Both intrinsic and extrinsic aging lead to a series of morphological changes in the skin including the flattening of the dermal–epidermal junction, increased stratum corneum dryness, reduction in ...sebaceous gland activity and enzyme activity as well as atrophy of blood vessels. In this study, the impact of these changes on the transport of molecules through the skin was revised. The increase in the number of transdermal formulations on the market in recent decades and life expectancy represent the main reasons for an in-depth discussion of this topic. Furthermore, elderly subjects have often been excluded from clinical trials due to polypharmacy, raising concerns in terms of efficacy and safety. In this way,
ex vivo
and
in vivo
studies comparing the transport of molecules through the mature and young skin were analyzed in detail. The reduced water content in mature skin had a significant impact on the transport rate of hydrophilic molecules. The lower enzymatic activity in aged skin, in turn, would explain changes in the activation of prodrugs. Interestingly, greater deposition of nanoparticles was also found in mature skin.
In vivo
models should be prioritized in future experimental studies as they allow to evaluate both absorption and metabolism simultaneously, providing more realistic information.
Graphical Abstract
Ethical restrictions as well as practical or economic issues related to use of animal and human skin has been the main reason the growth in the number of investigations with alternative models. ...Reconstructed skin models, for example, have been useful to evaluate the
in
vitro
toxicity of compounds; however, these models usually overestimate the amount of drug permeated due to impaired barrier properties. In this review, the performance of synthetic and biological skin models in transport studies was compared by considering two compounds with different physicochemical properties. The advantages and limitations of each skin model are discussed in detail. Although synthetic and reconstructed skin models have shown to be useful in the formulation optimization step, they present many limitations: (1) impaired barrier properties; (2) lack of follicular transport; (3) no metabolism in synthetic membranes; (4) differences in terms of lipid organization; (5) more affected by formulation constituents. Therefore, animal and human tissues should still be prioritized in drug transport studies until new advances in alternative models are achieved. Investigations of the impact of cell-culture conditions on skin formation, in turn, bring perspectives related to the development of unhealthy/injured skin models (an aspect that still deserves attention).
Graphical Abstract
The emergence of new materials with improved antibacterial, anti-inflammatory and healing properties compared to conventional wound dressings has both social and economic appeal. In this study, novel ...chitosan-based (CTS) membranes containing curcumin (CUR) incorporated in Pluronic (PLU) copolymers were developed and characterized to obtain suitable properties for applications as a wound healing dressing. The mechanical, thermal, swelling, wettability, release and permeation properties were evaluated by DSC, TGA, water contact angle measurements, FTIR, fluorescence and microscopic techniques. Membranes containing PLU and CUR presented wettability close to the ideal range for interaction with cellular components (contact angle ~40–70°), improved mechanical properties, higher thermal stability, high swelling degree (>800%) and CUR release (~60%) compared to samples without PLU addition. A higher retention of CUR in the epidermis than in the dermis layer was observed, which also was confirmed by confocal microscopy. Furthermore, the CTS-PLU membranes loaded with CUR showed to be active against Staphylococcus aureus and Pseudomonas aeruginosa (MIC = 25 and 100 mg mL−1, respectively), the microbial species most present in chronic wounds. Overall, the CTS-PLU-CUR membranes presented suitable properties to act as a new wound healing dressing formulation and in vivo studies should be performed to confirm these benefits.
•PLUs improved swelling capacity and mechanical properties of CUR-chitosan membranes.•Both crystallinity and Tg of PLUs and CUR were changed after membrane preparation.•Membranes results in higher CUR retention in the epidermis than in the dermis layer.•CTS-PLU-CUR showed a contact angle value close to the ideal for interaction with cells.•CTS-CUR-based membranes showed to be active against S. aureus and P. aeruginosa.
