Synthesizing porous nanospheres with highly efficient drug loading and sustained release through a thermal-controlled continuous stirred-tank reactor cascade

Abstract

Nanospheres hold great promise for drug delivery but face challenges in achieving both high drug loading and sustained release. Here, we present a novel approach to produce porous cyclosporin A-loaded poly(lactic-co-glycolic acid) (PLGA) nanospheres via a thermal-controlled continuous stirred-tank reactor (CSTR) cascade, featuring rapid solidification of nanoemulsion droplets. This process traps more drug molecules in the nanosphere core by limiting their diffusion towards the surface and surrounding medium, resulting in a core-loaded structure. The resulting PLGA nanospheres exhibit a high cyclosporin A loading capacity and enable sustained drug release through the hydrolytic degradation of the PLGA matrix. Moreover, the total synthesis time is reduced from several hours to 40 min. The CSTR assisted manufacturing approach offers an efficient route for engineering nanospheres with high drug payloads and improved release kinetics, with broad potential for nanomedicine manufacturing.

Introduction

Drug-loaded nanospheres represent a powerful strategy for delivering active pharmaceutical ingredients using inert nanoscale carriers. These nanospheres can protect drug molecules from degradation and promote their transport across biological barriers to reach a target site.1–4 The inert materials, such as biodegradable polymers, enable sustained drug release, thus allowing for tailored pharmacokinetic properties and reducing the need for repeated dosing.5,6 Moreover, increasing the drug load per nanosphere allows higher doses per injection, improving patient compliance and minimizing excipient-related side effects.7–9 For many treatments, achieving a high therapeutic mass fraction is a prerequisite due to strict volume limits on injectable formulations (0.1 mL intradermal, 1 mL subcutaneous, and 1–3 mL intramuscular).10 These constraints make the development of nanospheres with high drug content critically important.

Engineering high drug-loaded nanospheres is challenging due to inherent limitations arising from their high surface-to-volume ratio. Drugs positioned on the particle surface are susceptible to loss during the formulation and post-formulation processes.11–13 Nanospheres are primarily composed of non-therapeutic scaffold polymers, such as poly(lactic-co-glycolic acid) (PLGA). Drug loadings in most reported studies are lower than 4%; some are even substantially below 1%.11,14–27 Various strategies have been developed to improve drug loading efficiency through strengthening drug–carrier interactions, such as donor–receptor coordination and covalent conjugation.28–31 However, these approaches are limited, as they require both the drug and carrier molecules to have specific structural and chemical properties.

Encapsulating a larger fraction of drug molecules within the nanosphere core, rather than leaving a significant portion on the surface, helps overcome surface-to-volume ratio constraints and enhances overall drug loading. This strategy eliminates the dependence on specific molecular features of the drug and carrier. A core-loaded nanosphere structure not only increases the total drug content but also offers better control over the drug release. Drug release from nanospheres occurs in two phases: an initial burst release caused by the rapid diffusion of surface-located drugs, followed by a more sustained release through the hydrolytic degradation of the PLGA matrix.32–34 By increasing the amount of drug loaded in the core, the initial burst release and resulting toxicity risks can be reduced, leading to a more sustained and prolonged release profile. Nanospheres could be formed from nanoemulsion droplets as the organic solvent evaporates (Fig. 1c), leading us to reasonably hypothesize that the solvent removal process would play a critical role in determining the solidification of drug and polymer molecules. By optimizing this process, it may be possible to fabricate core-loaded nanospheres with high drug loading and improved release kinetics.

For continuous nanosphere synthesis, microfluidic nanoprecipitation is used in many studies.6,35–38 Although this technique can produce ultra-small nanospheres ranging from 20 to 100 nm, it struggles with a low drug loading capacity (<4%).14,39–41 Increasing the particle size can improve drug loading, but it will compromise the ability to cross biological barriers. This hinders particular applications like brain-targeted delivery, which requires particles to be below 100 nm to cross the blood–brain barrier.42–44 Furthermore, the small channel sizes required for rapid mixing in microfluidics can lead to issues like low throughput and microchannel clogging.45–47

Another commonly used synthesis method is emulsion-solvent evaporation. In 2007, Budhian et al.20 attempted to increase drug loading by adjusting the pH during solvent evaporation to reduce drug diffusion into the aqueous phase. However, they achieved a maximum drug loading of 2.5%. In 2016, de Solorzano et al.48 used microchannel emulsification for high-throughput synthesis (∼10 g h−1) of cyclosporin A-loaded PLGA nanospheres. However, the resulting particles had a mean size far exceeding 200 nm. Recently, Operti et al.49 introduced an inline sonicator for continuous emulsification, but the solvent evaporation was performed in a batch mode with dilution and stirring for 1 hour, and the smallest mean particle size achieved was 184.7 nm. To conclude, the synthesis of drug-loaded PLGA nanospheres through emulsion-solvent evaporation has not been fully transitioned to a continuous process. Achieving a mean particle size under 100 nm remains challenging, and the impact of solvent evaporation temperature on drug encapsulation was largely overlooked in previous studies.

In this work, we control the solvent removal process using a continuous stirred-tank reactor (CSTR) cascade (Fig. 1b), which provides thermal regulation, to solidify the drug and polymer molecules. This approach contrasts with previous studies,48–51 where solvent removal was performed in batch mode and remained largely unoptimized. This continuous manufacturing strategy eliminates batch-to-batch variations and provides a well-defined scale-up pathway,52,53 addressing two major challenges in the industrialization of nanomedicines.54–58 To validate our approach, cyclosporin A (CyA) is selected as a model peptide drug due to its poor water solubility and limited bioavailability (class II from the Biopharmaceutical Classification System, BCS). The solvent removal step is systematically optimized, and its impact on particle size distribution, morphology, and drug loading efficiency of cyclosporin A-loaded PLGA nanospheres (CyA-PLGA NPs) is assessed. Furthermore, in vitro drug release studies are conducted to evaluate the sustained release profile. Process efficiency and residual solvent content are also analysed to ensure the robustness and scalability of the developed method.

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Huiyu Chen, Aniket Pradip Udepurkar, Christian Clasen, Victor Sebastián Cabeza and Simon Kuhn, Synthesizing porous nanospheres with highly efficient drug loading and sustained release through a thermal-controlled continuous stirred-tank reactor cascade, from the journal: Nanoscale Advances, https://doi.org/10.1039/D5NA00897B