中国药学杂志

Model Drug	Type	Prescription Composition	Outcome	References
Budesonide	thermosensitive	0.002% budesonide, 18.31% P407, 2.00% P188,0.93% HPMC	rectal retention for 6 h and no leakage	[60]
Levosulpiride	thermosensitive	1% levosulpiride, 17% P407, 15% P188,3% Tween-80	increased dissolution, plasma concentration and AUC 1.7 times	[61]
Harmine	thermosensitive	1.2% harmine, 0.93% HPMC, 2.13% P188,20.7% P407, 0.02% benzalkonium bromide	rectal retention for 6h and induced apoptosis of CT26 cells	[62]
Chuanhuning	thermosensitive	10% chuanhuning, 18% P407,6% P188,0.5% benzyl alcohol, 6% HP-β-CD	gelation temperature(36.5±0.5)℃, preparations valid for 1.57 years	[63]
Metoclopramide hydrochloride	thermosensitive	2% metoclopramide hydrochloride, 25% P407,2.5% HPMC	sustained release over 8 h, bioavailability higher than oral administration	[64]
5-Fluorouracil	thermosensitive	18% P407, 0.5% sodium alginate, 0.4% PEG4000	stable quality and drug release	[65]
Protein	thermosensitive	P407、P188、MK4M	fast sol-gel transition at body temperature	[66]
Fenoterol hydrobromide	thermosensitive	25% P407, 15% P188, 0.6% sodium alginate	delayed drug release and can prevent histamine-induced bronchospasm in guinea pigs	[67]
Diclofenac sodium	thermosensitive	1.25% diclofenac sodium, 8.75% P407, 7.5% P188	good correlation in vivo and in vitro	[68]
5-Fluorouracil	thermosensitive	1% 5-Fu, 17% P407, 2.5% P188	higher than solid suppositories and intravenous administration	[69]
Epirubicin	pH-thermosensitive	50 μg·mL^-1Epi, 14%P407, 0.75%PAA	inhibition of tumor growth in mice	[70]
5-Fluorouracil	w/o microemulsion-thermo- sensitive	P407, P188, sodium alginate	increased permeability and no damage to the rectum	[37]
Baicalin	liposome-thermosensitive	18.9% P407, 5.9% P188, 0.59% K90	good stability, no irritation	[40]
5-Fluorouracil	cyclodextrin inclusion com- plex-thermosensitive	15% 5-Fu-HP-β-CD-inclusion complex,18.5% P407, 2.5% P188, 0.2% HPMC	increased permeability without stimulation	[43]
Irinotecan	SLNs-thermosensitive	10% SLNs, 15% P407, 17g P188, 4% Tween-80	sustained release of drugs, no damage	[46]
Tizanidine HCl	nanotransfersomes-thermosensitive	21% P407, 3% P188, 0.8% HPMC	bioavailability increased by about 2.18 times and t_1/2 extended by about 10 h	[49]
Ibuprofen	solid dispersion-thermosensitive	3% IBU, 20% P407, 1% HPMC	pharmacokinetic parameters were higher than those of solid suppositories and did not stimulate	[52]
Duloxetine HCl	nanoplatform-thermosensitive	0.8% DXH, 20% P407, 3% P188, 0.5% adhesive	bioavailability is 2.24 times higher than oral	[57]
Docetaxel	bile salt-nanomicelles-thermosensitive	0.25% DCT, 11% P407,15% P188, 10% Tween-80, 0.1% NatC	high bioavailability and significant antitumor effect	[58]

Model Drug	Type	Prescription Composition	Outcome	References
Budesonide	thermosensitive	0.002% budesonide, 18.31% P407, 2.00% P188,0.93% HPMC	rectal retention for 6 h and no leakage	[60]
Levosulpiride	thermosensitive	1% levosulpiride, 17% P407, 15% P188,3% Tween-80	increased dissolution, plasma concentration and AUC 1.7 times	[61]
Harmine	thermosensitive	1.2% harmine, 0.93% HPMC, 2.13% P188,20.7% P407, 0.02% benzalkonium bromide	rectal retention for 6h and induced apoptosis of CT26 cells	[62]
Chuanhuning	thermosensitive	10% chuanhuning, 18% P407,6% P188,0.5% benzyl alcohol, 6% HP-β-CD	gelation temperature(36.5±0.5)℃, preparations valid for 1.57 years	[63]
Metoclopramide hydrochloride	thermosensitive	2% metoclopramide hydrochloride, 25% P407,2.5% HPMC	sustained release over 8 h, bioavailability higher than oral administration	[64]
5-Fluorouracil	thermosensitive	18% P407, 0.5% sodium alginate, 0.4% PEG4000	stable quality and drug release	[65]
Protein	thermosensitive	P407、P188、MK4M	fast sol-gel transition at body temperature	[66]
Fenoterol hydrobromide	thermosensitive	25% P407, 15% P188, 0.6% sodium alginate	delayed drug release and can prevent histamine-induced bronchospasm in guinea pigs	[67]
Diclofenac sodium	thermosensitive	1.25% diclofenac sodium, 8.75% P407, 7.5% P188	good correlation in vivo and in vitro	[68]
5-Fluorouracil	thermosensitive	1% 5-Fu, 17% P407, 2.5% P188	higher than solid suppositories and intravenous administration	[69]
Epirubicin	pH-thermosensitive	50 μg·mL^-1Epi, 14%P407, 0.75%PAA	inhibition of tumor growth in mice	[70]
5-Fluorouracil	w/o microemulsion-thermo- sensitive	P407, P188, sodium alginate	increased permeability and no damage to the rectum	[37]
Baicalin	liposome-thermosensitive	18.9% P407, 5.9% P188, 0.59% K90	good stability, no irritation	[40]
5-Fluorouracil	cyclodextrin inclusion com- plex-thermosensitive	15% 5-Fu-HP-β-CD-inclusion complex,18.5% P407, 2.5% P188, 0.2% HPMC	increased permeability without stimulation	[43]
Irinotecan	SLNs-thermosensitive	10% SLNs, 15% P407, 17g P188, 4% Tween-80	sustained release of drugs, no damage	[46]
Tizanidine HCl	nanotransfersomes-thermosensitive	21% P407, 3% P188, 0.8% HPMC	bioavailability increased by about 2.18 times and t_1/2 extended by about 10 h	[49]
Ibuprofen	solid dispersion-thermosensitive	3% IBU, 20% P407, 1% HPMC	pharmacokinetic parameters were higher than those of solid suppositories and did not stimulate	[52]
Duloxetine HCl	nanoplatform-thermosensitive	0.8% DXH, 20% P407, 3% P188, 0.5% adhesive	bioavailability is 2.24 times higher than oral	[57]
Docetaxel	bile salt-nanomicelles-thermosensitive	0.25% DCT, 11% P407,15% P188, 10% Tween-80, 0.1% NatC	high bioavailability and significant antitumor effect	[58]

