DEVELOPMENT AND EVALUATION OF A PH-RESPONSIVE OFLOXACIN-LOADED NANOPARTICLE IN SITU GEL FOR SUSTAINED OCULAR DELIVERY
DOI:
https://doi.org/10.22159/ijap.2026v18i2.57216Keywords:
Bacterial conjunctivitis, pH Triggered polymer, Nanoparticle, In-situ gel, HET-CAM testAbstract
Objective: This study aims to develop an in situ gel formulation incorporating Ofloxacin-loaded nanoparticles to enhance ocular residence time and therapeutic efficacy of drug.
Methods: The formulation process included pre-formulation studies such as solubility and UV analysis of Ofloxacin. A pH-triggered in situ gel was prepared using Poloxamer 407, chitosan, and Eudragit L-100. Various post-formulation parameters were evaluated, including pH, viscosity, drug content, and in vitro drug release kinetics.
Results: Nanoparticles were confirmed using DLS with a particle size of 688 nm. The viscosity of in situ gel formulations followed a shear thinning process before contact with simulated tear fluid (STF). The viscosity reduced significantly (p<0.05, two-way ANOVA) for the in situ formulations after contact with STF. The formulation containing 4% Poloxamer 407 and 0.8% Gellan Gum (OFX3) demonstrated acceptable viscosity behavior and sustained drug release. OFX3 achieved a drug release of 97.81% over 6 h, adhering to Higuchi release models and expressing quasi-Fickian diffusion. The HET-CAM test confirmed the formulation non-irritant nature, while stability studies demonstrated no significant changes over a 3-month period.
Conclusion: The developed pH-sensitive in situ gel effectively enhances the solubility of Ofloxacin, providing a promising treatment option for bacterial conjunctivitis. The developed ofloxacin-loaded nanoparticulate in situ gel successfully integrates controlled release through prolonged ocular residence. Future in vivo studies will further consolidate its potential as a pioneering candidate for translational ophthalmic applications.
References
1. Tesfahunegn Nigusse A, Tesfay Weldearegay K, Assefa Mezgebu H, Gebrehawarya Bisheu Y, Weldemhret Teweldemedhnt L, Hafte Amaha M. Conjunctivitis outbreak among children in central zone of Tigray, Northern Ethiopia 2023. JIEPH. 2024;7(4):52. doi: 10.37432/jieph.2024.7.4.143.
2. Gin C, Crock C, Wells K. Conjunctivitis: a review. Austr J Gen Pract. 2024 Nov 1;53(11):847-52. doi: 10.31128/ajgp-09-23-6960, PMID 39499843.
3. Chatterjee S, Gangwe AB, Agrawal D. Attack rates risk factors and productivity loss during an outbreak of acute conjunctivitis in central India. J Clin Ophthalmol Res. 2025 Jul 1;13(3):286-94. doi: 10.4103/jcor.jcor_47_25.
4. Azari AA, Barney NP. Conjunctivitis: a systematic review of diagnosis and treatment. JAMA. 2013 Oct 22;310(16):1721-9. doi: 10.1001/jama.2013.280318, PMID 24150468.
5. Seitzman GD, Prajna L, Prajna NV, Sansanayudh W, Satitpitakul V, Laovirojjanakul W. Biomarker detection and validation for corneal involvement in patients with acute infectious conjunctivitis. JAMA Ophthalmol. 2024 Aug 15;142(9):865-71. doi: 10.1001/jamaophthalmol.2024.2891, PMID 39145969.
6. Kareem Rhumaid A, Alak Mahdi Al-Buhilal J, Al-Rubaey NK, Yassen Al-Zamily K. Prevalence and antibiotic susceptibility of pathogenic bacteria associated with ocular infections in adult patients. Arch Razi Inst. 2022 Oct 1;77(5):1917-24. doi: 10.22092/ARI.2022.359510.2437, PMID 37123163.
7. Singh S, Oberoi L, Singh K, Malhotra A, Soneja S, Singh K. Microbiological spectrum of ocular infections in patients of Tertiary Care Eye Hospital of Punjab. IJMMTD. 2021;7(3):154-9. doi: 10.18231/j.ijmmtd.2021.033.
8. Vatlin AA, Bekker OB, Shur KV, Ilyasov RA, Shatrov PA, Maslov DA. Kanamycin and ofloxacin activate the intrinsic resistance to multiple antibiotics in Mycobacterium smegmatis. Biology. 2023 Mar 27;12(4):506. doi: 10.3390/biology12040506, PMID 37106707.
