In situ gels loaded with naringin as ocular drug delivery carriers; development and preliminary characterization

Panoraia Siafaka; Ayşe Pınar Yağcilar Yağcılar; Gökçe Karaotmarli Güven; Ayşegül Yoltaş; Neslihan Üstündağ Okur

In situ gels loaded with naringin as ocular drug delivery carriers; development and preliminary characterization

Abstract

Ocular drug delivery of any molecule is quite complex and challenging due to the ophthalmic anatomy. The current ocular formulations such as drops, gels or ointments cannot deliver the active molecules efficiently, therefore newer dosage forms are being developed. In situ gels which are in the liquid state in room temperature or in certain pH but transform to gels when instilled onto the eye belongs to such innovative dosage forms. Herein, the fabrication of in situ gels for naringin ocular delivery is presented since there are very few studies examining the use of naringin as an active molecule for eye delivery. Naringin which is hydrolyzed in naringenin, is a flavonoid glucoside found on citrus fruits and has been studied as antioxidant and anti-inflammatory agent or potent antimicrobial agent. The naringin loaded in situ gels developed via cold method using Poloxamer 407, sodium alginate and hydroxypropyl methylcellulose E5. The temperature-responsive in situ gels were characterized for clarity, sol-gel transition temperature, gelling capacity, pH and viscosity. All the results were of desirable limits. Furthermore, in vitro drug release demonstrated that the in situ gels showed sustained pattern Antimicrobial studies indicated specific antimicrobial potency against Enterococcus faecalis. Future studies will involve in vivo studies and ocular irritation analysis.

Keywords

References

[1] Francini-Pesenti F, Spinella P, Calò LA. Potential role of phytochemicals in metabolic syndrome prevention and therapy. Diabetes, Metab Syndr Obes. 2019;12:1987–2002. https://doi.org/10.2147/DMSO.S214550
[2] Shin SA, Joo BJ, Lee JS, Ryu G, Han M, Kim WY, Park HH, Lee JH, Lee CS. Phytochemicals as anti-ınflammatory agents in animal models of prevalent ınflammatory diseases. Molecules. 2020;25(24):5932. https://doi.org/10.3390/molecules25245932
[3] Lee TY, Tseng YH. The potential of phytochemicals in oral cancer prevention and therapy: A review of the evidence. Biomolecules. 2020;10(8):1150. https://doi.org/10.3390/biom10081150
[4] Che CT, Wong MS, Lam CW. Natural products from Chinese medicines with potential benefits to bone health. Molecules. 2016;21(3):239. https://doi.org/10.3390/molecules21030239
[5] Mohanty S, Konkimalla VB, Pal A, Sharma T, Si SC. Naringin as sustained delivery nanoparticles ameliorates the anti-inflammatory activity in a Freund’s complete adjuvant-ınduced arthritis model. ACS Omega. 2021;6(43):28630–28641. https://doi.org/10.1021/acsomega.1c03066
[6] Kandhare AD, Ghosh P, Bodhankar SL. Naringin, a flavanone glycoside, promotes angiogenesis and inhibits endothelial apoptosis through modulation of inflammatory and growth factor expression in diabetic foot ulcer in rats. Chem Biol Interact. 2014;219:101–112. https://doi.org/10.1016/j.cbi.2014.05.012
[7] Auner BG, Wirth M, Valenta C. Antioxidative activity and cytotoxicity of four different flavonoids for dermal applications. J Drug Deliv Sci Technol. 2005;15(3):227–232. https://doi.org/10.1016/S1773-2247(05)50037-6
[8] Okur ME, Sakul AA, Ayla S, Karadag AE, Senyüz CS, Batur S, Daylan B, Özdemir EM, Yücelik SS, Sipahi H, Aydın A. Wound healing effect of naringin gel in alloxan induced diabetic mice. Ankara Univ Eczac Fak Derg. 2020;44(3):397–414. https://doi.org/10.33483/jfpau.742224

