烯丙孕素-β-环糊精水溶性衍生物包合物的制备及表征

doi:10.16431/j.cnki.1671-7236.2021.11.019

摘要/Abstract

摘要： 为了提高难溶性药物烯丙孕素（altrenogest，ALT）的水溶性，本试验采用冷冻干燥法来制备烯丙孕素-羟丙基-β-环糊精（ALT-HP-β-CD）及其衍生物2，6-二甲基-β-环糊精（DIME-β-CD）包合物载药体系，并对ALT的线性关系和专属性、仪器的精密度以及包合物的回收率和稳定性进行了测定。以包合物的收率和包合物中ALT的包合率为评价指标，采用正交试验设计优选2种包合物的最佳制备条件，并使用傅里叶变换红外光谱法、热重分析法和显微镜成像法对所制得的ALT包合物进行表征分析，采用溶解度法测定包合物中ALT的溶解度。结果表明，ALT在1~12 μg/mL范围内具有较好的线性关系且专属性良好，仪器的精密度良好；加入0.1、0.2和0.3 mL ALT标准液的ALT-HP-β-CD包合物的平均回收率分别为97.78%、99.38%和99.90%，加入0.1、0.2和0.3 mL ALT标准液的ALT-DIME-β-CD包合物的平均回收率分别为93.86%、97.72%和94.93%；ALT-HP-β-CD包合物的最佳制备工艺为在55 ℃条件下，ALT与HP-β-CD的投料摩尔比为1∶7，包合时间为4 h，溶液pH为8，溶剂水的加入量为110 mL/g药物；ALT-DIME-β-CD包合物的最佳制备工艺为在55 ℃条件下，ALT与DIME-β-CD的投料摩尔比为1∶4，包合时间为4 h，溶液pH为9，溶剂水的加入量为100 mL/g；经傅里叶变换红外光谱法、热重分析法和显微镜成像法表征，证实成功制得包合物；溶解度试验得出包合物的溶解度分别约为ALT原药的1 012和1 354倍，表明两种包合物均可有效增加ALT的溶解度。本试验包合物的制备方法简单，条件温和，易于产业化生产。

关键词: 烯丙孕素(ALT); β-环糊精衍生物; 冷冻干燥法; 包合物; 表征

Abstract: In order to improve the water solubility of the poorly soluble drug altrenogest(ALT), this experiment used freeze-drying to prepare altrenogest-hydroxypropyl-β-cyclodextrin (ALT-HP-β-CD) and its derivative 2, 6-dimethyl-β-cyclodextrin (DIME-β-CD) inclusion complex drug-carrying system, the linear relationship and specificity of ALT, the precision of the instrument, and the rate and stability of the inclusion complex were measured. Based on the yield of the inclusion complex and the inclusion rate of ALT in the inclusion complex, the orthogonal test design was used to optimize the optimal preparation conditions of the two types of inclusion complexes, and Fourier transform infrared spectroscopy, thermogravimetric analysis and microscopy imaging methods were used to characterize the prepared ALT inclusion complex, and the solubility method was used to determine the solubility of ALT in the inclusion complex. The results showed that:ALT had a good linear relationship in the range of 1~12 μg/mL, and the specificity was good, and the precision of the instrument was good. The average recoveries of ALT-HP-β-CD inclusion complex with 0.1, 0.2 and 0.3 mL ALT standard solution were 97.78%, 99.38% and 99.90%, respectively. The average recoveries of ALT-DIME-β-CD inclusion complex with 0.1, 0.2 and 0.3 mL of ALT standard solution were 93.86%, 97.72% and 94.93%, respectively. The best preparation process for the inclusion complex of ALT-HP-β-CD was at 55 ℃, the molar ratio of ALT to HP-β-CD was 1:7, the inclusion time was 4 h, the pH of the solution was 8, and the amount of solvent water added was 110 mL/g drug. The best preparation process of the inclusion complex of ALT-DIME-β-CD was at 55 ℃, the molar ratio of ALT to DIME-β-CD was 1:4, the inclusion time was 4 h, the pH of the solution was 9, and the amount of solvent water added was 100 mL/g drug. The inclusion complex was characterized by Fourier infrared spectroscopy, thermogravimetric analysis and microscopy imaging methods. The solubility test showed that the solubility of the inclusion complex was about 1 012 times and 1 354 times of the ALT drug, respectively, indicating that the two inclusion complexes could effectively increase the solubility of ALT. The preparation method of the inclusion complex was simple, the conditions were mild, and it was easy to industrialized production.

