PRELIMINARY STUDIES ON BRAIN TARGETING OF INTRANASAL ATOMOXETINE LIPOSOMES
Abstract
Objective: The objective of the present study was to evaluate the enhancement in brain uptake of liposomes containing atomoxetine (ATX-Lipo) for intranasal delivery in the management of Attention Deficit Hyperactivity Disorder (ADHD).
Methods: ATX-Lipo and ATX mucoadhesive liposomes (ATX-Muco Lipo) with and without a vasoconstrictor phenylephrine (PHE) were prepared by lipid film hydration method and characterized for physicochemical parameters. Biodistribution and pharmacokinetic evaluation of ATX-Lipo in the brain and blood of Sprague Dawley rats following intranasal (i. n.) and intravenous (i. v.) administrations were examined using optimized technetium-labeled ([99]m Tc-labeled) atomoxetine formulations. Gamma scintigraphy imaging was performed in Sprague Dawley rats.
Results: ATX-Lipo and ATX-Muco Lipo were found to be stable with average particle size of 404.35±1.86 nm and 510.50±1.22 nm respectively.[99]mTc tagged ATX-Lipo, ATX-Muco Lipo, ATX+PHE-Muco Lipo and ATX solution were found to be stable and suitable for in vivo studies. On comparing ATX concentrations after i. n. administrations of ATX-Lipo, ATX-Muco Lipo and ATX+PHE-Muco Lipo and i. v. administration of ATX-Lipo, brain/blood uptake ratios (BBR) at 30 min were found to be 0.161, 1.255, 0.331, and 0.003 respectively. These results revealed effective brain targeting following i. n. administration of mucoadhesive ATX liposomes. Higher drug targeting efficiency (% DTE) and direct transport percentage (%DTP) for mucoadhesive liposomes indicated considerable brain targeting from ATX-Muco liposomes. Gamma scintigraphy imaging of the rat brain conclusively demonstrated the greater extent of transport of atomoxetine by ATX+PHE-Muco Lipo (i. n.), when compared with ATX solution (i. n.) into the rat brain.
Conclusion: This preliminary investigation demonstrates a considerable extent of transport of ATX into the brain through i. n. ATX+PHE-Muco Lipo, which may prove to be a new platform for better management of ADHD.
Keywords: Intranasal delivery, Brain targeting, Mucoadhesive liposomes, Vasoconstrictor, Radiolabeling, Drug targeting efficiency, Direct transport percentage, Gamma scintigraphy.
Downloads
References
Faraone SV, Sergeant J, Gillberg C, Biederman J. The worldwide prevalence of ADHD: is it an American condition? World Psychiatry 2003;2:104.
Madaan V, Kinnan S, Daughton J, Kratochvil CJ. Innovations and recent trends in the treatment of ADHD; 2006.
De Sousa A, Kalra G. Drug therapy of attention-deficit hyperactivity disorder: current trends. Mens Sana Monograph 2012;10:45.
Sauer JM, Ring BJ, Witcher JW. Clinical pharmacokinetics of atomoxetine. Clin Pharmacokinet 2005;44:571-90.
Löscher W, Potschka H. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx 2005;2:86-98.
Elshafeey AH, Bendas ER, Mohamed OH. The intranasal microemulsion of sildenafil citrate: in vitro evaluation and in vivo pharmacokinetic study in rabbits. AAPS PharmSciTech 2009;10:361-7.
Fazil M, Haque S, Kumar M, Baboota S, Sahni JK, Ali J. Development and evaluation of rivastigmine loaded chitosan nanoparticles for brain targeting. Eur J Pharm Sci 2012;47:6-15.
Mahajan HS, Mahajan MS, Nerkar PP, Agrawal A. Nanoemulsion-based intranasal drug delivery system of saquinavir mesylate for brain targeting. Drug Delivery 2014;2:148-54.
Vyas TK, Babbar A, Sharma R, Singh S, Misra A. Intranasal mucoadhesive microemulsions of clonazepam: preliminary studies on brain targeting. J Pharm Sci 2006;95:570-80.
Jogani VV, Shah PJ, Mishra P, Mishra AK, Misra AR. The intranasal mucoadhesive microemulsion of tacrine to improve brain targeting. Alzheimer Dis Assoc Disord 2008;22:116-24.