[9] Okur ME, Köksal Karayıldırım Ç. Central possible antinociceptive mechanism of naringin. İstanbul J Pharm. 2021;51(2):204–211. https://doi.org/10.26650/IstanbulJPharm.2021.866954
[10] Sharma A, Bhardwaj P, Arya SK. Naringin: A potential natural product in the field of biomedical applications. Carbohydr Polym Technol Appl. 2021;2. https://doi.org/10.1016/j.carpta.2021.100068
[11] Okur NÜ, Yağcılar AP, Siafaka PI. Promising polymeric drug carriers for local delivery: The case of in situ gels. Curr Drug Deliv. 2020;17(8):675–693. https://doi.org/10.2174/1567201817666200608145748
[12] Üstündağ Okur N, Yozgatlı V, Okur ME, Yoltaş A, Siafaka PI. Improving therapeutic efficacy of voriconazole against fungal keratitis: Thermo-sensitive in situ gels as ophthalmic drug carriers. J Drug Deliv Sci Technol. 2019;49. https://doi.org/10.1016/j.jddst.2018.12.005
[13] Vigani B, Rossi S, Gentile M, Sandri G, Bonferoni MC, Cavalloro V, Martino E, Collina S, Ferrari F. Development of a mucoadhesive and an in situ gelling formulation based on κ-carrageenan for application on oral mucosa and esophagus walls. II. Loading of a bioactive hydroalcoholic extract. Mar Drugs. 2019;17(3):153. https://doi.org/10.3390/md17030153
[14] Reddy Hv R, Bhattacharyya S. In vitro evaluation of mucoadhesive in situ nanogel of celecoxib for buccal delivery. Ann Pharm Fr. 2021;79(4):418-430. https://doi.org/10.1016/j.pharma.2021.01.006
[15] Patel P, Patel P. Formulation and evaluation of clindamycin HCL in situ gel for vaginal application. Int J Pharm Investig. 2015;5(1):50. https://doi.org/10.4103/2230-973X.147233
[16] Alkholief M, Kalam MA, Almomen A, Alshememry A, Alshamsan A. Thermoresponsive sol-gel improves ocular bioavailability of Dipivefrin hydrochloride and potentially reduces the elevated intraocular pressure in vivo. Saudi Pharm J. 2020;28(8):1019–1029. https://doi.org/10.1016/j.jsps.2020.07.001
[17] Zhang Q, Li X, Jasti BR. Role of physicochemical properties of some grades of hydroxypropyl methylcellulose on in vitro mucoadhesion. Int J Pharm. 2021;609:121218. https://doi.org/10.1016/j.ijpharm.2021.121218
[18] Kesavan K, Nath G, Pandit JK. Sodium alginate based mucoadhesive system for gatifloxacin and its in vitro antibacterial activity. Sci Pharm. 2010;78(4):941–957. https://doi.org/10.3797/scipharm.1004-24
[19] Xu XR, Yu HT, Hang L, Shao Y, Ding SH, Yang XW. Preparation of naringenin/ β -cyclodextrin complex and its more potent alleviative effect on choroidal neovascularization in rats. Biomed Res Int. 2014;2014:623509. https://doi.org/10.1155/2014/623509
[20] Oguido APMT, Hohmann MSN, Pinho-Ribeiro FA, Crespigio J, Domiciano TP, Verri WA Jr, Casella AMB. Naringenin eye drops ınhibit corneal neovascularization by anti-ınflammatory and antioxidant mechanisms. Invest Ophthalmol Vis Sci. 2017;58(13):5764-5776. https://doi.org/10.1167/iovs.16-19702
[21] Zhang P, Liu X, Hu W, Bai Y, Zhang L. Preparation and evaluation of naringenin-loaded sulfobutylether-β-cyclodextrin/chitosan nanoparticles for ocular drug delivery. Carbohydr Polym. 2016;149:224–230. https://doi.org/10.1016/j.carbpol.2016.04.115
[22] Wang H, Li X, Yang H, Wang J, Li Q, Qu R, Wu X. Nanocomplexes based polyvinylpyrrolidone K-17PF for ocular drug delivery of naringenin. Int J Pharm. 2020;578:119133. https://doi.org/10.1016/j.ijpharm.2020.119133
[23] Borole P, Chaudhari Y, Dharashivkar S, Kumavat S, Shenghani K, Shah P. Preparation and evaluation of in situ gel of levofloxacin hemihydrate for treatment of peridontal disease. Int J Pharm Res Bio-Sci 2013;2(3):185–196.
