The beginning of the emergence and development of medicine and pharmacy in Russia was associated with the medicine of the Scythians. In the writings of Herodotus, Pliny: Scythian grass is mentioned " Scyphicam herbam"(rhubarb), used to treat wounds. The Scythians were well aware of the properties of many herbs and grew them for sale. For the first time, they began to use medicines of animal and mineral origin, yahont, beaver stream, amber, arsenic, etc.
Medical sciences began to penetrate into Russia at the end of the 9th century from Byzantium along with Christianity, so the first doctors were clerics. Monastic medicine practiced treatment with prayers, in addition, it widely used the rich experience of traditional medicine: treatment with herbs, ointments, waters, from this moment one can trace the development of pharmaceutical technology.
By the way, if you haven't read it, be sure to do so!
History and development of dosage form technology in Russia.
It started in the 15th-17th centuries, when folk healers were especially popular in Russia. Medicines could be obtained from green shops. The first descriptions of medicines used in Russia date back to the 13th-15th centuries. The manuscripts of traditional medicine spoke in detail about the equipment of pharmacies and the technology of medicines, sometimes one could even find ink sketches of pharmacy dishes and various devices for making medicines.
It is also mentioned what kind of dependence on the amount of prescribed medication and on the age and physical condition of the patient.
The first nationwide body in charge of medical affairs in Russia was the Apothecary Order, which included: doctors, healers, pharmacists, ophthalmologists, translators, herbalists, clerks, etc. The Apothecary Order was originally designed for the tsar and his entourage, organized the collection of medicinal plants throughout Russia .
The collected plants were carefully examined and carefully stored. In the first half of the 17th century, the Pharmaceutical Order established the production of medicines in the pharmaceutical garden in St. Petersburg from medicinal plants grown here. Russian craftsmen of the Aptekarsky Prikaz produced laboratory equipment, as well as pharmacy glassware, and the production of both earthenware and glassware was established.
The rapid development of drug technology is associated with the most important period in the development of the pharmacy business in Russia during the reign of Peter I. In 1701, a decree was issued to prohibit the sale of drugs in green shops and the opening of pharmacies. The sale of medicines was allowed only to pharmacies. The owner of a pharmacy must have the money to build a pharmacy and provide it with equipment and necessary medicines.
In St. Petersburg, an Apothecary Garden is being created, where medicinal plants were grown, and there was also a laboratory on site that was engaged in the production of "oils and vodkas" and other medicinal preparations. At that time, there were more than 150 types of medicinal vodkas, mixtures, extracts, essences, powders, ointments, oils, etc. In the manufacture of medicines, scales, mortars, etc. were used. Chemical analysis appeared. And in 1720, the first independent chemical laboratory appeared.
Under Peter I, the first pharmaceutical factories were created, the Academy of Sciences and other scientific institutions were opened. The pharmacy at that moment was a complex pharmaceutical enterprise engaged in the procurement and processing of medicinal plant materials; manufacture of prescription drugs. Each pharmacy had a well-equipped laboratory for the preparation of herbal preparations, the production of essential oils, salts, aromatic waters, etc.
The activity of pharmacies in the XIX-XX centuries has changed significantly. The manufacture of medicines has gone beyond pharmacies. Most drugs, tablets, solutions came to pharmacies already in finished form or semi-finished products from factories, while the pharmacies themselves were limited to the manufacture of medicines according to doctor's prescriptions. The number of drugs increased every year due to new groups of drugs (vaccines, alkaloids, etc.).
The increased need for medicines in the 70s served as the opening of steam laboratories for the manufacture of galenic preparations at pharmacies, and later the first pharmaceutical enterprises in Russia were created (Keller, Ferrein, Ermans). Plants, factories and laboratories at pharmacies were mainly engaged in the production of tablets, extracts, plasters, tinctures, ointments.
Pharmaceutical Technology (Drug Technology) slowly but surely rushed up, already in 1920 the Scientific Research Chemical-Pharmaceutical Institute was created, which was engaged in the synthesis of new drugs, the study of plant resources of the USSR, the development and improvement of methods for analyzing drugs. In the 1940s, enterprises became more specialized and profiled, special factories for the production of antibiotics were created.
After the war, there were significantly more products produced by the pharmaceutical industry. The manufacture of such important drugs as streptomycin, albomycin, biomycin, crystalline penicillin, diplacin, vikasol, corglicon, etc., began.
The development of drug technology in the 70-80s had the effect of increasing the pharmacy network, and it is worth noting that it developed not only by opening new pharmacies, but also by increasing their capacity and efficiency, and in the 90s, pharmacy organizations received the right to legal and economic independence and the structure of the pharmacy range has changed significantly, such groups of goods have appeared as: homeopathic remedies, dietary supplements, medical cosmetics, baby and diet food, hygiene products and others.
Directions for the development of modern pharmaceutical technology:
1) Development of medicines based on biotechnology and genetic engineering;
2) Experimental and theoretical substantiation of the improvement of the composition and technology of traditional dosage forms and the creation of completely new ones;
3) Creation of methodological bases for obtaining modern medicines from plant materials;
4) Development of theoretical foundations for the stabilization of medicines in order to extend the shelf life;
5) Directed search and study of new excipients that prolong the action, improve the bioavailability and stability of drugs;
6) Studying the technological and biopharmaceutical aspects of the bioavailability of drugs, establishing the relationship between bioavailability indicators, pharmacokinetics and biopharmaceutical factors;
7) Development of new production technologies and methods of drug analysis;
8) Research in the field of pediatric and geriatric dosage forms;
9) Creation of targeted drugs with specified pharmacological properties;
10) Study of the relationship between the components of the system: "Drug-Packaging-Atmosphere". Prediction and determination of the suitability of packaging and closures for long-term storage of medicines.
At the moment, the development of pharmaceutical technology in Russia is at the proper modern level, in our country there is practically no shortage of any drugs and preparations, a well-established pharmacy network practically does not fail, in addition, new developments are underway (see above) and various other related sciences, thereby continuing the history of pharmaceutical technology to which we are directly related.
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PROGRAM OF ENTRANCE EXAMINATIONS FOR
SPECIAL DISCIPLINES WHEN ENTRY TO
POSTGRADUATE IN THE DIRECTION OF TRAINING
33.06.01 PHARMACY
Focus (profile) – DRUG TECHNOLOGY
Current state and prospects for the development of pharmaceutical technology.
Pharmaceutical technology as a science and its tasks at the present stage.
State regulation of production and quality control of drugs.
Legislative basis for the manufacture of medicines. International and state (national) requirements and standards. Organization of the preparation of medicines in accordance with modern GMP requirements.
The main methodological approaches to the creation and design of therapeutic systems (intraocular, transdermal, implantation, etc.). Biopharmacy is a modern methodology and the basis for the creation of modern drugs, including those with controlled pharmacokinetics. The concept of the mechanisms of release and mechanisms of absorption of medicinal substances from various dosage forms.
Modern aspects of the use of excipients, their role, purpose, requirements for them. Classification of explosives by nature, chemical structure, functional role in the dosage form. Macromolecular compounds (HMC) as excipients. Shapers and dispersion media. Water and other solvents used in pharmaceutical technology. Pharmacopoeial and technological classifications of water. Non-aqueous solvents and co-solvents.
propellants. Solubilizers. pH regulators, buffer systems. Use of the Navy. Surfactant for stabilization of microheterogeneous disperse systems. Preservatives, requirements for them. Release and absorption rate regulators. Prolongators.
Corrigents of taste, color, smell. Isotonic explosives. Technological processes underlying pharmaceutical technology and their instrumentation.
Modern aspects of the implementation of the main processes and devices of pharmaceutical technology. Dissolution. Filtration. mass transfer processes. Extraction. Stages of the extraction process. Isolation and purification of biologically active substances.
Adsorption and ion exchange, crystallization. Mass transfer through semi-permeable membranes. Drying. Quality control of raw materials, semi-products, dosage forms and preparations, etc. Modern approaches to the organization of the technological process (international and regional GMP rules, industry standards, etc.). Excipients used in the manufacture of medicines and medical and cosmetic products. Innovative medicines. Features of the production of LF MIBP (including ensuring microbial purity, a range of modern excipients). Sprays and aerosols. Immobilization of cells and enzymes.
List of recommended literature 1. Validation of analytical methods for drug manufacturers. HPLC, TLC, titration and GLC. Justification of reference standards. System suitability tests, method transfer, revalidation. Translated by Zh.I. Aladysheva, O.R. Spitsky. Scientific edition of V.V. Coastal. M., 2008., 132 p.
2. Guidance on Good Practice for the Manufacture of Medicinal Products for Human Use. Guidelines. S.V. Maksimov, N.A. Lyapunov, E.P.
Bezuglaya, A.V. Bykov, V.A. Dmitriev, I.A. Kasakin, V.V. Kosenko, E.Yu.
Lopatukhin, A.P. Meshkovsky, O.V. Mirolyubova, T.Kh. Chibilyaev, T.A. Shmalko.
M., 2009., 157 p.
3. Beregovykh V.V., Pyatigorskaya N.V., Belyaev V.V., Aladysheva Zh.I., Meshkovsky A.P. Validation in the production of medicines M., 2010., 286 p.
4. Beregovykh V.V., Sapozhnikova E.A., Dzhalilov Kh.K., Kuzmicheva E.L.
Pyatigorskaya N.V. Theoretical foundations of drug technology.
Textbook, 2011., 244p.
Focus (profile) – PHARMACEUTICAL CHEMISTRY,
PHARMACOGNOSY
Pharmaceutical chemistry. Characterization of some therapeutically important groups of medicinal substances (in accordance with the program of the specialty "Pharmacy"). State standardization system. The current state and ways to improve the standardization of medicines. The role and place of metrology and standardization in drug quality control. General pharmacopoeial articles on statistical processing of the results of biological and chemical methods of analysis. The system of step-by-step control of medicines in pharmacies, ensuring the quality of products, the prospects for its development. Methods for the quantitative determination of medicinal substances (chemical analysis).Thin layer chromatography. The problem of counterfeit medicines.
Regulatory documentation for medicines. Standardization of medicines as an organizational and technical basis for product quality management.
State Pharmacopoeia, pharmacopoeial articles (FS) and pharmacopoeial articles of enterprises (FSP).
Pharmacognosy. Pharmacognosy as a science. Basic terms and concepts of the subject. Nomenclature of medicinal plants and medicinal plant raw materials. The main stages of the use and study of medicinal plants in world medicine. Fundamentals of the procurement process of medicinal plant materials.
The chemical composition of medicinal plants and the classification of medicinal plant materials. Standardization of medicinal plant materials. The main directions of scientific research in the field of study of medicinal plants.
Methods for identifying new species of medicinal plants. Medicinal plant raw materials "Leaves". Medicinal plant raw materials "Herbs". Medicinal plant raw materials "Roots". Medicinal plant raw materials "Rhizomes".
Medicinal plant material "Rhizomes and roots". Medicinal plant raw materials "Bark". Medicinal plant raw materials "Flowers". Medicinal plant raw materials "Fruits". Determination of the good quality of medicinal plant materials. Chromatography in the analysis of medicinal plant materials.
The concept of "essential oil". The concept of polysaccharides. The concept of "cardiac glycosides".
The concept of "saponins". The concept of flavonoids. The concept of "tannins". The concept of "anthracene derivatives". The concept of vitamins. The concept of alkaloids. The concept of alkaloids.
2. Belikov V.G. Pharmaceutical chemistry. M.: MEDpress-inform, 2007.
3. Functional analysis of organic medicinal substances. Slivkin A.I., Sadchikova N.P., Voronezh. VGU, 2007. 426s.
4. Muravieva D.A., Samylina I.A., Yakovlev G.P. Pharmacognosy, M., "Medicine", 2007. 652p.
5. Samylina I.A., Anosova O.G., Ermakova V.A., Bobkova N.V. Pharmacognosy.
Atlas. Volumes 1,2,3 M., "Geotar", 2007, 188s., 380s., 2009, 420s.
