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Vegetable Oil-based Hybrid Microparticles as a Green and Biocompatible System for Subcutaneous Drug Delivery
Koceïla Doufène, Ilaria Basile, Aurélien Lebrun, Nelly Pirot, Aurélie Escande, Joël Chopineau, Jean-Marie Devoisselle, Nadir Bettache, Anne Aubert-Pouëssel
Abstract
The aim of this study was to evidence the ability of vegetable oil-based hybrid microparticles (HMP) to be an efficient and safe drug delivery system after subcutaneous administration. The HMP resulted from a combination of a thermostabilized emulsification process and sol-gel chemistry. First of all, castor oil was successfully silylated by means of (3- Isocyanatopropyl) trimethoxysilane in solvent-free and catalyst-free conditions. Estradiol, as a model drug, was dissolved in silylated castor oil (ICOm) prior to emulsification, and then an optimal sol-gel crosslinking was achieved inside the ICOm microdroplets. The resulting estradiol-loaded microparticles were around 80 µm in size and allowed to entrap 4 wt.% estradiol. Their release kinetics in a PBS/octanol biphasic system exhibited a one-week release profile, and the released estradiol was fully active on HeLa ERE-luciferase ERα cells. The hybrid microparticles were cytocompatible during preliminary tests on NIH 3T3 fibroblasts (ISO 10993-5 standard) and they were fully biocompatible after subcutaneous injection on mice (ISO 10993-6 standard) underlining their high potential as a safe and long-acting subcutaneous drug delivery system.
1. Introduction
The therapeutic management of chronic diseases is a tricky challenge for both healthcare professionals and their patients. Although most of the drugs prescribed are orally administered, some formulation constraints (e.g. pH-sensitive active pharmaceutical ingredients (APIs)) and the non-compliance of some patients (e.g. mental disorders) may require alternative routes of administration (Sav et al., 2015). In these cases, the subcutaneous (SC) delivery of APIs offers a valuable alternative. Indeed, it is a relatively low-cost route compared to the intravenous one, it is safe, effective, and it allows patient self-administration (Jones et al., 2017). Nevertheless, the scientific community has agreed on the critical need for the development of new technologies and systems in this area (Collins et al., 2020). Indeed, the SC route is relatively unexplored and there is still plenty of room for improvement through long-acting delivery systems (Chen et al., 2018) and systems dedicated to biotherapeutics (e.g. antibodies, insulin, and antibiotics) (Bittner et al., 2018; Hernández-Ruiz et al., 2020; P.V. et al., 2017; Viola et al., 2018).
For a long time, injectable oils have been used to deliver APIs such as antipsychotics and steroid hormones (Gao et al., 1995; Kalicharan et al., 2017; Vintiloiu and Leroux, 2008). Among the used oils, castor oil (CO) and its derivatives (hydrogenated and polyoxylated CO) have been widely introduced in parenteral formulations since their approval by the US-FDA (Strickley, 2004). While the derivatives are used as hydrophilic surfactants in aqueous formulations, native CO is used to formulate oily depots for the sustainable release of poorly water-soluble APIs. Indeed, Riffkin et al. pointed out as early as the 1960s the interest of using CO as a parenteral vehicle for steroids (Riffkin et al., 1964). This oil in particular offers a greater API solubilization capacity and improved safety. Furthermore, we highlighted in a previous paper that silylated CO (ICO) synthesized with the aim of a further sol-gel crosslinking kept its solubilizing capacity of poorly water-soluble APIs. ICO was able to solubilize up to 160 mg of ibuprofen per milliliter and the hybrid microparticles (HMP) obtained after crosslinking of the ICO exhibited an interesting sustained release of ibuprofen in a subcutaneous simulated medium (Doufène et al., 2019).
In this present study, the chemistry of CO silylation was redesigned in order to improve the "green" conditions of HMP synthesis, i.e. in solvent-free and catalyst-free conditions. Estradiol (LogP = 4.01) was used as a model for poorly water-soluble APIs from the broad chemical family of steroids that includes corticosteroids and contraceptives. A comprehensive characterization of the new estradiol-loaded HMP is exposed with an emphasis on estradiol release kinetics, the in vitro activity of the released estradiol, and the in vivo biocompatibility of the HMP evaluated on mice.
4. Conclusion
New hybrid microparticles were synthesized in two steps consisting of a silylation of castor oil then emulsification throughout a thermostabilized emulsion process. In order to reduce the environmental impact, the green process requirements were fully complied with here since no catalyst and no solvents other than water were used, thanks to the high sol-gel reactivity of ICOm. Resulting HMPm were 80 µm sized and presented high condensation yield and degree reflecting the crosslinking quality, and when loaded with estradiol, they showed a satisfying effective loading. Moreover, the HMPm demonstrated complete stability at room temperature, and the entrapped API was unaltered over 12 months. Release kinetics in a PBS/octanol biphasic system exhibited a one-week release profile, and the released estradiol was fully active on HELN ERα cells pointing out the suitability of the formulation process. Finally, the HMP demonstrated their safety through their cytocompatibility on NIH 3T3 fibroblasts (ISO 10993- 5 standard) and their full biocompatibility after subcutaneous injection on mice (ISO 10993-6 standard). Hence, HMPm proved to be a promising green and biocompatible drug delivery system that can substantially contribute to the area of long-acting and subcutaneously delivered systems.
