ScienceRise: Pharmaceutical Science

Study of factors affecting some properties of hydrophilic suppository base

Tue, 31 Oct 2023 00:00:00 +0200

The aim. To study the effect of the composition of hydrophilic suppository bases on the physicochemical and osmotic properties of suppositories made from them.

Materials and methods. The bases were studied with varying compositions of excipients. The microstructure of the bases was evaluated, and the disintegration time and resistance to rupture of suppositories made from them were determined. The kinetics of water absorption and solvent release were studied by dialysis. The content of propylene glycol (PG) and macrogol 400 (M400) in the receptor medium was determined by gas chromatography. The melted bases were studied by rotational viscometry. The electron paramagnetic resonance spectra of spin probes in hydrophilic solvents and bases were obtained; the type of spectrum, isotropic constant (A_N), rotational correlation times (τ), and anisotropy parameter (ε) were determined.

Results. The disintegration times and resistance to rupture of suppositories were determined depending on such factors as the content and grade of poloxamers, the ratio between high molecular weight macrogols and the mixed solvent PG-M400 (60 : 40 % m/m), the ratio of nonionic surfactant and cetostearyl alcohol (CSA) and their total content, water and hard fat content. The introduction of solid fat and a mixture of surfactants and CSA provides the uniform structure of the bases. The mass ratio between surfactants and CSA and their total content are important factors that provide acceptable resistance to rupture and disintegration times for suppositories and reduce water absorption and solvent release. As the temperature decreases from 45 °C to 20 °C, the bases transform from Newtonian liquids to solids. At that time, the microviscosity of the environment of the spin probes increased by about 5 times, but the parameters of their rotational diffusion in solid bases and the mixed solvent PG-M400 are comparable. This indicates the dissolved state of the spin probes in the bases and the absence of the formation of mixed associates from molecules of surfactant and CSA.

Conclusions. By varying the composition of excipients, the properties of hydrophilic suppository bases can be controlled, significantly reducing their osmotic properties. The active substances in these bases may be in a dissolved state due to the high content of non-aqueous solvents

Current approaches of health technologies introduction in Ukrainian hospitals

Olena Filiniuk, Mykhailo Babenko, Kostyantin Kosyachenko, Rabia Sucu — Tue, 31 Oct 2023 00:00:00 +0200

The study aimed to gather insights regarding current decision-making approaches and identify challenges and opportunities related to health technology implementation in Ukrainian hospitals.

Materials and methods. A total of 28 respondents from three public hospitals across different regions of Ukraine participated in online semi-structured interviews conducted between September 2022 and March 2023. The respondents for this study encompassed a diverse range of stakeholders, including general managers, medical directors, economists, representatives from procurement departments, heads of clinical and diagnostic departments, clinicians, and pharmacists. To effectively guide the interview process, a comprehensive questionnaire was developed.

The data collected from the respondents were analyzed and synthesized to results and conclusions.

Results. The semi-structured interview study consistently revealed a common pattern in all the interviewed hospitals regarding the adoption of new health technologies.

The process of introducing these technologies entails several stages, each demanding meticulous planning, coordination, and active engagement from various stakeholders. What stood out was that stakeholders from the same speciality were consistently involved in the same decision-making stage across all the hospitals we studied.

The technical stages of implementing new health technologies, as outlined by the Law of Ukraine "On Public Procurement," are well-established in Ukrainian hospitals. However, there is room for improvement in selecting which type of health technology to procure. The current assessment process often relies on limited sources of information, lacking comprehensive literature reviews or robust comparisons with existing practices or placebos. This information gap hampers the ability to make well-informed decisions that account for all relevant factors.

The study also identifies specific challenges for the future implementation of the Hospital Health Thechnology Assessment (HB-HTA) in Ukraine. These challenges necessitate investment in building HTA expertise at the hospital level, cultivating strong leadership support, providing professional staff training, and establishing robust data collection and management systems. Overcoming these obstacles is crucial for hospitals to bolster their capacity to effectively implement new health technologies and make informed decisions about their utilization.

