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Vulvovaginal candidiasis (VVC) is an opportunistic and endogenous infection caused by a fungus of the Candida genus, which can cause pruritus, dysuria, vulvar edema, fissures and maceration of the vulva. The treatment of vaginal candidiasis is carried out mainly by antifungal agents of azole and polyene classes; however, fungal resistance cases have been often observed. For this reason, new therapeutic agents such as essential oils, probiotics and antimicrobial peptides are being investigated, which can be combined with conventional drugs. Local administration of antimicrobials has also been considered to allow greater control of drug delivery and reduce or avoid undesirable systemic adverse effects. Conventional dosage forms such as creams and ointments result in reduced residence time in the mucosa and non-sustained and variable drug delivery. Therefore, advanced solid formulations such as intravaginal rings, vaginal films, sponges and nanofibers have been purposed. In these systems, polymers in different ratios are combined aiming to achieve a specific drug release profile and high mucoadhesion. Overall, a more porous matrix structure leads to a higher rate of drug release and mucoadhesion. The advantages, limitations and technological aspects of each dosage form are discussed in detail in this review.

Topical formulations composed of API-pure crystals have been increasingly studied, especially in regards to the impact of particle size in penetration efficiency. Less attention, however, has been devoted to the solid-state properties of drugs delivered to the skin. In this study, we address the effect of formulation composition on the crystal form existing in topical products. Dapsone (DAP) gel formulations were prepared by mixing an organic solution containing DAP with an aqueous solution containing polymers and preservatives. The organic solvent was chosen as ethoxydiglycol (DEGEE), polyethylene glycol (PEG), or 1-methyl-2-pirrolidone (MPR) to assess the impact of composition on DAP crystal form. Such solvent variations resulted in different particulate matter. In terms of crystalline nature, the presence of DEGEE in formulations induced the crystallization of DAP hydrate, while PEG cocrystal and a mixture of hydrate and MPR solvate crystallized from the same amounts of PEG and MPR, respectively. Microscopic analysis of the gels showed heterogeneous particles with different characteristics. The behavior of gels after application to the skin was also tested. Interestingly, the different formulations seemed to accumulate in different regions of the skin. This could be the result of the effect of vehicle composition/excipients on the characteristics of the skin, such as hydration. The site-specific accumulation, however, was more pronounced in crystal-loaded gels as opposed to blank formulations. These results indicate that future studies should consider the effect of formulation composition on the API crystal form landscape as part of the strategies used to successfully target drug delivery to the skin.

To understand the anomalous behavior of Saquinavir Mesylate (SQVM) in sodium decyl sulfate (SDS) medium during a dissolution test through a crystallographic analysis of the crystal obtained. As a result, it will be possible to elucidate its crystal structure and carry out a complete solid-state characterization of the API.The solid form obtained was characterized by a structural analysis through X-ray single crystal and powder diffraction. The crystallographic structures of the new salt and the SQVM were compared. In addition, a complete solid-state characterization of SQVM raw material was carried out by techniques such as diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), Raman spectroscopy, scanning electron microscopy and a dissolution method.A new salt consisting of SQVM and SDS was crystallized and its crystal structure was elucidated and reported herein for the first time. The anionic part of SDS interacts with the cationic segment of SQVM to obtain a new salt designated as SQV-DS, which precipitates. The main difference between the two structures occurs in the c-axis expansion, which increases from 15.966 (5) to 21.1924 (14), respectively.Some of the strategies to enhance the dissolution rate of poorly aqueous soluble APIs include the use of surfactants such as SDS in the dissolution medium, as well as in the formulated products. However, there have been constant reports of a dissolution rate slowdown by some surfactants. The interaction mechanisms between the APIs and the dissolution medium containing surfactants need to be carefully investigated in current pharmaceutical formulations. Graphical Abstract.

In this study, three different combinations of essential oils (EO) of cinnamon, melaleuca and citronella were incorporated in polyhydroxybutyrate (PHB) films by conventional solution-casting method for food packaging applications. Although melaleuca and citronella EO films have been not demonstrated antimicrobial activity, they presented low UV transmission and high thermal stability. Films containing citronella and cinnamon EO or melaleuca and cinnamon EO, in turn, were active against all tested microorganisms and showed greater flexibility than pure PHB films. Aspergillus niger was the most sensitive microorganism to EO-based polymer films. Overall, the addition of EOs improved the thermal stability of films and reduced the polymer melting temperature as the result of its plasticization, affecting the elastic modulus and elongation at break of films. Taken together, these results suggest that EO-loaded PHB films could be used in designing of biodegradable active packaging for food products.