6. Samylina I.A., 6. Sorokina A.A. Atlas of medicinal plants and raw materials. M., "Author's Academy", 2008, 218p. Digital library. Volume of Pharmacognosy (compiled by I.A. Samylina, A.A. Sorokina). GOU VPO MMA, M., Orientation (profile) - ORGANIZATION OF PHARMACEUTICAL Marketing Pharmaceutical marketing: organization of product distribution in the pharmaceutical market. Pharma organization. aid as a science. Pharmacy as a retail link in the pharmacy system. Marketing methods for determining the need and studying the demand for medicines. Organization of the work of the pharmacy for taking prescriptions and dispensing medicines. Pharmaceutical examination of the prescription. Features of the manufacture of drugs.
Rational organization and certification of workplaces. Organization of intrapharmacy drug quality control. The main forms of drug provision for inpatients. Pharmacoeconomic analysis. Pharmaceutical logistics: marketing, purchasing, warehouse, transport. Warehousing logistics: pharmacy warehouse.
Introduction to pharmaceutical economics. Features of the action of the main economic laws and consumer behavior in the pharmaceutical market.
Fundamentals of drug pricing. Planning. Basic planning methods. Economic indicators of the activity of a trading pharmaceutical organization. Merchandise planning. Commodity resources and commodity supply of trade. Cost planning. Income planning, net profit planning. Information system "accounting". Types of accounting and accounting meters.
Regulatory framework and international accounting standards. Objects, subjects and methods of accounting: documentation, inventory, financial statements. Accounting methods: balance sheet and accounting accounts. Types of changes in the balance sheet. Accounting for fixed assets and intangible assets. Accounting for the movement of inventories. Accounting for cash and settlements. Accounting for labor and wages. Accounting for income and expenses, analysis of the economic and financial activities of a pharmacy organization. Documentary sources of scientific pharmaceutical information. Types of ASPI. Marketing methods for researching information needs. Methodological approaches to the advertising of drugs. Introduction to Pharmaceutical Management: Study Methodology, Methods and Models. Organizational design in pharmacy: types of organization, management structures, effective distribution of powers. Fundamentals of personnel management in pharmacy organizations. Communications in the management of pharmaceutical organizations. Technology for the development and implementation of solutions in pharmaceutical practice. Methodology for managing socio-psychological processes in a pharmacy team. Basics of office work in pharmacy organizations:
rules for documentation and workflow. Licensing of pharmaceutical activities: the procedure for documenting. Pharmaceutical business.
Pharmaceutical marketing concept.
M.: JSC "Medicine", 2004. 720 p.
2. Ibragimova G.Ya., Sboeva S.G. Pharmaceutical bioethics. Tutorial. Ufa: Virtual, 3. Ryzhkova M.V., Sboeva S.G. Logistics management of pharmaceutical organizations. M .: "Professional - Center", 2003. 218 p.
4. Dzhuparova I.A., Sboeva S.G., Belova Yu.V. Organizational and methodological foundations of benchmarking in pharmacy chain management. New pharmacy №8, 2010.
Literature, 2007. 256 p.
6. Federal Law of the Russian Federation "On the basics of protecting the health of citizens in the Russian Federation."
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As noted above, in the late 1950s and early 1960s, in pharmacy, against the backdrop of a scientific and technological revolution that engulfed all branches of knowledge and the national economy, events took place that marked the beginning of a qualitatively new stage in the development of the theory and practice of drug production. Among these events, the following had the greatest significance for the fate of pharmaceutical science:
1) establishing the facts of therapeutic non-equivalence of drugs and the discovery of the biological function of pharmaceutical factors;
2) development of the basics of biopharmacy, clinical pharmacokinetics and clinical pharmacy;
3) creation of a modern powerful research base of a special pharmaceutical profile;
4) equipping the pharmaceutical industry with the most advanced equipment with the actual determination of the production activity of the enterprise by the level of scientific developments;
5) discovery of new classes of medicinal substances with a strong pharmacological effect and new groups of excipients.
These and other objective situations did not arise suddenly by the end of the 1950s, but were gradually prepared by the entire course of the development of drug science and natural science.
The discovery of the phenomenon of therapeutic non-equivalence of drugs and its relationship with pharmaceutical factors was the most outstanding acquisition of pharmacy in the entire history of its existence and the prologue to the formation of biopharmacy.
Therapeutic non-equivalence of drugs is understood as cases when the same medicinal substance, prescribed in equal doses and identical dosage forms, but produced by different enterprises (or one enterprise, but in different series), has a different therapeutic effect.
A direct consequence of the phenomenon of therapeutic non-equivalence of drugs has been the general attention drawn to the ways of obtaining drugs, the processes of pharmaceutical technology and methods for assessing the quality of drugs. For the first time, pharmaceutical science, especially pharmaceutical technology, became the subject of general public attention and big science. This served as a powerful stimulus for the development of fundamental questions of pharmacy, a sharp increase in theoretical research in the field of mainly pharmaceutical technology, and the involvement of the largest scientists from various fields of natural science in the rapidly expanding specialized pharmaceutical laboratories. As a result, it was possible to significantly increase the effectiveness of many drugs through mainly scientifically based use of pharmaceutical technology processes, which also made it possible in some cases to reduce single and course doses of medicinal substances. These events also had moral consequences: the authority of the pharmacist, the pharmaceutical industry, and the pharmacist's belief in his need for medicine increased dramatically. The qualitative difference between scientific research in the field of drug production in the 60s and 70s is based on biopharmaceutical ideas - the discovery of new patterns, the establishment of new relationships in the "drug" system, a new interpretation of the main categories of drug science, which led to the realization of the need to study pharmaceutical factors as active drug ingredients.
In the former Soviet Union, scientific pharmaceutical research is carried out both in higher educational institutions of the corresponding profile, and in special research institutes of the USSR Ministry of Medical Industry, the USSR Ministry of Health, provided with highly qualified scientific personnel and appropriate equipment. In addition, a significant amount of experimental work is carried out by central factory laboratories (CPL) organized at chemical and pharmaceutical enterprises. The systematic implementation of relatively complete and constant provision of the needs of the country's population in medicines, carried out by many thousands of workers of enterprises of the Ministry of Medical Industry and the Ministry of Health, creates the prerequisites for the continuous expansion of research work in the most important areas of theory and practice of drug production and the steady increase in production capacity. The domestic industry fully met the needs of the country's population in the main groups of medicines, fully covering the needs of health care in chemotherapeutic agents.
The main efforts in the field of domestic pharmaceutical production were directed to the maximum equipping of enterprises engaged in the manufacture of medicines with the latest technological equipment, to the creation of fully mechanized automated lines. In this regard, it was planned to develop complex equipment for creating in-line production of tablets and dragees, ensuring automated production of ampouled drugs, ensuring automated production of drugs in the form of liquid, solid and soft dosage forms, in-line production of patches, as well as full mechanization of auxiliary operations, labor-intensive processes in the production of medicines.
All this made it possible to create more than 120 types of perfect domestic technological equipment, including 20 types for packaging in modern materials for dosage forms. These measures, provided for by the state plan for the development of Soviet pharmaceutical production, greatly contributed to an increase in the proportion of modern factory products and a gradual, natural change in the nature of the production function of the pharmacy. It should be noted that the pace of improvement and development of drug production in the former Soviet Union has no equal in the world.
In the 1970s, the chemical-pharmaceutical industry and research activities in the countries of the socialist community developed rapidly. Since 1965, the volume of pharmaceutical production in the European socialist countries has increased several times, due to a sharp increase in capital investments, the introduction of modern technology and the expansion of scientific research. For example, in the Hungarian Republic, spending on research in 1970 amounted to 1.5% of the cost of manufactured drugs, and in 1975 increased by 50%. Hungary currently ranks tenth in the world in terms of pharmaceutical output and second (after Switzerland) in pharmaceutical production per capita.
The production of drugs in the GDR grew just as rapidly - in 1977 it increased by more than 10% compared to 1976. Along with the modernization and reconstruction of a number of chemical and pharmaceutical enterprises in the GDR, new plants were built to produce various drugs: acetylsalicylic and ascorbic acids, barbiturates, phenacetin, as well as their dosage forms.
As well as in the USSR, in the countries of the socialist community, much attention was paid to scientific research and development in the field of drug production. For example, in Czechoslovakia, about 10% of all workers in the pharmaceutical industry were covered by scientific research. For research purposes, 10% of the amount of sold pharmaceutical products was annually spent.
The development of the pharmaceutical industry and pharmaceutical science in capitalist countries was wholly subordinated to the conjuncture of the capitalist market. Thus, the dynamic increase in pharmaceutical production in the most developed capitalist countries is due to the ever-growing demand for medicines and the increase in their cost. The constant pursuit of superprofits underlies the expansion of production capacity and research activities of capitalist pharmaceutical firms. Compared with the 60s of the XX century, the growth rate of the pharmaceutical industry in the main capitalist countries in the 70s of the XX century increased significantly, which led to an increase in the volume of pharmaceutical production over the period from 1965 to 1975 by more than 3 times; moreover, the most characteristic feature is the outstripping growth of appropriations for scientific research in comparison with the growth of production. Among the capitalist countries, the most significant appropriations for scientific research in the field of pharmacy are in the United States, increasing annually by an average of 10%, with a significant expenditure item being the purchase of scientific equipment.
The range of problems in pharmaceutical science that require theoretical and experimental substantiation is extremely wide. Among these problems, the study of the influence of pharmaceutical technology processes on the pharmacotherapeutic efficacy of drugs is the most relevant; development of new, more adequate methods for assessing the quality of medicines; study of the problem of age-related drugs; development of physiologically indifferent methods for stabilizing drugs and increasing their duration; development and research of new packaging and container materials; study of excipients as active components of drugs; development of new methods of sterilization and prediction of drug expiration dates; development of optimal dosage forms of new drugs; creation of models of absorption of medicinal substances in various ways of their introduction. The very list of only some of the problems requiring urgent resolution testifies to the scope and scope of modern pharmaceutical research. The particular relevance of these problems stems from the deep interest in solving them not only in production, but also in clinics. Such, in particular, is the problem of studying the influence of methods and processes for obtaining drugs on their pharmacotherapeutic activity. Now it is impossible to imagine how medicines can be offered to the clinic without a serious study of it. At the same time, it is difficult to overestimate the moral and economic benefits that society receives in the event of a scientifically successful solution to this problem for a particular drug.
The problem of age-related drugs has a deep scientific justification, the pharmaceutical aspect of which has been resolved in the theory of biopharmacy. Medicines for children and elderly patients (geriatric) are not similar to each other and to medicines for other groups of patients, which is explained by the physiological characteristics of their body.
The anatomical and physiological basis of the pharmacy of children's drugs is, as you know, the problems of taste, pain and aggregate state (we do not touch here on absorption and enzymatic features). The microbiological safety of children's medicines is also of particular importance. It should be emphasized that at present, pharmaceutical technology is able to solve these problems, based on an extensive biopharmaceutical experiment and perfect technology inherent in the industrial method of drug production.
In essence, children's medicines that meet modern requirements can only be prepared in the conditions of a perfect pharmaceutical enterprise based on strict biopharmaceutical research. At the same time, the problem of taste should be solved by using not random sweeteners, corrective substances, but scientifically based components, which, along with correcting the taste of drugs, would not change the absorption properties of the drug and its stability.
The problem of pain arising in connection with the prescription of a medicinal substance, with the exception of cases of an extreme condition, should be solved by the development and use of appropriate dosage forms (rectal, inhalation). Instead of solid dosage forms (tablets, dragees, powders), solutions, suspensions, emulsins, pastes, ointments (for oral use) should be used, manufactured by factories in the form of sterile dry suspensions - compositions that include the entire complex necessary to obtain a liquid dosage form directly at the bed child - in the form of a single-use package. This will simultaneously solve a very serious problem of microbiological safety of children's medicines.
