Hypotension and antiphlogistic potential of empagliflozin ocular film: swelling and release kinetics: Original scientific paper

Tanisha  Das; Subrata Mallick; Sourajit Parida; Mouli  Das; Rakesh  Swain; Sk Habibullah

doi:10.5599/admet.2941

Authors

Tanisha Das School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be University), Bhubaneswar, Odisha, India https://orcid.org/0000-0002-8854-5229
Subrata Mallick School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be University), Bhubaneswar, Odisha, India https://orcid.org/0000-0002-6606-1223
Sourajit Parida School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be University), Bhubaneswar, Odisha, India https://orcid.org/0009-0007-7495-763X
Mouli Das School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be University), Bhubaneswar, Odisha, India https://orcid.org/0009-0009-2246-0589
Rakesh Swain School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be University), Bhubaneswar, Odisha, India https://orcid.org/0000-0003-1907-1653
Sk Habibullah School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be University), Bhubaneswar, Odisha, India https://orcid.org/0000-0002-3646-7177

DOI:

https://doi.org/10.5599/admet.2941

Keywords:

SGLT2 inhibitor, hydration dynamics, drug dissolution, IOP, ocular anti-inflammation, SiO2

Abstract

Background and Purpose: Empagliflozin (EMP) is a sodium-glucose cotransporter 2 (SGLT2) inhibitor used for the management of type 2 diabetes mellitus. The danger of glaucoma in type 2 diabetes mellitus patients is known to be reduced using SGLT2 inhibitors. Empagliflozin is also believed to reduce the level of inflammatory markers. The present work has been undertaken for monitoring intraocular pressure and anti-inflammatory activity using the empagliflozin ocular film formulation. The effect of colloidal silicon dioxide upon the dynamics of swelling and drug release performance was also studied. Experimental Approach: Hydroxypropyl methylcellulose-based ocular film of empagliflozin was prepared, including silicon dioxide in different ratios as 1:0.00, 1:0.01, 1:0.02, 1:0.04, and 1:0.06 (namely, EMA0, EMA1, EMA2, EMA3 and EMA4, respectively) using casting and solvent evaporation. Swelling and drug release studies of the films were conducted in phosphate buffer solution (pH 7.4), and the kinetic mechanisms of swelling and drug release were evaluated. Intraocular pressure was measured after application of the film in the normotensive rabbit eye. Moreover, the anti-inflammatory effect was assessed using a rabbit ocular carrageenan-induced inflammation model. Key Results: Swelling behaviour followed Fickian mechanism in the order: EMA3<EMA2<EMA0<EMA4<EMA1, and partial relaxation with EMA3. Films containing silicon dioxide showed faster release than those without it (EMA0), following a diffusion pattern. The silicon dioxide-loaded film (EMA3) showed significantly lowered intraocular pressure and promising ocular anti-inflammation with favourable binding affinities of EMP to Interleukin-1β, Interleukin 6 and tumour necrosis factor-α. A good correlation between intraocular pressure and drug release was also established. Conclusion: A hydroxypropyl methylcellulose-based ocular film containing empagliflozin and silicon dioxide could be used to manage intraocular pressure and inflammation in a controlled manner in patients with type 2 diabetes mellitus.

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References

[1] R. Chilton, I. Tikkanen, U. Hehnke, H.J. Woerle, O.E. Johansen. Impact of empagliflozin on blood pressure in dipper and non-dipper patients with type 2 diabetes mellitus and hypertension. Diabetes, Obesity and Metabolism 19 (2017) 1620-1624. https://doi.org/10.1111/dom.12962 DOI: https://doi.org/10.1111/dom.12962

[2] K. Eng, N. Zebardast, V.M. Boland, J.E. Lo, S.S. Swaminathan, D.S. Friedman, K.S.-K. Ma. Sodium-glucose cotransporter 2 inhibitors for the primary prevention of glaucoma in patients with type 2 diabetes: a target trial emulation. American Journal of Ophthalmology 271 (2025) 286-298. https://doi.org/10.1016/j.ajo.2024.10.029 DOI: https://doi.org/10.1016/j.ajo.2024.10.029

[3] K. Kunzmann. SGLT-2 inhibitors reduce glaucoma risk in type 2 diabetes patients. American Academy of Ophthalmology, 2023. https://www.hcplive.com/view/sglt2-inhibitors-glaucoma-risk-type-2-diabetes-patients

