First-time oral administration of resveratrol-loaded layer-by-layer nanoparticles to rats - a pharmacokinetics study.

trans-Resveratrol (RSV) is a plant-derived polyphenol endowed with a broad spectrum of promising therapeutic activities. The applicability of RSV in vivo has, however, had limited success so far, largely due to its inefficient systemic delivery resulting from its low water solubility. Layer-by-Layer (LbL) nanotechnology constitutes an innovative formulation strategy to address this concern, and is based on the design of tunable onion-like multilayered nanoarchitectures on the surface of low solubility drug nanocores, such as RSV. The purpose of this study was the investigation of the bioavailability of an LbL nanoformulation composed of 5.5 bilayers of polyallylamine hydrochloride (PAH) and dextran sulfate (DS) (LbL NPs) by pharmacokinetic studies following oral dosing to Wistar rats (20 mg kg-1). The systemic exposure of LbL NPs was compared to the respective nanoformulation without LbL coatings (RSV nanocores) and the free RSV suspension. The results demonstrated that both LbL NPs and RSV nanocores significantly enhanced, respectively, 1.76-fold and 2.74-fold the systemic exposure of RSV compared to the free RSV suspension, emphasizing their biopharmaceutical advantage. Surprisingly, besides the modified drug release potential of the LbL NPs, these exhibited a slightly lower systemic exposure (0.36-fold) in comparison with non-LbL modified RSV nanocores. These results were justified only by the electrostatic interactions composition of the LbL shell composition, requiring further research towards the application of stronger interactions. For this study, due to the key role of the bioanalytical method in the in vivo data acquisition, a rapid, selective, and sensitive HPLC-DAD method has been successfully optimized and fully validated to confidently quantify RSV levels in the rat plasma matrix, together with the optimization of the sample preparation procedure. Moreover, the chemical stability of RSV was evaluated for 24 h in simulated gastric and intestinal fluids with enzymes. Overall, our findings suggest that LbL NPs should be given great attention, representing a potential drug delivery system for RSV in view of the application of RSV not solely as a supplement but also as a therapeutic drug.

Neoplastic Multifocal Skin Lesions: Biology, Etiology, and Targeted Therapies for Nonmelanoma Skin Cancers.

Neoplastic skin lesions are multifocal, diffuse skin infiltrations of particular relevance in the differential diagnosis of ulcerative, nodular, or crusting skin lesions. Nonmelanoma skin cancers (NMSCs), namely, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and also actinic keratosis (AK), are the most common malignant tumors in humans. BCCs do not proliferate rapidly and most of the times do not metastasize, while SCCs are more infiltrative, metastatic, and destructive. AKs are precursor lesions of cutaneous SCCs. The classical therapy of NMSCs makes use of photodynamic therapy associated with chemotherapeutics. With improved understanding of the pathological mechanisms of tumor initiation, progression, and differentiation, a case is made towards the use of targeted chemotherapy with the intent to reduce the cytotoxicity of classical treatments. The present review aims to describe the current state of the art on the knowledge of NMSC, including its risks factors, oncogenes, and skin carcinogenesis, discussing the classical therapy against new therapeutic options.

Encapsulation of DNA in macroscopic and nanosized calcium alginate gel particles.

Calcium alginate beads, which are biodegradable and biocompatible, have been widely employed as delivery matrices for biomacromolecules. In the present work, the feasibility of encapsulation of DNA (which is used as a model biomacromolecule) in calcium alginate nanobeads (sub-200 nm size), prepared using a recently developed protocol based on the phase inversion temperature (PIT) emulsification method [Machado et al. Langmuir 2012, 28, 4131-4141], was assessed. The properties of the nanobeads were compared to those of the corresponding macroscopic (millimeter sized) calcium alginate beads. It was found that DNA, representing a relatively stiff and highly charged polyanion (thus like-charged to alginate), could be efficiently encapsulated in both nanosized and macroscopic beads, with encapsulation yields in the range of 77-99%. Complete release of DNA from the beads could be accomplished on dissolution of the gel by addition of a calcium-chelating agent. Importantly, the DNA was not denatured or fragmented during the preparation and collection of the nanobeads, which are good indicators of the mildness of the preparation protocol used. The calcium alginate nanobeads prepared by the herein utilized protocol thus show good potential to be used as carriers of sensitive biomacromolecules.