9. Drago L, Minasi V, Lembo A, Uslenghi A, Benedetti S, Covi M. Antibiotic resistance profiles in eye infections: a local concern with a retrospective focus on a large hospital in Northern Italy. Microorganisms. 2024 May 14;12(5):984. doi: 10.3390/microorganisms12050984, PMID 38792813.
10. Dosmar E, Walsh J, Doyel M, Bussett K, Oladipupo A, Amer S. Targeting ocular drug delivery: an examination of local anatomy and current approaches. Bioengineering (Basel). 2022 Jan 17;9(1):41. doi: 10.3390/bioengineering9010041, PMID 35049750.
11. Han H, Li S, Xu M, Zhong Y, Fan W, Xu J. Polymer and lipid-based nanocarriers for ocular drug delivery: current status and future perspectives. Adv Drug Deliv Rev. 2023 Mar 7;196:114770. doi: 10.1016/j.addr.2023.114770, PMID 36894134.
12. Beal C, Giordano B. Clinical evaluation of red eyes in pediatric patients. J Pediatr Health Care. 2016 Mar 2;30(5):506-14. doi: 10.1016/j.pedhc.2016.02.001, PMID 26948259.
13. Vo A, Feng X, Patel D, Mohammad A, Kozak D, Choi S. Factors affecting the particle size distribution and rheology of brinzolamide ophthalmic suspensions. Int J Pharm. 2020 Jun 14;586:119495. doi: 10.1016/j.ijpharm.2020.119495, PMID 32553495.
14. Motwani SK, Chopra S, Talegaonkar S, Kohli K, Ahmad FJ, Khar RK. Chitosan–sodium alginate nanoparticles as submicroscopic reservoirs for ocular delivery: formulation optimisation and in vitro characterisation. Eur J Pharm Biopharm. 2007 Sep 25;68(3):513-25. doi: 10.1016/j.ejpb.2007.09.009, PMID 17983737.
15. Kumar D, Jain N, Gulati N, Nagaich U. Nanoparticles laden in situ gelling system for ocular drug targeting. J Adv Pharm Technol Res. 2013 Jan 1;4(1):9-17. doi: 10.4103/2231-4040.107495, PMID 23662277.
16. Bisen AC, Dubey A, Agrawal S, Biswas A, Rawat KS, Srivastava S. Recent updates on ocular disease management with ophthalmic ointments. Ther Deliv. 2024 Jun 2;15(6):463-80. doi: 10.1080/20415990.2024.2346047, PMID 38888757.
17. Yang Y, Lockwood A. Topical ocular drug delivery systems: innovations for an unmet need. Exp Eye Res. 2022 Mar 4;218:109006. doi: 10.1016/j.exer.2022.109006, PMID 35248559.
18. Tapply I, Broadway DC. Improving adherence to topical medication in patients with glaucoma. Patient Prefer Adherence. 2021 Jul 1;15:1477-89. doi: 10.2147/PPA.S264926, PMID 34239297.
19. Nair AB, Shah J, Jacob S, Al-Dhubiab BE, Sreeharsha N, Morsy MA. Experimental design formulation and in vivo evaluation of a novel topical in situ gel system to treat ocular infections. PLOS One. 2021 Mar 19;16(3):e0248857. doi: 10.1371/journal.pone.0248857, PMID 33739996.
20. Singh A, Rajora A, Mazumder R, Padhi S. Effect of Zein on ciprofloxacin floating tablets. Int J App Pharm. 2022 Nov 7;14(6):137-47. doi: 10.22159/ijap.2022v14i6.45354.
21. Suresh A, Gonde S, Mondal PK, Sahoo J, Chopra D. Improving solubility and intrinsic dissolution rate of ofloxacin API through salt formation via mechanochemical synthesis with diphenic acid. J Mol Struct. 2020 Jul 2;1221:128806. doi: 10.1016/j.molstruc.2020.128806.
22. Mushtaq K, Saeed M, Gul W, Munir M, Firdous A, Yousaf T. Synthesis and characterization of TiO2 via sol-gel method for efficient photocatalytic degradation of antibiotic ofloxacin. Inorg Nano-Met Chem. 2020 Feb 17;50(7):580-6. doi: 10.1080/24701556.2020.1722695.
23. Rajappa MC, Kannan A, Venkatasubramaniam N, Venkatachalam L, Karnan S, Antonysamy D. Improved wound healing activity through synergistic approach of pumpkin seed oil and curcumin loaded model in microgel. Int J App Pharm. 2025 Sep 7;18(4):238-52. doi: 10.22159/ijap.2025v17i5.54322.
24. Kesarla R, Tank T, Vora PA, Shah T, Parmar S, Omri A. Preparation and evaluation of nanoparticles loaded ophthalmic in situ gel. Drug Deliv. 2015 Jan 12;23(7):2363-70. doi: 10.3109/10717544.2014.987333, PMID 25579467.