[4] S. Ahmed, M.M. El-Sayed, M.A. Kandeil, M.M. Khalaf. Empagliflozin attenuates neurodegeneration through antioxidant, anti-inflammatory, and modulation of α-synuclein and Parkin levels in rotenone-induced Parkinson’s disease in rats. Saudi Pharmaceutical Journal 30 (2022) 863-873. https://doi.org/10.1016/j.jsps.2022.03.005 DOI: https://doi.org/10.1016/j.jsps.2022.03.005

[5] F. Iannantuoni, A.M. de Marañon, N. Diaz-Morales, R. Falcon, C. Bañuls, Z. Abad-Jimenez, V.M. Victor, A. Hernandez-Mijares, S. Rovira-Llopis. The SGLT2 inhibitor empagliflozin ameliorates the inflammatory profile in type 2 diabetic patients and promotes an antioxidant response in leukocytes. Journal of Clinical Medicine 8(1) (2019) 1814. https://doi.org/10.3390/jcm8111814 DOI: https://doi.org/10.3390/jcm8111814

[6] C. Ferrero, D. Massuelle, E. Doelker. Towards elucidation of the drug release mechanism from compressed hydrophilic matrices made of cellulose ethers. II. Evaluation of a possible swelling-controlled drug release mechanism using dimensionless analysis. Journal of Controlled Release 141 (2010) 223-233. https://doi.org/10.1016/j.jconrel.2009.09.011 DOI: https://doi.org/10.1016/j.jconrel.2009.09.011

[7] A. Pramanik, R.N. Sahoo, S. Nandi, A. Nanda, S. Mallick. Characterization of hydration behaviour and modeling of film formulation. Acta Chimica Slovenica 68 (2021) 159-169. https://doi.org/10.17344/acsi.2020.6298 DOI: https://doi.org/10.17344/acsi.2020.6298

[8] J.-H. Park, H. Jeong, J. Hong, M. Chang, M. Kim, R.S. Chuck, J.K. Lee, C.-Y. Park. The effect of silica nanoparticles on human corneal epithelial cells. Scientific Reports 6 (2016) 37762. https://doi.org/10.1038/srep37762 DOI: https://doi.org/10.1038/srep37762

[9] E.A. Mun, P.W.J. Morrison, A.C. Williams, V.V. Khutoryanskiy. On the barrier properties of the cornea: a microscopy study of the penetration of fluorescently labeled nanoparticles, polymers, and sodium fluorescein. Molecular Pharmaceutics 11 (2014) 3556-3564. https://doi.org/10.1021/mp500332m DOI: https://doi.org/10.1021/mp500332m

[10] A. Nieto, H. Hou, M.J. Sailor, W.R. Freeman, L. Cheng. Ocular silicon distribution and clearance following intravitreal injection of porous silicon microparticles. Experimental Eye Research 116 (2013) 161-168. https://doi.org/10.1016/j.exer.2013.09.001 DOI: https://doi.org/10.1016/j.exer.2013.09.001

[11] L. Cheng, E. Anglin, F. Cunin, D. Kim, M.J. Sailor, I. Falkenstein, A. Tammewar, W.R. Freeman. Intravitreal properties of porous silicon photonic crystals: a potential self-reporting intraocular drug-delivery vehicle. British Journal of Ophthalmology 92 (2008) 705-711. https://doi.org/10.1136/bjo.2007.133587 DOI: https://doi.org/10.1136/bjo.2007.133587

[12] R. Swain, S. Nandi, R.N. Sahoo, S.S. Swain, S. Mohapatra, S. Mallick. Bentonite clay incorporated topical film formulation for delivery of trimetazidine: control of ocular pressure and in vitro-in vivo correlation. Journal of Drug Delivery Science and Technology 67 (2022) 102956. https://doi.org/10.1016/j.jddst.2021.102956 DOI: https://doi.org/10.1016/j.jddst.2021.102956

[13] R. Swain, A. Moharana, S. Habibullah, S. Nandi, A. Bose, S. Mohapatra, S. Mallick. Ocular delivery of felodipine for the management of intraocular pressure and inflammation: effect of film plasticizer and in vitro-in vivo evaluation. International Journal of Pharmaceutics 642 (2023) 123153. https://doi.org/10.1016/j.ijpharm.2023.123153 DOI: https://doi.org/10.1016/j.ijpharm.2023.123153