Restoration of direct pathway glycogen synthesis flux in the STZ-diabetes rat model by insulin administration.

Type 1 diabetes subjects are characterized by impaired direct pathway synthesis of hepatic glycogen that is unresponsive to insulin therapy. Since it is not known whether this is an irreversible defect of insulin-dependent diabetes, direct and indirect pathway glycogen fluxes were quantified in streptozotocin (STZ)-induced diabetic rats and compared with STZ rats that received subcutaneous or intraperitoneal insulin (I-SC or I-IP). Three groups of STZ rats were studied at 18 days post-STZ treatment. One group was administered I-SC and another I-IP as two daily injections of short-acting insulin at the start of each light and dark period for days 9-18. A third group did not receive any insulin, and a fourth group of nondiabetic rats was used as control. Glycogen synthesis via direct and indirect pathways, de novo lipogenesis, and gluconeogenesis were determined over the nocturnal feeding period using deuterated water. Direct pathway was residual in STZ rats, and glucokinase activity was also reduced significantly from control levels. Insulin administration restored both net glycogen synthesis via the direct pathway and glucokinase activity to nondiabetic control levels and improved the lipogenic pathway despite an inefficient normalization of the gluconeogenic pathway. We conclude that the reduced direct pathway flux is not an irreversible defect of insulin-dependent diabetes.

Preparation of calcium alginate nanoparticles using water-in-oil (W/O) nanoemulsions.

A procedure for the preparation of calcium alginate nanoparticles in the aqueous phase of water-in-oil (W/O) nanoemulsions was developed. The emulsions were produced from mixtures of the nonionic surfactant tetraethylene glycol monododecyl ether (C(12)E(4)), decane, and aqueous solutions of up to 2 wt % sodium alginate by means of the phase inversion temperature (PIT) emulsification method. This method allows the preparation of finely dispersed emulsions without a large input of mechanical energy. With alginate concentrations of 1-2 wt % in the aqueous phase, emulsions showed good stability against Ostwald ripening and narrow, monomodal distributions of droplets with radii <100 nm. Gelation of the alginate was induced by the addition of aqueous CaCl(2) to the emulsions under stirring, and particles formed were collected using a simple procedure based on extraction of the surfactant on addition of excess oil. The final particles were characterized using cryo-transmission electron microscopy (cryo-TEM) and dynamic light scattering (DLS). They were found to be essentially spherical with a homogeneous interior, and their size was similar to that of the initial emulsion droplets. The herein presented "low-energy" method for preparation of biocompatible nanoparticles has the potential to be used in various applications, e.g., for the encapsulation of sensitive biomacromolecules.

Evaluation of hepatic glucose metabolism via gluconeogenesis and glycogenolysis after oral administration of insulin nanoparticles.

Nanoparticles were designed to promote insulin intestinal absorption via the oral route, to increase portal insulin levels to better mimic the physiological pathway, providing enhanced glucose control through glycogenolysis and gluconeogenesis. Nanoparticles were formulated with insulin encapsulated in the core material consisting of alginate and dextran sulfate, associated with poloxamer and subsequently coated with chitosan then albumin. A spherical and slightly rough core was observed in electron micrographs with the appearance of a concentration gradient of the polysaccharide structure toward the periphery of the nanoparticle. Atomic force microscopy showed that the fully formed nanoparticles are about 200 nm in diameter with smooth and spherical morphology. Histopathological analysis of organs and tissues of diabetic rats dosed daily for 15 days with insulin nanoparticles was used to evaluate toxicological issues. No morphological or pathological alterations were observed in rat liver, spleen, pancreas, kidney or intestinal sections. Following, the effect of nanoencapsulated insulin on inhibiting hepatic gluconeogenesis was evaluated after a single insulin administration and oral glucose tolerance test, which represents a significant metabolic challenge to the liver. Alterations in the hepatic glucose metabolism of fasted streptozotocin-diabetic rats were determined by the percent contribution of glycogenolysis and gluconeogenesis, measured by using metabolic tracers, however similar gluconeogenesis contribution to the hepatic metabolism was observed between diabetic rats receiving nanoencapsulated insulin or insulin solution. The metabolic results may be explained by the inability of a single dose in shifting the gluconeogenesis/glycogenolysis contributions, sampling time, fasting period or by influence of the kidney enzymes and impairment in insulin signaling observed in stz-diabetic rats.

