药学学报, 2021, 56(5): 1314-1331
引用本文:
张圆圆, 杜丽娜, 金义光. 环境敏感型水凝胶在药物递送中的应用[J]. 药学学报, 2021, 56(5): 1314-1331.
ZHANG Yuan-yuan, DU Li-na, JIN Yi-guang. Application of environmentally sensitive hydrogels in drug delivery[J]. Acta Pharmaceutica Sinica, 2021, 56(5): 1314-1331.

环境敏感型水凝胶在药物递送中的应用
张圆圆1,2, 杜丽娜1,2*, 金义光2
1. 山东中医药大学, 山东 济南 250355;
2. 军事科学院军事医学研究院辐射医学研究所, 北京 100850
摘要:
环境敏感型水凝胶是近年来发展迅速的一种药物递送新剂型,它能基于不同生理环境在用药局部形成黏附性较好的半固体,局部滞留时间长有利于持续释药,且制备工艺简单易于实现工业化。本综述从其分类、常用聚合物和给药途径角度总结归纳了环境敏感型水凝胶的最新研究进展:根据响应因素环境敏感型水凝胶具体可分为温度、pH、离子、光及多重敏感型水凝胶,其中以温度敏感型最为常见;常用环境敏感型聚合物包括壳聚糖、聚N-异丙烯基酰胺、泊洛沙姆等。作为一种新型药物递送系统,环境敏感型水凝胶给药途径广泛,包括经皮、眼用、鼻用、口腔、阴道、直肠和注射等,在临床应用中具有广阔前景。
关键词:    温度敏感型水凝胶      pH敏感型水凝胶      酶敏感型水凝胶      给药途径      聚合物      环境敏感型     
Application of environmentally sensitive hydrogels in drug delivery
ZHANG Yuan-yuan1,2, DU Li-na1,2*, JIN Yi-guang2
1. Shandong University of Traditional Chinese Medicine, Jinan 250355, China;
2. Beijing Institute of Radiation Medicine, Beijing 100850, China
Abstract:
Environmentally sensitive hydrogels are a novel formulation that has developed rapidly in recent years. It could form semi-solid with good adhesion in the topical sites based on different physiological environments. Its long local retention time is conducive for sustained drug release, and the preparation process is relatively simple and easy to realize industrialization. This review summarized the categories, commonly used polymer, and different administration routes based on the recently published literatures. According to different response factors, it can be divided into temperature, pH, ion, light, and multiple sensitive hydrogels, among which temperature-sensitive hydrogels are the most common. The most commonly used polymers include chitosan, poly N-isopropyl acrylamide, and poloxamer. There are different administration routes for environmentally sensitive hydrogels, such as transdermal, ophthalmic, nasal, oral, vaginal, rectal, injection, etc. Environmentally sensitive hydrogels have broad prospects in clinical application.
Key words:    temperature-sensitive hydrogel    pH-sensitive hydrogel    enzyme-sensitive hydrogel    administration route    polymer    environmentally sensitive   
收稿日期: 2020-12-04
DOI: 10.16438/j.0513-4870.2020-1873
基金项目: 北京自然科学基金面上资助项目(7202147).
通讯作者: 杜丽娜,Tel:86-10-66930216,E-mail:dulina@188.com
Email: dulina@188.com
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参考文献:
[1] Buwalda SJ, Boere KW, Dijkstra PJ, et al. Hydrogels in a historical perspective:from simple networks to smart materials[J]. J Control Release, 2014, 190:254-273.
[2] Dragan ES. Design and applications of interpenetrating polymer network hydrogels. A review[J]. Chem Eng J, 2014, 243:572-590.
[3] Sharpe LA, Daily AM, Horava SD, et al. Therapeutic applications of hydrogels in oral drug delivery[J]. Expert Opin Drug Deliv, 2014, 11:901-915.
[4] Narayanaswamy R, Torchilin VP. Hydrogels and their applications in targeted drug delivery[J]. Molecules, 2019, 24:603.
[5] Chai Q, Jiao Y, Yu X. Hydrogels for biomedical applications:their characteristics and the mechanisms behind them[J]. Gels, 2017, 3:6.
[6] Li J, Mooney DJ. Designing hydrogels for controlled drug delivery[J]. Nat Rev Mater, 2016, 1:16071.
[7] Hanafy NA, Leporatti S, El-Kemary MA. Mucoadhesive hydrogel nanoparticles as smart biomedical drug delivery system[J]. Appl Sci, 2019, 9:825.
[8] Caló E, Khutoryanskiy VV. Biomedical applications of hydrogels:a review of patents and commercial products[J]. Eur Polym J, 2015, 65:252-267.