Model Drug	In vitro model	Release conditions	Outcome	Mechanism	Kinetic model	References
Morphine	membrane-free release	purification water	9 h dissolution 92%		zero-order kinetics	[79]
Morphine sulfate	membrane-free release	purification water	9 h dissolution 92%		zero-order kinetics	[80]
Ibuprofen	membrane-free release	pH 7.4 phosphate-buffered	7 h released 98.1%	dissolution	zero-order kinetics	[81]
Ibuprofen-SLNs	dialysis bag-paddle method	pH 6.8 phosphate-buffered	20 h released 80%	diffusion	Higuchi	[72]
Insulim	membrane-free release	saline water	3 h released 90%	diffusion		[82]
	bovine intestinal mucosa	saline water	7 h released 80%	dissolution	Hixson-crowell
	sheep intestinal mucosa	saline water	7 h released 80%	diffusion and diffusion	Ritger-Peppas
	dialysis bag	artificial intestinal juice		diffusion and diffusion	Ritger-Peppas
Ketoprofen	dialysis tube、dissolution apparatus	pH 7.2 phosphate-buffered	8 h released 60%		Higuchi	[83]
Nimesulide	dialysis bag-paddle method	pH 9.1 borate buffer	8 h released 85%	diffusion and diffusion	Ritger-Peppas	[84]
Baicalin	dialysis bag-paddle method	pH 9.18 borate buffer			Ritger-Peppas	[85]

Model Drug	In vitro model	Release conditions	Outcome	Mechanism	Kinetic model	References
Morphine	membrane-free release	purification water	9 h dissolution 92%		zero-order kinetics	[79]
Morphine sulfate	membrane-free release	purification water	9 h dissolution 92%		zero-order kinetics	[80]
Ibuprofen	membrane-free release	pH 7.4 phosphate-buffered	7 h released 98.1%	dissolution	zero-order kinetics	[81]
Ibuprofen-SLNs	dialysis bag-paddle method	pH 6.8 phosphate-buffered	20 h released 80%	diffusion	Higuchi	[72]
Insulim	membrane-free release	saline water	3 h released 90%	diffusion		[82]
	bovine intestinal mucosa	saline water	7 h released 80%	dissolution	Hixson-crowell
	sheep intestinal mucosa	saline water	7 h released 80%	diffusion and diffusion	Ritger-Peppas
	dialysis bag	artificial intestinal juice		diffusion and diffusion	Ritger-Peppas
Ketoprofen	dialysis tube、dissolution apparatus	pH 7.2 phosphate-buffered	8 h released 60%		Higuchi	[83]
Nimesulide	dialysis bag-paddle method	pH 9.1 borate buffer	8 h released 85%	diffusion and diffusion	Ritger-Peppas	[84]
Baicalin	dialysis bag-paddle method	pH 9.18 borate buffer			Ritger-Peppas	[85]

直肠原位凝胶的应用研究进展

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雷晓萌 ¹^,² , 吴玉欢 ¹^,² , 彭颖 ¹^,² , 王灿坚 ¹^,² , 阳涛 ¹ , 李东勲 ¹^,² , 张国松 ¹^,²^,^* , 张文锍 ¹^,²^,^*

中国药学杂志 | 综述 2024,59(2): 101-110

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中国药学杂志 | 综述 2024, 59(2): 101-110

直肠原位凝胶的应用研究进展

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雷晓萌¹^,², 吴玉欢¹^,², 彭颖¹^,², 王灿坚¹^,², 阳涛¹, 李东勲¹^,², 张国松¹^,²^,^*, 张文锍¹^,²^,^*

作者信息

¹ 江西中医药大学, 南昌 330006

² 中药固体制剂制造技术国家工程研究中心, 南昌 330006

雷晓萌,女,硕士研究方向:药物新剂型与新技术研究

通讯作者:

*张文锍,男,副教授,硕士生导师研究方向:中药新型给药系统的研究;

张国松,男,教授,博士生导师研究方向:药物新剂型与新技术研究 Tel:(0791)87119623

Research Progress in the Application of Rectal in Situ Gel

LEI Xiaomeng¹^,², WU Yuhuan¹^,², PENG Ying¹^,², WANG Canjian¹^,², YANG Tao¹, LI Dongxun¹^,², ZHANG Guosong¹^,²^,^*, ZHANG Wenliu¹^,²^,^*

Affiliations

¹ Jiangxi University of Chinese Medicine,Nanchang 330006, China

² National Engineering Research Center of Chinese Medicine Solid Preparation Manufacturing Technology,Nanchang 330006, China

出版时间: 2024-01-22 doi: 10.11669/cpj.2024.02.001

文章导航

摘要

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直肠原位凝胶结合凝胶剂与直肠给药的双重特点,已成为目前研究的热点。直肠原位凝胶是一类以溶液状态给药后,能在用药部位立即发生相转变,由液态相转变为非化学交联半固体凝胶的制剂,具有独特的反向热凝胶性质、良好的缓释作用和生物利用度高等特点。笔者参考近10年来国内外相关文献,从直肠原位凝胶的特点、制备工艺、质量评价方法及应用等方面进行总结,通过分析直肠原位凝胶的研究进展,为研究和开发高效的直肠给药制剂提供新的思路。

关键词

直肠给药 / 原位凝胶 / 制备工艺 / 质量评价

Abstract

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Rectal in situ gel combines the double characteristics of gel and rectal administration, and has become the focus of pharmaceutics research. Rectal in situ gel is a kind of non-chemical crosslinked semi-solid gel which can be transformed from liquid to gel immediately after administration in solution. It has unique reverse hot gel properties, good sustained release effect and high bioavailability. Referring to the relevant literature at domestic and abroad in the past 10 years, the characteristics, preparation technology, quality evaluation methods and application of rectal in situ gel were summarized.By analyzing the research progress of rectal in situ gel new ideas for the research and development of efficient rectal administration preparations are provided.