25. Paradkar MU, Parmar M. Formulation development and evaluation of Natamycin niosomal in-situ gel for ophthalmic drug delivery. J Drug Deliv Sci Technol. 2017 Mar 7;39:113-22. doi: 10.1016/j.jddst.2017.03.005.
26. El-Emam GA, Motawea A, El Hady WE, Saber S, Mourad AA, Ramadan HA. Salutary influence of gemifloxacin mesylate nanocubosomes based-in situ ocular gel as a novel approach for the management of experimental keratitis induced by MRSA. J Drug Deliv Sci Technol. 2023 Oct 9;89:105012. doi: 10.1016/j.jddst.2023.105012.
27. Datta S, Bhowmik R, Nath R, Chakraborty R, Chakraborty A. Formulation and evaluation of a nanoparticle laden in situ gel system for enhancing the ocular delivery of ciprofloxacin. IJPSRR. 2021 Oct 15;70(2):156-63. doi: 10.47583/ijpsrr.2021.v70i02.018.
28. Wadhwa K, Sharma C, Goswami M, Thakur N. Formulation and evaluation of pH triggered in situ ocular gel of ofloxacin. Int J Pharm Sci Res. 2019 Oct 1;10(10):4507-12. doi: 10.13040/ijpsr.0975-8232.10(10).4507-12.
29. Gupta C, Juyal V, Nagaich U. Formulation optimization and evaluation of in situ gel of moxifloxacin hydrochloride for ophthalmic drug delivery. Int J App Pharm. 2019 Mar 6;11(4):147-58. doi: 10.22159/ijap.2019v11i4.30388.
30. Jagdale S, Shewale N, Kuchekar BS. Optimization of thermoreversible in situ nasal gel of timolol maleate. Scientifica. 2016 Jan 1;2016:6401267. doi: 10.1155/2016/6401267, PMID 27293975.
31. Chandira RM, Pethappachetty P, Venkatasubramaniam N, Antony Samy DA. Formulation and comparison of glucomannan metallocomplexes made of cobalt and copper. Asian J Biol Life Sci. 2022 Sep 20;11(2):564-9. doi: 10.5530/ajbls.2022.11.76.
32. Ondieki ASK, Rathore KS. Development and characterization of topical gel containing deep eutectic mixture of luliconazole for topical drug delivery system. Int J Pharm Chem Anal. 2023;10(4):294-302. doi: 10.18231/j.ijpca.2023.049.
33. Maddiboyina B, Jhawat V, Desu PK, Gandhi S, Nakkala RK, Singh S. Formulation and evaluation of thermosensitive flurbiprofen in situ nano gel for the ocular delivery. J Biomater Sci Polym Ed. 2021 May 12;32(12):1584-97. doi: 10.1080/09205063.2021.1927460, PMID 33977874.
34. Balu A, Johnson T, Sundara R, Seetharaman S. Optimization and evaluation of temperature triggered in situ gel formulation using design of experiments (DoE) and HET-CAM test. J Nanomed. 2020 Dec 9;3(1):1031. doi: 10.15520/jnm.v3i1.1031.
35. Vijaya Rani KR, Rajan S, Bhupathyraaj M, Priya RK, Halligudi N, Al-Ghazali MA. The effect of polymers on drug release kinetics in nanoemulsion in situ gel formulation. Polymers. 2022 Jan 21;14(3):427. doi: 10.3390/polym14030427, PMID 35160417.
36. Nautiyal D, Singh V, Ali S. Formulation and evaluation of sustained release of ofloxacin ocular inserts. Res J Pharm Technol. 2012 Dec;5(12):1497-9. doi: 10.52711/0974-360X.
37. Koska I, Purgat K, Glowacki R, Kubalczyk P. Simultaneous determination of ciprofloxacin and ofloxacin in animal tissues with the use of capillary electrophoresis with transient pseudo-isotachophoresis. Molecules. 2021 Nov 17;26(22):6931. doi: 10.3390/molecules26226931, PMID 34834024.
38. Meghna S, Usman S, Kumar CD, Thangabalan B. A review on reported analytical methods for estimation of ofloxacin. Int J Pharm Sci. 2025;3(5):734-65. doi: 10.5281/zenodo.15341908.
39. Qin Y, Qin J, Zhou X, Yang Y, Chen R, Tan J. Effects of pH on light absorption properties of water-soluble organic compounds in particulate matter emitted from typical emission sources. J Hazard Mater. 2021 Nov 3;424(C):127688. doi: 10.1016/j.jhazmat.2021.127688, PMID 34775306.
