Chitosan-Based Hydrogels for Controlled Delivery of Asiaticoside-Rich Centella asiatica Extracts with Wound Healing Potential.

Centella asiatica extract is a valued plant material with known anti-inflammatory and anti-microbiological properties. Using the Design of Experiment (DoE) approach, it was possible to obtain an optimized water/alcoholic extract from Centella asiatica, which allowed the preparation of the final material with biological activity in the wound healing process. Studies on the novel applications of Centella asiatica in conjunction with the multifunctional chitosan carrier have been motivated by the plant's substantial pharmacological activity and the need to develop new and effective methods for the treatment of chronic wounds. The controlled release of asiaticoside was made possible by the use of chitosan as a carrier. Based on the findings of investigations using the PAMPA skin assay, which is a model imitating the permeability of actives through skin, this compound, characterized by sustained release from the chitosan delivery system, was identified as being well able to permeate biological membranes such as skin. Chitosan and the lyophilized extract of Centella asiatica worked synergistically to block hyaluronidase, exert efficient microbiological activity and take part in the wound healing process, as proven in an in vitro model. A formulation containing 3% extract with 3% medium-molecular-weight chitosan was indicated as a potentially new treatment with high compliance and effectiveness for patients. Optimization of the chitosan-based hydrogel preparation ensured the required rheological properties necessary for the release of the bioactive from the chitosan delivery system and demonstrated a satisfactory antimicrobial activity.

The Antioxidant Potential of Resveratrol from Red Vine Leaves Delivered in an Electrospun Nanofiber System.

Despite the wide pharmacological action of polyphenols, their usefulness is limited due to their low oral bioavailability, which is due to their low solubility and rapid first-pass metabolism. Red vine leaf extract is an herbal medicine containing several polyphenols, with resveratrol and polydatin as the main compounds exhibiting antioxidant and anti-inflammatory properties. In the first stage of the work, using the Design of Experiment (DoE) approach, the red vine leaf extract (50% methanol, temperature 70 °C, and three cycles per 60 min) was obtained, which showed optimal antioxidant and anti-inflammatory properties. In order to circumvent the above-described limitations and use innovative technology, electrospun nanofibers containing the red vine leaf extract, polyvinylpyrrolidone (PVP), and hydroxypropyl-ß-cyclodextrin (HPßCD) were first developed. The optimization of the process involved the time of system mixing prior to electrospinning, the mixture flow rate, and the rotation speed of the collector. Dissolution studies of nanofibers showed improved resveratrol release from the nanofibers (over five-fold). Additionally, a PAMPA-GIT assay confirmed significantly better buccal penetration of resveratrol from this nanofiber combination (over ten-fold). The proposed strategy for electrospun nanofibers with the red vine leaf extract is an innovative approach to better use the synergy of the biological action of active compounds present in extracts that are beneficial for the development of nutraceuticals.

Iontophoresis to Overcome the Challenge of Nail Permeation: Considerations and Optimizations for Successful Ungual Drug Delivery.

Iontophoresis is a widely used drug delivery technique that has been used clinically to improve permeation through the skin for drugs and other actives in topical formulations. It is however not commonly used for the treatment of nail diseases despite its potential to improve transungual nail delivery. Instead, treatments for nail diseases are limited to relatively ineffective topical passive permeation techniques, which often result in relapses of nail diseases due to the thickness and hardness of the nail barrier resulting in lower permeation of the actives. Oral systemic antifungal agents that are also used are often associated with various undesirable side effects resulting in low patient compliance. This review article discusses what is currently known about the field of transungual iontophoresis, providing evidence of its efficacy and practicality in delivering drug to the entire surface of the nail for extended treatment periods. It also includes relevant details about the nail structure, the mechanisms of iontophoresis, and the associated in vitro and in vivo studies which have been used to investigate the optimal characteristics for a transungual iontophoretic drug delivery system. Iontophoresis is undoubtedly a promising option to treat nail diseases, and the use of this technique for clinical use will likely improve patient outcomes.Graphical abstract.

Development and in-vitro evaluation of co-loaded berberine chloride and evodiamine ethosomes for treatment of melanoma.

