药学学报, 2022, 57(5): 1235-1244
引用本文:
范冉冉, 刘原兵, 张婷, 王增明, 张慧, 李见春, 郑爱萍. 基于临床需求的温敏凝胶在不同给药部位的应用研究进展[J]. 药学学报, 2022, 57(5): 1235-1244.
FAN Ran-ran, LIU Yuan-bing, ZHANG Ting, WANG Zeng-ming, ZHANG Hui, LI Jian-chun, ZHENG Ai-ping. Based on clinical application research progress of thermosensitive gel in different drug delivery sites[J]. Acta Pharmaceutica Sinica, 2022, 57(5): 1235-1244.

基于临床需求的温敏凝胶在不同给药部位的应用研究进展
范冉冉1,2, 刘原兵3, 张婷4, 王增明2, 张慧2*, 李见春1*, 郑爱萍2*
1. 蚌埠医学院药学院, 安徽 蚌埠 233030;
2. 军事科学院军事医学研究院毒物药物研究所, 北京 100850;
3. 中国人民解放军 73101部队, 江苏 徐州 221000;
4. 郑州大学, 河南 郑州 450000
摘要:
局部给药的优势是直接在病灶部位释放药物,提高局部药物浓度,减少全身给药的不良反应。温敏凝胶是一种典型的局部给药制剂,具有随温度变化展现不同物理状态的特性,在低温或贮存温度下为溶胶状态,当温度上升到相变温度或接近于体温时,呈现半固体凝胶状态,具有一定黏弹性和快速自我恢复能力,增强药物在局部的黏附性,延长药物在局部的保留时间,控制和延长药物的释放,能显著提高药物的生物利用度。本文综述了温敏凝胶的特点、常用温敏材料及基于临床需求在鼻腔、眼、阴道、牙周、皮肤、瘤内、关节腔等不同给药部位中的应用研究。
关键词:    温敏凝胶      给药部位      局部给药      温敏材料      临床需求     
Based on clinical application research progress of thermosensitive gel in different drug delivery sites
FAN Ran-ran1,2, LIU Yuan-bing3, ZHANG Ting4, WANG Zeng-ming2, ZHANG Hui2*, LI Jian-chun1*, ZHENG Ai-ping2*
1. School of Pharmacy, Bengbu Medical College, Bengbu 233030, China;
2. Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing 100850, China;
3. Unit 73101 of Chinese PLA, Xuzhou 221000, China;
4. Zhengzhou University, Zhengzhou 450000, China
Abstract:
The advantages of local administration are as follow:release drugs directly at the lesion, increase the drug concentration in lesion location and reduce the side effects of systemic administration. Thermosensitive gel is one of typical local administration agents. It exhibits the different physical characteristics with the change of temperature. It is sol-gel at low temperature or storage temperature, while when the temperature rises to the transition temperature or near the body temperature, it is semisolid gel with a certain viscoelasticity, and can recover rapidly. It can enhance the local adhesion, which prolongs the local retention time of drugs. As a result, thermosensitive gel can control and display the release of drugs, which can significantly improve the bioavailability of drugs. This review summarizes the characteristics of thermosensitive gel, thermosensitive materials, and its application in different parts:nasal cavity, eye, vagina, periodontal, skin, tumor and joint cavity, based on clinical needs.
Key words:    thermosensitive gel    administration site    local administration    thermosensitive material    clinical need   
收稿日期: 2021-08-22
DOI: 10.16438/j.0513-4870.2021-1209
基金项目: 国家自然科学基金资助项目(82073793);国家“重大新药创制”科技重大专项资助项目(2018ZX09721003-007).
通讯作者: 张慧,Tel:86-10-66874665,E-mail:zhhui58@126.com;李见春,Tel:86-552-3175066,E-mail:Lijc66577@sohu.com;郑爱萍,Tel:86-10-66931694,E-mail:apzheng@163.com
Email: zhhui58@126.com;Lijc66577@sohu.com;apzheng@163.com
相关功能
PDF(522KB) Free
打印本文
0
作者相关文章
范冉冉  在本刊中的所有文章
刘原兵  在本刊中的所有文章
张婷  在本刊中的所有文章
王增明  在本刊中的所有文章
张慧  在本刊中的所有文章
李见春  在本刊中的所有文章
郑爱萍  在本刊中的所有文章

参考文献:
[1] Drozdov AD, Christiansen JD. Modulation of the volume phase transition temperature of thermo-responsive gels[J]. J Mech Behav Biomed Mater, 2021, 114:104215.