Conclusions. Our study has revealed that all the technical stages involved in implementing new health technologies in Ukraine are well established. It was observed that there is room for improvement in the process of selecting which new health technology to purchase. This stage, known as the decision-making process based on HTA, requires implementation at the hospital level.

Our study highlights the evident interest and potential benefits associated with adopting HB-HTA in the hospitals under investigation. By integrating HB-HTA into existing practices and approaches, hospitals can significantly enhance their decision-making processes when introducing new health technologies.

There is an urgent need to introduce the term "hospital-based HTA" into Ukrainian legislation, as well as to activate the training of HTA experts at the hospital level

The study of the stability of silver proteinate solutions prepared in pharmacies

Tue, 31 Oct 2023 00:00:00 +0200

Today, medicines made in pharmacies are increasingly attracting consumers' attention and are in growing demand in Ukraine. Pharmacy production faces a number of problems, including the study of the stability of extemporaneous dosage forms and the determination of an optimal shelf life. 1 % and 2 % water silver proteinate solutions used in ophthalmology, otolaryngology and nephrology are produced in Ukrainian pharmacies both extemporaneously and as a reserve.

The aim. The aim of the work is to develop methods for quality support and study the chemical stability of 1 % and 2 % water solutions of silver proteinate, and to study the microbiological purity to extend the storage time of nasal drops.

Materials and methods. A study of the chemical stability of 1 % and 2 % water silver proteinate solutions of pharmaceutical production is carried out using chemical identification reactions (to silver and protein), quantitative determination by thiocyanatometric titrimetric method and determination of microbiological purity.

Results. The validation characteristics of the method for the quantitative thiocyanatometric determination of silver proteinate were studied (the correlation coefficient r = 0.9995 and 0.9996; the systematic error – 0.26 % and 0.03 %, the relative confidence interval – 0.88 % and 0.74 % for 1 % and 2 % solutions, respectively), as well as its suitability for this purpose was proven. “Silver proteinate solution, 1.0 %” and “Silver proteinate solution, 2.0 %” prepared in the pharmacy were studied for 150 days by the “Microbiological purity” indicator and were biologically stable.

Conclusions. The chemical identification reactions and methods for the quantitative determination of silver proteinate in an extemporaneous dosage form used to study the chemical stability of the drug have been proposed. The study results of the chemical stability and microbiological purity allow us to recommend pharmacies to extend the shelf life of nasal drops containing silver proteinate as an active pharmaceutical ingredient for 150 days

Determination of risks for business entities in the sphere of manufacturing medicines in military conditions in Ukraine

Victoriia Zhurenko, Viacheslav Lebedynets — Tue, 31 Oct 2023 00:00:00 +0200

The aim: determination of risks for business entities in the field of production of medicinal products under the conditions of martial law in Ukraine.

Materials and methods. The research materials are the results of a sociological survey in the form of a questionnaire among representatives of the senior management heads of structural units related to the environmental component of business entities' activities in the pharmaceutical production field. Method of sociological survey was used to collect primary information. A questionnaire was conducted, and respondent’s answers were registered using google-forms. The method of comparative analysis and generalization of statistical data was used to process the results.

Results. The study identified, analyzed, and assessed risks for business entities in producing medicinal products under martial law in Ukraine.

Significant risks of the destruction of infrastructure and the occurrence of man-made disasters have been identified. Thus, 10 % of pharmaceutical enterprises received critical damage, which makes it impossible to operate the enterprise until the destructive consequences are eliminated; another 15 % received some damage, but the company's activities are carried out. More than 75 % of enterprises can fully comply with the current licensing conditions (LC) for producing and selling medicinal products under martial law.

How critical risks were assessed: supply of raw materials and materials (logistics problems) (60 %); decrease in demand for the company's products (45 %); termination of gas supply (45 %); power outage (40 %); inflation, rising prices of raw materials and energy resources (35 %); termination of communications (35 %); difficulties in purchasing equipment, consumables, devices (30 %); termination of water supply (30 %); lack of competent personnel (30 %).

