scholarly journals Involvement of Endocytosis in the Transdermal Penetration Mechanism of Ketoprofen Nanoparticles

2018 ◽  
Vol 19 (7) ◽  
pp. 2138 ◽  
Author(s):  
Noriaki Nagai ◽  
Fumihiko Ogata ◽  
Miyu Ishii ◽  
Yuya Fukuoka ◽  
Hiroko Otake ◽  
...  
Keyword(s):  
Skin Penetration ◽  
Cytochalasin D ◽  
Significant Information ◽  
Bead Mill ◽  
Penetration Mechanism ◽  
Auc Value ◽  
The Mean ◽  
Transdermal Penetration ◽  
Energy Dependent ◽  
Transdermal Formulation

We previously designed a novel transdermal formulation containing ketoprofen solid nanoparticles (KET-NPs formulation), and showed that the skin penetration from the KET-NPs formulation was higher than that of a transdermal formulation containing ketoprofen microparticles (KET-MPs formulation). However, the precise mechanism for the skin penetration from the KET-NPs formulation was not clear. In this study we investigated whether energy-dependent endocytosis relates to the transdermal delivery from a 1.5% KET-NPs formulation. Transdermal formulations were prepared by a bead mill method using additives including methylcellulose and carbopol 934. The mean particle size of the ketoprofen nanoparticles was 98.3 nm. Four inhibitors of endocytosis dissolved in 0.5% DMSO (54 μM nystatin, a caveolae-mediated endocytosis inhibitor; 40 μM dynasore, a clathrin-mediated endocytosis inhibitor; 2 μM rottlerin, a macropinocytosis inhibitor; 10 μM cytochalasin D, a phagocytosis inhibitor) were used in this study. In the transdermal penetration study using a Franz diffusion cell, skin penetration through rat skin treated with cytochalasin D was similar to the control (DMSO) group. In contrast to the results for cytochalasin D, skin penetration from the KET-NPs formulation was significantly decreased by treatment with nystatin, dynasore or rottlerin with penetrated ketoprofen concentration-time curves (AUC) values 65%, 69% and 73% of control, respectively. Furthermore, multi-treatment with all three inhibitors (nystatin, dynasore and rottlerin) strongly suppressed the skin penetration from the KET-NPs formulation with an AUC value 13.4% that of the control. In conclusion, we found that caveolae-mediated endocytosis, clathrin-mediated endocytosis and macropinocytosis are all related to the skin penetration from the KET-NPs formulation. These findings provide significant information for the design of nanomedicines in transdermal formulations.

scholarly journals Energy-Dependent Endocytosis Is Responsible for Skin Penetration of Formulations Based on a Combination of Indomethacin Nanoparticles and l-Menthol in Rat and Göttingen Minipig

2021 ◽  
Vol 22 (10) ◽  
pp. 5137
Author(s):  
Hiroko Otake ◽  
Mizuki Yamaguchi ◽  
Fumihiko Ogata ◽  
Saori Deguchi ◽  
Naoki Yamamoto ◽  
...  
Keyword(s):  
Skin Penetration ◽  
The Other ◽  
Skin Tissue ◽  
Significant Information ◽  
Detailed Mechanism ◽  
Carbopol Gel ◽  
Göttingen Minipig ◽  
Bead Mill ◽  
Transdermal Penetration ◽  
Energy Dependent

We previously designed a Carbopol gel formulation (N-IND/MEN) based on a combination of indomethacin solid nanoparticles (IND-NPs) and l-menthol, and we reported that the N-IND/MEN showed high transdermal penetration. However, the detailed mechanism for transdermal penetration of IND-NPs was not clearly defined. In this study, we investigated whether endocytosis in the skin tissue of rat and Göttingen minipig is related to the transdermal penetration of IND-NPs using pharmacological inhibitors of endocytosis. The pharmacological inhibitors used in this study are as follows: 54 µM nystatin, a caveolae-mediated endocytosis (CavME) inhibitor; 40 µM dynasore, a clathrin-mediated endocytosis (CME) inhibitor; and 2 µM rottlerin, a micropinocytosis (MP) inhibitor. The N-IND/MEN was prepared by a bead mill method, and the particle size of solid indomethacin was 79–216 nm. In both rat and Göttingen minipig skin, skin penetration of approximately 80% IND-NPs was limited by the stratum corneum (SC), although the penetration of SC was improved by the combination of l-menthol. On the other hand, the treatment of nystatin and dynasore decreased the transdermal penetration of indomethacin in rats and Göttingen minipigs treated with N-IND/MEN. Moreover, in addition to nystatin and dynasore, rottlerin attenuated the transdermal penetration of IND-NPs in the Göttingen minipigs’ skin. In conclusion, we found that l-menthol enhanced the SC penetration of IND-NPs. In addition, this study suggests that the SC-passed IND-NPs are absorbed into the skin tissue by energy-dependent endocytosis (CavME, CME, and/or MP pathways) on the epidermis under the SC, resulting in an enhancement in transdermal penetration of IND-NPs. These findings provide significant information for the design of nanomedicines in transdermal formulations.