The anti-inflammatory activity is mainly attributed to the phenolic compounds. Once the geographical location affects the phenolic content of honeys, a relationship between the collection spot and the anti-inflammatory effect of bracatinga (Mimosa scabrella Bentham) honeydew honeys was hypothesized. The inhibitory effect of 14 honey samples on NOx, TNF-α, IL-6, IL-12p70, MCP-1, INF-γ, and IL-10 in RAW 264.7 macrophages inflamed by LPS was evaluated. Fourteen phenolic compounds were identified, mainly syringic acid and rutin. Ten honeys inhibited nitrite production; at least six downregulated TNF-α, IL-12p70, MCP-1, and IFN-γ; only four honey samples inhibited IL-6; and one honey sample inhibited IL-10 levels, showing their variable effects on the inflammatory markers. Principal component analysis grouped samples according to the phenolic content and downregulation of specific inflammatory markers. The bracatinga honeydew honey effectiveness was associated with geographical location, as samples from areas with higher density and diversity of plants had a more significant anti-inflammatory effect. PRACTICAL APPLICATIONS: The present research study investigated the anti-inflammatory potential of bracatinga honeydew honey samples collected from regions with different vegetation coverages. Honey samples collected from locations presenting greater forest diversity and density inhibited inflammatory markers more efficiently. This study reinforces the role of the bracatinga honeydew honey in preventing inflammatory processes and the importance of preserving forests so that products with a greater diversity of compounds and consequently more active can be obtained.

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.

The current treatment for cutaneous tuberculosis consists of oral coadministration of isoniazid (INH) and rifampicin, which is often related to hepatotoxic events. Alternatively, INH could be administered on the skin aiming to avoid or minimize these side effects. The high cutaneous permeation of this drug motivated the obtainment of a cocrystal of INH and resveratrol (RES), a lipophilic compound, to provide a local effect. In this study, isoniazid–resveratrol cocrystal (INH-RES) was synthesized by reaction crystallization method, and its structure was determined from single-crystal X-ray diffraction data. Cocrystal, drug, and coformer aqueous solubility was determined in the initial pH range from 1.2 to 7.4. Mathematical models based on cocrystal constituent ionization constants (pKa), solution pH, and cocrystal solubility product (Ksp) were used to generate solubility diagrams as a function of pH. At all pH values studied, INH-RES was less soluble than INH. Permeation studies were performed with drug an...

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.

Dapsone (DAP) is a long-established molecule that remains a promising therapeutic agent for various diseases mainly because it combines antimicrobial and anti-inflammatory activities. Its oral application, however, is limited by the dose-dependent hematological side effects that may rise from systemic exposure. As an alternative to overcome this limitation, the administration of DAP to the skin has witnessed prominent interest in the past 20 years, particularly when applied to the treatment of dermatological disorders. In this review, all technological strategies proposed to the topical delivery of DAP are presented. Most of the reported studies have been devoted to the clinical use and safety of a gel formulation containing both solubilized and microcrystalline drug, however, the technological characteristics of such preparation are still missing. In parallel, the incorporation of DAP into vesicular and particulate carriers (e.g. nano- and microemulsions, niosomes, invasomes, bilosomes, cubosomes, solid lipid nanoparticles, nanostructured lipid carriers, polymeric nanocapsules and polymer-lipid-polymer hybrid nanoparticles) appears to be an alternative to provide greater drug release control, enhanced drug solubilization and follicular targeting. Indeed, the main application of DAP topical formulations reported in the literature was the treatment of acne vulgaris, a disease located in the hair follicle. Other diseases affecting different regions of the skin (e.g. cutaneous lupus erythematosus and cutaneous leishmaniasis), however, may also benefit from a topical therapeutic regimen containing DAP. Therefore, the investigation of appendageal route in comparison to passive transmembrane diffusion as a function of targeted disease, as well as pharmacokinetic studies, are perspectives highlighted herein. Such studies may drive future efforts towards the rational development of safe and effective technologies to deliver DAP to the skin. Graphical abstract.

The anti-inflammatory effect of bracatinga (Mimosa scabrella Bentham) honeydew honeys was evaluated by considering the modulation of inflammatory mediators in LPS-stimulated RAW 264.7 macrophages. Both tested bracatinga honeydew honey samples (BHH1 and BHH2) reduced the nitric oxide secretion as well as the inflammatory mediators: tumor necrosis factor-alpha, interleukin-6, monocyte chemoattractant protein 1, interleukin-12p70, interferon-gamma and interleukin-10. The phenolic compounds 3,4-dihydroxybenzoic acid, benzoic acid, salicylic acid, rutin, luteolin, and naringenin were found in BHH1 whereas only syringic acid was quantified in BHH2. Interestingly, 3 µg mL−1 of BHH1 provided a more significant anti-inflammatory effect than 30 µg mL−1 of BHH2, which seems to be strongly related to the presence of phenolic compounds, considering the differences in anti-inflammatory potential between the samples. This study confirmed for the first time that the bracatinga honeydew honey plays an important role as a functional food, suggesting its application for the auxiliary treatment of inflammatory disorders.

