . Cyclodextrin conjugate-based controlled release system: repeatedand prolonged releases of ketoprofen after oral administration in rats [J]. J Controlled Release ,2002 ,82 (223):407~ 416.
[42]唐晓荞,刘宏,杨祥良.双亲性环糊精纳米粒的制备和应用[J] .中国医药工业杂志,2003 ,34 (11) :586
[43] Duchene D , Ponchel G, Boudad H , et al. Use of cyclodextrins in the formulation of polyalkylcyanoacrylate nanoparticles charged with different active ingredients [J] . Ann Phar Fr , 2001 , 59 (6) : 384
[44]谢伯泰,杨国武,谢薇梅.羟丙基-β-环糊精特性及其在医药领域中的应用与安全性[J] .国外医药合成药、生化药、制剂分册,2002 ,23 (5) :302
[45] Brewter ME , Estes K, Loftsson T , et a1. Improved delivery through biological membrances XXXI : solubilization and stabillzation of an estadiol chemical delivery system by modified cyclodextrins [J] . J Pharm Sci , 1988 , 77 : 981
[46] Shinoda T , Maeda A , Kagatani S , et al. Specific interaction between galactose branched - cyclodextrins and hepatocytes in vitro [J] .Int J Pharm ,1998 ,167:147
[47]仇毓东,陈汉,沈锋,等.β-环糊精14硫酸酯选择性抑制微血管内皮细胞增殖的研究[J] .中华实验外科杂志,2000 ,17 (2) :165
[48] Masson M , Loftsson T , Masson G, et al. Cyclodextrins as permeation enhancers : some theoretical evaluations and in vit ro testing [J] . J Control Release , 1999 , 59 (1) :107
[49]方世平,杨宝玉.药剂学促进透皮吸收技术的机制[J] .中国医院药学杂志,2000 ,20 (12) :750
[50]夏金兰,蒋海明,聂珍媛.透皮给药制剂研究[J] .中南工业大学学报自然科学版,2003 ,34 (5) :494
[51] Babu R J , Pandit J K. Effect of cyclodextrins on the complexation and transdermal delivery of bupranolol through ratskin [J] . J Pharm. , 2004 , 271 (1 - 2) : 155
[52]张建宝.环糊精在医药领域中的新应用[J] .国外医药合成药、生化药、制剂分册,1992 ,13 (6) :350
[53] Lric T , Abe K, Uekama K. Enhanced nasal delivery of luteinizing hormone releasing hormone agonist buserelin by oleic acid solubilized and stabilized in hydroxypropyl -βcyclodextrin [J] . Chem Pharm Bull , 1995 , 43 ( 12 ) :2232
[54]赵晓斌(Zhao X B) ,何炳林(He B L ) ,离子交换与吸附( Ion Exchange and Adsorption) , 1994, 10 (5) ,472~ 478.
[55] Solms J, Egli R H, H elv. Chim. Acta, 1965, 48, 1225~1228.
[56]黄乃聚(Huang N J ) ,尤晨(You C) ,章道道(Zhang D D) ,有机化学(Chinese Journal of Organic Chemistry ) , 1987, (6) , 482~488.
[57] RuebnerA, et al.Synthesis of a linear polymer with pendent gammacyclodextrins. Macromol Chem Phys, 2000, 201: 1185.
[58] Chen SP, et al. Study onβ-cyclodextrin grafting with chitosan and slow release of its inclusion complex with radioactive iodine. J App. Polym Sci, 2001, 82:2414.
[59]刘琼,范晓东.功能高分子学报,2001,14:279~282.
[60]赵晓斌,何炳林.离子交换与吸附,1994,4:472 ~478
[61]李英杰,韩家军.以β-环糊精树脂为载体提纯肌醇的研究.吉林大学自然科学学报,2001(2):99～102
[62] Chino M, Kasama T, Noguchi Y, et a1. Sustmned-release of drugs from cyclodextrin-containing hydrogels. Proceedings of the International Symposium on Controlled Release of Bioactive Materials 19,Orlan do,1992,98~99.
[63] Watanabe J,Ooya T,Yui N.Chem Lett,1998,1031~1032.
[64]刘琼,范晓东.高分子通报,2002,5:41~48.
[65]李英杰,张文治,韩家军.分子科学学报,2001,17(2):105~108.
[66]董方言.现代实用中药新剂型新技术.北京:人民卫生出版社,2001.
[67] Longo W, Iwata H , Lindheimer T ,et al. Preparation of hydrophilicalbumin using polymeric dispersing agents. J Pharm Sci ,1982 ,71 :1323.
[68]陆彬,张景.肺靶向卡铂明胶微球的药物动力学和体内分布研究.中国医药工业杂志,2001 ,32 :251~253.
[69] Wang YM ,Sato H ,Adachi I ,et al. Preparationand characterizationof poly(lactic -glycolic acid) microspheres for targeted delivery of a novel anticancer agent ,taxol,Chem Pharm Bull ,1996 ,44(10) :1935.
