Lipid nanoparticles for topical delivery: solid lipid nanoparticles (SLN) & smartLipids

Abstract

1. Lipid-drug-conjugate (LDC) solid lipid nanoparticles (SLN®) for the delivery of nicotine to the oral cavity – optimization of nicotine loading efficiency.

Nicotine lipid-drug-conjugates (LDC) were prepared by mixing nicotine with a fatty acid (Kolliwax® S or stearic acid). Hydrogenated sunflower oil (HSO) combined with the LDC were used as the lipid matrix in the LDC-containing SLN® system, whereas non-LDC SLN® were produced as a reference using HSO and pure nicotine. Both LDC-containing SLN® and non-LDC SLN® were successfully produced using a hot high-pressure homogenization method. Following production, photon correlation spectroscopy (PCS) confirmed all formulations were in the submicron size range (150 to 350 nm diameter) with narrow size distributions (PDI around 0.25). The laser diffractometry (LD) results showed 90% of the particles had a diameter lower than 1,000 nm. Light microscopy images show no aggregation of the particles, which is good agreement with the LD result. Differential scanning calorimetry (DSC) was used to investigate the thermal behavior of the system, and showed the thermal response of the four formulations was dominated by the HSO. The onset temperature of the melting process (> 39 °C) was higher than mouth temperature (37 °C), showing good applicability for buccal delivery. The nicotine-loaded particles could be successfully separated from the water phase using Amicon® Ultra-4 centrifugal filter devices, and the encapsulation efficiency of nicotine in LDC-containing SLN® was about 50% w/w. This is an almost fivefold increase compared to the conventional nicotine loaded SLN® (around 10% w/w). The high degree of encapsulation makes the LDC-containing SLN® a promising system for buccal delivery of nicotine with low side effects, and incorporating the SLN® into nicotine chewing gum or lozenges has the potential to be an innovative nicotine replacement therapy.

2. smartLipids® as third solid lipid nanoparticle generation – stabilization of retinol for dermal application.

Following a screening of several stabilizers, Tween® 20 proved most suitable for smartLipids® production. smartLipids® were successfully produced by a hot high-pressure homogenization method, and loaded with different amounts of retinol (5%, 15%, 20% w/w). The mean diameter of smartLipids® formulations was about 200 nm, and remained unchanged during a storage period of two months as determined by PCS. DSC results showed an absence of polymorphic transitions, an indication of good physical stability. Furthermore, the onset temperatures of melting peaks were above 38 °C, ensuring the particles maintain their solid state during the skin penetration process (skin temperature is 32 °C). Results showed that after 60 days of storage, 37%, 59% and 75% w/w of retinol remained in the particle suspensions loaded with 5%, 15% and 20% retinol, respectively. Thus, the degradation of loaded retinol was reduced significantly by incorporating it into smartLipids® when compared to other studies. Since the loading capacity was superior to other studies as well, two major advantages characteristic for smartLipids®¬ were combined. Dispersing the smartLipids® suspension into a gel base as a dermal formulation did not change the particle size, and the same chemical stability was observed as for the lipid nanoparticle suspension. Thus, the concept of smartLipids® worked efficiently for retinol, improving not only the encapsulation efficiency but also physical and chemical stability, as well as showing good performance in a gel base.

3. The influencing factors of producing stable smartLipids®: lipids, surfactants and production parameters.

Although smartLipids® provide a more universal delivery approach owing to the possibility of stabilizing a wide spectrum of different actives, the stability of the lipid nanoparticle suspensions strongly depends on a variety of influencing factors, and developing stable formulations is generally a resource- and time-intensive process. This study investigated in more detail the influences of the lipid compositions, the type and concentration of the surfactants and the production parameters on the stability. Most of the produced formulations instantly gelated after production, or showed macroscopic particle growth. The investigated lipid composition 2 and 4 - combinations of low melting range lipids - showed nano-ranged particle sizes, narrow particle size distributions and were stable for 180 days. The addition of a liquid lipid increased the stability in lipid composition 2, 3 and 4, due to the enhanced miscibility of the lipid matrix. Formulations stabilized by surfactants with a high hydrophilic-lipophilic balance (HLB) showed better physical stability. On the contrary, increasing the concentration of surfactants did not successfully suppress aggregation when surfactants with a lower HLB value are used, likely owing to increased Ostwald ripening. Furthermore, the zeta potential value did not reliably predict the long-term stability of smartLipids®. Both stable lipid nanoparticle suspensions with low zeta potential were encountered as well as unstable formulations with a high zeta potential were encountered, showing that steric effects are important. Additionally, the most stable formulations were achieved by performing only 1 or 2 homogenization cycles.

4. Solid lipid nanoparticles (SLN®) for the delivery of α-tocopherol – an efficient method for improving the drug loading capability.

Solid lipid nanoparticle suspensions loaded with 5% and 10% α-tocopherol (w/w) were successfully developed. The mean particle sizes of these lipid nanoparticle suspensions remained in the nano-range following production, and their size distributions narrowed with an increasing number of homogenization cycles. After storing all suspensions at room temperature for 7 days, the SLN® suspensions produced with carnauba wax did not remain stable, except for the formulation produced with 10% α-tocopherol and 3 homogenization cycles. On the contrary, all SLN® suspensions produced with cetyl palmitate showed great physical stability. Zeta potential values of the produced lipid nanoparticle suspensions measured in original medium were higher than |40 mV|, and in conductivity water were higher than |60 mV|, a sign of potentially good physical stability. The thermal analysis of SLN® suspensions showed very weak peaks in 10% α-tocopherol-loaded SLN® produced with cetyl palmitate, indicative of an only slightly ordered matrix. Therefore, 10% α-tocopherol-loaded SLN® produced with carnauba wax and 3 homogenization cycles were recommended for further practical usage. Furthermore, the onset of the melting behavior of this SLN® suspension occurs above skin temperature, making it suitable for dermal application. Using carnauba wax and producing the formulation with 3 homogenization cycles, the loading of α-tocopherol could be increased to 10% w/w. Aside from increased drug loading, this formulation has a suitable particle size, narrow size distribution, good physical stability as well as a desirable thermal profile, making it highly promising for dermal application.