In isolated isoniazid (INH)-resistant strains, deletion or mutations in thekatGgene have been identified, which result in loss of catalase-peroxidase activity. This enzyme plays a key role in the activation of this prodrug. As an alternative, the coordination of the INH to metal complexes has been purposed to activate it regardless of enzyme functionality. Although pentacyanido(isoniazid)ferrate(II) complexes have shown to be effective against resistant strains of Mycobacterium tuberculosis, low oral bioavailability was found. In this context, buccal mucosa was selected as an alternative route to the metal complex delivery. Moreover, oral manifestations of tuberculosis(TB) have been observed in some patients, particularly when resistant strains are present, and no therapeutic options are currently available on the market. Pentacyanidoferrate (PCF-INH) and Prussian-blue (PB-INH) complexes were initially prepared and characterized, followed by buccal permeability studies in Franz-type diffusion cells. The electrochemical potential of the complexes demonstrated their ability to self-activate. Job's method suggested the presence of structural defects in PB-INH complexes, which was correlated with permeability results. In fact, PB-INH showed a higher dissociation rate in salt-rich aqueous medium and thus a high transport rate of INH through the buccal mucosa. Its passage through the tissue would not be possible due to the high molecular size. PCF-INH, in turn, presented a lower dissociation rate in the salt-rich aqueous medium, justifying its slower transport rate through the tissue. Taken together, these results suggest that INH-based metal complexes may be efficiently administered through the buccal route, impacting on both oral bioavailability and microbial resistance.

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.

Despite its large effectiveness, the long-term oral administration of high doses of meloxicam (MLX) may lead to gastrointestinal events such as abdominal pain, diarrhea, dyspepsia, ulceration, hemorrhage, and gastrointestinal perforation. Moreover, the pH-dependent solubility of MLX makes the development of new oral formulations even more challenging. As an alternative to overcome these limitations, the transdermal delivery of this drug has been purposed. Although various physical and chemical approaches to enhance the absorption of MLX may be found in literature, the use of cocrystallization has not been reported so far. Cutaneous permeation of MLX and 1:1 meloxicam-salicylic acid cocrystal (MLX-SLC) were evaluated using Franz diffusion cells. Cocrystal was suspended in an aqueous solution and in a gel to evaluate the vehicle effect on permeation parameters. In aqueous medium, the cocrystallization showed to enhance the drug permeation coefficient from 1.38 to 2.15 × 10−3 cm/h. MLX-SLC generated supersaturation with respect to the drug during dissolution studies simulating the conditions in the Franz cell donor chamber. This greater amount of free drug in the solution could contribute to explain the higher transdermal absorption and shorter lag time of this system. In addition, the acidic coformer ionization led to a pH reduction from 7.4 to 5.8, which, in turn, provided an increase in the unionized species of the drug, enhancing its permeation rate. The gel containing cocrystals reduced MLX permeation rate significantly (P = 0.42 × 10−3 cm/h), which was attributed to its higher viscosity.

Whole oat and rice flours were mixed to develop instant flours by a high pressure and low mechanical shear extrusion process. The screw profile was designed aiming to obtain an infant food with gelatinized starch and high hydration ability. Response surface methodology was selected to study the impact of operating parameters such as temperature and screw speed (73-186 °C; 109-391 rpm) on physicochemical and pasting properties of the final extruded product. The main challenge of this study was to process high oats content, since they are characterized by high lipid and fiber content, which impact on material processing.; Results: The optimal response was achieved at 170 °C and 350 rpm. The optimal expansion ratio, bulk density, water absorption index, and water solubility index were 2.24, 289.65 kg m-3 , 6.42 g g-1 , and 4.75 g g-1 respectively. Overall, both temperature and screw speed affected the responses studied, except for water absorption index (only screw speed affected this response). Although lipids from oats reduce the expansion ratio of extrudates compared with samples containing higher starch proportions, their lipids protect the starch granules from mechanical degradation when higher screw speed values are used. As a result, both ungelatinized and gelatinized starches may be found in extrudates, which was confirmed by pasting property analyses.; Conclusion: High oat content may be efficiently processed by optimizing the extruder conditions (temperature, screw speed, and profile), improving the nutritional properties of the final product. © 2017 Society of Chemical Industry.; © 2017 Society of Chemical Industry.

