In this study, solid lipid nanoparticle (SLN) suspensions were prepared using a base of hard fat with or without ethylcellulose (EC) and polyvinyl alcohols (PVA) and polysorbate (Tween) 60 surfactants. Commercially available PVAs vary in their degree of saponification and polymerization, and the appropriate PVAs to form SLNs from hard fat with or without EC were investigated. A relatively low-saponification-degree PVA was required to reproducibly form SLN suspensions without EC and relatively high-saponification-degree PVAs were suitable for SLNs with EC. The release of morin from SLNs with EC was more sustained than that from SLNs without EC. The maximum plasma concentration (C max ) of SLNs with and without EC were almost the same, and both were higher than that of a morin suspension. The area under the curve for 0 to 360 min (AUC 0-360 ) of SLNs with EC was increased compared with those of a morin suspension and SLNs without EC. The median diameter of SLNs with EC and a very low-saponification-degree PVA was decreased compared to other formulation, and morin release was more sustained for this formulation. SLNs with EC and a very low-saponification-degree PVA showed higher C max and AUC 0-360 than SLNs with EC lacking a very low-saponification-degree PVA. The optimized SLNs with EC and a very low-saponification-degree PVA improved bioavailability via increased accessibility to the enterocyte surface by decreased particle size and increased permeation of SLN encapsulated morin through the intestinal membrane by sustained release properties.Key words solid lipid nanoparticle; polyvinyl alcohol; morin; bioavailability; hard fat Polyphenols are a large and diverse class of compounds that are classified as flavonoids, hydroxycinnamic acids, stilbene derivatives, and polymers. 1) Many polyphenols occur naturally in foods, such as beans, cereals, fruits, vegetables, and red wine.2) The biological properties of polyphenols and their role in preventing or ameliorating diseases related to oxidation is attracting increasing interest. Morin (3,5,7,2′,4′-pentahydroxyflavone) is a flavonoid that has been identified in fruits, vegetables, tea, and many Asian medicinal herbs.3) Morin has a number of potentially useful biological activities, including anti-inflammatory, anticancer, antioxidant, antihypertensive, and anticlastogenic responses. [4][5][6][7][8] Unsaturated fatty acids are the most important structural components of biological membranes and help maintain the fluidity of the cellular membrane structure. The peroxidation of unsaturated fatty acids in biological membranes disrupts their structure and function.9,10) Lipid peroxidation has been implicated in the pathogenesis of various diseases, such as coronary heart disease, atherosclerosis, and cancer, as well as the ageing process. 11-14)Morin has been suggested as an inhibitor of lipid peroxidation. However, the absolute bioavailability of morin after a single oral dose is very low (less than 1%), likely because of its low aqueous solubility, P-glycoprotein (P-gp...
The aim of the present study was to investigate the influence of polysorbate 60 (Tween 60) on the development of morin-loaded nanoemulsions to improve the oral bioavailability of morin. Nanoemulsions were prepared using Tween 60 and polyvinyl alcohol (PVA) as emulsifiers, and medium chain triglycerides (MCT) as the lipid base. Low-saponification-degree PVA (LL-810) was also added to stabilize dispersed droplets. MCT-LL810 nanoemulsion containing LL-810 was prepared with a reduced amount of Tween 60. However, the area under the blood concentration-time curve (AUC) of MCT-LL810 (0.18) nanoemulsion containing a small amount of Tween 60 did not increase because the absorption of morin was limited by P-glycoprotein (P-gp)-mediated efflux. MCT-LL810 (0.24) nanoemulsion containing a large amount of Tween 60 showed the highest AUC, dispersed droplets containing Tween 60 may have been transported into epithelial cells in the small intestine, and P-gp transport activity appeared to be suppressed by permeated Tween 60. Based on the plasma concentration profile, dispersed droplets in MCT-LL810 (0.24) nanoemulsion permeated more rapidly through the mucus layer and the intestinal membrane than MCT (0.24) nanoemulsion without LL-810. In conclusion, a novel feature of Tween 60 incorporated into the dispersed droplets of a nanoemulsion interacting with P-gp was demonstrated herein. Dispersed droplets in MCT-LL810 (0.24) nanoemulsion containing LL-810 permeated rapidly through the mucus layer and intestinal membrane, and Tween 60 incorporated in dispersed droplets interacted with P-gp-mediated efflux, increasing the bioavailability of morin.Key words nanoemulsion; morin; polyvinyl alcohol; bioavailability; P-glycoprotein Morin (2′,4′,3,5,7-pentahydroxyflavonoid) is one of the flavonoids widely found in fruits, vegetables, tea, and numerous therapeutic herbs.1) Its wide spectrum of biological activities, including anti-inflammatory, anti-cancer, antioxidant, antiangiogenic, anti-hypertensive, and anti-clastogenic activities, have been reported. [2][3][4][5][6][7][8] We previously demonstrated that a treatment with morin induced basal nitric oxide production and rapid improvements in endothelial function in diabetic mice.9) Morin has been suggested to improve the development of endothelial dysfunction by diabetes. However, the absolute bioavailability of morin after its oral administration is very low (less than 1%), and this may be attributed to its low aqueous solubility, P-glycoprotein (P-gp)-mediated efflux, and low intestinal permeability. [10][11][12] Various approaches have been attempted in order to increase the area under the blood concentration-time curve (AUC) of low bioavailability drugs after their oral administration. Nanoemulsion systems have received increasing attention as appropriate carriers for insoluble active compounds to increase bioavailability and modify drug release characteristics. [13][14][15] Improvements in the solubility of drugs into nanoemulsion components such as the oil phase and surfactants repre...
The purpose of the present work was to evaluate polyvinyl alcohols (PVAs) as a mucoadhesive polymer for mucoadhesive buccal tablets prepared by direct compression. Various polymerization degree and particle diameter PVAs were investigated for their usability. The tensile strength, in vitro adhesive force, and water absorption properties of the tablets were determined to compare the various PVAs. The highest values of the tensile strength and the in vitro adhesive force were observed for PVAs with a medium viscosity and small particle size. The optimal PVA was identified by a factorial design analysis. Mucoadhesive tablets containing the optimal PVA were compared with carboxyvinyl polymer and hydroxypropyl cellulose formulations. The optimal PVA gives a high adhesive force, has a low viscosity, and resulted in relatively rapid drug release. Formulations containing carboxyvinyl polymer had high tensile strengths but short disintegration times. Higher hydroxypropyl cellulose concentration formulations had good adhesion forces and very long disintegration times. We identified the optimal characteristics of PVA, and the usefulness of mucoadhesive buccal tablets containing this PVA was suggested from their formulation properties.
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