40. Kaushal P, Kumar Kushawaha S, Majumder M, Singh Ashawat M. Validated analytical method for multicomponent analysis of famotidine and ofloxacin in bulk drug and tablet formulation by using UV-visible spectrophotometer and RP-HPLC. Asian J Pharm Anal. 2023 Sep 7;13(3):162-70. doi: 10.52711/2231-5675.2023.00026.
41. Abrash HI. The relative acidities of water and methanol. J Chem Educ. 2001 Nov 1;78(11):1496. doi: 10.1021/ed078p1496.
42. Khan A, Andleeb A, Azam M, Tehseen S, Mehmood A, Yar M. Aloe vera and ofloxacin incorporated chitosan hydrogels show antibacterial activity stimulate angiogenesis and accelerate wound healing in full thickness rat model. J Biomed Mater Res B Appl Biomater. 2022 Sep 2;111(2):331-42. doi: 10.1002/jbm.b.35153, PMID 36053925.
43. Jha KK, Jha AK. Synthesis and spectral characterization of fluoroquinolone-ofloxacin. Int J Chem Stud. 2020 Jan 1;4(4):1-3.
44. Ohashi S, Cassidy F, Huang S, Chiou K, Ishida H. Synthesis and ring-opening polymerization of 2-substituted 1,3-benzoxazine: the first observation of the polymerization of oxazine ring-substituted benzoxazines. Polym Chem. 2016 Jan 1;7(46):7177-84. doi: 10.1039/c6py01686c.
45. Datta D, Priyanka Bandi S, Colaco V, Dhas N, Siva Reddy DV, Vora LK. Fostering the unleashing potential of nanocarriers-mediated delivery of ocular therapeutics. Int J Pharm. 2024;658:124192. doi: 10.1016/j.ijpharm.2024.124192, PMID 38703931.
46. Hadinoto K, Sundaresan A, Cheow WS. Lipid–polymer hybrid nanoparticles as a new generation therapeutic delivery platform: a review. Eur J Pharm Biopharm. 2013 Jul 17;85(3 Pt A):427-43. doi: 10.1016/j.ejpb.2013.07.002, PMID 23872180.
47. Mok ZH. The effect of particle size on drug bioavailability in various parts of the body. Pharm Sci Adv. 2023 Nov 23;2:100031. doi: 10.1016/j.pscia.2023.100031, PMID 41550144.
48. Grassiri B, Zambito Y, Bernkop Schnurch A. Strategies to prolong the residence time of drug delivery systems on ocular surface. Adv Colloid Interface Sci. 2020 Dec 13;288:102342. doi: 10.1016/j.cis.2020.102342, PMID 33444845.
49. Li J, Tian S, Tao Q, Zhao Y, Gui R, Yang F. Montmorillonite/chitosan nanoparticles as a novel controlled-release topical ophthalmic delivery system for the treatment of glaucoma. Int J Nanomedicine. 2018 Jul 10;13:3975-87. doi: 10.2147/IJN.S162306, PMID 30022821.
50. Baba K, Nishida K. Steroid nanocrystals prepared using the nano spray dryer B-90. Pharmaceutics. 2013 Jan 25;5(1):107-14. doi: 10.3390/pharmaceutics5010107, PMID 24300400.
51. Gorantla S, Rapalli VK, Waghule T, Singh PP, Dubey SK, Saha RN. Nanocarriers for ocular drug delivery: current status and translational opportunity. RSC Adv. 2020 Jan 1;10(46):27835-55. doi: 10.1039/d0ra04971a, PMID 35516960.
52. Mota WS, Severino P, Kadian V, Rao R, Zielinska A, Silva AM. Nanometrology: particle sizing and influence on the toxicological profile. Front Nanotechnol. 2025 May 6;7:1559523. doi: 389/fnano.2025.1479464.
53. Masarudin MJ, Cutts SM, Evison BJ, Phillips DR, Pigram PJ. Factors determining the stability size distribution and cellular accumulation of small monodisperse chitosan nanoparticles as candidate vectors for anticancer drug delivery: application to the passive encapsulation of 14C-doxorubicin. Nanotechnol Sci Appl. 2015 Dec 11;8:67-80. doi: 10.2147/NSA.S91785, PMID 26715842.
54. Sikhondze SS, Makoni PA, Walker RB, Khamanga SM. Chitosan-coated sln: a potential system for ocular delivery of metronidazole. Pharmaceutics. 2023 Jun 30;15(7):1855. doi: 10.3390/pharmaceutics15071855, PMID 37514041.
