Journal of Chemical Reviews
8.1(Q1)
CiteScore
37
h-index

In Situ Gel Based Smart Drug Delivery Systems: Chemical Insights and Application in Diabetes

Articles in Press

Document Type : Review Article

Authors

Ratakonda Deepak Srinivas 1
P. Shanmugasundaram 2
J. Sangeetha 3
Venkata Ramana Singamaneni 4
Patibandla Jahnavi 5
Prem Shankar Gupta 6
A. Anka Rao 7
P. Balaji 8

1 Department of General Medicine, Vels Medical College and Hospital, Vels Institute of Science, Technology and Advanced Studies, Manjankaranai, Thiruvallur - 601 102, India

2 Department of Pharmaceutical Chemistry and Analysis, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies, Pallavaram, Chennai - 600 117, India

3 Department of Pharmacognosy, Malla Reddy Institute of Pharmaceutical Sciences, A Constituent College of Malla Reddy Vishwavidyapeeth (Deemed to be University), Maisammaguda, Dhulapally, Secunderabad – 500100, India

4 Department of Analytical Research and Development, Cambrex, Charles City, Iowa- 50616, USA

5 Department of Pharmaceutics, KVSR Siddhartha College of Pharmaceutical Sciences, Vijayawada, India

6 Department of Pharmaceutics, Teerthanker Mahaveer College of Pharmacy, Teerthanker Mahaveer University, Moradabad 244001 (U.P), India

7 KL College of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram, Guntur, Andhra Pradesh 522502, India

8 Department of Pharmacology, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies, Pallavaram, Chennai - 600 117, India

https://doi.org/10.48309/jcr.2026.549617.1507
Abstract
Stimuli-responsive in situ gel-based smart drug delivery systems represent an innovative approach to diabetes therapy that addresses the limitations of conventional formulations, such as poor bioavailability, short drug half-life, and frequent dosing. These systems undergo sol-to-gel transitions in response to physiological stimuli, including pH, temperature, ions, and enzymatic activity, enabling controlled and prolonged drug release. Synthetic polymers such as poloxamers, poly (ethylene glycol) (PEG) derivatives, and poly(N-isopropylacrylamide) (PNIPAAm) allow the precise modulation of gelation behavior, stability, and physicochemical properties. Due to their biocompatibility and stimuli-responsiveness, in situ gels have been explored via oral, nasal, ocular, injectable, and transdermal routes for the delivery of insulin, oral hypoglycemics, and peptide-based drugs. Recent advances have integrated nanoparticles and glucose-sensitive components for feedback-regulated insulin release, closely mimicking pancreatic β-cell function, and improving therapeutic precision. Despite challenges, such as limited mechanical strength, gelation variability, and regulatory constraints, continued progress in polymer chemistry, nanotechnology, and biomaterial design is expected to overcome these barriers. Collectively, the in-situ gel-based delivery systems offer a promising, patient-friendly, and physiologically adaptive platform for next-generation diabetes management.

Graphical Abstract

In Situ Gel Based Smart Drug Delivery Systems: Chemical Insights and Application in Diabetes

Keywords

In situ gel
Smart drug delivery
Insulin delivery
Polymeric hydrogels
Diabetes management
Controlled release
Stimuli-responsive polymers
Nanomedicine

