Pharmaceutical Chemistry Journal (v.52, #9)

Expert Evaluation of Preclinical Toxicokinetic Studies of Pharmaceuticals (Review) by R. D. Syubaev; G. N. Engalycheva; D. V. Goryachev; A. V. Sokolov; V. V. Chistyakov; E. S. Stepanova (753-757).
Literature data and domestic and foreign methodological documentation for preclinical studies of the safety and toxicokinetics of pharmaceuticals are analyzed. According to Marketing Authorization and Assessment Rules for Medicinal Products in the EAEU, a developer must include in a General Technical Document information on toxicokinetic studies that is evaluated during a review of preclinical test results. The main approaches to expert evaluation of drug toxicokinetic studies are formulated. The main content of the expert analysis includes the methodological basis and results of the research, safety profile characteristics, extrapolation of preclinical data, risk factor characteristics, and predicted clinical patient safety profile. The inclusion of toxicokinetic studies in a program of preclinical toxicological studies is important in principle for an adequate extrapolation of experimental data and prediction of the safety of pharmaceuticals in humans. Expert analysis of toxicokinetic data allows toxicology study results, drug toxicity profile characteristics, and the risk of toxic side effects to be interpreted correctly.
Keywords: toxicokinetics; preclinical studies; drug safety; expert criteria; interpretation of research results

Computer Prediction of Adverse Drug Effects on the Cardiovascular System by S. M. Ivanov; A. A. Lagunin; D. A. Filimonov; V. V. Poroikov (758-762).
A structure–activity relationship model was constructed to predict adverse drug effects on the cardiovascular system. Models were constructed using sets of drug structures compiled by us with information about adverse effects from analyses and data integrated from various sources. The five most common cardiovascular adverse effects, i.e., myocardial infarction, ischemic stroke, cardiac failure, ventricular tachycardia, and arterial hypertension were analyzed in the work. The PASS software that has proved to be efficient in numerous studies was used to construct the appropriate models. The obtained models were accurate enough to be useful for estimating cardiovascular adverse effects of new drugs. An appropriate evaluation could be made in the very early stages of drug discovery because only the structural formula was needed for the prediction.
Keywords: cardiovascular system; adverse effects; structure–activity relationship; spontaneous reports; electronic medical records

Synthesis and Biological Properties of a New Dipeptide Mimetic of Brain-Derived Neurotrophic Factor Loop 2** by N. M. Sazonova; A. V. Tarasyuk; A. N. Shumskii; P. Yu. Povarnina; S. V. Kruglov; T. A. Antipova; T. A. Gudasheva; S. B. Seredenin (763-770).
A dimeric dipeptide mimetic of brain-derived neurotrophic factor loop 2, bis-(N-hexanoyl-seryl-lysine) hexamethylenediamide or GTS-201, was designed and synthesized. It exhibited neuroprotective activity at concentrations of 10–5 – 10–8 M in HT-22 immortalized hippocampal neuronal cell culture under H2O2-induced oxidative stress. Western-blot analysis showed that it activated TrkB receptors and Erk but not Akt. GTS-201 did not exhibit antidepressant activity in a Porsolt forced swim test on BALB/c mice at i.p. doses of 0.1, 1.0, and 5.0 mg/kg, in contrast with previously synthesized GSB-106, a dimeric dipeptide mimetic of loop 4. The results confirmed the previous original hypothesis about the possible discrimination of neurotrophin functions by low-molecular-mass mimetics of their separate loops.
Keywords: GTS-201; mimetic; dipeptide; BDNF; neuroprotective activity; antidepressant activity; MAPK/Erk and PI3K/Akt, TrkB

Planning and Assessment of Bioequivalence Studies of Darunavir Preparations by N. E. Uvarova; N. N. Eremenko; G. V. Ramenskaya; D. V. Goryachev (771-775).
Planning issues for darunavir (DRV) bioequivalence studies are considered. DRV is an antiviral (HIV) agent classified as an HIV protease inhibitor. Bioequivalence test results must be submitted for registration of generic drugs in the RF according to Federal Law 61-FZ. Bioequivalence study protocols and reports for DRV preparations that were submitted for review to the SCEEMP were analyzed. Differences in study designs including administration after fasting or meals, with or without a low dose of ritonavir, numbers of volunteers included in the study, and intra-subject variability were found. The internet was also searched for data on DRV variability. Recommendations for planning bioequivalence studies of DRV preparations were formulated based on the analysis.
Keywords: bioequivalence studies; study design; darunavir; pharmacokinetics; intra-subject variability

An efficient synthesis of 21-acetoxypregna-1,4,9(11),16-tetraene-3,20-dione, a key intermediate in the synthesis of highly active fluorinated corticosteroids from phytosterols, was developed. The method consisted of an original sequence of chemical and microbiological reactions and could be used to synthesize betamethasone, sinaflan, triamcinolone, and other fluorinated corticoids.
Keywords: dexamethasone; fluorinated corticosteroids; 9_-hydroxylation; 1,2-dehydrogenation; cyanohydrin synthesis

Influence of Various Disintegrants on the Quality of Microcrystalline Cellulose Tablets by N. B. Demina; N. V. Bobkova; E. A. Solodun; M. N. Anurova; E. O. Bakhrushina; I. I. Krasnyuk (781-785).
The effects of the superdisintegrants sodium starch glycolate, croscarmellose sodium, polacrilin potassium Kyron T-314, and Amberlite IRP 88 on the quality parameters of placebo tablets prepared from microcrystalline cellulose were studied. Sodium starch glycolate was most effective with croscarmellose sodium and Amberlite IRP 88 slightly less. All studied disintegrants gave dosage forms of pharmacopoeial quality. The effects of disintegrant concentration and particle type on tablet hardness were determined. The dosage form hardness increased with increasing disintegrant content for croscarmellose sodium with fibrous particles and decreased for sodium starch glycolate and polacrilin potassium with round and irregularly shaped particles. The tablets were harder if polacrilin potassium was added to the formulation.
Keywords: disintegrants; disintegration; polacrilin potassium; microcrystalline cellulose

