Fundamentals of the development of new drugs. Stages of the process of creating a new drug. Stability and shelf life of medicines Stages of drug development
It is known that in the process of creating new medicines, as a rule, there are two main determining factors - objective and subjective. Each of these factors is important in its own way, but only if their force vectors are unidirectional can the ultimate goal of any pharmaceutical research be achieved - obtaining a new drug.
The subjective factor is determined primarily by the researcher’s desire to deal with a scientific problem, his erudition, qualifications and scientific experience. The objective side of the process is related to the identification of priority and promising research areas that can affect the level of quality of life (i.e., the QoL index), as well as commercial attractiveness.
A detailed consideration of the subjective factor ultimately comes down to finding an answer to one of the most intriguing philosophical questions: what place was assigned to His Majesty Chance in the fact that it was this researcher (or group of researchers) who happened to be at the right time and in the right place to relate to the development of this or that specific drug? One of the striking historical examples of the significance of this factor is the history of A. Fleming’s discovery of antibiotics and lysozyme. In this regard, the head of the laboratory in which Fleming worked wrote: “Despite all my respect for the father of English antibiotics, I must note that not a single self-respecting laboratory assistant, much less a bacteriologist, would ever allow himself to have for carrying out experiments, a Petri dish of such cleanliness that mold could grow.” And if we take into account the fact that the creation of penicillin took place in 1942, i.e. At the very height of the Second World War and, consequently, at the peak of infectious complications from gunshot wounds in hospitals, when humanity more than ever needed a highly effective antibacterial drug, the thought of providence involuntarily comes to mind.
As for the objective factor, its understanding is more amenable to logical cause-and-effect analysis. This means that at the stage of developing a new drug, the criteria that determine the directions of scientific research come to the fore. The primary factor in this process is the urgent medical need or the opportunity to develop new or improve old treatment, which can ultimately affect the quality of life. A good example is the development of new effective antitumor, cardiovascular, hormonal drugs, and means of combating HIV infection. It would be timely to remind you that indicators of the level of quality of life are a person’s physical and emotional state, intellectual activity, a sense of well-being and satisfaction with life, social activity and the degree of its satisfaction. It should be noted that the QoL index is directly related to the severity of the disease, which determines the financial costs of society for hospitalization, patient care, the cost of a course of therapy, and treatment of chronic pathology.
The commercial attractiveness of a drug is determined by the incidence rate of a particular pathology, its severity, the amount of treatment costs, the size of the sample of patients suffering from this disease, the duration of the course of therapy, the age of the patients, etc. In addition, there are a number of nuances related to the logistical and financial capabilities of the developer and future manufacturer. This is determined by the fact that, firstly, the developer spends most of the funds allocated for scientific research on maintaining the achieved and strongest positions in the market (where he is already, as a rule, a leader); secondly, the focus of the development of a new drug is the relationship between the expected costs and the actual profit figures that the developer expects to receive from the sale of the drug, as well as the time relationship between these two parameters. Thus, if in 1976 pharmaceutical companies spent an average of about $54 million on research and production of a new drug, then already in 1998 - almost $597 million.
The process of developing and marketing a new drug takes an average of 12-15 years. The increase in costs for the development of new medicines is associated with stricter society's requirements for the quality and safety of pharmaceuticals. In addition, if we compare the costs of research and development in the pharmaceutical industry with other types of profitable business, in particular with radio electronics, it turns out that they are 2 times higher, and in comparison with other industries - 6 times.
Methodology for finding new medicines
In the recent past, the main method of finding new drugs was elementary empirical screening of existing or newly synthesized chemical compounds. Naturally, there cannot be “pure” empirical screening in nature, since any study is ultimately based on previously accumulated factual, experimental and clinical material. A striking historical example of such screening is the search for antisyphilitic drugs conducted by P. Ehrlich among 10 thousand arsenic compounds and ending with the creation of the drug salvarsan.
Modern high-tech approaches involve the use of the HTS method (High Through-put Screening), i.e. method of empirical design of a new highly effective medicinal compound. At the first stage, using high-speed computer technology, hundreds of thousands of substances are tested for activity relative to the molecule under study (most often this means the molecular structure of the receptor). At the second stage, direct modeling of structural activity occurs using special programs such as QSAR (Quantitative Structure Activity Relationship). The end result of this process is the creation of a substance with the highest level of activity with minimal side effects and material costs. Modeling can proceed in two directions. The first is the construction of an ideal “key” (i.e., a mediator), suitable for a natural “lock” (i.e., a receptor). The second is the design of a “lock” for the existing natural “key”. Scientific approaches used for these purposes are based on a variety of technologies, ranging from molecular genetics and NMR methods to direct computer modeling of the active molecule in three-dimensional space using CAD (Computer Assisted Design) programs. However, ultimately, the process of designing and synthesizing potential biologically active substances is still based on the intuition and experience of the researcher.
Once a promising chemical compound has been synthesized and its structure and properties have been established, research begins. preclinical stage animal testing. It includes a description of the chemical synthesis process (data on the structure and purity of the drug is provided), experimental pharmacology (i.e. pharmacodynamics), and the study of pharmacokinetics, metabolism and toxicity.
