Formulation and In-vivo Pharmacokinetic Consideration of Intranasal Microemulsion and Mucoadhesive Microemulsion of Rivastigmine for Brain Targeting
Presence of tight junctions in blood brain barrier (BBB) pose a major hurdle for delivery of drug and severely affects adequate therapeutic concentration to reach the brain. In present work, we have selected Rivastigmine hydrogen tartrate (RHT), a reversible cholinesterase inhibitor, which exhibits extensive first-pass metabolism, resulting in limited absolute bioavailability (36%). RHT shows extremely low aqueous solubility and poor penetration, resulting in inadequate concentration reaching the brain, thus necessitating frequent oral dosing. To overcome these problems of RHT, microemulsion (ME) and mucoadhesive microemulsion (MME) of RHT were formulated for brain targeting via intranasal delivery route and compared on the basis of in vivo pharmacokinetics.
ME and MME formulations containing RHT were developed by water titration method. Characterization of ME and MME was done for various physicochemical parameters, nasal spray pattern, and in vivo pharmacokinetics quantitatively and qualitatively (gamma scintigraphy studies).
The developed ME and MME were transparent having globule size approximately in the range of 53–55 nm. Pharmacokinetic studies showed higher values for Cmax and DTP for intranasal RHT: CH-ME over RHT-ME, thus indicating the effect of chitosan in modulating tight junctions, thereby enhanced paracellular transport of RHT.
Gamma scintigraphy and in vivo pharmacokinetic study suggested enhanced RHT concentration, upon intranasal administration of RHT:CH-ME, compare with other groups administered formulations intranasally. These findings suggested the potential of non-invasive intranasal route for brain delivery, especially for therapeutics, facing challenges in oral administration.
KEY WORDSalzheimer’s disease brain targeting intranasal route microemulsion rivastigmine
Blood brain barrier
Cetyl trimethyl ammonium bromide
Drug targeting efficiency
Direct transport percentage
Rivastigmine hydrogen tartrate
World health organization
Acknowledgments and Disclosures
Authors are grateful to B.V. Patel PERD Centre for providing research facilities. Brijesh Shah is thankful to Lady Tata Memorial Trust (Bombay, India) for providing financial assistance. The project was also partially funded by Department of Science and Technology (Grant No. - IFA-LSBM-13, Delhi, India) and Industries commissionerate (Govt. of Gujarat). Authors would like to acknowledge, head of the Dept. of Pharmacology and Toxicology at B.V. Patel PERD Centre, Ahmedabad for providing animal facilities. Authors would like to express their gratitude to Dr. Seamus Murphy (Manger-Imaging division, Oxford lasers Ltd., UK) and Mr. Jitendra Nadgeer (Product Manager, Inkarp Instruments, India) for their help in nasal spray pattern studies. The authors have no conflict of interest. The contents of the manuscript and its drafting is solely done by the authors.
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