Formulation and optimization of Agomelatine loaded nanostructured lipid carriers for intranasal delivery

Year 2024, Volume: 28 Issue: 5, 1592 - 1608, 28.06.2025

Shailendra Salvankar Komal Thite Mukesh Ratnaparkhi Gajanan Kulkarni

Abstract

The current study aims to prepare agomelatine-loaded nanostructured lipid carriers (AGO-loaded NLCs) and their administration through the intranasal route in an attempt to circumvent hepatic metabolism, facilitate controlled release, and increase cerebral distribution, etc. Agomelatine faces several challenges such as a fast metabolic process, limited solubility, gastrointestinal vulnerability, enzymatic cleavage, and decreased bioavailability. These challenges collectively undermine its therapeutic effectiveness. Therefore, the goal of the current work is to develop agomelatine-loaded NLCs with enhanced drug entrapment, extended release, and improved stability. Agomelatine loaded NLCs were prepared by using Glyceryl monostearate and Neroli oil as solid lipid and liquid lipid respectively, While Tween 80 and poloxamer 188 were used as surfactant and co-surfactant. The technique of melt emulsification ultrasonication was employed to prepare these NLCs. The prepared formulation was optimized utilizing a three-factor, three-level Box-Behnken design with total lipid percentage, surfactant, and co-surfactant percentage, and ultrasonication time as independent variables and particle size, zeta potential, and percentage entrapment efficiency as dependent variables. The optimized NLCs size was found to be 122 ± 3.19 nm and the results from transmission electron microscopy are likewise within this size range (under 150 nm) and showed that the particles were homogeneous and nearly spherical, with porous and irregular surface features. Polydispersity index, zeta potential, entrapment efficiency, and drug release % were observed as 0.353 ± 0.15, -33.7 ± 2.35 mV, 90.57 ± 0.984% and 94.65 ± 2.39% respectively. The findings from the permeation study indicated a substantial enhancement in permeation for AGO-loaded NLCs when compared to AGO solution.

Keywords

Agomelatine , Blood brain barrier , Box-Behnken design , Intranasal delivery , Nanostructured lipid carriers