[9] Ahmed TA, El-Say KM. Transdermal film-loaded finasteride microplates to enhance drug skin permeation:two-step optimization study[J]. Eur J Pharm Sci, 2016, 88:246-256.
[10] Jeong B, Kibbey MR, Birnbaum JC, et al. Thermogelling biodegradable polymers with hydrophilic backbones:PEG-g-PLGA[J]. Macromolecules, 2000, 33:8317-8322.
[11] Kasiński A, Zielińska-Pisklak M, Oledzka E, et al. Smart hydrogels-synthetic stimuli-responsive antitumor drug release systems[J]. Int J Nanomedicine, 2020, 15:4541-4572.
[12] Singh B, Khurana RK, Garg B, et al. Stimuli-responsive systems with diverse drug delivery and biomedical applications:recent updates and mechanistic pathways[J]. Crit Rev Ther Drug Carrier Syst, 2017, 34:209-255.
[13] Zhu SQ, Pang LL, Ma JQ, et al. The treatment of chronic eczema in mice by matrine hydrogels[J]. J Int Pharm Res (国际药学研究杂志), 2020, 47:731-737.
[14] Ou G, Ma JQ, Zhu L, et al. Preparation of adenosine triphosphate liposome hydrogel and research of its anti-hypoxia effect[J]. Acta Pharm Sin (药学学报), 2020, 55:1288-1295.
[15] Ruan H, Yu Y, Liu Y, et al. Preparation and characteristics of thermoresponsive gel of minocycline hydrochloride and evaluation of its effect on experimental periodontitis models[J]. Drug Deliv, 2016, 23:525-531.
[16] Lee Y, Bae JW, Lee JW, et al. Enzyme-catalyzed in situ forming gelatin hydrogels as bioactive wound dressings:effects of fibroblast delivery on wound healing efficacy[J]. J Mater Chem B, 2014, 2:7712-7718.
[17] Klouda L, Perkins KR, Watson BM, et al. Thermoresponsive, in situ cross-linkable hydrogels based on N-isopropylacrylamide:fabrication, characterization and mesenchymal stem cell encapsulation[J]. Acta Biomater, 2011, 7:1460-1467.
[18] Koetting MC, Peters JT, Steichen SD, et al. Stimulus-responsive hydrogels:theory, modern advances, and applications[J]. Mater Sci Eng R Rep, 2015, 93:1-49.
[19] Kuckling D. Stimuli-responsive gels[J]. Gels, 2018, 4:60.
[20] Tang S, Floy M, Bhandari R, et al. Synthesis and characterization of thermoresponsive hydrogels based on N-isopropylacrylamide crosslinked with 4,4'-dihydroxybiphenyl diacrylate[J]. ACS Omega, 2017, 2:8723-8729.
[21] Zhang LH, Pang LL, Zhu SQ, et al. Intranasal tetrandrine temperature-sensitive in situ hydrogels for the treatment of microwave-induced brain injury[J]. Int J Pharm, 2020, 583:119384.
[22] Ma JQ, Pang LL, Zhu SQ, et al. Comparative study of oral and intranasal puerarin for prevention of brain injury induced by acute high-altitude hypoxia[J]. Int J Pharm (国际药学研究杂志), 2020, 591:120002.
[23] Gholizadeh H, Cheng S, Pozzoli M, et al. Smart thermosensitive chitosan hydrogel for nasal delivery of ibuprofen to treat neurological disorders[J]. Expert Opin Drug Deliv, 2019, 16:453-466.
[24] Qi XJ, Liu XY, Tang LM, et al. Anti-depressant effect of curcumin-loaded guanidine-chitosan thermo-sensitive hydrogel by nasal delivery[J]. Pharm Dev Technol, 2020, 25:316-325.
[25] Sheshala R, Quah SY, Tan GC, et al. Investigation on solution-to-gel characteristic of thermosensitive and mucoadhesive biopolymers for the development of moxifloxacin-loaded sustained release periodontal in situ gels[J]. Drug Deliv Transl Res, 2019, 9:434-443.
[26] Zhu M, Wang J, Li N. A novel thermo-sensitive hydrogel-based on poly(N-isopropylacrylamide)/hyaluronic acid of ketoconazole for ophthalmic delivery[J]. Artif Cells Nanomed Biotechnol, 2018, 46:1282-1287.
[27] Zheng Y, Wang W, Zhao J, et al. Preparation of injectable temperature-sensitive chitosan-based hydrogel for combined hyperthermia and chemotherapy of colon cancer[J]. Carbohydr Polym, 2019, 222:115039.