[24] Gadad AP, Wadklar PD, Dandghi P, Patil A. Thermosensitive in situ gel for ocular delivery of lomefloxacin. Indian J Pharm Educ Res. 2016;50(2):S96–105. https://doi.org/10.5530/ijper.50.2.24
[25] Purslow C, Wolffsohn JS. Ocular surface temperature: A review. Eye Contact Lens. 2005;31(3):117–123. https://doi.org/10.1097/01.ICL.0000141921.80061.17
[26] Makwana SB, Patel VA, Parmar SJ. Development and characterization of in-situ gel for ophthalmic formulation containing ciprofloxacin hydrochloride. Results Pharm Sci. 2016;6:1–6. https://doi.org/10.1016/j.rinphs.2015.06.001
[27] Harish NM, Prabhu P, Charyulu RN, Gulzar MA, Subrahmanyam EVS. Formulation and evaluation of in situ gels containing clotrimazole for oral candidiasis. Indian J Pharm Sci. 2009;71(4):421–427. https//doi.org/10.4103/0250-474X.57291
[28] Garcia-Valldecabres M, López-Alemany A, Refojo MF. pH Stability of ophthalmic solutions. Optom - J Am Optom Assoc. 2004;75(3):161–168. https://doi.org/10.1016/S1529-1839(04)70035-4
[29] Shen T, Yang Z. In vivo and in vitro evaluation of in situ gel formulation of pemirolast potassium in allergic conjunctivitis. Drug Des Develop Ther. 2021;15:2099–107. https://doi.org/10.2147/DDDT.S308448
[30] Chen KJ, Lai CC, Chen HC, Chong YJ, Sun MH, Chen YP, Wang NK, Hwang YS, Chao AN, Wu WC, Yeung L, Sun CC, Liu L, Chen YH, Chou HD. Enterococcus faecalis endophthalmitis: Clinical settings, antibiotic susceptibility, and management outcomes. Microorganisms. 2021;9(5):918.https://doi.org/10.3390/microorganisms9050918
[31] Kuriyan AE, Sridhar J, Flynn HW Jr, Smiddy WE, Albini TA, Berrocal AM, Forster RK, Belin PJ, Miller D. Endophthalmitis caused by Enterococcus faecalis: Clinical features, antibiotic sensitivities, and outcomes. Am J Ophthalmol. 2014;158(5):1018-1023.https://doi.org/10.1016/j.ajo.2014.07.038
[32] Gugleva V, Titeva S, Ermenlieva N, Tsibranska S, Tcholakova S, Rangelov S, Momekova D. Development and evaluation of doxycycline niosomal thermoresponsive in situ gel for ophthalmic delivery. Int J Pharm. 2020;591:120010. https://doi.org/10.1016/j.ijpharm.2020.120010
[33] Üstündağ Okur N, Yozgatlı V, Okur ME, Yoltaş A, Siafaka PI. Improving therapeutic efficacy of voriconazole against fungal keratitis: Thermo-sensitive in situ gels as ophthalmic drug carriers. J Drug Deliv Sci Technol. 2019;49:323–333. https://doi.org/10.1016/j.jddst.2018.12.005
[34] Rupenthal ID, Green CR, Alany RG. Comparison of ion-activated in situ gelling systems for ocular drug delivery. Part 1: Physicochemical characterisation and in vitro release. Int J Pharm. 2011;411(1–2):69–77. https://doi.org/10.1016/j.ijpharm.2011.03.042
[35] Aksu NB, Yozgatlı V, Okur ME, Ayla Ş, Yoltaş A, Üstündağ Okur N. Preparation and evaluation of QbD based fusidic acid loaded in situ gel formulations for burn wound treatment. J Drug Deliv Sci Technol. 2019;52(April):110–121. https://doi.org/10.1016/j.jddst.2019.04.015
[36] Ustundag Okur N, Yozgatli V, Senyigit Z. Formulation and detailed characterization of voriconazole loaded in situ gels for ocular application. Ankara Univ Eczac Fak Derg. 2020;44(1):33–49. https://doi.org/10.33483/jfpau.586590
[37] Clinical and Laboratory Standards Institute M7-A7. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically. 2018. p. 112.
[38] Performance Standards for Antimicrobial Susceptibility Testing. CLSI Document M100-S25. Institute, Clinical and Laboratory Standards. 2015.

