Development and testing of new drugs. Stages of the process of creating a new drug. Stability and shelf life of medicines Methods for creating new medicines

Ways to create new medicines I. Chemical synthesis of drugs; directed synthesis; empirical path. II. Obtaining drugs from medicinal raw materials and isolating individual substances: of animal origin; of plant origin; from minerals. III. Isolation of medicinal substances that are products of the vital activity of microorganisms and fungi. Biotechnology.

Chemical synthesis of drugs directed synthesis Reproduction of nutrients Adrenaline, norepinephrine, γ-aminobutyric acid, hormones, prostaglandins and other physiologically active compounds. Creation of antimetabolites Synthesis of structural analogues of natural metabolites with opposite effects. For example, antibacterial agents sulfonamides are similar in structure to para-aminobenzoic acid, which is necessary for the life of microorganisms, and are its antimetabolites:

Chemical synthesis of drugs directed synthesis Chemical modification of compounds with known activity The main task is to create new drugs that compare favorably with already known ones (more active, less toxic). 1. Based on hydrocortisone produced by the adrenal cortex, many much more active glucocorticoids have been synthesized, which have a lesser effect on water-salt metabolism. 2. Hundreds of synthesized sulfonamides are known, only a few of which have been introduced into medical practice. The study of a series of compounds is aimed at elucidating the relationship between their structure, physicochemical properties and biological activity. The establishment of such patterns allows for more targeted synthesis of new drugs. At the same time, it becomes clear which chemical groups and structural features determine the main effects of the substances.

Chemical modification of compounds with known activity: modification of substances of plant origin Tubocurarine (curare poison) and its synthetic analogues Relax skeletal muscles. What matters is the distance between two cationic centers (N+ - N+).

Chemical synthesis of drugs directed synthesis Study of the structure of the substrate with which the drug interacts. The basis is not the biologically active substance, but the substrate with which it interacts: receptor, enzyme, nucleic acid. The implementation of this approach is based on data on the three-dimensional structure of macromolecules that are the targets of the drug. A modern approach using computer modeling; X-ray diffraction analysis; spectroscopy based on nuclear magnetic resonance; statistical methods; genetic engineering.

Chemical synthesis of drugs; directed synthesis. Synthesis based on the study of chemical transformations of a substance in the body. Prodrugs. 1. Complexes “carrier substance - active substance” Provide directed transport to target cells and selectivity of action. The active substance is released at the site of action under the influence of enzymes. The function of carriers can be performed by proteins, peptides and other molecules. Carriers can facilitate the passage of biological barriers: Ampicillin is poorly absorbed in the intestine (~ 40%). The prodrug bacampicillin is inactive but is 9899% absorbed. In serum, under the influence of esterases, active ampicillin is cleaved.

Chemical synthesis of drugs; directed synthesis. Synthesis based on the study of chemical transformations of a substance in the body. Prodrugs. 2. Bioprecursors They are individual chemical substances that are inactive by themselves. In the body, other substances are formed from them - metabolites, which exhibit biological activity: prontosil - L-DOPA sulfonamide - dopamine

Chemical synthesis of drugs; directed synthesis. Synthesis based on the study of chemical transformations of a substance in the body. Agents affecting biotransformation. Based on knowledge of enzymatic processes that ensure the metabolism of substances, it allows the creation of drugs that change the activity of enzymes. Acetylcholinesterase inhibitors (prozerin) enhance and prolong the action of the natural mediator acetylcholine. Inducers of the synthesis of enzymes involved in the detoxification processes of chemical compounds (phenobarbital).

Chemical synthesis of drugs empirical way Random findings. The decrease in blood sugar levels found with the use of sulfonamides led to the creation of their derivatives with pronounced hypoglycemic properties (butamide). They are widely used for diabetes. The effect of teturam (antabuse), which is used in the production of rubber, was accidentally discovered. Used in the treatment of alcoholism. Screening. Testing chemical compounds for all types of biological activity. A labor-intensive and ineffective way. However, it is inevitable when studying a new class of chemical substances whose properties are difficult to predict based on their structure.

Preparations and individual substances from medicinal raw materials Various extracts, tinctures, and more or less purified preparations are used. For example, laudanum is a tincture of raw opium.

Preparations and individual substances from medicinal raw materials Individual substances: Digoxin - cardiac glycoside from foxglove Atropine - M-anticholinergic agent from belladonna Salicylic acid - anti-inflammatory substance from willow Colchicine - alkaloid of crocus, used in the treatment of gout.

Stages of drug development Preparation of the drug Testing on animals Natural sources Efficacy Selectivity Mechanisms of action Metabolism Safety assessment ~ 2 years Drug substance (active compound) Chemical synthesis ~ 2 years Clinical trials Phase 1 is the drug safe? Phase 2: Is the medicine effective? Phase 3: Is the drug effective in double-blind conditions? Metabolism Safety assessment ~ 4 years Marketing INTRODUCTION OF MEDICINES 1 year Phase 4 post-marketing surveillance Appearance of Genetics 17 years after approval for use Patent expiration

3. ON THE CREATION OF NEW MEDICINES

3. ON THE CREATION OF NEW MEDICINES

The progress of pharmacology is characterized by the continuous search and creation of new, more active and safe drugs. Their path from a chemical compound to a drug is presented in Scheme 1.1.

Recently, fundamental research has become increasingly important in obtaining new drugs. They concern not only chemical (theoretical chemistry, physical chemistry, etc.), but also purely biological problems. The successes of molecular biology, molecular genetics, and molecular pharmacology began to significantly affect such an applied aspect of pharmacology as the creation of new drugs. Indeed, the discovery of many endogenous ligands, secondary transmitters, presynaptic receptors, neuromodulators, the isolation of individual receptors, the development of methods for studying the function of ion channels and the binding of substances to receptors, advances in genetic engineering, etc. - all this played a decisive role in determining the most promising directions for the design of new drugs.

