Almaty, 2015

1. The concept of "pharmaceutical technology" and its main tasks

2. Brief historical information about the development of industrial production of drugs

3. Regulatory and technical documentation in the industrial production of drugs

4. Industrial production of medicines

5. Significance of pharmaceutical drug technology

GENERAL ISSUES OF DRUG TECHNOLOGY FOR INDUSTRIAL PRODUCTION

1.1. The concept of "pharmaceutical technology" and its main tasks

Technology - a set of methods for processing, preparing, changing the state, properties, form of raw materials, material or semi-finished products, carried out in the process of manufacturing products.

Technology as a science of ways and methods of processing raw materials arose in connection with the development of large-scale machine industry in late 18th century and, having formed, it quickly grew from applied to a vast fundamental science.

The development of technology is constantly under the powerful influence of the economic and ideological institutions of society. In turn, the social impact of technology on society goes, first of all, through an increase in labor productivity, through the specialization of the means of labor, which serve as the technical basis for its division, and, finally, through the replacement of human labor functions by technical means. The social impact of technology on society can be easily seen in the transition from manual labor to machine labor, and then to complex automation of production, but, changing working and living conditions, it also affects a person’s worldview, his psychology, and thinking.

All spheres of society's life are developing in a complex manner, taking into account social, economic and technical factors. Only those technological solutions are optimal, which contribute to the most complete satisfaction of the material and spiritual needs of people.

All of the above fully applies to the technology of chemical, food products, as well as pharmaceutical.

The modern concept of "technology" includes a set of techniques and methods for obtaining, processing or processing raw materials, materials, semi-finished products, products carried out in order to obtain finished pharmaceutical products. It should be noted that the concept of "technology" includes the operations of extraction, processing, dosing (packaging), transportation, storage and storage of raw materials and finished products (since they are an integral part of the production process), as well as technological control and scientifically based standardization of production in the form of technological regulations, methods, rules, schedules, etc.

The main tasks of pharmaceutical technology:

-development of technological foundations and production methods
new medicinal substances and preparations;

-improvement of existing drugs;

-search, study and use in the production of drugs
new excipients;

Study of stability and establishment of expiration dates of medicinal substances, preparations, semi-finished products and other products;

Studying the efficiency of the technological process, the main indicators of which are: the specific consumption of raw materials, energy and labor costs per unit of output, and the quality of the finished product; the intensity of the process; production cost.

The task of pharmaceutical technology as a science is to identify physical, chemical, mechanical and other regularities, as well as the most effective economic processes in order to use them in the production of medicines.

The significance of the pharmaceutical technology of drugs in healthcare is extremely high, since in providing medical care to patients in 90% of cases, specialists in this service use drugs. Emphasizing the importance of pharmacotherapy, I. P. Pavlov noted that the medicine is a universal tool of the doctor, and no intervention, whether surgical, obstetric or otherwise, is complete without the use of drugs.

1.2. Brief historical information about the development of industrial production of drugs

The first information about the preparation of medicines was mentioned in various cultural monuments of ancient peoples (Egyptians, Chinese, Indians) that have come down to our times.

Under the primitive communal system, medicines were used in the form in which they were found in nature - mainly plants and substances of mineral or animal origin. The preparation of medicines consisted mainly in grinding, sifting or mixing substances.

During the period of the slave system, dosage forms appeared and experience was gained in the use of drugs for various diseases.

Despite the primitive tools of production, pharmacy has reached a significant development in Egypt, China, India. Greek pharmaceutical technology was superior to that of Egypt. For example, the Greeks used the distillation of water to purify it.

Everyone who was involved in the preparation of medicines had stocks of raw materials that were stored in a separate room. From the name "apotece" (pantry, barn) the modern name "pharmacy" came about.

The preparation of medicines in ancient Rome reached a significant development. The famous physician and pharmacist of that time, Claudius Galen (131-201 AD), systematized the methods of preparing medicines known at that time. He described the production of powders, pills, boluses, soaps, ointments, plasters, mustard plasters, collections, infusions, decoctions, solutions, potions, plant juices, fatty vegetable oils, wines, lubricants, vegetable acetic acid, lotions, poultices. Galen had his own pharmacy with a laboratory, workshop or factory, that is, a room in which various dosage forms were made, as well as cosmetics in large quantities - tooth powders, hair products, etc. The drugs described by Galen , and others similar to them, proposed later, in the 16th century. called "galenic". This name has survived to the present day.

In the East, the outstanding Tajik philosopher, physician and pharmacist Avicenna (Abu Ali Ibn Sina, circa 980-1037), the author of the work "The Canon of Medical Science", consisting of five books, became widely known. Two of them are devoted to pharmacology, in which he described many drugs and prescriptions of dosage forms improved by him. The works of Avicenna served as a guide for doctors and pharmacists for several centuries.