Subjects

 Content

1. Introduction

1.1 Diabetes: An overview

1.2 Challenges in conventional antidiabetic drug delivery

1.3 Need for smart drug delivery systems

2. In situ Gel Systems: Fundamentals

2.1 Definition and concept of in situ gels

2.2 Mechanism of sol-to-gel transition

2.3 Classification of in situ gel systems

2.3.1 pH-triggered systems

2.3.2 Temperature-responsive systems

2.3.3 Temperature-responsive systems

2.3.4 Ion-activated systems

2.3.5 Enzyme-responsive systems

3. Chemical Insights into In situ Gelling Polymers

3.1 Natural polymers

3.2 Synthetic polymers

3.3 Crosslinking mechanisms and gelation chemistry

3.4 Physicochemical properties influencing drug release

4. Formulation Approaches for Antidiabetic Drug Delivery

4.1 Approaches for oral delivery

4.2 Nasal and ocular delivery systems

4.3 Injectable in situ gel systems

4.4 Transdermal applications

4.5 Combination therapies and co-delivery

5. Smart Features of In Situ Gel Systems

5.1 Controlled and sustained release profiles

5.2 Stimuli-responsive behaviour

5.3 Targeted delivery to pancreatic or extra-pancreatic sites

5.4 Biocompatibility and safety considerations

6. Applications in Diabetes Management

6.1 Delivery of insulin via in situ gels

6.2 Delivery of oral hypoglycemic agents

6.3 Emerging peptide and protein-based therapies

6.4 Nanoparticle-loaded in situ gels for diabetes

7. Challenges and Future Perspectives

7.1 Limitations of current in situ gel systems

7.2 Advances in polymer chemistry and nanotechnology

7.3 Future outlook for diabetes therapy

8. Conclusion

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[1] Tamboli, A., Tayade, S. In-depth investigation of berberine and tropane through computational screening as possible DPP-IV inhibitors for the treatment of T2DM. Journal of Pharmaceutical Sciences and Computational Chemistry, 2025, 1(1), 190-209.
[2] Iheagwam, F.N., Iheagwam, O.T. Diabetes mellitus: The pathophysiology as a canvas for management elucidation and strategies. Medicine in Novel Technology and Devices, 2025, 100351.
[3] Hossain, M.J., Al‐Mamun, M., Islam, M.R. Diabetes mellitus, the fastest growing global public health concern: Early detection should be focused. Health Science Reports, 2024, 7(3), e2004.
[4] Siam, N.H., Snigdha, N.N., Tabasumma, N., Parvin, I. Diabetes mellitus and cardiovascular disease: Exploring epidemiology, pathophysiology, and treatment strategies. Reviews in Cardiovascular Medicine, 2024, 25(12), 436.
[5] Li, Y., Liu, Y., Liu, S., Gao, M., Wang, W., Chen, K., Huang, L., Liu, Y. Diabetic vascular diseases: Molecular mechanisms and therapeutic strategies. Signal Transduction and Targeted Therapy, 2023, 8(1), 152.
[6] Sugandh, F., Chandio, M., Raveena, F., Kumar, L., Karishma, F., Khuwaja, S., Memon, U.A., Bai, K., Kashif, M., Varrassi, G. Advances in the management of diabetes mellitus: A focus on personalized medicine. Cureus, 2023, 15(8).
[7] Wang, X., Sun, H., Mu, T. Materials and structure of polysaccharide-based delivery carriers for oral insulin: A review. Carbohydrate Polymers, 2024, 323, 121364.
[8] Rolla, A. Pharmacokinetic and pharmacodynamic advantages of insulin analogues and premixed insulin analogues over human insulins: Impact on efficacy and safety. The American Journal of Medicine, 2008, 121(6), S9-S19.
[9] Bailey, C., Kodack, M. Patient adherence to medication requirements for therapy of type 2 diabetes. International Journal of Clinical Practice, 2011, 65(3), 314-322.
[10] Liu, M., Wang, R., Hoi, M.P.M., Wang, Y., Wang, S., Li, G., Vong, C.T., Chong, C.M. Nano-based drug delivery systems for managing diabetes: Recent advances and future prospects. International Journal of Nanomedicine, 2025, 6221-6252.
[11] Liu, J., Yi, X., Zhang, J., Yao, Y., Panichayupakaranant, P., Chen, H. Recent advances in the drugs and glucose-responsive drug delivery systems for the treatment of diabetes: A systematic review. Pharmaceutics, 2024, 16(10), 1343.
[12] Sarkhel, S., Shuvo, S.M., Ansari, M.A., Mondal, S., Kapat, P., Ghosh, A., Sarkar, T., Biswas, R., Atanase, L.I., Carauleanu, A. Nanotechnology-based approaches for the management of diabetes mellitus: An innovative solution to long-lasting challenges in antidiabetic drug delivery. Pharmaceutics, 2024, 16(12), 1572.
[13] Garg, A., Agrawal, R., Chauhan, C.S., Deshmukh, R. In-situ gel: A smart carrier for drug delivery. International Journal of Pharmaceutics, 2024, 652, 123819.
[14] Pal, S., Rakshit, T., Saha, S., Jinagal, D. Glucose-responsive materials for smart insulin delivery: From protein-based to protein-free design. ACS Materials Au, 2025, 5(2), 239-252.
[15] Jahanbekam, S., Asare-Addo, K., Alipour, S., Nokhodchi, A. Smart hydrogels and the promise of multi-responsive in-situ systems. Journal of Drug Delivery Science and Technology, 2025, 106758.
[16] Shreya, L., Suma, U. Recent advances in oral in-situ gel drug delivery system: A polymeric approach. Drug Development and Industrial Pharmacy, 2025, 1-16.
[17] Liu, B., Chen, K. Advances in hydrogel-based drug delivery systems. Gels, 2024, 10(4), 262.
[18] Park, K.M., Lee, S.Y., Joung, Y.K., Na, J.S., Lee, M.C., Park, K.D. Thermosensitive chitosan–pluronic hydrogel as an injectable cell delivery carrier for cartilage regeneration. Acta Biomaterialia, 2009, 5(6), 1956-1965.