The great importance of pharmacodynamic research for solving applied problems of modern pharmacology is obvious. Thus, the discovery of the mechanism of action of non-steroidal anti-inflammatory drugs has fundamentally changed the way of searching for and evaluating such drugs. A new direction in pharmacology is associated with the isolation, extensive research and introduction of prostaglandins into medical practice. The discovery of the prostacyclin-thromboxane system was a serious scientific basis for the targeted search and practical use of antiplatelet agents. The release of enkephalins and endorphins stimulated research on the synthesis and study of opioid peptides with different spectrum of receptor action. The establishment of the role of the proton pump in the secretion of hydrochloric acid from the stomach led to the creation of previously unknown drugs - proton pump inhibitors. The discovery of endothelial relaxing factor (NO) allowed

Scheme 1.1.Sequence of creation and introduction of medicines.

Note. Ministry of Health of the Russian Federation - Ministry of Health of the Russian Federation.

explain the mechanism of the vasodilatory effect of m-cholinomimetics. These works also contributed to the elucidation of the mechanism of the vasodilating effect of nitroglycerin and sodium nitroprusside, which is important for further searches for new physiologically active compounds. The study of the mechanisms of fibrinolysis made it possible to create a valuable selectively acting fibrinolytic - a tissue activator of profibrinolysin. Many such examples can be given.

The creation of medicines usually begins with research by chemists and pharmacologists, whose creative collaboration is the basis for the “design” of new drugs.

The search for new drugs is developing in the following directions.

I. Chemical synthesis of drugs A. Directed synthesis:

1) reproduction of nutrients;

2) creation of antimetabolites;

3) modification of molecules of compounds with known biological activity;

4) studying the structure of the substrate with which the drug interacts;

5) a combination of fragments of the structures of two compounds with the necessary properties;

6) synthesis based on the study of chemical transformations of substances in the body (prodrugs; agents affecting the mechanisms of biotransformation of substances).

B. Empirical way:

1) random finds;

2) screening.

II. Obtaining drugs from medicinal raw materials and isolating individual substances:

1) animal origin;

2) plant origin;

3) from minerals.

III.Isolation of medicinal substances that are products of the vital activity of fungi and microorganisms; biotechnology (cell and genetic engineering)

As already noted, drugs are currently obtained mainly through chemical synthesis. One of the important ways of directed synthesis is in reproduction of nutrients, formed in living organisms. For example, adrenaline, norepinephrine, γ-aminobutyric acid, prostaglandins, a number of hormones and other physiologically active compounds were synthesized.

Search for antimetabolites (antagonists of natural metabolites) also led to the development of new drugs. The principle of creating antimetabolites is the synthesis of structural analogs of natural metabolites that have the opposite effect of metabolites. For example, antibacterial agents sulfonamides are similar in structure to para-aminobenzoic acid (see below), which is necessary for the life of microorganisms, and are its antimetabolites. By changing the structure of fragments of the acetylcholine molecule, it is also possible to obtain its antagonists. Below

The structure of acetylcholine and its antagonist, the ganglioblocker hygronium, is given. In both cases, there is a clear structural analogy in each pair of compounds.

One of the most common ways to find new drugs is chemical modification of compounds with known biological activity. The main task of such research is to create new drugs (more active, less toxic), which compare favorably with the already known ones. The starting compounds can be natural substances of plant (Fig. I.8) and animal origin, as well as synthetic substances. Thus, on the basis of hydrocortisone produced by the adrenal cortex, many significantly more active glucocorticoids have been synthesized, which have a lesser effect on water-salt metabolism than their prototype. Hundreds of synthesized sulfonamides, barbiturates and other compounds are known, of which only individual substances, the structure of which provides the necessary pharmacotherapeutic properties, have been introduced into medical practice. Such studies of a series of compounds are also aimed at solving one of the main problems of pharmacology - elucidating the relationship between the chemical structure of substances, their physicochemical properties and biological activity. The establishment of such patterns allows for more targeted synthesis of drugs. In this case, it is important to find out which chemical groups and structural features determine the main effects of the substances under study.

In recent years, new approaches to the creation of drugs have emerged. The basis is not the biologically active substance, as was done previously, but the substrate with which it interacts (receptor, enzyme, etc.). For such studies, the most detailed data on the three-dimensional structure of those macromolecules that are the main “target” for the drug is required. Currently, there is a bank of such data, including a significant number of enzymes and nucleic acids. A number of factors have contributed to progress in this direction. First of all, X-ray diffraction analysis was improved, and spectroscopy based on nuclear magnetic resonance was developed. The latter method opened up fundamentally new possibilities, since it made it possible to establish the three-dimensional structure of substances in solution, i.e. in a non-crystalline state. Another significant point was that, with the help of genetic engineering, it was possible to obtain a sufficient amount of substrates for detailed chemical and physicochemical studies.

Using available data on the properties of many macromolecules, it is possible to simulate their structure using computers. This gives a clear idea of ​​the geometry of not only the entire molecule, but also its active centers that interact with ligands. Features of surface topography are studied

Rice. I.8.(I-IV) Obtaining drugs from plant materials and creating their synthetic substitutes (using the example of curare-like drugs).

I.Initially, the Indians isolated an arrow poison from a number of plants in South America - curare, which causes paralysis of skeletal muscles.

a, b - plants from which curare is obtained;V - dried pumpkin pots with curare and Indian hunting tools;G - hunting with curare. The Indians placed small light arrows with points lubricated with curare in long tubes (blow guns); with an energetic exhalation, the hunter sent an arrow to the target; Curare was absorbed from the point where the arrow hit, muscle paralysis occurred, and the animal became prey for hunters.

II.In 1935, the chemical structure of one of the main alkaloids of curare, tubocurarine, was established.

III.In medicine, purified curare containing a mixture of alkaloids (drugs curarin, intocostrin) began to be used in 1942. Then they began to use a solution of the alkaloid tubocurarine chloride (the drug is also known as “tubarin”). Tubocurarine chloride is used to relax skeletal muscles during surgical operations.

IV.Subsequently, many synthetic curare-like drugs were obtained. When creating them, they proceeded from the structure of tubocurarine chloride, which has 2 cationic centers (N+ - N+), located at a certain distance from each other.

substrate, the nature of its structural elements and possible types of interatomic interactions with endogenous substances or xenobiotics. On the other hand, computer modeling of molecules, the use of graphical systems and corresponding statistical methods make it possible to obtain a fairly complete picture of the three-dimensional structure of pharmacological substances and the distribution of their electronic fields. Such summary information about physiologically active substances and substrate should facilitate the efficient design of potential ligands with high complementarity and affinity. Until now, such opportunities could only be dreamed of, but now it is becoming a reality.