Although various compounds from Ilex paraguariensis present high antioxidant activity, limitations in terms of chemical stability may be found, impacting on the formulation step. In this context, nanotechnology may be alternatively used to provide an additional protection for these compounds, avoiding degradative reactions. Different formulation parameters (eg. particle size, zeta potential, internal phase fraction) were assayed to maximize a local antioxidant action. Firstly, the extraction procedure for obtaining increased concentrations of antioxidant compounds was optimized. High stirring speed and ethanol as extractor liquid were defined as key parameters. Nanoparticles were prepared by double emulsion solvent evaporation technique. Polycaprolactone-based nanoparticles showed to be more stable than poly(lactic-co-glycolic acid)-based nanoparticles. Instead of poly(vinyl alcohol), Pluronic® was selected as surfactant because it avoids aggregate formation and provides smaller particle size. While higher polymer content contributes positively to maintaining both reduced size particle and distribution, an increased extract concentration impacted negatively on these parameters. Stability studies were also performed using skin extracts and homogenates and confirmed that nanostructures provide an additional protection. Moreover, the incorporation of Ilex extract in nanoparticles significantly reduced the amount of chlorogenic acid permeated through the skin (no ex vivo permeation until 12 h for this system), extending its topical antioxidant effect.

In view of biopharmaceutical limitations of hydrochlorothiazide (HCTZ), Trojan-type mucoadhesive systems were proposed, aiming to improve HCTZ pharmacological properties by modulating its release. Nanoemulsions were formed spontaneously by combining medium-chain triglycerides (Lipoid® S75 and Pluronic® F68) and high encapsulation efficiency was obtained. The mucoadhesive properties were provided by chitosan and microencapsulation of nanoemulsions in spray-dryer was successfully achieved by using Aerosil® as wall material. The rapid redispersion of nanoemulsion in simulated fluids led to a fast and complete release of HCTZ in gastric medium. The pharmacodynamics of HCTZ was improved, extending the diuretic activity. Once a simple and low-energy method contributed to obtain stable mucoadhesive nanoemulsions, advantages in terms of production could also be achieved, allowing easy scaling up. This novel mucoadhesive Trojan particulate system of HCTZ showed to be a promising approach to overcome limitations in terms of absorption and consequently improve the therapeutic efficacy.

Edible carboxymethyl cellulose films containing α-tocopherol (TC) and a mixture of polysorbate 80 (T80) and lecithin were prepared and characterized physicochemically. The stability of TC into the CMC matrix over time, the physicochemical properties of the films, in vitro release profile of TC from films and its antioxidant capacity were investigated. Films containing each one or both surfactants were more homogenous and no phase separation was observed during the drying. TC-loaded CMC films were stable over a period of 8 weeks, regardless of surfactant type. The addition of T80 in CMC films provided a plasticizing effect, reducing Young's modulus and elongation-at-break. Conversely, the presence of lecithin together with the T80 reduced the water vapor permeability to values close to pure CMC (4 × 10 −7 g/h m Pa), improving the mechanical properties of the films. Lecithin-based films were able to release approximately 5 times more TC than T80-based films, probably due to differences in the interaction between surfactant and matrix. These findings also explain the higher antioxidant effect of lecithin-based films. Moreover, lecithin chemically interacts with TC, slowing down its degradation. The main contribution of this study is that combinations of surfactants are more effective to stabilize TC in a hydrophilic matrix, protecting it against degradation.

The objective of this study was to investigate and quantify the composition phenolic, reducing capacity, the free radical scavenging activity, as well as, the anti-inflammatory effect evaluated against lipopolysaccharides-stimulated RAW264.7 macrophages through modulation of inflammatory mediators, in eight stingless bee honey types (Meliponinae) from southern Brazil. Stingless bee honey did not show to be cytotoxic at the tested concentrations (1–100 µM) and also reduced nitric oxide and the secretion of the pro-inflammatory cytokine in the inflamed macrophages. Two honey samples showed the ability to increase the secretion of anti-inflammatory cytokine (interleukin-10), suggesting a significant anti-inflammatory effect. All these findings indicate that stingless bee honey could be an important source of natural compounds presenting anti-inflammatory and antioxidant effect, which could would provide health benefits when included in the diet.