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Cutaneous permeation assays are crucial to attest the performance or bioequivalence of topical or transdermal products. Although the official guidelines (e.g., FDA/EMA) play a key ...role in harmonizing the experimental design, alternative methods are often proposed by the scientific community, which makes it difficult to compare results from different studies. In this review, permeation assays with testosterone (TST) were selected to show this high variability in drug transport rate. The main sources of variation discussed were tissue thickness, animal model, donor and receptor fluid constitution, type of solubilizing agent used in aqueous fluids, drug concentration, degree of supersaturation, skin lipid content, number of experimental times and the physical–chemical stability of the molecule in test fluids. This variation becomes even more critical for molecules that present biopharmaceutical limitations such as TST. In addition, the skin presents specific receptors for this hormone due to its physiological action in this region of the body, which makes the evaluation of the TST transport rate in this tissue even more challenging. The impact of each experimental parameter mentioned above on the flux or permeation coefficient of TST is discussed in detail in the review. Assays used to evaluate tissue integrity are also presented.
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•A novel double-barrier nanomaterial (nanoparticles into nanofibers) was formed.•The nanoparticles increased the hydrophilicity of the nanofibers surfaces.•The nanomaterial showed a ...sustained and continuous release of the model compounds.•The nanoparticles decreased the IC50 against melanoma cells.•The nanoencapsulation increased both skin compound permeation and retention.
Intact carboxymethyl-hexanoyl chitosan/dodecyl sulfate nanoparticles loaded with pyrazoline H3TM04 were dispersed in biodegradable PEO-chitosan nanofiber mats (PEOChNps) for application in skin cancer treatment. The nanomaterial was formed by co-electrospinning in aqueous solution. The structural and morphological properties of the PEOChNps were investigated by FEG-SEM, TEM, AFM, FTIR, DSC and TGA. The PEOChNps nanofibers showed a narrow size distribution (197.8 ± 4.1 nm) with a homogenous distribution of the nanoparticles inside the nanofibers, promoting the controlled release of H3TM04 from both diffusion and erosion processes over a period of 120 h. An increased transport rate of H3TM04 through the epidermis was also found when PEOChNps was used as the carrier. In in vitro cytotoxicity assays, the incorporation of H3TM04 into the nanocarriers increased its cytotoxic effect toward B16F10 melanoma cells. These findings suggest that the proposed nanofiber mats could be used for controlled drug release in local chemotherapy treatment for skin cancer.
Benznidazole (BZN) represents the only drug currently available for the treatment of Chagas disease in most endemic countries. When administered orally, high doses are required due to its extensive ...hepatic metabolism and its toxicity represents the main reason for treatment withdrawals. Because of these complications, transbuccal administration of BZN was investigated. This route avoids the first-pass hepatic metabolism and presents high permeability, with direct access to the systemic circulation. BZN was applied on porcine buccal mucosa after pretreatment with pure eugenol, carvacrol or limonene. Thermal (DSC) and spectroscopic (FT-IR) analyzes were performed to investigate the mechanisms of drug absorption enhancement. The permeability coefficient values of BZN increased 2.6, 2.9 and 4.9-fold after pretreatment with eugenol, carvacrol and limonene, respectively. The lag time, in turn, was shortened in the pretreated samples. The DSC and FT-IR analyzes suggested that transport of BZN through the buccal mucosa is associated with log P and size of monoterpenes. Limonene, the most effective absorption enhancer, contributed to greater interaction with non-polar domains of the buccal epithelium. Overall, BZN showed to be efficiently transported through the buccal route, but in vivo pharmacokinetic studies should be performed to confirm these findings.
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•Thermosensitive and mucoadhesive hydrogels were composed of poloxamers and chitosan.•Hydrogels showed sol-gel transition temperature higher than 30 °C and fast gelling.•Chitosan affected the polymer ...network and mucoadhesion strength of the hydrogels.•The artificial mucin layer on the mucosa affected the secnidazole permeability.•An effective local treatment of trichomoniasis can be achieved with hydrogels.
Secnidazole (SEC) has been suggested as an alternative agent against Trichomonas vaginalis to overcome the adverse effects, antimicrobial resistance problems and poor adherence to the currently available therapy. Once no topical formulation may be found in the market until now, SEC was incorporated in thermosensitive bioadhesive systems to extend the contact time in the mucosa and to avoid a systemic drug disposition. Formulations containing 20% poloxamer 407, 1% poloxamer 188 and 1 or 2.5% chitosan showed suitable sol-gel transition temperature (> 30 °C), presenting a fast gelation time (100-115 s). Rheological, dynamic light scattering and infrared spectroscopy analysis suggested molecular interactions among polymers. Chitosan increased the mucoadhesion strength of the formulations. In addition, hydrogels showed a tendency to decrease the drug transport rate through mucosa when compared to the control. Mucin was also added onto mucosa for a more realistic simulation of permeability/retention. In the presence of this agent, hydrogels containing chitosan reduced the permeability/retention of the drug in approximately 2.0-fold when compared to the control. Therefore, the hydrogels presented suitable characteristics to remain in the vaginal environment, which would result in effective local treatment of trichomoniasis.