Genetic engineering opens up additional opportunities to study the significance of individual receptor components for their specific binding to agonists or antagonists. These methods make it possible to create complexes with individual receptor subunits, substrates without putative ligand binding sites, protein structures with a disrupted composition or amino acid sequence, etc.

There is no doubt that we are on the threshold of fundamental changes in the tactics of creating new drugs.

The possibility of creating new drugs attracts attention based on the study of their chemical transformations in the body. These studies are developing in two directions. The first direction is related to the creation of so-called prodrugs. They are either “carrier substance - active substance” complexes or are bioprecursors.

When creating “substance-carrier-active substance” complexes, directed transport is most often meant. The "carrier substance" is usually connected to the active substance through covalent bonds. The active compound is released under the influence of appropriate enzymes at the site of action of the substance. It is desirable that the carrier be recognized by the target cell. In this case, significant selectivity of action can be achieved.

The function of carriers can be performed by proteins, peptides and other compounds. For example, it is possible to obtain monoclonal antibodies to specific antigens of the mammary gland epithelium. Such carrier antibodies, in combination with anti-blastoma drugs, can obviously be tested in the treatment of disseminated breast cancer. Of the peptide hormones, β-melanotropin, which is recognized by malignant melanoma cells, is of interest as a carrier. Glycoproteins can interact quite selectively with hepatocytes and some hepatoma cells.

Selective dilation of renal vessels is observed with the use of γ-glutamyl-DOPA, which undergoes metabolic transformations in the kidneys leading to the release of dopamine.

Sometimes “carrier substances” are used to transport drugs across biological membranes. Thus, it is known that ampicillin is poorly absorbed from the intestine (about 40%). Its esterified lipophilic prodrug - bacampicillin - is absorbed from the digestive tract by 98-99%. Bacampicillin itself is inactive; antimicrobial activity is manifested only when ampicillin is cleaved by esterases in the blood serum.

To facilitate passage through biological barriers, lipophilic compounds are usually used. In addition to the example already given, we can mention γ-aminobutyric acid cetyl ester (GABA), which, unlike GABA, easily penetrates brain tissue. The pharmacologically inert dipivaline ester of adrenaline passes well through the cornea of ​​the eye. In the tissues of the eye, it undergoes enzymatic hydrolysis, which leads to the local formation of adrenaline. In this regard, the dipivaline ester of epinephrine, called dipivefrin, has been effective in the treatment of glaucoma.

Another type of prodrug is called bioprecursors (or metabolic precursors). Unlike the “carrier substance-active substance” complex, which is based on a temporary connection between both components, a bioprecursor is a new chemical substance. In the body, another compound is formed from it - a metabolite, which is the active substance. Examples of the formation of active metabolites in the body are well known (prontosyl-sulfanilamide, imipramine-desmethylimipramine, L-DOPA-dopamine, etc.). Based on the same principle, it was synthesized pro-2-RAM, which, unlike 2-RAM penetrates well into the central nervous system, where the active reactivator of acetylcholinesterase 2-RAM is released.

In addition to increasing the selectivity of action, increasing lipophilicity and, accordingly, bioavailability, prodrugs can be used

to create water-soluble drugs (for parenteral administration), as well as to eliminate undesirable organoleptic and physicochemical properties.

The second direction, based on the study of the biotransformation of substances, involves studying the mechanisms of their chemical transformations. Knowledge of enzymatic processes that ensure the metabolism of substances makes it possible to create drugs that change the activity of enzymes. For example, acetylcholinesterase inhibitors (prozerin and other anticholinesterase agents) have been synthesized, which enhance and prolong the action of the natural mediator acetylcholine. Inhibitors of the MAO enzyme, which is involved in the inactivation of norepinephrine, dopamine, and serotonin, have also been obtained (these include the antidepressant nialamide, etc.). Substances are known that induce (strengthen) the synthesis of enzymes involved in the detoxification processes of chemical compounds (for example, phenobarbital).

In addition to directed synthesis, the empirical route for obtaining drugs still retains a certain importance. A number of drugs were introduced into medical practice as a result of chance discoveries. Thus, the decrease in blood sugar levels found with the use of sulfonamides led to the synthesis of their derivatives with pronounced hypoglycemic properties. Now they are widely used in the treatment of diabetes mellitus (butamide and similar drugs). The effect of teturam (antabuse), used in the treatment of alcoholism, was also discovered accidentally in connection with its industrial use in the manufacture of rubber.

One type of empirical search is screening 1. In this case, any chemical compounds that may also be intended for non-medicinal purposes are tested for biological activity using a variety of techniques. Screening is a very labor-intensive and ineffective way of empirical search for medicinal substances. However, sometimes it is unavoidable, especially if a new class of chemical compounds is being studied, the properties of which, based on their structure, are difficult to predict.

In the arsenal of medicines, in addition to synthetic drugs, a significant place is occupied by preparations and individual substances from medicinal raw materials(plant, animal and mineral origin; Table I.2). In this way, many widely used medicines were obtained not only in the form of more or less purified preparations (galenic, novogalenic, organomedicines), but also in the form of individual chemical compounds (alkaloids 2, glycosides 3). Thus, the alkaloids morphine, codeine, papaverine are isolated from opium, reserpine is isolated from Rauwolfia serpentine, cardiac glycosides digitoxin and digoxin are isolated from digitalis, and hormones are isolated from a number of endocrine glands.

1 From English to screen- sift.

2 Alkaloids are nitrogenous organic compounds found mainly in plants. Free alkaloids are bases [hence the name alkaloids: al-qili(Arabic) - alkali, eidos(Greek) - view]. In plants they are usually found in the form of salts. Many alkaloids have high biological activity (morphine, atropine, pilocarpine, nicotine, etc.).