Berberine chloride (BBR) and evodiamine (EVO) are two main active ingredients of "ZuoJinWan", a classical Chinese herbal medicine, and these compounds are known to have a synergistic inhibitory effect on various cancer cell lines. Several recent studies have reported anti-melanoma effects for both BBR and EVO. However, topical delivery of the two compounds has been challenging, due to their poor aqueous solubility and their low skin penetration. In the current study, we have combined BBR and EVO into an ethosomes delivery system with the future aim to design a novel topical anti-melanoma formulation. The ethosomes formulations were characterized using particle size, entrapment efficiency and an in vitro skin drug deposition study. The ethosome formulation displaying maximum drug deposition in the epidermis was selected for further study. This formulation contained ethosomes with mean size of 171 nm and 90% or above entrapment efficiency for both BBR and EVO. Cell viability tests proved the optimized ethosomes increased the inhibitory effect on B16 melanoma cells. These results corroborate that ethosomes containing a combination of BBR and EVO are a promising delivery system for potential use in melanoma therapy.

Development and in vitro evaluation of pressure sensitive adhesive patch for the transdermal delivery of galantamine: Effect of penetration enhancers and crystallization inhibition.

The transdermal route offers an attractive alternative route of drug administration especially for Alzheimer's disease patients through eliminating gastrointestinal side effects and ultimately improving compliance. In this study, we prepared an optimized matrix-type patches for the transdermal delivery of galantamine free base with ex vivo and in vitro evaluation. Four pressure sensitive adhesives with different functional groups, ten penetration enhancers and four drug loadings were tested to determine the optimized patch. The ex vivo permeation of the different formulated patches through human cadaver skin using vertical Franz diffusion cells showed that GELVA GMS 788 was the best pressure sensitive adhesive among the tested polymers. FT-IR and rheological studies done to investigate any potential interactions of the polymer with the drug and/or additives showed the possibility of hydrogen bonding between the drug and pressure sensitive adhesive (PSA), also the additives had a plasticization effect causing increased flexibility of the polymer chains. The optimized formulation had 10%w/w drug loading, 5% w/w limonene as a penetration enhancer, and 5%w/w oleic acid as a crystallization inhibitor. The combination of limonene and oleic acid increased the flux of galantamine by 2.7-fold compared to 1.7-fold when limonene was used alone. The optimized patch exhibited diffusion release kinetics and fitted well to Higuchi's model and yielded a permeation rate of 32.4 ±â€¯1.41 µg/cm2/h across human cadaver skin.

Strat-M® synthetic membrane: Permeability comparison to human cadaver skin.

The aim of this work was to investigate the correlation of permeation behavior of transdermal formulations through a novel synthetic membrane (Strat-M® EMD Millipore, MA) and human cadaver skin. Strat-M® membranes were designed with the intent to share similar structural and chemical characteristics found in the human skin however, omitting any biological behavior due to the absence of viable cells. Both human skin and the membrane display a layered structure with a very tight top layer. Additionally, the Strat-M® membrane contains a combination of lipids in a specific ratio similar to what is found in the human stratum corneum (SC). Formulations containing nicotine and a chemical penetration enhancer (CPE) were used for evaluating drug penetration to understand how each enhancer impacts the permeability of nicotine as a model compound. The permeability measurements of human cadaver skin and Strat-M® membrane were performed with Franz diffusion cell methods accompanied by HPLC analysis. A good correlation of the permeability data was obtained through human cadaver skin and Strat-M® membrane. Thus, Strat-M® has the potential to be used as a screening tool for evaluating topical/transdermal formulations through the human cadaver skin.

Comparison of quercetin pharmacokinetics following oral supplementation in humans.