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Although a variety of chemical absorption enhancers (CAEs) have been included in transdermal preparations of testosterone (TST), local irritation or low efficacy of these agents have been often ...reported. In this context, three natural terpenes classified as safe by FDA were selected for this study, which could also provide secondary biological properties (e.g., antioxidant, anti-inflammatory and antimicrobial action). Ex vivo permeation studies were performed in the Franz-type diffusion cell model and human skin. An enhancement ratio of 7.61, 5.10 and 2.52 was achieved after treatment with carvacrol, α-bisabolol and menthol, respectively. Carvacrol provided higher permeation flux and cutaneous retention of TST than other terpenes. Mechanistic studies were also performed to evaluate the effect of CAEs on biophysical properties of the stratum corneum. Spectroscopic and thermal analyses showed structural changes in this tissue after all treatments and suggested that carvacrol causes a greater disorder in lipid domains. As this terpene affects the passive diffusion route more significantly (which is preferentially used by TST), it was considered the most effective CAE. Moreover, this agent could play a synergistic effect with TST in hypogonadism, but further studies are needed to prove the advantages of this association.
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Although rare, amoebic keratitis (AK) is a disease caused by Acanthamoeba spp. that can lead to blindness. The drugs currently available for its treatment are very toxic, which has ...motivated the investigation for more effective and safe therapeutic options. In this study, the in vitro activity of ß-caryophyllene (BCP) was exploited taking into account its action against other protozoans as well as its well-known healing and anti-inflammatory properties (aspects relevant for the AK pathogenesis). On the other hand, high volatilization and oxidation phenomena are found for this compound, which led to its incorporation into nanoemulsions (NEs). Two emulsifying agents were tested, resulting in monodisperse systems with reduced droplet size (<265 nm) and high surface charge (positive and negative for NEs prepared with cetrimonium bromide −CTAB and Phosal® 50+, respectively). NEs prepared with CTAB were shown to be more stable after long-term storage at 4 and 25 °C than those prepared with Phosal®. Pure BCP, at the highest concentration (500 µM), resulted in a level of inhibition of Acanthamoeba trophozoites equivalent to that of reference drug (chlorhexidine). This activity was even greater after oil nanoencapsulation. The reduced droplet size could improve the interaction of the oil with the microorganism, justifying this finding. Changes in surface charge did not impact the activity. Positively charged NEs improved the interaction and retention of BCP in the cornea and thus should be prioritized for further studies.
Vulvovaginal candidiasis (VVC) is an opportunistic infection caused by a fungus of the Candida genus, affecting approximately 75 % of women during their lifetime. Fungal resistance cases and adverse ...effects have been the main challenges of oral therapies. In this study, the topical application of thin films containing fluconazole (FLU) and thymol (THY) was proposed to overcome these problems. Vaginal films based only on chitosan (CH) or combining this biopolymer with pectin (PEC) or hydroxypropylmethylcellulose acetate succinate (HPMCAS) were developed by the solvent casting method. In addition to a higher swelling index, CH/HPMCAS films showed to be more plastic and flexible than systems prepared with CH/PEC or only chitosan. Biopolymers and FLU were found in an amorphous state, contributing to explaining the rapid gel formation after contact with vaginal fluid. High permeability rates of FLU were also found after its immobilization into thin films. The presence of THY in polymer films increased the distribution of FLU in vaginal tissues and resulted in improved anti-Candida activity. A significant activity against the resistant C. glabrata was achieved, reducing the required FLU dose by 50 %. These results suggest that the developed polymer films represent a promising alternative for the treatment of resistant vulvovaginal candidiasis, encouraging further studies in this context.
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