[2] Zhao Y, Wang XB, Zhang YR, et al. Research and application progress of thermosensitive gel[J]. Chin Pharm (中国药房), 2015, 26:132-135.
[3] Boonlai W, Tantishaiyakul V, Hirun N, et al. Thermosensitive Poloxamer 407/poly(acrylic acid) hydrogels with potential application as injectable drug delivery system[J]. AAPS PharmSciTech, 2018, 19:2103-2117.
[4] Dang LH, Huynh NT, Pham NO, et al. Injectable nanocurcumin-dispersed gelatin-pluronic nanocomposite hydrogel platform for burn wound treatment[J]. Bull Mater Sci, 2019, 42:53-59.
[5] Shriky B, Kelly A, Isreb M, et al. Pluronic F127 thermosensitive injectable smart hydrogels for controlled drug delivery system development[J]. J Colloid Interface Sci, 2020, 565:119-130.
[6] Petkova-Olsson Y, Oelschlaeger C, Ullsten H, et al. Structural, microrheological and kinetic properties of a ternary silica-Pluronic F127-starch thermosensitive system[J]. J Colloid Interface Sci, 2018, 514:459-467.
[7] Ma S, Zheng H, Chen Y, et al. Nanocomposite polymer hydrogels reinforced by carbon dots and hectorite clay[J]. J Wuhan Univ Technol Mater Sci Ed, 2020, 35:287-292.
[8] Yang Y, Zhu H, Tsai YT, et al. Study on the thermal stability of thermosensitive hydrogel[J]. Procedia Eng, 2016, 135:501-509.
[9] Goncharuk O, Samchenko Y, Sternik D, et al. Thermoresponsive hydrogels physically crosslinked with magnetically modified LAPONITE® nanoparticles[J]. Soft Matter, 2020, 16:5689-5701.
[10] Wu WX, Huang YC, Lee WF. Effect of poly(ethylene glycol)-derived crosslinkers on the properties of thermosensitive hydrogels[J]. Iran Polym J, 2020, 29:679-691.
[11] Maeda T, Kitagawa M, Hotta A. Degradation of thermoresponsive laponite/PEG-b-PLGA nanocomposite hydrogels controlled by blending PEG-b-PLGA diblock copolymers with different PLGA molecular weights[J]. Polym Degrad Stab, 2021, 187:222-228.
[12] Norouzi M, Firouzi J, Sodeifi N, et al. Salinomycin-loaded injectable thermosensitive hydrogels for glioblastoma therapy[J]. Int J Pharm, 2021, 598:120316.
[13] Velázquez NS, Turino LN, Luna JA, et al. Progesterone loaded thermosensitive hydrogel for vaginal application:Formulation and in vitro comparison with commercial product[J]. Saudi Pharm J, 2019, 27:1096-1106.
[14] Tentor FR, de Oliveira JH, Scariot DB, et al. Scaffolds based on chitosan/pectin thermosensitive hydrogels containing gold nanoparticles[J]. Int J Biol Macromol, 2017, 102:1186-1194.
[15] Mohammed AM, Osman SK, Saleh KI, et al. In vitro release of 5-fluorouracil and methotrexate from different thermosensitive chitosan hydrogel systems[J]. AAPS PharmSciTech, 2020, 21:131.
[16] Zheng W, Wang J, Xie L, et al. An injectable thermosensitive hydrogel for sustained release of apelin-13 to enhance flap survival in rat random skin flap[J]. J Mater Sci Mater Med, 2019, 30:106.
[17] Huang Y, Guo W, Zhang J, et al. Thermosensitive hydrogels based on methylcellulose derivatives for prevention of postoperative adhesion[J]. Cellulose, 2019, 27:1555-1571.
[18] Nigmatullin R, Gabrielli V, Muñoz-García JC, et al. Thermosensitive supramolecular and colloidal hydrogels via self-assembly modulated by hydrophobized cellulose nanocrystals[J]. Cellulose, 2019, 26:529-542.