Although an antiviral, antibacterial, antimycobacterial and antifungal potential have been reported for the tea tree oil (TTO), low solubility, high volatility and oil oxidation may limit the formulation development step. In this context, micro- and nanoparticles could be considered to avoid these chemical instability problems. Furthermore, an improved efficacy could be found due to a greater surface area, which would increase the interactions between TTO and microorganisms. Overall, TTO may be incorporated into micro- or nanoparticles or may be included as a constituent of oily phase. Microparticles would be preferentially selected if a long-term or sustained drug release is required whereas nanoparticles are more advantageous in terms of cell internalization or effectiveness. TTO-based systems have also been combined with Ag nanoparticles to further enhance the antimicrobial efficacy through a synergistic action and to reduce or avoid microbial resistance problems. These combined systems have been particulary considered to avoid the formation of bacterial biofilms, which often include more resistant microorganisms. In view of the advantages that can be obtained with the reduction of the particle size, this review aimed to report the various nano- and microparticulate systems already considered as a vehicle for the TTO in order to guide new researches with this agent.

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.

Honey is a natural ready-to-eat product rich in flavonoids, which is known by the wound healing properties due to both antibacterial and antioxidant activity. Flavonoids mitigate inflammatory processes, and thus it could currently support studies of anti-inflammatory potential of honeys. In this review, in vitro anti-inflammatory properties of flavonoids found in honey were prioritized. Mechanistic information of specific isolated flavonoids as modulators of inflammatory processes are summarized aiming to stimulate studies regarding the action of honey in inflammatory events. Lastly, a structure–activity relationship (SAR) of flavonoids was also included. Flavonoids found in honey have demonstrated antioxidant properties and ability to inhibit pro-inflammatory enzymes such as COX, LOX, iNOS, and pro-inflammatory mediators, including nitric oxide, cytokines and chemokines. Transcriptional factors such as NF-κB are also modulated by flavonoids, controlling the expression of several inflammatory mediators. SAR studies demonstrate the effect of flavonoids in the prevention of inflammatory cascades. Despite the promising reports of in vitro anti-inflammatory activity, well-designed clinical trials need yet to be performed to confirm the benefits of honeys from different botanical sources in diseases that include episodes of inflammation.

Hydrochlorothiazide (HCTZ) is a class IV drug according to the Biopharmaceutical Classification System. This study aimed the development of self-nanoemulsifying drug delivery system (SNEDDS) for HCTZ as an approach to overcome the biopharmaceutical limitations. Pre-formulation screening and ternary phase diagrams were carried out to select the oil phase, the surfactant, and the co-surfactant as the amount of each constituent. The optimized formulations, with reduced amount of surfactant, and composed of medium chain triglycerides, Cremophor EL and Transcutol P did not affect the pH or show drug incompatibilities. The SNEDDS were stabilized by the nanoscale globules and high negative zeta potential. All the physicochemical characterization assays were performed in biorelevant media to better predict the in vivo performance. The enhanced dissolution rate of the SNEDDS reflected in the in vivo diuretic activity, presenting a natriuresis, kaliuresis, and chloriuresis at early stages and an increased volume of total urine compared with HCTZ alone. The designed SNEDDS produced an improvement in the pharmacodynamics due to high dissolution and probable inhibition of intestinal efflux protein by Cremophor EL. The use of SNEDDS demonstrated to be an efficient approach to modulate the absorption of HCTZ and drug therapeutics.

It is well-known that nanoencapsulation may overcome biopharmaceutical limitations of curcumin (CUR), but studies regarding the contribution of the vesicular nature of CUR-loaded nanoparticles on skin permeation are still scarce. Therefore, the effect of three colloidal systems (solid lipid nanoparticles (SLN), nanoemulsion (NE), and polymeric nanoparticles (NP)) on the control of cutaneous permeation of CUR was investigated in porcine ear skin/Franz diffusion cells. Colloidal suspensions were designed to present a similar particle size (±170 nm), narrow size distribution (PdI 0.2), and high entrapment efficiency (99%). Zeta potential values were -0.13, -9.68 and -36.7 mV for the CUR-loaded NP, SLN and NE, respectively. Nanoencapsulation resulted in a cumulative amount of CUR in the more superficial layers of the skin. NP significantly enhanced the compound retention in the epidermis, which was approximately 2.49- and 3.32-fold more than SLN and NE, respectively. The CUR levels into the dermis were significantly increased after treatment with NE, which may be associated with repulsion phenomena in surface skin. Therefore, a more superficial or deeper action of CUR on the skin may be obtained depending on nanostructure type. While NPs are more effective in upper skin layers, NE should be prioritized when a dermal action for the CUR is required.

