Core-shell aerogel design for enhanced oral insulin delivery

Introduction

Insulin, a critical hormone responsible for regulating blood glucose levels, has long been administered via subcutaneous injections. However, the current standard of subcutaneous insulin injection (Alam et al., 2024) has been a source of distress and discomfort for many patients, highlighting the need for alternative delivery methods like oral and intranasal administration routes (Bashir et al., 2023). Namely, oral insulin delivery offers the potential to mimic the physiological insulin secretion patterns, improve patient compliance, and reduce the risk of hypoglycemia associated with injectable formulations (Arbit and Kidron, 2017, Khodaei et al., 2020).

Despite its potential, oral insulin delivery faces significant obstacles, primarily enzymatic degradation within the gastrointestinal tract and limited absorption across the intestinal epithelium (Cikrikci et al., 2018). To address these challenges, nanocarriers such as lipid-based and polymeric nanoparticles, can enhance the oral bioavailability of insulin (Iyer et al., 2022, Limenh, 2024, Zhang et al., 2021). Lipid nanocarriers, such as nanoemulsions and self-nanoemulsifying drug delivery systems (SNEDDS), can improve the permeability and stability of insulin, leading to increased intestinal absorption and reduced enzymatic degradation (Siram et al., 2019). Additionally, strategies like PEGylation and lipidization were employed to further enhance the oral delivery of insulin and GLP-1 receptor agonists (Poudwal et al., 2021). In another approach, polymeric nanoparticles can be designed to target specific transcytosis pathways in the intestinal epithelium, facilitating the transport of insulin and other therapeutic agents across the gastrointestinal barrier and into the systemic circulation (Zhang et al., 2021).

Aerogel carriers are herein regarded as an alternative for the oral delivery of insulin. Aerogels are highly porous, lightweight materials with a high surface area, making them suitable for drug encapsulation and controlled release (García-González et al., 2011, Illanes-Bordomás et al., 2023). Compared to traditional silica-based aerogels, polysaccharide-based aerogels can offer improved mechanical properties and enhanced biological functionality. The typical process for producing aerogels from polysaccharides includes producing a hydrogel, a solvent exchange (typically to ethanol), and the subsequent drying of the gel using supercritical carbon dioxide (sc-CO2). Sc-CO2 drying is a crucial step, as it allows for the removal of the liquid phase from the gel structure without causing significant shrinkage or density increase, resulting in the preservation of the high porosity and a low density in the final aerogel (Ajdary et al., 2021). In this context, polysaccharide-based aerogels have emerged as a promising platform for the oral delivery of drugs, including insulin (Abdul Khalil et al., 2023, García-González et al., 2021, García-González et al., 2015). In the case of aerogels for insulin oral delivery, chitosan and alginate aerogels possess mucoadhesive properties (Amin and Boateng, 2022, Ways et al., 2018), which can enhance the residence time of the insulin-loaded aerogels within the gastrointestinal tract, thereby improving drug absorption.

Conventional drug-loaded aerogel production includes the loading of the drug into the aerogel structure uniformly (García-González et al., 2021). The production of conventional aerogels involves a multi-step process that begins with gel formation, usually achieved dropping the solution containing the gel precursor and the drug into the crosslinking bath via automatic syringe pump and the resulting gel undergoes sc-CO2 drying. An innovative approach is the development of core–shell aerogels with a biopolymer-based core and a functionalized shell as drug delivery systems offering several benefits. The co-axial prilling technique is the primary method for fabricating core–shell aerogel particles. Using co-axial prilling and sc-CO2 drying, De Cicco et al. produced core–shell aerogels loaded with doxycycline utilizing alginate and amidated pectin for wound healing (De Cicco et al., 2016). The core–shell structure enabled controlled or delayed release profiles, achieving favorable encapsulation efficiencies, high surface area, and enhanced pore structure provided by sc-CO2 drying. These characteristics highlight the suitability of the core–shell structure for drug delivery applications.

This work evaluates the potential of polysaccharide-based aerogels as novel drug carriers for oral delivery of insulin. This is the first systematic study to explore the feasibility of using polysaccharide-based aerogels for the oral delivery of regular/short-acting insulin. Core-shell aerogel beads, which were used as oral drug delivery agent for the first time, loaded with insulin in the core were produced, and their performance was compared to that of insulin uniformly loaded in conventional alginate aerogel particles. The physicochemical characterization (SEM microscopy, nitrogen adsorption–desorption analysis, FTIR spectroscopy) of polysaccharide-based core–shell and conventional aerogels from different alginate sources, their ability to encapsulate (drug loading efficiency by HPLC), and the evaluation of in vitro insulin release profiles of core–shell aerogels (in SGF, SIF and SCF media) were carried out.

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Materials

Sodium alginate denoted as ALG-1 (alginic acid sodium salt from brown algae, medium viscosity, M/G ratio: 1.56, degree of polymerization: 400–600, MW: ca. 250–350 kDa) was purchased from Sigma (Irvine, UK). Sodium alginate denoted as ALG-2 (sodium alginate, M/G ratio: 1.56, MW: ca. 12–40 kDa) was purchased from Merck (Darmstadt, Germany). Calcium chloride anhydrous (MW: 110.99 g/mol) was purchased from Scharlau (Barcelona, Spain). Chitosan was purchased from Merck (deacetylation degree 75–85 %, MW: ca. 190–300 kDa, Darmstadt, Germany). Humulin R® U-100 (Eli Lilly & Company, Indianapolis, IN, USA) was purchased from a local pharmacy in the form of 10-mL vials containing human insulin (see composition in Table 1) and used for all drug-loaded particles. Carbon dioxide (CO2 > 99.8 % purity) was supplied by Nippon Gases (Madrid, Spain) and Linde (Gebze, Türkiye). Absolute ethanol from Merck (Darmstadt, Germany) and ISOLAB Laborgeräte GmbH (Eschau, Germany), acetic acid glacial from Scharlau (Barcelona, Spain) and ISOLAB Laborgeräte GmbH (Eschau, Germany), potassium dihydrogen phosphate and sodium dihydrogen phosphate from Merck (Darmstadt, Germany) were used throughout the experiments.

Gozde Ozesme Taylan, Carlos Illanes-Bordomás, Ozge Guven, Ece Erkan, Sevil Çıkrıkcı Erünsal, Mecit Halil Oztop, Carlos A. García-González, Core-shell aerogel design for enhanced oral insulin delivery, International Journal of Pharmaceutics, Volume 669, 2025, 125038, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.125038.

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14th November 2024