[19] Paul, S., Majumdar, S., Chakraborty, M. Revolutionizing ocular drug delivery: Recent advancements in in situ gel technology. Bulletin of the National Research Centre, 2023, 47(1), 154.
[20] Kouchak, M. In situ gelling systems for drug delivery. Jundishapur Journal of Natural Pharmaceutical Products, 2014, 9(3), e20126.
[21] Wang, S., Alvarez-Fernandez, A., Liu, X., Miron-Barroso, S., Wong, K., Guldin, S., Georgiou, T.K. Effect of composition on the thermo-induced aggregation of poloxamer-analogue triblock terpolymers. Macromolecules, 2025, 58(5), 2289-2302.
[22] Singh, J., Nayak, P. Ph‐responsive polymers for drug delivery: Trends and opportunities. Journal of Polymer Science, 2023, 61(22), 2828-2850.
[23] Purohit, P., Pakhar, P., Pawar, V., Dandade, S., Waghmare, M., Shaikh, F., Kale, R. Formulation and comparative evaluation of naproxen-based transdermal gels. Journal of Pharmaceutical Sciences and Computational Chemistry, 2025, 1(2), 83-105.
[24] Prasanth, V., Rangarao, V., Naga, V., Deeshitha, D., Veerla, G., Jahnavi, P. Herbal emulgel delivery systems for proctological applications: Current trends, mechanisms, and clinical perspectives. Journal of Pharmaceutical Sciences and Computational Chemistry, 2025, 1, 174–188.
[25] Ručigaj, A., Golobič, J., Kopač, T. The role of multivalent cations in determining the cross-linking affinity of alginate hydrogels: A combined experimental and modeling study. Chemical Engineering Journal Advances, 2024, 20, 100678.
[26] Gadziński, P., Froelich, A., Jadach, B., Wojtyłko, M., Tatarek, A., Białek, A., Krysztofiak, J., Gackowski, M., Otto, F., Osmałek, T. Ionotropic gelation and chemical crosslinking as methods for fabrication of modified-release gellan gum-based drug delivery systems. Pharmaceutics, 2023, 15(1), 108.
[27] Thang, N.H., Chien, T.B., Cuong, D.X. Polymer-based hydrogels applied in drug delivery: An overview. Gels, 2023, 9(7), 523.
[28] Wu, Y., Liu, Y., Li, X., Kebebe, D., Zhang, B., Ren, J., Lu, J., Li, J., Du, S., Liu, Z. Research progress of in-situ gelling ophthalmic drug delivery system. Asian Journal of Pharmaceutical Sciences, 2019, 14(1), 1-15.
[29] Milosavljević, N.B., Milašinović, N.Z., Popović, I.G., Filipović, J.M., Kalagasidis Krušić, M.T. Preparation and characterization of ph‐sensitive hydrogels based on chitosan, itaconic acid and methacrylic acid. Polymer International, 2011, 60(3), 443-452.
[30] Wei, H., Cheng, S.X., Zhang, X.Z., Zhuo, R.X. Thermo-sensitive polymeric micelles based on poly (n-isopropylacrylamide) as drug carriers. Progress in Polymer Science, 2009, 34(9), 893-910.
[31] Sobczak, M. Enzyme-responsive hydrogels as potential drug delivery systems—state of knowledge and future prospects. International Journal of Molecular Sciences, 2022, 23(8), 4421.
[32] Bustamante-Torres, M., Romero-Fierro, D., Arcentales-Vera, B., Palomino, K., Magaña, H., Bucio, E. Hydrogels classification according to the physical or chemical interactions and as stimuli-sensitive materials. Gels, 2021, 7(4), 182.
[33] Gupta, S., Vyas, S.P. Carbopol/chitosan based ph triggered in situ gelling system for ocular delivery of timolol maleate. Scientia Pharmaceutica, 2010, 78(4), 959.
[34] Al Tahan, M.A., Al-Khattawi, A., Russell, C. Oral peptide delivery systems: Synergistic approaches using polymers, lipids, nanotechnology, and needle-based carriers. Journal of Drug Delivery Science and Technology, 2025, 107205.
[35] Patil, R.R., Patil, A.S., Chougule, K., Patil, A.S., Ugare, P., Masareddy, R.S. Exploring the transformative potential of in situ gels: An overview of thermosensitive and ph‐sensitive gel systems for biomedical applications. Macromolecular Symposia, 2024, 413(2), 2300153.
[36] Russo, E., Villa, C. Poloxamer hydrogels for biomedical applications. Pharmaceutics, 2019, 11(12), 671.
[37] Bellotti, E., Schilling, A.L., Little, S.R., Decuzzi, P. Injectable thermoresponsive hydrogels as drug delivery system for the treatment of central nervous system disorders: A review. Journal of Controlled Release, 2021, 329, 16-35.
[38] Kurniawansyah, I.S., Rusdiana, T., Sopyan, I., Desy Arya, I.F., Wahab, H.A., Nurzanah, D. Comparative study of in situ gel formulation based on the physico-chemical aspect: Systematic review. Gels, 2023, 9(8), 645.
[39] Siew, C.K., Williams, P.A., Young, N.W. New insights into the mechanism of gelation of alginate and pectin: Charge annihilation and reversal mechanism. Biomacromolecules, 2005, 6(2), 963-969.
[40] Patel, A., Cholkar, K., Agrahari, V., Mitra, A.K. Ocular drug delivery systems: An overview. World Journal of Pharmacology, 2013, 2(2), 47.
[41] Rudko, M., Urbaniak, T., Musiał, W. Recent developments in ion-sensitive systems for pharmaceutical applications. Polymers, 2021, 13(10), 1641.
[42] Cao, L., Lu, W., Mata, A., Nishinari, K., Fang, Y. Egg-box model-based gelation of alginate and pectin: A review. Carbohydrate Polymers, 2020, 242, 116389.
[43] Li, S., Chen, L., Fu, Y. Nanotechnology-based ocular drug delivery systems: Recent advances and future prospects. Journal of Nanobiotechnology, 2023, 21(1), 232.
[44] Blagojevic, L., Kamaly, N. Nanogels: A chemically versatile drug delivery platform. Nano Today, 2025, 61, 102645.
[45] Das, S., Das, D. Rational design of peptide-based smart hydrogels for therapeutic applications. Frontiers in Chemistry, 2021, 9, 770102.
