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

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).

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Involvement of Endocytosis in the Transdermal Penetration Mechanism of Ketoprofen Nanoparticles

International Journal of Molecular Sciences ◽

10.3390/ijms19072138 ◽

2018 ◽

Vol 19 (7) ◽

pp. 2138 ◽

Cited By ~ 9

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.

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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

International Journal of Molecular Sciences ◽

10.3390/ijms22105137 ◽

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.

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The Permeability of Poly(lactic-co-glycolic acid) Nanoparticles Loaded with Psoralen to Human Skin in Medical Chemotherapy

Nanoscience and Nanotechnology Letters ◽

10.1166/nnl.2020.3088 ◽

2020 ◽

Vol 12 (2) ◽

pp. 163-169

Author(s):

Liangming Li ◽

Aihua Yang

Keyword(s):

Side Effects ◽

Human Skin ◽

Plga Nanoparticles ◽

Transdermal Drug Delivery System ◽

Franz Diffusion Cell ◽

Clinical Methods ◽

Solvent Replacement ◽

Polymer Deposition ◽

Laser Confocal Microscope

Objective: In order to improve the clinical efficacy and reduce the side effects, PLGA nanoparticles loaded with psoralen for external use were prepared, and the permeation, distribution and influencing factors of PLGA nanoparticles delivered via microneedles in human skin were investigated. Methods: The psoralen nanoparticles were prepared by solvent replacement and interfacial polymer deposition. The percutaneous process of PLGA nanoparticles loaded with psoralen was observed with Franz diffusion cell and laser confocal microscope. The distribution of the nanoparticles in each cortex was quantified by HPLC. Results: The retention of PLGA nanoparticles delivered via microneedles in the skin was significantly increased (P < 0.01), and the retention in the epidermis was greater than that in the dermis (P < 0.01); the release rate in vitro was 75.58% after 24 hours, and less than 0.5% after 48 hours. Conclusion: PLGA nanoparticles loaded with psoralen can effectively promote the penetration and distribution of PLGA nanoparticles in human skin after being delivered to human skin through microneedles. With the increase of depth, the amount of PLGA nanoparticles gradually decreases, and with the extension of time, the penetration promotion effect of microneedles is more obvious. PLGA nanoparticles loaded with psoralen may become one of the clinical methods to improve the photochemotherapy of psoralen and develop a new transdermal drug delivery system to reduce its toxic and side effects.

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Preparation and in vitro characterization of the transdermal drug delivery system containing tamoxifen citrate for breast cancer

Asian Journal of Pharmaceutics ◽

10.4103/0973-8398.80068 ◽

2011 ◽

Vol 5 (1) ◽

pp. 41 ◽

Cited By ~ 1

Author(s):

Anjana Adhyapak ◽

BG Desai

Keyword(s):

Breast Cancer ◽

Drug Delivery ◽

Drug Delivery System ◽

Delivery System ◽

Transdermal Drug Delivery ◽

Transdermal Drug Delivery System ◽

In Vitro Characterization ◽

Tamoxifen Citrate

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In vitro characterization of the percutaneous absorption of tramadol into inner ear domestic feline skin using the Franz skin finite dose model

Veterinary Medicine and Animal Sciences ◽

10.7243/2054-3425-3-3 ◽

2015 ◽

Vol 3 (1) ◽

pp. 3 ◽

Cited By ~ 1

Author(s):

August S Bassani ◽

Daniel Banov ◽

Chris Simmons ◽

Ha Phan

Keyword(s):

Inner Ear ◽

Percutaneous Absorption ◽

In Vitro Characterization ◽

Dose Model

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PENETRATION TEST OF CAFFEINE IN ETHOSOME AND DESMOSOME GEL USING AN IN VITRO METHOD

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2017.v9s1.69_76 ◽

2017 ◽

Vol 9 ◽

pp. 120

Author(s):

Iskandarsyah Iskandarsyah ◽

Alvina Wijaya Puteri ◽

Ernysagita Ernysagita

Keyword(s):

Dimethyl Sulfoxide ◽

Percutaneous Absorption ◽

Lipid Vesicles ◽

Penetration Enhancer ◽

Diffusion Cell ◽

Penetration Test ◽

In Vitro Method ◽

Franz Diffusion Cell

Objectives: Caffeine has many functions including its use in the field of cosmetics. Nonetheless, the percutaneous absorption of caffeine is very low(9%), and the penetration of a substance such as caffeine in the skin is not desirable. Ethosomes and desmosomes are lipid vesicles created by themodification of liposomes containing phospholipids and ethanol or dimethyl sulfoxide (DMSO) as the penetration enhancer. The purpose of this studywas to compare the effectiveness of ethosomes and desmosomes as vesicles in increasing the penetration of caffeine.Methods: Ethosomes and desmosomes were prepared using phosphatidylcholine, ethanol/DMSO, and caffeine. Phosphatidylcholine was used in theform of phospholipon 90 g that was obtained from soybeans. Observations were done including the characteristic of ethosomes and desmosomes,organoleptic observation, homogeneity observation, and in vitro penetration test using Franz diffusion cell method.Results: The cumulative penetration of caffeine ethosome gel is 3316.46±218.51 μg/cm2, with flux 249.45±30.06 μg·cm−2·hr−1, and 62.35±4.52%. Thecumulative penetration of the desmosome gel is 2954.95±222.87 μg/cm2 with flux 381.68±34.91 μg·cm−2·hr−1 and 53.4±3.65%.Conclusions: It can be concluded that ethosome is more effective than desmosome in increasing the penetration of caffeine.

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