In the era of feudalism, alchemy had a significant impact on the development of pharmacy. Alchemists discovered new substances, improved technological operations such as distillation, filtration and crystallization.

Significant changes were made to the nomenclature of medicines and methods of their preparation by iatrochemistry, or medicinal chemistry, the founder and adherent of which was Theophrastus Paracelsus Hohenheim (1493-1541). He and his followers developed the doctrine of drug dosages, proposed equipment for their preparation, introduced many chemical preparations and extracts from plant materials into medical practice.

In Ancient Russia, the development of traditional medicine took place in an original way. Medicinal products obtained from raw materials of plant or animal origin were used raw or subjected to primitive processing. The professions of a doctor and a pharmacist were not differentiated. So, the seller of medicines always gave medical advice, and the doctor always had medicines with him. Both of them were called "healers".

In Kievan Rus, "healers" did not require special knowledge. Anyone could deal with the treatment and sale of drugs

Human. "Healers" were also engaged in the processing of medicinal raw materials and the preparation of complex medicines. The tools of production and methods of work were primitive and small-scale handicrafts.

Gradually, such medicines as “potions”, “healing potions”, “water”, “drinking”, “mazun” (ointments), “gunpowders” (powders), etc., appear in folk medicine. juices, infusions, decoctions and fragrant waters are already being prepared. A little later, such dosage forms as patches, peas (pills), levashi (flat cakes) appear. They were prepared in mosquito, herbal and green shops, which were the prototype of future pharmacies.

Under Ivan the Terrible, the Apothecary Chamber was established, which in 1631 was transformed into the Apothecary Order, and in 1654 the first school for the training of doctors was opened. In 1681, the "Royal Pharmacy" was organized, acquiring raw materials in the green row and serving only the royal family and the court. By the end of the XVI century. in Moscow, several more pharmacies were opened with laboratories for the manufacture of herbal and other drugs.

In the 19th century drug technology in Russia continued to develop. By this time, methods for making extracts from plant materials were being developed, methods for preparing emulsions, suppositories, pills and other dosage forms were being improved. More advanced equipment appeared: weighing instruments, a machine for making pills and suppositories, tablet presses, percolators, sterilizers, etc. At the end of the 19th century. began to prepare dosage forms for injection.

After the revolution of 1917, all pharmacies and laboratories attached to them, as well as galenic factories, were nationalized. Small drug factories were closed, while large ones were rebuilt and refurbished. Everything that has been done has made it possible to mechanize and automate chemical and pharmaceutical enterprises.

Prospects for the development of pharmaceutical technology

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. Technologies have a significant impact on the future economic performance of production, require the development of low-operation, resource-saving and waste-free processes, their automation, maximum mechanization 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, technology has received modern methods of finding optimal end results at the lowest cost, which is an example of how science turns into a direct productive force.

As a result of the increased role and capabilities 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.

The development of pharmaceutical technology is determined by the requirements of modern pharmacotherapy, which strongly suggests the creation of such drugs that would be most effective from a therapeutic point of view with a minimum content of the drug substance and not have side effects. The solution of problems 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 step of the above formulated task. Further efforts should be directed to the implementation of the information obtained in the process of production and use of drugs in order to eliminate their shortcomings: short validity period; uneven flow of drugs into the pathological focus; lack of electoral action; lack of stability, etc.

The priority problems of pharmaceutical technology include increasing the solubility of sparingly soluble substances 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 specified pharmacokinetic properties.

Here it is appropriate to note the need to study and use in pharmaceutical technology the latest achievements of colloid chemistry and chemical technology: new methods of dispersion, advances in physical and chemical mechanics, colloid chemistry and polymer chemistry, the use of non-stoichiometric compounds, microencapsulation, new methods of drying, extraction, and much more. other.

It is quite obvious that the solution of these and other issues facing pharmaceutical technology will require the development of new methods for the production and analysis of the effectiveness of drugs, the use of new criteria for its evaluation, as well as the study of the possibilities of implementing the results obtained in practical pharmacy and medicine.

New abstracts:

INTRODUCTION

Prospects for the development of pharmaceutical technology are closely connected with the influence 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 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 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.

At the same time, 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 information obtained in the process of production and use of drugs in order to eliminate such shortcomings as a short duration of action; uneven flow of medicinal substances 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 medicines can also include traditional ones, for example, tablets, ointments, suppositories, etc., if they provide rational pharmacotherapy.

The priority tasks of pharmaceutical technology should include increasing the solubility of sparingly soluble medicinal substances 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 drug systems makes it possible to reduce the course dose, eliminate the irritating effect and overdose of drugs, and reduce the frequency 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 drugs and save them. About 90% of medicinal substances used today do not reach the goal, which indicates the relevance of this area in pharmaceutical technology.