Key words

rectal administration / in situ gel / preparation technology / quality evaluation method

引用本文

雷晓萌, 吴玉欢, 彭颖, 王灿坚, 阳涛, 李东勲, 张国松, 张文锍. 直肠原位凝胶的应用研究进展. 中国药学杂志, 2024 , 59 (2) : 101 -110 . DOI: 10.11669/cpj.2024.02.001

LEI Xiaomeng, WU Yuhuan, PENG Ying, WANG Canjian, YANG Tao, LI Dongxun, ZHANG Guosong, ZHANG Wenliu. Research Progress in the Application of Rectal in Situ Gel[J]. Chinese Pharmaceutical Journal, 2024 , 59 (2) : 101 -110 . DOI: 10.11669/cpj.2024.02.001

正文

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口服给药是患者的首要选择,具有无痛、方便、经济、安全、患者依从性好和感染少等优点^[1]。然而,对于恶心、呕吐或抽搐期间极不合作的患者(老人/婴儿)^[2],直肠给药可能是一种简便、安全的替代途径。其不易受酶降解影响,是一种无创的,能够局部靶向的递药系统^[3]。传统的固体栓剂在使用过程中通常会造成患者不适,依从性差。此外,栓剂在体内融化后,可能会到达结肠末端,产生首过代谢反应^[4-5]。因此,亟需一种易于管理且具有黏附性的直肠剂型。原位凝胶直肠给药又称“液体栓剂”,不仅具有灌肠剂分布广泛的优点,而且可以在用药部位快速凝胶,实现局部特异性给药^[6]。凝胶基质主要是利用响应外界刺激(如温度、离子强度或pH)的高分子材料,使聚合物在特定生理条件下分散或聚合,通过溶液到半固体凝胶状态的转变而改善药物的局部释放,已成为近年来制剂领域研究的热点^[7]。

查阅相关文献,从直肠原位凝胶的特点、制备工艺、质量评价及应用等方面进行综述,并对直肠原位凝胶制剂研究领域存在的问题进行总结和展望,为其进一步深入研究提供参考。

1 口服给药的限制

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随着药物剂型的多样化发展,口服给药仍然是最受欢迎的给药途径,具有无痛、方便、经济、安全及患者依从性好等优点,可用于小分子到大分子等多种药物的局部和全身给药。药物口服后,体内吸收主要包括两个过程:首先,药物必须从制剂释放到消化液中,即药物的溶解过程;其次,溶解的药物透过胃肠道上皮细胞进入血液循环,即药物的渗透过程^[8]。然而,诸如低水溶性、低生物利用度、恶劣的胃肠道环境、有限的膜通透性、多药物外排转运体和高肝脏首过代谢等问题限制了药物的吸收和转运。为了克服这些缺点,目前主要采用前药^[9]、固体分散体^[10]及脂质体^[11]等方法改善药物的理化性质,以提高药物的口服生物利用度。尽管这些方法有其各自的优点,但仍存在稳定性差、制备工艺复杂及局部毒性等问题。因此,寻找新的给药方式以提高药物的生物利用度和治疗效果是当前的研究热点,而在众多可供选择的非侵入性给药途径中,直肠给药是一种安全且有希望替代口服给药的途径。

2 直肠原位凝胶的特点

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2.1 直肠给药的优点

直肠给药是口服和非肠道治疗的有效替代方法,在我国汉代已有记载^[12]。直肠是大肠末端的15~19 cm,无绒毛,皱褶少,表面积小(0.02~0.04 m²),pH约为7.5~8.0,分泌液缓冲容积小,平均温度为36.9 ℃。直肠黏膜内含丰富的血管与淋巴细胞,与直肠上静脉、直肠中静脉和直肠下静脉相连。药物经直肠上皮细胞吸收后,通过3条途径进入体循环,第1条是通过直肠下静脉、直肠中静脉和髂内静脉直接进入体循环而发挥全身作用;第2条通过直肠上静脉、肛门静脉进入肝脏,代谢后由肝脏进入体循环;第3条是直肠淋巴系统吸收部分药物,但因淋巴流量很低,故经其吸收的药量实际上很少。这三条途径均不经过胃和小肠,避免了酸、碱和消化酶对药物的影响,减轻药物对胃肠道的刺激^[13]。直肠给药的优点^[14]:①起效快、副作用少,疗效确切(有研究表明,固体栓剂30 min就能起效,口服则需1 h,而两者血药浓度维持时间基本相同);②无创且易掌握;③可起到局部或全身作用。因此,与其他给药方式相比,直肠给药具有很好的优势。

2.2 直肠原位凝胶的优点

传统的直肠给药剂型有灌肠剂和固体栓剂^[15],在体内不易保留或软化后易从直肠流出,无黏附性的固体栓剂可逐渐到达结肠末端,产生肝脏首过效应。此外,在炎热天气下,也会给运输和储存带来困难。理想的栓剂应易于给药,在给药过程中没有任何疼痛,并具有适当的黏附力,以免到达结肠末端。原位凝胶是以溶液状态给药,在用药部位立即发生相转变,由液体转变为半固体凝胶的一种制剂。其具有使用便捷、黏膜组织亲和力强、滞留时间长及释药缓慢等特点^[16],已被广泛应用于鼻腔^[17]、眼部^[18]和阴道^[19]给药等。直肠原位凝胶结合直肠给药与原位凝胶的优点,不仅克服了直肠给药传统剂型中患者用药顺应性及首过效应的缺陷,而且可以作为缓释载体与脂质体、固体脂质纳米粒及包合物等新剂型结合增加药物的稳定性,达到缓释的目的,起局部或全身作用。制剂制备方法简单,适合于工业化大生产。

3 直肠原位凝胶的分类及制备工艺

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原位凝胶的形成取决于高分子基质对外界环境的响应,利用聚合物在生理条件下发生分散或聚合的可逆变化,完成溶液-凝胶的转变过程^[20]。按凝胶机制分类,常用的原位凝胶可分为温度敏感型、离子敏感型和pH敏感型^[21]。受直肠环境的限制,pH敏感型和离子敏感型原位凝胶应用于直肠给药的相关研究较少,其多应用于眼部^[22-23]及鼻腔^[24-25]。目前研究较多的直肠原位凝胶种类有非复合型和复合型。

3.1 非复合型原位凝胶

温度敏感型原位凝胶:温度敏感型原位凝胶对温度变化有响应,即环境温度低于最低临界相变温度(lower critical solution temperature,LCST)时是液体状态,高于LCST时呈半固体凝胶状态,大部分胶凝温度在32~34 ℃之间,故其用于直肠时形成半固体凝胶,可延长药物在直肠的滞留时间,从而提高生物利用度,是目前研究最为广泛和相对成熟的一类原位凝胶^[26],凝胶机制见图1。温度敏感型原位凝胶常用的基质有泊洛沙姆、壳聚糖(chitosan,CS)和纤维素衍生物等^[27],目前研究最多的是泊洛沙姆,是一种非离子型表面活性剂,由聚氧乙烯(polyethylene oxide,PEO)与聚氧丙烯(polypropylene oxide,PPO)组成的嵌段共聚物(PEO-PPO-PEO)。具有独特的反向热凝胶性质,且生物相容性好、安全性高,已被广泛应用于食品加工和制药行业。泊洛沙姆407(Poloxamer 407,P407)、泊洛沙姆188(Poloxamer 188,P188)是使用较为广泛的凝胶基质。有研究者单用泊洛沙姆或CS作为温敏型原位凝胶基质,亦有将两者合用。然而,泊洛沙姆作为热可逆凝胶基质的应用受到其机械力低和生物黏附性差的阻碍^[28],因此将泊洛沙姆与其他生物黏附性聚合物甲基纤维素或海藻酸钠等结合。Chen等^[29]采用响应曲面法优化了一种由泊洛沙姆和羟丙基纤维素组成的布地奈德温敏型原位凝胶的处方,具有合适的黏度以适于直肠给药。

