Synthesis and release behavior of layered double hydroxides-carbamazepine composites.

Carbamazepine (CBZ) was incorporated into layered double hydroxides (LDH) to be used as a controlled drug system in solid tumors. CBZ has a formal charge of zero, so its incorporation in the anionic clay implies a challenge. Aiming to overcome this problem, CBZ was loaded into LDH with sodium cholate (SC), a surfactant with negative charge and, for comparison, without SC by the reconstruction method. Surprisingly, it was found that both resultant nanocomposites had similar CBZ encapsulation efficiency, around 75%, and the LDH-CBZ system without SC showed a better performance in relation to the release kinetics of CBZ in simulated body fluid (pH 7.4) and acetate buffer simulating the cellular cytoplasm (pH 4.8) than the system with SC. The CBZ dimensions were measured with Chem3D and, according to the basal spacing obtained from X-ray patterns, it can be arranged in the LDH-CBZ system as a monolayer with the long axis parallel to the LDH layers. Fourier transform infrared spectroscopy and solid state NMR measurements confirmed the presence of the drug, and thermogravimetric analyses showed an enhanced thermal stability for CBZ. These results have interesting implications since they increase the spectrum of LDH application as a controlled drug system to a large number of nonionic drugs, without the addition of other components.

Exploring a new free-standing polyelectrolyte (PEM) thin film as a predictive tool for drug-mucin interactions: Insights on drug transport through mucosal surfaces.

The main objective of the present work was to design a biomimetic free-standing multilayered PEM film, constructed by the layer-by-layer (LbL) assembly approach, based on natural biopolymers and intended to recreate the complex mucus-mimetic matrices in order to provide mechanistic insights into biophysical interactions between drugs and the physiological gel-forming mucin network of mucus that covers the mucosal epithelia named as(CS/ALG)/(PGM) PEM film. The obtained results indicate that mucin may delay or increase drug precipitation on the mucus layer, depending on specific drug-mucin interactions driving drug supersaturation or drug crystallization phenomena. It was found that the drug lipophilicity characteristics governed the mucin binding degree, which had an influencing role on the drug translocation across this gel-like hydrogel. Moreover, the ionization of these drugs did not have a significant role on the drug binding ability to mucin as much as the lipophilicity properties did. The (CS/ALG)/(PGM) PEM film may be a promising tool to routine testing drug-mucus interactions to evaluate biophysical interactions between this protective barrier of the organism against different drug therapeutic products or external aggressive agents, leading to the optimization of drug delivery products or drugs for particular disease states.

Rifampicin loaded in alginate/chitosan nanoparticles as a promising pulmonary carrier against Staphylococcus aureus.

This study aims to explore the antimicrobial activity of rifampicin (RIF) and ascorbic acid (ASC) co-loaded into alginate (ALG)/chitosan (CS) nanoparticles (RIF/ASC NPs) and tested for their antibacterial activity against several strains of methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). Also, the present research focused on exploring the possible antibacterial mechanism of action of these RIF/ASC NPs, which demonstrated a significant biocide activity against the S. aureus strains with minimum inhibitory concentrations (MIC) between 2- and 8-fold lower than those one exhibited with the free antibiotic RIF. The proposed antimicrobial mechanism of action of the RIF/ASC NPs seems to be the result of collaborative effects between NPs and the RIF/ASC antibiotic combination. Moreover, results indicated that the functionalized RIF/ASC NP surface played a crucial role on the processes of NP adhesion into the bacterial surface, the alterations on the cell membrane integrity, and the cell uptake of the RIF/ASC antibiotic into bacteria. Further, the in vivo lung deposition pattern of empty NPs labeled (NPs-FITC) with isothiocyanate fluorescein in rats was investigated post intratracheal instillation of NPs. In summary, findings from this work show that our novel designed engineered RIF/ASC co-loaded NPs could be a suitable system for antibiotic lung administration with promising perspectives for effective treatments of pulmonary intracellular infections for those known antibiotics that are losing effectiveness due to antimicrobial resistance problems. Graphical Abstract.

Development and validation of a reversed-phase high-performance liquid chromatographic method with solid-phase extraction for the quantification of hydrochlorothiazide in ex vivo permeation studies.