[28] Le UM, Shaker DS, Sloat BR, et al. A thermo-sensitive polymeric gel containing a gadolinium (Gd) compound encapsulated into liposomes significantly extended the retention of the Gd in tumors[J]. Drug Devel Indus Pharm, 2008, 34:413-418.
[29] Bai X, Bao Z, Bi S, et al. Chitosan-based thermo/pH double sensitive hydrogel for controlled drug delivery[J]. Macromol Biosci, 2018, 18:5.
[30] 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.
[31] Ma JQ, Pang LL, Zhu SQ, et al. Effect of four drug-loaded hydrogels on prevention of hypoxic brain damage[J]. J Int Pharm Res (国际药学研究杂志), 2019, 46:516-521.
[32] Zhu HY, Yang FX. Advances of pH-sensitive in situ gels research[J]. Qilu Pharm Aff (齐鲁药事), 2006, 25:486-488.
[33] Nasir N, Ahmad M, Minhas MU, et al. pH-responsive smart gels of block copolymer pluronic F127-co-poly(acrylic acid) for controlled delivery of ivabradine hydrochloride:its toxicological evaluation[J]. J Polym Res, 2019, 26:212.
[34] Jaiswal M, Kumar M, Pathak K. Zero order delivery of itraconazole via polymeric micelles incorporated in situ ocular gel for the management of fungal keratitis[J]. Colloids Surf B Biointerfaces, 2015, 130:23-30.
[35] Cinay GE, Erkoc P, Alipour M, et al. Nanogel-integrated pH-responsive composite hydrogels for controlled drug delivery[J]. ACS Biomater Sci Eng, 2017, 3:370-380.
[36] You YC, Dong LY, Dong K, et al. In vitro and in vivo application of pH-sensitive colon-targeting polysaccharide hydrogel used for ulcerative colitis therapy[J]. Carbohydr Polym, 2015, 130:243-253.
[37] Gholamali I, Asnaashariisfahani M, Alipour E. Silver nanoparticles incorporated in pH-sensitive nanocomposite hydrogels based on carboxymethyl chitosan-poly (vinyl alcohol) for use in a drug delivery system[J]. Regen Eng Transl Med, 2019, 6:138-153.
[38] Liu HW, Yan YL, Zhou LL. Comparison of the brain pharmacokinetics of nasal tetramethylpyrazine phosphate pH-sensitive in situ gel in normal rats and model rats[J]. Acta Pharma Sin (药学学报), 2012, 47:677-679.
[39] Liu H, Shi X, Wu D, et al. Injectable, biodegradable, thermosensitive nanoparticles-aggregated hydrogel with tumor-specific targeting, penetration, and release for efficient postsurgical prevention of tumor recurrence[J]. ACS Appl Mater Interfaces, 2019, 11:19700-19711.
[40] Allam A, El-Mokhtar MA, Elsabahy M. Vancomycin-loaded niosomes integrated within pH-sensitive in-situ forming gel for treatment of ocular infections while minimizing drug irritation[J]. J Pharm Pharmacol, 2019, 71:1209-1221.
[41] Qi X, Wei W, Li J, et al. Salecan-based pH-sensitive hydrogels for insulin delivery[J]. Mol Pharm, 2017, 14:431-440.
[42] Li X, Fu M, Wu J, et al. pH-sensitive peptide hydrogel for glucose-responsive insulin delivery[J]. Acta Biomater, 2017, 51:294-303.
[43] Sun Y, Li L, Xie H, et al. Primary studies on construction and evaluation of ion-sensitive in situ gel loaded with paeonol-solid lipid nanoparticles for intranasal drug delivery[J]. Int J Nanomedicine, 2020, 15:3137-3160.
[44] Butani S. Fabrication of an ion-sensitive in situ gel loaded with nanostructured lipid carrier for nose to brain delivery of donepezil[J]. Asian J Pharm, 2018, 12:2838.
[45] Yu S, Wang QM, Wang X, et al. Liposome incorporated ion sensitive in situ gels for opthalmic delivery of timolol maleate[J]. Int J Pharm, 2015, 480:128-136.
[46] Rao MRP, Shelar SU. Controlled release ion sensitive floating oral in situ gel of a prokinetic drug using gellan gum[J]. Indian J Pharm Edu Res, 2015, 49:158-167.
[47] Dehghany M, Zhang H, Naghdabadi R, et al. A thermodynamically-consistent large deformation theory coupling photochemical reaction and electrochemistry for light-responsive gels[J]. J Mech Physics Solids, 2018, 116:239-266.