[46] Sahu, K., Firdous, A., Raza, M.A., Saoji, S.D., Patravale, V.B. Enzyme-responsive natural nanocarriers for rna delivery in the tumor microenvironment: A comprehensive review. Journal of Drug Delivery Science and Technology, 2025, 107455.
[47]Liu, Y., Ma, N., Gao, N., Ling, G., Zhang, P. Metal-organic framework-based injectable in situ gel for multi-responsive insulin delivery. Journal of Drug Delivery Science and Technology, 2022, 75, 103604.
[48] Kolawole, O.M., Cook, M.T. In situ gelling drug delivery systems for topical drug delivery. European Journal of Pharmaceutics and Biopharmaceutics, 2023, 184, 36-49.
[49] Zoeller, K., To, D., Bernkop-Schnuerch, A. Biomedical applications of functional hydrogels: Innovative developments, relevant clinical trials and advanced products. Biomaterials, 2025, 312, 122718.
[50] Saif, M., Raza, M.A., Patravale, V.B. Polysaccharide copolymeric conjugates and their applications in targeted cancer therapy. International Journal of Biological Macromolecules, 2025, 147380.
[51] Aranaz, I., Alcántara, A.R., Civera, M.C., Arias, C., Elorza, B., Heras Caballero, A., Acosta, N. Chitosan: An overview of its properties and applications. Polymers, 2021, 13(19), 3256.
[52] Bojorges, H., Martínez-Abad, A., Martinez-Sanz, M., Rodrigo, M.D., Vilaplana, F., López-Rubio, A., Fabra, M.J. Structural and functional properties of alginate obtained by means of high hydrostatic pressure-assisted extraction. Carbohydrate Polymers, 2023, 299, 120175.
[53] Abdl Aali, R.A.K., Al-Sahlany, S.T.G. Gellan gum as a unique microbial polysaccharide: Its characteristics, synthesis, and current application trends. Gels, 2024, 10(3), 183.
[54] Satchanska, G., Davidova, S., Petrov, P.D. Natural and synthetic polymers for biomedical and environmental applications. Polymers, 2024, 16(8), 1159.
[55] Raza, M.A., Khatoon, N., Parveen, R., Nirisha, V., Thakur, Y., Thakur, Y., Lata, K., Shifana, A., Disouza, J., Saoji, S.D. Natural macromolecules polysaccharide-based drug delivery systems targeting tumor necrosis factor alpha receptor for the treatment of cancer: A review. International Journal of Biological Macromolecules, 2025, 318, 145145.
[56] Prete, S., Dattilo, M., Patitucci, F., Pezzi, G., Parisi, O.I., Puoci, F. Natural and synthetic polymeric biomaterials for application in wound management. Journal of Functional Biomaterials, 2023, 14(9), 455.
[57] Sil, D., Kumar, M., Kumar, D., Saini, V., Kurmi, B.D., Pal, R.R., Srivastava, S. Engineering poloxamer copolymers for in situ gelling systems: Structural, compositional, and functional modifications. European Polymer Journal, 2025, 114259.
[58] Raza, M.A., Sharma, M.K., Nagori, K., Jain, P., Ghosh, V., Gupta, U. Recent trends on polycaprolactone as sustainable polymer-based drug delivery system in the treatment of cancer: Biomedical applications and nanomedicine. International Journal of Pharmaceutics, 2024, 666, 124734.
[59] Bento, C., Katz, M., Santos, M.M., Afonso, C.A. Striving for uniformity: A review on advances and challenges to achieve uniform polyethylene glycol. Organic Process Research & Development, 2024, 28(4), 860-890.
[60] Lanzalaco, S., Mingot, J., Torras, J., Alemán, C., Armelin, E. Recent advances in poly (n‐isopropylacrylamide) hydrogels and derivatives as promising materials for biomedical and engineering emerging applications. Advanced Engineering Materials, 2023, 25(4), 2201303.
[61] Mortier, C., Costa, D., Oliveira, M.B., Haugen, H.J., Lyngstadaas, S.P., Blaker, J., Mano, J. Advanced hydrogels based on natural macromolecules: Chemical routes to achieve mechanical versatility. Materials Today Chemistry, 2022, 26, 101222.
[62] Almawash, S., Osman, S.K., Mustafa, G., El Hamd, M.A. Current and future prospective of injectable hydrogels—design challenges and limitations. Pharmaceuticals, 2022, 15(3), 371.
[63] Hong, F., Qiu, P., Wang, Y., Ren, P., Liu, J., Zhao, J., Gou, D. Chitosan-based hydrogels: From preparation to applications, a review. Food Chemistry: X, 2024, 21, 101095.
[64] Mashabela, L.T., Maboa, M.M., Miya, N.F., Ajayi, T.O., Chasara, R.S., Milne, M., Mokhele, S., Demana, P.H., Witika, B.A., Siwe-Noundou, X. A comprehensive review of cross-linked gels as vehicles for drug delivery to treat central nervous system disorders. Gels, 2022, 8(9), 563.
[65] Morariu, S. Advances in the design of phenylboronic acid-based glucose-sensitive hydrogels. Polymers, 2023, 15(3), 582.
[66] Puttipipatkhachorn, S., Pongjanyakul, T., Priprem, A. Molecular interaction in alginate beads reinforced with sodium starch glycolate or magnesium aluminum silicate, and their physical characteristics. International Journal of Pharmaceutics, 2005, 293(1-2), 51-62.
[67] Pathan, I., Raza, M.A., Roy, A., Badwaik, H., Sakure, K. Recent advances in thermo-responsive hydrogels for ocular drug delivery: Materials, mechanisms, and clinical potential. Journal of Drug Delivery Science and Technology, 2025, 107537.
[68] Alexander, A., Khan, J., Saraf, S., Saraf, S. Poly (ethylene glycol)–poly (lactic-co-glycolic acid) based thermosensitive injectable hydrogels for biomedical applications. Journal of Controlled Release, 2013, 172(3), 715-729.