Calculations of Diffusion Coefficients of Iron Salts in Aqueous Solutions at 298.15 K: A Useful Tool for the Knowledge of the Structure of these Systems.

Diffusion coefficients, thermodynamic and mobility factors of iron salts in aqueous solutions are estimated from Onsager-Fuoss model. The influence of the ion size parameter a, "mean distance of closest approach of ions", determined from different approaches, on the variation of diffusion coefficients with concentration, is also discussed. The aim of this work is to have a better understanding of the structure of these systems and of the thermodynamic behaviour of iron salts in aqueous media.

Naringenin: A potential flavonoid phytochemical for cancer therapy.

Naringenin is an important phytochemical which belongs to the flavanone group of polyphenols, and is found mainly in citrus fruits like grapefruits and others such as tomatoes and cherries plus medicinal plants derived food. Available evidence demonstrates that naringenin, as herbal medicine, has important pharmacological properties, including anti-inflammatory, antioxidant, neuroprotective, hepatoprotective, and anti-cancer activities. Collected data from in vitro and in vivo studies show the inactivation of carcinogens after treatment with pure naringenin, naringenin-loaded nanoparticles, and also naringenin in combination with anti-cancer agents in various malignancies, such as colon cancer, lung neoplasms, breast cancer, leukemia and lymphoma, pancreatic cancer, prostate tumors, oral squamous cell carcinoma, liver cancer, brain tumors, skin cancer, cervical and ovarian cancer, bladder neoplasms, gastric cancer, and osteosarcoma. Naringenin inhibits cancer progression through multiple mechanisms, like apoptosis induction, cell cycle arrest, angiogenesis hindrance, and modification of various signaling pathways including Wnt/ß-catenin, PI3K/Akt, NF-ĸB, and TGF-ß pathways. In this review, we demonstrate that naringenin is a natural product with potential for the treatment of different types of cancer, whether it is used alone, in combination with other agents, or in the form of the naringenin-loaded nanocarrier, after proper technological encapsulation.

Solid dispersions of imidazolidinedione by PEG and PVP polymers with potential antischistosomal activities.

Solid dispersions have been used as a strategy to improve the solubility, dissolution rate, and bioavailability of poor water-soluble drugs. The increase of the dissolution rate presented by (5Z)-3-(4-chloro-benzyl)-5-(4-nitro-benzylidene)-imidazolidine-2,4-dione (LPSF/FZ4) from the solid dispersions is related to the existence of intermolecular interactions of hydrogen bond type (>N-H···O<) between the amide group (>N-H) of the LPSF/FZ4 and the ether group (-O-) of the polyethyleneglycol polymer, or the carbonyl (C=O) of the polyvinylpyrrolidone polymer (PVP). The intensity of these interactions is directly reflected in the morphology acquired by LPSF/FZ4 in these systems, where a new solid phase, in the form of amorphous aggregates of irregular size, was identified through scanning electron microscopy and confirmed in the characterizations achieved using X-ray diffraction and thermal analysis of DSC. The solid dispersions with the polymer PVP, in higher concentrations, were revealed to be the best option to be used in the formulations of LPSF/FZ4 in both theoretical and experimental studies.

Effects of galactose on direct and indirect pathway estimates of hepatic glycogen synthesis.

