Nanostructured lipid carrier (NLC) coated with Chitosan Oligosaccharides and its potential use in ocular drug delivery system

Abstract

The objective of the present investigation was to explore the potential of the Chitosan Oligosaccharides (COS)-coated NLC (nanostructured lipid carrier) for ocular drug delivery. NLC loaded with flurbiprofen was prepared by melt-ultrasonic method and then coated with COS with a molecular weight of 3000–6000 kDa. After coating, the particles reflected spherical morphology with smooth surface under transmission electron microscope (TEM) analysis and a changed zeta potential from −0.446 mV to +20.7 mV. The ocular bioadhesion property was evaluated by Gamma scintigraphic technique, revealing that the clearance of the formulations labeled with radioactive 99^mTc-DTPA was significantly delayed in the presence of COS, and the AUC of the COS-coated formulation had a 7.7-fold increase comparing with non-coated ones. Additionally, enhanced transcorneal penetration was achieved by using the COS coating with a corresponding apparent permeability coefficients (P_app) which had a 2.4-fold increase comparing with the reference. Consequently, COS coating modified the properties of NLCs and presented a series of notable advantages in ophthalmic application.

Introduction

Pharmaceutical preparations are applied topically to eyes to treat surface or intraocular conditions. Since the capacity of the eye can only retain a limited volume, excessive liquids, both normally produced and externally delivered, rapidly drain from the eye. Therefore, topical drug administration is restricted in small amount. On the other hand, due to the dynamics of the lacrimal system, the retention time of an ophthalmic solution on the eye surface is short, and the amount of drug absorbed is usually only a small fraction of the quantity administered. In addition, corneal and conjunctival epithelia of human eye, along with the tear film, construct a compact barrier preventing the drug absorption into the intraocular area (Li et al., 2009). This mechanism removes the exogenous substances involving entraps debris, microorganisms, and even drugs from the ocular surface, assisted by frequent blinking. These are the dominating reasons that many drugs have the difficulty in penetrating the ocular barrier and reaching the target tissues. Therefore, in clinical use of eye drops, frequent instillations are often required to get the expected therapeutic efficacy, which may lead to inconvenience and other system side effects through nasolacrimal absorption as well.

In recent years, studies on novel ocular drug delivery systems have been reported, such as in situ gel, microemulsion, microspheres, liposomes and solid lipid nanoparticles (SLN) (Qi et al., 2007, Chan et al., 2007, Gavini et al., 2004, Cavalli et al., 2002) all of which aim to prolong the pre-ocular retention and promote the absorption of the drug. As the second generation deriving from SLN (Müller et al., 2002a, Müller et al., 2002b), nanostructured lipid carriers (NLC) based on mixture of solid lipids with spatially incompatible liquid lipids (Müller et al., 2002a, Müller et al., 2002b) combines many features for application of pharmaceutics, i.e. controlled release of actives, drug targeting, and increasing the amount of drug penetrating into mucosa. On account of the physiological and/or biodegradable lipids, this carrier system also exhibits an excellent tolerability. Nevertheless, efforts are still needed to improve the drug delivery efficiency, especially, aiming to prolong the retention time of drug on the corneal surface to some extent.

Chitosan Oligosaccharides (COS), obtained through the decomposition of Chitosan, is a cationic polymer of low molecular weight. Unlike Polysaccharides Chitin and Chitosan, which are not water-soluble and therefore have some limitation in the use of pharmaceutics, high water solubility of COS makes it suitable for pharmaceutical application which is correlated to its structure and unique biological activities including favorable biocompatibility and mucoadhesiveness, in addition, its special property of antimicrobial (Xia et al., 2010) is also taken into consideration in ophthalmic application.

It is reported that cationic polymers were probably admirable mucoadhesive materials due to an ability to develop molecular attraction forces by electrostatic interactions with the negative charge of the mucus (Ludwig, 2005). Taking this into account, the polycationic COS has been investigated as an ophthalmic vehicle and its superiority was extensively studied in drug delivery. The linking of COS which has a molecular weight of 3000–6000 kDa with the surface of the nanoparticles would presumably modify the action of NLC and ameliorate its efficiency in ocular drug delivery.