Review
Potential of solid lipid nanoparticles in brain targeting

https://doi.org/10.1016/j.jconrel.2007.12.018Get rights and content

Abstract

Brain is a delicate organ, isolated from general circulation and characterized by the presence of relatively impermeable endothelial cells with tight junctions, enzymatic activity and the presence of active efflux transporter mechanisms (like P-gp efflux). These formidable obstacles often impede drug delivery to the brain. As a result several promising molecules (showing a good potential in in vitro evaluation) are lost from the market for a mere consequence of lack of in vivo response probably because the molecule cannot reach the brain in a sufficient concentration. The options to tailor make molecules for brain, though open to the medical chemist, are a costly proposition in terms of money, manpower and time (almost 50 years). The premedial existing approaches for brain delivery like superficial and ventricular application of chemical or the application of chemicals to brain parenchyma are invasive and hence are less patient friendly, more laborious and require skill and could also damage the brain permanently. In view of these considerations novel drug delivery systems such as the nanoparticles are presently being explored for their suitability for targeted brain delivery.

Nanoparticles are solid colloidal particles ranging in size from 1 to 1000 nm (< 1 µm) and composed of macromolecular material. Nanoparticles could be polymeric or lipidic (SLNs). SLNs are taken up readily by the brain because of their lipidic nature. The bioacceptable and biodegradable nature of SLNs makes them less toxic as compared to polymeric nanoparticles. Supplemented with small size which prolongs the circulation time in blood, feasible scale up for large scale production and absence of burst effect makes them interesting candidates for study.

In the present review we will discuss about the barriers to CNS drug delivery, strategies to bypass the blood–brain barrier and characterization methods of SLNs and their usefulness. The proposed mechanism of uptake, methods of prolonging the plasma retention and the in vivo and in vitro methods for assessment will also be discussed in some details.

Introduction

Delivery of drugs to the brain is a major challenge due to the presence of the blood–brain barrier. Successful delivery across the blood–brain barrier (BBB) has only been achieved in some cases, e.g. through the use of prodrugs. To reach therapeutic drug level in the brain, nanoparticulate systems as drug carriers with sufficiently high loading capacity and small particle size, which can bypass the Reticulo Endothelial System (RES system), are being looked into as suitable delivery systems [1], [2], [3], [4].

Considering the success of these nanoparticles to pass through the BBB and their limitation(s) especially with respect to toxicity and stability, another suitable option for drug delivery into the brain is solid lipid nanoparticles (SLNs). These consist of spherical solid lipid particles in the nanometer range, which are dispersed in water or in aqueous surfactant solution. They have thus a potential to carry lipophilic or hydrophilic drug(s) or diagnostics [5], [6], [7].

Section snippets

Blood–brain barrier (BBB)

The blood–brain barrier (BBB) is the specialized system of capillary endothelial cells that protects the brain from harmful substances in the blood stream, while supplying the brain with the required nutrients for proper function. Unlike peripheral capillaries that allow relatively free exchange of substances across/between cells, the BBB strictly limits transport into the brain through both physical (tight junctions) and metabolic (enzymes) barriers [3]. Thus the BBB is often the rate-limiting

Novel drug delivery system approach

Two main reasons for the failure of drug delivery to the brain are:

  • 1)

    Poor penetration of the drug molecule across the BBB.

  • 2)

    Back transport (efflux) of drugs from the brain to the blood.

Various colloidal delivery systems have been tried upon by different researchers to overcome, especially the first aspect. These systems include liposomes, microspheres, lipid microspheres, niosomes, nanoparticles, and solid lipid nanoparticles (SLNs) [24], [25], [26], [27], [28], [29].

For a delivery system to be

Analytical methods for characterization

In order to develop a drug product of high quality, a precise physicochemical characterization of the SLNs is necessary. The size of the nanoparticles is the most important feature; however other parameters such as density, molecular weight, and crystallinity influence the nanoparticle release and degradation properties. The in vivo fate vis-à-vis body distribution and interaction with the body environment are however influenced by surface charge, hydrophilicity, and hydrophobicity etc [46].

Dialysis tubing

In vitro drug release could be achieved using dialysis tubing. The solid lipid nanoparticle dispersion is placed in a prewashed dialysis tubing which can be hermetically sealed. The dialysis sac is then dialyzed against a suitable dissolution medium at room temperature, the samples are withdrawn from the dissolution medium at suitable intervals, centrifuged and analyzed for drug content using a suitable analytical method (U.V. spectroscopy, HPLC etc) [5], [57]. The maintenance of sink

Conclusions

SLN delivery can be an innovative way to administer molecules into the brain by possibly overcoming or alleviating the solubility, permeability and toxicity problems associated with the respective drug molecules. This will have an advantage over the conventional invasive methods of drug delivery to the brain. High physical stability of these systems is another advantage. The number of products based on polymeric micro or nanoparticles on the market is limited mainly because of the cytotoxicity

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