References

• [1] Gong Q, He Y. Depression, neuroimaging and connectomics: A selective overview. Biol Psychiatry. 2015;77(3):223–235. https://doi.org/10.1016/j.biopsych.2014.08.009
• [2] Vos T, Lim S, Abbafati C, Abbas K, Abbasi M, Abbasifard M, et al. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396(1204):1222. https://doi.org/10.1016/S01406736(20)30925-9
• [3] Kennedy SH, Guilleminault C. P.2.C.013 antidepressant efficacy of agomelatine 25-50 mg versus venlafaxine 75-150 mg: Two randomized, double blind studies. Eur Neuropsychopharmacol. 2006;16. https://doi.org/10.1016/s0924977x(06)70347-9
• [4] Cascade E, Kalali AH, Kennedy SH. Real-World Data on SSRI Antidepressant Side Effects. Psychiatry (Edgmont). 2009;6(2):16-18.
• [5] Marasine NR, Sankhi S, Lamichhane R, Marasini NR, Dangi NB. Use of antidepressants among patients diagnosed with depression: A scoping review. Biomed Res Int. 2021;2021:6699028. https://doi.org/10.1155/2021/6699028
• [6] De Berardis D, Fornaro M, Serroni N, Campanella D, Rapini G, Olivieri L, et al. Agomelatine beyond borders: Current evidences of its efficacy in disorders other than major depression. Int J Mol Sci. 2015;16(1):1111–1130. https://doi.org/10.3390/ijms16011111
• [7] Bourin M, Mocaer E, Porsolt R. Antidepressant-like activity of S 20098 (agomelatine) in the forced swimming test in rodents: Involvement of melatonin and serotonin receptors. J Psychiatry Neurosci. 2004;29(2):126-133.
• [8] Loo H, Hale A, Dhaenen H. Determination of the dose of agomelatine, a melatoninergic agonist and selective 5HT2C antagonist, in the treatment of major depressive disorder: A placebo-controlled dose range study. Int Clin Psychopharmacol. 2002;17(5):239–247. https://doi.org/10.1097/00004850-200209000-00004
• [9] Guardiola-Lemaitre B, De Bodinat C, Delagrange P, Millan MJ, Munoz C, Mocaer E. Agomelatine: Mechanism of action and pharmacological profile in relation to antidepressant properties. Br J Pharmacol. 2014;171(15):3604–3619. https://doi.org/10.1111/bph.12720
• [10] Gorwood P, Benichou J, Moore N, Wattez M, Secouard M-C, Desobry X, et al. Agomelatine in standard medical practice in depressed patients: Results of a 1-year multicentre observational study in France. Clin Drug Investig. 2020;40(11):1009–1020. https://doi.org/10.1007/s40261-020-00957-9
• [11] De Berardis D, Serroni N, Campanella D, Rapini G, Olivieri L, Feliziani B, et al. Alexithymia, responsibility attitudes and suicide ideation among outpatients with obsessive-compulsive disorder: An exploratory study. Compr Psychiatry. 2015;58:82–87. https://doi.org/10.1016/j.comppsych.2014.12.016
• [12] Kennedy SH, Rizvi SJ. Agomelatine in the treatment of major depressive disorder. CNS Drugs. 2010;24(6):479–499. https://doi.org/10.2165/11534420-000000000-00000
• [13] Engelhardt B, Liebner S. Novel insights into the development and maintenance of the blood–brain barrier. Cell Tissue Res. 2014;355(3):687–699. https://doi.org/10.1007/s00441-014-1811-2
• [14] Du W, Zhou Y, Gong Y, Zhao C. Investigation of physicochemical properties and in-vitro in-vivo evaluation of Agomelatine polymorphs. Asian J Pharm. 2013;8(3):181-190. https://doi.org/10.1016/j.ajps.2013.07.024
• [15] Mahajan HS, Mahajan MS, Nerkar PP, Agrawal A. Nanoemulsion-based intranasal drug delivery system of saquinavir mesylate for brain targeting. Drug Deliv. 2013;21(2):148–154. https://doi.org/10.3109/10717544.2013.838014
• [16] Gadhave D, Choudhury H, Kokare C. Neutropenia and leukopenia protective intranasal olanzapine-loaded lipid based nanocarriers engineered for brain delivery. Appl Nanosci. 2018;9(2):151–168. https://doi.org/10.1007/s13204-018-0909-3