[69] Xue, X., Hu, Y., Wang, S., Chen, X., Jiang, Y., Su, J. Fabrication of physical and chemical crosslinked hydrogels for bone tissue engineering. Bioactive Materials, 2022, 12, 327-339.
[70] Song, W., Ko, J., Choi, Y.H., Hwang, N.S. Recent advancements in enzyme-mediated crosslinkable hydrogels: In vivo-mimicking strategies. APL Bioengineering, 2021, 5(2).
[71] Barba, A.A., d'Amore, M., Cascone, S., Chirico, S., Lamberti, G., Titomanlio, G. On the behavior of hpmc/theophylline matrices for controlled drug delivery. Journal of Pharmaceutical Sciences, 2009, 98(11), 4100-4110.
[72] Karoyo, A.H., Wilson, L.D. A review on the design and hydration properties of natural polymer-based hydrogels. Materials, 2021, 14(5), 1095.
[73] Hawthorne, D., Pannala, A., Sandeman, S., Lloyd, A. Sustained and targeted delivery of hydrophilic drug compounds: A review of existing and novel technologies from bench to bedside. Journal of Drug Delivery Science and Technology, 2022, 78, 103936.
[74] Bookwala, M., Wildfong, P.L. The implications of drug-polymer interactions on the physical stability of amorphous solid dispersions. Pharmaceutical Research, 2023, 40(12), 2963-2981.
[75] Li, L., Wang, Y. Advancements in injectable hydrogels for controlled insulin delivery: A comprehensive review of the design, properties and therapeutic applications for diabetes and its complications. Polymers, 2025, 17(6), 780.
[76] Abbasi, M., Boka, D.A., DeLoit, H. Nanomaterial-enhanced microneedles: Emerging therapies for diabetes and obesity. Pharmaceutics, 2024, 16(10), 1344.
[77] Rizwan, M., Yahya, R., Hassan, A., Yar, M., Azzahari, A.D., Selvanathan, V., Sonsudin, F., Abouloula, C.N. pH sensitive hydrogels in drug delivery: Brief history, properties, swelling, and release mechanism, material selection and applications. Polymers, 2017, 9(4), 137.
[78] Harsha, S., Attimard, M., Khan, T.A., Nair, A.B., Aldhubiab, B.E., Sangi, S., Shariff, A. Design and formulation of mucoadhesive microspheres of sitagliptin. Journal of Microencapsulation, 2013, 30(3), 257-264.
[79] Chung, T.W., Liu, D.Z., Yang, J.S. Effects of interpenetration of thermo-sensitive gels by crosslinking of chitosan on nasal delivery of insulin: In vitro characterization and in vivo study. Carbohydrate Polymers, 2010, 82(2), 316-322.
[80] Mura, P., Maestrelli, F., Cirri, M., Mennini, N. Multiple roles of chitosan in mucosal drug delivery: An updated review. Marine Drugs, 2022, 20(5), 335.
[81] Gupta, H., Velpandian, T., Jain, S. Ion-and pH-activated novel in-situ gel system for sustained ocular drug delivery. Journal of Drug Targeting, 2010, 18(7), 499-505.
[82] Kouchak, M., Mahmoodzadeh, M., Farrahi, F. Designing of a ph-triggered carbopol®/hpmc in situ gel for ocular delivery of dorzolamide hcl: In vitro, in vivo, and ex vivo evaluation. AAPS PharmSciTech, 2019, 20(5), 210.
[83] Oh, K.S., Kim, J.Y., Yoon, B.D., Lee, M., Kim, H., Kim, M., Seo, J.H., Yuk, S.H. Sol–gel transition of nanoparticles/polymer mixtures for sustained delivery of exenatide to treat type 2 diabetes mellitus. European Journal of Pharmaceutics and Biopharmaceutics, 2014, 88(3), 664-669.
[84] Webber, M.J., Pashuck, E.T. (Macro) molecular self-assembly for hydrogel drug delivery. Advanced Drug Delivery Reviews, 2021, 172, 275-295.
[85] Chopra, H., Bibi, S., Kumar, S., Khan, M.S., Kumar, P., Singh, I. Preparation and evaluation of chitosan/pva based hydrogel films loaded with honey for wound healing application. Gels, 2022, 8(2), 111.
[86] Zhao, P., Zhou, Z., Wolter, T., Womelsdorf, J., Somers, A., Feng, Y., Nuutila, K., Tian, Z., Chen, J., Tamayol, A. Engineering microneedles for biosensing and drug delivery. Bioactive Materials, 2025, 52, 36-59.
[87] Abbas, M.N., Khan, S.A., Sadozai, S.K., Khalil, I.A., Anter, A., Fouly, M.E., Osman, A.H., Kazi, M. Nanoparticles loaded thermoresponsive in situ gel for ocular antibiotic delivery against bacterial keratitis. Polymers, 2022, 14(6), 1135.
[88] Peng, H., Wang, J., Chen, J., Peng, Y., Wang, X., Chen, Y., Kaplan, D.L., Wang, Q. Challenges and opportunities in delivering oral peptides and proteins. Expert Opinion on Drug Delivery, 2023, 20(10), 1349-1369.
[89] Kumar, R., Islam, T., Nurunnabi, M. Mucoadhesive carriers for oral drug delivery. Journal of Controlled Release, 2022, 351, 504-559.
[90] Baral, K.C., Choi, K.Y. Barriers and strategies for oral peptide and protein therapeutics delivery: Update on clinical advances. Pharmaceutics, 2025, 17(4), 397.
[91] Parvin, N., Joo, S.W., Mandal, T.K. Injectable biopolymer-based hydrogels: A next-generation platform for minimally invasive therapeutics. Gels, 2025, 11(6), 383.
[92] Ukwubile, C., Mathias, S., Pisagih, P. Acute and subchronic toxicity evaluation and gc-ms profiling of ajumbaise: A traditional nigerian polyherbal formulation for labor enhancement and pain relief. Journal of Pharmaceutical Sciences and Computational Chemistry, 2025, 1(2), 154-173.
[93] Tiwari, P., Prajapati, S., Dixit, V., Raza, M.A., Gupta, S.K., Sharma, M. Recent advancements in nanoparticle drug delivery systems to cure neurological disorders via the nasal route. Neurología Argentina, 2025.
[94] Maeng, J., Lee, K. Systemic and brain delivery of antidiabetic peptides through nasal administration using cell-penetrating peptides. Frontiers in Pharmacology, 2022, 13, 1068495.
