Journal
MOLECULAR PHARMACEUTICS
Volume 13, Issue 11, Pages 3816-3826Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.6b00613
Keywords
in vitro dissolution-permeation test; microflux; flux; electrospinning; nanofiber; meloxicam; Soluplus; supersaturation; cosolvent; DMSO
Funding
- New Szechenyi Development Plan [TAMOP-4.2.1/B-09/1/KMR-2010-0002]
- OTKA research fund [K112644, PD108975]
- MedInProt Synergy Program
- Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences
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The aim of this study was to investigate the impact of formulation excipients and solubilizing additives on dissolution, super saturation, and membrane transport of an active pharmaceutical ingredient (API). When a poorly water-soluble API is formulated to enhance its dissolution, additives, such as surfactants, polymers, and cyclodextrins, have an effect not only on dissolution profile but also on the measured physicochemical properties (solubility, pK(a), permeability) of the drug while the excipient is present, therefore also affecting the driving force of membrane transport. Meloxicam, a nonsteroidal anti-inflammatory drug, was chosen as a poorly water-soluble model drug and formulated in order to enhance its dissolution using solvent-based electrospinning. Three polyvinylpyrrolidone (PVP) derivatives (K30, K90, and VA 64), Soluplus, and (2-hydroxypropy)-beta-cydodextrin were used to create five different amorphous solid dispersions of meloxicam. Through experimental design, the various formulation additives that could influence the characteristics Donor compartment Acceptor compartment Membrane cm og, h (Zir of dissolution and permeation through artificial membrane were observed by carrying out a simultaneous dissolution permeation study with a side-by-side diffusion cell, mu FLUX. Although the dissolution profiles of the formulations were found to be very similar, in the case of Soluplus containing formulation the flux was superior, showing that the driving force of membrane transport cannot be simplified to the concentration gradient. Supersaturation gradient, the difference in degree of supersaturation (defined as the ratio of dissolved amount of the drug to its thermodynamic solubility) between the donor and acceptor side, was found to be the driving force of membrane transport. It was mathematically derived from Fick's first law, and experimentally proved to be universal on several meloxicam containing ASDs and DMSO stock solution.
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