• [17] Gorain B, Rajeswary DC, Pandey M, Kesharwani P, Kumbhar SA, Choudhury H. Nose to brain delivery of nanocarriers towards attenuation of demented condition. Curr Pharm Des. 2020;26(19):2233–2246. https://doi.org/10.2174/1381612826666200313125613
• [18] Md S, Gan SY, Haw YH, Ho CL, Wong S, Choudhury H. In vitro neuroprotective effects of naringenin nanoemulsion against β-amyloid toxicity through the regulation of amyloidogenesis and tau phosphorylation. Int J Biol Macromol. 2018;118:1211–1219. https://doi.org/10.1016/j.ijbiomac.2018.06.190
• [19] Micheli M-R, Bova R, Magini A, Polidoro M, Emiliani C. Lipid-based nanocarriers for CNS-targeted drug delivery. Recent Pat CNS Drug Discov. 2012;7(1):71–86. https://doi.org/10.2174/157488912798842241
• [20] Sapra B, Thatai P, Bhandari S, Sood J, Jindal M, Tiwary A. A critical appraisal of microemulsions for drug delivery: Part I. Ther Deliv. 2013;4(12):1547–1564. https://doi.org/10.4155/tde.13.116
• [21] Choudhury H, Gorain B, Karmakar S, Biswas E, Dey G, Barik R, et al. Improvement of cellular uptake, in vitro antitumor activity and sustained release profile with increased bioavailability from a nanoemulsion platform. Int J Pharm. 2014;460(1–2):131–143. https://doi.org/10.1016/j.ijpharm.2013.10.055
• [22] Choudhury H, Pandey M, Chin PX, Phang YL, Cheah JY, Ooi SC, et al. Transferrin receptors-targeting nanocarriers for efficient targeted delivery and transcytosis of drugs into the brain tumors: A review of recent advancements and emerging trends. Drug Deliv Transl Res. 2018;8(5):1545–1563. https://doi.org/10.1007/s13346-018-0552-2
• [23] Cunha S, Amaral MH, Lobo JM, Silva AC. Lipid nanoparticles for nasal/intranasal drug delivery. Crit Rev Ther Drug Carr Syst. 2017;34(3):257–282. https://doi.org/10.1615/critrevtherdrugcarriersyst.2017018693
• [24] Fachel FNS, Nemitz MC, Medeiros-Neves B, Veras KS, Bassani VL, Koester LS, et al. A novel, simplified and stability-indicating high-throughput ultra-fast liquid chromatography method for the determination of rosmarinic acid in nanoemulsions, porcine skin and nasal mucosa. J Chromatogr B. 2018;1083:233–241. https://doi.org/10.1016/j.jchromb.2018.03.020
• [25] Garces A, Amaral MH, Sousa Lobo JM, Silva AC. Formulations based on solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for cutaneous use: A Review. Eur J Pharm Sci. 2018; 112: 159–167. https://doi.org/10.1016/j.ejps.2017.11.023
• [26] Zheng M, Falkeborg M, Zheng Y, Yang T, Xu X. Formulation and characterization of nanostructured lipid carriers containing a mixed lipids core. Colloids Surf A: Physicochem Eng Asp. 2013; 430: 76–84. https://doi.org/10.1016/j.colsurfa.2013.03.070
• [27] Cirri M, Bragagni M, Mennini N, Mura P. Development of a new delivery system consisting in “Drug – in Cyclodextrin – in nanostructured lipid carriers” for ketoprofen topical delivery. Eur J Pharm Biopharm. 2012; 80(1): 46–53. https://doi.org/10.1016/j.ejpb.2011.07.015
• [28] Souto EB, Baldim I, Oliveira WP, Rao R, Yadav N, Gama FM, Mahant S. SLN and NLC for topical, dermal, and transdermal drug delivery. Expert Opin Drug Deliv. 2020; 17(3): 357–377. https://doi.org/10.1080/17425247.2020.1727883
• [29] Zheng M, Falkeborg M, Zheng Y, Yang T, Xu X. Formulation and characterization of nanostructured lipid carriers containing a mixed lipids core. Colloids Surf A: Physicochem. Eng. 2013; 430: 76–84. https://doi.org/10.1016/j.colsurfa.2013.03.070
• [30] Shukla T, Upmanyu N, Pandey SP, Gosh D. Chapter 1 – Lipid nanocarriers. Lipid Nanocarriers for Drug Targeting, 2018; 1–47. https://doi.org/10.1016/b978-0-12-813687-4.00001-3
• [31] Khan A, Imam SS, Aqil M, Ahad A, Sultana Y, Ali A, Khan K. Brain targeting of temozolomide via the intranasal route using lipid-based nanoparticles: Brain Pharmacokinetic and scintigraphic analyses. Mol Pharmaceutics. 2016; 13(11): 3773–3782. https://doi.org/10.1021/acs.molpharmaceut.6b00586
