Encapsulation of ascorbyl palmitate in nanostructured lipid carriers (NLC)—Effects of formulation parameters on physicochemical stability

Abstract

Enhancement of the chemical stability of ascorbyl palmitate (AP) after incorporation into nanostructured lipid carriers (NLC) has been reported. However, the formulation parameters of AP-loaded NLC have not been completely investigated. Moreover, the long-term chemical stability of AP in any colloidal systems has not been yet achieved. Therefore, in this study the formulation parameters affecting the stability of AP after incorporation into NLC were evaluated including types of lipids, types of surfactants, storage conditions, i.e. temperature and nitrogen gas flushing, the effects of drug loading as well as types of antioxidants. After storage for 90 days, the mean particle size analyzed by photon correlation spectroscopy (PCS) was lower than 350 nm. The zeta potential measured by the Zetasizer IV was higher than −30 mV in all developed AP-loaded NLC formulations which varied according to the types of lipid and surfactant. Concerning the chemical stability of AP, it was found that AP-loaded NLC prepared and stored in non-degassing conditions, a higher percentage of AP loading in NLC, lower storage temperature (4 °C), addition of antioxidants as well as selection of suitable surfactants and solid lipids improved the chemical stability of AP. Moreover, an improvement of long-term chemical stability of AP was achieved by addition of antioxidants with nitrogen gas flushing as compared to those without antioxidant. The percentage of drug remaining at both 4 °C and room temperature (25 °C) was higher than 85% during 90 days of storage.

Introduction

In recent years, nanotechnology has been intensively studied in many fields such as computer, engineering, electronic as well as pharmaceutical technology. In the pharmaceutical field, several advantages of drug delivery systems with nanosize range have been shown including increasing solubility, enhancing dissolution rate and improving bioavailability (Müller et al., 2000). Nanoparticles can be prepared using different kinds of materials, for example, biodegradable and biocompatible polymers, phospholipids, surfactants and lipids (Müller et al., 2000, Müller et al., 2002b).

Several advantages of nanoparticles prepared from lipid materials have been demonstrated including biocompatibility, drug targeting, modified release, lack of organic solvent during the production process and ease of large scale production (Mehnert and Mäder, 2001, Müller et al., 2000). Moreover, lipid nanoparticles have been intensively studied in various pharmaceutical applications, i.e. parenteral, peroral, dermal, ocular, and pulmonary administrations (Mehnert and Mäder, 2001, Müller et al., 1997, Müller et al., 2000, Pandey et al., 2005, Schwarz and Mehnert, 1997, Sivaramakrishnan et al., 2004, Cavalli et al., 2002). However, it has been reported that the physical state of lipid particles plays a major role in increasing stability of active compound after incorporation into lipid nanoparticles especially solid state lipids. This is due to the fact that the liquid state of colloidal system allows the active ingredients to partition between dispersed and continuous phase (Dingler et al., 1996). This leads to the instability of the active ingredient in the continuous phase during storage times. Therefore, lipid nanoparticles with solid dispersion phase have been introduced as alternative colloidal carriers and referred to as solid lipid nanoparticles (SLN). Since the last decade, they have been studied intensively both in pharmaceutical and cosmetic areas because they can be prepared using a simple method, i.e. high pressure homogenization (HPH), which is a simple technique commonly used in food and pharmaceutical industries. Nevertheless, SLN also possess some limitations, i.e. low drug payload and possibility of drug expulsion because of change of the lipid modification during the storage times (Mehnert and Mäder, 2001). As a result, the concept of less ordered inner structure has been introduced, namely nanostructured lipid carriers (NLC). NLC can be prepared either by blending any solid and liquid lipids or by mixing special combinations of solid and liquid lipids leading to amorphous solids, i.e. hydroxyoctacosanylhydroxystearate and isopropylmyristate (Müller et al., 2002a, Müller et al., 2002b). With regard to these features, high drug payload, avoidance or minimization of drug expulsion and enhancement of chemical stability can be achieved. Therefore, NLC have been represented as a new generation of promising colloidal carriers.

Due to the current ozone layer depletion in the atmosphere, radiation from the sun especially UVA and UVB can reach the earth in a higher amount. Consequently, the radiation can easily expose to skin leading to unwanted and harmful stresses on skin, i.e. skin cancer, wrinkle, dryness and mottled pigment abnormalities. These occur owing to photochemical reaction on the skin as a result of the oxidation reactions. However, the human body has a defense mechanism by producing naturally enzymes and non-enzymatic antioxidants (Hoppe et al., 1999, Kristl et al., 2003, Üner et al., 2005b). Nonetheless, in some situation the antioxidants produced by the body are inadequate. It can be supplemented by oral and/or topical administrations of antioxidants. In the cosmetic field, ascorbic acid has been widely used as an antioxidant for several years. However, due to its stability problem, ascorbyl palmiatate (AP), an ascorbic acid derivative, has been used as an alternative source of ascorbic acid. Its structure is an amphiphilic molecule which is chemically more stable and can penetrate into the skin more easily as compared to its acidic form. However, the chemical stability problem of AP has been demonstrated in many topical preparations (Špiclin et al., 2001, Špiclin et al., 2003, Kristl et al., 2003, Üner et al., 2005b). In previous reports, sensitive molecules such as retinols (Jenning and Gohla, 2001), ketoconazole (Souto and Müller, 2005) and AP (Üner et al., 2005b) had been successfully incorporated into NLC and the chemical stability was enhanced. Moreover, the enhancement of skin moisturizing of AP-loaded SLN and NLC was higher than that of AP-loaded NE (Üner et al., 2005a). Likewise, sustained release of AP through excised human skin was shown for AP-loaded SLN and NLC in comparison to AP-loaded NE (Üner et al., 2005a). Accordingly, AP-loaded NLC is a promising system in cosmetic use. However, the optimum conditions of AP-loaded NLC have not been reported yet. Therefore, in this study the formulation parameters affecting the stability of AP after incorporation into NLC were evaluated including different types of lipids, types of surfactants, storage conditions, i.e. temperature and nitrogen gas flushing, effects of drug loading as well as types of antioxidants. The investigated parameters in terms of particle size, zeta potential, lipid modification and chemical stability were evaluated.