[70] Hayashi Y, Yoshioka S ,Aso Y1Entrapment of protein in poly (L- lactide) microspheres using reversed micelle solvent evaporation ,Pharm Res ,1994 ,11 (2) :337~340.
[71] Park TG,Lee HY,Nam YS1A new preparation method for protein loaded poly (D - L - lactic - co - glycolic acid) microspheres and protein release mechanism study.[J] Controlled Release ,1998 ,55 (23) :181-191.
[72] TAN Zai-You, LIAO Qing-Jiang, Robin Y Xiao, Deniel Q. G. So.Characteristics of Epristeride Microspheres with TwoEmulsifying Preparation Methods.Journal of China Pharmaceutical University,2003,34 (4):309～312.
[73] McGee J P ,Davi SSS ,O′Hagan DT1Zero order release of protein from poly (D ,L - lactic - co - glycolide) microparticles preparedusing a modified phase separation technique[J] Controlled Release ,1995 ,34 (2) :77~86.
[74] Wang N , Wu XS. A novel approach to stabilization of protein drugs in poly (lactide2co2glycolic acid) microspheres using agarose hydrogel.[J] Pharm ,1998 ,166 (1) :1~14.
[75]尤国庆,邢春方.谈肝癌的介入疗法[J].中国医药导报。2006,3(17):55.56.
[76] Yamamoto K,TanakaY.Rlldio flequeney capacitive hyperthermia for unsechepatic cancers[J].J Gastroenerol,1997,32(3):361～366.
[77]马光辉,苏志国.高分子微球材料[M].北京:化学工业出版社,2OO5,267.
[78]马秀玲,黄丽梅,郑思宁等.磁性微球的制备及研究进展[J].广州化学,2003,28(3):58～64.
[79]马骚骚,封兴华.微球制剂的给药途径及在医学康复的应用进展[J].中国临床康复,2OO3,7(1):110～115.
[80]周友中,李锐,林佳洁.恩诺沙星肺靶向微球的研究[J].中国兽医杂志,2OO6,42(4):60～62.
[81]钟延强,任常顺,王春燕,等.关节腔内注射用氟比洛芬明胶微球[J].药学学报,1999,34(7):543～546.
[82] Ugwoke M I,AgI R U,Verbeke N,et a1.Nasal mucoadhesivearug delivery:background, application ,trends and future perspectives[J].Adv DrugDelive Rev,2OO5,57(11):1640～1665.
[83] Gavini E,Hegge A B,Rassu G,et a1.Nasal administration of carbsmazepine using chitosan microspheres:in vitro/in vivo studies[J]. J Pharm,2006,307(1):9～15.
[84] Yildiz A,Oi,yar A,Baktir G,et a1.Nasal administration of heparin-loaded microspheres based on poly(1actic acid)[J].Farmaco(erat),2005,60(11～l2):919～924.
[85] Genta I,Conti B,Perugini P,et a1.Bioadhesive microspheres for ophthalmic administration of acydovir[J].J Pharm Pharmacol,1997,49(8):737～742.
[86] Vyas S P,Jain C P.Bioadhesive poly-grafted starch microspheres bearing isosorbide dinitrate for buccal administration [J].J Microencapsul,1992,9(4):457～464.
[87]高萍,丁平田,陈大为.注射用长效微球体外释放特性的研究进展[J].中南药学,2OO4,3(2):105～108.
[88]田成华,司天梅,舒良.第一个长效非典型抗精神病药:注射用利培酮微球[J].中国新药与临床杂志,2OO4,23(1O):723.725.
[89] Le Guevello P,Le Cone P,Chevanne F,et a1.High-performance liquid ehramatolgaphic determination of bupivaeaine in plasma samples for biopharmaceutical studies in application to seven other local anaes thetics[J].J Chromatogr,1993,622(2):284～90.
[90]王亚敏,石庭.微球制剂药物控释研究进展.中国药学,1996,31(3):131～134
[91]王伟,杨永新,李岩.微球的释药特性研究[J].西北药学杂志,2OO4,19(3):138～139.
[92]王襄平,梅兴国.多肽及蛋白类药物微球包封率和释放的研究进展[J].国外医学药学分册,2OO6,33(3):219～223.
[93]何应,魏树礼.破伤风类毒素聚乳酸微球的制备工艺研究[J].北京医科大学学报,2OOO,31(3):239～243
[94]张洪涛,黄锦霞.乳液聚合新技术及应用.化学工业出版社,2007年1月,第一版,102.
[95]曹同玉,刘庆普,胡金生.聚合物乳液合成原理性能及应用[M]北京:化学工业出版社,1999:15~25.
[96]杜定准,汪月生,徐文英.1H NMR研究β-环糊精与环氧氯丙烷共聚物的反应机理和分子链结构.波谱学杂质,1992,9(2):121~129.
[97]吴文娟,郑敦胜,蔡诗填,黄远铿β-环糊精聚合物微球的合成及药物控释行为的研究中药材2007,30(3), 329~331
[98] Baille W E, Huang W Q, Nichifor M, Zhu X X. [J]. J. Macromol. Sci. Pure Appl.Chem, 2000, A37 (7):677～690.
