The Influence of Excipients on the Physicochemical and Biological Properties of a Bactericidal, Labile Ester Prodrug in a Salt Form – A Case Study of Cefetamet Pivoxil Hydrochloride

The article presents an innovative approach to a bactericidal drug design based on a cephem prodrug analogue – cefetamet pivoxil hydrochloride. The emergence of cefetamet pivoxil hydrochloride excipient systems (mannitol, hydroxypropyl methyl cellulose, pregelatinised starch, lactose monohydrate, magnesium stearate, polyvinylpyrrolidone) caused changes in the physicochemical properties of cefetamet pivoxil hydrochloride. They are significant for planning the development of an innovative pharmaceutical formulation. The biological activity profile of the prodrug was also modified. FTIR spectra were used to study interactions between cefetamet pivoxil hydrochloride and the excipients. The theoretical approach to the analysis of experimental spectra enabled precise indication of cefetamet pivoxil hydrochloride domains responsible for interaction with the excipients. The interactions between cefetamet pivoxil hydrochloride and the excipients resulted in some  important physicochemical modifications: acceptor fluid-dependent changes in solubility and the dissolving rate as well as a decrease in the chemical stability of cefetamet pivoxil hydrochloride in the solid state, especially during thermolysis. The interactions between cefetamet pivoxil hydrochloride and the excipients also had biologically essential effects. There were changes in its permeability through artificial biological membranes simulating the gastrointestinal tract, which depended on the pH value of the acceptor solution. Cefetamet pivoxil hydrochloride combined with the excipient systems exhibited greater bactericidal potential against Staphylococcus aureus. Its bactericidal potential against Enterococcus faecalis, Pseudomonas aeruginosa and Proteus mirabilis doubled. The new approach provides an opportunity to develop treatment of resistant bacterial infections. It will enable synergy between the excipient and the pharmacological potential of an active pharmaceutical substance with modified physicochemical properties induced by the drug carrier

Hydrophilic interaction chromatography (HILIC) for the determination of cetirizine dihydrochloride

AbstractA stability-indicating high-performance liquid chromatography (HPLC) of hydrophilic interactions was developed and validated for the determination of cetirizine dihydrochloride in bulk substance and in pharmaceutical dosage form. The separation was achieved on a Poroshell 120 Hilic (4.6×150mm, 2.7μm) column using a mobile phase composed of acetonitrile–0.1% formic acid (20:80 v/v) at a flow rate of 1.0mL/min. The injection volume was 5.0μL and the wavelength of detection was controlled at 235nm. The method was validated by evaluating linearity, accuracy, precision, selectivity and robustness. Cetirizine dihydrochloride was the susceptible to the action of an oxidation factor. The product of its degradation under those conditions was identified with an EIS-Q-MS mass spectrometer. The hydrophilic interactions between the main analyte, its oxidation product, and the mobile and stationary phases were discussed with the support of a theoretical investigation

"Cladonia uncialis" as a valuable raw material of biosynthetic compounds against clinical strains of bacteria and fungi

Cladonia uncialis is a lichen species with confirmed antibacterial activity and whose genome has been recently sequenced, enabling first attempts in its functional characterization. In this work, we investigated activity of the C. uncialis acetone extract (CUE) and usnic acid (UA) enantiomers against ten clinical microbial strains causing skin infections. The results showed that CUE, containing (–)-UA and squamatic acid, assayed at the same concentrations as UA, was noticeably more active than (–)-UA alone, in its pure form. The studied CUE displayed an activity that was comparable to that of (+)-UA observed for Staphylococcus epidermidis and Enterococcus faecium (18–24 mm zone of growth inhibition), but did not display any activity against fungal strains. The CUE demonstrated low cytotoxicity against HaCaT cells, in comparison to UA enantiomers, which is important for its therapeutic use. Results of the antioxidant assay (DPPH) indicated low antioxidant activity (IC50>200 µg/mL) of CUE, while the total phenolic content was 70.36 mg Gallic Acid Equivalent/g of the dry extrac

The Influence of pH and Temperature on the Stability of N

The influence of pH and temperature on the stability of N-[(piperidine)methylene]daunorubicin hydrochloride (PPD) was investigated. Degradation was studied using an HPLC method. Specific acid-base catalysis of PPD involves hydrolysis of protonated molecules of PPD catalyzed by hydrogen ions and spontaneous hydrolysis under the influence of water zwitterions, unprotonated molecules, and monoanions of PPD. The thermodynamic parameters of these reactions, energy, enthalpy, and entropy, were calculated. Also, the stability of daunorubicin and its new amidine derivatives (piperidine, morpholine, pyrrolidine, and hexahydroazepin-1-yl) in aqueous solutions was compared and discussed

Preclinical evaluation of 1,2,4-triazole-based compounds targeting voltage-gated sodium channels (VGSCs) as promising anticonvulsant drug candidates

Epilepsy is a chronic neurological disorder affecting nearly 65–70 million people worldwide. Despite the observed advances in the development of new antiepileptic drugs (AEDs), still about 30-40% of patients cannot achieve a satisfactory seizure control. In our current research, we aimed at using the combined results of radioligand binding experiments, PAMPA-BBB assay and animal experimentations in order to design a group of compounds that exhibit broad spectrum of anticonvulsant activity. The synthesized 4-alkyl-5-substituted-1,2,4-triazole-3-thione derivatives were primarily screened in the maximal electroshock-induced seizure (MES) test in mice. Next, the most promising compounds (17, 22) were investigated in 6 Hz (32 mA) psychomotor seizure model. Protective effect of compound 22 was almost similar to that of levetiracetam. Moreover, these compounds did not induce genotoxic and hemolytic changes in human cells as well as they were characterized by low cellular toxicity. Taking into account the structural requirements for good anticonvulsant activity of 4-alkyl-5-aryl-1,2,4-triazole-3-thiones, it is visible that small electron-withdrawing substituents attached to phenyl ring have beneficial effects both on affinity towards VGSCs and protective activity in the animal models of epilepsy

Fisetin—In Search of Better Bioavailability—From Macro to Nano Modifications: A Review

As secondary plant metabolites, polyphenols are abundant in fruits and vegetables. They are in high demand because of their many health benefits. However, their low bioavailability makes them complex compounds to use for therapeutic purposes. Due to the limited solubility of phytocompounds, dietary supplements made from them may only be partially effective. Such molecules include fisetin, found in strawberries, and have shown great promise in treating Alzheimer’s disease and cancer. Unfortunately, because of their limited water solubility, low absorption, and poor bioavailability, the assistance of nanotechnology is required to allow them to fulfil their potential fully. Here, we provide evidence that nanodelivery methods and structure modifications can improve fisetin bioavailability, which is linked to improvements in therapeutic efficacy. An open question remains as to which nanocarrier should be chosen to meet the abovementioned requirements and be able to enhance fisetin’s therapeutic potential to treat a particular disease