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Introduction. Due to increase in the frequency of detecting cases of tuberculosis caused by strains of mycobacteria with resistance not only to traditional, but also recently introduced into clinical circulation anti-tuberculosis drugs, it is urgent to search for and develop new drugs that can be effective against multidrug-resistant (MDR-TB) and extensively drug resistant (XDR-TB) strains. One of the most promising classes of such compounds are fluorine derivatives of benzothiazinones, and particularly compound PBTZ169 (INN macozinone). This antibiotic has a high specificity against mycobacteria tuberculosis (M. tuberculosis), inhibiting one of the key enzymes of cell wall synthesis. However, macozinone as an active pharmaceutical ingredient has significant features of physical and chemical properties that hinder the development of oral dosage forms based on it. It is classified as class IV by BCS and is characterized by a very low solubility and lipophilicity, a pronounced dependence of dissolution rate on the pH of the medium, and very low bioavailability when taken orally.Aim. To substantiate the target profile, critical quality attributes and to develop a prototype of an oral dosage form with modified release of macozinone, allowing to maximize its pharmacological activity.Materials and methods. Using pharmaceutical substance macozinone hydrochloride and various excipients, experimental tablets with a dosage of 500 mg macozinone were developed. The influence of the composition of the media and the added excipients on the solubility of macozinone in various biorelevant media, the degree of swelling in the liquid and the degree of mucoadhesion of the experimental tablets to the mucus of the pig stomach were evaluated. The HPLC method was used to evaluate the kinetics of the release of the active substance.Results and discussion. In this work, the expediency of creating macozinone-containing gastro-retentive dosage forms with a slow release of the active substance, the delay mechanism of which is provided by swelling and increased adhesion to the gastric mucosa, has been substantiated. Various tablet samples were experimentally tested in which the modification of the release of the active substance and the degree of swelling and mucoadhesion were varied by introducing various excipients into the formulations, including known swelling and bioadhesive matrix agents.Conclusion. According to the results of the experiments, samples of high-dose (500 mg) swellable and mucoadhesive tablets created by the technology of two-stage granulation with the inclusion of macozinone - hydroxypropyl-beta-cyclodextrin mixtures in the primary granules and introduction of combinations of soluble and insoluble hydrophilic matrix agents into the intergranular space were recognized as the most promising for subsequent pharmacokinetic studies.

Introduction. Neutropenia, which is an abnormally low concentration of neutrophils in the blood, is one of the common side effects in patients receiving radio- or chemotherapy. Neutropenia usually leads to higher risks of severe bacterial and fungal infections. Such medicines as colonystimulating factor filgrastim (and its conjugates) are used to prevent and treat neutropenia in oncology patients. Immunogenicity is a potential concern for any biological product, thus, its assessment is one of the most critical necessities during the development and registration of such products.Aim. The main aim of this study was to validate the ELISA method for anti-pegfilgrastim antibodies detection in human serum samples and to apply the validated method to pegfilgrastim drugs immunogenicity assessment.Materials and methods. To assess pegfilgrastim immunogenicity, the commercial ELISA kit «PEGylated Filgrastim (Neulasta®) ADA ELISA» was used for screening, confirmatory and titer assay. Moreover, to confirm the chosen commercial kit suits the study aims it was revalidated. The absorbance values were obtained using plate immunoassay analyzer Stat Fax 3200, plate washing was performed using an automatic twochannel plate washer.Results and discussion. The ELISA method for anti-pegfilgrastim antibodies determination in human serum samples was validated and applied to the analytical part of the comparative, multicenter, blind, randomized study of pegfilgrastim efficacy and safety in patients with breast cancer, receiving myelosuppressive chemotherapy. Human serum samples were first screened for anti-drug antibodies, then «screening positive» samples were analyzed in confirmatory assay with % inhibition calculation for each sample. The «confirmed positive» samples were further characterized in titer assay.Conclusions. The ELISA method for anti-pegfilgrastim antibodies determination in human serum samples was successfully validated and applied for pegfilgrastim drugs immunogenicity assessment.

A novel HPLC-ESI-MS/MS method for simultaneous gonadotropin-releasing hormone (GnRH) analogs and somatostatin analog quantitation was developed and validated. The developed method was successfully applied to pharmacokinetic studies. The sample preparation process included solid-phase extraction (SPE). Effective chromatographic separation of the analytes and internal standard (dalargin) was achieved with a C18 column, using a gradient elution with two mobile phases: 0.1% v/v formic acid (aqueous solution) and 0.1% v/v formic acid (acetonitrile solution). The linearity of the method was demonstrated within a concentration range of 0.5–20 ng/mL, with correlation coefficients between 0.998–0.999 for goserelin, buserelin, triptorelin, and octreotide, respectively. The relative standard deviation (RSD, %) values for method accuracy and precision did not exceed 20% at the lower level of quantitation (LLOQ) or 15% at other concentration levels.

Biowaiver is a procedure for establishing the bioequivalence of generic and reference products without in vivo studies. Regulatory requirements for this procedure, as described in a variety of documents, differ in certain features and aspects. These differences need to be analysed.The aim of the study was to compare international and Russian regulatory approaches to the Biopharmaceutics Classification System-based biowaivers, provide recommendations on comparative dissolution testing, and outline opportunities for streamlining the regulatory framework of the Eurasian Economic Union (EAEU).In this article, the authors analyse biowaiver requirements and describe procedures for assessing the permeability and pH-dependent solubility of medicines, comparing dissolution profiles in various media that simulate the gastrointestinal environment, and interpreting test results. This paper shows the role of excipients in the solubility and permeability of an active substance. The authors recommend a methodological approach to the biowaiver procedure for replacing in vivo bioequivalence studies with in vitro tests under the current EAEU regulatory framework and list the characteristics of medicines that limit the applicability of the procedure. In conclusion, this article provides a rationale for harmonising the existing guidelines and requirements.