药学学报, 2021, 56(6): 1696-1703
引用本文:
王雅蒙#, 邹丹璐#, 李钰, 柯学*. 十一酸睾酮Ⅲ型脂质制剂体外脂解过程及机制研究[J]. 药学学报, 2021, 56(6): 1696-1703.
WANG Ya-meng#, ZOU Dan-lu#, LI Yu, KE Xue*. In vitro lipolysis process and lipolysis mechanism of testosterone undecanoate type Ⅲ lipid formulations[J]. Acta Pharmaceutica Sinica, 2021, 56(6): 1696-1703.

十一酸睾酮Ⅲ型脂质制剂体外脂解过程及机制研究
王雅蒙#, 邹丹璐#, 李钰, 柯学*
中国药科大学药学院, 江苏省纳米药物制备与生物学评价公共服务中心, 江苏 南京 210009
摘要:
以十一酸睾酮为模型药物,制备Ⅲ型脂质制剂,利用体外脂解模型评价各处方的体外脂解速率及脂解程度,并以光学显微镜和电导率等手段进一步研究其消化机制。结果表明,在以蓖麻油为油相、Transcutol HP为助表面活性剂的十一酸睾酮Ⅲ型脂质制剂中,随着油相比例增加,脂解速率和脂解程度增加;表面活性剂比例过高,脂解过程中可观察到液晶相、脂解速率和脂解程度下降。含有不同表面活性剂的ⅢB型脂质制剂脂解速率排序为Labrasol>Tween 80>Cremophor EL,而ⅢA型的排序在快速消化期和慢速消化期有所不同,但两者脂解程度排序均为Cremophor EL>Tween 80>Labrasol。研究结果提示,处方含油量、表面活性剂比例及其结构对Ⅲ型脂质制剂体外脂解速率和脂解程度均具有较大影响且相互交织,进行处方筛选时需综合考虑各方面因素对制剂体内消化的影响。
关键词:    Ⅲ型脂质制剂      体外脂解模型      脂解速率      脂解程度      十一酸睾酮     
In vitro lipolysis process and lipolysis mechanism of testosterone undecanoate type Ⅲ lipid formulations
WANG Ya-meng#, ZOU Dan-lu#, LI Yu, KE Xue*
School of Pharmacy, China Pharmaceutical University, Jiangsu Public Technical Service Center for Nanometer Drug Preparation and Biological Evaluation, Nanjing 210009, China
Abstract:
The study evaluates the lipolysis rate and extent of type Ⅲ lipid formulations using testosterone undecanoate as a model drug after digestion with in vitro lipolysis model, and studies the digestive regularity with optical microscope and electrical conductivity. The results showed that for testosterone undecanoate type Ⅲ lipid formulations with castor oil as oil phase and Transcutol HP as latent solvent, the lipolysis rate and extent were increased with the increase of oil phase proportion and were decreased with excessive proportion of surfactant, in which can see liquid crystal phase during lipolysis process. The lipolysis rate of type ⅢB lipid preparations with different surfactant were ordered as Labrasol > Tween 80 > Cremophor EL, but the rate of type ⅢA is different in quick digestion phase and slow digestion phase. The lipolysis extent of type Ⅲ lipid formulations with different surfactant were ordered as Cremophor EL > Tween 80 > Labrasol. These may be related to the digestive effect of pancreatic lipase on different surfactants. This study implied that the lipolysis rate and extent of type Ⅲ lipid formulations are greatly influenced by the proportion of oil phase and surfactant, and the surfactant structure. These factors will affect the in vivo digestion and should be taken into account when screening type Ⅲ lipid formulations.
Key words:    type Ⅲ lipid formulation    in vitro lipolysis model    lipolysis rate    lipolysis extent    testosterone undecanoate   
收稿日期: 2020-12-21
DOI: 10.16438/j.0513-4870.2020-1938
通讯作者: 柯学,Tel:86-25-83271269,E-mail:kexue1973@vip.sina.com
Email: kexue1973@vip.sina.com
相关功能
PDF(1645KB) Free
打印本文
0
作者相关文章
王雅蒙#  在本刊中的所有文章
邹丹璐#  在本刊中的所有文章
李钰  在本刊中的所有文章
柯学*  在本刊中的所有文章

参考文献:
[1] Zhang Y, Cui T, Li SX, et al. Improving oral absorption of BCS II drugs by increasing solubility: frequently overlooked permeability[J]. Acta Pharm Sin (药学学报), 2019, 54: 1-7.