Hydrochlorothiazide (HCT) is a diuretic used to treat hypertension. In order to study its intestinal permeation behavior applying an ex vivo methodology, a rapid, sensitive and selective reversed-phase liquid chromatography (RP-HPLC) method coupled with UV detection (RP-HPLC UV) was developed for the analysis of HCT in TC199 culture medium used as mucosal and serosal solutions in the everted rat intestinal sac model. Also, analytical procedures for the quantification of HCT by RP-HPLC with UV detection required a sample preparation step by solid-phase extraction. The method was validated in the concentration range of 8.05 × 10-7 to 3.22 × 10-5 m for HCT. Chromatographic parameters, namely carry-over, lower limit of quantification (1.4491 × 10-7 m), limit of detection (3.8325 × 10-8 m), selectivity, inter- and intraday precision and extraction recovery, were determined and found to be adequate for the intended purposes. The validated method was successfully used for permeability assays across rat intestinal epithelium applying the ex vivo everted rat gut sac methodology to study the permeation behavior of HCT.

Permeability Profiles and Intestinal Toxicity Assessment of Hydrochlorothiazide and Its Inclusion Complex with ß-Cyclodextrin Loaded into Chitosan Nanoparticles.

Here, a novel drug delivery system was developed for the hydrochlorothiazide (HCT):ß-cyclodextrin (ßCD) inclusion complex loaded into chitosan (CS) nanoparticles (NPs) [CS/HCT:ßCD NPs]. It was found, for the first time, that exposure of the intestinal mucosa to free HCT resulted in an increased and abnormal intestinal permeability associated with several injuries to the intestinal epithelium. Nevertheless, the HCT delivery system obtained ameliorated the damage of the intestinal epithelium induced by HCT. Furthermore, we found that the corresponding permeability profiles for both the free HCT and the CS/HCT:ßCD NPs were exponential and lineal, respectively. We propose that the increased intestinal uptake and severe tissue injury of HCT to the intestinal epithelium could be directly related to possible effects of this drug on the ionoregulatory Na+/K+-ATPase channel. Thus, it is postulated that the CS/HCT:ßCD NPs may increase the gastrointestinal retention of the HCT, which would provide increased adherence to the mucus barrier that lines the intestinal epithelium; consequently, this would act as a slow HCT release delivery system and maintain lower drug levels of luminal gut in comparison with the administration of free HCT, leading to less severe local injury.

Efficacy of Argentine propolis formulation for topical treatment of canine otitis externa / Eficácia da formulação da propólis Argentina para o tratamento tópico de otite externa canina

The therapeutic effects of Argentine propolis ear drop formulation on canine otitis externa were evaluated. Forty-eight dogs with symptoms of otitis externa were randomly assigned to double-blinded, controlled clinical trial to evaluate the efficacy of topical formulation with propolis versus a topical placebo in the treatment of otitis externa. The propolis preparation and placebo were administrated into both external ear canals, twice daily for 14 days. Throughout the study, clinical examination and microbiological analysis of dogs ear exudates were made. The most frequent microorganisms isolated in culture media were: Malassezia pachydermatis (54.2 percent), Staphylococcus aureus (43.8 percent), coagulase-negative Staphylococcus (25.0 percent), Pseudomonas aeruginosa (20.8 percent), Candida albicans (18.8 percent), Proteus mirabilis (16.7 percent), Streptococcus spp. (16.7 percent), Enteroccocus faecalis (12.5 percent), Escherichia coli (12.5 percent), Staphylococcus intermedius (6.3 percent), Klebsiella spp. (4.2 percent), andCandida glabrata (2.1 percent). Whereas the control group did not recover from the infectious ear disease, the propolis preparation exhibited antimicrobial activity against most of the microorganisms isolated from samples of the treated group. In addition, no propolis-adverse effects were observed. This allowed propolis-treated patients to show a significant improvement of the clinical parameters. Thus, this new Argentine propolis ear drop formulation may be used for topical treatment of otitis externa in dogs.