[14] M. Das, S. Habibullah, T. Das, R. Swain, S. Mallick. Management of intraocular pressure and inflammation using febuxostat film: in vitro-in vivo correlation. ADMET and DMPK 13 (2025) 2601. https://doi.org/10.5599/admet.2601 DOI: https://doi.org/10.5599/admet.2601

[15] V. Vigoreaux, E.S. Ghaly. Fickian and relaxational contribution quantification of drug release in a swellable hydrophilic polymer matrix. Drug Development and Industrial Pharmacy 20 (1994) 2519-2526. https://doi.org/10.3109/03639049409042655 DOI: https://doi.org/10.3109/03639049409042655

[16] J. Balasubramaniam, A. Srinatha, J. Pandit, G. Nath. In vitro microbiological evaluation of polyvinyl alcohol-based ocular inserts of ciprofloxacin hydrochloride. Indian Journal of Pharmaceutical Sciences 68 (2006) 626-630. https://www.ijpsonline.com/abstract/in-vitro-microbiological-evaluation-of-polyvinyl-alcoholbased-ocular-inserts-of-ciprofloxacin-hydrochloride-397.html DOI: https://doi.org/10.4103/0250-474X.29631

[17] B. Hou, F. Wang, Z. Ye, X. Jin, Y. Fu, Z. Li. Study of minimally invasive radiofrequency ablation of the ciliary body for the treatment of glaucoma in rabbits. Molecular Medicine Reports 21(3) (2020) 1071-1076. https://doi.org/10.3892/mmr.2019.10906 DOI: https://doi.org/10.3892/mmr.2019.10906

[18] Acts, Rules & Guidelines, Committee for Control and Supervision of Experiments on Animals, Ministry of Fisheries, Animal Husbandry and Dairying, Department of Animal Husbandry and Dairying Government of India. https://ccsea.gov.in/Content/54_1_ACTS,RULESANDGUIDELINES.aspx Accessed November 6, 2025.

[19] N. Percie du Sert, V. Hurst, A. Ahluwalia, S. Alam, M.T. Avey, M. Baker, W.J. Browne, A Clark, I.C. Cuthill, U. Dirnagl, M. Emerson, P. Garner, S.T. Holgate, D.W. Howells, N.A. Karp, S. E. Lazic, K. Lidster, C.J. MacCallum, M. Macleod, E.J. Pearl, O.H. Petersen, F. Rawle, P. Reynolds, K. Rooney, E.S. Sena, S.D. Silberberg, T. Steckler, H. Würbel. The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. Journal of Cerebral Blood Flow & Metabolism 40(9) (2020) 1769-1777. https://doi.org/10.1177/0271678X20943823 DOI: https://doi.org/10.1177/0271678X20943823

[20] ICH Harmonised Tripartite Guideline: Stability Testing of New Drug Substances and Products Q1A(R2). International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2003. https://database.ich.org/sites/default/files/Q1A%28R2%29%20Guideline.pdf

[21] A. Topete, B. Saramago, A.P. Serro. Effect of sterilization by steam and pressure and gamma radiation on drug-loaded intraocular lenses for prophylaxis of endophthalmitis. Annals of Medicine 51 (sup1) (2024) 101-102. https://doi.org/10.1080/07853890.2018.1562706 DOI: https://doi.org/10.1080/07853890.2018.1562706

[22] S. Habibullah, J.R. Meher, M. Das, T. Das, R. Swain, B. Mohanty, et al. Moxifloxacin in HPMC-nanocellulose composite film for the management of ocular inflammation: effect of carboxymethylated gum on permeation and antimicrobial activity. International Journal of Biological Macromolecules 310(Part1) (2025) 143302. https://doi.org/10.1016/j.ijbiomac.2025.143302 DOI: https://doi.org/10.1016/j.ijbiomac.2025.143302

[23] S. Bashir, M. Hina, J. Iqbal, A.H. Rajpar, M.A. Mujtaba, N.A. Alghamdi, S. Wageh, K. Ramesh, S. Ramesh. Fundamental concepts of hydrogels: synthesis, properties, and their applications. Polymers (Basel) 12 (2020) 2702. https://doi.org/10.3390/polym12112702 DOI: https://doi.org/10.3390/polym12112702