[48] Unger K, Salzmann P, Masciullo C, et al. Novel light-responsive biocompatible hydrogels produced by initiated chemical vapor deposition[J]. ACS Appl Mater Interfaces, 2017, 9:17408-17416.
[49] Ayer MA, Schrettl S, Balog S, et al. Light-responsive azo-containing organogels[J]. Soft Matter, 2017, 13:4017-4023.
[50] Zhan TG, Lin MD, Wei J, et al. Visible-light responsive hydrogen-bonded supramolecular polymers based on ortho-tetrafluorinated azobenzene[J]. Polym Chem, 2017, 8:7384-7389.
[51] Chu CW, Stricker L, Kirse TM, et al. Light-responsive arylazopyrazole gelators:from organic to aqueous media and from supramolecular to dynamic covalent chemistry[J]. Chemistry, 2019, 25:6131-6140.
[52] Tong X, Qiu Y, Zhao X, et al. Visible light-triggered gel-to-sol transition in halogen-bond-based supramolecules[J]. Soft Matter, 2019, 15:6411-6417.
[53] Roth-Konforti ME, Comune M, Halperin-Sternfeld M, et al. UV light-responsive peptide-based supramolecular hydrogel for controlled drug delivery[J]. Macromol Rapid Commun, 2018, 39:1800588.
[54] Zhang YL, Chang R, Duan HZ, et al. Metal ion and light sequentially induced sol-gel-sol transition of a responsive peptide-hydrogel[J]. Soft Matter, 2020, 16:7652-7658.
[55] Skaalure SC, Akalp U, Vernerey FJ, et al. Tuning reaction and diffusion mediated degradation of enzyme-sensitive hydrogels[J]. Adv Healthc Mater, 2016, 5:432-438.
[56] Skaalure SC, Chu S, Bryant SJ. An enzyme-sensitive PEG hydrogel based on aggrecan catabolism for cartilage tissue engineering[J]. Adv Healthc Mater, 2015, 4:420-431.
[57] Gohil SV, Padmanabhan A, Kan HM, et al. Degradation-dependent protein release from enzyme sensitive injectable glycol chitosan hydrogel[J]. Tissue Eng Part A, 2020. DOI:10.1089/ten.TEA.2020.0124.
[58] da Silva LP, Jha AK, Correlo VM, et al. Gellan gum hydrogels with enzyme-sensitive biodegradation and endothelial cell biorecognition sites[J]. Adv Healthc Mater, 2018, 7:1700686.
[59] Milcovich G, Lettieri S, Antunes FE, et al. Recent advances in smart biotechnology:hydrogels and nanocarriers for tailored bioactive molecules depot[J]. Adv Colloid Interface Sci, 2017, 249:163-180.
[60] Meenach SA, Hilt JZ, Anderson KW. Poly(ethylene glycol)-based magnetic hydrogel nanocomposites for hyperthermia cancer therapy[J]. Acta Biomater, 2010, 6:1039-1046.
[61] Lin X, Nguyen Quoc B, Ulbricht M. Magnetoresponsive poly(ether sulfone)-based iron oxide cum hydrogel mixed matrix composite membranes for switchable molecular sieving[J]. ACS Appl Mater Interfaces, 2016, 8:29001-29014.
[62] He J, Zhang A, Zhang Y, et al. Novel redox hydrogel by in situ gelation of chitosan as a result of template oxidative polymerization of hydroquinone[J]. Macromolecules, 2011, 44:2245-2252.
[63] Heller A. Electron-conducting redox hydrogels:design, characteristics and synthesis[J]. Curr Opin Chem Biol, 2006, 10:664-672.
[64] Tomatsu I, Hashidzume A, Harada A. Redox-responsive hydrogel system using the molecular recognition of β-cyclodextrin[J]. Macromol Rapid Commun, 2006, 27:238-241.
[65] Tian Y, Guo R, Jiao Y, et al. Redox stimuli-responsive hollow mesoporous silica nanocarriers for targeted drug delivery in cancer therapy[J]. Nanoscale Horiz, 2016, 1:480-487.
[66] Phan VH, Thambi T, Duong HT, et al. Poly(amino carbonate urethane)-based biodegradable, temperature and pH-sensitive injectable hydrogels for sustained human growth hormone delivery[J]. Sci Rep, 2016, 6:1-12.
[67] Fallon M, Halligan S, Pezzoli R, et al. Synthesis and characterisation of novel temperature and pH sensitive physically cross-linked poly (N-vinylcaprolactam-co-itaconic acid) hydrogels for drug delivery[J]. Gels, 2019, 5:41.
