JCJC SIMI 8 - JCJC : Sciences de l'information, de la matière et de l'ingénierie : Chimie du solide, colloïdes, physicochimie

Ionogels for the Delivery of Drug-based Ionic Liquids – IDDILiq

Ionogels for controlled release of ionic liquids made up of Pharmaceutical Ingredients

Synthesis of new biodegradable materials composed of silica or polymers for the controlled release of ionic liquids made up of pharmaceutical ingredients. Effect of molecular interactions on drug release kinetics : experimental and molecular simulations evidences.

Synthesis of silica or polymers based materials for the controlled release of ionic liquids made up of active pharmaceutical ingredients

A tremendous effort is currently being undertaken by the scientific community to develop drug delivery systems in which the release of the active substance is controlled “on demand”. The key-issue is to control the physical and chemical properties of the drug encapsulated. Indeed, most of the drugs are poorly water-soluble in physiological media.<br />The aim of the present research project is to design a new route to the encapsulation and delivery of drugs based on the use (1) of Ionic Liquids containing active pharmaceutical ingredients (API-ILs) (2) a one step sol-gel synthesis to encapsulate the ionic liquid into the silica matrix. This method will allow increasing the solubility and controlling the release of the drug depending on IL/silica interactions. Moreover, the use of ionogels, makes the final pharmaceutical form process much simpler. A strong point of this research project lies in the combination of both experimental and molecular simulation approaches. A second approach using biodegradable polymers to encapsulate these API-ILs has also been tested.<br />

In order to increase drugs solubilities, we prepared them as an ionic liquid form. Ionic liquids are salts made up of an organic cation and an organic anion which allows them to be liquids at room temperature. This liquid state is highly advantageous as it renders the drugs more bioavailable. Moreover, in our case another advantage is their aqueous solubilities. These ILs are then encapsulated into silica matrix using a sol-gel synthesis leading to materials called “ionogels”. The sol gel process is a soft (made at room temperature) and simple method. One objective of this project is to understand drug-matrix interactions as they govern release kinetics. Our system, composed entirely of ions, is complicated and the mechanism is yet unknown. Another interesting aspect is the use of these drug-based ILs which have surfactant properties in order to obtain well-structured ionogels containing drugs. For this, we need a deep understanding of the physical and chemical properties of bulk ionic liquids. From a theoretical/molecular simulation view point, the novelty and originality of the present work lies in the fact that we considered for the first time the confinement of drug-based ionic liquid in silica matrices.

We synthesized several new ionic liquids containing ibuprofenate anion and imidazolium cation with various alkyl chain length.(n = 4, 6 et 8). Interfacial tension, electrical conductivity, NMR self-diffusion and DLS experiments have been used to investigate the self-aggregation in water of these ILs. Aggregates obtained were investigated by means of Dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM), 1H nuclear magnetic resonance measurements and SANS. Atom-scale molecular dynamics simulations were used to shed light on the main interactions governing the formation of the aggregates and their composition. Aggregates composition depends on the imidazolium alkyl chain length. Transitions from micelles to vesicles or ribbons were observed due to dilution effects and changes in the chemical composition of the aggregates. We also show that aggregation can be probed using simple microscopic quantities such as radial distribution functions and average solvation numbers. The nanoconfinement of theseAPI-ILS in ionogels mesoporous silica material were investigated. Effects off the modification of the Ionic Liquid/ silica interface on drug release kinetics have been investigated. A mechanism for drug release has been proposed taking into account drug diffusion process, silica matrix stability and the CnMImIbu-SiO2interactions. We also performed molecular simulations of a silica nanopore that is gradually filled with a typical imidazolium salt ionic liquid to obtain a realistic model of these ionogels. Despite the significant layering and stiffening of the ionic liquid in the vicinity of the silica surface, the pair correlation functions and magnitude of its dynamics clearly evidence liquid-like behavior. Finally we have prepared Poly(L-lactic acid) (PLLA) membranes containing API-ILs by simple film casting from solvent evaporation method. The release obtained strongly depends on polymer-IL compatibility and polymer degradation.