Details

Primary Language

English

Subjects

Pharmaceutical Delivery Technologies

Journal Section

Research Article

Authors

Panoraia Siafaka This is me
Cyprus

Ayşe Pınar Yağcilar Yağcılar This is me
0000-0001-5546-4601
Türkiye

Gökçe Karaotmarli Güven This is me
Türkiye

Ayşegül Yoltaş This is me
0000-0003-3115-0346
Türkiye

Neslihan Üstündağ Okur ^*
0000-0002-3210-3747
Türkiye

Publication Date

June 28, 2025

Submission Date

August 24, 2023

Acceptance Date

October 12, 2023

Published in Issue

Year 2024 Volume: 28 Number: 3

IZ

https://izlik.org/JA73TB25UW

Cite

RIS / Bibtex

APA

Siafaka, P., Yağcılar, A. P. Y., Karaotmarli Güven, G., Yoltaş, A., & Üstündağ Okur, N. (2025). In situ gels loaded with naringin as ocular drug delivery carriers; development and preliminary characterization. Journal of Research in Pharmacy, 28(3), 762-769. https://izlik.org/JA73TB25UW

AMA

1.Siafaka P, Yağcılar APY, Karaotmarli Güven G, Yoltaş A, Üstündağ Okur N. In situ gels loaded with naringin as ocular drug delivery carriers; development and preliminary characterization. J. Res. Pharm. 2025;28(3):762-769. https://izlik.org/JA73TB25UW

Chicago

Siafaka, Panoraia, Ayşe Pınar Yağcilar Yağcılar, Gökçe Karaotmarli Güven, Ayşegül Yoltaş, and Neslihan Üstündağ Okur. 2025. “In Situ Gels Loaded With Naringin As Ocular Drug Delivery Carriers; Development and Preliminary Characterization”. Journal of Research in Pharmacy 28 (3): 762-69. https://izlik.org/JA73TB25UW.

EndNote

Siafaka P, Yağcılar APY, Karaotmarli Güven G, Yoltaş A, Üstündağ Okur N (June 1, 2025) In situ gels loaded with naringin as ocular drug delivery carriers; development and preliminary characterization. Journal of Research in Pharmacy 28 3 762–769.

IEEE

[1]P. Siafaka, A. P. Y. Yağcılar, G. Karaotmarli Güven, A. Yoltaş, and N. Üstündağ Okur, “In situ gels loaded with naringin as ocular drug delivery carriers; development and preliminary characterization”, J. Res. Pharm., vol. 28, no. 3, pp. 762–769, June 2025, [Online]. Available: https://izlik.org/JA73TB25UW

ISNAD

Siafaka, Panoraia - Yağcılar, Ayşe Pınar Yağcilar - Karaotmarli Güven, Gökçe - Yoltaş, Ayşegül - Üstündağ Okur, Neslihan. “In Situ Gels Loaded With Naringin As Ocular Drug Delivery Carriers; Development and Preliminary Characterization”. Journal of Research in Pharmacy 28/3 (June 1, 2025): 762-769. https://izlik.org/JA73TB25UW.

JAMA

1.Siafaka P, Yağcılar APY, Karaotmarli Güven G, Yoltaş A, Üstündağ Okur N. In situ gels loaded with naringin as ocular drug delivery carriers; development and preliminary characterization. J. Res. Pharm. 2025;28:762–769.

MLA

Siafaka, Panoraia, et al. “In Situ Gels Loaded With Naringin As Ocular Drug Delivery Carriers; Development and Preliminary Characterization”. Journal of Research in Pharmacy, vol. 28, no. 3, June 2025, pp. 762-9, https://izlik.org/JA73TB25UW.

Vancouver

1.Panoraia Siafaka, Ayşe Pınar Yağcilar Yağcılar, Gökçe Karaotmarli Güven, Ayşegül Yoltaş, Neslihan Üstündağ Okur. In situ gels loaded with naringin as ocular drug delivery carriers; development and preliminary characterization. J. Res. Pharm. [Internet]. 2025 Jun. 1;28(3):762-9. Available from: https://izlik.org/JA73TB25UW