In the zone of critical risk at this stage remains the ability and willingness of enterprises to work following the plans of the state environmental policy following the Association Agreement between the EU countries and Ukraine. Respondents admit that the company lacks resources to comply with all requirements (20 %), that environmental aspects of activity are currently irrelevant (25 %), and that there are not enough competent specialists to implement the environmental policy and support the relevant procedures (25 %); that there is not enough informational support from the State (30 %).

Conclusions. In fact, 30 % of pharmaceutical enterprises are located in regions that are currently included in the List of territories where hostilities are (were) being waged or temporarily occupied. In general, Ukrainian business entities in the field of pharmaceutical production remain in the zone of uncertainty and significant risk of man-made disasters, non-fulfilment of requirements regarding production conditions, technological processes and constant quality control of production, non-fulfilment of environmental safety of production due to the direct threat of destruction of infrastructure and supply chains, due to the threat of termination of reliable supply of electricity, gas, water, resources, as well as due to high migration of qualified personnel.

Considering the current state of the economy and the environmental consequences of the war, particularly man-made disasters, the implementation of plans to comply with the state environmental policy and the fulfilment of some requirements of the Association Agreement between the EU and Ukraine is at risk.

In the long term, careful scientifically based planning of the rehabilitation program of the pharmaceutical sector is needed, taking into account the risks of pharmaceutical pollution and the adverse impact of the pharmaceutical industry on the natural environment, in particular through the implementation of environmental management systems (EMS) as part of the overall management system of the enterprise to manage environmental aspects; fulfilment of mandatory legal requirements and voluntary obligations following the goals and environmental policy of the enterprise; and to address issues related to risks and opportunities, especially concerning emergency preparedness and emergency response.

Research by choice of excipients ingredients of the gel for the therapy of radiation lesions of the skin based on rheological studies

Tue, 31 Oct 2023 00:00:00 +0200

The aim of this work is to conduct a research analysis of changes in the structural and mechanical properties of the gel from the addition of active substances and surfactants.

Materials and methods. In the presented work, model samples of the gel with active substances were studied: freshly obtained stonecrop juice, sea buckthorn oil, rosehip oil, St. John's wort oil and quercetin. As substances for the manufacture of bases hydrocolloids of cellulose derivatives were used: sodium carboxymethylcellulose (NaCMC) and hydroxyethylcellulose (HEC) with a surfactant Lanette SX.

A study of the rheological properties of the samples was performed using a rheoviscometer Rheolab QC (Anton Paar, Austria) using a system of coaxial cylinders C-CC27 / SS. The Rheolab QC rheometer is equipped with RheoPlus software, which allows you to set the necessary experimental conditions (shear rate gradient range, number of measuring points and measurement time of one point).

Results. The rheological properties of model samples of NaCMC and HEC gels, depending on the used concentration, were studied. With increasing concentrations of both NaCMC and HEC thixotropy of dispersed systems decreases. The change of structural and mechanical parameters of hydrogels from the addition of active ingredients and surfactant is analyzed, and established that adding them into the hydrogels increases the structural and mechanical parameters of model samples.

A study of gels with a constant concentration of sodium carboxymethylcellulose and hydroxyethylcellulose and different content of surfactant Lanette SX established that as the surfactant concentration increases, the area of the hysteresis loop and the resistance of the dispersed system to the applied mechanical fracture increase.

Conclusions. According to the results of the obtained structural and mechanical parameters and rheograms of the studied model samples of gels, it is rational to use in further studies of sodium carboxymethyl-cellulose (1.5 %) and hydroxyethylcellulose (1.25 %) stabilized Lannete SX in concentrations of 4-5 % and 3-5 % respectively

Synthesis, docking study and antimicrobial activity evaluation of pyridyl amides of thieno[2,3-d]pyrimidine-4-carboxylic acid

Tue, 31 Oct 2023 00:00:00 +0200

The aim. The combination in one molecule of pharmacophore fragments of thieno[2,3-d]pyrimidine-4-carboxylic acids with the fragments of 2- or 4-aminopyrimidine by peptide coupling promoted acylation in order to develop the new drug-like molecules with antimicrobial activity.