These preliminary studies opens up perspectives for the use of ILs based on pharmaceutical ingredients for drug delivery and materials synthesis. One way to continue this project will be to use stimuli-controlled polymer (temperature, pH, electric field) to control the release. One other objective is to control the shaping (spray-drying, emulsification, microfluidic).

To date, 3 papers have been published in high quality journals
(1) B. Coasne, L. Viau, A. Vioux,” Loading-controlled stiffening in nanoconfined ionic liquids”, J. Phys. Chem. Lett. 2011, 2, 1150.
(2) Tourne-Peteilh, C.; Devoisselle, J.-M.; Vioux, A.; Judeinstein, P.; In, M.; Viau L. “Surfactant properties of ionic liquids containing short alkyl chain imidazolium cations and ibuprofenate anions”, Phys. Chem. Chem. Phys. 2011, 13, 15523-15529.
(3) Tourne-Peteilh, C.; Coasne, B.; In, M. ; Brevet, D.; Devoisselle, J.-M.; Vioux, A.; Viau, L. “Surfactant Behavior of Ionic Liquids Involving a Drug: From Molecular Interactions to Self-Assembly«, Langmuir 2014, acceptée. dx.doi.org/10.1021/la404166y
4 papers are being written. These results have been presented to international and national conferences (10 oral and 3 poster communications).

A tremendous effort is currently being undertaken by the scientific community to develop drug delivery systems in which the release of the active substance is controlled “on demand”. The key-issue is to control the physical and chemical properties of the drug encapsulated in the delivery system as they directly affect the way the material is formulated and presented to the consumer and influence more fundamental features such as its solubility and dissolution rate. These factors, as well as the considerable financial gains to be realized by effective patent protection of new drug physical forms, have resulted in a flurry of activity in screening for novel solid forms, including salts, polymorphs, co-crystals. Mesoporous materials such as templated silicas or Metal Organic Framework (MOF) appear as potential drug delivery systems due to their interesting properties such as their uniform porous structure, high surface area, tunable pore sizes with narrow distribution and good biocompatibility. Up to now, drugs were physically adsorbed into the channels or cages of the mesoporous materials. Unfortunately, this loading method requires several steps to achieve the final drug loaded and functionalized materials. Moreover, the organic solvents have to be carefully chosen as they could affect the drug solubility, the drug/silica surface interactions, and, as a consequence, the loading and release behavior of the material. The aim of the present research project is to design a new route to the encapsulation and delivery of drugs based on materials called ionogels obtained by the confinement of ionic liquids in silica matrices by means of sol-gel synthesis. The use of ionogels will allow 1) increasing the solubility and 2) controlling the release of the drug. Moreover, they can be cast in different shapes which is a key-advantage as it makes the final pharmaceutical form process much simpler. In this research project, we propose to replace a component of the ionic liquid by the drug or active substance (such as ibuprofen) in order to obtain new tunable drug delivery systems. The main advantage of using ionogels is that the drug-based ionic liquid, which is the structuring agent, is firmly maintained inside the material: the ionic liquid has a dual role of structuring agent and drug. The synthesis is a one step process, in contrast to the loading method in classical mesoporous materials which is time and solvent consuming. The use of drug based ionic liquids will allow increasing considerably the solubility of the drug. Finally, the confinement in the silica matrix will allow controlling the relase of the drug by playing with the physical and chemical properties of the delivery system (guest/surface interaction, pore diameter, etc.). Our objective is to synthesize such drug-based ionogels and understand using both experimental and molecular simulation approaches the crucial parameters that control their physical and chemical properties. In particular, the key factor that has to be understood and controlled is the subtle balance between the structural stability and dynamics of the drug-based ionogels. On the one hand, the material has to show good mechanical stability in order to be considered as a promising candidate for the design of new pharmaceutical products (to take advantage of the different casting processes offered by ionogels). On the other hand, the dynamics of the confined substances has to remain fast enough to allow release of the drug in a simple, efficient, and controlled manner.

Project coordinator

Madame Lydie Viau (CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE LANGUEDOC-ROUSSILLON) – lydie.viau@univ-fcomte.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

ICGM CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE LANGUEDOC-ROUSSILLON

Help of the ANR 195,000 euros
Beginning and duration of the scientific project: - 36 Months

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