In the pharmacy of geriatric drugs, which began its journey together with biopharmacy, the following age-related features of the body of elderly patients are primarily taken into account: perversion of the absorption of drugs (for all routes of administration), violation of the usual intestinal microflora, chronic deficiency of vitamins, essential amino acids and trace elements, lability of the psychosomatic status and the desirability of using the oral route of administration. This obliges the development of geriatric drugs to conduct very extensive research, in which, along with the predominance of pharmaceutical topics, other issues are also integrated. As a result, a geriatric drug appears as a particularly complex physicochemical system, the integrity and unity of which is ensured by pharmaceutical factors - dosage form, excipients, manufacturing methods, the scientifically based choice of which in this case plays a paramount role.
No less acute is the problem of developing physiologically indifferent methods for stabilizing drugs and increasing their duration of action. The fact is that the loss of activity of medicinal substances during mass production can have significant economic consequences for the enterprise. No less dangerous in this case is the possible formation of toxic decomposition products of drugs. The production and the clinic are equally interested in the development of effective methods for stabilizing drugs. However, not all methods of drug stabilization are suitable from a physiological and biopharmaceutical point of view. The most acceptable are physical (coating with shells, microencapsulation, ampouling in a stream of inert gases, etc.) and the least acceptable are chemical methods of stabilization, including the use of preservatives. The development of new safe stabilization methods is a very acute problem in pharmaceutical technology.
The creation of drugs with a duration (prolonged) type of action is an old dream of clinicians. To reduce the number of medications, to ensure the maintenance of a uniform concentration of the drug in the blood means to reduce the number of possible adverse reactions and make the very prescription of many drugs more humane. This is especially true in cases of replacement therapy with hormones, enzymes (insulin, steroids, etc.). There are many methods of lengthening the action of drugs, each of which has positive and negative sides. The choice of the most rational of them in relation to a particular medicinal substance and method of administration, as well as the development of new ones, is currently being occupied by large teams of scientists in different countries of the world.
Despite the seeming simplicity and routine, the problem of developing and researching new materials for packaging and containers is one of the most complex, in the solution of which specialists of various profiles and a special packaging industry participate. The complexity of the problem is exacerbated, on the one hand, by the strict requirement for packaging and container materials in terms of tightness, stability, indifference and strength, and on the other hand, by the huge variety of physical and chemical properties of medicinal substances, strict technological regulations, which determine the continuous automatic introduction of materials into the production line packaging and a wide variety of properties of the packaging and container materials themselves. Evidence-based use of packaging materials and special forms of packaging usually improves the quality of medicines, not to mention the aesthetic side of things. The development and research of new materials for packaging and containers, as well as the creation of types of packaging in modern drug production is of great importance.
The widespread demand for the need for rationing and even the complete exclusion from drugs of microorganisms that can cause spoilage of medicinal and excipients forces us to look for new effective methods of sterilization. Such a method of drug production is considered ideal, in which the possibility of microbial contamination is completely excluded: closed automatic lines with back pressure of sterile inert gas from the inside and sterilization of places and objects that are dangerous in terms of microbial invasion.
Prediction of drug expiration dates is of particular interest for the theory and practice of pharmacology. It is known that the physical shelf life of a drug under normal conditions is determined by a systematic analysis of one or another of its dosage forms during the entire storage period. As a rule, this takes a lot of time and does not suit the modern pharmaceutical industry, which focuses on a rapid change in technological regimes. The development of a model of "accelerated storage methods" of drugs using the laws of chemical kinetics and mathematical methods of calculation has become widespread. Methods for accelerated drug storage are being developed by a large number of pharmaceutical laboratories.
The problem of creating optimal dosage forms of new drugs in modern conditions has a fundamentally different meaning, which differs from the previous formulation. This is a fully biopharmaceutical problem. We are talking not only about a dosage form convenient for storage, transportation and administration, which was implied in the pre-biopharmaceutical period, but also about a dosage form that provides maximum biological (physiological) availability of the drug. This problem is fundamental, one of the central problems of the modern theory of pharmacy. Its solution is a solution to the problem of therapeutic non-equivalence of drugs. In practice, the creation of an optimal dosage form means a scientific solution to the problem of pharmaceutical factors. That is why large research groups are working on its solution and it subordinates a number of pharmaceutical problems, including one of the most modern ones - the creation of models for the absorption of medicinal substances with various routes of their administration.
Along with the biopharmaceutical concept, such branches of drug science as pharmacokinetics , clinical pharmacy and clinical pharmacokinetics .
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3 1. Technology of drugs Current state and prospects for the development of pharmaceutical technology. Pharmaceutical technology as a science and its tasks at the present stage. The main stages in the development of drug technology and biomedical technology. The role of scientists (domestic and foreign) in the development of pharmaceutical and biomedical technologies. Comparative characteristics of extemporaneous manufacturing, small-scale and industrial production of drugs. Prospects for the development of each of these areas. State regulation of production and quality control of drugs. Legislative basis for the manufacture of medicines. International and state (national) requirements and standards. Pharmaceutical and biomedical technologies at the present stage. The main directions of their development. Organization of the manufacture of medicines in accordance with modern GMP requirements. Importance of microbiological purity. Sources of microbiological contamination. Norms of microbial contamination of non-sterile preparations. Dosage forms and preparations requiring aseptic manufacturing conditions. Improving methods of sterilization and sterility control. Modern methods of sterilization. Filtration sterilization, radiation sterilization, chemical sterilization, prospects for their development and application. Safety precautions when using various sterilization methods. Sterility control. Modern advances in the technology of manufacturing traditional dosage forms and drugs (powders, tablets, solutions, suspensions, emulsions, extractive preparations, drugs from animal and microbiological raw materials, ointments, suppositories, pills, dragees, dosage forms for injections (infusions), ophthalmic drugs forms, aerosols, dosage forms for inhalation, etc.). Prospects for their improvement. Features of the manufacture of powders for the preparation of injection solutions and dosage forms intended for wounds, burn surfaces, for newborns and children under the age of 1 year, in cavities that do not contain microorganisms, etc. Modern drug delivery systems and carriers of biologically active substances. Microcarriers, nanocarriers, therapeutic systems. 3
4 Basic methodological approaches to the creation and design of therapeutic systems (intraocular, transdermal, implantation, etc.) Compliance with environmental standards, safety and labor protection when conducting scientific research and organizing the process of manufacturing drugs. Biopharmacy is a modern methodology and the basis for the creation of modern drugs, including those with controlled pharmacokinetics. The history of the emergence and development of biopharmacy. Concepts: biopharmacy, pharmacokinetics, pharmacodynamics, bioequivalence, therapeutic non-equivalence, bioavailability (absolute, relative). Mathematical modeling of pharmacokinetics. Pharmaceutical factors and their influence on bioavailability. The dependence of bioavailability on the physicochemical properties and state of medicinal and excipients, technological factors of the preparation conditions, the type of dosage form and the route of administration. The concept of the mechanisms of release and mechanisms of absorption of medicinal substances from various dosage forms. Methods, tests and apparatus for studying the release of medicinal substances; their use to optimize the composition and technology of preparations. Mathematical methods for establishing the correlation dependence of pharmacokinetic parameters and biopharmaceutical characteristics. Excipients used in the creation of drugs. Modern aspects of the use of excipients, their role, purpose, requirements for them. Nomenclature of modern excipients (BB). Influence on bioavailability and stability of dosage forms. Classification of explosives by nature, chemical structure, functional role in the dosage form. Macromolecular compounds (HMC) as excipients. Surfactants (surfactants) used in pharmacy. Surfactant classification, stabilization mechanism. Shapers and dispersion media. Water and other solvents used in pharmaceutical technology. Pharmacopoeial and technological classifications of water. Water types according to international standards. Cleaning methods. Cleaning systems. Water quality control. Non-aqueous solvents and co-solvents. 4
5 propellants. Application and nomenclature. Solubilizers. Application. Physico-chemical foundations of the solubilization process. Stabilizers: inhibitors of chemical processes; stabilizers of thermodynamically unstable microheterogeneous systems; antimicrobial stabilizers (preservatives). pH regulators, buffer systems. Use of the Navy. Surfactant for stabilization of microheterogeneous disperse systems. Preservatives, requirements for them. Spectrum of antimicrobial action, physicochemical and chemical compatibility with the components of the drug, compliance with their requirement of biological safety. Application in various dosage forms. Permissible levels of content in medicinal preparations. Release and absorption rate regulators. Prolongators. Principles of prolonging the action of medicinal substances in dosage forms. suction activators. Influence on pharmacokinetics and bioavailability in various dosage forms. Corrigents of taste, color, smell. Isotonic explosives. Osmolarity and osmolality of infusion and ophthalmic solutions. Theoretical basis for calculating the active concentration of solutions. Physico-chemical processes and stabilization of drugs (physico-chemical, structural-mechanical, antimicrobial). Modern theories of creating stable drugs. stabilization mechanisms. Stabilizers. solubilization theory. Surfactants used as solubilizers. Hydrophilic-lipophilic balance. Critical micelle concentration. Practical application of solubilizers in the technology of dosage forms. Conditions determining aggregative and sedimentary stability. stabilization problems. The mechanism of stabilizing action depending on the nature of the dispersed system and the nature of the stabilizer. Features of the manufacture of suspensions and emulsions intended for injection. Types of destruction of drugs (chemical, physicochemical, microbiological, etc.). Accounting for the nature of hydrolytic, redox, thermodynamic, enzymatic and other processes in the development of stable drugs in various dosage forms. 5
6 The main types of physico-chemical and chemical incompatibility. The manifestation of pharmaceutical incompatibility in various dosage forms. Problems of compatibility of solutions in one syringe. The main ways to solve the problem of incompatibility. Ways to prevent interaction processes. Technological processes underlying pharmaceutical technology and their instrumentation. Modern aspects of the implementation of the main processes and devices of pharmaceutical technology. Mechanical (grinding, classification, mixing), thermal (heating, evaporation, etc.), mass transfer (extraction, adsorption, crystallization, distillation, etc.) and hydromechanical (dissolution, separation of heterogeneous systems) processes, their influence on the quality indicators of the final product . Grinding of solid materials, raw materials with a cellular structure, grinding in liquid and viscous media. Influence of the grinding process on the technology of drugs and their quality. Methods for obtaining microheterogeneous mixtures. Dispersion in liquid media. Dissolution. Factors that increase the solubility and speed of the dissolution process (heating, mixing, preliminary dispersion, complexation, solubilization, etc.). Filtration. Modern methods of control of the absence of mechanical inclusions. Problems of filtering solutions for injections, ophthalmic solutions, solutions of oxidizing agents, IUDs, solutions in viscous and volatile solvents. mass transfer processes. Extraction. Capillary phenomena, swelling, dissolution, desorption, osmosis, dialysis, ultrafiltration, molecular diffusion and convection processes. Stages of the extraction process. Factors affecting the speed, completeness of extraction and quality of extraction from medicinal plant and animal raw materials. Technological regimes for the manufacture of various extraction phyto- and organo-preparations, depending on the physico-chemical properties of the active, concomitant, ballast substances and extractant. Isolation and purification of biologically active substances. Methods and equipment for cleaning extracts, separating the amount of substances, isolating individual substances. Adsorption and ion exchange, crystallization. Extraction in the liquid-liquid system Modern aspects of use in pharmaceutical technology. Mass transfer through semi-permeable membranes. Characteristics of membrane processes. Main membrane methods: reverse osmosis, ultrafiltration, membrane evaporation, dialysis, electrodialysis. 6