Let us highlight the main priorities of the preclinical stage. For pharmacodynamics is a study of the specific pharmacological activity of a drug and its metabolites (including determination of the rate, duration, reversibility and dose dependence of effects in model experiments in vivo, ligand-receptor interactions, influence on the main physiological systems: nervous, musculoskeletal, genitourinary and cardiovascular); For pharmacokinetics And metabolism- this is the study of absorption, distribution, protein binding, biotransformation and excretion (including calculations of rate constants of elimination (Kel), absorption (Ka), excretion (Kex), drug clearance, area under the concentration-time curve, etc.); For toxicology- this is the determination of acute and chronic toxicity (on at least two types of experimental animals), carcinogenicity, mutagenicity, teratogenicity.
Experience shows that during testing, approximately half of candidate substances are rejected precisely due to low stability, high mutagenicity, teratogenicity, etc. Preclinical studies, like clinical studies, can be divided into four phases (stages):
Preclinical studies (stage I) (Selection of promising substances)
1.Evaluating patent opportunities and filing a patent application.
2.Basic pharmacological and biochemical screening.
3.Analytical study of the active substance.
4.Toxicological studies to determine maximum tolerated doses.
Preclinical studies (stage II) (Pharmacodynamics/kinetics in animals)
1.Detailed pharmacological studies (main effect, adverse reactions, duration of action).
2.Pharmacokinetics (absorption, distribution, metabolism, excretion).
Preclinical studies (stage III) (Security Assessment)
1.Acute toxicity (single administration to two animal species).
2.Chronic toxicity (repeated administration to two animal species).
3.Toxicity study on the effect on the reproductive system (fertility, teratogenicity, peri- and postnatal toxicity).
4.Mutagenicity study.
5.Impact on the immune system.
6.Skin allergic reactions.
Preclinical studies (stage IV) (Early technical development)
1.Synthesis under production conditions.
2.Development of analytical methods to determine the drug, breakdown products and possible contamination.
3.Synthesis of a drug labeled with radioactive isotopes for pharmacokinetic analysis.
4.Stability study.
5.Production of dosage forms for clinical trials.
Once, based on the necessary preclinical studies, evidence has been obtained of the safety and therapeutic effectiveness of the drug, as well as the possibility of conducting quality control, the developers complete and submit an application to the permitting and regulatory authorities for the right to conduct clinical trials. In any case, before the developer receives permission to conduct clinical trials, he must submit an application to the licensing authorities containing the following information: 1) data on the chemical composition of the medicinal product; 2) report on the results of preclinical studies; 3) procedures for obtaining the substance and quality control in production; 4) any other available information (including clinical data from other countries, if available); 5) description of the program (protocol) of the proposed clinical trials.
Thus, human trials can only begin if the following basic requirements are met: information from preclinical trials convincingly shows that the drug can be used in the treatment of this specific pathology; the clinical trial design is adequately designed and, therefore, clinical trials can provide reliable information about the effectiveness and safety of the drug; the drug is safe enough to be tested in humans and subjects will not be exposed to undue risk.
The transition stage from preclinical studies to clinical studies can be schematically represented as follows:
The human clinical trial program for a new drug consists of four phases. The first three are carried out before the drug is registered, and the fourth, called post-registration or post-marketing, is carried out after the drug is registered and approved for use.
Phase 1 clinical trials. Often this phase is also called medical-biological, or clinical-pharmacological, which more adequately reflects its goals and objectives: to establish the tolerability and pharmacokinetic characteristics of the drug in humans. As a rule, phase 1 clinical trials (CT) involve healthy volunteers ranging from 80 to 100 people (in our conditions, usually 10-15 young healthy men). An exception is the testing of anticancer drugs and anti-AIDS drugs due to their high toxicity (in these cases, tests are immediately carried out on patients with these diseases). It should be noted that in the 1st phase of the CI, on average, about 1/3 of the candidate substances are eliminated. In fact, the 1st phase of the trial should answer the main question: is it worth continuing work on a new drug, and if so, what will be the preferred therapeutic doses and routes of administration?
Phase 2 clinical trials — the first experience of using a new drug to treat a specific pathology. This phase is often called pilot, or pilot, studies, since the results obtained during these tests allow planning of more expensive and extensive studies. The 2nd phase includes both men and women in the amount of 200 to 600 people (including women of childbearing age, if they are protected from pregnancy and control pregnancy tests have been carried out). Conventionally, this phase is divided into 2a and 2b. At the first stage of the phase, the problem of determining the level of safety of the drug in selected groups of patients with a specific disease or syndrome that needs to be treated is solved, while at the second stage the optimal dose level of the drug is selected for the subsequent, 3rd phase. Naturally, phase 2 trials are controlled and imply the presence of a control group pp, which should not differ significantly from the experimental (main) one in terms of gender, age, or initial background treatment. It should be emphasized that background treatment (if possible) should be stopped 2-4 weeks before the start of the trial. In addition, groups should be formed using randomization, i.e. by random distribution using tables of random numbers.