Materials and methods. The molecular docking studies were performed with the AutoDock Vina та AutoDockTools 1.5.6 programs; TrmD Pseudomonas aeruginosa PDB ID – 5ZHN was used as the protein target. Synthetic methods of peptide coupling were used. 1H and 13C NMR spectra were recorded with a Varian-400 spectrometer at 400 MHz and Bruker Avance DRX 500 device at 500 MHz and 125 MHz in DMSO-d6 as a solvent, using TMS as the internal standard. LC-MS analysis of the compounds was carried out with Agilent 1100 HPLC з with atmospheric pressure chemical ionization (APCI). The studied derivates were tested in vitro for their antibacterial and anti-fungal activities using agar diffusion and serial dilutions resazurin-based microdilution assays (RBMA).

Results and discussion. By the combination of the pharmacophore fragments of thieno[2,3-d]pyrimidine-4-carboxylic acids with the fragments of 2- of 4-aminopyrimidine, the combinatorial library of amides was constructed. For this library of compounds, the potential of antimicrobial activity was revealed using docking studies to the TrmD enzyme isolated from P. aeruginosa. The peptide coupling promoted by 1,1'-carbonyldiimidazole was found to be effective for the synthesis of pyridyl amides of thieno[2,3-d]pyrimidine-4-carboxylic acids, and it allowed to combine these pharmacophores in one molecule. The results of antimicrobial activity study revealed the broad spectrum of antimicrobial activity for N-(pyridin-4-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-4-carboxamide (2g), while 5,6-dimethyl-N-(6-methylpyridin-2-yl)thieno[2,3-d]pyrimidine-4-carboxamide (2c) showed the best MIC value against the reference strain of Pseudomonas aeruginosa ATCC 10145. N-(6-Methylpyridin-2-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-4-carboxamide (2h) was also found to be active against Pseudomonas aeruginosa.

Conclusions. An effective method for the synthesis of pyridyl amides of thieno[2,3-d]pyrimidine-4-carboxylic acid has been developed. The amides molecular docking method showed their ability to inhibit TrmD enzyme isolated from P. aeruginosa; the further in vitro studies of the compounds showed the rationality of the further studies of the derivatives with 2-amino-6-methylpyridine in amide substituent because this fragment favoured the selectivity against Pseudomonas aeruginosa

Results of the expert survey assessing the efficiency level of the national regulatory system in the field of medicines turnover

Maxim Suvorov, Alla Kotvitska — Tue, 31 Oct 2023 00:00:00 +0200

The aim. The aim of the research is to analyze the efficiency level of the national regulatory system in the field of medicines circulation using self-diagnostic tools, which will allow identifying reserves for its optimization and further improvement.

Materials and methods. The research materials consisted of the results of a survey conducted among government officials of national regulatory authorities in the field of medicines circulation. The research utilized methods of sociological survey, descriptive statistics, graphical analysis, data grouping, and generalization techniques. The research includes the development of a questionnaire based on the World Health Organization's "Global Benchmarking Tool" methodology, adapted to the national healthcare system. The questionnaire consisted of 2 questions to determine respondent characteristics and 104 statements about the functioning of the national regulatory system in the field of drug circulation.

Results. According to 75 % of the surveyed officials in Ukraine, an effective regulatory system operates in the field of drug circulation. Based on the number of affirmative answers, all statements were divided into 4 groups: high, sufficient, moderate, and low. Thus, the quality management system of national regulatory authorities was evaluated at a high level, while the funding system of national regulatory authorities received the lowest ratings. The grouping allowed us to identify weaknesses in the activity of the national regulatory system in the field of drug circulation, such as the lack of funds in budgets for staff training and overall insufficient funding for national regulators, including insufficient funding from international donors, lack of clarity and comprehensiveness in the regulatory framework for the pharmaceutical sector, etc.

Conclusions. In accordance with the aim of the article, we conducted research on the efficiency level of the national regulatory system in the field of drug circulation, which revealed that the most mature and effective direction of its activity today is the development and implementation of quality systems in national regulatory authorities

Application of the direct encapsulation method in the technology of medicine with dry rauwolphia extract (Rauvolfia serpentina Benth.)