3.2 复合型原位凝胶

2种及以上的制剂结合起来制备的原位凝胶称为复合型原位凝胶。传统的微粒给药系统,如纳米粒、微球、脂质体等,存在稳定性差、制备工艺复杂及局部毒性等问题,因此微粒给药系统的应用受到一定程度的限制^[30]。原位凝胶可以克服微粒给药系统的弊端,但其存在“突释”现象^[31]。若将原位凝胶与微粒给药系统联用,药物的释放受到两层阻隔,较好地解决药物的突释问题,是一个广阔的研究前景。

3.2.1 pH-温敏双相原位凝胶

聚丙烯酸(PAA)是一种典型的pH响应型聚合物,当pH大于pKa(4.75)时形成凝胶^[32]。Ramadass等^[33]制备了一种pH-温度敏感的美沙拉嗪-胶原蛋白原位凝胶,在一定pH和温度下发生溶液-凝胶转变,且以可控的方式释放美沙拉嗪,有助于损伤黏膜的修复,从而产生治疗溃疡性结肠炎的协同效应。Lin等^[34]研制了一种可注射的泊洛沙姆-PAA奥沙利铂液体栓剂,直肠给药后的c_max和AUC值高于口服奥沙利铂溶液。由此表明,可以进一步开发一种方便有效的直肠给药形式的人用原位凝胶液体栓剂。

3.2.2 微乳-温敏原位凝胶

微乳是将药物与一定比例的油、乳化剂、助乳化剂和水制备得到热力学稳定的油水混合系统,可改善药物渗透、减少药物刺激及延长药物的释放时间^[35]。5氟尿嘧啶(5-Fu)是治疗直肠疾病的首选药物,但其血浆半衰期短,给药剂量大,有严重的骨髓抑制和胃肠道反应的毒副作用等问题^[36]。Wang等^[37]将微乳和原位凝胶首次结合,制备了一种用于直肠给药的5-Fu热敏凝胶介导的油包水微乳,延缓了药物的释放,增加了药物渗透,提高了药物稳定性,且未见直肠组织形态学损伤。

3.2.3 脂质体-温敏原位凝胶

脂质体作为一种新型给药载体,是由磷脂和胆固醇组成的双分子层结构,类似于生物膜。亲水药物分布于内外水相,疏水药物嵌在磷脂双分子层,可制得包封率较稳定的脂质体,具有靶向、无毒、可生物降解、缓释及高稳定性等特点^[38]。由于脂质体溶液的流动性,不能长时间滞留在给药部位。因此,研究人员将脂质体均匀混合在凝胶基质中制备成脂质体原位凝胶,能解决其流动性问题^[39]。Wang^[40]将黄芩苷制成脂质体温敏凝胶复合制剂,借助脂质体亲脂亲水的特性,以其为载体包裹黄芩苷,改善药物释放特性;再利用温敏凝胶能产生相变的特征,改善了常规剂型直肠给药体系的不足。Yang等^[41]利用脂质体和温敏凝胶,将布地奈德制备成脂质体后再进一步制成脂质体温敏凝胶,使其兼具脂质体和温敏凝胶的优势,实现靶向和缓释作用,提高疗效,降低不良反应。

3.2.4 包合物-温敏原位凝胶

羟丙基-β-环糊精可显著增加药物的溶解性、稳定性和生物利用度等^[42]。Wang等^[43]将5-Fu和环糊精制备成包合物后包埋在凝胶基质中形成包合物-温敏原位凝胶。结果发现,5-Fu的溶解度显著增加,且制剂具有良好的缓释效果。本课题组采用饱和水溶液法选用羟丙基-β-环糊精对美洛昔康进行包合,再进一步制成温敏凝胶,结果证明,包合物温敏凝胶具有良好的缓释作用,成功地解决了美洛昔康水溶性差、口服生物利用度低等问题。

3.2.5 固体脂质纳米粒-温敏原位凝胶

自90年代初以来,固体脂质纳米粒(solid lipid nanoparticles,SLNs)作为新型药物载体引起了广泛关注,被认为是乳剂、脂质体和聚合物纳米粒等的替代载体。结合其他药物载体的优点,可以包裹和输送亲脂和亲水化合物,使药物控制释放和靶向成为可能^[44]。Mohamed等^[45]采用高剪切均质(热均质)技术制备甲氧氯普胺-SLNs,以P407、P188和聚山梨酯80为凝胶基质,得到的SLNs-原位凝胶具有缓释作用,且给药剂量少。Din等^[46]将热敏性伊立替康SLNs分散在热敏性泊洛沙姆溶液中,制得双反向温敏纳米载体系统(DRTN)。在DRTN中,SLNs的固体形式和泊洛沙姆溶液的液体形式在25 ℃下保持不变,在36.5 ℃下,前者融化为液体,后者转变为凝胶。与传统的水凝胶和注射剂相比,具有良好的缓释作用。

3.2.6 纳米传递体-温敏原位凝胶

纳米传递体是一种超柔性脂质体,由磷脂、胆固醇和边缘活化剂组成,比传统的脂质体更具弹性,这归因于边缘活化剂的存在,能够调整脂质双分子层的膜流动性,增加其变形性和灵活性^[47]。边缘活化剂是具有高曲率半径的单链表面活性剂,如司盘、聚山梨酯、甘草酸二钾、胆酸钠和脱氧胆酸钠等都可被用作边缘活化剂^[48]。Moawad等^[49]将纳米传递体与温敏性原位凝胶结合,制备盐酸替扎尼定(Tizanidine HCl,TiZ)纳米传递体温敏原位凝胶,达到了延长TiZ释放和提高生物利用度的双重目的。

3.2.7 固体分散体-温敏原位凝胶

固体分散体用于改善药物的溶解度,特别是难溶性药物^[50]。布洛芬(Ibuprofen,IBU)水溶性低,生物半衰期短(0.5~2 h),频繁给药会刺激胃肠道,加重肾脏负担^[51]。Liu等^[52]结合P407和黏附性聚合物[羟丙甲基纤维素(HPMC)、海藻酸钠]将IBU通过固体分散体技术制备成原位凝胶,结果表明,IBU溶解度显著提高,且与栓剂相比,有更好的体外释药效果和更高的生物利用度。表明IBU直肠原位凝胶作为一种更方便、更有效的非甾体抗炎直肠给药剂型具有潜在的应用前景,特别是对婴儿和儿童。