Phase 3 clinical trials - these are clinical studies of the safety and effectiveness of a drug under conditions similar to those in which it will be used if it is approved for medical use. That is, during the 3rd phase, significant interactions between the study drug and other drugs are studied, as well as the influence of age, gender, concomitant diseases, etc. Typically these are blinded, placebo-controlled studies. , during which courses of treatment are compared with standard drugs. Naturally, a large number of patients (up to 10 thousand people) take part in this phase of the clinical trial, which makes it possible to clarify the features of the drug’s action and determine relatively rare adverse reactions with long-term use. During the 3rd phase of the clinical trial, pharmacoeconomic indicators are also analyzed, which are subsequently used to assess the quality of life of patients and their provision of medical care. Information obtained from phase 3 studies is fundamental for making a decision on the registration of a drug and the possibility of its medical use.
Thus, the recommendation of a drug for clinical use is considered justified if it is more effective; has better tolerability than known drugs; more economically beneficial; has a simpler and more convenient treatment method; increases the effectiveness of existing drugs in combination treatment. However, drug development experience shows that only about 8% of drugs that receive development approval are approved for medical use.
Phase 4 clinical trials - these are the so-called post-marketing, or post-registration, studies conducted after obtaining regulatory approval for the medical use of the drug. As a rule, CIs proceed in two main directions. The first is to improve dosing regimens, treatment timing, study interactions with food and other drugs, evaluate effectiveness in various age groups, collect additional data regarding economic indicators, study long-term effects (primarily affecting the reduction or increase in the mortality rate of patients receiving this drug). a drug). The second is the study of new (unregistered) indications for the drug, methods of its use and clinical effects when combined with other drugs. It should be noted that the second direction of the 4th phase is considered as testing a new drug in the early phases of the study.
All of the above is presented schematically in the figure.
Types and types of clinical trials: design, design and structure
The main criterion in determining the type of clinical trial is the presence or absence of control. In this regard, all clinical trials can be divided into uncontrolled (non-comparative) and controlled (with comparative control). At the same time, the cause-and-effect relationship between any effect on the body and the response can be judged only on the basis of comparison with the results obtained in the control group.
Naturally, the results of uncontrolled and controlled studies are qualitatively different. However, this does not mean that uncontrolled studies are not needed at all. Typically, they are designed to identify relationships and patterns that are then proven through controlled studies. In turn, uncontrolled studies are justified in phases 1 and 2 trials, when toxicity in humans is studied, safe doses are determined, “pilot” studies, purely pharmacokinetic studies are conducted, as well as long-term post-marketing trials aimed at identifying rare side effects.
At the same time, phase 2 and 3 trials, aimed at proving a certain clinical effect and analyzing the comparative effectiveness of different treatment methods, by definition must be comparative (i.e., have control groups). Thus, the presence of a control group is fundamental to a comparative (controlled) study. In turn, control groups are classified according to the type of treatment assignment and the method of selection. Based on the type of treatment assignment, the groups are divided into subgroups receiving placebo, receiving no treatment, receiving different doses of the drug or different treatment regimens, and receiving another active drug. According to the method of selecting patients into the control group, a distinction is made between selection with randomization from the same population and “external” (“historical”), when the population differs from the population of this trial. To minimize errors in group formation, a blind study method and randomization with stratification are also used.
Randomization is a method of assigning subjects to groups by random sampling (preferably using computer codes based on a sequence of random numbers), whereas stratification is a process that guarantees an even distribution of subjects into groups, taking into account factors that significantly influence the outcome of the disease (age, excess weight, medical history, etc.).
Blind study assumes that the subject is unaware of the treatment method. At double blind method The researcher does not know about the treatment being carried out, but the monitor does. There is also the so-called “triple blinding” method, when the monitor does not know about the treatment method, but only the sponsor does. The quality of the research has a significant impact compliance , i.e. strict adherence to the test regime on the part of the subjects.
One way or another, for high-quality clinical trials, it is necessary to have a well-written trial plan and design with a clear definition of inclusion/exclusion criteria for the study and clinical relevance (significance).
The design elements of a standard clinical trial are presented as follows: presence of a medical intervention; presence of a comparison group; randomization; stratification; use of disguise. However, although there are a number of commonalities in the design, its design will vary depending on the objectives and phase of the clinical trial. The structure of the most commonly used typical study designs in clinical trials is presented below.
1) Single group study design diagram: All subjects receive the same treatment, but its results are compared not with the results of the control group, but with the results of the initial state for each patient or with the results of control according to archival statistics, i.e. subjects are not randomized. Therefore, this model can be used in phase 1 studies or complement other types of studies (particularly those evaluating antibiotic therapy). Thus, the main drawback of the model is the lack of a control group.
2) Diagram of the parallel group study model: subjects in two or more groups receive different courses of treatment or different doses of drugs. Naturally, in this case, randomization is carried out (usually with stratification). This type of model is considered the most optimal for determining the effectiveness of treatment regimens. It should be noted that most clinical trials are conducted in parallel groups. Moreover, regulatory authorities prefer this type of CT, so the main phase 3 studies are also carried out in parallel groups. The disadvantage of this type of trial is that it requires a larger number of patients and therefore higher costs; The duration of research according to this scheme increases significantly.
3)Cross model diagram: subjects are randomized into groups that receive the same course of treatment, but with a different sequence. As a rule, a washout period of five half-lives is required between courses in order for patients to return to baseline values. Typically, crossover models are used in pharmacokinetics and pharmacodynamics studies because they are more cost-effective (requiring fewer patients) and when clinical conditions are relatively constant over the study period.
