Biopharmaceutical Profiling of New Antitumor Pyrazole Derivatives

Several new pyrazole derivatives have demonstrated promising antiproliferative and cytotoxic effects, but their poor solubility raised concerns over possible biopharmaceutical limitations. In order to improve their pharmaceutical potential we performed the biopharmaceutical profiling for nine pyrazole compounds using in vitro and computational methods. The experimental solubility was determined in five different media using a validated HPLC method. Although the experimental solubility was lower than the predicted one, a good linear relationship was observed. The results also indicated a minimal impact of endogenous tensioactives on solubility, suggesting dissolution rate limited absorption. The in silico experiments were focused on identification of molecular determinants of solubility, evaluation of drug-likeness, prediction of in vivo absorption based on mechanistic models, as well as identification of the main factors that could impact on the oral bioavailability. The results suggested that dose, solubility and particle size are the main determinants of absorption, whereas permeability has little effect, confirming the BCS Class II behavior of the compounds. The present investigation was able to rank the tested compounds in terms of biopharmaceutical behavior, and indicated the B3 series compounds as having a more favorable absorption profile making them the main candidates for advance to the pre-clinical in vivo studies

In Vitro–In Vivo Correlations Based on In Vitro Dissolution of Parent Drug Diltiazem and Pharmacokinetics of Its Metabolite

In this study a novel type of in vitro–in vivo correlation (IVIVC) is proposed: The correlation of the in vitro parent drug dissolution data with the in vivo pharmacokinetic data of drug’s metabolite after the oral administration of the parent drug. The pharmacokinetic data for the parent drug diltiazem (DTZ) and its desacetyl diltiazem metabolite (DTZM) were obtained from an in vivo study performed in 19 healthy volunteers. The pharmacokinetics of the parent drug and its metabolite followed a pseudomono-compartmental model and deconvolution of the DTZ or DTZM plasma concentration profiles was performed with a Wagner–Nelson-type equation. The calculated in vivo absorption fractions were correlated with the in vitro DTZ dissolution data obtained with USP 2 apparatus. A linear IVIVC was obtained for both DTZ and DTZM, with a better correlation observed for the case of the metabolite. This type of correlation of the in vitro data of the parent compound with the in vivo data of the metabolite could be useful for the development of drugs with active metabolites and prodrugs

Electrospun PCL Wires Loaded with Vancomycin on Zirconium Substrate

The current study presents research about electrodeposition in relation to electrospinning PCL wires on a Zr substrate and loading the coating with vancomycin. The structural composition of the coatings was investigated via FT-IR analysis. The morphology evaluated using scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy, for the composition (SEM-EDS), evidenced the presence of the polymer wires, with and without drug vancomycin loading. The wettability of the coatings was evaluated from the hydrophobic–hydrophilic point of view, and the characterization was completed with mechanical and electrochemical tests. All the electrochemical tests performed in simulated body fluid highlighted that PCL represents a barrier against corrosion processes. The quantitative method to evaluate the loading efficiency shows that almost 80% of the total loaded vancomycin is released within 144 h; after the initial burst at 24 h, a steady release of vancomycin is observed over 7 days. A kinetic model of the drug release was also constructed

Chlorpheniramine Potentiates the Analgesic Effect in Migraine of Usual Caffeine, Acetaminophen, and Acetylsalicylic Acid Combination

Previous studies indicated that addition of the antihistaminic chlorpheniramine to the usual combination of acetylsalicylic acid, acetaminophen, and caffeine further increases their synergism both in terms of anti-inflammatory and analgesic effect. The present non-interventional study tested the superiority of two Algopirin® tablets, containing a total of 250 mg acetylsalicylic acid (ASA), 150 mg acetaminophen (paracetamol, PAR), 30 mg caffeine (CAF) and 4 mg chlorpheniramine (CLF) vs. a combination containing 250 mg ASA, 250 mg PAR, and 65 mg CAF recognized as “safe and effective” by FDA in treating migraine. Patients evaluated their pain intensity on the Visual Analog Scale—VAS(PI) before and 30, 60, 120, 180, and 240 min after drug intake. Interpretation of the pain curves as “survival pain curves” was considered as a method for direct comparison of the pain curves. This interpretation permitted the application of the log rank test for comparison of pain hazards. The results of the applied parametric and non-parametric statistical tests indicated significant differences between the main endpoints: both Areas Under Pain Curves and time to decrease of the pain intensity to less than 50% of the initial value comparisons highlighted that Algopirin® was more efficient in spite of smaller doses of PAR and CAF. Comparison of “survival of pain” led to the same conclusion concerning the superiority of Algopririn. Consequently, the addition of CLF permitted decreasing of ASA, PAR, and CAF doses as well as their potential side effects, without a loss of analgesic effect