3.2.8 甘油体-温敏原位凝胶

脂质体是第一代以磷脂为基础的囊泡,由一个或多个围绕水核的脂质双分子层组成,能够包裹各种亲水或亲脂的药物分子^[53]。在过去的几十年里,各种添加剂,如乙醇和表面活性剂等被用来改变脂质体的物理化学性质,使药物能够更有效地穿过生物膜^[54]。新一代脂质体如醇质体、转移体和甘油体等,常用于真皮、透皮、黏膜和直肠给药^[55-56]。甘油体(glycerosome,GLYS)于2012年首次被引入,是一种新型的柔性囊泡型纳米载体。甘油改变磷脂双分子层流动性,增强了GLYS的通透性,从而改善了甘油体的渗透和吸收^[57]。Salem等^[58]制备了盐酸度洛西汀甘油体直肠原位凝胶,结果表明,其渗透率和生物利用度均得到了提高,且抗抑郁疗效优于口服给药。

3.2.9 吸收促进剂-纳米胶束-温敏原位凝胶

为了改善BCS Ⅳ类药物低溶解性及低渗透性的问题,人们尝试了微粒给药系统、前药和吸收促进剂等方法对其理化性质进行改善。但上述方法的药物效果甚微。因此,Kim等^[59]采用冷法制备了具有热敏性和黏附性的泊洛沙姆纳米胶束,并利用吸收促进剂胆盐(牛磺胆酸钠)提高了多西紫杉醇的生物利用度和抗肿瘤疗效。

近年来应用于直肠给药的各种原位凝胶见表1。

4 直肠原位凝胶质量控制的相关参数研究

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直肠原位凝胶是一种新型给药系统,为保证直肠给药的安全性和有效性,完善制剂质量评价方法非常重要。参考近几年的研究报道,直肠原位凝胶的质量评价方法主要包括:体外和体内两方面。体外评价主要包括凝胶的外观形态、胶凝温度、胶凝时间、流变学性质、载药量及体外释放等;体内评价主要包括安全性、直肠滞留时间、药动学和药效学等。传统的直肠给药剂型主要包括灌肠剂和栓剂。在质量控制相关参数研究方面,2020年版《中国药典》中灌肠剂通则项下仅包含装量和微生物限度检查项,在其他方面的研究甚少;栓剂除2020年版《中国药典》规定的通则项检查外,如融变时限等,在体内外释药行为等方面尚有研究报道。总体而言,相较于直肠原位凝胶,对灌肠剂和栓剂两种剂型特性相关的质量控制参数研究较少,缺乏系统性。

4.1 直肠原位凝胶的体外质量评价

4.1.1 胶凝温度

温敏型原位凝胶常以胶凝温度为评价指标,是原位凝胶重要的物理性质之一。胶凝温度在33~37 ℃之间是直肠原位凝胶给药的先决条件。一般来说,较低的凝胶温度(30 ℃)可能会出现给药困难的情况,而较高的胶凝温度(37 ℃)会导致凝胶渗漏的结果。常用的测定胶凝温度的方法有目测法、磁力搅拌法和流变学法。Liu等^[52]制备了IBU直肠用温敏型原位凝胶,并采用磁力搅拌法对该制剂的胶凝温度进行了测定。Tenci等^[71]采用流变学方法对直肠原位凝胶的胶凝温度进行测定,通过测定该凝胶20至40 ℃过程中储存模量G'和损耗模量G″的变化,确定其胶凝温度。因磁力搅拌法影响因素较多,采用流变学方法的测定结果更准确。

4.1.2 胶凝时间

原位凝胶从液体转变为凝胶所需的时间称为胶凝时间。原位凝胶的胶凝性决定了给药剂量的准确性,胶凝时间越短,药物流失越慢,发生“突释”反应的可能性越小。胶凝时间的测定方法有试管倒置法和流变学方法。多数文献中将原位凝胶溶液置于西林瓶或离心管中,放入温度可控约37 ℃的恒温水浴锅中,待溶液凝胶后,记录该过程的时间即为胶凝时间。Lei等^[72]制备了包合物温度敏感原位凝胶,将装有凝胶的小瓶浸入37 ℃恒温水浴锅中,隔半分钟倾斜观察样品状态变化,记录达到凝胶时所需的时间为胶凝时间。

4.1.3 流变学性质

流变学指标通常包括黏度、黏附力和胶凝强度等。黏度是温敏型原位凝胶的评价指标之一,多采用旋转黏度计测定黏度。Li等^[73]用黏度计测定了凝胶和溶液两种形式的黏度。当原位凝胶具有合适的黏附力,药物才能在给药部位滞留一定时间,防止从肛门漏出。因此,生物黏附力是评价原位凝胶质量的重要指标之一。Han等^[74]制备了赖氨酸布洛芬缓释液体栓剂,并采用剥离试验测其生物黏附力,将黏膜分别牢固黏附于上、下平板,固定其中一块平板,再将样品置于两块黏膜中间,压紧,90°或180°拉另一块平板,直到凝胶与黏膜完全分离,此时的剥离力即为生物黏附力。Yeo等^[75]制备了多西紫杉醇液体栓剂,并通过自制装置测其黏附力。凝胶强度是液体栓剂在体温下黏度的一个指标,这对于液体栓剂是否容易给药而不渗漏至关重要。合适的凝胶强度必须在10~50 s范围内,低于10 s可能会从肛门流出,高于50 s过于僵硬,可能会导致直肠不适^[76]。Xiong等^[77]采用实验室自制装置,用约35 g圆盘从凝胶上端下降5 cm所需时间来衡量凝胶强度的大小。

4.1.4 药物含量

药物含量是评价凝胶质量的关键。目前对于直肠原位凝胶的药物含量测定一般釆用高效液相色谱法(HPLC)。Chen等^[78]将制备的氟尿嘧啶原位凝胶利用具有高灵敏度HPLC进行测定,结果表明,该方法能够快速准确地测定出氟尿嘧啶含量,且药物含量均一稳定。