Os efeitos terapêuticos da formulação em gotas óticas de própolis procedentes da Argentina foram avaliados no tratamento da otite externa canina. Quarenta e oito cães com sintomas de otite externa foram distribuídos aleatoriamente em ensaio clínico duplo-cego controlado para avaliar a eficácia da formulação tópica com a própolis contra um placebo tópico no tratamento da otite externa. A preparação de própolis e placebo foi administrada em ambos os canais da orelha externa, duas vezes por dia, durante 14 dias. Ao longo do estudo, os cães foram submetidos a exame físico e à análise microbiológica de exsudatos auriculares. Os mais frequentes microrganismos isolados em meios de cultura foram: Malassezia pachydermatis (54,2 por cento), Staphylococcus aureus (43,8 por cento), Staphylococcus coagulase-negativo (25,0 por cento), Pseudomonas aeruginosa (20,8 por cento), Candida albicans (18,8 por cento), Proteus mirabilis (16,7 por cento), Streptococcus spp.(16,7 por cento), Enterococcus faecalis (12,5 por cento), Escherichia coli (12,5 por cento), Staphylococcus intermedius (6,3 por cento), Klebsiella spp.(4,2 por cento) e Candida glabrata (2,1 por cento). A preparação de própolis apresentou atividade antimicrobiana contra a maioria dos microrganismos isolados de amostras do grupo de tratamento, sendo que os do grupo-controle não se recuperaram da doença infecciosa auricular, e não foram observados efeitos adversos à própolis. Isso permitiu aos pacientes tratados com própolis melhora significativa dos parâmetros clínicos. Essa nova formulação da própolis argentina para o ouvido apresenta potencial utilidade no tratamento tópico da otite externa em cães.

Biowaiver monographs for immediate release solid oral dosage forms: furosemide.

Literature and new experimental data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing furosemide are reviewed. The available data on solubility, oral absorption, and permeability are sufficiently conclusive to classify furosemide into Class IV of the Biopharmaceutics Classification System (BCS). Furosemide's therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) problems are also taken into consideration. In view of the data available, it is concluded that the biowaiver procedure cannot be justified for either the registration of new multisource drug products or major postapproval changes (variations) to existing drug products.

Biowaiver monographs for immediate release solid oral dosage forms: acetazolamide.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing acetazolamide are reviewed. Acetazolamide's solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), as well as its therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) problems are taken into consideration. The available data on solubility, on oral absorption and permeability are not sufficiently conclusive to classify acetazolamide with certainty. Taking a conservative approach, no biowaiver is considered justified for the registration of new multisource drug products. However, SUPAC level 1 and level 2 postapproval changes and most EU Type I variations can be approved waiving in vivo BE studies.

Rapid in vivo dissolution of ketoprofen: implications on the biopharmaceutics classification system.

The aim of this paper was to investigate the in vivo dissolution behavior of ketoprofen, a Class II drug according to the Biopharmaceutics Classification System (BCS), in the upper small intestine of dogs. An intubations method was used, where no blocking balloons were used to prevent luminal drug transport along the GI tract. Our design allowed the drug to be transported freely to more distal parts of the GI tract and also, it was supported by a pharmacokinetic study. Pharmacokinetic parameters of ketoprofen were determined in dogs after administering approximately 0.27 mg kg(-1) (solution) or approximately 1.47 mg kg(-1) (suspension) in oral bolus doses. There were not statistical significant differences in plasma concentrations for both formulations, either in the maximum concentrations C(max) or AUC following oral dose administration. The rapid disappearance of ketoprofen from the intestinal lumen, reflected by low mass recovery in the supernatant and sediment of the collected intestinal fluid samples, in comparison to that recovery of the non-absorbable marker phenol red, suggests that ketoprofen is emptying into the small intestine and is rapidly dissolved and absorbed. In this study, the in vivo results clearly show that the absorption rate of ketoprofen is not dissolution limited; therefore ketoprofen would be essentially equivalent to Class I drugs and could be considered for waiver of bioavailability and bioequivalence testing.

Isoxazoles. 8. Preformulation studies of an isoxazolylnaphthoquinone derivative.

The degradation kinetics of 2-hydroxy-N-(3,4-dimethyl-5-isoxazolyl)-1,4-naphthoquinone 4-imine (1) in a 25% solution of ethyl alcohol in water has been studied. The rate constants were observed to follow pseudo-first-order kinetics in all cases. The pH-rate profile indicated a negligible decomposition at pH values higher than its pKa2 value [5.4 +/- 0.14 (*n = 6)]. Un-ionized 1 was subject to specific acid catalysis. The ionic strength did not affect the stability of the drug. These data can be used to develop a stable oral liquid dosage form of the drug.