Thus, throughout the entire stage of clinical trials, from the moment of planning to the interpretation of the data obtained, statistical analysis occupies one of the strategic places. Considering the variety of nuances and specifics of conducting clinical trials, it is difficult to do without a specialist in specific biological statistical analysis.
Bioequivalent clinical studies
Clinicians are well aware that drugs that have the same active substances but are produced by different manufacturers (so-called generic drugs) differ significantly in their therapeutic effect, as well as in the frequency and severity of side effects. An example is the situation with diazepam for parenteral administration. Thus, neurologists and resuscitators who worked in the 70-90s know that in order to stop seizures or perform induction anesthesia, it was enough for the patient to inject 2-4 ml of seduxen intravenously (i.e. 10-20 mg diazepam), produced by Gedeon Richter (Hungary), while to achieve the same clinical effect, sometimes 6-8 ml of relanium (i.e. 30-40 mg of diazepam), produced by Polfa (Poland) was not enough . To relieve withdrawal symptoms, of all the “diazepams” for parenteral administration, the most suitable was apaurin produced by KRKA (Slovenia). This phenomenon, as well as the significant economic benefits associated with the production of generic drugs, formed the basis for the development and standardization of bioequivalence studies and associated biological and pharmacokinetic concepts.
A number of terms need to be defined. Bioequivalence is a comparative assessment of the effectiveness and safety of two drugs under the same conditions of administration and in the same doses. One of these drugs is a standard or reference drug (usually a well-known original drug or a generic drug), and the other is an investigational drug. The main parameter studied in bioequivalence clinical studies is bioavailability (bioavailability) . To understand the significance of this phenomenon, we can recall a situation that occurs quite often during antibiotic therapy. Before prescribing antibiotics, determine the sensitivity of microorganisms to them in vitro. For example, sensitivity to cephalosporins in vitro may be an order of magnitude (i.e. 10 times) higher than that of ordinary penicillin, while during therapy in vivo the clinical effect is higher with the same penicillin. Thus, bioavailability is the rate and degree of accumulation of the active substance at the site of its intended action in the human body.
As mentioned above, the problem of bioequivalence of drugs is of great clinical, pharmaceutical and economic importance. Firstly, the same drug is produced by different companies using different excipients, in different quantities and using different technologies. Secondly, the use of generic drugs in all countries is associated with a significant difference in cost between original drugs and generic drugs. Thus, the total value of sales of generics in the UK, Denmark, and the Netherlands on the prescription drug market in 2000 amounted to 50-75% of all sales. Here it would be appropriate to give the definition of a generic drug in comparison with the original drug: generic- this is a medicinal analogue of the original drug (manufactured by another company that is not the patent holder), the period of patent protection for which has already expired. It is typical that a generic drug contains an active substance (active substance) identical to the original drug, but differs in auxiliary (inactive) ingredients (fillers, preservatives, dyes, etc.).
A number of conferences were held to develop and standardize documents for assessing the quality of generic drugs. As a result, rules for conducting bioequivalence studies were adopted. In particular, for the EU these are the “State Regulations on Medical Products in the European Union” (last edition adopted in 2001); for the USA, similar rules were adopted in the latest edition in 1996; for Russia - on August 10, 2004, the order of the Ministry of Health of the Russian Federation “On conducting high-quality studies of the bioequivalence of medicines” came into force; for the Republic of Belarus - this is Instruction No. 73-0501 dated May 30, 2001 “On registration requirements and rules for conducting the equivalence of generic medicines.”
Taking into account a number of provisions from these fundamental documents, it can be stated that drugs are considered bioequivalent if they are pharmaceutically equivalent, and their bioavailability (i.e. the rate and degree of absorption of the active substance) is the same and, after administration, they can provide the required effectiveness and safety in the same dose.
Naturally, the performance of bioequivalence studies must comply with GCP principles. However, conducting clinical trials on bioequivalence has a number of features. First, studies should be carried out in healthy, preferably non-smoking, volunteers of both sexes aged 18-55 years, with precise inclusion/exclusion criteria and an appropriate design (controlled, crossover clinical trials with random assignment of volunteers). Secondly, the minimum number of subjects is at least 12 people (usually 12-24). Thirdly, the ability to participate in the study must be confirmed by standard laboratory tests, medical history and general clinical examination. Moreover, both before and during the test, special medical examinations can be carried out, depending on the characteristics of the pharmacological properties of the drug being studied. Fourthly, appropriate standard conditions must be created for all subjects for the period of research, including a standard diet, exclusion of other medications, the same motor and daily routine, physical activity regime, exclusion of alcohol, caffeine, narcotic substances and concentrated juices, time spent in the research center and time of completion of the trial. Moreover, it is necessary to study bioavailability both when administering a single dose of the drug under study, and when a stable state is achieved (i.e., a stable concentration of the drug in the blood).
Of the pharmacokinetic parameters used to assess bioavailability, the maximum drug concentration (Cmax) is usually determined; time to achieve maximum effect (T max reflects the rate of absorption and onset of the therapeutic effect); area under the pharmacokinetic curve (AUC - area under concentration - reflects the amount of the substance entering the blood after a single administration of the drug).