4.1.5 体外释放

体外释放指的是药物从原位凝胶中释放到接收介质的过程,是评价凝胶释药行为的重要指标。由于直肠容积小,肠液量约为2~3 mL,目前尚未见统一的直肠给药制剂体外释放测定方法及装置。常用的体外释放模型有2种,一种是有膜释放模型,以药物的溶出和扩散为主,主要有Franz扩散池法以及透析袋法,释放机制通常符合Higuchi方程;另一种是无膜释放模型,凝胶直接与释放介质接触,凝胶的溶蚀是药物释放的主要机制,可更好地模拟体内环境考察凝胶溶蚀及药物释放动力学。通过对近10年来直肠原位凝胶的体外释放评价方法的总结(表2),发现不论是采用哪种模型进行体外释放评价,直肠原位凝胶对药物都有良好的缓释效果。直肠原位凝胶的释放过程及吸收途径见图2。

4.2 直肠原位凝胶的体内评价

直肠原位凝胶的体内评价主要包括安全性、直肠滞留时间、药动学和药效学,主要是利用动物模型考察其在体内的作用特点。

4.2.1 安全性评价

原位凝胶的安全性评价一般为动物给药部位黏膜的刺激性和毒性评价。不同给药部位刺激性的评价方式不同。对于直肠原位凝胶来说,常用的动物主要有家兔和大小鼠,观察指标则是动物在直肠给药后的全身毒性反应以及直肠部位的局部病理变化。Al-Joufi等^[86]制备了利福平直肠原位凝胶,毒性研究显示其直肠损伤不明显,见图3。Chen等^[87]以家兔为实验对象,观察使用咪达唑仑原位凝胶7 d后的直肠黏膜无明显变化,实验发现直肠细胞形态无异常,无明显刺激性。刺激性研究表明直肠给药的安全性和可接受性,以符合直肠给药制剂的规定。

4.2.2 直肠滞留时间

局部给药系统应具有足够的黏度和强度,能附着在黏膜表面,避免在体内被破坏。而直肠滞留时间是为了确保温敏型原位凝胶在直肠内的凝胶状态、位置及滞留时间。主要的测定方法包括:①用灌胃针将含有亚甲基蓝染料的直肠温敏凝胶1 mL经肛门,给予至肛门以上4 cm直肠段,分别于给药后一定时间内,观察大鼠肛门周围毛色,以判断泄漏情况,处死动物解剖并观察凝胶在直肠的分布范围及黏附情况;②以荧光为标记物,利用小动物活体成像技术模拟温敏型原位凝胶在动物直肠的滞留性能。Wang等^[88]比较了5-Fu温敏型原位凝胶与5-Fu水溶液的直肠内滞留情况。Zhao^[89]以新吲哚菁绿为标记物,用来模拟布地奈德脂质体温敏型原位凝胶在小鼠直肠内的滞留情况。

4.2.3 药动学评价

药动学通常是利用动物模型结合相应的参数考察制剂的吸收作用。Akl等^[90]研究了托美汀钠液体栓剂体内药动学,与市售Rhumtol^®胶囊相比,生物利用度提高了4.6倍。Yong等^[91]以大鼠为实验对象研究双氯芬酸钠液体栓剂体内药动学,发现液体栓剂较固体栓剂具有更高的血药浓度和t_max,且吸收更快。

4.2.4 药效学评价

药效学评价通常是利用动物模型与细胞模型结合相应检测指标考察制剂的治疗效果。例如,Xue等^[92]采用葡聚糖硫酸钠(DSS)建立溃疡性结肠炎(UC)小鼠模型,通过炎症症状缓解程度、结肠长度、结肠MPO水平和结肠镜检查,全面评价康复心液温敏凝胶对UC的治疗作用。Ramadass等^[93]制备了一种pH-温度敏感的美沙拉嗪-胶原蛋白原位凝胶用于治疗DSS诱导的小鼠UC模型,结果表明其以可控的方式释放美沙拉嗪,并促进受损黏膜的恢复。

5 直肠原位凝胶的应用

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直肠给药有效避免肝脏首过效应,适用于不能注射和不便口服的药物。直肠原位凝胶通过长时间附着在给药部位而缓慢释放药物,避免了峰谷峰底的出现,从而维持了体内良好的血药浓度。相较于传统直肠制剂,有效改善了药物生物利用度,患者用药依从性,同时避免了对非病灶部位的伤害。迄今为止,已在止吐药、精神药、抗癌药及止痛药等方面有广泛应用。

5.1 止吐药

口服或静脉注射是止吐药常用的给药方式,易受到急性呕吐或侵入性非肠道给药的阻碍,患者依从性差^[94]。针对呕吐的典型问题,直肠途径可以作为一种替代途径。昂丹司琼是一种5-HT₃拮抗剂,用于预防和治疗恶心呕吐^[95]。Ban等^[96]开发了由P407、P188和HPMC组成的温敏型昂丹司琼液体栓剂,可用于吞咽困难的患者。盐酸甲氧氯普胺是一种有效的止吐药,用于预防各种形式的呕吐,半衰期短,需频繁给药^[97]。El-Sonbaty^[98]等使用P407/P188/HPMC将盐酸甲氧氯普胺制成一种热可逆液体栓剂。这说明直肠原位凝胶可能成为一种有前途用于胃肠外治疗呕吐的替代品。

5.2 精神药

精神类药物的主要给药途径是口服给药,然而,在病人转送至医院的过程中或医务人员到达延误的情况下,亟需一种更快捷的给药方式。目前已有的替代给药方式有直肠或静脉给药。其中静脉给药效果最为迅速,但其存在注射疼痛或注射部位发炎等问题。因此,通常选用直肠给药作为口服给药的替代给药方式。Montazam等^[99]采用泊洛沙姆作为地西泮液体栓剂的基质,用于治疗癫痫。El-Kamel等^[100]通过P407、P188和甲基纤维素(MC)制备了卡马西平(CBZ)液体栓剂,与CBZ口服混悬液相比,液体栓剂的相对生物利用度为97.7%。

5.3 抗癌药

抗癌药给药方式多样,诸如静脉、口服、皮下和肌肉等。然而,抗癌药物通常具有较强毒性,因此可采用直肠给药将药物毒性降至最低。Li等^[73]制备了一种骆驼蓬碱直肠原位凝胶,用于结肠癌的治疗。Chen等^[101]以P407为基质制备了具有合适胶凝温度和胶凝强度的姜黄素液体栓剂。Zhang等^[102]制备了一种L-亮氨酸温敏凝胶,用于治疗直肠癌。因此,直肠原位凝胶可为结直肠癌的治疗提供基础。

5.4 止痛药

止痛药通常是口服片剂或胶囊剂,然口服给药使其无法发挥良好的止痛效果。而Salatin等^[103]将热敏液体栓剂与镇痛药舒马曲坦联合应用,并以P407和CS作为凝胶基质,制备成原位凝胶,为克服首过代谢,减少给药次数和给药剂量的研究提供了基础。