Koceïla Doufène, Ilaria Basile, Aurélien Lebrun, Nelly Pirot, Aurélie Escande, Joël Chopineau, Jean-Marie Devoisselle, Nadir Bettache, Anne Aubert-Pouëssel
Abstract
The aim of this study was to evidence the ability of vegetable oil-based hybrid microparticles (HMP) to be an efficient and safe drug delivery system after subcutaneous administration. The HMP resulted from a combination of a thermostabilized emulsification process and sol-gel chemistry. First of all, castor oil was successfully silylated by means of (3- Isocyanatopropyl) trimethoxysilane in solvent-free and catalyst-free conditions. Estradiol, as a model drug, was dissolved in silylated castor oil (ICOm) prior to emulsification, and then an optimal sol-gel crosslinking was achieved inside the ICOm microdroplets. The resulting estradiol-loaded microparticles were around 80 µm in size and allowed to entrap 4 wt.% estradiol. Their release kinetics in a PBS/octanol biphasic system exhibited a one-week release profile, and the released estradiol was fully active on HeLa ERE-luciferase ERα cells. The hybrid microparticles were cytocompatible during preliminary tests on NIH 3T3 fibroblasts (ISO 10993-5 standard) and they were fully biocompatible after subcutaneous injection on mice (ISO 10993-6 standard) underlining their high potential as a safe and long-acting subcutaneous drug delivery system.
1. Introduction
The therapeutic management of chronic diseases is a tricky challenge for both healthcare professionals and their patients. Although most of the drugs prescribed are orally administered, some formulation constraints (e.g. pH-sensitive active pharmaceutical ingredients (APIs)) and the non-compliance of some patients (e.g. mental disorders) may require alternative routes of administration (Sav et al., 2015). In these cases, the subcutaneous (SC) delivery of APIs offers a valuable alternative. Indeed, it is a relatively low-cost route compared to the intravenous one, it is safe, effective, and it allows patient self-administration (Jones et al., 2017). Nevertheless, the scientific community has agreed on the critical need for the development of new technologies and systems in this area (Collins et al., 2020). Indeed, the SC route is relatively unexplored and there is still plenty of room for improvement through long-acting delivery systems (Chen et al., 2018) and systems dedicated to biotherapeutics (e.g. antibodies, insulin, and antibiotics) (Bittner et al., 2018; Hernández-Ruiz et al., 2020; P.V. et al., 2017; Viola et al., 2018).
For a long time, injectable oils have been used to deliver APIs such as antipsychotics and steroid hormones (Gao et al., 1995; Kalicharan et al., 2017; Vintiloiu and Leroux, 2008). Among the used oils, castor oil (CO) and its derivatives (hydrogenated and polyoxylated CO) have been widely introduced in parenteral formulations since their approval by the US-FDA (Strickley, 2004). While the derivatives are used as hydrophilic surfactants in aqueous formulations, native CO is used to formulate oily depots for the sustainable release of poorly water-soluble APIs. Indeed, Riffkin et al. pointed out as early as the 1960s the interest of using CO as a parenteral vehicle for steroids (Riffkin et al., 1964). This oil in particular offers a greater API solubilization capacity and improved safety. Furthermore, we highlighted in a previous paper that silylated CO (ICO) synthesized with the aim of a further sol-gel crosslinking kept its solubilizing capacity of poorly water-soluble APIs. ICO was able to solubilize up to 160 mg of ibuprofen per milliliter and the hybrid microparticles (HMP) obtained after crosslinking of the ICO exhibited an interesting sustained release of ibuprofen in a subcutaneous simulated medium (Doufène et al., 2019).
In this present study, the chemistry of CO silylation was redesigned in order to improve the "green" conditions of HMP synthesis, i.e. in solvent-free and catalyst-free conditions. Estradiol (LogP = 4.01) was used as a model for poorly water-soluble APIs from the broad chemical family of steroids that includes corticosteroids and contraceptives. A comprehensive characterization of the new estradiol-loaded HMP is exposed with an emphasis on estradiol release kinetics, the in vitro activity of the released estradiol, and the in vivo biocompatibility of the HMP evaluated on mice.
4. Conclusion
New hybrid microparticles were synthesized in two steps consisting of a silylation of castor oil then emulsification throughout a thermostabilized emulsion process. In order to reduce the environmental impact, the green process requirements were fully complied with here since no catalyst and no solvents other than water were used, thanks to the high sol-gel reactivity of ICOm. Resulting HMPm were 80 µm sized and presented high condensation yield and degree reflecting the crosslinking quality, and when loaded with estradiol, they showed a satisfying effective loading. Moreover, the HMPm demonstrated complete stability at room temperature, and the entrapped API was unaltered over 12 months. Release kinetics in a PBS/octanol biphasic system exhibited a one-week release profile, and the released estradiol was fully active on HELN ERα cells pointing out the suitability of the formulation process. Finally, the HMP demonstrated their safety through their cytocompatibility on NIH 3T3 fibroblasts (ISO 10993- 5 standard) and their full biocompatibility after subcutaneous injection on mice (ISO 10993-6 standard). Hence, HMPm proved to be a promising green and biocompatible drug delivery system that can substantially contribute to the area of long-acting and subcutaneously delivered systems.
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