scholarly journals Combination with l-Menthol Enhances Transdermal Penetration of Indomethacin Solid Nanoparticles

2019 ◽  
Vol 20 (15) ◽  
pp. 3644 ◽  
Author(s):  
Noriaki Nagai ◽  
Fumihiko Ogata ◽  
Mizuki Yamaguchi ◽  
Yuya Fukuoka ◽  
Hiroko Otake ◽  
...  
Keyword(s):  
Percutaneous Absorption ◽  
Skin Penetration ◽  
Particle Characterization ◽  
Transdermal Drug Delivery System ◽  
Franz Diffusion Cell ◽  
Bead Mill ◽  
Transdermal Penetration ◽  
Energy Dependent

This study designed the transdermal formulations containing indomethacin (IMC)—1% IMC was crushed with 0.5% methylcellulose and 5% 2-hydroxypropyl-β-cyclodextrin by the bead mill method, and the milled IMC was gelled with or without 2% l-menthol (a permeation enhancer) by Carbopol® 934 (without menthol, N-IMC gel; with menthol, N-IMC/MT gel). In addition, the drug release, skin penetration and percutaneous absorption of the N-IMC/MT gel were investigated. The particle sizes of N-IMC gel were approximately 50–200 nm, and the combination with l-menthol did not affect the particle characterization of the transdermal formulations. In an in vitro experiment using a Franz diffusion cell, the skin penetration in N-IMC/MT gel was enhanced than the N-IMC gel, and the percutaneous absorption (AUC) from the N-IMC/MT gel was 2-fold higher than the N-IMC gel. On the other hand, the skin penetration from the N-IMC/MT gel was remarkably attenuated at a 4 °C condition, a temperature that inhibits all energy-dependent endocytosis. In conclusion, this study designed transdermal formulations containing IMC solid nanoparticles and l-menthol, and found that the combination with l-menthol enhanced the skin penetration of the IMC solid nanoparticles. In addition, the energy-dependency of the skin penetration of IMC solid nanoparticles was demonstrated. These findings suggest the utility of a transdermal drug delivery system to provide the easy application of solid nanoparticles (SNPs).

scholarly journals In Situ Gelling Systems Using Pluronic F127 Enhance Corneal Permeability of Indomethacin Nanocrystals

2020 ◽  
Vol 21 (19) ◽  
pp. 7083
Author(s):  
Noriaki Nagai ◽  
Takumi Isaka ◽  
Saori Deguchi ◽  
Misa Minami ◽  
Mizuki Yamaguchi ◽  
...  
Keyword(s):  
Pluronic F127 ◽  
Significant Information ◽  
Corneal Permeability ◽  
Enhanced Absorption ◽  
Bead Mill ◽  
Resident Time ◽  
Energy Dependent ◽  
Corneal Permeation ◽  
In Situ Gelling

