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

Noriaki Nagai,Mizuki Yamaguchi,Fumihiko Ogata,Naohito Kawasaki,Yosuke Nakazawa,Yuya Fukuoka,Hiroko Otake

doi:10.3390/ijms20153644

Noriaki Nagai, Mizuki Yamaguchi + Show 5 more

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https://doi.org/10.3390/ijms20153644

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Abstract

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).

Highlights

Indomethacin (IMC) is a non-steroidal anti-inflammatory drug (NSAIDs) that is widely prescribed as therapy for inflammation, fever and pain
The particles were uniformly dispersed in the transdermal formulations containing IMC solid nanoparticles (SNPs) with (N-IMC/MT gel) or without l-menthol (N-IMC gel), and no drug degradation was observed after 30 days (Figures 2A and 3D)
It was found that the skin penetration of 50–200 nm IMC was low, the combination with l-menthol enhanced the skin penetration of IMC SNPs with 50–200 nm particles

Summary

Introduction

Indomethacin (IMC) is a non-steroidal anti-inflammatory drug (NSAIDs) that is widely prescribed as therapy for inflammation, fever and pain. The Biopharmaceutical Classification System (BCS) lists indomethacin as a Class II drug, and the pK and logP of IMC are 4.5, 2.2, respectively. The IMC acts by blocking cyclooxygenase (COX), which is involved in the synthesis of prostaglandins from arachidonic acid. The inhibition of COX by the oral administration of IMC decreases defense functions in the gastrointestinal system and is associated with undesirable side effects involving gastroduodenal mucosal injury [1,2,3]. It has been reported that the decreased defense function increased the direct stimulation by IMC in the gastrointestinal system, and that this stimulation was related to the onset of gastroduodenal mucosal injury [4,5]. One well-known method to avoid the problems associated with these side effects involves transdermal drug delivery (TDD)

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