Key words: altrenogest(ALT); β-cyclodextrin derivative; freeze-drying method; inclusion complex; characterization

中图分类号:

S859.1

杨玉帅, 李泽, 金天明, 杨升. 烯丙孕素-β-环糊精水溶性衍生物包合物的制备及表征[J]. 中国畜牧兽医, 2021, 48(11): 4094-4104.

YANG Yushuai, LI Ze, JIN Tianming, YANG Sheng. Preparation and Characterization of Altrenogest-β-cyclodextrin Water-soluble Derivative Inclusion Complex[J]. China Animal Husbandry and Veterinary Medicine, 2021, 48(11): 4094-4104.

参考文献

[1] BAEK S Y, SA S J, JEONG Y D, et al. Altrenogest affects expression of galectin-3 and fibroblast growth factor 9 in the reproductive tract of sows[J]. Animal Biotechnology, 2020, 30(2):1-7.
[2] SHIMATSU Y, UCHIDA M, NIKI R, et al. Effects of a synthetic progestogen, altrenogest, on oestrus synchronisation and fertility in miniature pigs[J]. The Veterinary Record, 2004, 155(20):633-635.
[3] ESTIENNE M J, CRAWFORD R J.Characteristics of estrous cycles in gilts treated with gonadotropins after estrus or treatment with a progestogen[J]. Theriogenology, 2015, 83(4):459-465.
[4] 王双, 李艳艳, 杨海峰, 等.两种烯丙孕素口服液在猪体内的比较药动学研究[J]. 畜牧与兽医, 2018, 50(7):45-50. WANG S, LI Y Y, YANG H F, et al. Comparative pharmacokinetics of two kinds of altrenogest oral liquids in sow[J]. Animal Husbandry & Veterinary Medicine, 2018, 50(7):45-50.(in Chinese)
[5] 陈志林, 师晓杰, 张凯, 等.烯丙孕素对乏情后备母猪繁殖性能的影响[J]. 养猪, 2018, 4:28-29. CHEN Z L, SHI X J, ZHANG K, et al. The effect of altrenogest on anoestrus gilts reproductive performance[J]. Swine Production, 2018, 4:28-29.(in Chinese)
[6] 方礼禄, 王朝军, 徐利, 等.四烯雌酮对乏情母猪同期发情的影响[J]. 饲料博览, 2014, 10:5-7. FANG L L, WANG C J, XU L, et al. Effects of altrenogest on oestrus synchronization in anestrus pigs[J]. Feed Review, 2014, 10:5-7.(in Chinese)
[7] 杨光, 王朝军, 徐利, 等.四烯雌酮对后备母猪同期发情的影响[J]. 饲料博览, 2014, 5:37-39. YANG G, WANG C J, XU L, et al. Effect of altrenogest treatment on synchronization of gilts estrus[J]. Feed Review, 2014, 5:37-39.(in Chinese)
[8] 王忠, 王立琦, 林埴, 等.同期发情剂四烯雌酮的应用进展[J]. 动物医学进展, 2018, 39(6):95-99. WANG Z, WANG L Q, LIN Z, et al. Progress on estrus synchronization agent altrenogest[J]. Progress in Veterinary Medicine, 2018, 39(6):95-99.(in Chinese)
[9] 冯言言, 徐恩民, 郑莉, 等.烯丙孕素口服液调控母猪同期发情的研究进展[J]. 中国兽药杂志, 2018, 52(4):66-72. FENG Y Y, XU E M, ZHENG L, et al. Progress of altrenogest oral solution in the regulation of synchronous estrus of mature sows[J]. Chinese Journal of Veterinary Drug, 2018, 52(4):66-72.(in Chinese)
[10] 王双, 杨海峰, 余波, 等.烯丙孕素口服液在猪体内的残留消除研究[J]. 畜牧兽医学报, 2018, 49(9):2005-2014. WANG S, YANG H F, YU B, et al. Study on residue elimination of altrenogest oral solution in pigs[J]. Acta Veterinaria et Zootechnica Sinica, 2018, 49(9):2005-2014.(in Chinese)
[11] 李艳艳, 李宇琛, 姚诗贇, 等.烯丙孕素内服溶液调控母猪同期发情的临床药效试验[J]. 畜牧与兽医, 2019, 51(6):124-127. LI Y Y, LI Y C, YAO S Y, et al. Clinical efficacy of altrenogest oral solution in regulation of synchronous estrus in mature sows[J]. Animal Husbandry & Veterinary Medicine, 2019, 51(6):124-127.(in Chinese)
[12] 刘明智, 孙洁, 刘闯, 等.影响母猪定时输精效果的关键因素[J]. 黑龙江畜牧兽医, 2020, 13:40-43. LIU M Z, SUN J, LIU C, et al. Key factors for influencing timed artificial insemination in sow[J]. Heilongjiang Animal Science and Veterinary Medicine, 2020, 13:40-43.(in Chinese)
