Detection of Raspberry Ketone after Percutaneous Absorption of Rhododendrol-Containing Cosmetics and Its Mechanism of Formation

Here, we aimed to elucidate the mechanism of rhododendrol (RD)-induced leukoderma. We investigated the skin permeability of RD in an aqueous solution and in different cosmetic formulations (lotion and emulsion) in an in vitro skin permeation study. The samples were analyzed using high-performance liquid chromatography (HPLC), and an unknown substance appeared on the spectrum. For identification, we analyzed various possible substances, such as raspberry ketone (RK) and rhododendrol quinone, using HPLC and then compared the detected absorption spectra and further verified the matched components using liquid chromatography–mass spectrometry. The unknown substance was found to be RK. To clarify the mechanism of formation of RK, we conducted a 24-hour skin permeation test on heat-treated skin. By quantifying the RK in the samples using HPLC, we observed that an enzyme in the skin seemed to be the cause of RK generation and that the components of the emulsion formulation could also be a cause. To investigate the enzyme, we reacted alcohol dehydrogenase with RD and observed that it was one of the converting enzymes. As RK has been reported to be a substance that causes leukoderma, the intraepidermal metabolism of RD to RK may be one of the mechanisms of susceptibility to leukoderma.

Glimepiride-Loaded Nanoemulgel; Development, In Vitro Characterization, Ex Vivo Permeation and In Vivo Antidiabetic Evaluation

Glimepiride (GMP), an oral hypoglycemic agent is extensively employed in the treatment of type 2 diabetes. Transdermal delivery of GMP has been widely investigated as a promising alternative to an oral approach but the delivery of GMP is hindered owing to its low solubility and permeation. The present study was designed to formulate topical nanoemulgel GMP system and previously reported solubility enhanced glimepiride (GMP/βCD/GEL-44/16) in combination with anti-diabetic oil to enhance the hypoglycemic effect. Nanoemulsions were developed using clove oil, Tween-80, and PEG-400 and were gelled using xanthan gum (3%, w/w) to achieve the final nanoemulgel formulations. All of the formulations were evaluated in terms of particle size, zeta potential, pH, conductivity, viscosity, and in vitro skin permeation studies. In vivo hypoglycemic activity of the optimized nanoemulgel formulations was evaluated using a streptozocin-induced diabetes model. It was found that a synergistic combination of GMP with clove oil improved the overall drug permeation across the skin membrane and the hypoglycemic activity of GMP. The results showed that GMP/βCD/GEL-44/16-loaded nanoemulgel enhanced the in vitro skin permeation and improved the hypoglycemic activity in comparison with pure and marketed GMP. It is suggested that topical nano emulsion-based GMP gel and GMP/βCD/GEL-44/16 could be an effective alternative for oral therapy in the treatment of diabetes.

In Vitro Skin Permeation of Idebenone from Lipid Nanoparticles Containing Chemical Penetration Enhancers

Lipid nanoparticles (LNPs) have been proposed as carriers for drug skin delivery and targeting. As LNPs effectiveness could be increased by the addition of chemical penetration enhancers (PE), in this work, the feasibility of incorporating PE into LNPs to improve idebenone (IDE) targeting to the skin was investigated. LNPs loading IDE 0.7% w/w were prepared using hydrophilic (propylene glycol, PG, 10% w/w or N-methylpyrrolidone, NMP, 10% w/w) and/or lipophilic PE (oleic acid, OA, 1% w/w; isopropyl myristate, IPM, 3.5% w/w; a mixture of 0.5% w/w OA and 2.5% w/w IPM). All LNPs showed small sizes (<60 nm), low polydispersity index and good stability. According to the obtained results, IDE release from LNPs was not the rate-limiting step in IDE skin penetration. No IDE permeation was observed through excised pigskin from all LNPs, while the greatest increase of IDE penetration into the different skin layers was obtained using the mixture OA/IPM. The antioxidant activity of IDE-loaded LNPs, determined by the oxygen radical absorbance capacity assay, was greater than that of free IDE. These results suggest that the use of suitable PE as LNPs components could be regarded as a promising strategy to improve drug targeting to the skin.

Design and optimization of nano invasomal gel of Glibenclamide and Atenolol combination: in vitro and in vivo evaluation

