对乙酰氨基酚栓剂的制备、表征及兔体内外评价

doi:10.3969/j.issn.1000-1565.2018.04.005

摘要/Abstract

摘要： 采用固体分散体技术,制备对乙酰氨基酚-聚乙二醇-6000(PEG 6000)基质栓剂.经FTIR和XRD验证,固体分散体中药物与基质形成分子间氢键,保证药物以无定型状态分散于基质,利于药物快速溶出.体外溶出实验显示,药基比(m(对乙酰氨基酚)∶m(PEG-6000))为1∶7时,固体分散体药物溶出较优,该比例的药物体外溶出接近零级方程,故选择此投料比自制药物栓剂.选用新西兰兔,分别给予对乙酰氨基酚栓剂和注射剂,测定药-时曲线,药代动力学表明:肌注组血药质量浓度60 min达峰值,ρ_max为169.1 μg/mL,血药峰谷明显;栓剂组血药质量浓度90 min时达峰值,ρ_max为35.4 μg/mL,血药质量浓度平稳并在6 h内持续释放.研究表明自制药物栓剂体内外释放呈良好的相关性,即可通过药物体外释放状况预测药物的体内吸收.

关键词: 对乙酰氨基酚, 聚乙二醇-6000, 固体分散体, 栓剂

Abstract: In this paper, acetaminophen-PEG 6000 suppositories were prepared by solid dispersion technique. The FTIR and XRD spectra confirmed that the hydrogen bonds between drugs and matrix in solid dispersion formed and ensured the drug to be dispersed in the PEG matrix with an amorphous state, which could contribute to the rapid dissolution of the drug. The release behavior of the solid dispersion was studied in vitro. The weight ratio of drug and PEG 6000(1∶7)showed the best drug release profile among the solid dispersion samples and the drug release behaviour in vitro was close to zero order equation. Therefore, the weight ratio of drug and PEG 6000(1∶7)was chosen to prepare the acetaminophen suppositories using solid dispersion technique. Moreover, the acetaminophen suppositories and intramuscular injection dosage forms were evaluated in vivo by New Zealand rabbits experiment. The time-concentration curve of acetaminophen was determined.The pharmacokinetics showed that the ρ_max reached to 169.1 μg/mL at 60 min, and the curve displayed obvious peak and valley when administrated by intramuscular injection. The pharmacokinetics of the suppositories group was obtained at 90 min and ρ_max was 35.4 μg/mL,the blood drug concentration was stable and maintained continued release. There was a good correlation between - DOI:10.3969/j.issn.1000-1565.2018.04.005对乙酰氨基酚栓剂的制备、表征及兔体内外评价杨文智,章一,李凯悦,吴桐,李海鹰(河北大学药学院,河北保定 071002)摘要:采用固体分散体技术,制备对乙酰氨基酚-聚乙二醇-6000(PEG 6000)基质栓剂.经FTIR和XRD验证,固体分散体中药物与基质形成分子间氢键,保证药物以无定型状态分散于基质,利于药物快速溶出.体外溶出实验显示,药基比(m(对乙酰氨基酚)∶m(PEG-6000))为1∶7时,固体分散体药物溶出较优,该比例的药物体外溶出接近零级方程,故选择此投料比自制药物栓剂.