[13] 贾敬亮, 刘博, 宋凤格, 等.母猪批次化生产管理技术的应用[J]. 养猪, 2020, 6:29-31. JIA J L, LIU B, SONG F G, et al. Application of sows batch production management technology[J]. Swine Production, 2020, 6:29-31.(in Chinese)
[14] 蔡红芹, 王春梅.羟丙基-β-环糊精的制备及应用[J]. 南通大学学报(自然科学版), 2014, 13(2):54-59. CAI H Q, WANG C M.Preparation and application of hydroxypropyl-β-cyclodextrin[J]. Journal of Nantong University (Natural Science Edition), 2014, 13(2):54-59.(in Chinese)
[15] 周艳, 唐亮, 周咏梅.芦丁-羟丙基-β-环糊精包合物的制备与验证[J]. 中国药学杂志, 2011, 46(16):1262-1264. ZHOU Y, TANG L, ZHOU Y M.The preparation and authentication of the Rutin HP-β-CD inclusion complexes[J]. Chinese Pharmaceutical Journal, 2011, 46(16):1262-1264.(in Chinese)
[16] 艾凤伟, 张加伟, 钱楠, 等.芦丁-二甲基-β-环糊精包合物的制备、物理化学表征及体外溶出研究[J]. 药学研究, 2015, 34(11):650-653. AI F W, ZHANG J W, QIAN N, et al. Preparation, physicochemical characterization and dissolution studies in vitro of rutin DM-β-CD inclusion complexes[J]. Journal of Pharmaceutical Research, 2015, 34(11):650-653.(in Chinese)
[17] DUA K, PABREJA K, RAMANA M V, et al. Dissolution behavior of beta-cyclodextrin molecular inclusion complexes of aceclofenac[J]. Journal of Pharmacy and Bioallied Sciences, 2011, 3(3):417-425.
[18] NANDA A, SAHOO R N, PRAMANIK A, et al. Drug-in-mucoadhesive type film for ocular anti-inflammatory potential of amlodipine:Effect of sulphobutyl-ether-beta-cyclodextrin on permeation and molecular docking characterization[J]. Colloids and Surfaces B:Biointerfaces, 2018, 172:555-564.
[19] FERRATI S, NICOLOV E, BANSAL S, et al. Docetaxel/2-hydroxypropyl β-cyclodextrin inclusion complex increases docetaxel solubility and release from a nanochannel drug delivery system[J]. Current Drug Targets, 2015, 16(14):1645-1649.
[20] 才燕, 杨琳燕, 杨升.烯丙孕素-β-环糊精和羟丙基-β-环糊精包合物制备工艺优选[J]. 动物医学进展, 2020, 41(9):46-50. CAI Y, YANG L Y, YANG S.Optimization of preparation technology of inclusion compound of altrenogest-β-cyclodextrin and its derivatives[J]. Progress in Veterinary Medicine, 2020, 41(9):46-50.(in Chinese)
[21] 宁宁.难溶性药物增溶材料的研究进展[J]. 新材料产业, 2014, 6:46-49. NING N.Research progress of insoluble drug solubilizing materials[J]. Advanced Materials Industry, 2014, 6:46-49.(in Chinese)
[22] 杨云汉, 赵雪秋, 杜瑶, 等.长春胺与羟丙基-β-环糊精包合物的制备、表征及理论研究[J]. 中草药, 2019, 50(2):352-363. YANG Y H, ZHAO X Q, DU Y, et al. Preparation, characterization and theoretical study of inclusion complex of vinblastine with hydroxypropyl-β-cyclodextrin[J]. Chinese Herbal Medicine, 2019, 50(2):352-363.(in Chinese)
[23] 周桂芝, 吴珏, 杨雪晗, 等.水飞蓟素-磺丁基-β-环糊精包合物的制备[J]. 中草药, 2019, 50(17):4100-4107. ZHOU G Z, WU J, YANG X H, et al. Preparation of silymarin-SBE-β-CD inclusion complex[J]. Chinese Traditional and Herbal Drugs, 2019, 50(17):4100-4107.(in Chinese)
[24] 陈刚, 何盛江.银杏内酯N水溶性磺丁基-β-环糊精包合物的研究[J]. 西北药学杂志, 2018, 33(2):230-233. CHEN G, HE S J.Study on the inclusive reaction of sulfobutylether-β-cyclodextrin with ginkgolide N[J]. Northwest Pharmaceutical Journal, 2018, 33(2):230-233.(in Chinese)