Background There are many circumstances where chronic disease is associated with other disorders, especially in diseases such as diabetes with noncommunicable disease risk factors, such as hypertension. The current therapies for treating such chronic comorbid diseases are limited and challenging due to the difficulties in overcoming the side effects from complex therapeutic treatment regimen. The present study is aimed to develop and optimize the combinational nano invasomal gel of Glibenclamide (GLB) and Atenolol (ATN) as a novel combination therapy for comorbid treatment of diabetic hypertensive patients. The developed formulations were characterized for various parameters, including in-vitro skin permeation, skin irritation, in-vivo antidiabetic, and antihypertensive activities. Results OCNIG showed that the % entrapment efficiency of GLB is 96.67 ± 0.65% and % entrapment efficiency of ATN is 93.76 ± 0.89%, flux of GLB (240.43 ± 1.76 μg/cm2/h), and flux of ATN (475.2 ± 1.54 μg/cm2/h) which was found to conform to the expected value. The results indicated desired release and permeation profiles. Optimized formulation showed significant pharmacokinetic properties, which shows improvement in bioavailability by 134.30% and 180.32% respectively for two drugs, when compared to marketed oral preparation. Pharmacodynamic studies showed improved and prolonged management of diabetes and hypertension in Wistar rats, compared to oral and drug-loaded nano invasomes formulations. Conclusion Overall, the results showed that nano invasomal gel was found to be a useful and promising transdermal delivery system for the treatment of concurrent diseases.

In vitro investigation of metabolic fate of α-mangostin and gartanin via skin permeation by LC-MS/MS and in silico evaluation of the metabolites by ADMET predictor™

Background Mangosteen, Garciniam angostana L., is a juicy fruit commonly found in Thailand. The rinds of Garciniam angostana L.have been used as a traditional medicine for the treatment of trauma, diarrhea and skin infection. It is also used in dermatological product such as in cosmetics. The mangosteen pericarp can be used to extract valuable bioactive xanthone compounds such as α-mangostin and gartanin. This study is aimed to predict the metabolism of α-mangostin and gartanin using in silico and in vitro skin permeation strategies. Methods Based on their 2D molecular structures, metabolites of those compounds were predicted in silico using ADMET Predictor™. The Km and Vmax, for 5 important recombinant CYP isozymes 1A2, 2C9, 2C19, 2D6 and 3A4 were predicted. Moreover, the in vitro investigation of metabolites produced during skin permeation using human epidermal keratinocyte cells, neonatal (HEKn cells) was performed by LC-MS/MS. Results It was found that the results derived from in silico were in excellent alignment with those obtained from in vitro studies for both compounds. The prediction referred that gartanin and α-mangostin were the substrate of CYP1A2, 2C9, 2C19 and 3A. In the investigation of α-mangostin metabolites by LC-MS/MS system, the MW of the parent compound was increased from 411.200 to 459.185 Da. Therefore, α-mangostin might be metabolized via tri-oxidation process. The increased molecular weight of parent compound (397.200 to 477.157 Da) illustrated that gartanin might be conjugated to sulfated derivatives. Conclusions In all the studies, α-mangostin and gartanin were predicted to be. metabolized via phase I and phase II metabolism (sulfation), respectively.

The influence of Propylene glycol/Water and Ethanol/Water Binary Solvents on the in vitro Permeation of Garcinia mangostana L. Pericarp Extract across Shed Snakeskin

Garcinia mangostana pericarp (GMP) has antioxidant activity thus may be developed into a topical antioxidant formulation. This research aimed to study the topical delivery of GMP extract. Initially, some commonly used topical solvents, i.e., water and binary solvents of propylene glycol (PG)/water and ethanol/water (0; 10; 20 and 40%), were used to dissolve GMP extract and further tested on GMP extract in vitro skin permeation using shed snakeskin. The influence of solvents' effects was evaluated based on radical DPPH scavenging activity and expressed as radical scavenging activity equivalent GMP Extract (RSGMPE). The results showed that RSGMPE could be delivered into shed snakeskin. The extent of RSGMPE shed snakeskin retention was similar among water and all PG/water or ethanol/water binary solvents. RSGMPE was also found in the receptor phase from all PG/water binary solvents, whereas that from ethanol/water solvents only shown from 20% ethanol/water solvent even though all ethanol-water solvents produced significantly higher RSGMPE compared to water and PG/water binary solvents

Viscosified Solid Lipidic Nanoparticles Based on Naringenin and Linolenic Acid for the Release of Cyclosporine A on the Skin

Psoriasis is one of the most common human skin disorders. Although its pathogenesis is complex and not completely know, the hyperactivation of the immune system seem to have a key role. In this regard, among the most effective systemic therapeutics used in psoriasis, we find cyclosporine, an immunosuppressive medication. However, one of the major problems associated with the use of cyclosporine is the occurrence of systemic side effects such as nephrotoxicity, hypertension, etc. The present work fits in this context and its aim is the design of suitable platforms for cyclosporine topical release in psoriasis treatment. The main objective is to achieve local administration of cyclosporine in order to reduce its systemic absorption and, consequently, its side effects. In order to improve dermal penetration, solid lipid nanoparticles (SLNs) are used as carriers, due to their lipophilicity and occlusive properties, and naringenin and linolenic acid are chosen, due to their properties, as starting materials for SLNs design. In order to have dermatological formulations and further modulate drug release, SLNs are incorporated in several topical vehicles obtaining gels with different degree of lipophilicity. Potential applications for psoriasis treatment were evaluated by considering the encapsulation efficiency, release profiles, in vitro skin permeation, and anti-inflammatory effects.