Hepatic glycogen is formed by direct and indirect pathways whose activities reflect altered nutrition or disease. Direct/indirect pathway measurements often involve test meals where ∼ 10% of carbohydrate is galactose, but its effects on direct/indirect pathway estimates are unknown. Therefore, direct/indirect pathway contributions in 24-h fasted rats given 2g/kg 100% glucose (GLU, n=6) or 90% glucose-10% galactose (GLU+GAL, n=6) were measured by [U-(13)C]glucose dilution and by position-5/position-2 glycogen enrichment (H5/H2) from 2H(2)O. For GLU+GAL, galactose glycogenesis was independently measured with [1-(13)C]galactose. Glycogenesis was equivalent in both groups but for GLU+GAL, 23 ± 4% of glycogen was derived from galactose. [U-(13)C]glucose reported a 30 ± 3% direct pathway contribution to glycogenesis for GLU but only 20 ± 3% for GLU+GAL (p=0.012 vs. GLU). H5/H2 yielded identical direct pathway estimates (32 ± 3% GLU, 29 ± 6% GLU+GAL). Thus, galactose glycogenesis was undetected by H5/H2 while [U-(13)C]glucose reported a reduced direct/indirect pathway ratio. With [1-(13)C]galactose also present, correct glycogenic source contributions were obtained.

Interactions between DNA and nonionic ethylene oxide surfactants are predominantly repulsive.

In the present work, the interactions between double-stranded (ds) or single-stranded (ss) DNA and nonionic ethylene oxide (EO) surfactants, with special attention to the possible contributions from hydrophobic interactions, have been investigated using a multitechnique approach. It was found that the presence of ss as well as dsDNA induces a slight decrease of the cloud point of pentaethylene glycol monododecyl ether (C(12)E(5)). Assessment of the partitioning of DNA between the surfactant-rich and surfactant-poor phases formed above the cloud point showed that the polymer was preferably located in the surfactant-poor phase. Surface tensiometry experiments revealed that neither of the DNA forms induced surfactant micellization. Finally, it was shown by DNA melting measurements that another EO surfactant (C(12)E(8)) did not affect the relative stabilities of ss and dsDNA. To summarize, all experiments suggest that the net interaction between DNA and nonionic surfactants of the EO type is weakly repulsive, which can be attributed mainly to steric effects. In general, the results were practically identical for the ds and ss forms of DNA, except those from the cloud point experiments, where the decrease of the cloud point was less pronounced with ssDNA. This finding indicates the presence of an attractive component in the interaction, which can reasonably be ascribed to hydrophobic effects.

A comprehensive development strategy in buccal drug delivery.

This work combines several methods in an integrated strategy to develop a matrix for buccal administration. For this purpose, tablets containing selected mucoadhesive polymers loaded with a model drug (omeprazole), free or in a complexed form with cyclodextrins, and in the absence and presence of alkali agents were subjected to a battery of tests. Mucoadhesion studies, including simple factorial analysis, in vitro release studies with both model-dependent and model-independent analysis, and permeation studies were performed. Mucoadhesive profiles indicated that the presence of the drug decreases the mucoadhesion profile, probably due its hydrophobic character. In tablets loaded with the drug complexed with ß-cyclodextrin or methyl-ß-cyclodextrin, better results were obtained with the methylated derivative. This effect was attributed to the fact that in the case of ß-cyclodextrin, more hydroxyl groups are available to interact with the mucoadhesive polymers, thus decreasing the mucoadhesion performance. The same result was observed in presence of the alkali agent (L: -arginine), in this case due to the excessive hydrophilic character of L: -arginine. Drug release from tablets was also evaluated, and results suggested that the dissolution profile with best characteristics was observed in the matrix loaded with omeprazole complexed with methyl-ß-cyclodextrin in the presence of L: -arginine. Several mathematical models were applied to the dissolution curves, indicating that the release of the drug, in free or in complexed state, from the mucoadhesive matrices followed a super case II transport, as established on the basis of the Korsmeyer-Peppas function. The feasibility of drug buccal administration was assessed by permeation experiments on porcine buccal mucosa. The amount of drug permeated from mucoadhesive tablets presented a maximum value for the system containing drug complexed with the methylated cyclodextrin derivative in presence of L: -arginine. According to these results, the system containing the selected polymer mixture and the drug complexed with methyl-ß-cyclodextrin in presence of L: -arginine showed a great potential as a buccal drug delivery formulation, in which a good compromise among mucoadhesion, dissolution, and permeation properties was achieved.

