Thermal Stability Kinetics and Shelf Life Estimation of the Redox-Active Therapeutic and Mimic of Superoxide Dismutase Enzyme, Mn(III) meso-Tetrakis(N-ethylpyridinium-2-yl)porphyrin Chloride (MnTE-2-PyPCl5, BMX-010).

Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin chloride (MnTE-2-PyPCl5, BMX-010, and AEOL10113) is among the most studied superoxide dismutase (SOD) mimics and redox-active therapeutics, being currently tested as a drug candidate in a phase II clinical trial on atopic dermatitis and itch. The thermal stability of active pharmaceutical ingredients (API) is useful for estimating the expiration date and shelf life of pharmaceutical products under various storage and handling conditions. The thermal decomposition and kinetic parameters of MnTE-2-PyPCl5 were determined by thermogravimetry (TG) under nonisothermal and isothermal conditions. The first thermal degradation pathway affecting Mn-porphyrin structural integrity and, thus, activity and bioavailability was associated with loss of ethyl chloride via N-dealkylation reaction. The thermal stability kinetics of the N-dealkylation process leading to MnTE-2-PyPCl5 decomposition was investigated by using isoconversional models and artificial neural network. The new multilayer perceptron (MLP) artificial neural network approach allowed the simultaneous study of ten solid-state kinetic models and showed that MnTE-2-PyPCl5 degradation is better explained by a combination of various mechanisms, with major contributions from the contraction models R1 and R2. The calculated activation energy values from isothermal and nonisothermal data were about 90 kJ mol-1 on average and agreed with one another. According to the R1 modelling of the isothermal decomposition data, the estimated shelf life value for 10% decomposition (t 90%) of MnTE-2-PyPCl5 at 25°C was approximately 17 years, which is consistent with the high solid-state stability of the compound. These results represent the first study on the solid-state decomposition kinetics of Mn(III) 2-N-alkylpyridylporphyrins, contributing to the development of this class of redox-active therapeutics and SOD mimics and providing supporting data to protocols on purification, handling, storage, formulation, expiration date, and general use of these compounds.

Synthesis and characterization of a molecularly imprinted polymer (MIP) for solid-phase extraction of the antidiabetic gliclazide from human plasma.

Gliclazide is a sulfonylurea frequently prescribed for the management of type 2 diabetes mellitus in elderly patients and for patients with chronic renal or hepatic diseases. Even though it is considered a safer alternative, the drug can provoke side effects in some patients, especially hypoglycemia, due to the high interindividual variability. Therefore, the quantification of gliclazide in biological samples is usually recommended in order to assure efficacy and safety of the pharmacotherapy. However, due to the complexity of biological matrices, therapeutic monitoring can be very challenging, especially in the sample preparation step. For that reason, the synthesis and characterization of a novel and selective molecularly imprinted polymer (MIP) was proposed to be employed as sorbent for the extraction of gliclazide from human plasma samples by a molecularly imprinted solid-phase extraction (MISPE) procedure. Synthesis conditions were optimized (monomer, crosslinker and porogen) and the polymer was characterized for its morphological, physicochemical and stability properties. The influence of drug concentration, solvent composition and pH on the coefficient of distribution (Kd) and imprinting factor (IF) were studied, as well as repeatability between batches and selectivity. A bioanalytical method was developed applying the developed MIP as sorbent in solid phase extraction and liquid chromatography using a Poroshell 120 C18 (100 × 4.6 mm, 4 µm) column, acetonitrile and 10 mM potassium phosphate buffer pH 3.0 (50:50) at a flow-rate of 1.2 mL/min as mobile phase, temperature of 30 °C, injection volume of 40 µL and detection at 230 nm. The best reaction yield, extraction capacity, and selectivity was obtained using 2-hydroxyethyl methacrylate (2-HEMA), ethyleneglycol dimethacrylate (EGDMA) and acetonitrile. The optimized MIP showed coefficient of distribution (Kd) of 59.85 µg/g, imprinting factor (IF) of 1.60, and selectivity for gliclazide and other sulfonylureas compared to possible concurrent drugs. The developed method by MISPE-HPLC-UV showed to be appropriate to determine gliclazide in human plasma samples.