[68] Li X, Du L, Chen X, et al. Nasal delivery of analgesic ketorolac tromethamine thermo- and ion-sensitive in situ hydrogels[J]. Int J Pharm, 2015, 489:252-260.
[69] Wang J, He W. Preparationand in-vitro properties of thermo-ion sensitive in-situ gel of rizatriptan benzoate for in-tranasal administration[J]. China Pharmacist (中国药师), 2019, 22:1143-1145.
[70] Chen W, Li R, Zhu S, et al. Nasal timosaponin BII dually sensitive in situ hydrogels for the prevention of Alzheimer's disease induced by lipopolysaccharides[J]. Int J Pharm, 2020, 578:119115.
[71] Xia J, Liu Z, Chen Y, et al. Fabrication of thermo-sensitive lignocellulose hydrogels with switchable hydrophilicity and hydrophobicity through an sipn strategy[J]. RSC Adv, 2019, 9:29600-29608.
[72] Jiang P, Sheng X, Yu S, et al. Preparation and characterization of thermo-sensitive gel with phenolated alkali lignin[J]. Sci Rep, 2018, 8:1-10.
[73] Liu M, Song X, Wen Y, et al. Injectable thermoresponsive hydrogel formed by alginate-g-poly(N-isopropylacrylamide) that releases doxorubicin-encapsulated micelles as a smart drug delivery system[J]. ACS Appl Mater Interfaces, 2017, 9:35673-35682.
[74] Jovancic P, Vilchez A, Molina R. Synthesis of thermo-sensitive hydrogels from free radical copolymerization of NIPAAm with MBA initiated by atmospheric plasma treatment[J]. Plasma Proc Polym, 2016, 13:752-760.
[75] Yang N, Wang Y, Zhang QS, et al. γ-Polyglutamic acid mediated crosslinking PNIPAAm-based thermo/pH-responsive hydrogels for controlled drug release[J]. Polym Degrad Stabil, 2017, 144:53-61.
[76] Giuliano E, Paolino D, Cristiano MC, et al. Rutin-loaded poloxamer 407-based hydrogels for in situ administration:stability profiles and rheological properties[J]. Nanomaterials, 2020, 10:1069.
[77] Zeng Y, Chen J, Li Y, et al. Thermo-sensitive gel in glaucoma therapy for enhanced bioavailability:in vitro characterization, in vivo pharmacokinetics and pharmacodynamics study[J]. Life Sci, 2018, 212:80-86.
[78] Yu S, Zhang X, Tan G, et al. A novel pH-induced thermosensitive hydrogel composed of carboxymethyl chitosan and poloxamer cross-linked by glutaraldehyde for ophthalmic drug delivery[J]. Carbohydr Polym, 2017, 155:208-217.
[79] Dahake PT, Baliga SM, Punse T, et al. Formulation and physical characterization of bio-degradable chitosan-poloxamer gel base for local drug delivery[J]. J Drug Deliv Ther, 2020, 10:59-66.
[80] Chatterjee S, Hui PC, Kan CW. Thermoresponsive hydrogels and their biomedical applications:special insight into their applications in textile based transdermal therapy[J]. Polymers, 2018, 10:480.
[81] Chen CC, Fang CL, Al-Suwayeh SA, et al. Transdermal delivery of selegiline from alginate-pluronic composite thermogels[J]. Int J Pharm, 2011, 415:119-128.
[82] Wang W, Wat E, Hui PC, et al. Dual-functional transdermal drug delivery system with controllable drug loading based on thermosensitive poloxamer hydrogel for atopic dermatitis treatment[J]. Sci Rep, 2016, 6:24112.
[83] Wang WY, Hui PCL, Wat E, et al. Enhanced transdermal permeability via constructing the porous structure of poloxamer-based hydrogel[J]. Polymers, 2016, 8:406.
[84] Das M, Giri TK. Hydrogels based on gellan gum in cell delivery and drug delivery[J]. J Drug Deliv Sci Technol, 2020, 56:101586.
[85] Hao J, Zhao J, Zhang S, et al. Fabrication of an ionic-sensitive in situ gel loaded with resveratrol nanosuspensions intended for direct nose-to-brain delivery[J]. Colloids Surf B Biointerfaces, 2016, 147:376-386.
[86] Zhu L, Ao J, Li P. A novel in situ gel base of deacetylase gellan gum for sustained ophthalmic drug delivery of ketotifen:in vitro and in vivo evaluation[J]. Drug Des Devel Ther, 2015, 9:3943-3949.
[87] Guo S, Okubo T, Kuroda K, et al. A photoresponsive azobenzene-bridged cubic silsesquioxane network[J]. J Sol Gel Sci Technol, 2016, 79:262-269.
