Vol 52, No 7 (2018)

Experiments on female Chinchilla rabbits addressed the effects of progesterone on the functional activity of P-glycoprotein (Pgp). Animals were divided into four groups: animals of group 1 underwent sham operations; group 2 underwent ovariectomy; groups 3 and 4 underwent ovariectomy followed 15 days later by p.o. treatment with progesterone (2 and 15 mg/rabbit respectively). The functional activity of Pgp was determined seven days before the experiment started and on post-operative days 14, 28, and 42 by analysis of the pharmacokinetics of its marker substrate fexofenadine and serum sex hormone concentrations. At the end of the study, animals of each group were harvested by air embolism and specimens of large intestine were collected for immunohistochemical analysis. Ovariectomy led to a decrease in the functional activity of Pgp and a decrease in the staining intensity of the apical and lateral membranes of enterocytes, providing indirect evidence of a decrease in the expression of the transporter protein. Administration of progesterone at a dose of 2 mg/rabbit on the background of ovariectomy increased the functional activity of Pgp from the level seen in the ovariectomy group, though its activity remained decreased compared with the baseline level. This group showed no changes in the staining intensity of enterocyte membranes as compared with the ovariectomy group. Use of progesterone at a dose of 15 mg/rabbit after ovariectomy increased the functional activity of Pgp and the staining intensity of enterocyte apical and lateral membranes from the level seen in the ovariectomy group, restoring the level of transporter protein activity to that of intact animals, probably because of increased expression.

The polypeptide analgesic compounds APCH3 (a TRPV1 receptor inhibitor) and PT1 (a P₂X₃ receptor inhibitor) were shown not to act on the cardiovascular system or respiratory system when given either as single or multiple doses in mice. The low molecular weight compound sevanol (an ASIC3 receptor inhibitor) had no effect on the cardiovascular system, but prolonged use for 14 days affected measures of the respiratory system, significantly increasing respiratory rate and peak expiratory flow rate.

We report here the synthesis and our studies of the structure, physicochemical properties, and anticaries activity of a novel potential anticaries substance 2-amino-4,6-dihydroxypyrimidinium hexafluorosilicate. IR spectra, EI mass spectra, and ¹⁹F NMR spectra were obtained and their properties were studied. Biological investigations were performed on animals kept on the Stephan caries-inducing diet (50% sucrose). Alkaline phosphatase (AlkP) and acid phosphatatase (AcP) were assayed in pulp homogenates and the AlkP:AcP ratio was used to assess the mineralization index (MI). AlkP activity was measured in serum, along with alanine aminotransferase (ALT). The number and depth of caries lesions to the teeth were assessed and caries prophylactic efficacy (CPE) was computed. The data showed that 2-amino-4,6-dihydroxypyrimidinium hexafluorosilicate decreased the number of caries lesions by 45.5% and had high anticaries efficacy, five times greater than that of sodium fluoride.

The present study aims to prepare ocular inserts of cetirizine hydrochloride, an antihistamine used to treat allergic conjunctivitis, allergic rhinitis, uveitis and urticaria. Solvent casting method was used to prepare inserts of hydroxypropyl methylcellulose (HPMC) and polyvinyl alcohol (PVA) as film forming polymers, and polyethylene glycol (PG) and glycerin were used as plasticizers. Various physicochemical parameters of six ocular insert compositions were evaluated, including swelling behavior and in vitro drug release and kinetics. Formulation F4 showed results of in vitro studies in most appropriate range, with sustained drug release (99.12% at 210 min) following non-fickian diffusion. Drug – polymer compatibility study verified no chemical interaction between the drug and polymer. Therefore, formulation F4 was selected for in vivo studies in albino rabbits. The values of C_max, AUC, and T_max of formulation F4 were 478.70 ng/mL, 3013.58 ng/(mL h), and 2.3 h, respectively. Ocular inserts of cetirizine hydrochloride provide a valuable alternative for the treatment of ocular inflammatory diseases as these formulations ensure sustained drug release and increased residence time.

A new means of preparing phenazepam is proposed. The new manufacturing technology for phenazepam implements the general principles for medicinal substance quality by using synthesis conditions and schemes yielding compounds as pure as possible.

A procedure for validation of an assay method for fluorine in residual trifluoroacetates in the pharmaceutical substance glatiramer acetate by ¹⁹F NMR spectroscopy is described. The method provides for assay of the content of trifluoroacetates without destruction of the substance under analysis. The validation process established the detection limit and assessed the linearity, accuracy, convergence, intralaboratory precision, and specificity of the method under validation. Measurement of “found:added” coefficients were used to calculate standard deviations, coefficients of variation, significance intervals, and systematic errors, using Fisher’s F test and Student’s t test to assess the assay results. The statistical characteristics were found to satisfy the criteria for acceptability of the validation parameters given in Russian and foreign normative documentation.