3 Glycosides are a group of organic compounds of plant origin that decompose when exposed to enzymes or acids on sugar, or glycone (from the Greek. glykys- sweet), and the non-sugar part, or aglycone. A number of glycosides are used as medicines (strophanthin, digoxin, etc.).

Table I.2.Preparations of natural origin

Some drugs are waste products of fungi and microorganisms.

The successful development of this path led to the creation of modern biotechnology, laying the foundation for the creation of a new generation of medicines. The pharmaceutical industry is already undergoing major changes, and radical changes are expected in the near future. This is due to the rapid development of biotechnology. In principle, biotechnology has been known for a long time. Already in the 40s of the twentieth century. began to produce penicillin by fermentation from a culture of certain types of mold fungus penicillium. This technology has also been used in the biosynthesis of other antibiotics. However, in the mid-70s there was a sharp leap in the development of biotechnology. This is due to two major discoveries: the development of hybridoma technology (cell engineering) and the recombinant DNA method (genetic engineering), which determined the progress of modern biotechnology.

Biotechnology is a multi-discipline in which molecular biology plays a major role, including molecular genetics, immunology, various fields of chemistry and a number of technical disciplines. The main content of biotechnology is the use of biological systems and processes in industry. Typically, microorganisms, cell cultures, plant and animal tissues are used to obtain the necessary compounds.

Based on biotechnology, dozens of new medicines have been created. Thus, human insulin was obtained; a growth hormone; interferons; interleukin-2; growth factors regulating hematopoiesis - erythropoietin, filgrastim, molgramostim; anticoagulant lepirudin (recombinant version of hirudin); fibrinolytic urokinase; tissue activator of profibrinolysin alteplase; anti-leukemic drug L-asparaginase and many others.

Of great interest are also monoclonal antibodies that can be used in the treatment of tumors (for example, the drug of this group, trastuzumab, is effective against breast cancer, and rituximab, against lymphogranulomatosis). The group of monoclonal antibodies also includes the antiplatelet agent abciximab. In addition, monoclonal antibodies are used as antidotes, in particular for intoxication with digoxin and other cardiac glycosides. One such antidote is marketed under the name Digoxin immune fab (Digibind).

It is quite obvious that the role and prospects of biotechnology in relation to the creation of new generations of drugs are very great.

In the pharmacological study of potential drugs, the pharmacodynamics of substances are studied in detail: their specific activity, duration of effect, mechanism and localization of action. An important aspect of the study is the pharmacokinetics of substances: absorption, distribution and transformation in the body, as well as routes of elimination. Special attention is paid to side effects, toxicity with single and long-term use, teratogenicity, carcinogenicity, mutagenicity. It is necessary to compare new substances with known drugs of the same groups. In the pharmacological assessment of compounds, a variety of physiological, biochemical, biophysical, morphological and other research methods are used.

Of great importance is the study of the effectiveness of substances in corresponding pathological conditions (experimental pharmacotherapy). Thus, the therapeutic effect of antimicrobial substances is tested on animals infected with pathogens of certain infections, anti-blastoma drugs - on animals with experimental and spontaneous tumors. In addition, it is desirable to have information about the peculiarities of the action of substances against the background of those pathological conditions in which they can be used (for example, atherosclerosis, myocardial infarction, inflammation). This direction, as already noted, was called “pathological pharmacology”. Unfortunately, existing experimental models rarely fully correspond to what is observed in the clinic. Nevertheless, they to some extent imitate the conditions under which drugs are prescribed, and thereby bring experimental pharmacology closer to practical medicine.

The results of the study of substances that are promising as medicines are transferred to the Pharmacological Committee of the Ministry of Health of the Russian Federation, which includes experts from various specialties (mainly pharmacologists and clinicians). If the Pharmacological Committee considers the experimental studies conducted to be exhaustive, the proposed compound is transferred to clinics that have the necessary experience in studying medicinal substances. This is a very important stage, since clinicians have the final say in evaluating new drugs. A large role in these studies is given to clinical pharmacologists, whose main task is the clinical study of the pharmacokinetics and pharmacodynamics of medicinal substances, including new drugs, and the development on this basis of the most effective and harmless methods of their use.

At clinical trial new medicines should be based on a number of principles (Table I.3). First of all, they need to be studied on a large number of patients. In many countries, this is often preceded by testing on healthy people (volunteers). It is very important that each new substance is compared with well-known drugs of the same group (e.g.

Table I.3.Principles of clinical research of new drugs (their pharmacotherapeutic effectiveness, side and toxic effects)

opioid analgesics - with morphine, cardiac glycosides - with strophanthin and digitalis glycosides). A new drug must be different from existing ones for the better.

When clinically testing substances, it is necessary to use objective methods to quantify the observed effects. A comprehensive study using a large set of adequate techniques is another requirement for clinical trials of pharmacological substances.

In cases where the element of suggestion (suggestion) can play a significant role in the effectiveness of substances, placebos are used 1 - dosage forms that, in appearance, smell, taste and other properties, imitate the drug taken, but do not contain a medicinal substance (consist only of indifferent formative substances). substances). In “blind control,” the drug and placebo are alternated in a sequence unknown to the patient. Only the attending physician knows when a patient is taking a placebo. In case of “double-blind control,” a third party (the head of the department or another doctor) is informed about this. This principle of studying substances allows for a particularly objective assessment of their effect, since in a number of pathological conditions (for example, with some pain), a placebo can have a positive effect in a significant proportion of patients.

The reliability of data obtained by different methods must be confirmed statistically.

An important element of clinical research of new drugs is compliance with ethical principles. For example, patients' consent is required to be included in a particular program to study a new drug. Tests should not be conducted on children, pregnant women, or patients with mental illness. The use of placebo is excluded if the disease is life-threatening. However, resolving these issues is not always easy, since in the interests of patients sometimes it is necessary to take certain risks. To solve these problems, there are special ethical committees that

1 From lat. placeo- I'll like it.

review relevant aspects when testing new drugs.

In most countries, clinical trials of new drugs usually go through 4 phases.

1st phase.Conducted on a small group of healthy volunteers. Optimal dosages are established that cause the desired effect. Pharmacokinetic studies concerning the absorption of substances, their half-life, and metabolism are also advisable. It is recommended that such studies be performed by clinical pharmacologists.

