Innovative Aqueous Nanoemulsion Prepared by Phase Inversion Emulsification with Exceptional Homogeneity
Formulating low-solubility or low-permeability drugs is a challenge, particularly with the low administration volumes required in intranasal drug delivery. Nanoemulsions (NE) can solve both issues, but their production and physical stability can be challenging, particularly when a high proportion of lipids is necessary. Hence, the aim of the present work was to develop a NE with good solubilization capacity for lipophilic drugs like simvastatin and able to promote the absorption of drugs with low permeability like fosphenytoin. Compositions with high proportion of two lipids were screened and characterized. Surprisingly, one of the compositions did not require high energy methods for high droplet size homogeneity. To better understand formulation factors important for this feature, several related compositions were evaluated, and their relative cytotoxicity was screened.
Optimized compositions contained a high proportion of propylene glycol monocaprylate NF, formed very homogenous NE using a low-energy phase inversion method, solubilized simvastatin at high drug strength, and promoted a faster intranasal absorption of the hydrophilic prodrug fosphenytoin. Hence, a new highly homogeneous NE obtained by a simple low-energy method was successfully developed, which is a potential alternative for industrial application for the solubilization and protection of lipophilic actives, as well as (co-)administration of hydrophilic molecules.
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Materials
The hydrophilic surfactants Kolliphor® RH 40 (Macrogolglycerol hydroxy stearate), Kolliphor® EL (Macrogolglycerol ricinoleate), Kolliphor® P124 (Poloxamer 124), Kolliphor® HS 15 (Polyethylene glycol 660 12-hydoxystearate), and the oil Kollicream® IPM (Isopropyl Myristate) were kindly offered by BASF (Ludwigshafen, Germany); Transcutol® HP (Diethylene glycol monoethyl ether), a cosolvent, Labrasol® ALF (Caprylocaproyl polyoxyl-8 glycerides), a hydrophilic surfactant, and the oils Capryol® 90 (Propylene Glycol Monocaprylate (type II) NF), Capryol® PGMC (Propylene glycol monocaprilate, Type I), Labrafac TM PG (Propylene glycol dicaprylocaprate), Maisine® CC (Glycerol monolinoleate), and Peceol TM (Glycerol mono-oleate) were kindly offered by Gattefossé (Saint-Priest, France); the oils Imwitor® 948 (Glyceryl mono-oleate), Imwitor® 988 (Glycerol monocaprilate, Type I), and Softisan® 64S (Bis-diglyceryl polyacyladipate-2) were kindly offered by IOI Oleo GmbH (Hamburg, Germany); Capmul® MCM (Glycerol monocaprilocaprate), Capmul® 808G EP/NF (Glycerol monocaprylate Type II), Capmul® PG-8 (Propylene glycol monocaprylate), and Capmul® PG-8-70 NF (Propylene glycol monocaprylate Type II) were kindly offered by Abitec; Miglyol® 812 (medium-chain triglycerides; Caprylic/Capric Triglyceride), Soybean oil, Span® 80 (Sorbitane mono-oleate), Vitamin E Acetate, Cetiol V (Decyl oleate), the hydrophilic surfactants Tween® 20 (Polysorbate 20) and Tween® 80 (polysorbate 80), and the polymers Polyethylene glycol (PEG) 4000, (Hydroxypropyl)methyl cellulose (HPMC, corresponding to Hypromellose Viscosity 4000 mPa·s), and Polyvinylpyrrolidone (PVP, corresponding to Povidone K30) were acquired from Acofarma® (Madrid, Spain); the surfactant Tyloxapol was from Acros Organics (Thermo Fisher ScientificGeel, Belgium); Malic acid was acquired from Applichem (Darmstadt, Germany). Ultra-pure water was obtained from a Mili-Q® purification system from Millipore (Billerica, MA, USA). Simvastatin (98.03% purity) was purchased from Bld Pharmatech GmbH. (Kaiserslautern, Germany.) and kept at 4 °C under a nitrogen atmosphere during utilization. The bovine serum albumin (BSA) was acquired from Sigma-Aldrich, Inc (St. Louis, MO, USA). Acetonitrile and methanol were high-performance liquid chromatography (HPLC) gradient grade. The symbols TM and® will be omitted from now on for simplification.
Pires, P.C.; Fernandes, M.; Nina, F.; Gama, F.; Gomes, M.F.; Rodrigues, L.E.; Meirinho, S.; Silvestre, S.; Alves, G.; Santos, A.O. Innovative Aqueous Nanoemulsion Prepared by Phase Inversion Emulsification with Exceptional Homogeneity. Pharmaceutics 2023, 15, 1878. https://doi.org/10.3390/pharmaceutics15071878
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