Sonication-assisted Layer-by-Layer self-assembly nanoparticles for resveratrol delivery.

This paper advances the development of a novel drug nanodelivery solution to the oral administration of resveratrol (RSV), a low soluble drug whose recognized therapeutic applications are circumscribed when administered in the free compound form. Layer-by-Layer (LbL) self-assembly is an emergent nanotechnology proposed to address this concern with means to afford control over key formulation parameters, which are able to ultimately promote an improved pharmacokinetics. LbL self-assembly consists in the sequential adsorption of oppositely charged polyelectrolytes upon a low soluble drug nanoparticle (NP) template, giving rise to onion-like multilayered nanoarchitectures. In this work, RSV nanoprecipitation followed by LbL self-assembly of polyelectrolytes, led by a washless approach, was carried out by using the cationic poly(allylamine hydrochloride) (PAH) and the anionic dextran sulfate (DS) as polyelectrolytes towards the nanoencapsulation of RSV. Each saturated polyelectrolyte layer deposition involved the rigorous polyelectrolyte concentration assessment which was accomplished by tracing titration curves. This way, aqueous RSV nanocores and RSV LbL nanoformulations with a distinct number of PAH/DS bilayers were developed, including 2.5 (RSV-(PAH/DS)2.5 NPs), 5.5 (RSV-(PAH/DS)5.5 NPs) and 7.5 (RSV-(PAH/DS)7.5 NPs) bilayered nanoformulations. Homogenous particle size distributions at the desired nanoscale interval (ca. 116-220 nm; polydispersity index below 0.15), good colloidal (zeta potential magnitudes ca. ± 20-30 mV) and chemical stabilizations, high encapsulation efficiency (above 90%) together with an excellent cytocompatibility with Caco-2 cells (cell viability above 90%) were observed for all the nanoformulations. Eventfully, LbL NPs promoted a controlled release of RSV pursuant to the number of polyelectrolyte bilayers under simulated gastrointestinal conditions, particularly in the intestine medium, emphasizing their biopharmaceutical advantage. Our findings manifestly pinpoint that LbL PAH/DS NPs constitute a promising nanodelivery system for the oral delivery of RSV, providing a rational strategy to enlarge the implementation range of this interesting polyphenol, which is possibly the most actively investigated phytochemical worldwide.

Public numbers on monetary valuation of fish landings.

This article presents a dataset that combines several time series of economic variables for Portugal, from 1969 to 2015, which can be used to accurately measure the change in value of different series in the fisheries sector. Raw data includes total nominal revenue from fish landings measured in thousands of euros, a consumer price index, and the nominal exchange rate of the Portuguese escudo against the US dollar (only until 1998). We use these raw data series to correct for inflation and to produce information on fish landings measured in constant prices in euros and to discuss the impact of the exchange rate depreciation in the fish sector if measured in US dollars. Data was retrieved from publicly accessible sources such as Statistics Portugal (Instituto Nacional de Estatística, INE) for fish landing revenue, AMECO (European Commission) for Consumer Price Index data, and International Financial Statistics (International Monetary Fund) for exchange rate data. The dataset is useful to academics, policymakers and advocacy groups alike for understanding the real production of the fisheries sector.

Solid-state characterization and dissolution profiles of the inclusion complexes of omeprazole with native and chemically modified beta-cyclodextrin.