2nd phase.It is carried out on a small number of patients (usually up to 100-200) with the disease for which this drug is proposed. The pharmacodynamics (including placebo) and pharmacokinetics of the substances are studied in detail, and any side effects that occur are recorded. This phase of testing is recommended to be carried out in specialized clinical centers.

3rd phase.Clinical (randomized 1 controlled) trial on a large cohort of patients (up to several thousand). The effectiveness (including “double-blind control”) and safety of the substances are studied in detail. Special attention is paid to side effects, including allergic reactions, and toxicity of the drug. A comparison is made with other drugs in this group. If the results of the study are positive, the materials are submitted to the official organization, which gives permission to register and release the drug for practical use. In our country, this is the Pharmacological Committee of the Ministry of Health of the Russian Federation, whose decisions are approved by the Minister of Health.

The main tasks of pharmacology are to search and study the mechanisms of action of new drugs for their subsequent introduction into widespread medical practice. The process of creating a drug is quite complex and includes several interrelated stages. It must be emphasized that in the creation and study of medicines, in addition to pharmacologists, synthetic chemists, biochemists, biophysicists, morphologists, immunologists, geneticists, toxicologists, industrial engineers, pharmacists, and clinical pharmacologists are directly involved. If necessary, other specialists are involved in their creation. At the first stage of drug creation, synthetic chemists begin their work, synthesizing new chemical compounds with potential biological activity. Typically, synthetic chemists carry out targeted synthesis of compounds or modify the chemical structure of already known endogenous (produced in the body) biologically active substances or drugs. Targeted synthesis of medicinal substances involves the creation of biologically active substances with predetermined pharmacological properties. As a rule, such a synthesis is carried out in a series of chemical compounds in which substances with specific activity have previously been identified. For example, it is known that aliphatic phenothiazine derivatives (promazine, chlorpromazine, etc.) belong to the group of drugs that are effective in the treatment of psychoses. The synthesis of aliphatic phenothiazine derivatives similar in chemical structure suggests the presence of antipsychotic activity in the newly synthesized compounds. Thus, antipsychotic drugs such as alimemazine, levomepromazine, etc. were synthesized and then introduced into widespread medical practice. In some cases, synthetic chemists modify the chemical structure of already known drugs. For example, in the 70s. XX century In Russia, the antiarrhythmic drug moracizine was synthesized and introduced into widespread medical practice, which, according to the leading US cardiologist B. Lown, was recognized as the most promising antiarrhythmic drug of that time. Replacing the morpholine group in the moracisine molecule with diethylamine made it possible to create a new, original, highly effective antiarrhythmic drug etacizine. It is also possible to create new highly effective drugs by synthesizing exogenous analogues (obtained artificially) of endogenous (existing in the body) biologically active substances. For example, it is well known that the high-energy compound creatine phosphate plays an important role in energy transfer in the cell. Currently, a synthetic analogue of creatine phosphate, the drug neoton, has been introduced into clinical practice, which is successfully used to treat unstable angina, acute myocardial infarction, etc. In some cases, not a complete structural analogue of an endogenous biological substance is synthesized, but a chemical compound close to it in structure. In this case, sometimes the molecule of the synthesized analogue is modified in such a way as to give it some new properties. For example, a structural analogue of the endogenous biologically active substance norepinephrine, the drug phenylephrine, has a similar vasoconstrictor effect, but unlike norepinephrine, phenylephrine in the body is practically not destroyed by the enzyme catechol-O-methyltransferase, and therefore acts longer. Another way of directed synthesis of drugs is also possible - changing their solubility in fats or water, i.e. change in lipophilicity or hydrophilicity of drugs. For example, the well-known acetylsalicylic acid is insoluble in water. The addition of lysine to the acetylsalicylic acid molecule (the drug lysine acetylsalicylate) makes this compound easily soluble. Absorbed into the blood, this drug is hydrolyzed to acetylsalicylic acid and lysine. There are many examples of targeted synthesis of drugs. Biologically active compounds can also be obtained from microorganisms, plant and animal tissues, i.e. biotechnologically. Biotechnology - a branch of biological science in which various biological processes are used to produce materials, including drugs. For example, the production of natural antibiotics is based on the ability of a number of fungi and bacteria to produce biologically active substances that have a bacteriolytic (causing the death of bacteria) or bacteriostatic (causing the loss of the ability of bacterial cells to reproduce) effect. Also, with the help of biotechnology, it is possible to grow cell cultures of medicinal plants, which are close in biological activity to natural plants. An important role in the creation of new highly effective medicines belongs to such areas of biotechnology as Genetic Engineering. Recent discoveries in this area, which have shown that human genes can be cloned (cloning is the process of artificially obtaining cells with given properties, for example, by transferring a human gene into bacteria, after which they begin to produce biologically active substances with given properties), have made it possible to begin a wide industrial production of hormones, vaccines, interferons and other highly effective drugs with predetermined properties. For example, transplantation of a human gene responsible for the production of insulin in his body to a non-pathogenic microorganism - Escherichia coli (E.coli), made it possible to produce human insulin on an industrial scale. Recently, another direction has emerged in the creation of new highly effective drugs, based on the study of the characteristics of their metabolism (transformation) in the body. For example, it is known that parkinsonism is based on a deficiency of the neurotransmitter dopamine in the extrapyramidal system of the brain. It would be natural to use exogenous dopamine to treat parkinsonism, which would compensate for the lack of endogenous dopamine. Such attempts were made, but it turned out that exogenous dopamine, due to its chemical structure, is not able to penetrate the blood-brain barrier (the barrier between the blood and brain tissue). Later, the drug levodopa was synthesized, which, unlike dopamine, easily penetrates the blood-brain barrier into brain tissue, where it is metabolized (decarboxylated) and converted into dopamine. Another example of such drugs are some angiotensin-converting enzyme inhibitors (ACE inhibitors) - perindopril, ramipril, enalapril, etc. Thus, biologically inactive enalapril, being metabolized (hydrolyzed) in the liver, forms a biologically highly active metabolite enalaprilat, which has a hypotensive (lowering blood pressure) effect. Such drugs are called prodrugs, or bioprecursors(metabolic precursors). Another possible way to create drugs based on studying their metabolism is the creation of “carrier substance” complexes - biologically active substance." For example, it is known that a semisynthetic antibiotic from the penicillin group, ampicillin, is poorly absorbed in the gastrointestinal tract (GIT) - no more than 30-40% of the dose taken. To increase the absorption (bioavailability) of ampicillin, a semi-synthetic penicillin of the third generation was synthesized - bicampicillin, which does not have an antimicrobial