Tue, 31 Oct 2023 00:00:00 +0200

The aim: development of the composition and technology of a medicinal drug in the form of capsules with a dry extract of Rauwolfia for the treatment of hypertension.

Materials and methods. Experimental samples of masses for encapsulation contained 2.0 mg of dry Rauwolfia extract and various excipients used in the technology of solid dosage forms. The study of pharmaco-technological characteristics was carried out on the devices of the company "Pharma Test" (Germany). The time of decay was determined on the device of the company "Erweka" (Germany). A comparative analysis of the cost calculation of the production of tablets and capsules with dry rauwolfia extract was carried out by the "cost plus" method.

Results. The use of PROSOLV^® SMCC HD 90 improved the flowability, homogeneity and homogeneity of the mass with Rauwolfia dry extract powder, considering the low dosage of the substance of 2 mg. It has been experimentally proven that PROSOLV^® SMCC HD 90 shortens the disintegration time as a disintegrant, because due to silicate moisture easily penetrates into the MCCC, hydrophilic bridges are formed, wettability increases and mass swelling occurs. The multifunctionality of PROSOLV^® SMCC HD 90 three-in-one excipient, which has the properties of a filler, a disintegrant and a glidant, makes it easy to apply direct encapsulation technology, replace and reduce the number of excipients and thus increase production efficiency.

Conclusions. When developing the composition of capsules with dry rauwolfia extract, the effect of various excipients on the pharmaco-technological properties of encapsulating masses and ready-made capsules was investigated. The combined excipient, namely PROSOLV^® SMCC HD 90, having the properties of a filler, a disintegrant and a lubricant, in direct encapsulation technology is more effective in influencing the fluidity of the mass and disintegration of the capsules. The introduction of the direct encapsulation method will allow to expand the range of new medicines and improve existing technologies, in particular in the form of tablets, which are widely produced in industrial production. it is possible to attach specifically to Rauwolfia

"Greening" of the industrial technology of enoxaparin sodium synthesis

Yuliia Bovsunovska, Vitalii Rudiuk, Victoriya Georgiyants — Tue, 31 Oct 2023 00:00:00 +0200

The aim: carrying out stages of synthesis of intermediates of Enoxaparin sodium, considering the variation of synthesis parameters. Correlation analysis between the technological parameters of the synthesis and the quality of the obtained samples. Evaluation of the influence of the quality of semi-finished products on the quality of the final substance. Implementation of the principles of green chemistry in the synthesis of Enoxaparin sodium by reducing the production cycle and using the most environmentally friendly solvents and reagents.

Materials and methods: samples of intermediates of the substance Enoxaparin sodium were synthesized according to the method described in the patent, as well as with a variation of the selected critical technological parameters. The obtained samples of intermediate products were analyzed according to the internal specification. In addition, an NMR-spectroscopy analysis was carried out for detailed structural characterization of Enoxaparin sodium intermediate molecules.

Results: the method of synthesis of intermediates of the Enoxaparin substance proposed in the patent was evaluated and the critical parameter for the formation of the final molecule was selected, namely the reaction mass holding time. The intermediate of Enoxaparin sodium - benzethonium salt of heparin and benzyl ester of heparin were developed according to the selected parameters and the analysis of the obtained samples was carried out according to the internal ND. Taking into account the principles of green chemistry, the method of synthesis of the intermediate product - benzyl ester of heparin was optimized by solvent regeneration.

Conclusions: As a result of the research, the methods of synthesis of intermediates of Enoxaparin were evaluated and the technological parameters of the synthesis of intermediates were determined, allowing to obtain a substance equivalent to the original Clexane® and Lovenox®. Evaluation of the method of synthesis of intermediate products according to the principles of green chemistry was carried out. The possibilities of greening the synthesis were analyzed. The holding time of the reaction mass of the benzethonium salt of heparin was reduced from 6 to 4 hours, and the benzyl ester of heparin from 25 to 22 hours. The E-factor indicator was reduced by regeneration of the solvent at the stage of synthesis of heparin benzyl ester

Method approaches to assessing the adaptation potential of the industrial pharmaceutical enterprise to changing economic conditions

Tue, 31 Oct 2023 00:00:00 +0200

The aim of the article is to develop a methodology for assessing the potential of IPE adaptation to changes in external conditions and internal influencing factors.