[95] Soliman, K.A., Ullah, K., Shah, A., Jones, D.S., Singh, T.R. Poloxamer-based in situ gelling thermoresponsive systems for ocular drug delivery applications. Drug Discovery Today, 2019, 24(8), 1575-1586.
[96] Akhter, M.H., Ahmad, I., Alshahrani, M.Y., Al-Harbi, A.I., Khalilullah, H., Afzal, O., Altamimi, A.S., Najib Ullah, S.N.M., Ojha, A., Karim, S. Drug delivery challenges and current progress in nanocarrier-based ocular therapeutic system. Gels, 2022, 8(2), 82.
[97] Gandhi, S., Shastri, D.H., Shah, J., Nair, A.B., Jacob, S. Nasal delivery to the brain: Harnessing nanoparticles for effective drug transport. Pharmaceutics, 2024, 16(4), 481.
[98] Ibrahim, T.M., Ayoub, M.M., El-Bassossy, H.M., El-Nahas, H.M., Gomaa, E. Investigation of alogliptin-loaded in situ gel implants by 23 factorial design with glycemic assessment in rats. Pharmaceutics, 2022, 14(9), 1867.
[99] García-Couce, J., Tomás, M., Fuentes, G., Que, I., Almirall, A., Cruz, L.J. Chitosan/pluronic f127 thermosensitive hydrogel as an injectable dexamethasone delivery carrier. Gels, 2022, 8(1), 44.
[100] Bakhrushina, E.O., Mikhel, I.B., Buraya, L.M., Moiseev, E.D., Zubareva, I.M., Belyatskaya, A.V., Evzikov, G.Y., Bondarenko, A.P., Krasnyuk Jr, I.I., Krasnyuk, I.I. Implantation of in situ gelling systems for the delivery of chemotherapeutic agents. Gels, 2024, 10(1), 44.
[101] Davodabadi, F., Sargazi, S., Baino, F. Recent advances in hydrogel-based drug delivery systems for enhanced cancer therapy: A review. Materials Today Communications, 2025, 113615.
[102] Balu, P., Srikanth, S., Gnandhas, D.P., Durai, R.D., Ulaganathan, V., B Narayanan, V.H. Development and optimization of an injectable in-situ gel system for sustained release of anti-tuberculosis drugs. Scientific Reports, 2025, 15(1), 21383.
[103] Liu, S., Deng, T., Cheng, H., Lu, J., Wu, J. Advances in transdermal drug delivery systems and clinical applications in inflammatory skin diseases. Pharmaceutics, 2025, 17(6), 746.
[104] Zhao, J., Xu, G., Yao, X., Zhou, H., Lyu, B., Pei, S., Wen, P. Microneedle-based insulin transdermal delivery system: Current status and translation challenges. Drug Delivery and Translational Research, 2022, 12(10), 2403-2427.
[105] Ramadon, D., McCrudden, M.T., Courtenay, A.J., Donnelly, R.F. Enhancement strategies for transdermal drug delivery systems: Current trends and applications. Drug Delivery and Translational Research, 2022, 12(4), 758-791.
[106] Bakhrushina, E.O., Shumkova, M.M., Avdonina, Y.V., Ananian, A.A., Babazadeh, M., Pouya, G., Grikh, V.V., Zubareva, I.M., Kosenkova, S.I., Krasnyuk Jr, I.I. Transdermal drug delivery systems: Methods for enhancing skin permeability and their evaluation. Pharmaceutics, 2025, 17(7), 936.
[107] Crasta, A., Painginkar, T., Sreedevi, A., Pawar, S.D., Sathyanarayana, M.B., Vasantharaju, S., Osmani, R.A.M., Ravi, G. Transdermal drug delivery system: A comprehensive review of innovative strategies, applications, and regulatory perspectives. OpenNano, 2025, 24, 100245.
[108] Xie, X., Wu, C., Hao, Y., Wang, T., Yang, Y., Cai, P., Zhang, Y., Huang, J., Deng, K., Yan, D., Lin, H. Benefits and risks of drug combination therapy for diabetes mellitus and its complications: A comprehensive review. Frontiers in Endocrinology, 2023, 14, 1301093
[109] Chen, R., Li, J., Chen, D., Wen, W., Zhang, S., Li, J., Ruan, Y., Zhang, Z., Sun, J., Chen, H. Efficacy and safety of dpp-4 inhibitors and metformin combinations in type 2 diabetes: A systematic literature review and network meta-analysis. Diabetes, Metabolic Syndrome and Obesity, 2024, 2471-2493.
[110] Sultana, A., Zare, M., Thomas, V., Kumar, T.S., Ramakrishna, S. Nano-based drug delivery systems: Conventional drug delivery routes, recent developments and future prospects. Medicine in Drug Discovery, 2022, 15, 100134.
[111] Akpoveso, O.-O.P., Ubah, E.E., Obasanmi, G. Antioxidant phytochemicals as potential therapy for diabetic complications. Antioxidants, 2023, 12(1), 123.
[112] Malhotra, S., Lijnse, T., O’Cearbhaill, E., Brayden, D.J. Devices to overcome the buccal mucosal barrier to administer therapeutic peptides. Advanced Drug Delivery Reviews, 2025, 115572.
[113] Shi, Y., Li, X., Li, Z., Sun, J., Gao, T., Wei, G., Guo, Q. Nano-formulations in disease therapy: Designs, advances, challenges, and future directions. Journal of Nanobiotechnology, 2025, 23(1), 396.
[114] Zhou, H., Yuan, M., Zhang, T. A bibliometric analysis and systematic review of research advances in in situ gel drug delivery systems from 2003 to 2023. Pharmaceutics, 2025, 17(4), 451.
[115] Gilroy, C.A., Luginbuhl, K.M., Chilkoti, A. Controlled release of biologics for the treatment of type 2 diabetes. Journal of Controlled Release, 2016, 240, 151-164.
[116] Croitoru, C., Roata, I.C., Pascu, A., Stanciu, E.M. Diffusion and controlled release in physically crosslinked poly (vinyl alcohol)/iota-carrageenan hydrogel blends. Polymers, 2020, 12(7), 1544.
[117] Mitragotri, S., Burke, P.A., Langer, R. Overcoming the challenges in administering biopharmaceuticals: Formulation and delivery strategies. Nature Reviews Drug Discovery, 2014, 13(9), 655-672.
[118] Wang, X., Burgess, D.J. Drug release from in situ forming implants and advances in release testing. Advanced Drug Delivery Reviews, 2021, 178, 113912.