7 Drying. Modern types of drying. Factors affecting the drying kinetics. Approaches to the choice of drying method and equipment. Influence of the drying method on the characteristics of the dried product. General principles for the selection and evaluation of the quality and operation of technological equipment used for the implementation of technological processes (filtering plants, grinding apparatuses and machines, sieving plants, etc.). Mechanization of technological processes in pharmacies and small-scale production (instruments, devices, etc.). Instruments and apparatus for pharmacies and small-scale production, their specificity. Instruments and apparatus used for dosing by weight, volume, drops; dispersion of powdered substances; melting bases for ointments and suppositories; sterilization of air, medicinal and excipients, utensils, auxiliary materials, finished products. Apparatus for sterilization by filtration. Mechanization of the dissolution process. Agitators of various types, mixers. Filtration installations. Suspension and emulsion mixers, tissue grinders. Infundirno-sterilization devices. Apparatus for filling, packaging, capping. Apparatus for obtaining purified water and for injections. Production modules in the technology of manufacturing injection and infusion solutions. Quality control of raw materials, semi-finished products, dosage forms and drugs, etc. Quality control of drugs at all stages of their development, production and storage. State regulation. Regulations. Indicators, tests, methods and instruments used in drug development. Requirements for the quality of medicines, excipients, dispersion media, extractants, taking into account the specific features of dosage forms and routes of drug administration. Quality control of intermediates and control points at the stages of obtaining a medicinal product. State control of the quality of dosage forms and preparations. Modern types of packaging materials and types of packaging. Regulation of requirements for packaging materials, their quality indicators. Influence of packaging on stability during storage, transportation and use of the medicinal product. Justification of the choice of rational packaging. Conditions for storage and transportation of various dosage forms. Modern approaches to the organization of the technological process (international and regional GMP rules, industry standards, etc.). 7
8 Organization of the technological process and ensuring the sanitary regime, aseptic conditions for the manufacture of the drug in accordance with international and domestic requirements and standards (orders, OSTs, GMP, etc.). Air purification methods. Prince and validation parameters. Technological modules. Automated flow technological lines, installations for the production of various types of finished medicines. Automation, computerization of technological processes. Licensing and validation of production. General principles for the development, testing and registration of drugs in various dosage forms, methodology for optimizing existing drugs. Screening of promising biologically active compounds obtained from various sources in order to use them as medicines. Organization of development, research and production of medicines in accordance with the international system of requirements, as well as national requirements and standards: GLP, GCP, GMP, GPP, and the basic principles of these standards. Creation of rational dosage forms from new drugs and optimization of technology and formulations of existing drugs based on modern technologies, biopharmaceutical research and control methods in accordance with the international system of requirements. Conducting research in the field of biopharmaceutical evaluation of drugs, using modern tests and devices for comprehensive control of drug substances, excipients, intermediates and drugs, as well as mathematical methods for establishing the correlation dependence of pharmacokinetic parameters and biopharmaceutical characteristics. General principles for the development of regulatory documentation governing the conditions, manufacturing technology and quality control of medicinal products (FSP, industrial and other types of regulations, guidelines, etc.). Mathematical planning of experiment. Forecasting the shelf life of drugs. Medicines and dosage forms for newborns and children under 1 year old. Children's dosage forms. Requirements for this group of dosage forms and preparations. Their justification, taking into account the anatomical and physiological characteristics of the child's body. Auxiliary selection principle 8
9 substances. Characteristics of dosage forms, the most promising for pediatrics. Solving the packaging problem. Directions for improving and creating dosage forms for children. Dosage forms used in homeopathy. The history of the development of homeopathy. Basic principles of homeopathy. General principles of prescription. Regulations. Recipe. Dosage forms used in homeopathy. General principles for the manufacture of homeopathic preparations. Substances. Essences. Tinctures. Excipients. Homeopathic dose (dilution, amount per dose, number of doses, regimens of homeopathic preparations. Making triturations. Making solutions (dilutions). Making granules (grains). Making ointments, suppositories in a homeopathic pharmacy. Combined homeopathic medicines. Quality control of homeopathic remedies and preparations Possibility of in-pharmaceutical procurement Theoretical foundations of homeopathy The current state of homeopathy in Russia and abroad The technology of medical and cosmetic preparations The history of the development of cosmetics Taking into account the structure and physiological characteristics of the skin and mucous membranes in normal and pathological conditions in the creation and manufacture of medical cosmetics preparations Excipients and their role in ensuring the optimal therapeutic and cosmetic effect Production of cosmetic preparations: powders (powders), lotions, emulsions, creams, ointments, etc. Solving the problem of microbial contamination Prospects for the development of medical cosmetics and. Dosage forms used in veterinary medicine. Features of dosage forms and preparations for animals. requirements for them. Dosage forms specific for animals: boluses, granules, porridges, pastes, etc. Features of the technology for manufacturing veterinary dosage forms. Quality control. Technology for the manufacture of dosage forms in extreme conditions. Reasons for the formation of high-risk zones and emergencies. Optimization of the production activities of pharmacies in extreme conditions. Solving the problem of obtaining purified water for injections. The specifics of the manufacture of dosage forms (injection, infusion, etc.). nine
10 Drug technology and environmental problems. Environmental protection. Wastewater treatment and atmospheric emissions. Technological hygiene. Microecology of man. Environmental protection in the production of antimicrobial and anticancer drugs. Biomedical technologies and environmental problems. Nanotechnologies. Nanopharmacy, nanocarriers. The use of nanotechnology in pharmacy: directions and prospects. Innovative dosage forms: prolonged and instant models. Literature 1. State Pharmacopoeia XI edition, vol.1,2. M.: Medicine, 1987. X editions, M.: Medicine, 1968. 2. Pharmacopoeias: USA, Great Britain, Germany, European Pharmacopoeia, International Pharmacopoeia. 3. Rules for the organization of production and quality control of medicines (GMP) OST Technology of dosage forms in 2 volumes: v. 1, ed. T.S. Kondratieva, vol. 2, ed. L.A. Ivanova. M.: Medicine, 1991. 5. Biotechnology: Textbook for universities in 8 books, ed. N.S. Egorova, V.D. Samuilova, M.: Higher school, 1987. 6. Dytnersky Yu.I. Processes and apparatuses of chemical technology. 2 vol. M.: Chemistry, 1995. 7. Krasnyuk I.I. and others. Determination of the ionic composition and osmolality on the example of solutions "Acesol", "Chlosol". Collection of NIIF "Modern problems of pharmaceutical science and practice". M., 1999, v. 38, part 1. 8. Krasnyuk I.I., Mikhailova G.V., Zelikson Yu.I. etc. Homeopathic medicinal forms of pharmaceutical production. Moscow GOU VUNMTs Ministry of Health of the Russian Federation, 2001, 80 p. 9. Sarukhanov A.V., Bykov V.A. Equipment for microbiological production: a Handbook, M.: Kolos, 1993. 10. Chubarev V.N. pharmaceutical information. Ed. Academician of the Russian Academy of Medical Sciences, Dr. farm. sciences, prof. A.P. Arzamastsev. M., 2000. 11. Shilova S.V., Puzakova S.M. etc. Organization of the production of medicines in accordance with the rules of GMP. Chemical and pharmaceutical production. Overview information. M.: VNIISENTI, 1990. 12. Biomedical technologies. Sat. works of NPO VILAR. M.: Interkhim, 1995, 1996 13. Polymers in pharmacy (under the editorship of A.I. Tentsova, M.T. Alyushin), M.: Medicine, 1985. 14. Chizhova E.T., Mikhailova G .AT. Medical and cosmetic powders, M .: VUNMTs, 1998 10
11 15. Chizhova E.T., G.V. Mikhailov. Medical and medical-cosmetic ointments. M.: VUNMTs, 1999. 16. Guide to laboratory studies on pharmacy technology of dosage forms (edited by T.S. Kondratieva). M.: Medicine, 1986. 17. Guide to laboratory studies on the factory technology of dosage forms (under the editorship of Corresponding Member of the Academy of Medical Sciences A.I. Tentsova), M.: Medicine, 1986. 18. State Register of Medicines. 19. Formulary directory of medicines. /IS HE. Davydova, VL. Dorofeev, T.A. Zatsepilova, V.N. Chubarev. Ed. member - corr. RAMS A.P. Arzamastsev. M.: Russian doctor, 1998. 20. Kharkevich D.A. Pharmacology. M., 1996. 21. Code of Ethics for a pharmaceutical worker in Russia (pharmacist and pharmacist). Pharmacy. 1997, t Orders, instructions, guidelines approved by the Ministry of Health of the Russian Federation. 23. Journals: Pharmacy, Pharmaceutical Chemistry, Pharmateka, MRM, RJH, etc.; foreign magazines. Additional literature 1. Mashkovsky M.D. Medicines. M.: 2000, ed.14, v. 1.2. 2. Tentsova A.I., Azhgikhin I.S. Dosage form and therapeutic efficacy of drugs. M.: Medicine, 1974. 3. Chirkov A.I. Pharmacy of a medical institution. M.: Medicine, 1991. 4. Tentsova A.I., Gretsky V.M. Modern aspects of research and production of ointments. M.: Medicine, 1985. 5. Shvabe V. Homeopathic medicines. Guidelines for the manufacture of homeopathic medicines. M., 1950. 6. Hahnemann S. Organon of medical art. M., 1991. 7. Villamo H. Cosmetic chemistry (translated from Finnish). M.: Mir, 1990. 8. Plakhova A.A., Plakhov Yu.M. Phytotherapy, phytocosmetics, phytoprotection. M., 1992. 9. Pashina G.V. Plants and cosmetics. Minsk, 1993. 10. Bertram G. Katzung. Basic and clinical pharmacology: in 2 volumes / Per. from English. M.-SPb.: Binomevsky dialect, 1998. 11. Drug Actions: basis principles and therapeutic aspects. / E. Mutschler, H. Derendorf In collaboration with Monika Schafer-Korting - Stuttgart: Medfarm; Boca Raton; Ann Arbor; Boston: CRC Press, Drug Information for the Health Care Professional, USP DI. 17th ed., European Drug Index. - 4th ed. / Edited by Niels F. Muller, RudolfP. Dessing. - Alkmaar: Amsterdam Medical Press, Joel G. Hardman, Alfred Goodman Gilman, Lee E. Limbird. The Pharmacological Basis Therepeutics. - 9th ed.,
12 15. Pharmacy ethics./ Mickey Smith, Steven Strauss, H. John Baldwin, Kelly T. Alberts./ - Binghampton, NY: Pharmaceutical Products Press, Philip D. Hansten, John. Drug Interactions, Analysis and Management. - Applied Therapeutics, Inc., The American Hospital Formulary Service: Drug Information. /Editors, Gerald K. Mc Evoy et al., The Merck Manual of Diagnosis and Therapy. 16th ed. / Editors, Robert Berkow et al. - Rahway, NJ: Merck Research Laboratories,
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2 Current state and prospects for the development of pharmaceutical technology. Pharmaceutical technology as a science and its tasks at the present stage. Milestones in Drug Technology Development and Fundamentals
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1 Compiler/s (I.O.F., academic degree, academic title, position): N.G. Selezenev, Ph.D., Associate Professor, Head. Department of Pharmaceutical Technology A.N. Nikolashkin, Ph.D., Associate Professor, Department of Pharmaceutical Technology
Belarusian state university
CLASSIFICATION AND ORGANIZATION OF PREMISES FOR THE MANUFACTURING OF NON-STERILE DRUGS METHODOLOGICAL INSTRUCTIONS MU 64-02-005-2002 FOREWORD Introduction date-2003-04-15
A Page 1 of 20 1. Goals and objectives of the practice The goal is to familiarize students with the work of pharmaceutical enterprises, the scientific organization of labor, the work of central factory laboratories, technical departments
The problem of compatibility of excipients and substances in dosage forms for injection Skachilova S.Ya., Tereshkina O.I., Rudakova I.P., Shilova E.V., Samylina I.A.
State Budgetary Educational Institution of Higher Professional Education "Stavropol State Medical University" of the Ministry of Health of the Russian Federation Department
Ministry of Health of Ukraine
Lugansk State Medical University
Department of Technology and Organization of Pharmacy Economics.
Head of department Gudzenko A.P..
Course work
with pharmaceutical drug technology
on the topic: "Improvement of drugs and new pharmaceutical technologies"
Is done by a student : 3 courses, 58 gr., Faculty of Pharmacy, Yurchilo V.A.
Supervisor: Kucherenko N.V.