Given that oral preparations of benznidazole (BZN) have demonstrated limited efficacy in the treatment of Chagas' disease due to pharmacokinetic or toxicological problems, the development of buccal polymeric films was purposed in this study. These systems ensure high patient acceptability and direct access to the systemic circulation, improving drug bioavailability and toxicological profile. Polymer films were prepared through a thermopressing method by mixing BZN and polyvinyl alcohol (PVAL). In some preparations, propylene glycol (PG) and thymol (TM) were also included as plasticizer and chemical absorption enhancer, respectively. Morphology, X-ray diffraction, spectroscopic, thermal, mechanical, and water uptake properties, as well as ex vivo permeability studies, were performed to characterize the film formulations. BZN remained stable and in an amorphous form over 90 days. The addition of PG and TM improved the mechanical properties of the films, making them soft, flexible and tear-resistant. Also, these additives increased the water sorption rate of the films at 50 and 75% relative humidity and the TM increased the film erosion properties and drug permeability (close to 6×) compared to control. It was hypothesized that the permeability improvement of thymol-based films that follow a drug release profile through erosion is also associated with the inhibition of the crystallization of BNZ when the film is in contact with the buccal mucosa. Once the thymol has previously demonstrated a significant in vivo and in vitro trypanocidal action and even improved film characteristics, these systems may be considered promising for Chagas' disease treatment.

Dendrimers are defined as globular, repeatedly branched, macromolecular structures presenting high density of surface functional groups. They have been exploited as targeted drug delivery systems due to their well-defined size and structure. Drugs can be encapsulated in the dendrimer core or complexed to the surface functional groups by electrostatic interactions or covalent conjugations. Dendrimers can improve the absorption of poorly permeable molecules such as hydrophilic compounds and also provide controlled drug release. Their low polydispersity contributes to reducing the experimental and biological variability, providing a more reproducible pharmacokinetic behavior. Interestingly, dendrimers can be tailored to preferably penetrate the skin via the follicular route and a systemic effect should be achieved. The physicochemical and biological properties of dendrimers depend on their surface functional groups, charge, size, and generation which impacts the interaction type of the drug with the skin. Cationic dendrimers, for example, are characterized by enhanced interaction with the skin due to the fact that most proteins are negatively charged. Given that various transport mechanisms may be found according to the type of dendrimer, this chapter will focus on the correlation among their physicochemical and drug absorption properties through the skin. The advantages of combining physical permeation enhancement techniques and dendrimers are also presented.

The high biocompatibility, flexible nature, and adhesive effect of hydrogels are attractive properties for their application as controlled drug-delivery systems. On the other hand, hydrogels in the swollen state are characterized by a low mechanical strength, which represents an important limitation for their biomedical application. The incorporation of nanoparticles in hydrogels is a promising alternative to overcome this limitation, by which multiresponsive hydrogels with improved mechanical, physical, and biological properties may be obtained. The resulting chemical interactions between nanoparticles and the polymeric network can provide hydrogel nanocomposite systems that are characterized by a unique network structure. These systems may be defined as hydrated polymeric networks, physically or covalently crosslinked with one another and/or with nanoparticles. A wide range of nanoparticles, such as carbon nanotubes and ceramic, metal, polymeric, and liposomal nanoparticles, have been incorporated in hydrogels to obtain drug-delivery systems with superior properties and tailored functionality. In this chapter, general aspects and advances in the development, functionalization, characterization, and application of hydrogel nanocomposites are presented, focusing on drug-delivery systems.

The benzopyran HP1, a compound isolated from Hypericum polyanthemum, has demonstrated significant opioid-mediated antinociceptive activity after its oral administration. Despite the pharmacological potential, the poor aqueous solubility limits the oral absorption of this compound. For this reason, HP1 has been alternatively incorporated in lipid-based drug delivery systems. Given that nanoemulsions showed higher antinociceptive action than the free compound in a previous report, in this study, the main objective was to investigate the intestinal transport mechanisms of this system. The Ussing chamber model and rat jejunum were selected for this purpose. The apparent permeability coefficient of HP1 increased approximately 5.3 times after its incorporation in nanoemulsions. Considering that the absorptive transport of HP1 was significantly higher than the secretory transport, the participation of active transporters was suggested. The amount of HP1 in the acceptor chamber was reduced during permeability assays performed at 4 °C, supporting the hypothesis that active transporters are involved in the intestinal transport of this compound. The amount of free fatty acids released from nanoemulsion was approximately 60% after 90 min, demonstrating that part of this system is disassembled before absorption. Nanoemulsion constituents would be able to form new structures with biological constituents, leading to a rapid solubilization of HP1. A mucoadhesion rate of 50% was achieved by nanoemulsion after 30 min, which would also contribute to explain the higher absorption of this system. The particle size of the nanoemulsion is also compatible with endocytosis-mediated transport. Taken together, these results suggest that nanoemulsions containing HP1 could be efficiently delivered to humans considering that different absorption mechanisms are exploited.

