Optimization of Curcumin Nanocrystals as Promising Strategy for Nose-to-Brain Delivery Application.

Angela Bonaccorso,Teresa Musumeci,Giovanni Puglisi,Claudia Carbone,Maria Rosa Gigliobianco,Piera Di Martino,Debora Santonocito,Rosalia Pellitteri

doi:10.3390/pharmaceutics12050476

Abstract

Intranasal (IN) drug delivery is recognized to be an innovative strategy to deliver drugs to the Central Nervous System. One of the main limitations of IN dosing is the low volume of drug that can be administered. Accordingly, two requirements are necessary: the drug should be active at a low dosage, and the drug solubility in water must be high enough to accommodate the required dose. Drug nanocrystals may overcome these limitations; thus, curcumin was selected as a model drug to prepare nanocrystals for potential IN administration. With this aim, we designed curcumin nanocrystals (NCs) by using Box Behnken design. A total of 51 formulations were prepared by the sonoprecipitation method. Once we assessed the influence of the independent variables on nanocrystals’ mean diameter, the formulation was optimized based on the desirability function. The optimized formulation was characterized from a physico-chemical point of view to evaluate the mean size, zeta potential, polidispersity index, pH, osmolarity, morphology, thermotropic behavior and the degree of crystallinity. Finally, the cellular uptake of curcumin and curcumin NCs was evaluated on Olfactory Ensheathing Cells (OECs). Our results showed that the OECs efficiently took up the NCs compared to the free curcumin, showing that NCs can ameliorate drug permeability.

Highlights

Intranasal (IN) drug delivery is known to be a convenient and alternative route to oral and parenteral delivery
Curcumin NCs were prepared by the sonoprecipitation method, a simple technique which combines precipitation and sonication
After a comparison between NCs prepared by using a bath sonicator and a probe sonicator, we selected the probe sonicator because it allowed us to recover smaller and more homogenous NCs; this is possible because the probe sonicator is in direct contact with the sample, it vibrates rapidly and thereby can transfer its ultrasonic power with massive amounts of energy instead of spread energy diffusely

Summary

Introduction

Intranasal (IN) drug delivery is known to be a convenient and alternative route to oral and parenteral delivery. The trigeminal nerve innervates the respiratory and olfactory epithelium of the nasal cavity, enters the CNS in the pons, and a small portion of the trigeminal nerve terminates in the olfactory bulb This pathway plays a key role in the distribution of intranasally administered drugs to the caudal brain regions and the spinal cord. Part of the trigeminal neural pathway enters the brain through the cribriform plate alongside the olfactory pathway, it is difficult to distinguish whether intranasally administered drugs reach the olfactory bulb and other rostral brain areas via the olfactory or trigeminal pathways or if both are involved [8] In addition to these direct pathways, transport may occur via blood vasculature, lymphatics, and cerebrospinal fluid present in the nasal mucosa tissue which is highly vascularized. Many problems may arise with systemic delivery due to drug elimination via hepatic and renal mechanisms, and some other limiting factors such as the BBB, drug binding to plasma proteins, degradation by plasma proteases, and potential peripheral side effects [9]

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