Thèse Couplage de Procédés Assistés par Co Supercritique pour la Production de Systèmes d'Administration de Solides Auto-Émulsionnables S-Sedds H/F - Doctorat.Gouv.Fr

Établissement : IMT Mines Albi École doctorale : MEGEP - Mécanique, Energétique, Génie civil, Procédés Laboratoire de recherche : RAPSODEE - Centre de Recherche d'Albi en Génie des Procédés, des Solides Divisés, de l'Energie et de l'Environnement Direction de la thèse : Fabienne ESPITALIER Début de la thèse : 2026-11-02 Date limite de candidature : 2026-06-30T23:59:59 Les systèmes d'administration de solides auto-émulsionnables (SEDDS) se sont imposés comme une solution prometteuse pour améliorer la solubilité et l'absorption des médicaments. Généralement formulés sous forme liquide dans des gélules de gélatine, ils se heurtent à des limites
liées au coût, à la stabilité et à la complexité de fabrication. Pour surmonter ces limites, les SEDDS solides (S-SEDDS) allient les avantages biopharmaceutiques des systèmes liquides à une meilleure
stabilité physico-chimique et à une manipulation plus aisée des formes solides. Les méthodes de préparation actuelles sont souvent grandes consommatrices d'énergie, ont un faible rendement et nécessitent de grandes quantités de tensioactifs ou de solvants organiques, ce qui limite
leur utilisation industrielle. Ce projet propose une alternative innovante et respectueuse de l'environnement utilisant la technologie du CO supercritique couplé, combinant l'expansion rapide de solutions supercritiques (RESS) et processus d'anti-solvant supercritique (SAS) pour permettre la cristallisation en une seule étape de composés auto-émulsifionnables, en utilisant la nifédipine (NIF) comme modèle de médicament. Les objectifs sont les suivants : (i) développement
d'un procédé couplé CO-SC-RESS-SAS pour la production de S-SEDDS de NIF ; (ii) la caractérisation physico-chimique et biopharmaceutique par modélisation in vitro et in silico ; et (iii) l'évaluation de la perméabilité intestinale et de la cytotoxicité à l'aide de modèles de culture cellulaire. À terme, le projet présente un potentiel de transposition à l'échelle industrielle, d'application à d'autres médicaments, de réduction de l'impact environnemental (par exemple, absence d'utilisation de solvants) et d'amélioration de la santé humaine (par exemple, amélioration de l'accessibilité aux médicaments). The question of S-SEDDS production methods remains relatively new. Several approaches
have been reported, including adsorption onto inert carriers, spray drying, hot-melt extrusion
(HME), and freeze drying. Some studies describe drug impregnation into mesoporous silica
using solvent evaporation [7,13]. Spray drying and HME are widely applied in the
pharmaceutical, cosmetic, and food industries and has been proposed for S-SEDDS
preparation [12,14,15,16,17]. Freeze drying represents another option, particularly for
thermolabile drugs [18], [19]. Nevertheless, it requires careful control of cryoprotectant type
and concentration, freezing conditions, and cooling rates to maintain formulation stability and
ensure acceptable powder recovery [20]. Based in this context the team aims to develop,
green CO2-SFC CO2-SFC assisted process, readily scalable, which seems to be the best
choice to produce S-SEDDS from among the others described processes, as CO2-SFC
is non-toxic, affordable, and recyclable. Further, the absence or reduction of organic
solvents, soft process conditions of temperature and pressure are key process
parameters in manufacturing pharmaceutical process required many sensitive drugs as
macromecules and heat sensitive ones. Some CO2-SFC properties such as density,
viscosity, solvency, and diffusivity can be considered as a critical point of this
technology. Regarding the model API, spontaneous emulsifying powders have previously
been prepared by adsorbing liquid lipid formulations onto solid carriers using manual mixing
[21]. Although improved dissolution and oral bioavailability of NIF were demonstrated, the
adsorption process itself was not systematically evaluated or optimized.This is where
RAPSODEE Laboratory becomes central to the project. The laboratory specializes in powder
and process technologies, particularly in the generation of structured solids of varying
complexity-from nanometric to micrometric scales-designed to optimize functional
properties such as reactivity, bioavailability, dispersion, wettability, granular texture, and
mechanical performance. RAPSODEE is equipped with advanced characterization techniques
to assess physical and physicochemical properties, enabling a systematic understanding of
the relationship between solid structure and process parameters. The Institute of Technical
Chemistry at Leibniz University of Hannover will contribute with a complementary expertise to
the project by evaluating cellular bioavailability of adopted formulation strategy. This research
group is dedicated to advancing innovative approaches for in vitro expansion and precise
optimization of culture conditions for human and mammalian cells. A preliminary study of the proposed research topic, supervised by Suênia de Paiva Lacerda, was performed as
part of a PhD thesis for dermopharmaceutic application (T. Massias, 2019-2023) at
RAPSODEE/LAGEPP. A proof of concept of different S-SEDDS formulations (binary,
ternary and quaternary systems) were produced containing Nifedipine (NIF)-BCS Class
II using coupled CO2-SFC-RESS-SAS green process (Figure 1 A-C). This study was
conducted in three steps: i) the development and adjustment of operating conditions to produce
nanosuspension using solvent injection process, ii) the optimization of the formulation to
produce a nanosuspension with a mean particle size diameter close to 100 nm and stable at
least 24 h, iii) the transposition of the formulation composition into coupled CO2-SFC-RESS-
SAS green process to produce S-SEDDS. These first S-SEDDS produced present a good
emulsifying property. This work led to the first two publications on the subject [22], [23].
However, several questions remain to unanswered regarding process dynamics
understanding, particle structure/composition, physicochemical stability of
formulations, emulsifying behaviour in realistic environments (e.g., the gastrointestinal
tract) and of the mechanism enhancing bioavailability of high lipophilic drugs. Expected
scientific achievements are: i) the progress in knowledge on this new process
approach; ii) advances on the understanding the synergy of process parameters and
formulation composition on API biopharmaceutical properties in real environments (e.g.
intestinal); iii) advancements in insight on the relevance of the approach developed to
test the impact of new S-SEDDS forms for drugs belonging to BCS Class II.

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