Prediction of the composition of prolonged release tablets based on 4,4'-(propandiamido) sodium dibenzoate using the SeDeM method

Introduction. Direct compression technology is one of the most common tablet technologies. As known, many active pharmaceutical ingredients are not suitable for this technology without the addition of special excipients. A useful tool for determining the suitability of powdered materials for direct compression technology is the Sediment Delivery Model (SeDeM) method, based on the concept of Quality by Design. The presented method allows not only to assess the suitability of a material for direct compression, but also helps to predict the composition of a solid dosage form in the form of a tablet, which, in turn, leads to a significant reduction in experimental work carried out in the development of a new drug.Aim. Prediction of the compositions of matrix tablets based on sodium 4,4'-(propanediamido)dibenzoate with prolonged release, obtained by direct compression using the method of mathematical modeling SeDeM.Materials and methods. The objects of the study were the original substance sodium 4,4'-(propanediamido)dibenzoate, as well as a number of auxiliary substances, which included polymers used for dosage forms with prolonged release, a dusting component – magnesium stearate, and a filler – lactose monohydrate. Physicochemical and technological properties of APIs, explosives, obtained tablet mixtures and tablets were studied in accordance with the requirements of the State Pharmacopoeia of the Russian Federation XIV ed. and EP 9th ed.Results and discussion. The properties of the substance and excipients were assessed in accordance with the SeDeM method. It was found that the substance 4,4'-(propanediamido) sodium dibenzoate is not suitable for direct pressing due to poor flowability and low compressibility. Hypromellose Methocel K4M had good compressibility, but it did not have sufficient flowability. The other tested polymers had satisfactory properties for the direct compression technology. The composition of the tablet mixtures was calculated using the SeDeM method, the obtained tablet mixtures had satisfactory technological characteristics for obtaining tablets by direct compression. The tablets obtained as a result of the experiment also met the pharmacopoeial requirements.Conclusion. Prediction of the composition of sustained-release tablets based on the original substance sodium 4,4'-(propanediamido)dibenzoate was carried out using the SeDeM method. It was found that this method is suitable for the development of the composition of tablets based on sodium 4,4'-(propanediamido)dibenzoate.

Evolution of Diploid Progenitor Lung Cell Applications: From Optimized Biotechnological Substrates to Potential Active Pharmaceutical Ingredients in Respiratory Tract Regenerative Medicine

The objective of this review is to describe the evolution of lung tissue-derived diploid progenitor cell applications, ranging from historical biotechnological substrate functions for vaccine production and testing to current investigations around potential therapeutic use in respiratory tract regenerative medicine. Such cell types (e.g., MRC-5 or WI-38 sources) were extensively studied since the 1960s and have been continuously used over five decades as safe and sustainable industrial vaccine substrates. Recent research and development efforts around diploid progenitor lung cells (e.g., FE002-Lu or Walvax-2 sources) consist in qualification for potential use as optimal and renewed vaccine production substrates and, alternatively, for potential therapeutic applications in respiratory tract regenerative medicine. Potentially effective, safe, and sustainable cell therapy approaches for the management of inflammatory lung diseases or affections and related symptoms (e.g., COVID-19 patients and burn patient severe inhalation syndrome) using local homologous allogeneic cell-based or cell-derived product administrations are considered. Overall, lung tissue-derived progenitor cells isolated and produced under good manufacturing practices (GMP) may be used with high versatility. They can either act as key industrial platforms optimally conforming to specific pharmacopoeial requirements or as active pharmaceutical ingredients (API) for potentially effective promotion of lung tissue repair or regeneration.

A COMPREHENSIVE REVIEW ON BERGENIA LIGULATA (PAASHANBHEDA) AND ITS ROLE IN THE TREATMENT OF KIDNEY STONE FORMATION

Bergenia ligulata, a member of the saxifragaceae family, is a well-known Ayurvedic medicine Paashanbheda. Bergenia ligulata is a highly regarded medicinal herb and one of the most well-known examples of controversial drugs in Indian medicine, commonly referred to as "Paashanbheda." This plant is well-known for its ability to dissolve kidney stones. Bergenia comes in three varieties: B. ligulata, B. ciliata and B. stracheyi. Bergenin is the species' key chemical constituent. Many secondary metabolites belonging to coumarins, flavonoids, benzenoids, lactone, fructose, tannins, phenols, and sterols have been discovered in phytochemical studies. Anti-urolithic, antiviral, free radical scavenging, anti-diabetic, hepatoprotective, diuretic, antipyretic, anti-oxaluria, antitumor, antibacterial, antifungal, anti-inflammatory, anti-implantation and cardio-protective activities have been observed in crude extracts and isolated compounds from B. ligulata. Bergenin, (+) afzelechin, (+) catechin and -sitosterol were discovered in the plant's phytochemistry. Many pharmacological activities of plants have been studied, including antipyretic, anti-diabetic, anti-inflammatory, antitussive, antiurolithic and antimalarial. The aim of this review is to present the most current knowledge on botany, Pharmacognosy, conventional uses, phytochemistry, pharmacopoeial requirements, pharmacology of B. ligulata, as well as the biological activities of Bergenin (active constituent from Bergenia ligulata). It covers the information collected from scientific journals, books, theses and reports via a library and electronic search (Google Scholar and PubMed).