6 问题与展望

收起

由于受到传统观念的影响,直肠给药系统的研发与应用一直较少,2017年国家重大专项鼓励开展适宜儿童直肠给药的关键技术研究,表明了对直肠给药系统研发的高度重视。直肠给药技术有利于提高用药安全性、有效性和顺应性,并且可以在紧急情况下(昏迷或呕吐的人)给药。直肠原位凝胶独特的溶液-凝胶转变性质可使药物在直肠的滞留时间增加,减少给药次数,可有效调节药物的释放,增强患者依从性。

本研究总结了基于不同原理制备的各类药物直肠原位凝胶及体内外评价研究,系统分析了剂型设计特点、处方组成、制备工艺、体内外释药行为及制剂学相关特性等相关内容,为直肠递药系统的设计、构建与评价提供了思路与指导。此外,综述了直肠原位凝胶制剂技术在止吐药、精神药、抗癌药及止痛药等方面的研究与应用,为直肠原位凝胶新产品开发提供了方向。直肠原位凝胶虽具有良好的开发前景,但在实际的研究与应用中仍然面临着诸多问题:①使用部分高分子材料时,生物相容性低,所需浓度较大,这对黏膜有一定的刺激性,从而引起一些不良反应;②目前研究较多的还是以泊洛沙姆为基质的温敏型原位凝胶,凝胶基质与药物成分可能会发生相互作用而影响制剂质量及治疗效果,且凝胶基质材料种类少,不能满足日益多样化的临床需求;③原位凝胶的制备方法及质量控制缺乏统一的标准^[104];④直肠原位凝胶相关研究报道多为处方筛选及质量控制方面,少见药理、药动学及临床应用方面的研究;⑤原位凝胶的“突释”问题,凝胶从溶液转变为半固态的这段时间,是以液体形式存在,此时黏度较小,容易造成“突释”效应,因此有必要结合其他技术解决药物在原位凝胶中的“突释”问题;⑥原位凝胶的体内释药动力学研究以及相关临床应用研究还不完善,目前应用最多的还是治疗局部结肠炎/癌,全身的药效学研究很少;⑦大多数原位凝胶仅设计用于递送单一活性成分^[105],对于中药复方有效成分研究较少。

因此,基于原位凝胶制剂在其他黏膜系统如眼、鼻、颊及阴道等广泛应用的基础上,聚焦上述问题与挑战,系统开展直肠原位凝胶载体材料、制剂关键技术、制剂特性评价、药物吸收机制及体内传递过程等共性技术研究,突破关键共性技术问题,加快推动原位凝胶制剂技术在药物制剂当中的应用是此领域的重要方向。

基金

收起

国家自然科学基金项目资助(81960720)
江西省主要学科学术和技术带头人资助项目(20182BCB22023)
南昌市高层次科技创新人才“双百计划”项目资助
江西中医药大学博士科研启动基金项目资助(2021BSZR014)
江西省大学生创新创业训练计划项目资助(S202210412091)

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2024年第59卷第2期

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doi: 10.11669/cpj.2024.02.001

接收时间：2022-08-16
首发时间：2025-11-13
出版时间：2024-01-22

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收稿日期：2022-08-16

基金

国家自然科学基金项目资助(81960720)

江西省主要学科学术和技术带头人资助项目(20182BCB22023)

南昌市高层次科技创新人才“双百计划”项目资助

江西中医药大学博士科研启动基金项目资助(2021BSZR014)

江西省大学生创新创业训练计划项目资助(S202210412091)

作者信息

¹ 江西中医药大学, 南昌 330006

² 中药固体制剂制造技术国家工程研究中心, 南昌 330006

通讯作者:

*张文锍,男,副教授,硕士生导师研究方向:中药新型给药系统的研究;

张国松,男,教授,博士生导师研究方向:药物新剂型与新技术研究 Tel:(0791)87119623

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Model Drug	Type	Prescription Composition	Outcome	References
Budesonide	thermosensitive	0.002% budesonide, 18.31% P407, 2.00% P188,0.93% HPMC	rectal retention for 6 h and no leakage	[60]
Levosulpiride	thermosensitive	1% levosulpiride, 17% P407, 15% P188,3% Tween-80	increased dissolution, plasma concentration and AUC 1.7 times	[61]
Harmine	thermosensitive	1.2% harmine, 0.93% HPMC, 2.13% P188,20.7% P407, 0.02% benzalkonium bromide	rectal retention for 6h and induced apoptosis of CT26 cells	[62]
Chuanhuning	thermosensitive	10% chuanhuning, 18% P407,6% P188,0.5% benzyl alcohol, 6% HP-β-CD	gelation temperature(36.5±0.5)℃, preparations valid for 1.57 years	[63]
Metoclopramide hydrochloride	thermosensitive	2% metoclopramide hydrochloride, 25% P407,2.5% HPMC	sustained release over 8 h, bioavailability higher than oral administration	[64]
5-Fluorouracil	thermosensitive	18% P407, 0.5% sodium alginate, 0.4% PEG4000	stable quality and drug release	[65]
Protein	thermosensitive	P407、P188、MK4M	fast sol-gel transition at body temperature	[66]
Fenoterol hydrobromide	thermosensitive	25% P407, 15% P188, 0.6% sodium alginate	delayed drug release and can prevent histamine-induced bronchospasm in guinea pigs	[67]
Diclofenac sodium	thermosensitive	1.25% diclofenac sodium, 8.75% P407, 7.5% P188	good correlation in vivo and in vitro	[68]
5-Fluorouracil	thermosensitive	1% 5-Fu, 17% P407, 2.5% P188	higher than solid suppositories and intravenous administration	[69]
Epirubicin	pH-thermosensitive	50 μg·mL^-1Epi, 14%P407, 0.75%PAA	inhibition of tumor growth in mice	[70]
5-Fluorouracil	w/o microemulsion-thermo- sensitive	P407, P188, sodium alginate	increased permeability and no damage to the rectum	[37]
Baicalin	liposome-thermosensitive	18.9% P407, 5.9% P188, 0.59% K90	good stability, no irritation	[40]
5-Fluorouracil	cyclodextrin inclusion com- plex-thermosensitive	15% 5-Fu-HP-β-CD-inclusion complex,18.5% P407, 2.5% P188, 0.2% HPMC	increased permeability without stimulation	[43]
Irinotecan	SLNs-thermosensitive	10% SLNs, 15% P407, 17g P188, 4% Tween-80	sustained release of drugs, no damage	[46]
Tizanidine HCl	nanotransfersomes-thermosensitive	21% P407, 3% P188, 0.8% HPMC	bioavailability increased by about 2.18 times and t_1/2 extended by about 10 h	[49]
Ibuprofen	solid dispersion-thermosensitive	3% IBU, 20% P407, 1% HPMC	pharmacokinetic parameters were higher than those of solid suppositories and did not stimulate	[52]
Duloxetine HCl	nanoplatform-thermosensitive	0.8% DXH, 20% P407, 3% P188, 0.5% adhesive	bioavailability is 2.24 times higher than oral	[57]
Docetaxel	bile salt-nanomicelles-thermosensitive	0.25% DCT, 11% P407,15% P188, 10% Tween-80, 0.1% NatC	high bioavailability and significant antitumor effect	[58]