The aim of this work was to investigate the formation of the inclusion complex between omeprazole (OME), a benzimidazolic derivative and a methylated cyclodextrin, methyl-beta-cyclodextrin (MbetaCD), with an average degree of substitution of 0.5. Inclusion complex between OME and beta-cyclodextrin (betaCD), a natural cyclodextrin, was used as reference. In aqueous media, apparent stability constants (K(s)), which describe the extent of formation of the complexes, have been determined by UV spectroscopy and 1H NMR experiments. The stoichiometry of the complexes was found to be 1:1 mol:mol OME:cyclodextrin (CD) and the value of K(s) was higher for OME:MbetaCD than for OME:betaCD inclusion complexes. Solid binary systems of OME and CDs were prepared by different techniques, namely kneading, spray-drying and freeze-drying. The formation and physicochemical characterization of solid inclusion complexes were investigated by differential scanning calorimetry (DSC), Fourier transform-infrared (FTIR), X-ray diffractometry (XRD) and scanning electron microscopy (SEM). The results show that freeze-drying method produces true inclusion complexes between OME and both CDs. In contrast, crystalline drug was detectable in kneaded and spray-drying products. The dissolution of OME from the binary systems was studied to select the most appropriate system for the development of a buccal drug delivery formulation. It was concluded that the preparation technique played an important role in the dissolution behaviour of the drug and the inclusion complex between OME and MbetaCD obtained by spray-drying and freeze-drying allowed better performances.

Cyclodextrin multicomponent complexation and controlled release delivery strategies to optimize the oral bioavailability of vinpocetine.

In the present work, to maintain a suitable blood level of vinpocetine (VP) for a long period of time, VP-cyclodextrin-tartaric acid multicomponent complexes were prepared and formulated in hydroxypropylmethylcellulose matrix tablets. In vitro and in vivo performances of these formulations were investigated over a VP immediate release dosage form. Solubility studies were performed to evaluate the drug pH solubilization profile and to assess the effect of multicomponent complexation on VP solubility. The drug release process was investigated using United States Pharmacopeia apparatus 3 and a comparative oral pharmacokinetic study was subsequently undertaken in rabbits. Solubility studies denoted the pH-solubility dependence of VP and solubility improvement attained by complexation. Dissolution results showed controlled and almost complete release behavior of VP over a 12-h period from complex hydroxypropylmethylcellulose-based formulations. A clear difference between the pharmacokinetic patterns of VP immediate release and VP complex-based formulations was revealed. The area under the plasma concentration-time curve after oral administration of complex-based formulations was 2.1-2.9 times higher than that for VP immediate release formulation. Furthermore, significant differences found for mean residence time, elimination half-life, and elimination rate constant values corroborated prolonged release of VP from complex-based formulations. These results suggest that the oral bioavailability of VP was significantly improved by both multicomponent complexation and controlled release delivery strategies.

Methyl-ß-cyclodextrin Inclusion Complex with ß-Caryophyllene: Preparation, Characterization, and Improvement of Pharmacological Activities.

ß-Caryophyllene (BCP) is a sesquiterpene that shows high potential in pharmacological applications. However, these have been drastically limited by the respective volatility and poor water solubility. The present study investigates the formation of inclusion complexes between BCP and methyl-ß-cyclodextrin (MßCD) and shows that these complexes promote a significant improvement of the anti-inflammatory, gastric protection, and antioxidant activities relative to neat BCP. It is shown that the solubility of BCP is significantly increased through complexation in phase solubility studies. Inclusion complexes with MßCD in solid state were prepared by three different methods, kneading, rotary evaporation, and lyophilization, with the latter confirmed by differential scanning calorimetry, Fourier transformed infrared spectroscopy, scanning electron microscopy, 1H NMR spectroscopy, and molecular dynamics studies. This study provides for the first time a full characterization of inclusion complexes between BCP and MßCD and highlights the impact of complex formation upon pharmacological activity.

Diclofenac-ß-cyclodextrin for colonic drug targeting: In vivo performance in rats.