• [32] Madane RG, Mahajan HS. Curcumin-loaded nanostructured lipid carriers (NLCs) for nasal administration: Design, characterization, and in vivo study. Drug Deliv. 2016; 23(4): 1326–1334. https://doi.org/10.3109/10717544.2014.975382
• [33] Graeser, KA, Patterson JE, Zeitler JA, Rades T. The role of configurational entropy in amorphous systems. Pharmaceutics. 2010; 2: 224–244.
• [34] Meghana M, Thota S, Venisetty RK. Development and validation of stability- indicating RP-HPLC method for the estimation of Agomelatine in API. Res J Pharm Biol Chem Sci. 2014; 5(1): 621-628.
• [35] Alam M, Ahmed S, Nikita, Moon G, Aqil Mohd, Sultana Y. Chemical engineering of a lipid nano-scaffold for the solubility enhancement of an antihyperlipidaemic drug, simvastatin; Preparation, optimization, physicochemical characterization and pharmacodynamic study. Artif Cells Nanomed Biotechnol. 2018; 1908-1919. https://doi.org/10.1080/21691401.2017.1396223
• [36] Gadhave DG, Kokare CR. Nanostructured lipid carriers engineered for intranasal delivery of teriflunomide in multiple sclerosis: Optimization and in vivo studies. Drug Dev Ind Pharm. 2019; 45(5): 839–851. https://doi.org/10.1080/03639045.2019.1576724
• [37] Pokharkar V, Patil-Gadhe A, Palla P. Efavirenz loaded nanostructured lipid carrier engineered for brain targeting through intranasal route: In-vivo pharmacokinetic and toxicity study. Biomed Pharmacother. 2017; 94: 150–164. https://doi.org/10.1016/j.biopha.2017.07.067
• [38] Kawish SM, Ahmed S, Gull A, Aslam M, Pandit J, Aqil M, Sultana Y. Development of nabumetone loaded lipid nano-scaffold for the effective oral delivery; optimization, characterization, drug release and pharmacodynamic study. J Mol Liq. 2017; 231: 514–522. https://doi.org/10.1016/j.molliq.2017.01.107 Salvankar et al. Journal of Research in Pharmacy AGO-loaded nanostructured lipid carriers for intranasal delivery Research Article
• [39] Iqbal R, Ahmed S, Jain GK, Vohora D. Design and development of letrozole nanoemulsion: A comparative evaluation of brain targeted nanoemulsion with free letrozole against status epilepticus and neurodegeneration in mice. Int J Pharm. 2019; 565: 20–32. https://doi.org/10.1016/j.ijpharm.2019.04.076
• [40] Mahmood S, Mandal UK, Chatterjee B. Transdermal delivery of raloxifene HCl via ethosomal system: Formulation, advanced characterizations and pharmacokinetic evaluation. Int J Pharm. 2018; 542(1–2): 36–46. https://doi.org/10.1016/j.ijpharm.2018.02.044
• [41] Galgatte UC, Kumbhar AB, Chaudhari PD. Development of institute for nasal delivery: Design, optimization, in vitro and in vivo evaluation. Drug Deliv. 2014; 21(1): 62–73. https://doi.org/10.3109/10717544.2013.849778
• [42] Sood S, Jain K, Gowthamarajan K. Optimization of curcumin nanoemulsion for intranasal delivery using design of experiment and its toxicity assessment. Colloids Surf B. 2014; 113: 330–337. https://doi.org/10.1016/j.colsurfb.2013.09.030
• [43] Kumar P, Sharma G, Kumar R, Singh B, Malik R, Katare OP, Raza K. Promises of a biocompatible nanocarrier in improved brain delivery of quercetin: Biochemical, pharmacokinetic and biodistribution evidences. Int J Pharm. 2016; 515(1–2): 307–314. https://doi.org/10.1016/j.ijpharm.2016.10.024
• [44] Anand A, Arya M, Kaithwas G, Singh G, Saraf SA. Sucrose stearate as a biosurfactant for development of rivastigmine containing nanostructured lipid carriers and assessment of its activity against dementia in C. elegans model. J Drug Deliver Sci Technol. 2019; 49: 219–226. https://doi.org/10.1016/j.jddst.2018.11.021