[88] Choi YJ, Kim JT, Yoon WJ, et al. Azobenzene molecular machine:light-induced wringing gel fabricated from asymmetric macrogelator[J]. ACS Macro Lett, 2018, 7:576-581.
[89] Yan H, Qiu Y, Wang J, et al. Wholly visible-light-responsive host-guest supramolecular gels based on methoxy azobenzene and β-cyclodextrin dimers[J]. Langmuir, 2020, 36:7408-7417.
[90] Wang W, Hu J, Zheng M, et al. Multi-responsive supramolecular hydrogels based on merocyanine-peptide conjugates[J]. Org Biomol Chem, 2015, 13:11492-11498.
[91] Zhao D, Tang Q, Zhou Q, et al. A photo-degradable injectable self-healing hydrogel based on star poly(ethylene glycol)-b-polypeptide as a potential pharmaceuticals delivery carrier[J]. Soft Matter, 2018, 14:7420-7428.
[92] Fathi M, Sahandi Zangabad P, Majidi S, et al. Stimuli-responsive chitosan-based nanocarriers for cancer therapy[J]. Bioimpacts, 2017, 7:269-277.
[93] Wang B, Wu X, Li J, et al. Thermosensitive behavior and antibacterial activity of cotton fabric modified with a chitosan-poly(N-isopropylacrylamide) interpenetrating polymer network hydrogel[J]. Polymers, 2016, 8:110.
[94] Bhattarai N, Matsen FA, Zhang M. PEG-grafted chitosan as an injectable thermoreversible hydrogel[J]. Macromol Biosci, 2005, 5:107-111.
[95] Li Z, Shim H, Cho MO, et al. Thermo-sensitive injectable glycol chitosan-based hydrogel for treatment of degenerative disc disease[J]. Carbohydr Polym, 2018, 184:342-353.
[96] Pourjavadi A, Bagherifard M, Doroudian M. Synthesis of micelles based on chitosan functionalized with gold nanorods as a light sensitive drug delivery vehicle[J]. Int J Biol Macromol, 2020, 149:809-818.
[97] Che Y, Li D, Liu Y, et al. Physically cross-linked pH-responsive chitosan-based hydrogels with enhanced mechanical performance for controlled drug delivery[J]. RSC Adv, 2016, 6:106035-106045.
[98] Zhang N, He J, Wu F. Tuning the gelation behavior and cellular response of thermo-sensitive chitosan hydrogels[J]. Mater Lett, 2020, 260:126903.
[99] Wang T, Chen L, Shen T, et al. Preparation and properties of a novel thermo-sensitive hydrogel based on chitosan/hydroxypropyl methylcellulose/glycerol[J]. Int J Biol Macromol, 2016, 93:775-782.
[100] Walimbe T, Panitch A, Sivasankar PM. A review of hyaluronic acid and hyaluronic acid-based hydrogels for vocal fold tissue engineering[J]. J Voice, 2017, 31:416-423.
[101] Raia NR, Partlow BP, McGill M, et al. Enzymatically crosslinked silk-hyaluronic acid hydrogels[J]. Biomaterials, 2017, 131:58-67.
[102] Donnelly PE, Chen T, Finch A, et al. Photocrosslinked tyramine-substituted hyaluronate hydrogels with tunable mechanical properties improve immediate tissue-hydrogel interfacial strength in articular cartilage[J]. J Biomater Sci Polym Ed, 2017, 28:582-600.
[103] Tan H, Ramirez CM, Miljkovic N, et al. Thermosensitive injectable hyaluronic acid hydrogel for adipose tissue engineering[J]. Biomaterials, 2009, 30:6844-6853.
[104] Nief RA, Tamer MA, Abd Alhammid SN. Mucoadhesive oral in situ gel of itraconazole using pH-sensitive polymers:preparation, and in vitro characterization, release and rheology study[J]. Drug Invent Today, 2019, 11:1451-1455.
[105] Huang Y, Shi F, Wang L, et al. Preparation and evaluation of bletilla striata polysaccharide/carboxymethyl chitosan/carbomer 940 hydrogel for wound healing[J]. Int J Biol Macromol, 2019, 132:729-737.
[106] Jalil A, Khan S, Naeem F, et al. The structural, morphological and thermal properties of grafted pH-sensitive interpenetrating highly porous polymeric composites of sodium alginate/acrylic acid copolymers for controlled delivery of diclofenac potassium[J]. Desig Mono Polym, 2017, 20:308-324.