Mathematical Modeling of Release Kinetics from Supramolecular Drug Delivery Systems

Embedding of active substances in supramolecular systems has as the main goal to ensure the controlled release of the active ingredients. Whatever the final architecture or entrapment mechanism, modeling of release is challenging due to the moving boundary conditions and complex initial conditions. Despite huge diversity of formulations, diffusion phenomena are involved in practically all release processes. The approach in this paper starts, therefore, from mathematical methods for solving the diffusion equation in initial and boundary conditions, which are further connected with phenomenological conditions, simplified and idealized in order to lead to problems which can be analytically solved. Consequently, the release models are classified starting from the geometry of diffusion domain, initial conditions, and conditions on frontiers. Taking into account that practically all solutions of the models use the separation of variables method and integral transformation method, two specific applications of these methods are included. This paper suggests that “good modeling practice„ of release kinetics consists essentially of identifying the most appropriate mathematical conditions corresponding to implied physicochemical phenomena. However, in most of the cases, models can be written but analytical solutions for these models cannot be obtained. Consequently, empiric models remain the first choice, and they receive an important place in the review

Phytochemical Profile and Biological Activities of Satureja hortensis L.: A Review of the Last Decade

Satureja hortensis L. (summer savory) is an annual herbaceous crop, native to Europe and in our days spread and used all over the world. Although its use as spice and medicinal plant is known since ancient times, peer-reviewed studies presenting the scientific data are scarce. The natural products obtained from summer savory (extracts and essential oil) are dominated by polyphenols and flavonoids, responsible for their antioxidant, antimicrobial, antiparasitic, pesticidal, anti-inflammatory, analgesic, hepatoprotective and anticancer properties, among others. The current study presents the progress made in the last decade regarding the potential applications of summer savory, being the first review study focused on S. hortensis, in the same time suggesting future research opportunities, as they appear from the properties of other Satureja species. The available data presenting the properties of summer savory represents a scientific support for application in industry, for developing “clean label” food products

A Short Overview of Recent Developments on Antimicrobial Coatings Based on Phytosynthesized Metal Nanoparticles

The phytosynthesis of metallic nanoparticles represents an exciting new area of research, with promising perspectives, gaining in the last decades an increasing importance. Nanotechnology represents an important tool and an efficient option for obtaining particles with controlled morphology and shapes, phytosynthesized nanoparticles (NPs) being a good alternative to remove hazardous reagents. Due to the practical applications of the phytosynthesized nanoparticles, which are mainly associated with their antimicrobial potential, the abundance of scientific literature in this domain is given by researches in the phytosynthesis of metallic nanoparticles (3654 articles) and the evaluation of their antimicrobial properties (2338 papers). The application of phytosynthesized nanoparticles as antimicrobial coatings represented the subject of only 446 works, which lead us to the subject of this review paper. Application of antimicrobial coatings containing phytosynthesized nanoparticles for the development of antimicrobial textiles, other biomedical applications, protection of food (including fruits and vegetables), as well as for other types of applications based on their antimicrobial potential are covered by the present review

Leonurus cardiaca L. as a Source of Bioactive Compounds: An Update of the European Medicines Agency Assessment Report (2010)

