Production of Fluconazole-Loaded Polymeric Micelles Using Membrane and Microfluidic Dispersion Devices

Abstract

Polymeric micelles with a controlled size in the range between 41 and 80 nm were prepared by injecting the organic phase through a microengineered nickel membrane or a tapered-end glass capillary into an aqueous phase. The organic phase was composed of 1 mg·mL−1 of PEG-b-PCL diblock copolymers with variable molecular weights, dissolved in tetrahydrofuran (THF) or acetone. The pore size of the membrane was 20 μm and the aqueous/organic phase volumetric flow rate ratio ranged from 1.5 to 10. Block copolymers were successfully synthesized with Mn ranging from ~9700 to 16,000 g·mol−1 and polymeric micelles were successfully produced from both devices. Micelles produced from the membrane device were smaller than those produced from the microfluidic device, due to the much smaller pore size compared with the orifice size in a co-flow device. The micelles were found to be relatively stable in terms of their size with an initial decrease in size attributed to evaporation of residual solvent rather than their structural disintegration. Fluconazole was loaded into the cores of micelles by injecting the organic phase composed of 0.5–2.5 mg·mL−1 fluconazole and 1.5 mg·mL−1 copolymer. The size of the drug-loaded micelles was found to be significantly larger than the size of empty micelles.

Encapsulation and Controlled Release of Rapamycin from Polycaprolactone Nanoparticles Prepared by Membrane Micromixing Combined with Antisolvent Precipitation

“…Thus, compared to acetone, THF must be diluted with water to a greater extent for PCL to begin to precipitate, which means that the growing NPs are less likely to agglomerate. The same type of behavior with smaller NPs formed using THF than acetone was observed for fluconazole-loaded polymeric micelles produced by membrane and microfluidic nanoprecipitation . Although PCL NPs are smaller in the presence of THF, in subsequent experiments RAPA-PCL NPs will be formed using acetone, because RAPA is sparingly soluble in THF and the difference in size between the NPs formed using acetone and THF is only 3–8%.…”

“…The same type of behaviour with smaller NPs formed using THF than acetone was observed for fluconazole-loaded polymeric micelles produced by membrane and microfluidic nanoprecipitation. 46 Although PCL NPs are smaller in the presence of THF, in subsequent experiments RAPA-PCL NPs will be formed using acetone, because RAPA is sparingly soluble in THF and the difference in size between the NPs formed using acetone and THF is only 3-8 %. To obtain the smallest possible NPs size, the ratio V aq /V or will be kept at 10.…”

Electrohydrodynamic Mixing-Mediated Nanoprecipitation for Polymer Nanoparticle Synthesis

“…As a consequence, more controlled, lower volume synthesis can be difficult to achieve when only a limited amount of cargo is available, although progress has been made in the form of a simplified, hand operated, confined impinging jet mixer with dilution . Some of these challenges can be addressed using microfluidic platforms or membrane dispersion devices, but incorporating such devices into large manufacturing processes may require specialized fabrication techniques. There remains a strong need to develop simple, yet scalable FNP platforms that are not directly dependent on high flow rates or high fluid velocities.…”

Microfluidic-Assisted Preparation of Targeted pH-Responsive Polymeric Micelles Improves Gemcitabine Effectiveness in PDAC: In Vitro Insights

“…In addition, to improve specific targeting to the PDAC, the surface of such micelles was properly functionalized with a selective ligand for uPAR receptor, which is highly expressed in PDAC cells [ 12 , 13 ], such as the peptide AE105 [ 5 ]. The microfluidic technique has already been successfully employed to control the size, shape, and polydispersity of polymeric micelles [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]; however, to the best of our knowledge, there have been few reports on microfluidics-based pH-responsive polymeric micellar delivery systems [ 37 , 38 , 39 ] and no one has applied these to PDAC cancer research. In particular, Feng et al [ 37 ] obtained the pH-responsive micelles by mixing two different block copolymers (the PLGA and the poly(ethylene glycol)-poly(2-(diisopropylamino)ethyl methacrylate(PEG-b-PDPA)); additionally, Albuquerque et al [ 38 ], using the poly([N-(2-hydroxypropyl)]methacrylamide)-bpoly [2-(diisopropylamino)ethyl methacrylate] (PHPMAm-b-PDPAn), blocked copolymers, thus obtaining quasi-monodisperse assemblies, characterized by more consistent biodistribution and cellular uptake.…”