[107] Tally M, Atassi Y. Optimized synthesis and swelling properties of a pH-sensitive semi-IPN superabsorbent polymer based on sodium alginate-g-poly(acrylic acid-co-acrylamide) and polyvinylpyrrolidone and obtained via microwave irradiation[J]. J Polym Res, 2015, 22:181.
[108] Chowhan A, Giri TK. Polysaccharide as renewable responsive biopolymer for in situ gel in the delivery of drug through ocular route[J]. Int J Biol Macromol, 2020, 150:559-572.
[109] Wu XL, Ma JF, Fan XY, et al. Research in rheological properties of four types of ophthalmic preparations[J]. Acta Pharma Sin (药学学报), 2017, 52:146-152.
[110] Okur NU, Yozgatli V, Okur ME, et al. Improving therapeutic efficacy of voriconazole against fungal keratitis:thermo-sensitive in situ gels as ophthalmic drug carriers[J]. J Drug Deliv Sci Technol, 2019, 49:323-333.
[111] Mustak H, Fiaschetti D, Goldberg RA. Filling the periorbital hollows with hyaluronic acid gel:long-term review of outcomes and complications[J]. J Cosmet Dermatol, 2018, 17:611-616.
[112] 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.
[113] Song LN, Li HR, Wang HY, et al. Preparation and properties of thermosensitive in situ gel for ophthalmic formulation containing pearl hydrolyzate[J]. Acta Pharm Sin (药学学报), 2016, 51:1622-1628.
[114] Rezazadeh M, Jafari N, Akbari V, et al. A mucoadhesive thermosensitive hydrogel containing erythropoietin as a potential treatment in oral mucositis:in vitro and in vivo studies[J]. Drug Deliv Transl Res, 2018, 8:1226-1237.
[115] Yadav R, Kanwar IL, Haider T, et al. In situ gel drug delivery system for periodontitis:an insight review[J]. Fut J Pharm Sci, 2020, 6:1-13.
[116] Swain GP, Patel S, Gandhi J, et al. Development of moxifloxacin hydrochloride loaded in-situ gel for the treatment of periodontitis:in-vitro drug release study and antibacterial activity[J]. J Oral Biol Craniofac Res, 2019, 9:190-200.
[117] Ruan H, Yu Y, Guo X, et al. The possibility of healing alveolar bone defects with simvastatin thermosensitive gel:in vitro/in vivo evaluation[J]. Drug Des Devel Ther, 2018, 12:1997-2003.
[118] Hao WY, Zhang LH, Zheng ZJ, et al. Therapeutic effect of curcumin hydrogel on rats with periodontitis[J]. Chin J Mod Appl Pharm (中国现代应用药学), 2019, 36:1773-1778.
[119] Awartani FA, Tatakis DN. Interdental papilla loss:treatment by hyaluronic acid gel injection:a case series[J]. Clin Oral Investig, 2016, 20:1775-1780.
[120] Almomen A, Cho S, Yang CH, et al. Thermosensitive progesterone hydrogel:a safe and effective new formulation for vaginal application[J]. Pharm Res, 2015, 32:2266-2279.
[121] Zhang S, Zhang Y, Wang Z, et al. Temperature-sensitive gel-loaded composite nanomedicines for the treatment of cervical cancer by vaginal delivery[J]. Int J Pharm, 2020, 586:119616.
[122] Deshkar SS, Palve VK. Formulation and development of thermosensitive cyclodextrin-based in situ gel of voriconazole for vaginal delivery[J]. J Drug Deliv Sci Technol, 2019, 49:277-285.
[123] N'Guessan Gnaman KC, Bouttier S, Yeo A, et al. Characterization and in vitro evaluation of a vaginal gel containing Lactobacillus crispatus for the prevention of gonorrhea[J]. Int J Pharm, 2020, 588:119733.
[124] Patel P. Formulation and evaluation of clindamycin hcl in situ gel for vaginal application[J]. Int J Pharm Investig, 2015, 5:50-56.
[125] Chen X, Chen WY, Ma PP, et al. Curcumin temperature-sensitivein situhydrogels for treatment of vaginal candidiasis[J]. J Int Pharm Res (国际药学研究杂志), 2017, 44:947-952.
[126] Askari E, Seyfoori A, Amereh M, et al. Stimuli-responsive hydrogels for local post-surgical drug delivery[J]. Gels, 2020, 6:14.
[127] Ruan C, Liu C, Hu H, et al. NIR-II light-modulated thermosensitive hydrogel for light-triggered cisplatin release and repeatable chemo-photothermal therapy[J]. Chem Sci, 2019, 10:4699-4706.