[19] Dashtimoghadam E, Salimi-Kenari H, Nasseri R, et al. Tunable viscoelastic features of aqueous mixtures of thermosensitive ethyl(hydroxyethyl)cellulose and cellulose nanowhiskers[J]. Colloids Surf A Physicochem Eng Asp, 2020, 590:124489.
[20] Fu C, Ren F, Zhang Q, et al. Effects of collagen incorporation on thermogelation and hydrogel characteristics of aqueous Pluronic F127 copolymer system[J]. Colloid Polym Sci, 2015, 293:2191-2200.
[21] Jarak I, Varela CL, Tavares da Silva E, et al. Pluronic-based nanovehicles:recent advances in anticancer therapeutic applications[J]. Eur J Med Chem, 2020, 206:112526.
[22] Long KH, Huang XY, Wang CL, et al. Optimization of paeonol NLC thermosensitive gel formulation by box-behnken response surface methodology[J]. Chin J Inf Tradit Chin Med (中国中医药信息杂志), 2018, 25:73-76.
[23] Zarrintaj P, Ramsey JD, Samadi A. Poloxamer A versatile tri-block copolymer for biomedical applications[J]. Acta Biomater, 2020, 110:37-67.
[24] Wei D, Ge L, Guo R. Effect of hydrophilically modified ibuprofen on thermoresponsive gelation of pluronic copolymer[J]. Colloids Surf A Physicochem Eng Asp, 2018, 553:1-10.
[25] Sivashanmugam A, Arun Kumar R, Vishnu Priya M, et al. An overview of injectable polymeric hydrogels for tissue engineering[J]. Eur Polym J, 2015, 72:543-565.
[26] Al Sabbagh C, Seguin J, Agapova E, et al. Thermosensitive hydrogels for local delivery of 5-fluorouracil as neoadjuvant or adjuvant therapy in colorectal cancer[J]. Eur J Pharm Biopharm, 2020, 157:154-164.
[27] Lu W, Jiang GW. New progress in the application of carbomer and polycarbofe in pharmacy[J]. Chin J Hosp Pharm (中国医院药学杂志), 2002, 22:491-493.
[28] Tang JL, Ma J. Synthesis and properties of thermo-sensitive and pH-sensitive poly(N-isopropylacrylamide)/AAC[J]. J Funct Mater (功能材料), 2017, 9:9157.
[29] Feng Q, Zhao Y, Li H, et al. Frontal polymerization and characterization of interpenetrating polymer networks composed of poly(N-isopropylacrylamide) and polyvinylpyrrolidone[J]. Colloid Polym Sci, 2017, 296:165-172.
[30] Klouda L. Thermoresponsive hydrogels in biomedical applications:a seven-year update[J]. Eur J Pharm Biopharm, 2015, 97:338-349.
[31] Luo LJ, Nguyen DD, Lai JY. Benzoic acid derivative-modified chitosan-g-poly(N-isopropylacrylamide):methoxylation effects and pharmacological treatments of Glaucoma-related neurodegeneration[J]. J Control Release, 2020, 317:246-258.
[32] Yu L, Zheng Z, Zhang H, et al. Mixing a sol and a precipitate of block copolymers with different block ratios leads to an injectable hydrogel[J]. Biomacromolecules, 2009, 10:1547-1553.
[33] Kitagawa M, Maeda T, Hotta A. PEG-based nanocomposite hydrogel:thermo-responsive sol-gel transition and degradation behavior controlled by the LA/GA ratio of PLGA-PEG-PLGA[J]. Polym Degrad Stab, 2018, 147:222-228.
[34] Guo XF, He ZJ. A PLGA-PEG-PLGA thermosensitive gel enabling sustained delivery of ropivacaine hydrochloride for postoperative pain relief[J]. Chem Pharm Bull, 2017, 65:229-235.
[35] Chan PS, Li Q, Zhang B, et al. In vivo biocompatibility and efficacy of dexamethasone-loaded PLGA-PEG-PLGA thermogel in an alkali-burn induced corneal neovascularization disease model[J]. Eur J Pharm Biopharm, 2020, 155:190-198.
[36] Zhu L, Zhang YQ. Postoperative anti-adhesion ability of a novel carboxymethyl chitosan from silkworm pupa in a rat cecal abrasion model[J]. Mater Sci Eng C Mater Biol Appl, 2016, 61:387-395.