Although lipid-based drug delivery systems have gained much importance in recent years due to their ability to improve the solubility and bioavailability of poorly soluble drugs, compartmental pharmacokinetic analyses have not been extensively explored. The oral pharmacokinetics of commercial liquid formulation and a developed semisolid system containing saquinavir mesylate (SQVM) were compared in Beagle dogs. A compartmental analysis after intravenous bolus administration of this drug (1 mg/kg) was also performed. Pharmacokinetic profiles were analyzed using both non-compartmental and compartmental approaches. Plasma concentration of the drug was determined by high-performance liquid chromatography/tandem mass spectrometry (LC/MS/MS). The disposition curve of SQVM given intravenously was better described by a three-compartment model. In contrast, plasma profiles obtained following the oral administration were fitted to a two-compartment model with lag time due to the fact that the distribution phase was masked by the absorption phase in these formulations. The proposed semisolid lipid system was found to be a promising formulation for commercial purposes given the similarity of SQVM absorption rate to that from the commercial liquid formulation.

Edible films have been studied as potential substitutes for conventional plastics in food packaging. Their development provides a new alternative for the application of hydrocolloids, following global trends of environmental preservation. Taking this into account, the aim of this study was to develop and evaluate physicochemical properties (thickness, solubility in water and acid, water vapor permeability, opacity, tensile strength and elongation at break) of composite films based on corn starch (native, modified waxy or waxy) and gelatin, plasticized with glycerol or sorbitol. After this initial screening, the formulation presenting the physicochemical properties more appropriate was applied as an edible composite coating onto Red Crimson grapes to extend the shelf-life. The addition of gelatin significantly increased mechanical strength, solubility in water, permeability to water vapor, and thickness of the biofilms, while also decreasing the opacity. Composite films prepared with sorbitol had significantly lower permeability to water vapor and higher tensile strength than the films plasticized with glycerol. Improved appearance was observed in coated grapes after 21 days storage under refrigerated conditions, which had lower weight loss than the control group. Sensory evaluation showed that all the coatings did not affect acceptability scores.

The aim of this study was to investigate the effects of solid dispersions (SDs) containing a mixture of PVP K30 and different carriers (PEG 4000 or Gelucire® 44/14) on in vitro dissolution and intestinal permeability of saquinavir mesylate (SQVM), and to evaluate their impact on the oral bioavailability of SQVM in a dog model by comparing with Svir® (commercial formulation). Although hydrophilic carriers such as PEG may provide advantages in terms of drug release, their limited solubilization capacity led to precipitation of drug and therefore to a reduced and variable oral bioavailability, as observed for SQVM from this carrier. On the other hand, self-emulsifying systems composed of Gelucire® 44/14 or oleic acid/Castor oil mixture (Svir®) were more effective at improving oral bioavailability of SQVM (approximately 5-fold higher than PEG-based formulations), probably due to the improved solubility of SQVM in GI tract, reduced particle size and inhibitory effects on P-gp (a 2.3-fold reduction of efflux ratio). The selection of carriers and other excipients which display a solubilizing effect and inhibitory effect on P-gp seems to be key factors for increasing the oral bioavailability of SQVM. Gelucire might be considered as a promising carrier for the development of a SQVM commercial formulation.

Natural resources are becoming more limited and degraded. This studysought to evaluate the possible correlation between genotoxicity and cytotoxicityt, via theAllium cepa,and caffeine concentration in the water ofan urban river. A positive correlation (R = 0.504 and p = 0.095) was foundbetween the concentration of caffeine and the aberrations index chromosome (IAC), obtained from a bioassay, representing dependence betweenthe variables. The results of cytotoxicity and genotoxicity showed variation inmitotic index (MI) and chromosomal aberrations, respectively. The bioassayresults when related to the presence of caffeine indicate sewage contamination containing substances that may have caused these changes, e.g., drugs.The study herein demonstrates the potentiality of using those techniques toassist in decision making for protecting water resources. Os recursos naturais se tornam cada vez mais limitados, em consequênciada degradação ambiental. O presente trabalho teve como objetivo verificarpossível correlação entre dados de genotoxicidade/citotoxicidade, viateste de Allium cepa, em amostras de águas superficiais e determinaçõesde concentração do micropoluente cafeína. Analisando-se amostras deágua de um rio urbano, foi encontrada uma correlação positiva, R = 0,504e p = 0,095, entre os valores de concentração de cafeína na água e o índicede aberrações cromossômicas (IAC), obtido no bioensaio, representandocerta dependência entre as variáveis. Os resultados de citotoxicidade egenotoxicidade apresentaram variação no índice mitótico (IM) e aberraçõescromossômicas (AC), respectivamente. Os resultados do bioensaio, quandorelacionados à presença de cafeína, indicam a contaminação por esgotocontendo substâncias que podem levar a essas alterações, por exemplo,fármacos. Demonstra-se, assim, a potencialidade do uso das técnicas paraauxiliar nas tomadas de decisão para proteção dos mananciais.