选用新西兰兔,分别给予对乙酰氨基酚栓剂和注射剂,测定药-时曲线,药代动力学表明:肌注组血药质量浓度60 min达峰值,ρ_max为169.1 μg/mL,血药峰谷明显;栓剂组血药质量浓度90 min时达峰值,ρ_max为35.4 μg/mL,血药质量浓度平稳并在6 h内持续释放.研究表明自制药物栓剂体内外释放呈良好的相关性,即可通过药物体外释放状况预测药物的体内吸收.关键词:对乙酰氨基酚;聚乙二醇-6000;固体分散体;栓剂中图分类号:O625 文献标志码:A 文章编号:1000-1565(2018)04-0368-07Preparation, characterization, and in vitro and in vivo evaluation ofacetaminophen-PEG 6000 suppositoriesYANG Wenzhi, ZHANG Yi,LI Kaiyue,WU Tong,LI Haiying(College of Pharmacy,Hebei University,Baoding 071002,China)Abstract: In this paper, acetaminophen-PEG 6000 suppositories were prepared by solid dispersion technique. The FTIR and XRD spectra confirmed that the hydrogen bonds between drugs and matrix in solid dispersion formed and ensured the drug to be dispersed in the PEG matrix with an amorphous state, which could contribute to the rapid dissolution of the drug. The release behavior of the solid dispersion was studied in vitro. The weight ratio of drug and PEG 6000(1∶7)showed the best drug release profile among the solid dispersion samples and the drug release behaviour in vitro was close to zero order equation. Therefore, the weight ratio of drug and PEG 6000(1∶7)was chosen to prepare the acetaminophen suppositories using solid dispersion technique. Moreover, the acetaminophen suppositories and intramuscular injection dosage forms were evaluated in vivo by New Zealand rabbits experiment. The time-concentration curve of acetaminophen was determined.The pharmacokinetics showed that the ρ_max reached to 169.1 μg/mL at 60 min, and the curve displayed obvious peak and valley when administrated by intramuscular injection. The pharmacokinetics of the suppositories group was obtained at 90 min and ρ_max was 35.4 μg/mL,the blood drug concentration was stable and maintained continued release. There was a good correlation between - 收稿日期:2017-10-14 基金项目:河北省高等学校科学技术项目(ZD2016102);河北省自然科学基金资助项目(H2017201052,H2018201045);河北大学精品实验项目(2017-BZ-JPSY26);河北大学2016年实验室开放项目(sy201668) 第一作者:杨文智(1972—),男,内蒙古锡林浩特人,河北大学副教授,从事生物医用材料及药物缓控释制剂方面研究.E-mail:wenzhi_yang@sina.com第4期杨文智等:对乙酰氨基酚栓剂的制备、表征及兔体内外评价in vitro drug release and in vivo drug absorption using acetaminophen suppositories, and the drug release in vitro could well predict its absorption in vivo.