55. Pham DT, Navesit K, Wiwatkunupakarn L, Chomchalao P, Tiyaboonchai W. Nanoparticles-hydrogel composites: a promising innovative system for local antimicrobial applications. J Drug Deliv Sci Technol. 2023 Oct 10;89:105055. doi: 10.1016/j.jddst.2023.105055.
56. Abbas MN, Khan SA, Sadozai SK, Khalil IA, Anter A, Fouly ME. Nanoparticles loaded thermoresponsive in situ gel for ocular antibiotic delivery against bacterial keratitis. Polymers. 2022 Mar 11;14(6):1135. doi: 10.3390/polym14061135, PMID 35335465.
57. Ozturk K, Kaplan M, Calıs S. Effects of nanoparticle size shape and zeta potential on drug delivery. Int J Pharm. 2024 Oct 1;666:124799. doi: 10.1016/j.ijpharm.2024.124799, PMID 39369767.
58. Salamah M, Sipos B, Schelz Z, Zupko I, Kiricsi A, Szalenko Tokes A. Development in vitro and ex vivo characterization of lamotrigine-loaded bovine serum albumin nanoparticles using QbD approach. Drug Deliv. 2025 Feb 3;32(1):2460693. doi: 10.1080/10717544.2025.2460693, PMID 39901331.
59. Zaman M, Ahmad E, Qadeer A, Rabbani G, Khan RH. Nanoparticles in relation to peptide and protein aggregation. Int J Nanomedicine. 2014 Feb 1;9:899-912. doi: 10.2147/IJN.S54171, PMID 24611007.
60. Johnson L, Gray DM, Niezabitowska E, McDonald TO. Multi-stimuli-responsive aggregation of nanoparticles driven by the manipulation of colloidal stability. Nanoscale. 2021 Jan 1;13(17):7879-96. doi: 10.1039/d1nr01190a, PMID 33881098.
61. Rodriguez-Loya J, Lerma M, Rodriguez-Loya JL. Dynamic light scattering and its application to control nanoparticle aggregation in colloidal systems: a review. Micromachines. 2023 Dec 22;15(1):24. doi: 10.3390/mi15010024, PMID 38258143.
62. Farkas N, Kramar JA. Dynamic light scattering distributions by any means. J Nanopart Res. 2021 May 1;23(5):120. doi: 10.1007/s11051-021-05220-6, PMID 39381776.
63. Kurniawansyah IS, Rusdiana T, Sopyan I, Ramoko H, Wahab HA, Subarnas A. In situ ophthalmic gel forming systems of poloxamer 407 and hydroxypropyl methyl cellulose mixtures for sustained ocular delivery of chloramphenicole: optimization study by factorial design. Heliyon. 2020 Nov 1;6(11):e05365. doi: 10.1016/j.heliyon.2020.e05365, PMID 33251348.
64. Anbarasan B, Kumar RS, Thanka J, Ramaprabhu S, Shanmuganathan S. Preparation and characterization of pH based carbopol 934P in situ hydrogels for the treatment of harmful bacterial infections. Int J Pharm Sci Res. 2019 Jan 1;10(1):232-44. doi: 10.13040/ijpsr.0975-8232.10(1).232-44.
65. Wu Y, Liu Y, Li X, Kebebe D, Zhang B, Ren J. Research progress of in-situ gelling ophthalmic drug delivery system. Asian J Pharm Sci. 2018 May 24;14(1):1-15. doi: 10.1016/j.ajps.2018.04.008, PMID 32104434.
66. Chiodza K, Goosen NJ. Viscosity mixing regime and power consumption analysis during enzymatic hydrolysis of fish (Sardina pilchardus) processing by-products through development of power number and Reynolds number correlations. Food Bioprod Process. 2024;143:178-90. doi: 10.1016/j.fbp.2023.11.008.
67. Brahmavale M. From liquid to solid: unravelling the magic of in situ gels. IJRASET. 2024 May 23;12(5):3829-37. doi: 10.22214/ijraset.2024.62471.
68. Harish NM, Prabhu P, Charyulu RN, Gulzar MA, Subrahmanyam EV. Formulation and evaluation of in situ gels containing clotrimazole for oral candidiasis. Indian J Pharm Sci. 2009 Jul;71(4):421-7. doi: 10.4103/0250-474X.57291, PMID 20502548.
69. Maslii Y, Ruban O, Kasparaviciene G, Kalveniene Z, Materiienko A, Ivanauskas L. The influence of pH values on the rheological textural and release properties of carbomer Polacril® 40P-based dental gel formulation with plant-derived and synthetic active components. Molecules. 2020 Oct 29;25(21):5018. doi: 10.3390/molecules25215018, PMID 33138200.