[128] Jung YS, Park W, Park H, et al. Thermo-sensitive injectable hydrogel based on the physical mixing of hyaluronic acid and pluronic F-127 for sustained NSAID delivery[J]. Carbohydr Polym, 2017, 156:403-408.
[129] Wu H, Wang K, Wang H, et al. Novel self-assembled tacrolimus nanoparticles cross-linking thermosensitive hydrogels for local rheumatoid arthritis therapy[J]. Colloids Surf B Biointerfaces, 2017, 149:97-104.
[130] Chen ZP, Liu W, Chen HX, et al. Brucine chitosan thermosensitive hydrogel for intra-articular injection[J]. Acta Pharm Sin (药学学报), 2012, 47:652-656.
[131] Du LN, Jin YG. Brain-targeted nasaldrug delivery systems for the treatment of neurodegenerative diseases[J]. J Int Pharm Res (国际药学研究杂志), 2016, 43:104-109.
[132] 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.
[133] Ma JQ, Pang LL, Zhu SQ, et al. Effect of four drug-loaded hydrogels on prevention of hypoxic brain damage[J]. J Int Pharm Res (国际药学研究杂志), 2019, 46:516-521.
[134] Beirami E, Oryan S, Seyedhosseini Tamijani SM, et al. Intranasal insulin treatment alleviates methamphetamine induced anxiety-like behavior and neuroinflammation[J]. Neurosci Lett, 2017, 660:122-129.
[135] Naresh WR, Dilip DV, Sunil KP. Xyloglucan based nasal in situ gel formulation of mirtazapine for treatment of depression[J]. Indian J Pharm Edu Res, 2020, 54:210-219.
[136] 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.
[137] Gholizadeh H, Cheng S, Pozzoli M, et al. Smart thermosensitive chitosan hydrogel for nasal delivery of ibuprofen to treat neurological disorders[J]. Expert Opin Drug Deliv, 2019, 16:453-466.
[138] Chen Y, Cheng G, Hu R, et al. A nasal temperature and pH dual-responsive in situ gel delivery system based on microemulsion of huperzine a:formulation, evaluation, and in vivo pharmacokinetic study[J]. AAPS PharmSciTech, 2019, 20:301.
[139] Qiu HY, Bi HY, Chen X, et al. Curcumin hydrogel combined with photodynamics to treat acne[J]. J Int Pharm Res (国际药学研究杂志), 2017, 44:33-39.
[140] Sosa L, Calpena AC, Silva-Abreu M, et al. Thermoreversible gel-loaded amphotericin B for the treatment of dermal and vaginal candidiasis[J]. Pharmaceutics, 2019, 11:312.
[141] Lei Z, Singh G, Min Z, et al. Bone marrow-derived mesenchymal stem cells laden novel thermo-sensitive hydrogel for the management of severe skin wound healing[J]. Mater Sci Eng C Mater Biol Appl, 2018, 90:159-167.
[142] Hashmat D, Shoaib MH, Ali FR, et al. Lornoxicam controlled release transdermal gel patch:design, characterization and optimization using co-solvents as penetration enhancers[J]. PLoS One, 2020, 15:e0228908.
[143] AMAE Razek, Hasan AA, Sabry SA, et al. Metoclopramide hydrochloride thermally sensitive rectal in situ gelling system, a novel out-patient treatment for vomiting in pediatric age[J]. J Drug Deliv Sci Technol, 2019, 50:9-17.
[144] Liu Y, Wang X, Liu Y, et al. Thermosensitive in situ gel based on solid dispersion for rectal delivery of ibuprofen[J]. AAPS PharmSciTech, 2018, 19:338-347.
[145] Abbasi M, Sohail M, Minhas MU, et al. Novel biodegradable pH-sensitive hydrogels:an efficient controlled release system to manage ulcerative colitis[J]. Int J Biol Macromol, 2019, 136:83-96.
[146] Yang WW, Pierstorff E. Reservoir-based polymer drug delivery systems[J]. J Lab Autom, 2012, 17:50-58.
[147] Caccavo D, Lamberti G, Cafaro MM, et al. Mathematical modelling of the drug release from an ensemble of coated pellets[J]. Br J Pharmacol, 2017, 174:1797-1809.
[148] Kong BJ, Kim A, Park SN. Properties and in vitro drug release of hyaluronic acid-hydroxyethyl cellulose hydrogels for transdermal delivery of isoliquiritigenin[J]. Carbohydr Polym, 2016, 147:473-481.
[149] Drury JL, Mooney DJ. Hydrogels for tissue engineering:scaffold design variables and applications[J]. Biomaterials, 2003, 24:4337-4351.