2007
PLAN
Introduction
1.1. Ways to search and develop new tools.
2. Ways to improve traditional medicines.
2.1.Biotechnology of traditional medicines and medicines of the future.
2.2. State and prospects for the development of the production of therapeutic systems.
5. The main directions of improvement of suppository drugs.
6. New solid dosage forms of prolonged action.
Conclusion
Bibliography
Introduction
Prospects for the development of pharmaceutical technology are closely related to the impact of scientific and technological progress. On the basis of the latest scientific discoveries, fundamentally new, more advanced and productive technological processes are being created that dramatically increase labor productivity and improve the quality of finished products.
Technology has a significant impact on the future economic performance of production, requires the development of low-operation, resource-saving and waste-free processes, their maximum mechanization, automation and computerization.
To predict and optimize technological processes, mathematical planning of an experiment is successfully used, which has become firmly established in technological science and practice. This method makes it possible to obtain mathematical models that relate the optimization parameter to the factors influencing it, and makes it possible to identify their optimal technological modes without a long process.
Thus, technologies have received new modern methods for determining the optimal end results at the lowest cost, which is a clear example of how science turns into a direct productive force.
As a result of the increased role and possibilities of technology, the time from the emergence of an idea, the first results of scientific research to their implementation in industrial production is unusually shortened.
Prospects for the development of pharmaceutical technology are determined by the requirements of modern pharmacotherapy, which involve the creation of the most effective drugs from a therapeutic point of view, while containing a minimum of medicinal substances that do not have side effects. The solution to this problem is based on the provisions and principles of biopharmacy, based on the optimal selection of the composition and type of dosage form and the use of optimal technological processes. This explains the widespread and deepening of biopharmaceutical research in many countries.
However, the study of biopharmaceutical aspects of obtaining and prescribing drugs, the study of the "fate" of drugs in the body is only the first stage in solving the problem formulated above. Further efforts should be directed to the implementation of the obtained information in the process of production and use of drugs in order to eliminate such shortcomings as a short duration of action; uneven flow of drugs into the pathological focus; lack of electoral action; lack of stability, etc.
Only those drugs can be considered rational, which provide optimal bioavailability of active substances. Therefore, modern drugs can also include traditional ones, for example, tablets, ointments, suppositories, etc., if they provide rational pharmacotherapy.
The priority tasks of pharmaceutical technology include increasing the solubility of sparingly soluble drugs in water and lipids; increasing the stability of homogeneous and heterogeneous drug systems; prolongation of the time of action of drugs; creation of targeted drugs with desired pharmacological properties.
Improving the controllability and direction of action of biologically active substances is the main direction in the development of pharmaceutical technology. The developed drug systems with controlled release of active substances make it possible to quickly achieve a therapeutic effect, to maintain a constant level of their therapeutic concentration in blood plasma for a long time. As practice has shown, the use of such medicinal systems makes it possible to reduce the course dose, eliminate the irritating effect and overdose of medicinal substances, and reduce the incidence of side effects.
Of particular note are the so-called therapeutic systems for oral and transdermal use (see Chapter 9), the range of which is expanding every year in many countries.
The most promising in the field of modern pharmacotherapy are therapeutic systems with targeted delivery of drugs to organs, tissues or cells. Targeted delivery can significantly reduce the toxicity of medicinal substances and use them economically. About 90% of drugs currently used do not reach the goal, which indicates the relevance of this area in pharmaceutical technology.
Therapeutic systems with targeted delivery of drugs are usually divided into three groups:
· carriers of drugs of the first generation (microcapsules, microspheres) are intended for intravascular administration near a specific organ or tissue;
· second-generation drug carriers (nanocapsules, liposomes) less than 1 µm in size are combined into one group called colloidal carriers. They are distributed mainly in the spleen and liver - tissues rich in cells -
· Komi reticuloendothelial system. Methods have been developed for obtaining nanocapsules with phenobarbital, diazepam, prednisolone, insulin, prostaglandins; nanospheres with cytostatics, corticosteroids; liposomes are being studied for the delivery of enzymes, chelating and chemotherapeutic, anti-inflammatory, antiviral and protein (insulin) substances;
· carriers of third-generation drugs (antibodies, glycoproteins) open up new possibilities for providing a high level of selective action and targeted delivery.
For transport and local delivery of medicinal substances to the target organ, magnetically controlled systems can be used. By creating a drug depot in the organ, they can prolong its action.
1. Creation, preclinical study and preclinical testing of drugs.
The main source of obtaining drugs from plant, animal and mineral raw materials, which has existed since ancient times, in the middle of the 19th century was replaced by medicinal substances obtained by chemical synthesis, which exists to this day. At the beginning of the 20th century, a method for obtaining substances in the form of antitoxic, antimicrobial sera and preventive vaccines became widespread. In the 1940s, the technology of antibiotics and sulfonamides was developed. The 1970s were marked by the development of biotechnology, which, rapidly developing, has now moved to the forefront of scientific and technological progress.
Over the past 20 years, the possibilities and effectiveness of drug therapy have significantly expanded, which is due to the creation and introduction into medical practice of a large number of new drugs, primarily such highly effective ones as new generation antibiotics and sulfonamides, as well as psychotropic, hypotensive, antidiabetic, etc. The range of medicines used in medical practice has been updated by 60-80% and includes over 40 thousand items of individual and combined formulations. This was facilitated primarily by the fundamental successes of chemical, pharmaceutical, biomedical and other related sciences, which ensured the further development of the pharmaceutical industry.
1.1. Ways to search for and develop new drugs (drugs)
The creation of new medicinal substances and preparations is a very laborious and expensive process, which involves representatives of many professions: chemists, pharmacists, pharmacologists, toxicologists, clinicians, biologists, etc. These joint efforts of specialists do not always end successfully. So, out of 7 thousand synthesized compounds, only one becomes a drug.
To search for new synthetic medicinal substances or substances from medicinal plant raw materials, stable theories have not yet been developed.
The generally accepted canon of a targeted search for synthesized drugs is the establishment of relationships between pharmacological action and structure, taking into account their physicochemical properties. Currently, the search for new drugs (according to A.N. Kudrin) is carried out in the following areas.
Empirical study of biologically active substances is based on the idea that many substances have a certain pharmacological activity. This study is based on the "trial and error" method, with the help of which the pharmacologist determines whether the obtained substances belong to one or another pharmacotherapeutic group. Then, among them, the most active substances are selected and the degree of their specific activity and toxicity is established in comparison with existing drugs - analogues in action. This way of selecting pharmacologically active substances is called screening. This is a very expensive and time-consuming method, since one has to deal with a large number of different biologically active substances.
Modification of the structures of existing drugs is a very common direction. Chemists replace one radical in an existing compound with another, for example, methyl ethyl, propyl and other alkyl radicals with a higher molecular weight, or, conversely, introduce new chemical elements into the original molecule, in particular halogens, nitro groups, or make other modifications of the basic structure. This way allows you to change the structure of the substance molecule, which leads to a change in its activity, a decrease in negative properties and toxicity, and gives a completely new direction to the therapeutic effect.
With the development of science, it became quite obvious that the optimal search for new drugs should be based on the identification of biologically active substances involved in vital processes, on the disclosure of pathophysiological and pathochemical processes underlying the pathogenesis of various diseases, as well as on an in-depth study of the mechanisms of the pharmacological effect. Approaches to screening studies should not be based on the method of random observations, but on the directed synthesis of substances with improved properties and expected activity.
Targeted synthesis of medicinal substances means the search for substances with predetermined pharmacological properties. The synthesis of new structures with the expected activity is most often carried out in the class of chemical compounds where substances have already been found that have a certain direction of action in the aspect necessary for the researcher. Purposeful synthesis of substances is more difficult to carry out in new chemical classes of compounds due to the lack of the necessary initial information about the relationship between pharmacological activity and the structure of the substance. Further, various radicals are introduced into the selected basic substance. It is very important to obtain a substance that is soluble in water and fats so that it can be absorbed into the blood, pass from it through the hemato-tissue barriers into the organs and then enter into contact with cell membranes or penetrate through them into the cell and combine with biomolecules. the most common radicals in medicinal substances and their affinity for water and lipids are presented. With the help of these and similar radicals, it is possible to increase the therapeutic activity of lipotropic substances. For example, the introduction of fluorine into the molecule of psychotropic drugs of the phenothiazine series and into the molecule of glucocorticoid hormones significantly increases their activity. The search for new biologically active substances gives satisfactory results in the synthesis of antagonists of those substances that are involved in the life of the body (mediators, vitamins, hormones) or are indispensable participants in biochemical processes (enzyme substrates, coenzymes, etc.).
In the synthesis of new medicinal substances, their pharmacological activity is determined not only by the size and shape of the molecule, but also to a large extent by steric factors that affect the position of the molecules in space. For example, trans-amine (tranylcypromine) has an antidepressant effect.
with a stimulating effect. Its geometric isomer, cis-amine, retains its antidepressant effect, but at the same time, its stimulating effect disappears and an opposite tranquilizing component of action appears, which is very valuable in practical terms.
Isomers can change not only pharmacological activity, but also toxicity. The toxicity of cis-amine in terms of LDso (in mice) is 6 times less than that of trans-amine, therefore, in the targeted synthesis of a new drug substance, it becomes necessary to study its isomers.
Randomized screening makes it possible to obtain fundamentally new synthetic or natural substances based on a screening study on animals using a set of tests to study the efficacy and safety of new compounds. Recently, with the help of this complex screening study, a psychotropic antidepressant drug - pyrazidol, an antiviral drug - arbidol, etc. have been introduced into medical practice.
Of great importance in medical practice are medicinal substances derived from plant materials, which have a number of advantages over synthetic substances (softer, often prolonged action); they usually do not cause allergic complications.
It should be noted that the search for original drug substances is not always economically viable, especially for underdeveloped countries, since it requires high costs to bring them to production, and the high cost of drugs made on the basis of these substances makes them inaccessible to the consumer. Therefore, many pharmaceutical companies use imported substances to create drugs, which are well-behaved.
proven in medical practice and whose patent protection time has expired. These drugs are called generics (ge-nerics). An example of such an approach can be the production of septrim (English company "Welcome") and biseptol (Polish company "Polfa") based on sulfamethoxazole (0.4 g) and trimethoprim (0.08 g). This way of creating drugs allows you to quickly saturate the market with them, significantly reduce the economic costs of their creation, improving the quality due to a more optimal selection of excipients and technological methods.
It should be noted that the cost of generic drugs sometimes amounts to 20-60% of the cost of similar imported drugs.
Identification of new properties in drugs already used in the clinic by carefully monitoring their effects on various body systems. Thus, the hypotensive property of p-blockers, the anti-thrombotic activity of acetylsalicylic acid was established.
Compilation of compositions of combined preparations is one of the ways to search for new drugs. The principles on the basis of which these drugs are created may be different.
Most often, combined preparations include medicinal substances that have an adequate effect on the cause of the disease and the main links in the pathogenesis of the disease. The combination drug usually includes medicinal substances in small or medium doses, when there are synergistic phenomena between them - mutual enhancement of the action in the form of potentiation or summation. Combination drugs are interesting in that the principles of synergy, on the basis of which they are created, make it possible to achieve a therapeutic effect in the absence or minimum of negative effects. In addition, the introduction of small doses of medicinal substances does not violate the natural protective or compensatory mechanisms that develop in the body in response to the disease. It is desirable to add medicinal substances that stimulate the body's defenses to the means that suppress individual links of the pathology.
Combined drugs that regulate the activity of the central nervous system must include substances that, respectively, affect the activity of the executive organs - the heart, blood vessels, kidneys, etc.
Combined antimicrobial preparations are composed of such ingredients, each of which damages different systems of reproduction and life support of microbes.
Combination preparations very often include additional ingredients that enhance (extend) the effectiveness of the main substance or eliminate its negative effect. So, the combined preparation "Solpadein R", containing paracetamol and codeine, provides a more pronounced analgesic effect compared to the substances used, taken separately, since pain impulses "overlap" all the way from the periphery to the center and vice versa (codeine has a central effect, and paracetamol along with this - peripheral). In addition, this combination of two substances allows you to reduce their dose, while maintaining the duration and effectiveness of the action.