We previously designed an ophthalmic dispersion containing indomethacin nanocrystals (IMC-NCs), showing that multiple energy-dependent endocytoses led to the enhanced absorption of drugs from ocular dosage forms. In this study, we attempted to prepare Pluronic F-127 (PLF-127)-based in situ gel (ISG) incorporating IMC-NCs, and we investigated whether the instillation of the newly developed ISG incorporating IMC-NCs prolonged the precorneal resident time of the drug and improved ocular bioavailability. The IMC-NC-incorporating ISG was prepared using the bead-mill method and PLF-127, which yielded a mean particle size of 50–150 nm. The viscosity of the IMC-NC-incorporating ISG was higher at 37 °C than at 10 °C, and the diffusion and release of IMC-NCs in the IMC-NC-incorporating ISG were decreased by PLF-127 at 37 °C. In experiments using rabbits, the retention time of IMC levels in the lacrimal fluid was enhanced with PLF-127 in the IMC-NC-incorporating ISG, whereby the IMC-NC-incorporating ISG with 5% and 10% PLF-127 increased the transcorneal penetration of the IMCs. In contrast to the results with optimal PLF-127 (5% and 10%), excessive PLF-127 (15%) decreased the uptake of IMC-NCs after instillation. In conclusion, we found that IMC-NC-incorporating ISG with an optimal amount of PLF-127 (5–10%) resulted in higher IMC corneal permeation after instillation than that with excessive PLF-127, probably because of the balance between higher residence time and faster diffusion of IMC-NCs on the ocular surface. These findings provide significant information for developing ophthalmic nanomedicines.

scholarly journals Nanocrystalline Suspensions of Irbesartan Enhance Oral Bioavailability by Improving Drug Solubility and Leading Endocytosis Uptake into the Intestine

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1404
Author(s):  
Saori Deguchi ◽  
Fumihiko Ogata ◽  
Masaki Watanabe ◽  
Hiroko Otake ◽  
Naoki Yamamoto ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Intestinal Absorption ◽  
Antihypertensive Effect ◽  
The Other ◽  
Drug Solubility ◽  
Inclusion Complex Formation ◽  
Significant Information ◽  
Spontaneously Hypertensive ◽  
Bead Mill ◽  
The Mean

We attempted to design irbesartan nanocrystalline (IRB-NC) suspensions by the bead mill method, and we evaluated the bioavailability (BA) in the oral administration of the nanocrystalline drug. The mean particle size of the IRB-NC suspensions was approximately 140 nm, and the crystalline structure of irbesartan in these suspensions was different using the bead mill method. The aggregation and degradation of irbesartan were not observed for one month, and the solubility increased. Moreover, the inclusion complex formation of IRB-NC suspensions with 2-hydroxypropyl-β-cyclodextrin was higher than that in traditional IRB powder (IRB-P). In addition, the intestinal absorption of IRB-NC suspensions was higher than that of IRB-P suspensions, and the reducing effect on blood pressure in spontaneously hypertensive SHR-SP rats orally administered IRB-NC suspensions was significantly higher than in those administered IRB-P suspensions. On the other hand, the intestinal penetration of IRB-NC suspensions was attenuated by the inhibitors of clathrin-dependent endocytosis (CME). In conclusion, we improved the low oral BA of irbesartan by preparing IRB-NC suspensions and showed that both the solubility and CME are related to the enhanced intestinal absorption of IRB-NC suspensions, resulting in an increase in their antihypertensive effect. These findings provide significant information for the development of oral nanomedicines.

Study on the transdermal penetration mechanism of ibuprofen nanoemulsions

2018 ◽  
Vol 45 (3) ◽  
pp. 465-473
Author(s):  
Li Zhengguang ◽  
Huang Jie ◽  
Zhang Yong ◽  
Cao Jiaojiao ◽  
Wang Xingqi ◽  
...  
Keyword(s):  
Penetration Mechanism ◽  
Transdermal Penetration

scholarly journals Mean Received Resources Meet Machine Learning Algorithms to Improve Link Prediction Methods

Information ◽  
2022 ◽  
Vol 13 (1) ◽  
pp. 35
Author(s):  
Jibouni Ayoub ◽  
Dounia Lotfi ◽  
Ahmed Hammouch
Keyword(s):  
Machine Learning ◽  
Link Prediction ◽  
Learning Algorithms ◽  
Area Under The Curve ◽  
Machine Learning Algorithms ◽  
Actual State ◽  
The Future ◽  
Auc Value ◽  
The Mean ◽  
Analysis Of Social Networks

The analysis of social networks has attracted a lot of attention during the last two decades. These networks are dynamic: new links appear and disappear. Link prediction is the problem of inferring links that will appear in the future from the actual state of the network. We use information from nodes and edges and calculate the similarity between users. The more users are similar, the higher the probability of their connection in the future will be. The similarity metrics play an important role in the link prediction field. Due to their simplicity and flexibility, many authors have proposed several metrics such as Jaccard, AA, and Katz and evaluated them using the area under the curve (AUC). In this paper, we propose a new parameterized method to enhance the AUC value of the link prediction metrics by combining them with the mean received resources (MRRs). Experiments show that the proposed method improves the performance of the state-of-the-art metrics. Moreover, we used machine learning algorithms to classify links and confirm the efficiency of the proposed combination.