The aim of this in vivo study was to assess the ability of the prodrug conjugate diclofenac-ß-cyclodextrin to release diclofenac in the colon following oral administration, using sulfapyridine (a metabolite of sulfasalazine) as a marker of colonic absorption. Two groups of rats were used; the test rats received a suspension containing the two prodrugs, diclofenac-ß-cyclodextrin and sulfasalazine, while the control rats received a suspension containing the corresponding free drugs, sodium diclofenac and sulfapyridine. The rats were fasted overnight with free access to water before and throughout the first 12h of the study. Blood was collected from the tail vein at pre-determined time points and the plasma analyzed for the concentrations of diclofenac and sulfapyridine. Following the oral administration of the two prodrugs, a more extended absorption profile was observed and Cmax was achieved 10h post-dose, in contrast to rapid absorption of the free drugs (tmax of diclofenac being 1.3h, and that of sulfapyridine being 2.1h). In addition to a later tmax, conjugation of diclofenac to ß-cyclodextrin also resulted in a reduced Cmax and a reduced AUC. The same tmax for diclofenac-ß-cyclodextrin as for sulfasalazine confirms the colonic metabolism of diclofenac-ß-cyclodextrin. This study shows the potential of this new cyclodextrin-based prodrug to target and release diclofenac specifically in the colon following oral administration.

Biopharmaceutical evaluation of epigallocatechin gallate-loaded cationic lipid nanoparticles (EGCG-LNs): In vivo, in vitro and ex vivo studies.

Cationic lipid nanoparticles (LNs) have been tested for sustained release and site-specific targeting of epigallocatechin gallate (EGCG), a potential polyphenol with improved pharmacological profile for the treatment of ocular pathologies, such as age-related macular edema, diabetic retinopathy, and inflammatory disorders. Cationic EGCG-LNs were produced by double-emulsion technique; the in vitro release study was performed in a dialysis bag, followed by the drug assay using a previously validated RP-HPLC method. In vitro HET-CAM study was carried out using chicken embryos to determine the potential risk of irritation of the developed formulations. Ex vivo permeation profile was assessed using rabbit cornea and sclera isolated and mounted in Franz diffusion cells. The results show that the use of cationic LNs provides a prolonged EGCG release, following a Boltzmann sigmoidal profile. In addition, EGCG was successfully quantified in both tested ocular tissues, demonstrating the ability of these formulations to reach both anterior and posterior segment of the eye. The pharmacokinetic study of the corneal permeation showed a first order kinetics for both cationic formulations, while EGCG-cetyltrimethylammonium bromide (CTAB) LNs followed a Boltzmann sigmoidal profile and EGCG-dimethyldioctadecylammonium bromide (DDAB) LNs a first order profile. Our studies also proved the safety and non-irritant nature of the developed LNs. Thus, loading EGCG in cationic LNs is recognised as a promising strategy for the treatment of ocular diseases related to anti-oxidant and anti-inflammatory pathways.

In vitro controlled release of vinpocetine-cyclodextrin-tartaric acid multicomponent complexes from HPMC swellable tablets.

The objective of this study was to investigate the effect of multicomponent complexation (MCC) of vinpocetine (VP), a poorly soluble base-type drug, with beta-cyclodextrin (betaCD), sulfobutylether beta-cyclodextrin (SBEbetaCD), tartaric acid (TA), polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC), on the design of controlled release hydrophilic HPMC tablets and to evaluate their in vitro release profiles by a pH gradient method. Multicomponent complexation led to enhanced dissolution properties of VP both in simulated gastric and intestinal fluids, and became possible the development of HPMC tablet formulations with more independent pH dissolution profiles. Drug release process was investigated experimentally using USP apparatus 3 and by means of model-independent parameters. Responses studied included similarity of dissolution profiles, time for 60% of the drug to dissolve (T(60%)), percent of VP released after 7 h (PD(7 h)) and the dissolution efficiency parameter at 12 h (DE(12 h)). Influence of multicomponent complexation was proved to increase the release of VP from HPMC tablets and superior PD(7 h) and DE(12 h) values were obtained in formulations containing VP-CD-TA complexes. Results supported the use of HPMC matrices to provide a useful tool in retarding the release of VP and that dissolution characteristics of the drug may be modulated by multicomponent complexation in these delivery systems, suggesting an improvement on VP bioavailability.