For the prevention and treatment of many diseases, as well as to increase the body's resistance to infections and in many other cases, multivitamin preparations are used, often containing trace elements. Their compositions are formed taking into account the purpose: general purpose multivitamins ("Alvitil", "Vit-room", "Duovit", "Megavit", "Multi-tabs", "Oligovit", "Supra-din", "Unicap Yu" and others); for the prevention of diseases of the nervous and cardiovascular systems ("Biovital", "Multivitamins Plus", "Jelly Royal"); for the prevention of caries ("Wee-Daylin F", "Wee-Daylin F-ADS with iron", "Vitaftor"); for the prevention of cancer ("Children's antioxidant", "Suprantioksidant", "Triovit"); for use during pregnancy (Gravinova, Materna, Polivit nova Vita, Pregnavit). They have different dosage forms (tablets, effervescent tablets, dragees, syrups, drops, capsules, solutions, etc.), different dosing regimens and conditions of use.
A wide range of combined vitamin formulations allows for individual selection of drugs for each specific case.
1.2.Experimental study and clinical trials of drugs.
Implementation of the strict requirement of modern pharmacotherapy - the minimum dose of the drug to ensure the optimal therapeutic effect without side effects - is possible only with a thorough study of new drugs at the preclinical and clinical stages.
Preclinical (experimental) study of biologically active substances is conventionally divided into pharmacological and toxicological. These studies are interdependent and are based on the same scientific principles. The results of an acute toxicity study of a potential pharmacological substance provide information for subsequent pharmacological studies, which in turn determine the extent and duration of the study of chronic toxicity of the substance.
The purpose of pharmacological research is to determine the therapeutic efficacy of the investigated product - the future medicinal substance, its effect on the main body systems, as well as to establish possible side effects associated with pharmacological activity.
It is very important to establish the mechanism of action of a pharmacological agent, and if available, non-main types of action, as well as possible interactions with other drugs.
Pharmacological studies are carried out on models of relevant diseases or pathological conditions using single, constantly increasing doses of substances in order to find the desired effect. Data from initial pharmacological studies can already give some insight into the toxicity of a substance, which should be deepened and expanded in special studies.
In toxicological studies of a pharmacological agent, the nature and severity of a possible damaging effect on the body of experimental animals is established. There are four stages of research.
1. The study of the main type of pharmacological activity in several experimental models in animals, as well as the establishment of the pharmacodynamics of the drug.
2. The study of acute toxicity of the agent with a single dose
change (introduction) is carried out in order to determine the presence of side effects
reactions with a single dose of an increased dose and
leniye of the reasons of a lethality; breadth of therapeutic action or
therapeutic index Ehrlich (the ratio of the maximum transfer
this dose to the maximum therapeutic one), which is impossible
set in a clinical setting. When studying acute toxic
data determine the DLso index for various animal species
and calculate the coefficient of species sensitivity relative to
DL50max/DE50min. If this factor is 1 or
is close to it, then this indicates the absence of species sensitivity
vitality. If the ratio is significantly different from
units, this indicates a different severity of toxic
the action of a pharmacological agent on different types of mammal
which must be taken into account when recalculating the experimental
effective dose for humans.
3. Determination of the chronic toxicity of the compound, which
includes repeated administration of a pharmacological agent
over a period of time, depending on
the planned course of its application in the clinic. Investigational agent
usually administered daily in three doses: close to therapeutic,
estimated therapeutic and maximum in order to identify
toxicity. During the experiment, the volume is determined by
consumption of feed and water by animals, dynamics of their mass, change
general condition and behavior (reactions); conducted by hematologists
cal and biochemical research. At the end of the experiment
animals are slaughtered and pathomorphological studies are carried out
internal organs, brain, bones, eyes.
4. Establishment of specific toxicity pharmacology
chemical agent (carcinogenic™, mutagenicity, embryotoxic
ness, gonadotoxicity, allergenic properties, as well as
ability to cause drug dependence, immunotoxicity
whom action).
Identification of the damaging effect of the test drug on the body of experimental animals gives researchers information about which organs and tissues are most sensitive to a potential drug and what should be paid special attention to during clinical trials.
The study of new pharmacological agents in animals is based on data on the existence of a certain correlation between the effect of these compounds on animals and humans, whose physiological and biochemical processes are largely similar. Due to the fact that there are significant species differences between animals in the intensity of metabolism, the activity of enzyme systems, sensitive receptors, etc., studies are carried out on several animal species, including cats, dogs, monkeys, which are phylogenetically closer to to a person.
It should be noted that a similar scheme for conducting laboratory (experimental) studies is acceptable for both a simple and a complex drug, in the experiment with which mandatory additional biopharmaceutical studies are planned, confirming the optimal choice of the type of dosage form and its composition.
An experimental preclinical study of a new agent (its pharmaceutical, pharmacological and toxicological properties) is carried out according to standard unified methods, which are usually described in the guidelines of the Pharmacological Committee, and must meet the requirements of Good Laboratory Practice (GLP) - Good Laboratory Practice (GLP).
Preclinical studies of pharmacological substances make it possible to develop a scheme for rational testing of drugs in a clinic, to improve their safety. Despite the great importance of preclinical studies of new substances (drugs), the final judgment on their efficacy and tolerability is formed only after clinical trials, and often after a certain period of their widespread use in medical practice.
Clinical trials of new medicines and preparations should be carried out with the maximum observance of the requirements of the international standard "Good Clinical Practice" (Good Clinical Practice (GCP)), which regulates planning, conduct (design), monitoring, duration, audit, analysis, reporting and documentation research.
When conducting clinical trials of drugs, special terms are used, the content of which has a certain meaning. Consider the main terms adopted by the GCP.
Clinical trials - the systematic study of an investigational drug in humans to test its therapeutic effect or to identify an adverse reaction, as well as the study of absorption, distribution, metabolism and excretion from the body to determine its effectiveness and safety.
Investigational Product - The pharmaceutical form of the active substance or placebo being studied or used for comparison in a clinical trial.
Sponsor (customer) - an individual or legal entity that assumes responsibility for the initiative, management and / or financing of clinical trials.
Investigator - The person responsible for conducting a clinical trial.
Trial Subject - A person who participates in clinical trials of an investigational product.
Quality assurance of clinical trials - a set of measures to ensure compliance of ongoing trials with GCP requirements, based on the norms of general and professional ethics, standard operating procedures and reporting.
To conduct clinical trials, the manufacturer produces a certain amount of the drug, controls its quality in accordance with the requirements laid down in the VFS project, then it is packaged, labeled (indicated "For clinical trials") and sent to medical institutions. Simultaneously with the medicinal product, the following documentation is sent to the clinical sites: submission, decision of the SNETSLS, clinical trial program, etc.
The decision to conduct clinical trials from a legal point of view and their ethical justification is based on an assessment of experimental data obtained in animal experiments. The results of experimental, pharmacological and toxicological studies should convincingly indicate the advisability of testing a new drug in humans.
In accordance with existing legislation, clinical trials of a new drug are carried out on patients suffering from the diseases for which the drug is intended to be treated.
The Ministry of Health approved methodological recommendations for the clinical study of new drugs belonging to various pharmacological categories. They are developed by leading scientists of medical institutions, discussed and approved by the Presidium of the GNETSLS. The application of these recommendations ensures the safety of patients and contributes to the improvement of the level of clinical trials.
Any study on humans should be well organized and carried out under the supervision of specialists. Incorrectly conducted tests are recognized as unethical. In this regard, much attention is paid to the planning of clinical trials.
In order to prevent narrow professional interests from showing up in the work of doctors, which do not always meet the interests of the patient and society, and also in order to ensure human rights, in many countries of the world (USA, Great Britain, Germany, etc.) special ethical committees have been created to control scientific research. drug research in humans. An ethical committee has also been created in Ukraine.
International acts on the ethical aspects of conducting medical research on people have been adopted, for example, the Nuremberg Code (1947), which reflects the protection of human interests, in particular, the inviolability of his health, as well as the Declaration of Helsinki (1964), which contains recommendations for doctors on biomedical research on people. The provisions set forth in them are advisory in nature and at the same time do not exempt from criminal, civil and moral liability provided for by the laws of these countries.
The medical and legal foundations of this system guarantee both safety and timely adequate treatment of patients, as well as providing society with the most effective and safe medicines. Only on the basis of official trials, methodically correctly planned, objectively assessing the condition of patients, as well as scientifically analyzed experimental data, can correct conclusions be drawn about the properties of new drugs.
Clinical trial programs for different pharmacotherapeutic groups of drugs can differ significantly. However, there are a number of basic provisions that are always reflected in the program: a clear formulation of the goals and objectives of the test; defining selection criteria for testing; an indication of the methods of distribution of patients in the test and control groups; number of patients in each group; method for establishing effective doses of the medicinal product; the duration and method of testing the controlled product; an indication of the comparator and/or placebo; methods for quantifying the effect of the drug used (indicators subject to registration); methods of statistical processing of the obtained results (Fig. 2.3).
The clinical trial program is subject to mandatory review by the Ethics Commission.
Patients (volunteers) participating in the trial of a new drug should receive information about the essence and possible consequences of the trials, the expected effectiveness of the drug, the degree of risk, conclude a life and health insurance contract in the manner prescribed by law, and during the trials be under constant supervision of qualified personnel. In the event of a threat to the health or life of the patient, as well as at the request of the patient or his legal representative, the head of clinical trials is obliged to suspend the trials. In addition, clinical trials are suspended in case of lack or insufficient efficacy of the drug, as well as violation of ethical standards.
Clinical testing of generic drugs in Ukraine is carried out under the "Limited Clinical Trials" program to establish their bioequivalence.
In the process of clinical trials, drugs are divided into four interrelated phases: 1 and 2 - pre-registration; 3 and 4 - post-registration.
The first phase of the study is carried out on a limited number of patients (20-50 people). The goal is to establish the tolerability of the drug.
The second phase - for 60-300 patients in the presence of the main and control groups and the use of one or more reference drugs (standards), preferably with the same mechanism of action. The goal is to conduct a controlled therapeutic (pilot) study of the drug (determining the ranges: dose - regimen and, if possible, dose - effect) in order to optimally support further trials. The evaluation criteria are usually clinical, laboratory and instrumental indicators.
The third phase - for 250-1000 people and more. The goal is to establish a short-term and long-term balance between safety and efficacy of a medicinal product, to determine its overall and relative therapeutic value; to study the nature of the occurring adverse reactions, factors that change its action (interaction with other drugs, etc.). Tests should be as close as possible to the intended use of the medicinal product.
The results of the clinical trial are recorded in the individual standard card of each patient. At the end of the test, the results obtained are summed up, processed statistically and issued in the form of a report (in accordance with the requirements of the SNETSLS), which ends with reasoned conclusions.
The report on clinical trials of the medicinal product is sent to the GNETSLS, where it is subjected to a thorough examination. The end result of the examination of all materials received by the SNETSLS is an instruction for the use of a medicinal product that regulates its use in a clinical setting.
A drug can be recommended for clinical use if it is more effective than known drugs of a similar type of action; has better tolerance compared to known drugs (with the same efficiency); effective in conditions where the use of existing drugs is unsuccessful; more economically advantageous, has a simpler method of application or a more convenient dosage form; in combination therapy, it increases the effectiveness of existing drugs without increasing their toxicity.
The fourth phase (post-marketing) research is carried out on 2000 or more people after the approval of the medicinal product for medical use and industrial production (after the drug is received by the pharmacy). The main goal is to collect and analyze information about side effects, evaluate the therapeutic value and strategies for prescribing a new drug. Studies in the fourth phase are carried out on the basis of information in the instructions for use of the drug.
When conducting clinical trials of new drugs, the most important task is to ensure their quality. To achieve this goal, monitoring, auditing and inspection of clinical trials is carried out.