A composition and preparation method for new analgesic rectal suppositories containing a nonsteroidal anti-inflammatory drug (ketorolac), tricyclic antidepressant (amitriptyline), and transmucosal conductor (silicon glycerolates) as the active ingredients in a poly(ethylene glycol) (PEG-4000) base were proposed. The acute toxicity was determined and showed they were safe to use. The high analgesic activity of the suppositories was confirmed using electrical stimulation. Their high transmucosal activity in vitro was revealed by measuring the degree of diffusion of one of the active ingredients (amitriptyline) through a natural biological membrane. The results indicated that the developed suppositories could be recommended for further investigations of future medical use to relieve pain of various etiologies.
Keywords: analgesia; nonsteroidal anti-inflammatory drugs; tricyclic antidepressants; rectal suppositories; transmucosal conductors

Physicochemical Properties and Analytical Method Development for Drug Substance of GML-1, a Novel Original Anxiolytic Preparation by L. M. Gaevaya; L. N. Grushevskaya; M. S. Sergeeva; A. A. Illarionov; N. I. Avdyunina; B. M. Pyatin; F. S. Baiburtskii; G. V. Mokrov (790-795).
The physicochemical properties of the novel original anxiolytic GML-1 drug substance were studied, analytical techniques for it were developed, and its main pharmacopoeial quality parameters were determined using IR spectroscopy, UV spectrophotometry, HPLC, and the Kjeldahl method.
Keywords: GML-1; IR spectroscopy; UV spectrophotometry; HPLC; Kjeldahl method

Unfractionated Heparin Activity Testing in Preparations and Substances by A. L. Berkovskii; E. V. Sergeeva; A. V. Suvorov (796-798).
The development of efficient production of unfractionated heparin (UFH) preparations, which are widely used in clinical practice, is currently a critical problem. According to WHO guidelines, specific and selective methods for monitoring heparin activity in preparations and substances must be used in the quality assurance system for producing pharmaceutical preparations. A clotting method for measuring UFH activity in its preparations and substances according to the coagulation method recommended by the State Pharmacopoeia of the Russian Federation was developed based on the created test system. The method was evaluated using the main analytical characteristics. The results obtained from the developed test were shown to be comparable with those from UFH activity determinations using the chromogenic method recommended by the State and European pharmacopoeias. The established accuracy, sensitivity, and precision allowed the validated coagulation method and the created test system to be recommended for inclusion in UFH process monitoring.
Keywords: unfractionated heparin; coagulation methods; test systems; APTT reagents; process control

Validation of an Assay Procedure for Ormustine in a Liposomal Dosage Form by N. D. Bunyatyan; N. A. Oborotova; L. L. Nikolaeva; E. V. Ignat’eva; I. V. Yartseva; A. V. Lantsova; A. B. Prokof’ev (799-802).
A spectrophotometric assay for ormustine active ingredient for a liposomal dosage form with antitumor activity was selected and validated for specificity, linearity, accuracy, precision, and intermediate (intralaboratory) precision in order to ensure accurate and precise results. The obtained statistical characteristics were shown to satisfy acceptance criteria for the validation parameters given in domestic regulatory documentation. Ormustine was determined at 396 ± 2 nm because excipients in the dosage form did not absorb in this spectral region. The correlation coefficient for the linearity was >0.997. The relative error of the mean result was <1% for the accuracy. The confidence interval included 100%. The coefficient of variation for the precision and intermediate precision determinations was <1%. The studied method could be used in the range 80 – 120% of the nominal ormustine content in the liposomal dosage form.
Keywords: ormustine; liposomal dosage form; spectrophotometry; validation

Development and Validation of a Quantitative Determination Technique for Phenibut in Microcapsules by Yu. A. Polkovnikova; K. N. Koryanova; A. I. Slivkin; U. A. Tul’skaya; S. P. Senchenko (803-807).
A capillary electrophoresis technique for quantitative determination of phenibut in microcapsules was developed and validated. Rather high efficiencies (~200,000 theoretical plates) and the required resolution (R s ≥ 1.5) were attained using sodium tetraborate decahydrate solution (10 mM) at pH 9.2 as the supporting electrolyte. Validation of the technique showed that it was specific and complied with requirements of the SP XIIIth Ed. with respect to analytical range and linearity.
Keywords: phenibut; microcapsules; capillary electrophoresis; validation

A quantitative spectrophotometric determination method for papaverine in medicinal preparations based on formation of a colored ionic associate of papaverine, Ti(IV), and bromopyrogallol red (BPR) was developed. The conditions for forming {[TiO(H2R)2]2– · 2PP+} were determined. Addition of papaverine to a solution of anionic Ti-BPR caused a bathochromic shift to 640 nm with a simultaneous intensity gain. The molar absorption coefficient (ε = 8,800) indicated that the reaction was rather sensitive. The specificity of the reaction for papaverine enabled it to be determined without separating excipients. The method was highly sensitive, simple to perform, and adaptable to scale up. Toxic reagents were not required. The results had good precision (S r = 0.007 – 0.02) and accuracy.
Keywords: ionic associate; complex formation; Ti(IV); bromopyrogallol red; spectrophotometry; method development; papaverine determination