[119] Ezike, T.C., Okpala, U.S., Onoja, U.L., Nwike, C.P., Ezeako, E.C., Okpara, O.J., Okoroafor, C.C., Eze, S.C., Kalu, O.L., Odoh, E.C. Advances in drug delivery systems, challenges and future directions. Heliyon, 2023, 9(6).
[120] Padmasri, B., Nagaraju, R., Prasanth, D. A comprehensive review on in situ gels. International Journal of Appllied Pharmaceutics, 2020, 12(6), 24-33.
[121] Huang, H., Qi, X., Chen, Y., Wu, Z. Thermo-sensitive hydrogels for delivering biotherapeutic molecules: A review. Saudi Pharmaceutical Journal, 2019, 27(7), 990-999.
[122] Du, H., Liu, M., Yang, X., Zhai, G. The design of pH-sensitive chitosan-based formulations for gastrointestinal delivery. Drug Discovery Today, 2015, 20(8), 1004-1011.
[123] Rao, M.R.P., Shelar, S.U. Controlled release ion sensitive floating oral in situ gel of a prokinetic drug using gellan gum. Indian Journal of Pharmaceutical Education and Research, 2015, 49(2), 158-167.
[124] Rege, N.K., Phillips, N.F., Weiss, M.A. Development of glucose-responsive ‘smart’insulin systems. Current Opinion in Endocrinology, Diabetes and Obesity, 2017, 24(4), 267-278.
[125] Hu, M., Zhang, Q., Qin, L. Innovative applications of multidimensional engineered hydrogels in wound healing. Journal of Advanced Research, 2025.
[126] Caturano, A., Nilo, R., Nilo, D., Russo, V., Santonastaso, E., Galiero, R., Rinaldi, L., Monda, M., Sardu, C., Marfella, R. Advances in nanomedicine for precision insulin delivery. Pharmaceuticals, 2024, 17(7), 945.
[127] Viegas, C., Patrício, A.B., Prata, J., Fonseca, L., Macedo, A.S., Duarte, S.O., Fonte, P. Advances in pancreatic cancer treatment by nano-based drug delivery systems. Pharmaceutics, 2023, 15(9), 2363.
[128] Gastaldelli, A., Stefan, N., Häring, H.U. Liver-targeting drugs and their effect on blood glucose and hepatic lipids. Diabetologia, 2021, 64(7), 1461-1479.
[129] Paul, S., Majumdar, S., Chakraborty, M., Mukherjee, S., Sarkar, N., Prajapati, B., Ali, N., AlAsmari, A.F., Nishat, S. In-situ gel bases ocular delivery system of ganciclovir, in-vivo and in-vitro investigation. BMC Pharmacology and Toxicology, 2025, 26(1), 102.
[130] Chen, X., Dai, W., Li, H., Yan, Z., Liu, Z., He, L. Targeted drug delivery strategy: A bridge to the therapy of diabetic kidney disease. Drug Delivery, 2023, 30(1), 2160518.
[131] Agrawal, A.K., Das, M., Jain, S. In situ gel systems as ‘smart’carriers for sustained ocular drug delivery. Expert Opinion on Drug Delivery, 2012, 9(4), 383-402.
[132] Manandhar, B., Ahn, J.M. Glucagon-like peptide-1 (glp-1) analogs: Recent advances, new possibilities, and therapeutic implications. Journal of Medicinal Chemistry, 2015, 58(3), 1020-1037.
[133] Li, L., Zhao, R., Hong, H., Li, G., Zhang, Y., Luo, Y., Zha, Z., Zhu, J., Qiao, J., Zhu, L. 68ga-labelled-exendin-4: New glp1r targeting agents for imaging pancreatic β-cell and insulinoma. Nuclear Medicine and Biology, 2021, 102, 87-96.
[134] Chen, Y., Wang, X., Tao, S., Wang, Q., Ma, P.Q., Li, Z.-B., Wu, Y.L., Li, D.W. Research advances in smart responsive-hydrogel dressings with potential clinical diabetic wound healing properties. Military Medical Research, 2023, 10(1), 37.
[135] Jarosinski, M.A., Chen, Y.S., Varas, N., Dhayalan, B., Chatterjee, D., Weiss, M.A. New horizons: Next-generation insulin analogues: Structural principles and clinical goals. The Journal of Clinical Endocrinology & Metabolism, 2022, 107(4), 909-928.
[136] Padhi, S., Nayak, A.K., Behera, A. Type ii diabetes mellitus: A review on recent drug based therapeutics. Biomedicine & Pharmacotherapy, 2020, 131, 110708.
[137] Gabai, A., Zeppieri, M., Finocchio, L., Salati, C. Innovative strategies for drug delivery to the ocular posterior segment. Pharmaceutics, 2023, 15(7), 1862.
[138] Raus, R.A., Nawawi, W.M.F.W., Nasaruddin, R.R. Alginate and alginate composites for biomedical applications. Asian Journal of Pharmaceutical Sciences, 2021, 16(3), 280-306.
[139] Souza, P.R., de Oliveira, A.C., Vilsinski, B.H., Kipper, M.J., Martins, A.F. Polysaccharide-based materials created by physical processes: From preparation to biomedical applications. Pharmaceutics, 2021, 13(5), 621.
[140] Agarwal, P., Rupenthal, I.D. Non-aqueous formulations in topical ocular drug delivery–a paradigm shift? Advanced Drug Delivery Reviews, 2023, 198, 114867.
[141] Desai, N., Rana, D., Patel, M., Bajwa, N., Prasad, R., Vora, L.K. Nanoparticle therapeutics in clinical perspective: Classification, marketed products, and regulatory landscape. Small, 2025, 2502315.
[142] Lee, Y.J., Kim, M.S. Advances in drug-loaded microspheres for targeted, controlled, and sustained drug delivery: Potential, applications, and future directions. Biomedicine & Pharmacotherapy, 2025, 189, 118244.
[143] Kharbikar, B.N., Chendke, G.S., Desai, T.A. Modulating the foreign body response of implants for diabetes treatment. Advanced Drug Delivery Reviews, 2021, 174, 87-113.
[144] Pathak, V., Pathak, N.M., O’Neill, C.L., Guduric-Fuchs, J., Medina, R.J. Therapies for type 1 diabetes: Current scenario and future perspectives. Clinical Medicine Insights: Endocrinology and Diabetes, 2019, 12, 1179551419844521.
[145] Boonlai, W., Tantishaiyakul, V., Hirun, N., Sangfai, T., Suknuntha, K. Thermosensitive poloxamer 407/poly (acrylic acid) hydrogels with potential application as injectable drug delivery system. AAPS PharmSciTech, 2018, 19(5), 2103-2117.