Key words: acetaminophen, polyethylene glycol-6000, solid dispersion, suppositories

中图分类号:

O625

杨文智,章一,李凯悦,吴桐,李海鹰. 对乙酰氨基酚栓剂的制备、表征及兔体内外评价[J]. 河北大学学报(自然科学版), 2018, 38(4): 368-374.

YANG Wenzhi, ZHANG Yi,LI Kaiyue,WU Tong,LI Haiying. Preparation, characterization, and in vitro and in vivo evaluation of acetaminophen-PEG 6000 suppositories[J]. Journal of Hebei University (Natural Science Edition), 2018, 38(4): 368-374.

参考文献

[1] 李喜香,刘效栓,包强,等.新型栓剂制备工艺及其药动学特征研究进展[J]. 中国药事,2013,27(7):740-744.DOI: 10.16153/j.1002-7777.2013.07.002. LI X X, LIU X S, BAO Q, et al. Research progress on preparation procedures and pharmacokinetic characteristics of novel suppositories[J]. Chinese Pharmaceutical Affairs, 2013, 27(7): 740-744. DOI: 10.16153/j.1002-7777.2013.07.002.
[2] 曲宏烜,陈新梅,徐溢明,等.微囊栓制剂降低尼美舒利豚鼠肝毒性的实验研究[J]. 药学研究,2015,37(7):379-380.DOI: 10.13506/j.cnki.jpr.2015.07.003. QU H X, CHEN X M, XU Y M, et al. The preliminary inquiry of nimesulide microcapsule suppository reduce Guinea pig liver toxicity[J]. Journal of Pharmaceutical Research, 2015, 37(7): 379-380. DOI: 10.13506/j.cnki.jpr.2015.07.003.
[3] 迟彩霞,苏适,乔秀丽,等. 对乙酰氨基酚/MCM-41载药体系的制备及其缓释性能的研究[J]. 华西药学杂志,2015,30(2):140-142. DOI: 10.13375 /j.cnki.wcjps.2015.02.004. CHI C X, SU S, QIAO X L, et al. Preparation of paracetamol/MCM-41 drug delivery system and its sustained-release properties [J]. West China Journal of Pharmaceutical Sciences, 2015, 30(2): 140-142. DOI: 10.13375 /j.cnki.wcjps.2015.02.004.
[4] OWCZARZAK V, JR H J. Comparison of oral versus rectal administration of acetaminophen with codeine in postoperative pediatric adenotonsillectomy patients.[J]. Laryngoscope, 2006, 116(8): 1485-1488. DOI: 10.1097/01.mlg.0000227530.64179.1f.
[5] BERTILLE N, FOURNIER-CHARRIèRE E, PONS G, et al. Enduring large use of acetaminophen suppositories for fever management in children: a national survey of French parents and healthcare professionals' practices[J]. European Journal of Pediatrics, 2016, 175(7): 987-992. DOI: 10.1007/s00431-016-2732-8.
[6] 鄢寒,黄月英,沈一唯,等.无定型固体分散体载体及制备技术研究进展[J]. 中国新药杂志,2017,26(4):427-432. YAN H, HUANG Y Y, SHEN Y W, et al. A review on carriers and preparation techniques of amorphous solid dispersion[J]. Chinese Journal of New Drugs, 2017, 26(4): 427-432.
[7] 李晓芳,金描真,林卓辉.茶碱脉冲栓剂的制备及其体外释药性考察[J].中国药房,2009, 20(28):2206-2208. LI X F, JIN M Z, LIN Z H. Preparation and in vitro release characterics of theophylline pulse suppository[J]. Chinese Pharmacy, 2009,20(28): 2206-2208.
[8] 黄茂胜,黄嗣航,陈求芳,等. 基于高斯过程对乙酰氨基酚在不同环境溶解机制的研究[J]. 广东药学院学报,2017,33(3):322-325. DOI: 10.16809/j.cnki.2096-3653.2017031301. HUANG M S, HUANG S H, CHEN Q F, et al. Study on dissolution mechanism of paracetamol in different environments by Gaussian Process [J]. Journal of Guangdong Pharmaceutical University, 2017, 33(3): 322-325. DOI: 10.16809/j.cnki.2096-3653.2017031301.
[9] ALNEMRAWI N K, DAVE R H. Formulation and characterization of acetaminophen nanoparticles in orally disintegrating films[J]. Drug Delivery, 2016, 23(2): 540-549. DOI: 10.3109/10717544.2014.936987.
[10] MATSUMOTO K, KIMURA S, TAKAHASHI K, et al. Pharmaceutical studies on and clinical application of olanzapine suppositories prepared as a hospital preparation[J]. Journal of Pharmaceutical Health Care & Sciences, 2016, 2(1): 1-7. DOI: 10.1186/s40780-016-0055-6.
[11] LIU G, DONG L, LU K, et al. Preparation and in vivo pharmacokinetics of the Tongshu suppository[J]. Biomed Research International, 2016, 2016: 1691579. DOI: 10.1155/2016/1691579.
[12] 何晨,田茜,贺敬霞,等. 柿叶总黄酮固体分散体的制备[J]. 中成药,2017,39(2):417-420. DOI: 10. 3969 /j.issn.1001-1528.2017.02.042. HE C, TIAN Q, HE J X, et al. Preparation of persimmon leaf flavonoids solid dispersion[J]. Chinese Traditional Patent Medicine, 2017, 39(2): 417-420. DOI: 10. 3969 /j.issn.1001-1528.2017.02.042.
[13] 杨文智,李霞霞,王树根,等. 格列美脲水凝胶剂体内外透皮释放的评价[J]. 河北大学学报(自然科学版),2015,35(6):599-604. DOI: 10.3969/j.issn.1000-1565.2015.06.008. YANG W Z, LI X X, WANG S G, et al. The drug release evaluation of glimepiride hydrogel in vitro and in vivo[J]. Journal of Hebei University(Natural Science Edition), 2015, 35(6): 599-604. DOI: 10.3969/j.issn.1000-1565.2015.06.008.