Haque S, Sahni JK, Ali J, Baboota S. Development and evaluation of brain targeted intranasal alginate nanoparticles for treatment of depression. J Psychiatr Res 2014;48:1-12.
Biju S, Talegaonkar S, Mishra P, Khar R. Vesicular systems: an overview. Indian J Pharm Sci 2006;68:141.
Arumugam K, Subramanian G, Mallayasamy S, Averineni R, Reddy M, Udupa N. A study of rivastigmine liposomes for delivery into the brain through intranasal route. Acta Pharm 2008;58:287-97.
Shinde LR, Jindal BA, Devarajan VP. Microemulsions and nanoemulsions for targeted drug delivery to the brain. Curr Nanosci 2011;7:119-33.
Dhuria SV, Hanson LR, Frey WH. Novel vasoconstrictor formulation to enhance intranasal targeting of neuropeptide therapeutics to the central nervous system. J Pharmacol Exp Ther 2009;328:312-20.
Hathout RM, Mansour S, Mortada ND, Guinedi AS. Liposomes as an ocular delivery system for acetazolamide: in vitro and in vivo studies. AAPS PharmSciTech 2007;8:1-12.
Aher ND, Nair HA. Bilayered films based on novel polymer derivative for improved ocular therapy of gatifloxacin. Sci World J 2014. Doi.org/10.1155/2014/297603. [Article in Press]
Saha GB. Physics and Radiobiology of Nuclear Medicine. Springer; 2010.
Kumar M, Misra A, Mishra A, Mishra P, Pathak K. Mucoadhesive nanoemulsion-based intranasal drug delivery system of olanzapine for brain targeting. J Drug Targeting 2008;16:806-14.
Glavas-Dodov M, Fredro-Kumbaradzi E, Goracinova K, Simonoska M, Calis S, Trajkovic-Jolevska S, et al. The effects of lyophilization on the stability of liposomes containing 5-FU. Int J Pharm 2005;291:79-86.
Caddeo C, TeskaÄ K, Sinico C, Kristl J. Effect of resveratrol incorporated in liposomes on proliferation and UV-B protection of cells. Int J Pharm 2008;363:183-91.
Law S, Huang K, Chou V, Cherng J. Enhancement of nasal absorption of calcitonin loaded in liposomes. J Liposome Res 2001;11:165-74.
Laouini A, Jaafar-Maalej C, Sfar S, Charcosset C, Fessi H. Liposome preparation using a hollow fiber membrane contactor—Application to spironolactone encapsulation. Int J Pharm 2011;415:53-61.
Ugwoke MI, Sam E, Van Den Mooter G, Verbeke N, Kinget R. Nasal mucoadhesive delivery systems of the antiparkinsonian drug, apomorphine: influence of drug-loading on in vitro and in vivo release in rabbits. Int J Pharm 1999;181:125-38.
Charlton ST, Davis SS, Illum L. Evaluation of the effect of ephedrine on the transport of drugs from the nasal cavity to the systemic circulation and the central nervous system. J Drug Targeting 2007;15:370-7.
Järvinen K, Urtti A. Duration and long-term efficacy of phenylephrine-induced reduction in the systemic absorption of ophthalmic timolol in rabbits. J Ocul Pharmacol Ther 1992;8:91-8.
Kyyrönen K, Urtti A. Effects of epinephrine pretreatment and solution pH on the ocular and systemic absorption of ocularly applied timolol in rabbits. J Pharm Sci 1990;79:688-91.
Thakkar HP, Patel AA, Chauhan NP. The intranasal mucoadhesive microemulsion of mirtazapine: pharmacokinetic and pharmacodynamic studies. Asian J Pharm 2013;7:36.
Patel MR, Patel RB, Bhatt KK, Patel BG, Gaikwad RV. Paliperidone microemulsion for nose-to-brain targeted drug delivery system: a pharmacodynamic and pharmacokinetic evaluation. Drug Delivery 2016;23:346-54.
Vyas TK, Babbar A, Sharma R, Misra A. Intranasal mucoadhesive microemulsions of zolmitriptan: preliminary studies on brain-targeting. J Drug Targeting 2005;13:317-24.
Patel S, Chauhan S, Soni H, Babbar A, Mathur R, Mishra A, et al. Brain targeting of risperidone-loaded solid lipid nanoparticles by the intranasal route. J Drug Targeting 2011;19:468-74.