[24] Mohamed Rizk, A.K. Attia, H.Y. Mohamed, M.S. Elshahed. Thermo analytical study and purity determination of Anti-diabetic drugs Linagliptin and Empagliflozin in drug substances. Chemistry Research Journal 5(4) (2020) 6-20. https://chemrj.org/download/vol-5-iss-4-2020/chemrj-2020-05-04-6-20.pdf

[25] R.P. Bhole, F.R. Tamboli. Development and validation of stability-indicating HPTLC-MS method for estimation of empagliflozin in pharmaceutical dosage form. Analytical Chemistry Letters 8 (2018) 244-256. https://doi.org/10.1080/22297928.2017.1404929 DOI: https://doi.org/10.1080/22297928.2017.1404929

[26] D.M. Widjonarko, J. Jumina, I. Kartini, N. Nuryono. Phosphonate modified silica for adsorption of Co(II), Ni(II), Cu(II), and Zn(II). Indonesian Journal of Chemistry 14 (2014) 143-151. https://doi.org/10.22146/ijc.21251 DOI: https://doi.org/10.22146/ijc.21251

[27] E. Guler, A. Nur Hazar-Yavuz, E. Tatar, M. Morid Haidari, G. Sinemcan Ozcan, G. Duruksu, et al. Oral empagliflozin-loaded tri-layer core-sheath fibers fabricated using tri-axial electrospinning: enhanced in vitro and in vivo antidiabetic performance. International Journal of Pharmaceutics 635 (2023) 122716. https://doi.org/10.1016/j.ijpharm.2023.122716 DOI: https://doi.org/10.1016/j.ijpharm.2023.122716

[28] D.O. Corrigan, A.M. Healy, O.I. Corrigan. The effect of spray drying solutions of polyethylene glycol (PEG) and lactose/PEG on their physicochemical properties. International Journal of Pharmaceutics 235(1-2) (2002) 193-205. https://doi.org/10.1016/S0378-5173(01)00990-5 DOI: https://doi.org/10.1016/S0378-5173(01)00990-5

[29] A.V. Patil, H.S. Mahajan. Modified pea starch-based ocular films of azelastine hydrochloride: development and characterization. Carbohydrate Polymer Technologies and Applications 2 (2021) 100078. https://doi.org/10.1016/j.carpta.2021.100078 DOI: https://doi.org/10.1016/j.carpta.2021.100078

[30] R. Swain, S. Nandi, R.N. Sahoo, S.S. Swain, S. Mohapatra, S. Mallick. Bentonite clay incorporated topical film formulation for delivery of trimetazidine: control of ocular pressure and in vitro-in vivo correlation. Journal of Drug Delivery Science and Technology 67 (2022) 102956. https://doi.org/10.1016/j.jddst.2021.102956 DOI: https://doi.org/10.1016/j.jddst.2021.102956

[31] S. Nandi, R. Swain, S. Habibullah, R.N. Sahoo, A.K. Nayak, S. Mallick. Lipid-Gelucire based rectal delivery of ramipril prodrug exhibits significant lowering of intraocular pressure in normotensive rabbit: sustained structural relaxation release kinetics and IVIVC. Pharmaceutical Development and Technology 29 (2024) 468-476. https://doi.org/10.1080/10837450.2024.2345807 DOI: https://doi.org/10.1080/10837450.2024.2345807

[32] H.S. Mahajan, S.R. Deshmukh. Development and evaluation of gel-forming ocular films based on xyloglucan. Carbohydrate Polymers 122 (2015) 243-247. https://doi.org/10.1016/j.carbpol.2015.01.018 DOI: https://doi.org/10.1016/j.carbpol.2015.01.018

[33] European Glaucoma Society Terminology and Guidelines for Glaucoma, 4th Edition - Chapter 3: Treatment principles and options. British Journal of Ophthalmology 101 (2017) 130-195. https://doi.org/10.1136/bjophthalmol-2016-EGSguideline.003 DOI: https://doi.org/10.1136/bjophthalmol-2016-EGSguideline.003

[34] S. Nandi, A. Nanda, R.N. Sahoo, R. Swain, S. Mallick. Formulation and administration of ramipril prodrug for improving bioactivity significantly: in vitro and in vivo correlation. Journal of Drug Delivery Science and Technology 74 (2022) 103597. https://doi.org/10.1016/j.jddst.2022.103597 DOI: https://doi.org/10.1016/j.jddst.2022.103597