scholarly journals Exposure of Agriculture Workers to Pesticides: The Effect of Heat on Protective Glove Performance and Skin Exposure to Dichlorvos

2019 ◽  
Vol 16 (23) ◽  
pp. 4798 ◽  
Author(s):  
Leigh Thredgold ◽  
Sharyn Gaskin ◽  
Chloe Quy ◽  
Dino Pisaniello
Keyword(s):  
Skin Penetration ◽  
Fold Increase ◽  
Organophosphate Insecticide ◽  
Temperature Dependent ◽  
Thermal Environments ◽  
Transdermal Penetration ◽  
Dermal Uptake ◽  
Chemical Permeation ◽  
Published Research ◽  
Kinetics Of

Dichlorvos is a toxic organophosphate insecticide that is used in agriculture and other insecticide applications. Dermal uptake is a known exposure route for dichlorvos and chemical protective gloves are commonly utilized. Chemical handling and application may occur in a variety of thermal environments, and the rates of both chemical permeation through gloves and transdermal penetration may vary significantly with temperature. There has been no published research on the temperature-dependent kinetics of these processes for dichlorvos and thus, this study reports on the effects of hot conditions for the concentrated and application strength chemical. Dichlorvos breakthrough times for non-disposable polyvinyl chloride (PVC) gloves at 60 °C were approximately halved compared to 25 °C for the concentrate (2 vs. 4 h) and more than halved at application strength (3 vs. >8 h). From permeation experiments covering 15–60 °C, there was a 460-fold increase in cumulative permeation over 8 h for the concentrated dichlorvos and the estimated activation energy halved. Elevated temperature was also shown to be a significant factor for human skin penetration increasing the cumulative penetration of concentrate dichlorvos from 179 ± 37 to 1315 ± 362 µg/cm2 (p = 0.0032) and application strength from 29.8 ± 5.7 to 115 ± 19 µg/cm2 (p = 0.0131). This work illustrates the important role temperature plays in glove performance and health risk via dermal exposure. As such, it is important to consider in-use conditions of temperature when implementing chemical hygiene programs.

scholarly journals Prediction of malignant glioma grades using contrast-enhanced T1-weighted and T2-weighted magnetic resonance images based on a radiomic analysis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Takahiro Nakamoto ◽  
Wataru Takahashi ◽  
Akihiro Haga ◽  
Satoshi Takahashi ◽  
Shigeru Kiryu ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Malignant Glioma ◽  
Prediction Models ◽  
Magnetic Resonance Images ◽  
Validation Dataset ◽  
Independent Validation ◽  
Contrast Enhanced ◽  
Auc Value ◽  
The Mean ◽  
Grade Iii

AbstractWe conducted a feasibility study to predict malignant glioma grades via radiomic analysis using contrast-enhanced T1-weighted magnetic resonance images (CE-T1WIs) and T2-weighted magnetic resonance images (T2WIs). We proposed a framework and applied it to CE-T1WIs and T2WIs (with tumor region data) acquired preoperatively from 157 patients with malignant glioma (grade III: 55, grade IV: 102) as the primary dataset and 67 patients with malignant glioma (grade III: 22, grade IV: 45) as the validation dataset. Radiomic features such as size/shape, intensity, histogram, and texture features were extracted from the tumor regions on the CE-T1WIs and T2WIs. The Wilcoxon–Mann–Whitney (WMW) test and least absolute shrinkage and selection operator logistic regression (LASSO-LR) were employed to select the radiomic features. Various machine learning (ML) algorithms were used to construct prediction models for the malignant glioma grades using the selected radiomic features. Leave-one-out cross-validation (LOOCV) was implemented to evaluate the performance of the prediction models in the primary dataset. The selected radiomic features for all folds in the LOOCV of the primary dataset were used to perform an independent validation. As evaluation indices, accuracies, sensitivities, specificities, and values for the area under receiver operating characteristic curve (or simply the area under the curve (AUC)) for all prediction models were calculated. The mean AUC value for all prediction models constructed by the ML algorithms in the LOOCV of the primary dataset was 0.902 ± 0.024 (95% CI (confidence interval), 0.873–0.932). In the independent validation, the mean AUC value for all prediction models was 0.747 ± 0.034 (95% CI, 0.705–0.790). The results of this study suggest that the malignant glioma grades could be sufficiently and easily predicted by preparing the CE-T1WIs, T2WIs, and tumor delineations for each patient. Our proposed framework may be an effective tool for preoperatively grading malignant gliomas.