Leonurus cardiaca L. (motherwort) is a perennial herb, native to Asia and southeastern Europe, with widespread global occurrence in present days. The plant was historically used as cardiotonic and for treating gynaecological afflictions (such as amenorrhea, dysmenorrhea, menopausal anxiety, or postpartum depression). Although its use in oriental and occidental medicine is relatively well documented, the recent progress registered raises the need for an update of the Medicines Agency assessment report on Leonurus cardiaca L., herba (2010). The current study presents the progress made within the 2010-2018 timeframe regarding the potential applications and scientific evidences supporting the traditional use of motherwort, in the same time suggesting future research opportunities

The Influence of the Polymer Type on the Quality of Newly Developed Oral Immediate-Release Tablets Containing Amiodarone Solid Dispersions Obtained by Hot-Melt Extrusion

The present study aims to demonstrate the influence of the polymer-carrier type and proportion on the quality performance of newly developed oral immediate-release tablets containing amiodarone solid dispersions obtained by hot-melt extrusion. Twelve solid dispersions including amiodarone and different polymers (PEG 1500, PEG 4000; PEG 8000, Soluplus®, and Kolliphor® 188) were developed and prepared by hot-melt extrusion using a horizontal extruder realized by the authors in their own laboratory. Only eleven of the dispersions presented suitable physical characteristics and they were used as active ingredients in eleven tablet formulations that contain the same amounts of the same excipients, varying only in solid dispersion type. The solid dispersions’ properties were established by optical microscopy with reflected light, volumetric controls and particle size evaluation. In order to prove that the complex powders have appropriate physical characteristics for the direct compression process, they were subjected to different analyses regarding their flowability and compressibility behavior. Additionally, the Fourier transform infrared spectroscopy and X-ray diffraction analysis were performed on the obtained solid dispersions. After confirming the proper physical attributes for all blends, they were processed into the form of tablets by direct compression technology. The manufactured tablets were evaluated for pharmacotechnical (dimensions–diameter and thickness, mass uniformity, hardness and friability) and in vitro biopharmaceutical (disintegration time and drug release) performances. Furthermore, the influence of the polymer matrix on their quality was determined. The high differences in flow and compression performances of the solid dispersions prove the relevant influence of the polymer type and their concentration-dependent plasticizing properties. The increase in flowability and compressibility characteristics of the solid dispersions could be noticed after combining them with direct compression excipients owning superior mechanical qualities. The influence of the polymer type is best detected in the disintegration test, where the obtained values are quite different between the studied formulations. The use of PEG 1500 alone or combined in various proportions with Soluplus® leads to rapid disintegration. In contrast, the mixture of PEG 4000 and Poloxamer 188 in equal proportions determined the increase in disintegration time to 120 s. The use of Poloxamer 188 alone and a 3:1 combination of PEG 4000 and Soluplus® also generates a prolonged disintegration time for the tablets

Formation and Physico-Chemical Evaluation of Nifedipine-hydroxypropyl-β-cyclodextrin and Nifedipine-methyl-β-cyclodextrin: The Development of Orodispersible Tablets

The novelty in this study is the development of new orodispersible tablets containing nifedipine (NIF) as the active ingredient. Initially, the formation of inclusion complexes between nifedipine and two derivatives of beta-cyclodextrin, namely, hydroxypropyl-β-cyclodextrin (HP-β-CD) and methyl-β-cyclodextrin (Me-β-CD), was established. Inclusion complexes of nifedipine were prepared by different procedures: kneading, coprecipitation and lyophilization methods, using a 1:1 molar ratio among the drug and cyclodextrin compounds. A physical mixture was also developed for comparison, with the same molar ratio. The physicochemical and structural properties of these obtained complexes were subsequently analysed using Fourier-transform infrared spectroscopy, scanning electron microscopy, differential scanning calorimetry and X-ray diffraction techniques. The lyophilization method of preparation leads to obtaining the complete inclusion of nifedipine in the used cyclodextrin cavity, for both the derivative cyclodextrins. After that, preformulation studies and manufacturing of orodispersible tablets containing NIF-HP-β-CD and NIF-Me-β-CD, respectively, inclusion complexes were advanced. The obtained findings show that only F3 (which contains NIF-HP-β-CD) and F6 (which contains NIF-Me-β-CD) have a suitable flowability for the direct compression materials