Materials and methods. The research used the methods of theoretical generalization, analysis and synthesis, correlation analysis and expert survey.

Results. It is proposed to define the essence of the adaptation potential of an industrial pharmaceutical enterprise to changes in business conditions, under which it is appropriate to understand the enterprise's readiness to respond flexibly, quickly, and adequately to changes occurring in the external and internal environment, in order to increase its level of competitiveness. A technique for determining the level of industrial adaptation potential (the technique cannot be a model; the technique is stages that are related to each other) and a ranking model by its degree by parametrization is proposed. Based on the study of scientific works and the experience of global companies, it was determined that the model for ranking the level of adaptation potential by parameterization involves ranking elements according to the degree of readiness of the management system of an industrial pharmaceutical enterprise for adaptation. The components of parameters for assessing the adaptation potential of an industrial pharmaceutical enterprise have been formed. The limits of adaptation potential are defined.

Conclusions. A methodology for assessing the adaptation potential of industrial pharmaceutical enterprises to the influence of external factors (martial law, the outflow of qualified personnel, a decrease in the purchasing power of the population, etc.) and taking into account the internal capabilities of the enterprise (resources (material, financial, labour, information, service, etc.), organizational structure and management decision-making) with the aim of increasing the competitiveness of the enterprise and its fulfilment of the social component of functioning, namely timely provision of the population with high-quality medicines in full in the right place at affordable prices.

Assessment of medical technologies in the formation of government programs to assist patients with rare metabolic diseases

Tue, 31 Oct 2023 00:00:00 +0200

The aim: carrying out an assessment of the technologies of nutritional and pharmacological therapy of phenylketonuria (PKU) to justify a set of measures for the implementation of the government program to support patients with rare diseases (RD).

Materials and methods: scientific publications, regulatory acts, treatment protocols, statistical data, epidemiological indicators, results of patient questionnaires, marketing information, data from the electronic procurement system "ProZorro" were used in the research process. The research was conducted using the methodology of health technology assessment (HTA), methods of marketing analysis, questionnaire survey, document analysis, comparison, systematization and generalization of data.

Research results. An analysis of the evaluation of modern approaches to the treatment of hereditary rare metabolic disease (PKU) was carried out. According to clinical protocols, the main technology for the treatment of PKU is nutritional therapy - a diet (diet-for-life) with restriction of the use of phenylalanine (Phe) and the use of food products for special medical purposes (Special low protein foods for phenylketonuria - SLPF-PKU). Innovative drugs "Kuvan" and "Palynziq" are recommended in the case of atypical PKU.

For RD, specific and innovative cost-effective medical technologies (MT) are usually used, which have insufficient evidence due to limited experience, low availability, and small patient populations. Centralized procurement and managed entry agreements (MEA) make it possible to expand the availability of MT to patients and obtain real data on their safety and effectiveness. Integration into the global information space, participation in international projects, joint clinical assessment (JCA) in accordance with Regulation (EU) 2021/2282 on HTA, cooperation with Orphanet, EURORDIS, other professional and patient organizations are extremely important.

The key components of HTA for RD are socio-economic and organizational and legal aspects, in particular the special status of MT, which provides certain preferences. The foreign experience of providing orphan patients (in particular, reimbursement) is summarized. The legal framework for RD is systematized.

Based on the results of the analysis of PKU prevalence indicators, modelling and budget impact calculations were carried out, considering that SLPF-PKU products are purchased from local budgets.

An analysis of prescriptions, assortment, and prices of SLPF-PKU was carried out using data from the ProZorro procurement system. A survey of 156 patients with PKU made it possible to identify unmet needs and formulate recommendations for expanding the SLPF-PKU food basket.

Conclusions: Conducting the HTA made it possible to identify key problems, as well as to justify a set of measures for the development and implementation of the government program to support patients with rare diseases, based on the obtained results