Pharmacopeial aspects of preparation of infusions and decoctions in pharmacies

An analytical review of pharmacopoeial aspects of preparation of infusions and decoctions in pharmacies is presented. The aim of this work is to conduct a comparative analysis of pharmacopoeial requirements for the technology of infusions and decoctions in pharmacies. Materials and methods of the research. Comparative analysis of pharmacopoeial requirements was performed using methods of systematic and structural-logical analysis. Results and discussions. It was found that in many pharmacopoeias (European, British, Italian, French, Czech, Kazakh) there are no instructions on the pharmacy technology of these dosage forms. Only the pharmacopoeias of Japan, Austria, Belarus and Russia contain separate monographs on the extemporaneous preparation of infusions and decoctions. After analyzing these monographs, it was found that the definition of infusions and decoctions as a dosage form differs. It was found that the Japanese Pharmacopoeia regulates the preliminary preparation of medicinal plant raw materials (soaking for 5 minutes in water), in other pharmacopoeias there is no such requirement. When conducting a comparative analysis of the technology of preparation of infusions and decoctions, we observe that the ratio of medicinal plant raw materials (MPRM) and extractant and extraction modes differ. Conclusions. An analytical review of pharmacopoeial aspects of preparation of infusions and decoctions in pharmacies is presented. A comparative analysis of the requirements for technology and quality control of infusions and decoctions in accordance with pharmacopoeial articles revealed both different and similar information. The results of the research showed that despite the differences in the structures of articles and names, as well as approaches to the definition of this dosage form, some requirements are similar (particle size of MPRM). The differences that were found include the ratio of MPRM and extractant, extraction modes. Taking into account the data of the analysis and the existing national requirements, the authors proposed a draft general pharmacopoeial article “Infusions and decoctions made in pharmacies”.

Current Requirements for the Degree of Fineness of Herbal Substances and Herbal Medicinal Products

The introduction of monographs on new types of herbal substances, which were not included in the previous editions of the State Pharmacopoeia of the Russian Federation (Ph. Rus.), and the introduction of the new powder dosage form of herbal medicinal products require alignment of requirements for the degree of fineness of medicinal products. The aim of the study was to compare Russian and foreign pharmacopoeial requirements for the degree of fineness of herbal substances and herbal medicinal products. The analysis demonstrated that in the case of cut herbal substances and powder, the Ph. Rus., XIV edition, establishes limits for the percent of particles that pass through and particles that are retained by a sieve with a specified pore diameter. In the case of whole herbal substances, the Ph. Rus. establishes limits for the percent of particles that pass through a sieve with a specified pore diameter. The monographs of the world leading pharmacopoeias include general requirements for the size of particles in all powders produced from chemically synthesized substances, as well as from naturally occurring and mineral substances, while individual monographs have no requirements for the degree of fineness of herbal substances. The national pharmacopoeias of the Eurasian Economic Union member states also include requirements for the degree of fineness of herbal substances, but they are not sufficient. The results of the analysis of the established limits demonstrate the need to change the controlled size of small and large particles for some types of herbal substances.

DEVELOPMENT OF THE COMPOSITION AND TECHNOLOGY FOR THE PRODUCTION OF ENCAPSULATED DRUGS BASED ON 3,7-DIAZABICYCLO[3.3.1]NONANE

The following biological and pharmaceutical factors influence the therapeutic efficacy and bioequivalence of drugs: physicochemical properties of a pharmaceutical substance, bioavailability, type of dosage form, route of administration, nature of excipients, their compatibility, as well as technological conditions of production, including the preparation of drugs forms. Before mass production of a drug, the technological parameters and characteristics of the pharmaceutical substance must be carefully studied and scientifically substantiated. This work is devoted to the study of the technological properties of an original pharmaceutical substance based on the derivative of 3.7-diazabicyclo[3.3.1]nonane with the chemical name IUPAC 6-[4methoxy-3- (1H-pyrazol-1-ylmethyl) benzyl] -1,11dimethyl-3,6,9-triazatricyclo[7.3.1.1]tetradecane-4,8,12-trion, used as an active substance for the development of the composition and technology for the preparation of oral dosage forms in capsule form. The article presents the results of the development and testing of a drug in the form of capsules of the original pharmaceutical substance of the nootropic action of 3,7-diazabicyclo[3.3.1]nonanane, which is practically insoluble in water. The study identified and evaluated the technological and biological properties of a pharmaceutical substance that can affect the pharmacological activity in the production of a dosage form. The study examined the key indicators: solubility, particle size, flowability, bulk density. The technological characteristics of the pharmaceutical substance are studied not only by certain values of the indicated characteristics but also by the values of the Hausner and Carr indices. The data obtained suggest the content and progress of further stages of pharmaceutical development. The presence of the lag phase when dissolving hypromellose capsules in a medium with a pH of 1,2 and relatively low disintegration rates in media with a pH of 1,2, pH 4,5, and pH 6,8 served as the basis for the choice of gelatin capsules. The developed dosage form meets modern pharmacopoeial requirements, including the dissolution kinetics: according to the results obtained, in 45 minutes (77,6 ± 2,5)% of the substance passes into the dissolution medium with a pH of 4,5. The results of the study are used to develop a technological scheme for obtaining the dosage form of 3,7-diazabicyclo[3.3.1]nonane, its indicators, and quality standards.