[146] Martínez-Navarrete, M., Pérez-López, A., Guillot, A.J., Cordeiro, A.S., Melero, A., Aparicio-Blanco, J. Latest advances in glucose-responsive microneedle-based systems for transdermal insulin delivery. International Journal of Biological Macromolecules, 2024, 263, 130301.
[147] Nair, A.B., Shah, J., Jacob, S., Al-Dhubiab, B.E., Sreeharsha, N., Morsy, M.A., Gupta, S., Attimarad, M., Shinu, P., Venugopala, K.N. Experimental design, formulation and in vivo evaluation of a novel topical in situ gel system to treat ocular infections. PloS one, 2021, 16(3), e0248857.
[148] Javanbakht, S., Poursadegh, H., Darvishi, S., Mohammadzadeh, A., Saboury, A., Joulaei, M., Mohammadi, R. Application or function of cyclodextrin in insulin and cell delivery for efficient diabetic treatment. Hybrid Advances, 2025, 10, 100462.
[149] Gieroba, B., Kryska, A., Sroka-Bartnicka, A. Type 2 diabetes mellitus–conventional therapies and future perspectives in innovative treatment. Biochemistry and Biophysics Reports, 2025, 42, 102037.
[150] Gheorghita, R., Sirbu, I.-O., Lobiuc, A., Covasa, M. Sodium alginate–starch capsules for enhanced stability of metformin in simulated gastrointestinal fluids. Biomimetics, 2024, 9(11), 716.
[151] Sen, O., Manna, S., Nandi, G., Jana, S., Jana, S. Recent advances in alginate based gastroretentive technologies for drug delivery applications. Medicine in Novel Technology and Devices, 2023, 18, 100236.
[152] Ali, H.S., Namazi, N., Elbadawy, H.M., El-Sayed, A.A., Ahmed, S.A., Bafail, R., Almikhlafi, M.A., Alahmadi, Y.M. Repaglinide–solid lipid nanoparticles in chitosan patches for transdermal application: Box–behnken design, characterization, and in vivo evaluation. International Journal of Nanomedicine, 2024, 209-230.
[153] Kalra, S., Bahendeka, S., Sahay, R., Ghosh, S., Md, F., Orabi, A., Ramaiya, K., Al Shammari, S., Shrestha, D., Shaikh, K. Consensus recommendations on sulfonylurea and sulfonylurea combinations in the management of type 2 diabetes mellitus–international task force. Indian Journal of Endocrinology and Metabolism, 2018, 22(1), 132-157.
[154] Wiwattanapatapee, R., Klabklay, K., Raksajit, N., Siripruekpong, W., Leelakanok, N., Petchsomrit, A. The development of an in-situ biopolymer-based floating gel for the oral delivery of metformin hydrochloride. Heliyon, 2023, 9(4).
[155] Gilbert, M.P., Pratley, R.E. Glp-1 analogs and dpp-4 inhibitors in type 2 diabetes therapy: Review of head-to-head clinical trials. Frontiers in Endocrinology, 2020, 11, 178.
[156] Olukorode, J.O., Orimoloye, D.A., Nwachukwu, N.O., Onwuzo, C.N., Oloyede, P.O., Fayemi, T., Odunaike, O.S., Ayobami-Ojo, P.S., Divine, N., Alo, D.J. Recent advances and therapeutic benefits of glucagon-like peptide-1 (glp-1) agonists in the management of type 2 diabetes and associated metabolic disorders. Cureus, 2024, 16(10).
[157] Lebovitz, H.E. Pramlintide: Profile of an amylin analog. Expert Review of Endocrinology & Metabolism, 2012, 7(6), 599-609.
[158] Alfaris, N., Waldrop, S., Johnson, V., Boaventura, B., Kendrick, K., Stanford, F.C. Glp-1 single, dual, and triple receptor agonists for treating type 2 diabetes and obesity: A narrative review. EClinicalMedicine, 2024, 75.
[159] Jin, Q., Liu, T., Qiao, Y., Liu, D., Yang, L., Mao, H., Ma, F., Wang, Y., Peng, L., Zhan, Y. Oxidative stress and inflammation in diabetic nephropathy: Role of polyphenols. Frontiers in Immunology, 2023, 14, 1185317.
[160] Raina, N., Rani, R., Thakur, V.K., Gupta, M. New insights in topical drug delivery for skin disorders: From a nanotechnological perspective. ACS omega, 2023, 8(22), 19145-19167.
[161] Guo, Z., Zhang, Y.n., Zhao, M., Zhang, W., Li, X., Zhou, F., Peng, H., Wang, Q., Chen, Z. Intelligent transdermal nanoparticles as synergizing advanced delivery systems for precision therapeutics. Materials Today Bio, 2025, 102220.
[162] Ismail, R., Bocsik, A., Katona, G., Gróf, I., Deli, M.A., Csóka, I. Encapsulation in polymeric nanoparticles enhances the enzymatic stability and the permeability of the glp-1 analog, liraglutide, across a culture model of intestinal permeability. Pharmaceutics, 2019, 11(11), 599.
[163] Liu, Y., Liang, Y., Yuhong, J., Xin, P., Han, J.L., Du, Y., Yu, X., Zhu, R., Zhang, M., Chen, W. Advances in nanotechnology for enhancing the solubility and bioavailability of poorly soluble drugs. Drug Design, Development and Therapy, 2024, 1469-1495.
[164] Tong, M.Q., Luo, L.Z., Xue, P.P., Han, Y.H., Wang, L.F., Zhuge, D.L., Yao, Q., Chen, B., Zhao, Y.Z., Xu, H.L. Glucose-responsive hydrogel enhances the preventive effect of insulin and liraglutide on diabetic nephropathy of rats. Acta Biomaterialia, 2021, 122, 111-132.
[165] Islam, S., Ahmed, M.M.S., Islam, M.A., Hossain, N., Chowdhury, M.A. Advances in nanoparticles in targeted drug delivery-a review. Results in Surfaces and Interfaces, 2025, 100529.
[166] Sriram, A., Ithape, H., Singh, P.K. Deep-insights: Nanoengineered gel-based localized drug delivery for arthritis management. Asian Journal of Pharmaceutical Sciences, 2025, 20(1), 101012.
Journal of Chemical Reviews

Articles in Press, Accepted Manuscript
Available Online from 25 December 2025

  • Receive Date 27 September 2025
  • Revise Date 28 October 2025
  • Accept Date 11 November 2025

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