70. Sulaiman HT, Jabir SA, Kadhem Al-kinani K. Investigating the effect of different grades and concentrations of PH-sensitive polymer on preparation and characterization of lidocaine hydrochloride as in situ gel buccal spray. Asian J Pharm Clin Res. 2018;11(11):401. doi: 10.22159/ajpcr.2018.v11i11.28492.
71. Kolawole OM, Cook MT. In situ gelling drug delivery systems for topical drug delivery. Eur J Pharm Biopharm. 2023 Jan 13;184:36-49. doi: 10.1016/j.ejpb.2023.01.007, PMID 36642283.
72. Chowhan A, Ghosh B, Giri TK. Composite ion responsive in situ gel based on Gellan/carboxymethyl cellulose blend for improved gelation and sustained acyclovir ocular release. Ind J Pharm Sci. 2023 Jan 1;85(3):581-91. doi: 10.36468/pharmaceutical-sciences.1125.
73. Terreni E, Zucchetti E, Tampucci S, Burgalassi S, Monti D, Chetoni P. Combination of nanomicellar technology and in situ gelling polymer as ocular drug delivery system (ODDS) for cyclosporine-a. Pharmaceutics. 2021 Feb 1;13(2):192. doi: 10.3390/pharmaceutics13020192, PMID 33535607.
74. Barentin C, Liu AJ. Shear thickening in dilute solutions of wormlike micelles. Europhys Lett. 2001 Aug 1;55(3):432-8. doi: 10.1209/epl/i2001-00432-x.
75. Serra GF, Oliveira L, Gurgen S, De Sousa RJ, Fernandes FA. Shear thickening fluid (STF) in engineering applications and the potential of cork in STF-based composites. Adv Colloid Interface Sci. 2024;327:103157. doi: 10.1016/j.cis.2024.103157, PMID 38626554.
76. Prabhu A, Koland M. Development and evaluation of an in situ thermogelling system of ofloxacin for controlled ocular delivery. Asian J Pharm Clin Res. 2019 Mar;12(3):567-70. doi: 10.22159/ajpcr.2019.v12i3.31233.
77. Kim BH, Lee W, Kim YL, Lee JH, Hong J. Efficient matrix cleanup of soft-gel-type dietary supplements for rapid screening of 92 illegal adulterants using EMR-lipid dSPE and UHPLC-Q/TOF-MS. Pharmaceuticals (Basel). 2021 Jun 15;14(6):570. doi: 10.3390/ph14060570, PMID 34203614.
78. Peterfi O, Meszaros LA, Szabo Szocs B, Ficzere M, Sipos E, Farkas A. UV-vis imaging-based investigation of API concentration fluctuation caused by the sticking behaviour of pharmaceutical powder blends. Int J Pharm. 2024 Mar 15;655:124010. doi: 10.1016/j.ijpharm.2024.124010, PMID 38493839.
79. Khan FU, Nasir F, Iqbal Z, Neau S, Khan I, Hassan M. Improved ocular bioavailability of moxifloxacin HCl using PLGA nanoparticles: fabrication characterization in vitro and in vivo evaluation. Iran J Pharm Res. 2021 Jan 1;20(3):592-608. doi: 10.22037/ijpr.2021.114478.15054, PMID 34904011.
80. Raut R, Deore R, Patil S, Pachorkar S, Mungse V. Sustained release drug delivery system: a review. Int J Pharm Res Appl. 2021 Jul;6(4):953-66. doi: 10.35629/7781-0604953966.
81. Shen J, Lu GW, Hughes P. Targeted ocular drug delivery with pharmacokinetic/pharmacodynamic considerations. Pharm Res. 2018 Sep 25;35(11):217. doi: 10.1007/s11095-018-2498-y, PMID 30255364.
82. Khurana AK, Moudgil SS, Parmar IP, Ahluwalia BK. Tear film flow and stability in acute and chronic conjunctivitis. Acta Ophthalmol (Copenh). 1987 Jun;65(3):303-5. doi: 10.1111/j.1755-3768.1987.tb08510.x, PMID 3618153.
83. Narayana S, Ahmed MG. Design and evaluation of ocular hydrogel containing combination of ofloxacin and dexamethasone for the treatment of conjunctivitis. Braz J Pharm Sci. 2022 Jan 1;58:e20180. doi: 10.1590/s2175-97902022e20180.
84. Drago L. Topical antibiotic therapy in the ocular environment: the benefits of using moxifloxacin eyedrops. Microorganisms. 2024 Mar 25;12(4):649. doi: 10.3390/microorganisms12040649, PMID 38674593.