Formation of Docetaxel-related Substances in the Polymer Particles During Storage and Gamma-treatment

Introduction. Docetaxel is widely used for cancer treatment. Actual issue for newly developed polymer-based Docetaxel formulations is applicability of current quality requirements. The technology of polymeric forms, including gamma-sterilization, are differ from actual Docetaxel injections technology. In this study were used PLGA-based particles with Docetaxel. The main attention was directed to studying qualitative and quantitative content of related impurities in polymeric forms during long-term storage and gamma-sterilization in comparison with pharmacopoeial requirements for Docetaxel injections.Aim. Studying of possible patterns of Docetaxel-related impurities formation between intact and gamma-irradiated batches.Materials and methods. Objects of study – lyophilizates of Docetaxel polymeric forms was previously obtained by the authors. Qualitative and quantitative analysis was performed by high pressure liquid chromatography.Results and discussion. Docetaxel-related impurities was determined and evaluated in the intact and gamma-treated batches. It was cleared, that related substances in the gamma-treated batches was different in comparison with non-treated but after vary storage periods.Conclusion. Docetaxel-loaded polymeric drugs shown proper stability during long term storage. The influence of gamma-treatment to Docetaxelrelated impurities content was found. Gamma sterilization can be promising method for novel drugs, but it needs individual study in the each case.

Comparative Analysis of Russian and Foreign Pharmacopoeial Requirements for the Quality Control of Water for Injection: Challenges and Ways of Harmonisation

Parenteral dosage forms are dissolved using sterile water for injection whose quality is regulated by special requirements. The lack of a monograph on sterile water for injection in the State Pharmacopoeia of the Russian Federation, as well as the concept of harmonisation of pharmacopoeial standards adopted by the member states of the Eurasian Economic Union (EEU), which promotes the development of a unified system of product quality attributes, test methods and means of control, support the need for and importance of the elaboration of a special document. The aim of the work was to study the possibility of harmonisation of Russian and international pharmacopoeial requirements for the quality control of sterile water for injection used as a solvent for medicinal products. The article presents the results of a comparative analysis of requirements of the nine leading world pharmacopoeias and pharmacopoeias of the EEU member states for the quality control of sterile water for injection (lists of test parameters, norms, test methods). The Russian and foreign requirements for the quality control of sterile water for injection differ both in terms of test parameters and test methods used. The analysis of monographs showed that the quality of sterile water for injection is controlled using 12–18 parameters. The most significant differences in the pharmacopoeial requirements of the EEU member states affect nine quality attributes. The authors propose approaches that are harmonised with international requirements and involve the use of more accurate modern test procedures, optimisation of the list of test parameters and establishment of impurity limits for containers with different capacities in order to prepare a monograph on sterile water for injection for inclusion into the State Pharmacopoeia of the Russian Federation and the EEU Pharmacopoeia.

Low Endotoxin Recovery—Masking of Naturally Occuring Endotoxin

Endotoxins are cell wall components of Gram-negative bacteria. A release of endotoxins into the human blood stream results in an inflammation reaction that can lead to life-threatening conditions like sepsis. Therefore, control for endotoxin contamination of intravenously administered drugs is crucial. Drugs are usually tested for putative endotoxin contamination with Limulus-based tests. However, validity of the compendial test procedures is questioned in the case of low endotoxin recovery (LER). To assure validity, regulatory authorities request hold-time studies of endotoxin in addition to pharmacopoeial requirements. Within these studies, endotoxin is added (spiked) to an undiluted product. The spiked product is held for a certain period of time and subsequently diluted for endotoxin determination. Due to the known heterogeneity of endotoxin the question has been raised as to which source represents the most adequate endotoxin spike. In the present study, endotoxin hold-time studies were analyzed by using different sources of endotoxin. Highly purified endotoxin, crude endotoxin extracts (Naturally Occurring Endotoxin) from different bacterial species and varied growth conditions as well as endogenous endotoxin contaminations were investigated. The results clearly demonstrate that endotoxin masking—an effect of LER—is dependent on the endotoxin source used. Various parameters such as bacterial strain and growth conditions lead to different masking susceptibilities. Due to these effects it is impossible to predict the susceptibility of bacterial endotoxin contamination to LER. In order to determine whether a sample is prone to LER, an endotoxin spike that is susceptible to LER is required.