Amphotericin B-loaded Eudragit RL100 nanoparticles coated with hyaluronic acid for the treatment of vulvovaginal candidiasis.

The treatment of vulvovaginal candidiasis (VVC) is based on oral and vaginal formulations which show limited effectiveness. In this study, amphotericin B-loaded Eudragit RL100 nanoparticles coated with hyaluronic acid (AMP EUD nanoparticles/HA) were developed to overcome the drawbacks of the conventional formulations. AMP EUD nanoparticles/HA were synthesized by nanoprecipitation, formulated by statistical experimental design, and characterized. AMP release from EUD nanoparticles/HA and its antifungal activity in a murine model of VVC were evaluated. Nanoparticles showed 147.6 ±â€¯16.7 nm of diameter, 0.301 ±â€¯0.09 of polydispersity index, - 29.9 ±â€¯3.76 mV of zeta potential, and 87.27 % of encapsulation efficiency. They released about 81 % of AMP in 96 h; and provided the elimination of 100 % of the vaginal fungal burden in 24 h. It was suggested that the AMP EUD nanoparticles/HA penetrated into the vaginal epithelium via CD44 receptors. These AMP EUD nanoparticles/HA represent a non-conventional vaginal formulation to improve the treatment of VVC.

Polymorphic and Quantum Chemistry Characterization of Candesartan Cilexetil: Importance for the Correct Drug Classification According to Biopharmaceutics Classification System.

The recommended method for the biopharmaceutical evaluation of drug solubility is the shake flask; however, there are discrepancies reported about the solubility of certain compounds measured with this method, one of them is candesartan cilexetil. The present work aimed to elucidate the solubility of candesartan cilexetil by associating others assays such as stability determination, polymorphic characterization and in silico calculations of intrinsic solubility, ionized species, and electronic structures using quantum chemistry descriptors (frontier molecular orbitals and Fukui functions). For the complete biopharmaceutical classification, we also reviewed the permeability data available. The polymorphic form used was previously identified as the form I of candesartan cilexetil. The solubility was evaluated in biorelevant media in the pH range of 1.2-6.8 at 37.0°C according to the stability previously assessed. The solubility of candesartan cilexetil is pH dependent and the dose/solubility ratios obtained demonstrated the low solubility of the prodrug. The in silico calculations supported the found results and evidenced the main groups involved in the solvation, benzimidazole, and tetrazol-biphenyl. The human absolute bioavailability reported demonstrates that candesartan cilexetil has low permeability and when associated with the low solubility allows to classify it as class 4 of the Biopharmaceutics Classification System.

Development of thalidomide-loaded biodegradable devices and evaluation of the effect on inhibition of inflammation and angiogenesis after subcutaneous application.

PURPOSE: To develop thalidomide-loaded poly-lactide-co-glycolide implants and evaluate its in vivo release and biological activity against inflammation and angiogenesis after subcutaneous administration. METHODS: Implants were prepared by the hot molding technique and characterized using stereomicroscopy, thermal analysis and X-ray diffraction. Swiss mice, divided in groups 1-3, received a subcutaneous implant containing 25% (w/w), 50% (w/w) or 75% (w/w) of thalidomide, respectively (n=6). The drug levels were determined during a 28-day study period. The toxicity associated with the implants was evaluated by light microscopy. The potential of the developed implant in the inhibition of inflammation and angiogenesis was evaluated in vivo using the sponge model. RESULTS: Thalidomide implant was developed and its characterization proved the stability of the drug and the polymer during preparation. Release profiles in vivo demonstrated an extended release of thalidomide from the implants during the 28 days. Histological evaluation did not show any sign of intense local inflammatory response to the presence of the implants in the subcutaneous pouch. The thalidomide implant reduced the number of vessels and N-acetyl-b-glucosaminidase (NAG) in vivo. CONCLUSION: The biodegradable implants delivered safe doses of thalidomide that were also effective to induce angiogenesis and inflammation regression.