甲殼素/聚己內酯共聚合物之合成與性質研究

Abstract

過去十幾年間藥物遞送系統的發展日漸進步。材料來源都是以生物可分解性與生體相容性為前提，希望利用合成的方式製備出具有雙性特質的材料，因此本實驗室利用世界上含量第二豐富的幾丁聚醣與已通過美國食品藥物管理局核可之己內酯與聚乙二醇為材料，用合成方式製備聚乙二醇-g-幾丁寡-g-聚己內酯之接枝共聚合物。 實驗上，首先改變幾丁聚醣的分子量至2000 g/mol，以達到水溶特性，再利用傅立葉轉換紅外光光譜儀與質子核磁共振光譜儀確認與聚己內酯和聚乙二醇接枝合成的每一個產物。另以示差掃描熱分析儀鑑定接枝共聚合物的熱變化性，並測試此材料的臨界微膠粒濃度，同時測試未含藥微膠粒的粒徑分佈，表面電荷與微膠粒的安定性，再分別以indomethacin與theophtlline為模式藥製備微膠粒劑型，探討藥物包覆率(E.E.)和藥物含量(D.L.)，也利用質子核磁共振光譜測試藥物與微膠粒的關係，最後並探討接枝共聚合物與三聚磷酸鈉(TPP)形成錯合物奈米粒的粒徑分佈與表面電荷關係。 所合成的三批聚乙二醇-g-幾丁寡醣-g-聚己內酯共聚合物，其結果如下： 1.粒徑分佈分別為124±9.31nm(#10)、563.57±54.11nm(#11-12)與206.53±9.28nm(#13)。 2.表面電荷3±0.2mV(#10)、2.57±0.32mV(#11-12)與2.80±0.17mV(#13)。 3.吲哚美洒辛的藥物包覆率38.56±2.6%(#10)、38.19±7.37%(#11-12)與23.70±3.04%(#13)。 4.無水茶鹼的包覆率則是10.28±5.65%(#11-12)與2.08±0.09%(#13)。 5.經過數週安定性測試顯示未含藥微膠粒十分穩定。 6.三聚磷酸鈉與接枝共聚合物(#13)混合的表面電荷最負可達到-20~-30mV，粒徑分佈比未添加之前提高約幾十奈米，二者根據共聚合物與三聚磷酸鈉混合的濃度而有所不同。

The development of drug delivery systems were going well, and the releated researches were very numerous in the past few decade. The resources of materials were having two characteristics which were biocompatible and biodegradable. We attempted to synthesize a new amphiphillc graft copolymer, mPEG-g-DADP-CS-g-PCL. The all part of materials were non-toxic. Chitosan is very abundant material in the world, poly(ε-caprolactone) and mPEG are the materials that already approved by FDA. In this research, chitosan was depolymerized until it can dissolve in the water, where the Mn was around 2000 g/mol. Each sample was identified by IR and NMR, and the thermal properties by DSC. The CMC of this new material was measured by using pyrene. Indomethaicn and theophylline were chosen as the model drugs to evaluate the drug loading and loading efficiency in the micelles. The interaction of the drug and micelles were measured by NMR. Finally, the surface charge and size distribution of complex of TPP and graft copolymer were investigated. The properities of three graft copolymers, mPEG-g-DADP-CS-g-PCL, were listed below: 1、 The size distributions were 124±9.31nm(#10), 563.57±54.11nm(#11-12), and 206.53±9.28nm(#13). 2、 The surface charge of this three polymers were 3±0.2mV(#10), 2.57±0.32mV(#11-12), and 2.80±0.17mV(#13). 3、 The entrapment of efficiency(%) of indomethacin were 38.58±2.6%(#10), 38.19±7.37%(#11-12), and 23.70±3.04%(#13). 4、 The entrapment of efficiency(%) of theophylline were 10.28±5.65%(#11-12) and 2.08±0.09%(#13). 5、 The unloaded micelles were very stable during a few weeks. 6、 The surface charge of the complex of the TPP and graft copolymer was reaching -20 to -30mV, and the size was higher than without TPP. Both depended on the concentration of polymer and TPP.