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Skyepharma harnesses Microfluidizer® Technology to improve bioavailability of APIs
Saint-Quentin-Fallavier, France: – Oral dosage specialist CDMO Skyepharma Productions S.A.S. (Skyepharma) has collaborated with Lyon University on NanoMicS program with the aim to study the potential of microfluidizer technology as a greener way to improve the therapeutic effectiveness of tablets.
Their preliminary joint study ‘Microfluidization : an eco-friendly process to improve oral bioavailability of poorly soluble API’ involved Skyepharma research scientist Dr. Vanessa Bourgeaux, working in partnership with Pr. Stéphanie Briançon, Dr. Sandrine Bourgeois and PhD student Oksana Lemasson , from Lyon University’s Laboratory of Automatic Control, Chemical and Pharmaceutical Engineering (LAGEPP).
Potential of SLNs and NLCs
Their research focused on ways to harness the potential of high-pressure homogenization to meet the challenge of improving bioavailability of poorly soluble APIs. The research demonstrated that very promising results could be obtained with different Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs) when combined with Skyepharma’s expertise in Microfluidizer® API particle size reduction.
Oral drug administration is a preferred route for medicinal administration because it enables better patient compliance to their therapeutic regimes. However, many factors limit the effectiveness of oral treatments, including the poor bioavailability of some Active Pharmaceutical Ingredients (APIs). It is estimated that 60% of new available APIs are rated as Class II and Class IV under the Biopharmaceutics Classification System (BCS) as poorly water-soluble. Most of these APIs also have a low oral bioavailability due to significant hepatic metabolism or efflux by P-glycoprotein.
In response, encapsulation of a BCS class II or IV API in lipid-based nanoparticles has become an innovative strategy to improve its solubility and also to control its release and avoid hepatic first pass effects.
The main objective of the study was to develop SLNs and NLCs that would improve the oral efficacy of therapeutic molecules with poor water solubility and permeability. Both SLN and NLC have the advantage of being biocompatible and biodegradable. Furthermore, they are produced from an ecologically friendly manufacturing process that does not require chemical solvents.
The advanced Microfluidizer® technology relying on high pressure homogenization process also has the advantage of being easy to scale-up and the study explored a model process to transpose lab-scale nanoencapsulation to an industrial scale at Skyepharma.
Proof of concept
The researchers selected Spironolactone (SPI) as the selected model of BCS class II API for the proof of concept. Lipidic excipients, Precirol® ATO5 (PATO5), Capryol® 90 (C90) and Maisine® CC (MAI) were contributed by Gattefossé, based at Saint Priest, France, while BASF at Levallois-Perret provided the surfactant poloxamer Kolliphor® P188 (KOL188).
Formulations of SLN and NLC were developed at LAGEPP according to a previous study (Dumont, et al. 2019), with SLN nanosuspensions composed of two phases: the lipidic with spironolactone dissolved in PATO5 and the aqueous with a surfactant KOL188 dissolved in deionized water. The two phases were heated separately to 70°C and then homogenized by Ultra-turrax® IKA high shear agitation at 11000 rpm for three minutes. This pre-emulsion was inserted in the Microfluidizer® LM20 (Microfluidics) tank and pumped through the system into the Z-type chamber G10Z between 500 and 1000 bars pressure. Finally, this nanoemulsion was cooled to around 4°C, allowing the PATO5 to solidify and become lipid nanoparticles. For NLC formulation, SPI was first dissolved in a liquid lipid (C90 or MAI) and added to melted PATO5 to form the lipid phase of the pre-emulsion.
Characterization and quantification
Nanoparticle mean diameters (D50) and their polydispersity index (PDI) were quantified by Diffraction Light Scattering with a Zetasizer Nano ZS (Malvern), with morphology of nanoparticles characterized by Transmission Electron Microscopy (TEM) with a JEM-1400 Flash Electron Microscope. The samples were diluted 10-fold in deionized water to allow clearer identification.
The amount of loaded SPI was expressed with the encapsulation efficiency (EE), which represents the amount of API effectively encapsulated compared to the total amount of API used. SPI was quantified with an Acquity Arc UHPLC (Waters).
TEM confirmed satisfactory particle size characteristics for blank NLCs (Table 1). Both C90 and MAI NLC formulations provided higher particle sizes, though with mean diameter still below 200 nm and 0.2 PDI. The nanosuspension observation also demonstrated that SLN and NLC were spherical shaped, in line with expectations.
Compared to the blank nanoparticles, the SPI encapsulation in both SLN and NLC improved their size results with smaller nanoparticles and PDI (Table 2).
Concerning NLC formulation, MAI allowed the formation of slightly smaller nanoparticles with a narrow distribution, similarly to C90. With encapsulation, NLC-MAI allowed the highest efficiency rate with 72.8 % of SPI encapsulated, compared with 60.7% of SPI retrieved in SLN and 50.2% in NLC-C90.
The study confirmed that Microfluidizer® technology allowed the formation of SLN and NLC with mean diameters lower than 200 nm. The addition of a liquid lipid did not have a significant impact on the size or polydispersity index of the nanoparticles but significantly improved the entrapment efficiency of spironolactone, especially for Maisine® CC NLC. The release profile of SPI from these nanoparticles has yet to be investigated.
“The Microfluidizer® technology thus presents a real interest in formulation but also an ability of industrial transposition, which will be the main prospect of this project,” the study team reports.
“Moreover, a drying process of these lipid nanoparticles will be studied in order to develop solid dosage forms for oral administration of these nanoencapsulated BCS II or IV API,” they add.
About Skyepharma Production
Skyepharma is an independent French pharmaceutical CDMO, 100% owned by its management team and Bpifrance. Skyepharma is an expert CDMO specialised in the formulation, development and manufacturing of complex oral solid forms (OSD), with a specific expertise and proprietary technologies on modified release products.
Skyepharma is based in Saint-Quentin-Fallavier, France. The current factory, dedicated to its OSD activity, occupies 22,000m2, on a 60,000m2 piece of land. Skyepharma has decided to allocate a portion of the available land (more than 20,000m2) to establish its SkyeHub Bioproduction, an innovative model designed to offer clinical and commercial production capacities to biotech companies. This SkyeHub model includes the construction of dedicated buildings, with specifically designed surfaces and premises, together with transverse support services such as quality, maintenance, batch release, etc.
Learn more at: www.skyepharma.fr
LAGEPP is a laboratory at the interface between the sciences, engineering, processes and health whose ambition is to federate teachers -researchers in automatic, chemical engineering, and pharmaceutical engineering. Through two themes, they develop fundamental research and ensure its transfer (in relation with the industrial activity in the Rhone Alpes Region). www.lagepp.univ-lyon1.fr/
Click on Microfluidization: an eco-friendly process to improve oral bioavailability of poorly soluble API for more information
Click on Triglide™ for example of Microfluidizer drug application
Dumont, C.; Jannin, V.; Miolanea, C.; Lelong, Q.; Valour, J.P.; Urbaniak, S.; Fessi, H. and Bourgeois, S. A proof-of-concept for developing oral lipidized peptide Nanostructured Lipid Carrier formulations. J. Drug Deliv Sci Technol. 54 (2019)
Basic Microfluidizer process: sample is poured into inlet reservoir and subjected to suction and compression through intensifier pump which first aspirates the fluid, thanks to a one-way valve, before pushing sample through interaction chamber and jacketed cooling coil/heat exchanger to be cooled, ready for collection. (Source: Microfluidics®, Poster AAPS 2015, number W5343).