UNLABELLED: The objective of the study was to investigate the absorption of quercetin aglycone in 18 healthy human subjects administered via the following oral carrier systems: suspension of quercetin (quercetin QU995 powder in Tang(®) and spring water), nutritional bars (First Strike™), and chews (RealFX™ Q-Plus™). Subjects were divided into 3 groups of 6 individuals each receiving 500 mg quercetin in one of the aforementioned formulations. Blood levels were monitored immediately pre- and for 32 h postadministration. The concentration of total quercetin in blood samples was determined by solid phase extraction followed by high-performance liquid chromatography analysis. Pharmacokinetic parameters were determined by noncompartmental modeling using Kinetica software. The C(max) of quercetin was highest with RealFX™ Q-Plus™ Chews (1051.9 ± 393.1 µg/L) achieved within 3.3 h as compared to that for First Strike™ Bars (698.1 ± 189.5 µg/L in 2.3 h) and Tang(®) suspension (354.4 ± 87.6 µg/L in 4.7 h). The results showed no statistically significant difference in quercetin absorption among groups due to high variability within groups receiving quercetin from same dosage form. This study represents the first comprehensive evaluation of quercetin absorption from quercetin fortified oral food products at doses commonly used for quercetin supplementation. PRACTICAL APPLICATION: The current study describes for the first time, comprehensive evaluation of quercetin PK in humans from quercetin fortified oral food products at doses commonly used for quercetin supplementation. Owing to quercetin's potent antioxidant and anti-inflammatory actions, quercetin is widely being used as a nutritional supplement. In order to maximize the bioavailability of quercetin for its use in efficacy studies, it is important to determine its ideal oral carrier system and route for its delivery. The current research unveils vital information about quercetin supplementation to the international community, especially to soldiers, athletes, and the dietary supplement industry.

Effects of short-term quercetin supplementation on soldier performance.

The purpose was to assess the short-term effects of quercetin supplementation on aerobically demanding soldier performance. In a double-blind crossover study, 16 male soldiers performed 3 days of aerobically demanding exercise under 3 conditions: Baseline (B), Placebo (P), and Quercetin (Q). Day 1 was a treadmill V[Combining Dot Above]O2peak test. Days 2 and 3 were identical, consisting of 75 minutes of loaded treadmill marching (LM) and a subsequent cycling time trial (TT) to complete 200 kJ of work. After B condition, the soldiers consumed 2 energy bars, each containing 0 mg (placebo) or 500 mg of quercetin (1,000 mg·d⁻¹) for 8.5 days. Beginning day 6 of supplementation, the soldiers performed the 3 exercise days. There was a significant (p < 0.05) increase in plasma Q after Q supplementation. Repeated measures analyses of variance revealed no differences after P or Q supplementation as compared with B in V[Combining Dot Above]O2peak (B = 48.9 ± 1.1, P = 49.3 ± 1.1, Q = 48.8 ± 1.2 ml·kg⁻¹·min⁻¹) or TT time (B = 18.4 ± 1.0, P = 18.5 ± 1.1, Q = 18.3 ± 1.0 minutes [mean day 1 and day 2]). The respiratory exchange ratio during LM did not differ across treatments (B = 0.87 ± 0.03, P = 0.87 ± 0.03, Q = 0.86 ± 0.04 [mean day 1 and day 2]). Ratings of perceived exertion were not affected by Q supplementation during the V[Combining Dot Above]O2peak test, LM or TT. Supplementation of 1,000 mg·d⁻¹ of quercetin for 8.5 days had no positive effect on aerobically demanding soldier performance. It is possible that a different dosing regimen, a combination of antioxidants or a different form of quercetin supplementation, may be needed to produce an increase in soldier performance.

Effect of quercetin supplementation on maximal oxygen uptake in men and women.

Quercetin is a naturally occurring flavonoid with anti-oxidant and anti-inflammatory properties. The effect of quercetin supplementation on maximal oxygen uptake (VO(2max)) is unknown. The purpose of this investigation was to test the effects of quercetin supplementation on VO(2max) in untrained, sedentary individuals. After baseline treadmill VO(2max) testing, 11 participants (5 males, 6 females) ingested either placebo or quercetin-supplemented (1000 mg x day(-1)) food bars in a randomized, double-blind, counterbalanced, crossover research design. The participants ingested food bars for six consecutive mornings (5 days). On the sixth morning, participants underwent repeat VO(2max) testing. After a 22 day wash-out, the participants repeated baseline VO(2max) testing, daily consumption of the opposite food bars, and post-supplementation VO(2max) testing. The condition x time interaction for VO(2max) was non-significant when expressed in absolute (litres x min(-1); P = 0.929) and relative (ml x kg(-1) x min(-1); P = 0.778) terms. These findings were similar when taking sex into account (P > 0.05). The mean difference in VO(2max) change from pre to post between groups (quercetin vs. placebo) was 0.139 ml x kg(-1) x min(-1) (P = 0.780). Other physiological measures also were similar between conditions (P > 0.05). In conclusion, 5 days of quercetin supplementation did not influence VO(2max) or related variables in sedentary men and women.

