Design of controlled release systems for THEDES—Therapeutic deep eutectic solvents, using supercritical fluid technology
Graphical abstract
Introduction
Deep eutectic solvents (DES) have been presented as alternative solvents for a variety of applications, similarly to the developments observed with ionic liquids (ILs) in the early 90’s (Abbott et al., 2004, Paiva et al., 2014, Pena-Pereira and Namiesnik, 2014). DES present, however, two major advantages that overcome the limited applicability of ILs. DES, and particularly natural deep eutectic solvents (NADES), are produced from naturally occurring molecules and have therefore inherent low toxicity (Dai et al., 2013). Additionally they are formed by combining two or more compounds that are solid at room temperature, which upon mixing at a particular composition become liquid.
The development of therapeutic deep eutectic solvents (THEDES) is a field of research that has not been extensively explored. Stott and co-workers reported that ibuprofen formed eutectic mixtures with different terpenes that were shown to promote enhanced skin permeation. It has also been reported that DES can dissolve model drugs, increasing their solubility, permeation and absorption (Stott et al., 1998). The enhancement of the permeation of THEDES has been demonstrated by Wang et al. (2014). The permeation of the lidocaine:ibuprofen system can be finely tuned depending on the molar ratio of the two components, allowing the development of tailor-made, transdermal drug delivery systems (Wang et al., 2014). Tuntarawongsa and Phaechamud, 2012a, Tuntarawongsa and Phaechamud, 2012b reported on the preparation of a DES with therapeutic properties, consisting of a mixture of menthol and camphor with dissolved ibuprofen. DES dissolved considerable higher amounts of ibuprofen when compared to water. With the addition of a polymer, a polymeric eutectic drug delivery system was formed (Tuntarawongsa and Phaechamud, 2012b). The same behavior was observed by Morrison et al. (2009) who studied the solubilisation of benzoic acid, danazol, griseofulvin, AMG517 and itraconazole in urea:choline chloride and malonic acid:choline chloride DES. Bica et al. (2012) reported on the synthesis of new therapeutic ILs, namely tetrabutylphosphonium ibuprofenate and ephedrinium ibuprofenate and on the controlled release of these ILs from porous silica particles. The possibility to couple a THEDES with a second component, particularly a polymer, and to synthesize bioactive eutectic systems opens a broad spectrum of future developments in pharmaceutical and biomedical applications of these systems. The doping of biopolymers with THEDES is a new strategy for the delivery of the therapeutic agent. Biodegradable polymers made from renewable resources are an important innovation in materials science (Malafaya et al., 2007, Mano et al., 2007). Starch-based polymers in particular have been studied for a wide range of applications including the development of controlled drug delivery systems (Balmayor et al., 2009, Lu et al., 2009, Reis et al., 2008, Silva et al., 2004). Their natural origin, together with their mechanical properties and biocompatibility, are behind the potential of starch-based materials in the biomedical field (Marques et al., 2002).
The combination of THEDES, biodegradable natural based polymers, and supercritical carbon dioxide (scCO2) is a viable alternative for the production of drug delivery systems. The use of scCO2 for the development of enhanced biomaterials for pharmaceutical and/or biomedical applications has been reported in different reviews (Duarte et al., 2009a, Duarte et al., 2009b; Knez et al., 2011, Salerno and Pascual, 2015, Zhang et al., 2014). CO2 is the most commonly used solvent at supercritical conditions due to its low critical parameters (Tc = 31.1 °C and Pc = 73.8 bar) and to the fact that it is environmentally benign, non-toxic, non-flammable, non-corrosive, readily available and inexpensive. Supercritical fluid sintering was proposed by Singh et al. (2010) for the preparation of highly porous and interconnected structures, under mild conditions. The supercritical sintering technique, similarly to supercritical fluid foaming, relies on the plasticizing effect of CO2, which reduces the glass transition temperature (Tg) of the polymer. In the case of sintering, polymeric particles are softened and fused together creating a three dimensional (3D) structure (Alves et al., 2012). Supercritical fluid sintering is a technique which relies on the decrease of the Tg of the polymer (Duarte et al., 2013). The softening of the polymer under a CO2 atmosphere allows the sintering of the particles, promoting their adhesion while leaving empty pores inside the formed structure. Supercritical fluid sintering has been described in the literature for the preparation of different scaffolds, particularly for tissue engineering, and it is particularly attractive due to the mild operating conditions, which allow the processing of thermolabile substances (Bhamidipati et al., 2013, Singh et al., 2010). The main objective of this work was the development of a controlled delivery system based on a starch polymer blend impregnated with menthol:ibuprofen THEDES, obtained by supercritical fluid sintering.
