自组装法构建的疏水药物新型口服递送系统及其体内外评价

赵阳; 刘仁凤; 窦寅; 郭嘉伟; 张建祥

doi:10.16016/j.1000-5404.202001169

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自组装法构建的疏水药物新型口服递送系统及其体内外评价

药学 | 更新时间：2026-01-09

- 自组装法构建的疏水药物新型口服递送系统及其体内外评价
- In vitro and in vivo evaluation ofanovel self-assembled oral delivery system for hydrophobic drugs
- 第三军医大学学报 2020年42卷第10期页码：1053-1063
- 作者机构：
  
  400038 重庆，陆军军医大学(第三军医大学)药学与检验医学系药剂学教研室
- 作者简介：
  
  [张建祥，E-mail: jxzhang1980@gmail.comZHANG Jianxiang. E-mail:jxzhang1980@gmail.com
- 基金信息：
  
  国家自然科学基金(81971727);陆军军医大学杰青人才库项目(2017年度)
- DOI：10.16016/j.1000-5404.202001169
  中图分类号： R914.2;R944.9;R965
- 收稿：2020-01-19，
  
  修回：2020-02-19，
  
  纸质出版：2020-05-30
- 稿件说明：
移动端阅览
赵阳, 刘仁凤, 窦寅, 等. 自组装法构建的疏水药物新型口服递送系统及其体内外评价[J]. 第三军医大学学报, 2020,42(10):1053-1063.

Yang ZHAO, Renfeng LIU, Yin DOU, et al. In vitro and in vivo evaluation ofanovel self-assembled oral delivery system for hydrophobic drugs[J]. Journal of Third Military Medical University, 2020, 42(10): 1053-1063.
赵阳, 刘仁凤, 窦寅, 等. 自组装法构建的疏水药物新型口服递送系统及其体内外评价[J]. 第三军医大学学报, 2020,42(10):1053-1063. DOI： 10.16016/j.1000-5404.202001169.

Yang ZHAO, Renfeng LIU, Yin DOU, et al. In vitro and in vivo evaluation ofanovel self-assembled oral delivery system for hydrophobic drugs[J]. Journal of Third Military Medical University, 2020, 42(10): 1053-1063. DOI： 10.16016/j.1000-5404.202001169.

摘要

目的

新设计并合成一种亲水性天冬氨酸多肽衍生物聚(异丙基)天冬酰胺(PIPAA)，考察PIPAA能否有效负载含羧基疏水药物形成pH响应性微球，增加其在肠道pH条件下的溶出，并提高其口服生物利用度。

方法

以浓磷酸催化

L-

天冬氨酸在高温条件下聚合成聚琥珀酰亚胺(PSI)，并用异丙胺氨解PSI得到PIPAA；PSI和PIPAA结构经红外(FT-IR)和核磁(

H NMR)进行谱学表征。采用透析法制备负载吲哚美辛(IND)的IND/PIPAA微球，并对其形态、粒径、载药量和包封率进行表征；利用FT-IR、

H NMR、差示扫描量热法(DSC)和X射线衍射法(XRD)分析IND与PIPAA分子间的相互作用及IND分子在微球中的存在形式；体外评价了微球的pH响应性释药行为；灌胃给予大鼠载药微球后，高效液相色谱(HPLC)法测定不同时间点血样中的IND含量；利用角叉菜胶诱导的大鼠足跖肿胀模型评价IND/PIPAA微球的抗炎效果。

结果

FT-IR和

H NMR图谱证明PSI和PIPAA的成功合成。IND和PIPAA可以通过静电力、氢键和疏水作用自组装形成形态规整、粒径均一的载药微球，其中IND载药量和载药效率高，且IND以无定型形式存在于微球中。该微球在体外表现出良好的pH响应性释药行为。大鼠体内药动学研究表明IND/PIPAA微球组的药时曲线下面积(AUC)为IND组的2.4倍。在急性足跖肿胀模型中，与生理盐水和IND相比，IND/PIPAA微球可以显著减轻足跖部位的炎症程度(

=0.046，

=0.002)。

结论

含羧基小分子疏水药物IND与亲水性天冬氨酸多肽衍生物PIPAA可以通过多重非共价键作用自组装形成形态规整、粒径均一的IND/PIPAA微球，该递送系统可有效增加IND在肠道环境的溶出速率，并提高其口服生物利用度和疗效。

Abstract

Objective

To design and synthesize a new hydrophilic aspartic acid peptide derivative

poly(isopropyl

-D

L-

aspartamide) (PIPAA)

and investigate its efficiency to self-assemble with carboxy-containing therapeutics into pH-sensitive microspheres to enhance the dissolution and oral bioavailability of hydrophobic drugs.

Methods

With phosphoric acid as the catalyst

-aspartic acid was polymerized into polysuccinimide (PSI) at 180 ℃ followed by ring-opening reaction with isopropylamine to form PIPAA. The successful synthesis of PSI and PIPAA was characterized by Fourier transform infrared spectroscopy (FT-IR) and

H NMR spectroscopy. The morphology

size

drug loading content and loading efficiency of IND/PIPAA microspheres were characterized. FT-IR and

H NMR spectroscopy were used to determine non-covalent forces between IND and PIPAA in IND/PIPAA microspheres

and the existence form of IND in IND/PIPAA microspheres was examined by differential scanning calorimetry (DSC) and Xray diffraction (XRD) measurement. We carried out

in vitro

tests to investigate pH-responsive release profiles of IND/PIPAA microspheres. We also examined plasma concentrations of IND using high-performance liquid chromatogrpahy (HPLC) in rats after oral administration of IND/PIPAA microspheres

and evaluated the anti-inflammatory efficacy of IND/PIPAA microspheres in rats with carrageen-induced paw edema.

Results

FT-IR and

H NMR spectra demonstrated successful synthsis of PSI and PIPAA. Morphological observation and size determination revealed a spherical shape and uniform particle size of the IND/PIPAA microspheres

which were self-assembled through electrostatic force

hydrogen bonding

and hydrophobic interactions between IND and PIPAA as confimred by FT-IR and

H NMR spectra. DSC and XRD measurements

indicated that IND molecules entrapped in the microspheres were essentially amorphous. While drug release was almost completely suppressed at a gastric pH level

rapid IND release from the microspheres in vitro was observed at pH 7.4. After oral administration in rats

IND/PIPAA microspheres

as compard with raw IND

obviously enhanced plasma concentrations of IND with a 2.4-fold higher AUC. In rats with carrageen-induced acute inflammation in the paws

IND/PIPAA microspheres exhibited much stronger anti-inflammatory activity than saline (

=0.046) and raw IND (

=0.002).

Conclusion

The carboxyl-containing hydrophobic drug IND and the hydrophilic aspartic acid peptide derivative PIPAA can self-assemble into well-defined microspheres with a uniform size to serve as an efficient drug delivery system that increases intestinal dissolution of IND to enhance its oral bioavailability and efficacy.

关键词

Keywords

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