85. Desai N, Colley HE, Krishna Y, Bosworth LA, Kearns VR. Mucoadhesive nanofibers for ocular drug delivery: mechanisms design strategies and applications. Drug Deliv Transl Res. 2025 Jun 25;15(6):1-40. doi: 10.1007/s13346-025-01894-w, PMID 40562965.
86. Herdiana Y, Wathoni N, Shamsuddin S, Muchtaridi M. Drug release study of the chitosan-based nanoparticles. Heliyon. 2021 Dec 24;8(1):e08674. doi: 10.1016/j.heliyon.2021.e08674, PMID 35028457.
87. Nayak D, Kondepati HV, Rathnanand M, Tippavajhala VK. Statistical optimization and evaluation of in situ gel for the ocular delivery of cromolyn sodium. Int J App Pharm. 2024 Mar 7;16(2):124-31. doi: 10.22159/ijap.2024v16i2.49781.
88. Cam ME, Yildiz S, Alenezi H, Cesur S, Ozcan GS, Erdemir G. Evaluation of burst release and sustained release of pioglitazone-loaded fibrous mats on diabetic wound healing: an in vitro and in vivo comparison study. J R Soc Interface. 2020 Jan 1;17(162):20190712. doi: 10.1098/rsif.2019.0712, PMID 31964272.
89. Kalaria VJ, Saisivam S, Alshishani A, Aljariri Alhesan JS, Chakraborty S, Rahamathulla M. Design and evaluation of in situ gel eye drops containing nanoparticles of gemifloxacin mesylate. Drug Deliv. 2023 Dec;30(1):2185180. doi: 10.1080/10717544.2023.2185180, PMID 36876464.
90. Jalwal P, Deepak, Shailja J, Ajit, Gourav SG, Sardana S. Formulation and characterization of ofloxacin-loaded nanoparticles. J Pharm Innov J. 2017;7(8):615-7.
91. Fu Y, Kao WJ. Drug release kinetics and transport mechanisms of non-degradable and degradable polymeric delivery systems. Expert Opin Drug Deliv. 2010 Apr;7(4):429-44. doi: 10.1517/17425241003602259, PMID 20331353.
92. Murthy GL, Kumar VG, Sravani B, Kumar SS, Kumar DA, Prasad AB, Sri B, Prasanna DDGL, Prasad MR, Prasad RS. Design and development of ofloxacin insitu gel using mucoadhesive polymers. Sch Acad J Pharmacol. 2017;6(5):212-20. doi: 10.21276/sajp.
93. Gadad AP, Wadklar PD, Dandghi P, Patil A. Thermosensitive in situ gel for ocular delivery of lomefloxacin. Ind J Pharm Edu Res. 2015;50(2s):S96-S105. doi: 10.5530/ijper.50.2.24.
94. Gurav NH, Husukale PS. Development and evaluation of in situ gel formation for treatment of mouth ulcer. Turk J Pharm Sci. 2023;20(3):185-97. doi: 10.4274/tjps.galenos.2022.25968, PMID 37417201.
95. Shreya L, Suma US, Zohmingliani R. Recent advances in oral in situ gel drug delivery system: a polymeric approach. Drug Dev Ind Pharm. 2025 Sep 8;51(12):1639-49. doi: 10.1080/03639045.2025.2559033, PMID 40920034.
96. Adepu S, Ramakrishna S. Controlled drug delivery systems: current status and future directions. Molecules. 2021 Sep 29;26(19):5905. doi: 10.3390/molecules26195905, PMID 34641447.
97. Ahmed L, Atif R, Eldeen TS, Yahya I, Omara A, Eltayab M. Study the using of nanoparticles as drug delivery system based on mathematical models for controlled release. Int J Latest Technol Eng Manag Appl Sci. 2019;8(5):52-6.
98. Costa P, Sousa Lobo JM. Modeling and comparison of dissolution profiles. Eur J Pharm Sci. 2001 May 1;13(2):123-33. doi: 10.1016/s0928-0987(01)00095-1, PMID 11297896.
99. Sheshala R, Ming NJ, Kok YY, Raj Singh TR, Dua K. formulation and characterization of ph induced in situ gels containing sulfacetamide sodium for ocular drug delivery: a combination of carbopol®/ HPMC polymer. Ind J Pharm Educ Res. 2019 Sep 25;53(4):654-62. doi: 10.5530/ijper.53.4.127.
100. Upadhyay Shivam U, Chavan Siddhi K, Gajjar Devarshi U, Upadhyay Umeshkumar M, Jayvadan KP. Nanoparticles laden in situ gel for sustained drug release after topical ocular administration. J Drug Deliv Sci Technol. 2020;57:101736. doi: 10.1016/j.jddst.2020.101736.