Section snippets
Materials
The reagents used in the preparation of THEDES were menthol (≥98%, CAS 89-78-1, Sigma) and ibuprofen, which was obtained from ibuprofen sodium salt (98%, CAS 31121-93-4, Sigma). A 50 mg/mL solution of this compound in distilled water was prepared, and the pH was adjusted to 1-2 by adding small amounts of a solution of hydrochloric acid (1 M) (36.5-38%, CAS 764-01-0, Scharlau). The two compounds react, yielding ibuprofen in its acid form, and sodium chloride. Ibuprofen is extracted with
Preparation of THEDES
As referred in Section 2, the 3:1 menthol:ibuprofen THEDES remained a liquid at room temperature, with no evidence of phase separation or deposition (Fig. 1).
Thermal properties
A DSC analysis of the 3:1 menthol:ibuprofen THEDES was performed, as well as for the individual components. In the thermogram of menthol (Fig. 2), two asymmetric peaks corresponding to melting are observed, yielding melting temperatures (Tm) of 29 and 35 °C, in good agreement with data from Corvis et al. (2012). The two melting peaks are
Conclusions
In this work we have developed a delivery system for therapeutic deep eutectic solvents (THEDES), namely for 3:1 menthol:ibuprofen. Supercritical fluid sintering was used to prepared 3D porous structures impregnated with THEDES. The results demonstrate that the solubility profiles of ibuprofen in powder form and in THEDES in PBS are similar, nonetheless, when they are incorporated in a matrix the liquid form has a faster release profile. The drug release in this system is mostly governed by
Acknowledgements
Rita Craveiro, Alexandre Paiva and Ângelo Rocha are grateful for financial support from Fundação para a Ciência e a Tecnologia (FCT) through the grants PTDC/EQU-EPR/12191/2010/ENIGMA, SFRH/BPD/44946/2008 and SFRH/BD/93049/2013. The research leading to these results has received funding from through the projects ENIGMA - PTDC/EQU-EPR/121491/2010, PTDC/QUI-QUI/119210/2010, PTDC/EQU-EQU/122106/2010, PEst-C/EQB/LA0006/2013 from the European Union’s Seventh Framework Programme (FP7/2007-2013) under
References (37)
- et al.
PDLLA enriched with ulvan particles as a novel 3D porous scaffold targeted for bone engineering
J. Supercrit. Fluids
(2012) - et al.
Subcritical CO2 sintering of microspheres of different polymeric materials to fabricate scaffolds for tissue engineering
Mater. Sci. Eng. C
(2013) - et al.
Modeling and comparison of dissolution profiles
Eur. J. Pharm. Sci.
(2001) - et al.
Natural deep eutectic solvents as new potential media for green technology
Anal. Chim. Acta
(2013) - et al.
Dexamethasone-loaded scaffolds prepared by supercritical-assisted phase inversion
Acta Biomater.
(2009) - et al.
Unleashing the potential of supercritical fluids for polymer processing in tissue engineering and regenerative medicine
J. Supercrit. Fluid
(2013) - et al.
Natural-origin polymers as carriers and scaffolds for biomolecules and cell delivery in tissue engineering applications
Adv. Drug Deliv. Rev.
(2007) - et al.
The biocompatibility of novel starch-based polymers and composites: in vitro studies
Biomaterials
(2002) - et al.
Characterization of thermal behavior of deep eutectic solvents and their potential as drug solubilization vehicles
Int. J. Pharm.
(2009) - et al.
Bio-based polymers, supercritical fluids and tissue engineering
Process Biochem.
(2015)
Mathematical modeling of bioerodible, polymeric drug delivery systems
Adv. Drug Deliv. Rev.
Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC)
Adv. Drug. Deliv. Rev.
Higuchi equation: derivation, applications, use and misuse
Int. J. Pharm.
Microsphere-based scaffolds for cartilage tissue engineering: using subcritical CO2 as a sintering agent
Acta Biomater.
Transdermal delivery from eutectic systems: enhanced permeation of a model drug, ibuprofen
J. Controlled Release
Deep eutectic solvents formed between choline chloride and carboxylic acids: versatile alternatives to ionic liquids
J. Am. Chem. Soc.
Starch-poly-N-caprolactone Microparticles Reduce the Needed Amount of BMP-2
Clin. Orthop. Relat. Res.
Pharmaceutically active ionic liquids with solids handling, enhanced thermal stability, and fast release
Chem. Commun.
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