Nanoparticles based on block copolymers of oligosaccharides [β-cyclodextrin (βCyD) and maltoheptaose (Mal7)] and poly(e-caprolactone) (PCL) were prepared by microphase inversion method. Zeta-potential, particle size measurements and morphological analysis of drug-free and drug-loaded nanoparticles were performed by using, respectively, laser-doppler anemometry, dynamic and static light scattering and transmission electron microscopy. ρ-Ratio values were correlated with transmission electron microscopy observations. Both types of amphiphilic block copolymers, βCyD-b-PCL5k and Mal7-b-PCL5k, self-assembled in water to form spherical vesicles, presented a hydrodynamic diameter of 72 and 34 nm, respectively. The incorporation of drugs into nanoparticles did not affect significantly the particle size for βCyD-b-PCL5k-based nanoparticles with progesterone, unlike the other tested systems. On the other hand, all nanoparticles (with and without drug) were negatively charged. Both nanoparticulate systems showed high drug loading efficiency (higher than 95%), confirming their suitability as delivery system for lipophilic drugs.

In this study, the standardized dry extract of C. glaziovii (SDE) provided a significant vasorelaxant effect after contractions induced by phenylephrine in rat aortic rings in an endothelium-dependent manner, confirming that endothelial factors are needed to stimulate this response. A vasorelaxation close to that of acetylcholine was achieved, justifying the development of new formulations for this plant material. In this context, microparticles were selected to encapsulate SDE and the double emulsion technique was considered because of the hydrophilic nature of plant material. Two experimental designs were applied. Firstly, the effect of formulation parameters on particle size, size distribution and encapsulation efficiency (EE) was evaluated. As low EE was achieved, the effect of the osmotic pressure of the external phase was evaluated in a second experimental design. The presence of the osmotic agent (NaCl) impacted positively on the EE and slower in vitro release profile was obtained, which is desired in controlled release systems. The formation of denser and less porous particle surface, which was identified by SEM analysis, contributes to explain these findings. Microstructures showed to be a promising delivery system for the C. glaziovii SDE considering that a sustained release was achieved.

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.

Background/Aim Some cases of tooth loss related to dental trauma require bone-grafting procedures to improve the aesthetics before prosthetic rehabilitation or to enable the installation of dental implants. Bone regeneration is often a challenge and could be largely improved by mesenchymal stem cells therapy. However, the appropriate scaffold for these cells still a problem. This study evaluated the in vivo effect of human adipose-derived stem cells incorporated into autogenous platelet-rich plasma in bone regeneration and maturation. Material and methods Adipose-derived stem cells were isolated from lipoaspirate tissues and used at passage 4. Immunophenotyping and multilineage differentiation of cells were performed and mesenchymal stem cells characteristics confirmed. Bicortical bone defects (10 mm diameter) were created in the tibia of six beagle dogs to evaluate the effect of adipose-derived stem cells incorporated into platelet-rich plasma scaffolds, platelet-rich plasma alone, autogenous bone grafts, and clot. Samples were removed 6 weeks postsurgeries and analyzed by quantification of primary and secondary bone formation and granulation tissue. Results Adipose-derived stem cells incorporated into platelet-rich plasma scaffolds promoted the highest bone formation (primary + secondary bone) (P

With continuing advances in biotechnology and genetic engineering, there has been a dramatic increase in the availability of new biomacromolecules, such as peptides and proteins that have the potential to ameliorate the symptoms of many poorly-treated diseases. Although most of these macromolecular therapeutics exhibit high potency, their large molecular mass, susceptibility to enzymatic degradation, immunogenicity and tendency to undergo aggregation, adsorption, and denaturation have limited their ability to be administered via the traditional oral route. As a result, alternative noninvasive routes have been investigated for the systemic delivery of these macromolecules, one of which is the buccal mucosa. The buccal mucosa offers a number of advantages over the oral route, making it attractive for the delivery of peptides and proteins. However, the buccal mucosa still exhibits some permeability-limiting properties, and therefore various methods have been explored to enhance the delivery of macromolecules via this route, including the use of chemical penetration enhancers, physical methods, particulate systems and mucoadhesive formulations. The incorporation of anti-aggregating agents in buccal formulations also appears to show promise in other mucosal delivery systems, but has not yet been considered for buccal mucosal drug delivery. This review provides an update on recent approaches that have shown promise in enhancing the buccal mucosal transport of macromolecules, with a major focus on proteins and peptides.