101. Mod Razif MR, Chan SY, Widodo RT, Chew YL, Hassan M, Hisham SA. Optimization of a luteolin-loaded TPGS/poloxamer 407 nanomicelle: the effects of copolymers hydration temperature and duration and freezing temperature on encapsulation efficiency particle size and solubility. Cancers (Basel). 2023 Jul 24;15(14):3741. doi: 10.3390/cancers15143741, PMID 37509402.
102. Suhail M, Wu PC, Minhas MU. Using carbomer-based hydrogels for control the release rate of diclofenac sodium: preparation and in vitro evaluation. Pharmaceuticals (Basel). 2020 Nov 17;13(11):399. doi: 10.3390/ph13110399, PMID 33212866.
103. Laracuente ML, Yu MH, McHugh KJ. Zero-order drug delivery: state of the art and future prospects. J Control Release. 2020 Sep 12;327:834-56. doi: 10.1016/j.jconrel.2020.09.020, PMID 32931897.
104. Sharma A, Sharma S, Tomar DS. Optimization of in-situ nanoparticulate gel of ofloxacin using factorial design to improve treatment strategy for conjunctivitis and corneal ulcers. Ind J Pharm Educ Res. 2020 Mar 3;54(2):284-92. doi: 10.5530/ijper.54.2.33.
105. Huang C, Peng L, Xu X, Lu Y, Wang X, Lan Z. Preparation and characteristics of a thermosensitive in situ gel loaded with chitosan nanoparticles for optimal ocular delivery of chloramphenicol. J Drug Deliv Sci Technol. 2023 Oct 14;89:104962. doi: 10.1016/j.jddst.2023.104962.
106. Hussain Z, Sahudin S. Preparation characterisation and colloidal stability of chitosan-tripolyphosphate nanoparticles: optimisation of formulation and process parameters. Int J Pharm Pharm Sci. 2016;8(3):297-308.
107. Shah VA, Patel JK. Optimization and characterization of doxorubicin loaded solid lipid nanosuspension for nose to brain delivery using design expert software. Int J Pharm Pharm Sci. 2021 May 1;13(5):45-57. doi: 10.22159/ijpps.2021v13i5.41137.
108. Jokubaite M, Marksa M, Ramanauskiene K. Application of poloxamer for in situ eye drop modeling by enrichment with propolis and balsam poplar buds phenolic compounds. Gels. 2024 Feb 21;10(3):161. doi: 10.3390/gels10030161, PMID 38534579.
109. Zirak MB, Pezeshki A. Effect of surfactant concentration on the particle size stability and potential zeta of beta carotene nano lipid carrier. Int J Curr Microbiol Appl Sci. 2014;4(9):924-32.
110. Russo E, Villa C. Poloxamer hydrogels for biomedical applications. Pharmaceutics. 2019 Dec 10;11(12):671. doi: 10.3390/pharmaceutics11120671, PMID 31835628.
111. Smail SS. Ex vivo irritation evaluation of a novel brimonidine nanoemulsion using the hen’s egg test on chorioallantoic membrane (HET-CAM). Cureus. 2024 Aug 31;16(8):e68280. doi: 10.7759/cureus.68280, PMID 39350816.
112. Batista Duharte A, Jorge Murillo GJ, Perez UM, Tur EN, Portuondo DF, Martinez BT. The hen’s egg test on chorioallantoic membrane: an alternative assay for the assessment of the irritating effect of vaccine adjuvants. Int J Toxicol. 2016 Oct 13;35(6):627-33. doi: 10.1177/1091581816672187, PMID 27733445.
113. Kapoor A. HET CAM irritancy study for development of gatifloxacin in situ gel formulation. Int J Adv Res. 2019 May 31;7(5):1218-25. doi: 10.21474/ijar01/9154.
114. McKenzie B, Kay G, Matthews KH, Knott RM, Cairns D. The hen’s egg chorioallantoic membrane (HET-CAM) test to predict the ophthalmic irritation potential of a cysteamine-containing gel: quantification using Photoshop® and ImageJ. Int J Pharm. 2015 May 13;490(1-2):1-8. doi: 10.1016/j.ijpharm.2015.05.023, PMID 25980731.
115. Samimi MS, Mahboobian MM, Mohammadi M. Ocular toxicity assessment of nanoemulsion in-situ gel formulation of fluconazole. Hum Exp Toxicol. 2021 May 26;40(12):2039-47. doi: 10.1177/09603271211017314, PMID 34036827.
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Copyright (c) 2026 MARGRET CHANDIRA RAJAPPA, GRACY GLADIN SOLOMON, NAGASUBRAMANIAN VENKATASUBRAMANIAM, MANOJ KUMAR KUMAR, DHARSHINI VELMURUGAN
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