No effect of nutritional adenosine receptor antagonists on exercise performance in the heat.

Nutritional adenosine receptor antagonists can enhance endurance exercise performance in temperate environments, but their efficacy during heat stress is not well understood. This double-blinded, placebo-controlled study compared the effects of an acute dose of caffeine or quercetin on endurance exercise performance during compensable heat stress (40 degrees C, 20-30% rh). On each of three occasions, 10 healthy men each performed 30-min of cycle ergometry at 50% Vo2peak followed by a 15-min performance time trial after receiving either placebo (Group P), caffeine (Group C; 9 mg/kg), or quercetin (Group Q; 2,000 mg). Serial blood samples, physiological (heart rate, rectal, and mean skin body temperatures), perceptual (ratings of perceived exertion, pain, thermal comfort, motivation), and exercise performance measures (total work and pacing strategy) were made. Supplementation with caffeine and quercetin increased preexercise blood concentrations of caffeine (55.62 +/- 4.77 microM) and quercetin (4.76 +/- 2.56 microM) above their in vitro inhibition constants for adenosine receptors. No treatment effects were observed for any physiological or perceptual measures, with the exception of elevated rectal body temperatures (0.20-0.30 degrees C; P < 0.05) for Group C vs. Groups Q and P. Supplementation did not affect total work performed (Groups P: 153.5 +/- 28.3, C: 157.3 +/- 28.9, and Q: 151.1 +/- 31.6 kJ; P > 0.05) or the self-selected pacing strategy employed. These findings indicate that the nutritional adenosine receptor antagonists caffeine and quercetin do not enhance endurance exercise performance during compensable heat stress.

Cutaneous biotransformation of N-(4-bromobenzoyl)-S,S-dimethyliminosulfurane and its product, 4-bromobenzamide, leading to percutaneous penetration enhancement of drugs: initial evidence using hydrocortisone.

The role of the skin's metabolism of N-(4-bromobenzoyl)-S,S-dimethyliminosulfurane (DMBIS), an effective penetration enhancer, on its enhancement activity was investigated. It has been found that DMBIS hydrolyzes very fast in physiological buffer to 4-bromobenzamide (BBA), and even faster and almost completely in the presence of skin tissue. It was further shown that in the presence of skin from different species incubated at physiological conditions, the concentration of BBA (DMBIS' immediate product) dropped sharply to 70-80% in 10 min followed by a slower decrease of 0.35-0.50 microg/h. This metabolism was partially inhibited by a continuous application of iodine, and more profoundly, by iodoacetic acid (IAA) and dithiothreitol (DTT) combination treatment. This indicates that at least a part of the metabolism of BBA involves enzymes that are sensitive to reactions with their sulfhydryl groups. In an in vitro permeation study using human epidermis and conventional diffusion cells, we compared between the permeabilities of untreated epidermis and IAA/DTT-treated epidermis to hydrocortisone in the presence of BBA. Due to its metabolic inhibition, we noted a higher penetration of BBA through IAA/DTT-treated epidermis than through the untreated epidermis. Contrary to these results, the extent of the penetration of hydrocortisone was higher through the untreated epidermis with only 1.6 h lag time relative to its penetration through IAA/DTT-treated epidermis, which exhibited a lag time of 12.4 h. It is evident, therefore, that the skin enhancement activity of DMBIS/BBA depends on BBA metabolism in the skin, presumably through its in situ biotransformation into an active enhancer.