Naturally, the methods used to determine bioavailability and bioequivalence must be accurate, reliable and reproducible. According to WHO regulations (1994, 1996), it is determined that two drugs are considered bioequivalent if they have similar pharmacokinetic parameters and the differences between them do not exceed 20%.
Thus, a bioequivalence study allows one to make an informed conclusion about the quality, effectiveness and safety of the drugs being compared based on a smaller amount of primary information and in a shorter time than when conducting other types of clinical trials.
When performing equivalence studies between two drugs in a clinical setting, there are situations where the drug or its metabolite cannot be quantitatively determined in blood plasma or urine. In this case tea is estimated pharmacodynamic equivalence. At the same time, the conditions in which these studies are conducted must strictly comply with GCP requirements. This, in turn, means that the following requirements must be met when planning, conducting and evaluating results: 1) the measured response must represent a pharmacological or therapeutic effect that confirms the effectiveness or safety of the drug; 2) the technique must be validated in terms of accuracy, reproducibility, specificity and reliability; 3) the response must be measured quantitatively in a double-blind manner, and the results must be recorded using an appropriate instrument with good reproducibility (if such measurements are not possible, data recording is carried out using a visual analogue scale, and data processing will require special non-parametric statistical analysis (for example, the use of the Mann test -Whitney, Wilcoxon, etc.); 4) if there is a high probability of a placebo effect, it is recommended to include a placebo in the treatment regimen; 5) the study design should be cross-sectional or parallel.
Closely related to bioequivalence are concepts such as pharmaceutical and therapeutic equivalence.
Pharmaceutical equivalence refers to the situation where the drugs being compared contain the same amount of the same active substance in the same dosage form, meet the same comparable standards and are administered in the same way. Pharmaceutical equivalence does not necessarily imply therapeutic equivalence, since differences in excipients and manufacturing processes may result in differences in drug efficacy.
Under therapeutic equivalence understand a situation where drugs are pharmaceutically equivalent and their effects on the body (i.e. pharmacodynamic, clinical and laboratory effects) are the same.
Literature
1. Belykh L.N. Mathematical methods in medicine. - M.: Mir, 1987.
2. Valdman A.V.. Experimental and clinical pharmacokinetics: collection. tr. Research Institute of Pharmacology of the USSR Academy of Medical Sciences. - M.: Medicine, 1988.
3.Lloyd E. Handbook of Applied Statistics. - M., 1989.
4. Maltsev V.I.. Clinical drug trials.—2nd ed. - Kyiv: Morion, 2006.
5. Rudakov A.G.. Handbook of clinical trials / trans. from English - Brookwood Medical Publication Ltd., 1999.
6. Soloviev V.N., Firsov A.A., Filov V.A. Pharmacokinetics (guide). - M.: Medicine, 1980.
7. Stefanov O.V. Preclinical studies of medicinal products (methodological recommendations). - Kiev, 2001.
8. Stuper E. Machine analysis of the relationship between chemical structure and biological activity. - M.: Mir, 1987.
9. Darvas F., Darvas L. // Quantitative structure-activity analysis / ed. by R. Franke et al. - 1998. - R. 337-342.
10.Dean P.M.. // Trends Pharm. Sci. - 2003. - Vol. 3. - P. 122-125.
11. Guideline for Good Clinical Trials. - ICN Harmonized Tripartite Guideline, 1998.
Medical news. - 2009. - No. 2. - pp. 23-28.
Attention! The article is addressed to medical specialists. Reprinting this article or its fragments on the Internet without a hyperlink to the source is considered a violation of copyright.
Introduction
Despite the achievements of modern anesthesia, the search continues for less dangerous drugs for anesthesia, the development of various options for multicomponent selective anesthesia, which can significantly reduce their toxicity and negative side effects.
The creation of new medicinal substances includes 6 stages:
Creation of a medicinal substance using computer modeling.
Laboratory synthesis.
Bioscreening and preclinical testing.
Clinical trials.
Industrial production.
Recently, computer modeling has increasingly entered into the technology of creating new synthetic medicinal substances. Pre-conducted computer screening saves time, materials and effort during analogue drug discovery. The local anesthetic drug Dicain was chosen as the object of study, which has a higher level of toxicity among its analogues, but is not replaceable in ophthalmic and otorhinolaryngological practice. To reduce and maintain or enhance the local anesthetic effect, compositions are being developed that additionally contain antihistamines, amino blockers, and adrenaline.
Dicaine belongs to the class of esters P-aminobenzoic acid (β-dimethylaminoethyl ester P-butylaminobenzoic acid hydrochloride). The C -N distance in the 2-aminoethanol group determines the two-point contact of the dicaine molecule with the receptor through dipole-dipole and ionic interactions.
The basis for modifying the dicaine molecule to create new anesthetics is the principle of introducing chemical groups and fragments into the existing anesthesiophore, which enhance the interaction of the substance with the bioreceptor, reduce toxicity and produce metabolites with positive pharmacological effects.
Based on this, we have proposed the following options for new molecular structures:
An “ennobling” carboxyl group was introduced into the benzene ring, and the dimethylamino group was replaced by a more pharmacoactive diethylamino group.