[37] Zhang Y, Gao C, Li X, et al. Thermosensitive methyl cellulose-based injectable hydrogels for post-operation anti-adhesion[J]. Carbohydr Polym, 2014, 101:171-178.
[38] Zhang E, Guo Q, Ji F, et al. Thermoresponsive polysaccharide-based composite hydrogel with antibacterial and healing-promoting activities for preventing recurrent adhesion after adhesiolysis[J]. Acta Biomater, 2018, 74:439-453.
[39] Schnell CN, Galván MV, Zanuttini MA, et al. Hydrogels from xylan/chitosan complexes for the controlled release of diclofenac sodium[J]. Cellulose, 2019, 27:1465-1481.
[40] Zang BJ, Zou ZH, Nie XQ. Research progress in chitosan thermosensitive hydrogel[J]. Shandong Chem Indust (山东化工), 2020, 49:49-52.
[41] Fang W, Yang L, Hong L, et al. A chitosan hydrogel sealant with self-contractile characteristic:from rapid and long-term hemorrhage control to wound closure and repair[J]. Carbohydr Polym, 2021, 271:118428.
[42] Aparna RL, Prasad RV, Nirmal NP. An injectable in-situ conducting thermosensitive gel for controlled delivery of vancomycin in osteomyelitis treatment and bone regeneration[J]. Sci Adv Mater, 2016, 8:1470-1477.
[43] Tao F, Cheng Y, Shi X, et al. Applications of chitin and chitosan nanofibers in bone regenerative engineering[J]. Carbohydr Polym, 2020, 230:115658.
[44] Xia Y, Li L, Huang X, et al. Performance and toxicity of different absorption enhancers used in the preparation of Poloxamer thermosensitive in situ gels for ketamine nasal administration[J]. Drug Dev Ind Pharm, 2020, 46:697-705.
[45] Gu FG, Zhang YX, Wang Y, et al. Preparation and in vitro quality evaluation of rasagiline mesylate nasal gel[J]. Chin J New Drugs (中国新药杂志), 2017, 26:351-356.
[46] Kumar MUP, Shankar R, Joshi M, et al. Chlorpheniramine maleate containing chitosan-based[J]. Drug Deliv Transl Res, 2019, 9:1017-1026.
[47] Pastor Y, Ting I, Martinez AL, et al. Intranasal delivery system of bacterial antigen using thermosensitive hydrogels based on a Pluronic-Gantrez conjugate[J]. Int J Pharm, 2020, 579:119-154.
[48] Agrawal M, Saraf S, Saraf S, et al. Stimuli-responsive in situ gelling system for nose-to-brain drug delivery[J]. J Control Release, 2020, 327:235-265.
[49] Wu JJ, Sheng AQ, Wu YY, et al. Pharmacodynamic effects of breviscapine in situ nasal thermoreversible gel in experimental cerebral infarction[J]. Chin Arch Tradit Chin Med (中华中医药学刊), 2017, 35:1690-1695.
[50] Sridhar V, Wairkar S, Gaud R, et al. Brain targeted delivery of mucoadhesive thermosensitive nasal gel of selegiline hydrochloride for treatment of Parkinson's disease[J]. J Drug Target, 2018, 26:150-161.
[51] Xu K, Chen Q, Liang LN. Research progress on topical administration of drug for retinal diseases[J]. China J Chin Ophthalmol (中国中医眼科杂志), 2017, 27:128-131.
[52] Sun T, Xu WN, Leng JW, et al. Study on rheological properties and release of gatifloxacin eye thermosensitive gel in vitro[J]. J Pharm Res (药学研究), 2019, 38:468-470.
[53] Cu Y, Zhao Y. Preparation and quality evaluation of chondroitin sulfate ophthalmic thermosensitive gels[J]. China Pharm (中国药师), 2020, 23:651-654.
[54] Ma MZ, Yu SH, Yu YB, et al. Irritation study on insoluble drug meloxicam liposome thermo sensitive hydrogel for ocular delivery[J]. Cent South Pharm (中南药学), 2017, 15:288-292.
[55] Shi Z, Li SK, Charoenputtakun P, et al. RNA nanoparticle distribution and clearance in the eye after subconjunctival injection with and without thermosensitive hydrogels[J]. J Control Release, 2018, 270:14-22.