Therapeutic systems with targeted delivery of medicinal substances are usually divided into three groups:

· first-generation drug carriers (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;

· third-generation drug carriers (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 is 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 70s 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, and, first of all, such highly effective ones as new generation antibiotics and sulfonamides, as well as psychotropic, hypotensive, antidiabetic and etc. The nomenclature 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 .one. Ways to search for and develop new drugs (drugs)

The creation of new medicinal substances and preparations is a very laborious and expensive process, in which representatives of many professions participate: 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 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 substances obtained 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.

The scope of primary studies of the substance under study depends on its nature. If it is a derivative of a known series of compounds, then, as a rule, they are limited only to a comparative study of its specific action. If the substance is original, then a purposeful comprehensive study of it is planned. Such a compound is considered as a potential medicinal substance. Already at the initial stage of planning, research includes the study of chemical and physical properties, the development of methods for standardization and quality control. Subsequent experimental studies should be carried out only with batches of a substance obtained using a technology that provides its standard qualitative and quantitative characteristics.

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 produce other basic structure modifications. This path 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 life processes, on the disclosure of pathophysiological and pathochemical processes underlying the pathogenesis of various diseases, as well as on 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 with all this, 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, pyrazidol, an antiviral drug, arbidol, etc., have been introduced into medical practice.

The importance in medical practice of medicinal substances derived from plant materials, which have a number of advantages compared to 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 effect on various body systems. Thus, the hypotensive property of p-blockers, the antithrombic 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 medicines 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. In a combined preparation, medicinal substances are usually included in small or medium doses, when there are phenomena of synergy between them - mutual enhancement of the action in the form of potentiation or summation. Combination drugs are interesting because 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 illness. 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 (expand) the effectiveness of the main substance or eliminate its negative effect. So, the combined drug "Solpadein R", containing paracetamol and codeine, provides a more pronounced analgesic effect compared to the substances used, taken separately, since the 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, a peripheral one). In addition, this combination of two substances allows you to reduce their dose, while maintaining the duration and effectiveness of 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 studying the acute toxicity 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 product under study - 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. The data of initial pharmacological studies can already give some ideas about the toxicity of the 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 application
change (introduction) is carried out in order to determine the presence of side effects
reactions with a single dose of an increased dose and established
leniye of the reasons of a lethality; breadth of therapeutic action or
therapeutic Ehrlich index (the ratio of the maximum tolerable
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 mammals
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 certain period of time, depending on the
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 of
consumption of feed and water by animals, dynamics of their mass, change
general condition and behavior (reactions); carried out hematology
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 of pharmacological
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 agent 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 the 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 effectiveness 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 drugs 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 the planning, conduct (design), monitoring, duration, audit, analysis, reporting and documentation of research.

When conducting clinical trials of medicinal preparations, special terms are used, the content of which has a certain meaning. Consider the main terms adopted by the GCP.

Clinical trials are 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 is 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.

The subject of the test is a person participating in clinical trials of an investigational product.

Clinical Trial Quality Assurance is a set of measures to ensure that trials comply with GCP requirements based on 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 testify to 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 manifesting 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 supervise scientific 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 physicians on biomedical research in humans. The provisions set forth in them are advisory in nature and at the same time do not exempt from criminal, civil and moral responsibility provided for by the laws of these countries.

The medical and legal foundations of this system guarantee both the safety and timely adequate treatment of patients, and the provision of 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. At the same time, 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 drug; 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 program of clinical trials undergoes a mandatory review by the Ethics Commission.

Patients (volunteers) participating in the trial of a new drug must 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 the 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 effectiveness 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 course 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 tolerance of the drug.

The second phase is 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 - mode of application and, if possible, dose - effect) for optimal provision of further trials. The evaluation criteria are usually clinical, laboratory and instrumental indicators.

The third phase is for 250-1000 people and more. The goal is to establish a short-term and long-term balance between safety and efficacy of the drug, 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 expected conditions of use of this 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, statistically processed and drawn up in the form of a report (in accordance with the requirements of the GNETSLS), which ends with reasoned conclusions.

A report on clinical trials of a medicinal product is sent to the State Scientific and Clinical Medical Center, where it undergoes a thorough examination. The end result of the examination of all the materials received by the State Scientific and Medical Center for Drugs and Drugs 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 a better tolerability 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 is 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 (correspondence of the data obtained with the protocol data, compliance with ethical standards, etc.), assisting the researcher in conducting the trial, ensuring his relationship with the sponsor.

Audit is an independent verification of a clinical trial, which is carried out by services or persons not participating in it.