Monitoring - The activity of control, observation and verification of a clinical trial carried out by a monitor. The monitor is a trustee of the organizer of clinical trials (sponsor), who is responsible for directly monitoring the progress of the study (compliance of the data obtained with the protocol data, compliance with ethical standards, etc.), assisting the researcher in conducting the trial, and ensuring his communication with the sponsor.
An audit is an independent review of a clinical trial, which is carried out by services or persons not involved in it.
Working in parallel to achieve a common goal, the monitor, auditors and official inspectors ensure the required quality of clinical trials.
When conducting clinical trials involving a large number of patients, it becomes necessary to quickly process the results of the study. To this end, Pfizer Corporation has developed new informatics methods (the Q-NET computer program for processing the database obtained during the study of the Viagra drug), which makes it possible to get acquainted within a day with the results of clinical trials involving 1450 patients, which are conducted in 155 clinical centers located in various countries. The creation of such programs allows minimizing the time for promoting new drugs at the stage of clinical trials.
Thus, the effectiveness and safety of drugs is guaranteed:
· clinical trials;
· post-marketing clinical trials in the wide medical use of drugs;
· careful examination of the results at all the above stages.
The presence of a comprehensive assessment of the efficacy and safety of drugs and extrapolation of the results at three stages makes it possible to identify the mechanisms of possible side effects, the level of drug toxicity, and also to develop the most optimal schemes for its use.
There is a prospect of an integrated approach based on the optimal combination of the principles of biopharmacy, the latest achievements in chemical and pharmaceutical technologies, with a wide involvement of clinical experience in the creation and production of new drugs. Such an approach to this problem is qualitatively new in pharmaceutical practice and, obviously, will open up new possibilities in the complex process of creating and using drugs.
2. Ways to improve traditional medicines
When developing new drugs with known effects, attempts are being made to increase their specificity. Thus, salbutanol, one of the new bronchodilators, stimulates β-adrenergic receptors at doses that have little effect on adrenergic receptors in the heart. Prednisolone is a more valuable steroid than cortisone, since with the same anti-inflammatory effect it retains salts in the body to a lesser extent.
In order to overcome such undesirable properties of medicinal substances as bitter or sour taste, unpleasant odor, irritant effect of the gastrointestinal tract, pain upon injection, slight absorption, slow or fast metabolic processes, instability and others, in pharmacotherapy
various modifications of medicinal substances are used (biological, physicochemical, chemical). In order to show the presence of a change in the structure of a drug substance, the term "prodrug" has been introduced, which means a chemical modification of the substance. In the body, this new compound is fermented and released as its unmodified form. Currently, more than 100 types of drugs containing antibiotics, steroid hormones, prostaglandins in the form of prodrugs are produced abroad.
Particularly noteworthy are the so-called combined drugs, in which the combination of constituent components is carried out on the basis of a well-founded scientific experiment.
Since the pathogenesis (the cause of the onset and development of a disease process in the body) of viral respiratory infections is a complex process that affects different parts of the upper respiratory tract, then anti-cold drugs should be complex and have polypharmacotherapeutic effects. In other words, a complex preparation should include substances that act on various links in the pathogenetic chain and eliminate the main symptoms of colds.
Coldrex tablets consist of 500 mg of paracetamol, 5 mg of phenylephrine hydrochloride (methasone), 25 mg of caffeine, 20 mg of terpinhydrate, 30 mg of ascorbic acid.
Paracetamol has an analgesic and antipyretic effect, is similar in chemical structure to phenacetin and is its active metabolite, which causes an analgesic effect. However, unlike phenacetin, it does not cause methemoglobinemia, does not have a toxic effect on the tubular apparatus of the kidneys. In addition, unlike aspirin, paracetamol does not have an ulcerogenic effect, does not cause gastrointestinal bleeding and can be used even by patients with peptic ulcer; unlike analgin, it does not cause blood complications in the form of granulocytopenia and granulocytosis.
Phenylephrine hydrochloride (methasone), by acting on alpha-adrenergic receptors, causes narrowing of arterioles in the nasal mucosa, helping to relieve swelling and eliminate mucus, a feeling of nasal congestion, reduce rhinorrhea and normalize nasal breathing.
Caffeine potentiates the analgesic effect of paracetamol, has a general tonic effect, improves the patient's well-being.
Terpinhydrate contributes to the decomposition of the secret in the bronchi and its easier expectoration; freeing the airways from blockage, helps to facilitate breathing; has an anti-inflammatory effect.
Ascorbic acid compensates for the deficiency of vitamin C in the body, activates the immune system, normalizes tissue respiration, thus contributing to the strengthening of the body's defense mechanisms.
Other combination preparations of Coldrex are also known: Coldrex Hot Rem (powder in bags for dissolving in hot water) and Coldrex Night (syrup), which contain, in addition to paracetamol, promethazine hydrochloride, which has sedative and antipyretic effects, as well as antiallergic properties, and dextramethorphan hydrobromide, which has an antitussive effect. Unlike codeine, it does not depress breathing, it is not addictive. These combination drugs are useful for sore throats or difficulty breathing. Taking them in the evening provides an antitussive effect during the night, which helps to normalize sleep.
An example of a combined preparation is also "Solpadeine solubl", produced by the same pharmaceutical company in the form of tablets (500 mg of paracetamol, 8 mg of codeine, 30 mg of caffeine). Due to the rapid multidirectional effect on peripheral and central pain receptors, the drug is recommended for the relief of postoperative pain. It surpasses analgin in efficiency.
Combined drug "Pafein", produced in the form of tablets containing 500 mg of paracetamol and 50 mg of caffeine (manufacturer FF "Darnitsa"), has a mild analgesic, antipyretic and anti-inflammatory effect. Caffeine, which is part of Pafein, increases, prolongs and accelerates the pharmaceutical action of paracetamol. Under the influence of "Pafein" catarrhal phenomena (lacrimation, sore throat, runny nose) decrease, the symptoms of intoxication (weakness, sweating, etc.) quickly disappear. "Pafein" is especially effective when the first signs of the disease appear.
The combined preparation "Panadol extra" contains 500 mg of paracetamol and 65 mg of caffeine, is an effective analgesic.
In recent years, numerous combined preparations containing paracetamol and antihistamine, expectorant, antitussive, bronchodilator and anti-inflammatory drugs have been sold on the drug market. So in Tomapirin (manufactured by Boehringer Inchelheim), paracetamol (200 mg) is combined with acetylsalicylic acid (250 mg), which leads to potentiation of the analgesic and antipyretic effects of these substances. The combination of these substances with caffeine (50 mg) leads to an increase in the effectiveness of the combination of this composition by about 40%, due to which it becomes possible to reduce the dose of paracetamol and acetylsalicylic acid. In addition, this leads to an improvement in the tolerability of the combination drug.
Diphenhydramine and other antihistamines in combination with paracetamol are used to alleviate the symptoms of the disease in bronchitis, allergic rhinitis. Such drugs as phenylephrine, ephedrine, pseudoephedrine, etc. are effective vasoconstrictor drugs that reduce swelling of the mucous membrane of the nasal passages. In combination with paracetamol, they are used to relieve headache, fever, congestion in the mucous membrane of the upper respiratory tract in children with rhinitis, acute respiratory diseases. Antitussives (diphenhydramine) in combination with paracetamol are used to relieve headache, fever, sore throat and cough in patients with influenza and colds. Combination formulations containing paracetamol and three additional components, in the case of their use to relieve symptoms associated with colds, flu, allergic rhinitis, bronchitis.
The well-known combined drug "Ginalgin" in the form of vaginal tablets (manufacturer "Polfa") contains chlorhinaldol and metronidazole. Due to this, it has a wide spectrum of action against anaerobic gram-negative and gram-positive bacteria. "Ginalgin" is highly effective in the treatment of vaginitis caused by bacterial flora, vaginal trichomoniasis and vaginitis caused by the simultaneous action of bacteria, Trichomonas and fungi.
Recently, scientifically based compositions of combined preparations in the form of ointments are widely used in medical practice.
The use of combined drugs that have a multidirectional effect on the symptoms of a particular disease makes it possible to maximize the requirements of modern pharmacotherapy, increase its effectiveness and avoid many, often unforeseen, side effects.
An important issue in pharmaceutical technology is the increase in the solubility of sparingly soluble drugs in water and lipids, since their bioavailability largely depends on the particle size. It is also known that the process of dissolution of a substance is associated with the phenomena of a phase transition at the solid-solution interface. The intensity of this process depends on the surface area of the interface. However, dispersion, even micronization of substances does not always lead to an increase in the rate of their dissolution and absorption. An increase in intermolecular cohesive forces, the presence of an electric charge of particles leads to their enlargement - aggregation. All this does not allow obtaining aqueous solutions of sparingly soluble substances, and hence avoiding such undesirable phenomena as abscesses, protein denaturation, necrosis, tissue dehydration, embolism, and other complications that are observed when using oil and alcohol solutions in the form of injections.
Increasing the solubility of drugs in water and other solvents implies a significant increase in their effectiveness. This can be achieved by using:
· co-solvents (benzyl benzoate, benzyl alcohol, propylene glycol, polyethylene oxides, etc.);
· hydrotropic agents (hexamethylenetetramine, urea, sodium benzoate, sodium salicylate, novocaine, etc.);
· solubilization phenomena, for example, vitamins A, D, E, K, steroid hormones, barbiturates, antibiotics, sulfonamides, essential oils, etc., which allows not only increasing the solubility of substances, but also significantly increasing their stability. An example is the drug system in an aerosol package "Ingalipt";
· complex formation phenomena, for example, iodine dissolves well in concentrated solutions of potassium iodide, polyene antibiotics - in the presence of polyvinylpyrrolidone. In addition to increasing the solubility of medicinal substances, the phenomenon of complex formation can significantly reduce the irritant ability of the medicinal substance to the mucous membrane or skin. For example, such an antiseptic as iodine, forming a complex compound with polyvinyl alcohol, loses its inherent cauterizing effect, which is used in the preparation of "Iodinol". In some cases, the formation of complex compounds leads to a noticeable increase in the bioavailability of the resulting product and, at the same time, to a significant increase in its therapeutic efficacy. Thus, the complex of levomycetin - polyethylene oxide is 10-100 times more effective than the antibiotic itself.
A significant increase in the dissolution rate of sparingly soluble substances can be facilitated by the use of so-called solid disperse systems, which are a medicinal substance dispersed by fusion or dissolution (with subsequent distillation of the solvent) in a solid carrier-matrix. So, the solubility of Aymaline increases 40 times, cinarizine - 120 times, reserpine - 200 times, etc. In addition, by changing the physicochemical properties of carrier polymers (molecular weight, solubility), it is possible to regulate the bioavailability of the drug substance and create targeted dosage forms.
The most important problem in pharmaceutical technology is the stabilization of drug systems. This is due to the fact that medicinal substances, mainly in the process of preparation of drugs and their storage, under the influence of chemical (hydrolysis, saponification, oxidation, polymerization, racemization, etc.), physical (evaporation, change in consistency, delamination, coarsening of particles) and biological (souring, etc.) phenomena change their properties. To this end, to stabilize homogeneous drug systems (solutions for injections, eye drops, etc.), various chemical (adding stabilizers, antioxidants, preservatives, etc.) or physical methods (use of non-aqueous solvents, ampouling in current) are widely used. inert gas, paracondensation method, coating of tablets and dragees, microencapsulation, etc.).
To stabilize heterogeneous drug systems (suspensions, emulsions), thickeners and emulsifiers in the form of surfactants and IUDs are used.
Here it is appropriate to give an example of "immobilized" drugs: enzymes, hormones, mucopolysaccharides, iron derivatives of dextrans and albumin for the treatment of anemia; gamma globulins, nucleic acids, interferon, etc., which are created to stabilize and prolong their action (see subsection 9.2).