[56] Caramella CM, Rossi S, Ferrari F, et al. Mucoadhesive and thermogelling systems for vaginal drug delivery[J]. Adv Drug Deliv Rev, 2015, 92:39-52.
[57] Wang YH, Li HJ, Yang L, et al. Research progress of vaginal mucosal drug delivery system[J]. Chin J Exp Tradit Med Form (中国实验方剂学杂志), 2019, 25:219-225.
[58] Zhou XB. New vaginal lubricant-acid buffered thermosensitive gel lubricant is licensed for sale[J]. Chin J Fam Plann (中国计划生育学杂志), 2012, 2:102.
[59] Chen X, Chen WY, Ma PP, et al. Curcumin temperature-sensitive in situ hydrogels for treatment of vaginal candidiasis[J]. J Int Pharm Res (国际药学研究杂志), 2017, 44:947-952.
[60] Qu XY, Zhang SX, Tao LN, et al. Investigation on preparation and release property in vitro of butenafine hydrochloride thermosensitive hydrogel for vagina administration[J]. Chin J Hosp Pharm (中国医院药学杂志), 2015, 35:1572-1575.
[61] Liu YF. Clinical observation of emodin thermosensitive hydrogel in the treatment of acute wisdom tooth pericoronitis[J]. Jilin Med J (吉林医学), 2017, 38:1884-1885.
[62] Wang L, Yang XY. Evaluation on efficacy of thermosensitive minoeycline and omidazole complex gel in treatment of chronic periodontis[J]. J Oral Sci Res (口腔医学研究), 2019, 35:647-650.
[63] Xia XA, Jiang ZL, Li SY, et al. Preparation and transdermal penetration of timolol maleate thermosensitive gel[J]. China Pharm (中国药师), 2020, 23:1453-1458.
[64] Elkomy MH, El-Menshawe SF, Ali AA, et al. Betahistine dihydrochloride transdermal delivery via optimized thermosensitive gels:percutaneous absorption evaluation using rat growth as a biomarker[J]. Drug DelivTransl Res, 2018, 8:165-177.
[65] Guan L, Zhang ZP, Liu YJ, et al. Application of injectable thermosensitive gels in local cancer therapy[J]. Chin J Pharm (中国医药工业杂志), 2020, 51:1091-1098.
[66] Zhuang B, Chen T, Xiao Z, et al. Drug-loaded implantable surgical cavity-adaptive hydrogels for prevention of local tumor recurrence[J]. Int J Pharm, 2020, 577:119048.
[67] Xie MH, Cai XJ, Peng JB, et al. Study on preparation and anti-hepatoma of norcantharidin thermosensitive in-situ gel[J]. Chin J Mod Appl Pharm (中国现代应用药学), 2017, 34:1262-1265.
[68] Shan H, Li K, Zhao D, et al. Locally controlled release of methotrexate and alendronate by thermo-sensitive hydrogels for synergistic inhibition of osteosarcoma progression[J]. Front Pharmacol, 2020, 11:573.
[69] Gong YB,MH, Liu JG. Controlled WISP-1 shRNA delivery using thermosensitive biodegradable hydrogel in the treatment of osteoarthritis[J]. J Bionic Eng, 2015, 12:285-293.
[70] Zhang TT. Preparation of Thermosensitive In Situ Gel of Glucosamine Hydrochloride for Intra-articular Injection and Its Pharmacological Effects on Osteoarthritis (盐酸氨基葡萄糖关节腔注射用温敏凝胶的制备及其对骨关节炎的药效研究)[D]. Chengdu:Sichuan Agricultural University, 2019.
[71] Mura P, Mennini N, Nativi C, et al. In situ mucoadhesive-thermosensitive liposomal gel as a novel vehicle for nasal extended delivery of opiorphin[J]. Eur J Pharm Biopharm, 2018, 122:54-61.
[72] Pang LL, Gao Y, Zhang LH, et al. Intranasal tetrandrine temperature-sensitive gel for treatment of post-traumatic stress disorder[J]. Acta Pharm Sin (药学学报), 2019, 54:1680-1687.
[73] Huang PQ, Gao LL, Yu YC, et al. Preparation and quality evaluation of levocarnitine thermosensitive in situ gel[J]. Acta Pharm Sin (药学学报), 2019, 54:1115-1122.