[99]严春美,刘郁杨,范晓东.β-环糊精球的制备及其药物控释行为研究.化工新型材料,2004,32(6):39~42.
[100]Mark E. Davis, Marcus E. Brewster.Cyclodextrin-baesd pharmaceutics:past, present, future.Nature,Drug discovery, 2004.12,(3):1023~1035.
[101]黄一平,贾晓斌.藏药学域抗风湿胶囊成型工艺的研究.第四届全国药用辅料与中药制剂新技术应用研讨会(资料汇编),2007.
[102]曹春林.中药药剂学[M].上海:上海科学技术出版社,1986:291.
[103]刘郁杨.用于新型抗癌药物定向控制释放的高分子载体的合成与表征.西北工业大学博士学位论文,2003年.
[104]杜定准,汪月生,徐文英.1H NMR研究β-环糊精与环氧氯丙烷共聚物的反应机理和分子链结构.波谱学杂质,1992,9(2):121~129.
[105] Anderson JM,Shiver MS.Biodegradation and biocompatibility of PLA and PLGA microsphere[J].A dv Drug Deliv Rev,1997,28(11):5~24
[106]谷福根,柳翠敬.双氯芬酸钠-β-环糊精包合物的研制.中国药学杂志,1998,33(3):153.
[107]杨瑞芹,陈尔凡,杨春艳等. MMA-AA共聚物的合成及其玻璃化温度(Tg)的测定.沈阳化工学院学报.1998,12(4):282~6.
[108]王晓明.聚β-环糊精缓释微球的制备、结构表征及其释药性能的研究.广东药学院硕士学位论文.2007年.
[109] tella V J, et al. J Pharm Res, 1997, 14:556. ibby D C, et al. Int J Pharm,2000,197:1.
[110] ee Y B, et al. Pharm Res, 1991,8:531.
[111] Bae YH,et a1“.On-of”thermocontrol of solute transport.I.Temperature dependence of swelling of N-isopro phylaerylamide networks modified with hydrophobic com-ponents in water.Pharm Res,1991,8:531.
[112] Unsal E,Camli S T,Tuncel A.[J].Journal of Applied Polymer Science,2004,92:607~618.
[113]徐晖,丁平田,郑俊民.聚合物系统中药物的非扩散控制释放.药学学报.2000,35(9):710～740.
[114]李希明,刘成杰,陈文明,高分子学报,1989,5:519
[115] Ritger PL ,Peppas NA.A simple equation for description of solute release.Ⅱ.Fickian and anamalous release from swellable devices.J Controlled Release,1987.5(1):37～42
[116] Peppas NA.Relea.~ of bioative agents from swellable polymers.Anderson JM,Kim SW.Recent advances in drug delivery system.New York and London:Plenum Press.1984.279～290
[117] Hariharan D,Peppas NA.Modeling of water transport and solute release in physiologically sensitive gels.J Controlled Release.1993.23(2):123～136
[118]李凌冰,徐明瑜.溶剂在玻璃状高分子材料中非Fick扩散机理的研究.中国生物医学工程学报.1999.4:441～450.
[119] Cohen DS,Erneux T.Free boundary problems in controlled release pharmaceuticals.SIAM Appl Math,1988.48(6)1466～1469
[120]潘吉铮.聚乳酸微球载体的结构与控释性能关系及模型.华南理工大学博士论文,2004年.
[121]中国药典,2005版,附录XI XD缓释、控释制剂指导原则
[122] Mulye, N. V., Turco, S. J., A simple model based on first order kinetics to explain release of highly water soluble drugs from porous dicalcium phosphate dehydrate matrices, Drug Dev. Ind. Pharm., 21, 943~953.
[123] Higuchi, T., Rate of release of medicaments from ointment bases containing drugs in suspensions, J. Pharm. Sci., 1961,50,874~75.
[124] Chandrasekaran SK, Paul DR. Dissolution-controlled transport from dispersed matrixes[J]J Pharm Sci, 1982, 71(12):1339~402.
[125] Zheng JM, Yang L, He YQ. A simplified expression for a diffusion-dissolution controlled release of drug from matrix in TDDS[J].J Chin Pharm Sci (in Chinese), 1995, 4(3):125~9.
[126] John W. Skoug, Martin V. Mikelsons, Cynthia N,et al. Qualitative evaluation of the mechanism of release of matrix sustained release dosage forms by measurement ofpolymer release. Journal of Controlled Release, 1993(27):227~245.
[127] Peppas NA. Release of bioactive agents from swellable polymers[A].Anderson JM, Kim SW. Recent Advances in Drug Delivery Systems[M]. New York and London: Plenum Press, 1984.279~90.
[128] Jean-maurice vergnaud. Controlled drug release of oral dosageforms.Ellis Horwood Limited, 1993:59~69.
[129] Crank, J The mathematics of diffusion, ED.Carendon.Carendon press,1975 Oxford, U.K.
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