Aliphatic n-butyl radical is replaced by an adrenaline fragment.
Aromatic base P-aminobenzoic acid is replaced by nicotinic acid.
The benzene ring is replaced by a piperidine ring, which is characteristic of the effective anesthetic promedol.
The work carried out computer modeling of all these structures using the HyperChem program. At subsequent stages of computer design, the biological activity of new anesthetics was studied using the PASS program.
1. Literature review
1.1 Medicines
Despite the huge arsenal of available drugs, the problem of finding new highly effective drugs remains relevant. This is due to the lack or insufficient effectiveness of drugs to treat certain diseases; the presence of side effects of certain medications; restrictions on the shelf life of medicines; long shelf life of drugs or their dosage forms.
The creation of each new original medicinal substance is the result of the development of fundamental knowledge and achievements of medical, biological, chemical and other sciences, intensive experimental research, and the investment of large material costs. The successes of modern pharmacotherapy were the result of deep theoretical studies of the primary mechanisms of homeostasis, the molecular basis of pathological processes, the discovery and study of physiologically active compounds (hormones, mediators, prostaglandins, etc.). The development of new chemotherapeutic agents has been facilitated by advances in the study of the primary mechanisms of infectious processes and the biochemistry of microorganisms.
A medicinal product is a single-component or complex composition that has preventive and therapeutic effectiveness. A medicinal substance is an individual chemical compound used as a medicine.
Dosage form is the physical state of a drug that is convenient for use.
A medicinal product is a dosed medicinal product in a dosage form adequate for individual use and in optimal design with an annotation about its properties and use.
Currently, each potential drug substance undergoes 3 stages of study: pharmaceutical, pharmacokinetic and pharmacodynamic.
At the pharmaceutical stage, the beneficial effect of the drug substance is determined, after which it is subjected to preclinical study of other indicators. First of all, acute toxicity is determined, i.e. lethal dose for 50% of experimental animals. Subchronic toxicity is then determined under conditions of long-term (several months) administration of the drug in therapeutic doses. At the same time, possible side effects and pathological changes in all body systems are observed: teratogenicity, effects on reproduction and the immune system, embryotoxicity, mutagenicity, carcinogenicity, allergenicity and other harmful side effects. After this stage, the drug can be admitted to clinical trials.
At the second stage - pharmacokinetic - the fate of the drug in the body is studied: the routes of its administration and absorption, distribution in biofluids, penetration through protective barriers, access to the target organ, pathways and speed of biotransformation, routes of excretion from the body (with urine, feces, sweat and breathing).
At the third - pharmacodynamic - stage, problems of recognition of a drug substance (or its metabolites) by targets and their subsequent interaction are studied. Targets can be organs, tissues, cells, cell membranes, enzymes, nucleic acids, regulatory molecules (hormones, vitamins, neurotransmitters, etc.), as well as bioreceptors. The issues of structural and stereospecific complementarity of interacting structures, functional and chemical correspondence of a drug substance or metabolite to its receptor are considered. The interaction between a drug substance and a receptor or acceptor, leading to activation (stimulation) or deactivation (inhibition) of the biotarget and accompanied by a response from the body as a whole, is mainly ensured by weak bonds - hydrogen, electrostatic, van der Waals, hydrophobic.
1.2 Creation and research of new medicines. Main search direction
The creation of new medicinal substances turned out to be possible on the basis of advances in the field of organic and pharmaceutical chemistry, the use of physicochemical methods, and technological, biotechnological and other studies of synthetic and natural compounds.
The generally accepted foundation for creating a theory of targeted searches for certain groups of drugs is the establishment of connections between pharmacological action and physical characteristics.
Currently, the search for new drugs is carried out in the following main areas.
1. Empirical study of one or another type of pharmacological activity of various substances obtained chemically. This study is based on the “trial and error” method, in which pharmacologists take existing substances and determine, using a set of pharmacological techniques, their belonging to a particular pharmacological group. Then the most active substances are selected from among them and the degree of their pharmacological activity and toxicity is determined in comparison with existing drugs that are used as a standard.
2. The second direction is to select compounds with one specific type of pharmacological activity. This direction is called directed drug discovery.
The advantage of this system is the faster selection of pharmacologically active substances, but the disadvantage is the lack of identification of other, possibly very valuable types of pharmacological activity.
3. The next direction of search is modification of the structures of existing drugs. This route to finding new drugs is now very common. Synthetic chemists replace one radical with another in an existing compound, introduce other chemical elements into the composition of the original molecule, or make other modifications. This route allows you to increase the activity of the drug, make its action more selective, and also reduce the undesirable aspects of the action and its toxicity.
Targeted synthesis of medicinal substances means the search for substances with predetermined pharmacological properties. The synthesis of new structures with putative activity is most often carried out in the class of chemical compounds in which substances have already been found that have a specific effect on a given organ or tissue.
For the basic skeleton of the desired substance, those classes of chemical compounds that include natural substances involved in the performance of body functions can also be selected. Targeted synthesis of pharmacological substances is more difficult to carry out in new chemical classes of compounds due to the lack of necessary initial information about the relationship between pharmacological activity and the structure of the substance. In this case, data on the benefits of the substance or element are required.