effect, but is almost completely absorbed in the intestine (90 - 99%). Once in the blood, bicampicillin is metabolized (hydrolyzed) within 30 - 45 minutes to ampicillin, which has a pronounced antimicrobial effect. Medicines related to bioprecursors and carrier substances are collectively called prodrugs. In addition to studying pharmacologically active chemical compounds obtained by targeted synthesis or modification of the structure of known drugs, it is possible to search for biologically active substances among various classes of chemical compounds or products of plant and animal origin that have not previously been studied as potential drugs. In this case, using various tests, substances with maximum biological activity are selected from among these compounds. Such empirical(from Greek empeiria - experience) the approach was called screening pharmacological drugs. Screening (from English. screening) - selection, screening, sorting. In the case when the entire spectrum of their pharmacological activity is assessed when studying compounds, they speak of full-scale screening, and in the case of searching for substances with any specific pharmacological activity, for example anticonvulsant, we talk about targeted screening of medicinal substances. After this, in animal experiments (in vivo) and/or experiments carried out outside the body, for example in cell culture (in vitro), move on to a systematic study of the spectrum and characteristics of the pharmacological activity of newly synthesized or empirically selected compounds. In this case, the study of the biological activity of the compounds is carried out both on healthy animals and in model experiments. For example, the study of the spectrum of pharmacological activity of substances with antiarrhythmic activity is carried out on models of heart rhythm disorders, and antihypertensive (lowering blood pressure - BP) compounds - in experiments on spontaneously hypertensive rats (a specially bred line of rats with congenital hypertension - high blood pressure). After identifying high specific activity in the studied compounds, which is not inferior, at least, to the activity of already known (reference) drugs, they proceed to study the features of their mechanism of action, i.e., study the features of the influence of these compounds on certain biological processes in the body, through which realize their specific pharmacological effect. For example, the local anesthetic (analgesic) effect of local anesthetics is based on their ability to reduce the permeability of nerve fiber membranes for Na + ions and thereby block the conduction of efferent impulses through them, or the effect of b-adrenergic blockers on the heart muscle is due to their ability to block b 1 -adrenergic receptors, located on the cell membrane of myocardial cells. In addition to pharmacologists themselves, biochemists, morphologists, electrophysiologists, etc. take part in these studies. Upon completion of pharmacological studies and after determining the mechanisms of action of the studied compounds, a new stage begins - assessing the toxicity of potential drugs. Toxicity(from Greek toxicon - poison) - the effect of a drug that causes harm to the body, which can be expressed in a disorder of physiological functions and/or disruption of the morphology of organs and tissues, up to their death. The toxicity of newly synthesized compounds is studied in special toxicological laboratories, where, in addition to toxicity itself, the mutagenicity, teratogenicity and oncogenicity of these compounds are determined. Mutagenicity(from lat. mutatio - change, Greek. genes - generative) - a type of toxicity that characterizes the ability of a substance to cause changes in the genetic spectrum of a cell, leading to the inheritance of its altered properties. Teratogenicity(from Greek teras - monster, freak, Greek. genes - generating) - a type of toxicity that characterizes the ability of a substance to have a damaging effect on the fetus. Oncogenicity(from Greek onkoma - tumor, Greek genes - generating) - a type of toxicity that characterizes the ability of a substance to cause cancer. In parallel with the study of the toxicity of a substance, process engineers develop a dosage form of the substance being studied, determine methods for storing the dosage form, and, together with synthetic chemists, develop technical documentation for the industrial production of the substance. Substance(active substance, active principle) - a component of a medicinal product that has its own therapeutic, preventive or diagnostic effect. The dosage form (a state that is convenient for use in clinical practice and in which the desired effect is achieved) also includes excipients (sugar, chalk, solvents, stabilizers, etc.) that do not have pharmacological activity on their own. In cases where, after toxicological studies, the safety of the studied substance for the body is proven, the results of pharmacological and toxicological studies are summarized, a temporary Pharmacopoeial monograph is drawn up and the materials are submitted to the Federal State Institution “Scientific Center for Expertise of Medicinal Products” (FGU “NTsESMP”) under the Ministry of Health and Social development of the Russian Federation to obtain permission to conduct phase I clinical trials. Pharmacopoeial article - state drug standard containing a list of indicators and methods for monitoring their quality. FGU "NTsESMP" is an expert body of the Ministry of Health and Social Development of the Russian Federation, dealing with issues related to the practical use of domestic and foreign medicinal, preventive, diagnostic and physiotherapeutic agents, as well as excipients. The main issue that the Federal State Institution “NTsESMP” is addressing is the preparation of recommendations to the Ministry of Health and Social Development of the Russian Federation for authorization of the medical use of new drugs. After the documents are received by the Federal State Institution "NTsESMP", all materials of the preclinical study of the drug are reviewed in detail by a special expert council, which includes leading experts of the country (pharmacologists, toxicologists, clinical pharmacologists, clinicians), and in case of a positive assessment of the submitted materials, a decision is made to conduct phase I clinical trials. tests. If permission is received from the Federal State Institution "NTsESMP", the test drug is transferred to clinical pharmacologists for phase I clinical trials, which are carried out on a limited number of patients. In some countries, phase I clinical trials are carried out on healthy subjects - volunteers (20 - 80 people). In this case, special attention is paid to studying the safety and tolerability of single and multiple doses of the test drug and the characteristics of its pharmacokinetics. Phase II clinical trials of a new drug are carried out on patients (200 - 600 people) suffering from a disease for the treatment of which the drug under study is supposed to be used. The main goal of phase II clinical trials is to prove the clinical effectiveness of the drug being studied. In the event that phase II clinical trials have shown the effectiveness of the drug, they move on to phase III studies, which is carried out on a larger number (more than 2,000) of patients. The main objective of phase III clinical trials is to determine the effectiveness and safety of the drug under study under conditions as close as possible to those in which it will be used if permission for widespread medical use of the drug is received. If this stage of clinical trials is successfully completed, all available documentation is summarized, an appropriate conclusion is made, and the materials are transferred to the Ministry of Health and Social Development of the Russian Federation to obtain final approval for widespread clinical use of the drug. The last stage (phase IV) of clinical trials is carried out after receiving permission from the Ministry of Health and Social Development of the Russian Federation for the clinical use of a new drug; Phase IV clinical trials are called post-marketing studies. - postmarketing trials). The purpose of phase IV clinical trials is:

• improvement of drug dosage regimens;
• comparative analysis of the effectiveness of treatment with the studied drugs and reference drugs used for pharmacotherapy of this pathology;
• identifying differences between the drug being studied and other drugs of this class;
• identification of features of interaction of the studied drug with food and/or other drugs;
• identification of features of the use of the studied drug in patients of various age groups;
• identification of long-term treatment results, etc.

The development of new medicines is carried out jointly by many branches of science, with the main role played by specialists in the field of chemistry, pharmacology, and pharmacy. The creation of a new drug is a series of successive stages, each of which must meet certain provisions and standards approved by government agencies - the Pharmacopoeial Committee, the Pharmacological Committee, the Department of the Ministry of Health of the Russian Federation for the Introduction of New Medicines.
The process of creating new medicines is carried out in accordance with international standards - GLP (Good Laboratory Practice), GMP (Good Manufacturing Practice - Quality

industrial practice) and GCP (Good Clinical Practice).
A sign of compliance of a new drug being developed with these standards is the official approval of the process of further research - IND (Investigation New Drug).
The production of a new active substance (active substance or complex of substances) proceeds in three main directions.
Chemical synthesis of medicinal substances

• Empirical path: screening, incidental findings;
• Directed synthesis: reproduction of the structure of endogenous substances, chemical modification of known molecules;
• Targeted synthesis (rational design of a chemical compound), based on an understanding of the “chemical structure - pharmacological action” relationship.

1. the clinical trial phase is carried out with the participation of a small number of volunteers (from 4 to 24 people). Each study is carried out in one center and lasts from several days to several weeks.

• pharmacodynamics and pharmacokinetics of a single dose and multiple doses under different routes of administration;
• bioavailability;
• metabolism of the active substance;
• the influence of age, gender, food, liver and kidney function on the pharmacokinetics and pharmacodynamics of the active substance;
• interaction of the active substance with other drugs.

1. The clinical trial phase is intended to evaluate the effectiveness of the active substance (medicinal substance) in patients with a profile disease, as well as to identify negative side effects associated with the use of the drug. Phase II studies are carried out under very strict control and observation on patients in a group of 100-200 people.
2. the clinical trial phase is a multicenter extension study. They are carried out after receiving preliminary results indicating the effectiveness of the drug substance, and their main task is to obtain additional information on the effectiveness and safety of various dosage forms of the drug, which are necessary to assess the overall balance of benefits and risks from its use, as well as to obtain additional information for preparation of medical labeling. A comparison is made with other drugs in this group. These studies usually involve several hundred to several thousand people (average 1000-3000). Recently, the term “mega-studies” has emerged, in which more than 10,000 patients can participate. During phase III, optimal doses and administration regimens are determined, the nature of the most common adverse reactions, clinically significant drug interactions, the influence of age, concomitant conditions, etc. are studied. The research conditions are as close as possible to the real conditions of use of the drug. Such studies are initially conducted using an open method (the doctor and the patient know which drug is being used - new, control or placebo). Further studies are carried out using a single-blind method (the patient does not know which drug is being used - new, control or placebo), double-blind (double-blind) method, in which neither the doctor nor

the patient does not know which drug is being used - a new one, control or placebo, and a triple-blind method, when neither the doctor, nor the patient, nor the organizers and statisticians know the prescribed therapy for a particular patient. This phase is recommended to be carried out in specialized clinical centers.
Data obtained in phase III clinical trials are the basis for creating instructions for the use of the drug and an important factor for official decision-making on its registration and the possibility of medical use.
Bioequivalence studies of drugs
Assessing the bioequivalence of medicinal products is the main type of quality control of reproduced (generic) drugs - medicinal products containing the same medicinal substance in the same dose and dosage form as the original medicinal product.
Two drugs (in the same dosage form) are bioequivalent if they provide the same bioavailability of the drug substance and the same rate of achievement of the maximum concentration of the substance in the blood.
Bioequivalence studies allow one to make informed conclusions about the quality of the drugs being compared using a relatively smaller amount of primary information and in a shorter period of time than during clinical trials. In the Russian Federation, bioequivalence studies are regulated by “Methodological recommendations for conducting high-quality clinical studies of bioequivalence of medicinal products.”
Registration of a medicinal product
The data obtained during the research is formalized in the form of appropriate documents, which are sent to government organizations that register the drug and give permission for its medical use. In the Russian Federation, registration of medicinal products is carried out by the Ministry of Health of the Russian Federation.
Post-marketing testing
Registration of a drug does not mean that research into its pharmacological properties has been stopped. There is phase IV clinical trials, which is called “post-marketing studies,” i.e. Phase IV clinical trials are carried out after the start of drug sales in order to obtain more detailed information about the safety and effectiveness of the drug in various dosage forms and doses, with long-term use in various groups of patients, which allows for a more complete assessment of the strategy for using the drug and identifying long-term treatment results. The studies involve a large number of patients, which makes it possible to identify previously unknown and rarely encountered adverse effects. Phase IV studies are also aimed at assessing the comparative effectiveness and safety of the drug. The data obtained is compiled in the form of a report, which is sent to the organization that has given permission for the release and use of the drug.
If, after registration of a drug, clinical trials are conducted, the purpose of which is to study new, unregistered properties, indications, methods of use or combinations of medicinal substances, then such clinical trials are considered as tests of a new medicinal product, i.e. are considered early phase studies.