An equally important problem of pharmaceutical technology is the extension of the time of action of drugs, since in many cases it is necessary to maintain a strictly defined concentration of drugs in biological fluids and body tissues for a long time. This requirement of pharmacotherapy is especially important to comply with when taking antibiotics, sulfonamides and other antibacterial drugs, with a decrease in the concentration of which the effectiveness of treatment decreases and resistant strains of microorganisms are produced, the destruction of which requires higher doses of the drug, and this, in turn, leads to an increase in side effects. .
Prolonged action of drugs can be achieved using various methods:
· physiological, which provides a change in the rate of absorption or excretion of a substance from the body. This is most commonly achieved by cooling the tissues at the injection site, using a blood-sucking jar, or by administering hypertonic or vasoconstrictive solutions, suppressing the excretory function of the kidneys;
· chemical - by changing the chemical structure of the medicinal substance (by complexation, polymerization, esterification, etc.);
· technological - by selecting a carrier with certain properties, changing the viscosity of the solution, selecting the type of dosage form, etc. For example, eye drops with pilocarpine hydrochloride, prepared with distilled water, are washed out from the surface of the cornea of the eye after 6-8 minutes. These same
· drops prepared on a 1% methylcellulose solution and having a high viscosity, and hence adhesion to the suction surface, are held on it for 1 hour.
Replacing eye drops with ointment, you can increase the duration of the latter in comparison with an aqueous solution of pilocarpine hydrochloride by almost 15 times. Thus, by changing such a technological indicator as viscosity or type of dosage form, it is possible to increase the time of action of the drug and its effectiveness.
There are other problems in pharmaceutical technology, the solution of which can lead to the creation of more advanced drugs and, consequently, to their higher therapeutic efficacy, for example, the creation of age-related drugs, increasing the microbial purity of drugs, the creation of more advanced containers and closures, the introduction low-waste and environmentally friendly technologies, further development of biotechnology, etc., which, in turn, will step by step improve the quality and therapeutic efficacy of medicines.
Recently, pharmacotechnologists and other specialists have been attracted by the problem of creating drugs of a fundamentally new type, the so-called targeted drugs with specified pharmacokinetic properties, which, unlike traditional or classical drugs, are characterized by:
· prolonged action;
· controlled release of active substances;
· their target transport to the target.
New generation drugs are commonly called therapeutic systems that partially or fully meet the above requirements.
A therapeutic drug system (TLS) is a device containing a drug substance or substances, a drug release control element, a platform on which the system is placed, and a therapeutic program.
TLS provides a constant supply of the body with medicinal substances in a strictly defined period of time. They are used for both local and systemic treatment. An example of such drugs can be "Ocusert", "Progestasert", "Transderm" and others, which are passive systems (see subsection 9.9). There are samples of active therapeutic systems, the action of which is programmed from the outside or self-programmed. Such therapeutic systems are created abroad, they are expensive and, therefore, are not widely used in medical practice.
It should be noted that the optimal strategy for the creation of modern drugs can only be developed on the basis of carefully planned technological and biopharmaceutical experimental studies and a qualified interpretation of the data obtained.
2.1. Biotechnology of traditional medicines and medicines of the future
In order to improve the medicinal properties of traditional drugs, the efforts of all specialists developing drugs are aimed at using new technologies for their production, improving compositions, increasing specificity and studying the fullest possible mechanism of their action on various human systems and organs. Progress in this direction is becoming more tangible and there is hope that drugs in the next millennium will become more effective and effective means of treating many diseases. Drugs will be widely used in the form of therapeutic systems and bioproducts, especially such as peptides and proproteins, which are practically impossible to obtain synthetically. Therefore, the increasing importance of biotechnology for the pharmaceutical industry becomes clear.
Today, biotechnology is rapidly advancing to the forefront of scientific and technological progress. This, on the one hand, is facilitated by the rapid development of modern molecular biology and genetics, based on the achievements of chemistry and physics, and on the other hand, by the urgent need for new technologies that can improve the state of health and environmental protection, and most importantly, eliminate food shortages, energy and mineral resources.
As a priority, biotechnology is faced with the creation and development of the production of medicines for medicine: interferons, insulins, hormones, antibiotics, vaccines, monoclonal antibodies and others, allowing early diagnosis and treatment of cardiovascular, malignant, hereditary, infectious, including viral diseases.
According to experts, the world market for biotechnological products by the mid-1990s amounted to about 150 billion dollars. In terms of production volume and the number of registered patents, Japan ranks first among countries that succeed in the field of biotechnology, and second in the production of pharmaceutical products. In 1979, 11 new antibiotics were released to the world market, 7 of them were synthesized in Japan. In 1980, the Japanese pharmaceutical industry mastered the production of a wide range of substances: penicillins, cephalosporin C, streptomycin, semi-synthetic antibiotics of the second and third generations, anticancer drugs and immunomodulators. Among the top ten world manufacturers of interferon are five Japanese ones. Since 1980, firms have been actively involved in the development of technologies related to immobilized enzymes and cells. There is active research aimed at obtaining heat-resistant and acid-resistant enzymes. 44% of new products obtained through biotechnology have found application in pharmacy, and only 23% - in the food or chemical industry.
Biotechnology has an impact on various industries in Japan, including the production of wine and spirits, beer, amino acids, nucleides, antibiotics; is considered as one of the most promising areas for the development of food and pharmaceutical production and, on this basis, is included in the research program for the creation of new industrial technologies. There is a state program aimed at developing new technologies for the production of hormones, interferons, vaccines, vitamins, amino acids, antibiotics and diagnostic products.
The second place after Japan in terms of biotechnology products and the first place in the production of pharmaceutical products belongs to the United States. Antibiotics account for 12% of world production. Significant advances have been made in the synthesis of insulin, human growth hormone, interferon, coagulation factor VIII, diagnostic tests, hepatitis B vaccine and other drugs, and the continuous process of converting sugar into ethyl alcohol. High purity human leukocyte interferon was synthesized in 1983. Many US pharmaceutical companies have mastered the methods of genetic engineering. Biotechnology-related media are developing rapidly. There are some successes in the field of biotechnology in other countries of the world.
The concept of "biotechnology" is collective and covers such areas as fermentation technology, the use of biofactors using immobilized microorganisms or enzymes, genetic engineering, immune and protein technologies, technology using cell cultures of both animal and plant origin.
Biotechnology is a set of technological methods, including genetic engineering, using living organisms and biological processes for the production of medicines, or the science of the development and application of living systems, as well as non-living systems of biological origin, within the framework of technological processes and industrial production.
Modern biotechnology is chemistry, where the change and transformation of substances occurs through biological processes. In intense competition, two chemistries are successfully developing: synthetic and biological. Synthetic chemistry, combining and shuffling atoms, remaking molecules, creating new substances unknown in nature, has surrounded us with a new world that has become familiar and necessary. These are medicines, detergents and dyes, cement, concrete and paper, synthetic fabrics and furs, records and precious stones, perfumes and artificial diamonds. But in order to obtain substances of "second nature" harsh conditions and specific catalysts are necessary. For example, nitrogen fixation occurs in rugged industrial apparatuses at high temperature and enormous pressure. At the same time, columns of smoke are thrown into the air, and streams of sewage are thrown into the rivers. For nitrogen-fixing bacteria, this is not required at all. The enzymes at their disposal carry out this reaction under mild conditions, forming a pure product without waste. But the most unpleasant thing is that a person's stay in an environment of "second nature" began to turn into allergies and other dangers. It would be nice to stay close to Mother Nature. And if artificial tissues, films are made, then at least from microbial protein, if drugs are used, then first of all those that are produced in the body. From here, the prospects for the development and use of biotechnologies in the pharmaceutical industry, where living cells are used (mainly microorganisms such as bacteria and yeast fungi or individual enzymes that act as catalysts for only certain chemical reactions) emerge. Possessing phenomenal selectivity, enzymes carry out a single reaction and allow you to get a pure product without waste.
However, enzymes are unstable and quickly destroyed, for example, when the temperature rises, it is difficult to isolate, they cannot be used repeatedly. This was the main reason for the development of the science of immobilized (immobilized) enzymes. The basis on which the enzyme is "planted" can be in the form of granules, fibers, polymer films, glass, and ceramics. Enzyme losses are minimal, and activity persists for months. At present, they have learned how to obtain immobilized bacteria that produce enzymes. This simplified their use in production and made the method cheaper (no need to isolate the enzyme, purify it). In addition, bacteria work ten times longer, making the process more economical and easier. Traditional fermentation technology has evolved into biotechnology with all the hallmarks of advanced technology.
Enzyme technologies with great economic effect began to be used to obtain pure amino acids, processing starch-containing raw materials (for example, corn into a syrup consisting of glucose and fruit). In recent years, this production has turned into a large-scale one. Developing industries for the processing of sawdust, straw, household waste into feed protein or alcohol, which is used to replace gasoline. Enzymes are now widely used in medicine as fibroiolytic preparations (fibrinolysin + heparin, streptolyase); with digestive disorders (pepsin + hydrochloric acid, pepsi-dil, abomin, pancreatin, orase, pankurmen, festal, digestal, tri-enzyme, cholenzym, etc.); for the treatment of purulent wounds, in the formation of adhesions, scars after burns and operations, etc. Biotechnology makes it possible to obtain a large number of enzymes for medical purposes. They are used to dissolve blood clots, treat hereditary diseases, remove non-viable, denatured structures, cell and tissue fragments, free the body from toxic substances. Thus, with the help of thrombolytic enzymes (streptokinase, urokinase), the lives of many patients with thrombosis of the extremities, lungs, and coronary vessels of the heart have been saved. Proteases in modern medicine are used to rid the body of pathological products and to treat burns.
About 200 hereditary diseases are known to be caused by a deficiency of an enzyme or other protein factor. Currently, attempts are being made to treat these diseases with the use of enzymes.
Genetic engineering and other biotechnological methods open up new opportunities in the production of antibiotics with high selective physiological activity against certain groups of microorganisms. However, antibiotics also have a number of disadvantages (toxicity, allergenicity, resistance of pathogenic microorganisms, etc.), which can be significantly weakened by their chemical modification (penicillins, cephalosporins), mutasynthesis, genetic engineering, and other methods. A promising approach is the encapsulation of antibiotics, in particular, their inclusion in liposomes, which allows targeted delivery of the drug only to certain organs and tissues, increases its effectiveness and reduces side effects.
With the help of genetic engineering, it is possible to force bacteria to produce interferon, a protein secreted by human cells in low concentrations when a virus enters the body. It enhances the body's immunity, inhibits the reproduction of abnormal cells (antitumor effect), is used to treat diseases caused by herpes, rabies, hepatitis, cytomegalovirus, which causes dangerous damage to the heart, and also to prevent viral infections. Inhalation of interferon aerosol can prevent the development of acute respiratory infections. Interferons have a therapeutic effect in breast, skin, larynx, lung, brain cancer, as well as multiple sclerosis. They are useful in the treatment of persons suffering from acquired immunodeficiencies (multiple myeloma and Kapozi's sarcoma).
Several classes of interferon are produced in the human body: leukocyte (a), fibroblast (p-interferon, convenient for mass production, since fibroblasts, unlike leukocytes, multiply in culture), immune (y) from T-lymphocytes and e-interferon, formed by epithelial cells.
Before the introduction of genetic engineering methods, interferons were obtained from donated blood leukocytes. The technology is complicated and expensive: 1 mg of interferon (one injection dose) was obtained from 1 liter of blood.
Currently, a-, (3- and y-interferons are obtained using an E. coli strain, yeast, cultivated insect cells (Dro-zophila). Purified using monoclonal (clone - a set of cells or individuals descended from a common ancestor by asexual reproduction) antibodies or other means.
Interleukins are also obtained by the biotechnological method - relatively short (about 150 amino acid residues) polypeptides involved in the organization of the immune response. They are formed in the body by a certain group of leukocytes (microphages) in response to the introduction of an antigen. Used as a remedy for immune disorders. By cloning the appropriate genes in E. coli or by in vitro cultivation of lymphocytes, interleukin-L is obtained (for the treatment of a number of tumor diseases), blood factor VIII (by culturing mammalian cells), factor IX (required for the treatment of hemophilia), and also growth factor)