Model Drug

Type

Prescription Composition

Outcome

References

Budesonide

thermosensitive

0.002% budesonide, 18.31% P407, 2.00% P188,0.93% HPMC

rectal retention for 6 h and no leakage

[60]

Levosulpiride

thermosensitive

1% levosulpiride, 17% P407, 15% P188,3% Tween-80

increased dissolution, plasma concentration and AUC 1.7 times

[61]

Harmine

thermosensitive

1.2% harmine, 0.93% HPMC, 2.13% P188,20.7% P407, 0.02% benzalkonium bromide

rectal retention for 6h and induced apoptosis of CT26 cells

[62]

Chuanhuning

thermosensitive

10% chuanhuning, 18% P407,6% P188,0.5% benzyl alcohol, 6% HP-β-CD

gelation temperature(36.5±0.5)℃, preparations valid for 1.57 years

[63]

Metoclopramide hydrochloride

thermosensitive

2% metoclopramide hydrochloride, 25% P407,2.5% HPMC

sustained release over 8 h, bioavailability higher than oral administration

[64]

5-Fluorouracil

thermosensitive

18% P407, 0.5% sodium alginate, 0.4% PEG4000

stable quality and drug release

[65]

Protein

thermosensitive

P407、P188、MK4M

fast sol-gel transition at body temperature

[66]

Fenoterol hydrobromide

thermosensitive

25% P407, 15% P188, 0.6% sodium alginate

delayed drug release and can prevent histamine-induced bronchospasm in guinea pigs

[67]

Diclofenac sodium

thermosensitive

1.25% diclofenac sodium, 8.75% P407, 7.5% P188

good correlation in vivo and in vitro

[68]

5-Fluorouracil

thermosensitive

1% 5-Fu, 17% P407, 2.5% P188

higher than solid suppositories and intravenous administration

[69]

Epirubicin

pH-thermosensitive

50 μg·mL^-1Epi, 14%P407, 0.75%PAA

inhibition of tumor growth in mice

[70]

5-Fluorouracil

w/o microemulsion-thermo-
sensitive

P407, P188, sodium alginate

increased permeability and no damage to the rectum

[37]

Baicalin

liposome-thermosensitive

18.9% P407, 5.9% P188, 0.59% K90

good stability, no irritation

[40]

5-Fluorouracil

cyclodextrin inclusion com-
plex-thermosensitive

15% 5-Fu-HP-β-CD-inclusion complex,18.5% P407, 2.5% P188, 0.2% HPMC

increased permeability without stimulation

[43]

Irinotecan

SLNs-thermosensitive

10% SLNs, 15% P407, 17g P188, 4% Tween-80

sustained release of drugs, no damage

[46]

Tizanidine HCl

nanotransfersomes-thermosensitive

21% P407, 3% P188, 0.8% HPMC

bioavailability increased by about 2.18 times and t_1/2 extended by about 10 h

[49]

Ibuprofen

solid dispersion-thermosensitive

3% IBU, 20% P407, 1% HPMC

pharmacokinetic parameters were higher than those of solid suppositories and did not stimulate

[52]

Duloxetine HCl

nanoplatform-thermosensitive

0.8% DXH, 20% P407, 3% P188, 0.5% adhesive

bioavailability is 2.24 times higher than oral

[57]

Docetaxel

bile salt-nanomicelles-thermosensitive

0.25% DCT, 11% P407,15% P188, 10% Tween-80, 0.1% NatC

high bioavailability and significant antitumor effect

[58]

Model Drug	In vitro model	Release conditions	Outcome	Mechanism	Kinetic model	References
Morphine	membrane-free release	purification water	9 h dissolution 92%		zero-order kinetics	[79]
Morphine sulfate	membrane-free release	purification water	9 h dissolution 92%		zero-order kinetics	[80]
Ibuprofen	membrane-free release	pH 7.4 phosphate-buffered	7 h released 98.1%	dissolution	zero-order kinetics	[81]
Ibuprofen-SLNs	dialysis bag-paddle method	pH 6.8 phosphate-buffered	20 h released 80%	diffusion	Higuchi	[72]
Insulim	membrane-free release	saline water	3 h released 90%	diffusion		[82]
	bovine intestinal mucosa	saline water	7 h released 80%	dissolution	Hixson-crowell
	sheep intestinal mucosa	saline water	7 h released 80%	diffusion and diffusion	Ritger-Peppas
	dialysis bag	artificial intestinal juice		diffusion and diffusion	Ritger-Peppas
Ketoprofen	dialysis tube、dissolution apparatus	pH 7.2 phosphate-buffered	8 h released 60%		Higuchi	[83]
Nimesulide	dialysis bag-paddle method	pH 9.1 borate buffer	8 h released 85%	diffusion and diffusion	Ritger-Peppas	[84]
Baicalin	dialysis bag-paddle method	pH 9.18 borate buffer			Ritger-Peppas	[85]

Model Drug

In vitro model

Release conditions

Outcome

Mechanism

Kinetic model

References

Morphine

membrane-free release

purification water

9 h dissolution 92%

zero-order kinetics

[79]

Morphine sulfate

membrane-free release

purification water

9 h dissolution 92%

zero-order kinetics

[80]

Ibuprofen

membrane-free release

pH 7.4 phosphate-buffered

7 h released 98.1%

dissolution

zero-order kinetics

[81]

Ibuprofen-SLNs

dialysis bag-paddle method

pH 6.8 phosphate-buffered

20 h released 80%

diffusion

Higuchi

[72]

Insulim

membrane-free release

saline water

3 h released 90%

diffusion

[82]

bovine intestinal mucosa

saline water

7 h released 80%

dissolution

Hixson-crowell

sheep intestinal mucosa

saline water

7 h released 80%

diffusion and diffusion

Ritger-Peppas

dialysis bag

artificial intestinal juice

diffusion and diffusion

Ritger-Peppas

Ketoprofen

dialysis tube、dissolution apparatus

pH 7.2 phosphate-buffered

8 h released 60%

Higuchi

[83]

Nimesulide

dialysis bag-paddle method

pH 9.1 borate buffer

8 h released 85%

diffusion and diffusion

Ritger-Peppas

[84]

Baicalin

dialysis bag-paddle method

pH 9.18 borate buffer

Ritger-Peppas

[85]