Sources for obtaining medications may be:

• Products of chemical synthesis. Currently, most drugs are obtained this way. There are several ways to find drugs among chemical synthesis products:
• Pharmacological screening toscreen- sift). A method of searching for substances with a certain type of pharmacological activity among a variety of chemical compounds synthesized by chemists on a special order. Pharmacological screening was first used by the German scientist Domagk, who worked at the chemical concern IG-FI and searched for antimicrobial agents among compounds synthesized for dyeing fabrics. One of these dyes, red streptocide, has been found to have an antimicrobial effect. This is how sulfonamide drugs were discovered. Conducting screening is an extremely time-consuming and expensive process: to detect one drug, a researcher must test several hundred or thousand compounds. Thus, Paul Ehrlich, when searching for antisyphilitic drugs, studied about 1000 organic compounds of arsenic and bismuth, and only the 606th drug, salvarsan, turned out to be quite effective. Currently, to carry out screening, it is necessary to synthesize at least 10,000 initial compounds in order to be confident that among them there is one (!) potentially effective drug.
• Molecular drug design. The creation of scanning tomography and X-ray analysis, the development of computer technologies have made it possible to obtain three-dimensional images of the active centers of receptors and enzymes and to select molecules for them, the configuration of which exactly matches their shape. Molecular design does not require the synthesis of thousands of compounds and their testing. The researcher immediately creates several molecules that are ideally suited to the biological substrate. However, in terms of its economic cost, this method is not inferior to screening. Neuraminidase inhibitors, a new group of antiviral drugs, were obtained using the molecular design method.
• Reproduction of nutrients. In this way, mediators were obtained - adrenaline, norepinephrine, prostaglandins; drugs with the activity of hormones of the pituitary gland (oxytocin, vasopressin), thyroid gland, adrenal glands.
• Targeted modification of molecules with already known activity. For example, it was found that the introduction of fluorine atoms into drug molecules, as a rule, increases their activity. By fluoridating cortisol, powerful glucocorticoid drugs were created; by fluoridating quinolones, the most active antimicrobial agents, fluoroquinolones, were obtained.
• Synthesis of pharmacologically active metabolites. When studying the metabolism of the tranquilizer diazepam, it was found that in the liver it produces a substance with tranquilising activity - oxazepam. Currently, oxazepam is synthesized and released as a separate drug.
• Random finds (“serendipite” method). The method got its name from the fairy tale “The Three Princesses of Serendipe” by Horace Walpole. These sisters often made successful discoveries and found solutions to problems themselves without specifically meaning to. An example of a “serendipitous” drug production is the creation of penicillin, which occurred largely due to the fact that A. Fleming accidentally noticed that microorganisms had died in a moldy cup forgotten in the thermostat at Christmas. Sometimes accidental discoveries are made as a result of error. For example, mistakenly believing that the anticonvulsant effect of phenytoin is due to the fact that it is a folic acid antagonist, employees of the Glaxo Wellcome concern synthesized lamotrigine, a new anticonvulsant. However, it turned out that, firstly, the effect of phenytoin is not associated with folic acid, and secondly, lamotrigine itself does not interfere with folate metabolism.
• Components of plant raw materials. Many plants contain substances that have beneficial pharmacological properties, and the discovery of more and more new compounds continues to this day. Well-known examples of drugs obtained from medicinal plant materials are morphine, isolated from the opium poppy ( Papaversomniferum), atropine derived from belladonna ( Atropabelladonna).
• Animal tissues. Some hormonal drugs are obtained from animal tissues - insulin from the pancreas tissue of pigs, estrogens from the urine of stallions, FSH from the urine of women.
• Products of the vital activity of microorganisms. A number of antibiotics and drugs for the treatment of atherosclerosis from the group of statins are obtained from the culture fluid of various fungi and bacteria.
• Mineral raw materials. Petroleum jelly is obtained from by-products of petroleum refining and is used as an ointment base.

Each drug, before it begins to be used in practical medicine, must undergo a certain study and registration procedure, which would guarantee, on the one hand, the effectiveness of the drug in the treatment of a given pathology, and on the other hand, its safety. The introduction of medicines is divided into a number of stages (see Table 1).

Diagram 2 shows the main stages of drug movement in the process of its development and study. After completion of phase III clinical trials, the documentation is again received by the Pharmacological Committee (the volume of the complete dossier can be up to 1 million pages) and within 1-2 years is registered in the State Register of Medicines and Medical Products. Only after this does the pharmaceutical concern have the right to begin industrial production of the drug and its distribution through the pharmacy chain.
Table 1. Brief description of the main stages in the development of new drugs.

Scheme 2. Main stages of research and implementation of medicines in medical practice.
However, in parallel with the sale of the drug, the pharmaceutical concern organizes phase IV clinical trials (post-marketing studies). The purpose of this phase is to identify rare but potentially dangerous adverse effects of the drug. Participants in this phase include all practitioners who prescribe the drug and the patient who uses it. If serious deficiencies are discovered, the drug may be recalled by the concern. For example, after a new third-generation fluoroquinolone, grepafloxacin, successfully passed all stages of testing and went on sale, the manufacturer recalled the drug less than a year later. Post-marketing studies have found that grepafloxacin may be a cause of fatal arrhythmias.
When organizing and conducting clinical trials, the following requirements must be met:

• The study must be controlled - i.e. In parallel with the group receiving the study drug, a group should be recruited that receives a standard comparator drug (positive control) or an inactive drug that superficially mimics the study drug (placebo control). This is necessary in order to eliminate the element of self-suggestion when treating with this medicine. Depending on the type of control, there are:
• Single-blind study: the patient does not know whether he is taking a new drug or a control drug (placebo).
• Double-blind study: both the patient and the doctor who dispenses the drugs and evaluates their effect do not know whether the patient is receiving a new drug or a control drug. Only the director of the study has information about this.
• Triple-blind study: Neither the patient, the physician, nor the study director knows which group is receiving the new drug and which is receiving the control. Information about this is available from an independent observer.
• The study must be randomized - i.e. a homogeneous group of patients should be randomly divided into experimental and control groups.
• The research must be organized in compliance with all ethical standards and principles set out in the Declaration of Helsinki.