The audit can also be carried out by representatives of the state authorities responsible for the registration of medicines in the country. In these cases, the audit is called an inspection.

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, there is a need for prompt processing of the results of the study. For this purpose, the 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 who are held 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 medicines is guaranteed:

· clinical trials;

· post-marketing clinical trials for widespread 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.

The prospect of an integrated approach is emerging, 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. So, salbutanol - one of the new bronchodilators - stimulates p-adrenergic receptors in doses that have a slight effect on the adrenergic receptors of 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, injection pain, 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 the drug substance, the term "prodrug" was 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.

Particular attention deserves 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. At the same time, 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 from blockage of the respiratory tract, helps to facilitate breathing; has anti-inflammatory action.

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 combined preparations of "Coldrex" are also known: "Coldrex Hot Rem" (powder in packages for dissolving in hot water) and "Coldrex Night" (syrup), which contain, in addition to paracetamol, promethazine hydrochloride, which has a 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 combined 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 combination drug is also Solpadein 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 syndrome. It surpasses analgin in efficiency.

Combined drug "Pafein", produced in the form of tablets containing 500 mg of paracetamol and 50 mg of caffeine (manufactured by 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, if used 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 of pharmaceutical technology is to increase 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 boundary. The intensity of this process depends on the surface area of ​​the interface. At the same time, dispersion, even micronization of substances does not always lead to an increase in the rate of their dissolution and absorption. An increase in intermolecular cohesion 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 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 you to increase not only the solubility of substances, but also significantly increase their stability ness. 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 irritating 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 medicinal substances dispersed by fusion or dissolution (with subsequent distillation of the solvent) in a solid carrier-matrix. Thus, the solubility of Aymalin increases 40 times, cynarizine - 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, ampoule in an inert gas flow, paracondensation method, application of protective shells on 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, leading to increased 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 usually 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, an element that controls the release of a drug substance, 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 medicines, the efforts of all specialists developing medicinal preparations 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 pro-proteins, which are practically impossible to obtain synthetically. Therefore, the growing 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 shortages of food, energy and mineral resources.

As a priority, biotechnology faces the creation and development of the production of medicines for medicine: interferons, insulins, hormones, antibiotics, vaccines, monoclonal antibodies and others, allowing for early diagnosis and treatment of cardiovascular, malignant, hereditary, infectious, in 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, antitumor 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. Active research is being carried out aimed at obtaining heat-resistant and acid-resistant enzymes. 44% of new biotechnology-derived products are used in pharmaceuticals and only 23% in the food or chemical industries.

Biotechnology has an impact on various industries in Japan, including the production of wine and vodka products, beer, amino acids, nucleic acids, 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 the development of new technologies for the production of hormones, interferons, vaccines, vitamins, amino acids, antibiotics and diagnostic preparations.

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 progress has been made in the synthesis of insulin, human growth hormone, interferon, coagulation factor VIII, diagnostic tests, hepatitis B vaccine and other drugs, as well as 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 drugs, or the science of developing and applying 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 with the help of 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 drugs, 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 takes place 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 medicinal preparations 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 yeasts or individual enzymes that act as catalysts for only certain chemical reactions) emerge. Possessing a phenomenal selectivity, enzymes carry out a single reaction and allow you to get a pure product without waste.

At the same time, enzymes are unstable and quickly destroyed, for example, when the temperature rises, they are difficult to be isolated, 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. With all this, the loss of the enzyme is minimal, and the 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.

In recent years, more attention has been paid to enzyme inhibitors. Protease inhibitors obtained from actinomycetes (leupeptin, antipain, chymostatin) and genetically engineered strains of E. coli (eglin) and yeast (os-1 antitrypsin) are effective in septic processes, myocardial infarction, pancreatitis, pulmonary emphysema. The concentration of glucose in the blood of diabetic patients can be reduced by the use of inhibitors of intestinal invertases and amylases, which are responsible for the conversion of starch and sucrose into glucose. A special task is the search for enzyme inhibitors, with the help of which pathogenic microorganisms destroy antibiotics introduced into the patient's body.

Genetic engineering and other biotechnology methods open up new possibilities in the production of antibiotics, which have a high selective physiological activity in relation to certain groups of microorganisms. At the same time, antibiotics also have a number of disadvantages (toxicity, allergenicity, resistance of pathogenic microorganisms, etc.), which can be significantly weakened due to their chemical modification (penicillins, cephalosporins), mutasynthesis, genetic engineering, and other methods. Encapsulation of antibiotics, in particular, their inclusion in liposomes, can serve as a promising approach, 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 viruses, 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). They are purified using monoclonal (clone - a set of cells or individuals that occurred from a common ancestor by asexual reproduction) by antibodies or by 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)