An HPLC-ECD analytical method with high reproducibility and wide linearity range has been developed and validated. Moxifloxacin was separated and identified using this method with a simple mobile phase comprising Britton Robinson buffer pH 5.0 and methanol (93: 7 v/v) flowing at a rate of 0.5 mL/min through Acclaim C₁₈ column (150 mm × 4.6 mm × 5 im) maintained at 35°C and detected at redox potential value of 1.0 V. The LOD and LOQ were found to be 2.2 and 6.6 μg/mL, respectively. The HPLC-ECD method of moxifloxacin analysis was validated as per ICH Q₂R₁ guidelines and applied for assay of marketed moxifloxacin formulations to establish the acceptable recovery.

With the aim of establishing a structure-analgesic activity relationship, a series of picolylamides of 2-hydroxy-4-oxo-4H-pyrido[1,2-a]-pyrimidine-3-carboxylic acids were synthesized. The characteristics of the spatial structure of this group of substances were assessed. The results of pharmacological studies identified compounds in the study series with marked analgesic properties. However, it was noted that the transition from 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides to the structurally similar pyrido[1,2-a]pyrimidine derivatives was generally accompanied by some decrease in analgesic activity.

The accumulation of inulin in the dried rhizomes with roots of Echinacea purpurea cultivated in the non-chernozem zone of the Russian Federation in 2008 – 2010 was studied in plants of different ages (2, 3, 4, 5, and 7 years of vegetation) and times of harvesting the above-ground parts (in the phenological phases of stem extension, budding, flowering, and repeatedly during the vegetation period). Inulin contents were also studied in infusions made from this species in 40% and 70% ethanol with different particle sizes after passage through sieves with mesh sizes of 0.1, 0.5, and 1 mm. The most extensive accumulation of inulin in material in 2008 and 2009 was seen after repeated removal of shoots, and in 2010 after harvesting of the above-ground part in the stem extension phase. Increases in the age of the producing plants to seven years of vegetation was associated with a significant decrease in the raw material inulin content. The infusion in 40% ethanol contained much more inulin than the infusion in 70% ethanol, i.e., this was a water-soluble polyfructan. The greatest quantity of inulin was extracted form raw material particles of 1 mm. Meal contained about 10% inulin, allowing its further use.

The physicochemical and technological properties of an interpolymer complex of polymethyacrylic acid and polyethylene glycol, known under its commercial name “Polymer Carrier Composition” (FGUP Science Research Institute of Polymers, Russia), were studied. This polymer is an excipient substance used in the technology of solid dosage forms as a matrix former and as a film-forming agent for making long-acting and slow-release formulations. With the aim of widening the potential uses of the polymer carrier composition, the solubility of the polymer in aqueous solutions and organic solvents was studied, along with the technological and surfactant properties of the polymer; the critical gel-forming concentration was also determined. Experimental samples of tablets and oral gels of model substances with similar physicochemical properties were prepared, based on different concentrations of the Polymer Carrier Composition, and the technological, rheological, and biopharmaceutical properties of these were studied. The potential for using the polymer in both hard and soft dosage forms to obtain prolonged-release medicinal formulations is demonstrated.

Attention is drawn to a contradiction associated with assessments of the compatibility of medicinal (MS) and excipient (ES) substances: that ES and MS able to react with each other chemically are regarded as incompatible, yet at the same time, the compositions of several original medicines include ES and MS which are able to undergo chemical interactions. To remove this contradiction, the concept of “potential incompatibility” of ES and MS is introduced, i.e., the ability of substances to undergo direct or indirect chemical or undesirable physical interactions which may potentially become apparent during the manufacture or storage of a medicinal formulation and influence its quality. It is emphasized that incompatibility between an ES and an MS can be regarded as existing only when it is not possible to ensure their compatibility in a medicinal formulation. Approaches to assessing the compatibility between ES and MS are discussed: stress experiments using chromatographic analysis methods; stress experiments using spectral analysis methods; experiments using thermal analysis methods and calorimetry. A systematic “step-by-step” approach to studying the compatibility between ES and MS is proposed, based on express testing of the interaction between ES and MS not only in model mixtures, but also in samples of the medicinal formulation under development. This has decisive value for drawing reliable conclusions regarding the compatibility between the ES and the MS. Known types of potentially incompatible substance important for predicting potential incompatibility between ES and MS based on the structural characteristics and chemical properties of the molecules are presented. Recommendations are made in relation to studies of the compatibility of ES and MS.