[2] Beck LW. Intermediates formed during the digestion of trigly-cerides[J]. J Nutrit, 1952, 48: 335-344.
[3] Carrière F. Impact of gastrointestinal lipolysis on oral lipid-based formulations and bioavailability of lipophilic drugs[J]. Biochimie, 2016, 125: 297-305.
[4] Pouton CW. Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and ‘self-microemulsifying’ drug delivery systems[J]. Eur J Pharm Sci, 2000, 11: S93-S98.
[5] Pouton CW. Formulation of poorly water-soluble drugs for oral administration physicochemical and physiological issues and the lipid formulation classification system[J]. Eur J Pharm Sci, 2006, 29: 278-287.
[6] Thomas N, Müllertz A, Graf A, et al. Influence of lipid composition and drug load on the in vitro performance of self-nanoemulsifying drug delivery systems[J]. J Pharm Sci, 2012, 101: 1721-1731.
[7] Porter CJ, Pouton CW, Cuine JF, et al. Enhancing intestinal drug solubilisation using lipid-based delivery systems[J]. Adv Drug Deliv Rev, 2008, 60: 673-691.
[8] Liu Y, Yi T, Huan D, et al. Use of an in vitro lipolysis model to evaluate type Ⅰ lipid formulations[J]. Acta Pharm Sin (药学学报), 2010, 45: 1307-1311.
[9] Christensen JO, Schultz K, Mollgaard B, et al. Solubilisation of poorly water-soluble drugs during in vitro lipolysis of medium-chain and long-chain triacylglycerols[J]. Eur J Pharm Sci, 2004, 23: 287-296.
[10] Porter CJH, Kaukonen AM, Taillardat-Bertschinger A, et al. Use of in vitro lipid digestion data to explain the in vivo performance of triglyceride-based oral lipid formulations of poorly water-soluble drugs: studies with halofantrine[J]. J Pharm Sci, 2004, 93: 1110-1121.
[11] Dahan A, Hoffman A. Rationalizing the selection of oral lipid based drug delivery systems by an in vitro dynamic lipolysis model for improved oral bioavailability of poorly water soluble drugs[J]. J Control Release, 2008, 129: 1-10.
[12] Xiao L, Yi T, Liu Y, et al. The in vitro lipolysis of lipid-based drug delivery systems: a newly identified relationship between drug release and liquid crystalline phase[J]. Biomed Res Int, 2016, 2016: 2364317.
[13] Cuiné JF, Charman WN, Pouton CW, et al. Increasing the proportional content of surfactant (Cremophor EL) relative to lipid in self-emulsifying lipid-based formulations of danazol reduces oral bioavailability in Beagle dogs[J]. Pharm Res, 2007, 24: 748-757.
[14] Cuiné JF, Mcevoy CL, Charman WN, et al. Evaluation of the impact of surfactant digestion on the bioavailability of danazol after oral administration of lipidic self-emulsifying formulations to dogs[J]. J Pharm Sci, 2008, 97: 995-1012.
[15] Kossena GA, Charman WN, Wilson CG, et al. Low dose lipid formulations: effects on gastric emptying and biliary secretion[J]. Pharm Res, 2007, 24: 2084-2096.
[16] Mullertz A, Fatouros DG, Smith JR, et al. Insights into intermediate phases of human intestinal fluids visualized by atomic force microscopy and cryo-transmission electron microscopy ex vivo[J]. Mol Pharm, 2012, 9: 237-247.
[17] Patton J, Carey M. Watching fat digestion[J]. Science, 1979, 204: 145-148.
[18] Fatouros DG, Walrand I, Bergenstahl B, et al. Colloidal structures in media simulating intestinal fed state conditions with and without lipolysis products[J]. Pharm Res, 2008, 26: 361.
[19] Fatouros DG, Bergenstahl B, Mullertz A. Morphological observations on a lipid-based drug delivery system during in vitro digestion[J]. Eur J Pharm Sci, 2007, 31: 85-94.
[20] Mun S, Decker EA, Park Y, et al. Influence of interfacial composition on in vitro digestibility of emulsified lipids: potential mechanism for chitosan's ability to inhibit fat digestion[J]. Food Biophys, 2006, 1: 21-29.