scholarly journals Energy-Dependent Endocytosis is Involved in the Absorption of Indomethacin Nanoparticles in the Small Intestine

2019 ◽  
Vol 20 (3) ◽  
pp. 476 ◽  
Author(s):  
Miyu Ishii ◽  
Yuya Fukuoka ◽  
Saori Deguchi ◽  
Hiroko Otake ◽  
Tadatoshi Tanino ◽  
...  
Keyword(s):  
Small Intestine ◽  
Intestinal Epithelium ◽  
Cytochalasin D ◽  
Therapeutic Effects ◽  
Rat Intestine ◽  
Drug Nanoparticles ◽  
Oral Formulations ◽  
Basolateral Side ◽  
Energy Dependent ◽  
High Bioavailability

We previously reported that oral formulations containing indomethacin nanoparticles (IND-NPs) showed high bioavailability, and, consequently, improved therapeutic effects and reduced injury to the small intestine. However, the pathway for the transintestinal penetration of nanoparticles remained unclear. Thus, in this study, we investigated whether endocytosis was related to the penetration of IND-NPs (72.1 nm) using a transcell set with Caco-2 cells or rat intestine. Four inhibitors of various endocytosis pathways were used [nystatin, caveolae-dependent endocytosis (CavME); dynasore, clathrin-dependent endocytosis (CME); rottlerin, macropinocytosis; and cytochalasin D, phagocytosis inhibitor], and all energy-dependent endocytosis was inhibited at temperatures under 4 °C in this study. Although IND-NPs showed high transintestinal penetration, no particles were detected in the basolateral side. IND-NPs penetration was strongly prevented at temperatures under 4 °C. In experiments using pharmacological inhibitors, only CME inhibited penetration in the jejunum, while in the ileum, both CavME and CME significantly attenuated penetration. In conclusion, we found a novel pathway for the transintestinal penetration of drug nanoparticles. Our hypothesis was that nanoparticles would be taken up into the intestinal epithelium by endocytosis (CME in jejunum, CavME and CME in ileum), and dissolved and diffused in the intestine. Our findings are likely to be of significant use for the development of nanomedicines.

Accurate measurements of mean inner potential of crystal wedges using electron holography

1992 ◽  
Vol 50 (1) ◽  
pp. 134-135
Author(s):  
M. Gajdardziska-Josifovska ◽  
M. R. McCartney ◽  
J. K. Weiss
Keyword(s):  
Phase Change ◽  
Electron Holography ◽  
Specimen Thickness ◽  
Electron Wave ◽  
Flat Surfaces ◽  
Numerical Reconstruction ◽  
Digital Holograms ◽  
The Mean ◽  
Energy Dependent ◽  
Magnetic Electron

The phase of an electron wave which has interacted with a material is measured in electron holography experiments with respect to a coherent reference wave which has travelled through vacuum. In non-magnetic electron-transparent materials, and under kinematical diffracting conditions, the phase change (Δφ) of the transmitted electron wave depends only on the thickness (t) and the mean inner potential (Ui) of the material: Δφ = c |Ui| t; c being an energy-dependent constant. This phase change measured from electron holograms has been used previously to determine the mean inner potential of amorphous and polycrystalline films of known thicknesses. Refraction effects in RHEED patterns have also been used to determine the mean inner potential of several crystals with flat surfaces. The reported accuracies in these studies have ranged from 2.5% to 9.5%, although uncertainties in specimen thickness and the unknown effects of surface contamination and/or reconstruction are very likely sources of systematic errors. This paper shows that numerical reconstruction of digital holograms, combined with use of cleaved crystal wedges, enables measurement of the mean inner potential of crystals with enhanced accuracy.

Sign in / Sign up

Export Citation Format

Share Document