Next, various radicals are added to the selected basic skeleton of the substance, which will promote the dissolution of the substance in lipids and water. It is advisable to make the synthesized structure soluble in both water and fats so that it can be absorbed into the blood, pass from it through the blood-tissue barriers into tissues and cells and then come into contact with cell membranes or penetrate through them into the cell and connect with molecules of the nucleus and cytosol.
Targeted synthesis of medicinal substances becomes successful when it is possible to find a structure that, in size, shape, spatial position, electron-proton properties and a number of other physicochemical parameters, will correspond to the living structure to be regulated.
Targeted synthesis of substances pursues not only a practical goal - obtaining new medicinal substances with the desired pharmacological and biological properties, but is also one of the methods for understanding the general and particular patterns of life processes. To build theoretical generalizations, it is necessary to further study all the physicochemical characteristics of the molecule and clarify the decisive changes in its structure that determine the transition from one type of activity to another.
The formulation of combination drugs is one of the most effective ways to find new drugs. The principles on the basis of which multicomponent drugs are formulated can be different and change along with the methodology of pharmacology. Basic principles and rules for the preparation of combined products have been developed.
Most often, combination drugs include medicinal substances that affect the etiology of the disease and the main links in the pathogenesis of the disease. A combination drug usually includes medicinal substances in small or medium doses if there are phenomena of mutual enhancement of action between them (potentiation or summation).
Combined remedies, formulated taking into account these rational principles, are distinguished by the fact that they cause a significant therapeutic effect in the absence or minimum of negative effects. Their last property is due to the introduction of small doses of individual ingredients. A significant advantage of small doses is that they do not disrupt the body’s natural protective or compensatory mechanisms.
Combined preparations are also formulated on the principle of including additional ingredients that eliminate the negative effects of the main substance.
Combined preparations are formulated with the inclusion of various corrective agents that eliminate the undesirable properties of the main medicinal substances (smell, taste, irritation) or regulate the rate of release of the medicinal substance from the dosage form or the rate of its absorption into the blood.
Rational formulation of combined drugs allows one to purposefully increase the pharmacotherapeutic effect and eliminate or reduce possible negative aspects of the effect of drugs on the body.
When combining drugs, the individual components must be compatible with each other in physicochemical, pharmacodynamic and pharmacokinetic terms.
Send your good work in the knowledge base is simple. Use the form below
Students, graduate students, young scientists who use the knowledge base in their studies and work will be very grateful to you.
Posted on http://www.allbest.ru/
STATE EDUCATIONAL INSTITUTION
HIGHER PROFESSIONAL EDUCATION
NOVOSIBIRSK STATE MEDICAL UNIVERSITY
FEDERAL HEALTH AGENCY
AND SOCIAL DEVELOPMENT OF THE RUSSIAN FEDERATION
(GOU VPO NSMU ROSZDRAVA)
Department of Pharmaceutical Chemistry
TOURSOVMY JOB
in pharmaceutical chemistry
on the topic: “Creation and testing of new drugs”
Completed by: 4th year correspondence student
departments of the Faculty of Pharmacy
(shortened form of training based on VChO)
Kundenko Diana Alexandrovna
Checked by: Pashkova L.V.
Novosibirsk 2012
1. Stages of the process of creating a new drug. Stability and shelf life of medicines
2. Clinical trials of medicinal products (GCP). GCP Stages
3. Quantitative analysis of mixtures without preliminary separation of components by physical and chemical methods
4. Quality control system in chemical and pharmaceutical plants and factories
5. Main tasks and features of biopharmaceutical analysis
6. Types of state standards. Requirements of general standards for dosage forms
7. Hydrochloric acid: physical properties, authenticity, quantitative determination, application, storage
8. Oxygen: physical properties, authenticity, quality, quantification, application, storage
9. Bismuth nitrate basic: physical properties, authenticity testing, quantitative determination, application, storage
10. Preparations of magnesium compounds used in medical practice: physical properties, authenticity, quantitative determination, use, storage
11. Preparations of iron and its compounds: physical properties, authenticity, quantitative determination, application, storage
12. Pharmacopoeial radioactive drugs: authenticity, establishment of radiochemical composition, specific activity
1. Stages of the process of creating a new drug. Stability and shelf life of medicines
The creation of medicines is a long process, including several main stages - from forecasting to sale in pharmacies.
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, and the Department of the Ministry of Health of the Russian Federation for the Introduction of New Medicines.
The development of a new drug includes the following stages:
1) The idea of creating a new drug. It usually arises as a result of the joint work of scientists of two specialties: pharmacologists and synthetic chemists. Already at this stage, a preliminary selection of synthesized compounds is carried out, which, according to experts, may be potentially biologically active substances.
2) Synthesis of pre-selected structures. At this stage, selection is also carried out, as a result of which substances, etc., are not subjected to further research.
3) Pharmacological screening and preclinical testing. The main stage, during which unpromising substances synthesized at the previous stage are eliminated.
4) Clinical testing. It is performed only for promising biologically active substances that have passed all stages of pharmacological screening.
5) Development of technology for the production of a new drug and a more rational dosage form.
6) Preparation of regulatory documentation, including methods for quality control of both the drug itself and its dosage form.
