Abstract

Nanoparticles (NPs) offer noteworthy advantages in the treatment of several diseases by prompting, among other benefits, the site-specific delivery of drugs. Ultra-small nanostructured lipid carriers (usNLCs) are no exception. These correspond to a class of NPs composed of a blend of solid and liquid lipids, the latter usually in a higher proportion, which promotes a less ordered solid lipid matrix, providing a higher drug loading capacity, drug release modulation, and improved stability in comparison with other lipid nanoparticles. Several manufacturing methods have been described for obtaining usNLCs. However, a comprehensive understanding of the process is imperative to warrant the final quality of the NPs. In the present work, the hot high pressure homogenization (HPH) method, which is characterized by easy scaling-up, simplicity and ease of use, was used for the development of highly concentrated small size NLCs. Critical process parameters (CPPs) and critical material attributes (CMAs) were evaluated to investigate the manufacturing process reproducibility, inter-batch consistency, long-term formulation stability, drug loading capacity and drug release. To gain a broader understanding of this method, multivariate analysis was applied to investigate how the physicochemical properties of the usNLC are affected by the variation in CPPs/CMAs. CPPs include HPH-time, and HPH-pressure, while CMAs, such as lipid content, are also taken into consideration. The results show that a high lipid content (15% w/w), an intermediate pressure and a short HPH time seem to be the crucial parameters to obtain both a small particle size (<100 nm) and a narrow size distribution (polydispersity index <0.2) in usNLC prepared by the hot-HPH method, without affecting zeta potential (>|30| mV).

Highlights

  • Multivariate analysis is a practical approach to evaluate the influence of the independent variables (CPPs and critical material attributes (CMAs), High-pressure homogenization (HPH) pressure and time, and lipid content, respectively) on the dependent variables (CQAs)

  • The ideal particle size (PS), particle distribution (PI), and ZP of Ultra-small nanostructured lipid carriers (usNLCs) were observed to be as low as possible PS and PI, and higher than |30| mV for zeta potential, along with the highest lipid content (Table 2)

  • Multivariate analyses were applied to infer about the critical parameters influencing the physicochemical characteristics, such as PS, PI, and ZP, of the usNLC formulated by the hot high-pressure homogenization (hot-HPH) method

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Summary

Introduction

Following the principles of Quality by Design (QbD) facilitate the understanding of the relationship between material attributes and process parameters [1,2,3]. QbD is a systematic approach to development, based on prior knowledge and the quality risk management of the formulation components and the production method, ensuring the final product quality. In this way, QbD has been applied to the development of nanoparticles (NPs) with the aim of simplifying the manufacturing process and saving costs by implementing the quality specifications of the final product, as part of an overall control strategy

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