7) Introduction of drugs into industrial production and testing of all stages of production in the factory.
The production of a new active substance (active substance or complex of substances) proceeds in three main directions.
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.
The empirical way (from the Greek empeiria - experience) of creating medicinal substances is based on the “trial and error” method, in which pharmacologists take a number of chemical compounds and determine using a set of biological tests (at the molecular, cellular, organ levels and on the whole animal) the presence or their lack of certain pharmacological activity. Thus, the presence of antimicrobial activity is determined on microorganisms; antispasmodic activity - on isolated smooth muscle organs (ex vivo); hypoglycemic activity based on the ability to lower blood sugar levels in test animals (in vivo). Then, among the chemical compounds being studied, the most active ones are selected and the degree of their pharmacological activity and toxicity is compared with existing drugs that are used as a standard. This method of selecting active substances is called drug screening (from the English screen - sift out, sort). A number of drugs were introduced into medical practice as a result of accidental discoveries. Thus, the antimicrobial effect of an azo dye with a sulfonamide side chain (red streptocide) was revealed, as a result of which a whole group of chemotherapeutic agents, sulfonamides, appeared.
Another way to create medicinal substances is to obtain compounds with a certain type of pharmacological activity. It is called the directed synthesis of medicinal substances.
The first stage of such synthesis is the reproduction of substances formed in living organisms. This is how adrenaline, norepinephrine, a number of hormones, prostaglandins, and vitamins were synthesized.
Chemical modification of known molecules makes it possible to create medicinal substances that have a more pronounced pharmacological effect and fewer side effects. Thus, a change in the chemical structure of carbonic anhydrase inhibitors led to the creation of thiazide diuretics, which have a stronger diuretic effect.
The introduction of additional radicals and fluorine into the nalidixic acid molecule made it possible to obtain a new group of antimicrobial agents, fluoroquinolones, with an extended spectrum of antimicrobial action.
Targeted synthesis of medicinal substances involves the creation of substances with predetermined pharmacological properties. The synthesis of new structures with putative activity is most often carried out in that class of chemical compounds where substances with a certain direction of action have already been found. An example is the creation of H2 histamine receptor blockers. It was known that histamine is a powerful stimulator of hydrochloric acid secretion in the stomach and that antihistamines (used for allergic reactions) do not eliminate this effect. On this basis, it was concluded that there are subtypes of histamine receptors that perform different functions, and these receptor subtypes are blocked by substances of different chemical structures. It was hypothesized that modification of the histamine molecule could lead to the creation of selective antagonists of gastric histamine receptors. As a result of the rational design of the histamine molecule, the antiulcer drug cimetidine, the first H2 histamine receptor blocker, appeared in the mid-70s of the 20th century. Isolation of medicinal substances from tissues and organs of animals, plants and minerals
In this way, medicinal substances or complexes of substances are isolated: hormones; galenic, novogalenic preparations, organopreparations and mineral substances. Isolation of medicinal substances that are products of the vital activity of fungi and microorganisms using biotechnology methods (cellular and genetic engineering). Biotechnology deals with the isolation of medicinal substances that are products of the vital activity of fungi and microorganisms.
Biotechnology uses biological systems and biological processes on an industrial scale. Microorganisms, cell cultures, plant and animal tissue cultures are commonly used.
Semi-synthetic antibiotics are obtained using biotechnological methods. Of great interest is the production of human insulin on an industrial scale using genetic engineering. Biotechnological methods have been developed for the production of somatostatin, follicle-stimulating hormone, thyroxine, and steroid hormones. After obtaining a new active substance and determining its basic pharmacological properties, it undergoes a series of preclinical studies.
Different drugs have different expiration dates. The shelf life is the period during which the medicinal product must fully meet all the requirements of the relevant State quality standard. The stability (stability) of a medicinal substance (DS) and its quality are closely related. The criterion for stability is the preservation of drug quality. A decrease in the quantitative content of a pharmacologically active substance in a drug confirms its instability. This process is characterized by a drug decomposition rate constant. A decrease in quantitative content should not be accompanied by the formation of toxic products or changes in the physicochemical properties of the drug. As a rule, a decrease in the amount of drugs by 10% should not occur within 3-4 years in finished dosage forms and within 3 months in drugs prepared in a pharmacy.
The shelf life of drugs is understood as the period of time during which they must fully retain their therapeutic activity, harmlessness and, in terms of qualitative and quantitative characteristics, comply with the requirements of the State Fund or the Federal Pharmacopoeia, in accordance with which they were released and stored under the conditions provided for in these articles.
After the expiration date, the drug cannot be used without re-control of quality and a corresponding change in the established expiration date.
Processes that occur during storage of drugs can lead to changes in their chemical composition or physical properties (formation of sediment, change in color or state of aggregation). These processes lead to a gradual loss of pharmacological activity or to the formation of impurities that change the direction of the pharmacological action.
The shelf life of drugs depends on the physical, chemical and biological processes occurring in them. These processes are greatly influenced by temperature, humidity, light, pH, air composition and other factors.
The physical processes that occur during drug storage include: absorption and loss of water; change in phase state, for example melting, evaporation or sublimation, delamination, enlargement of dispersed phase particles, etc. Thus, during storage of highly volatile substances (ammonia solution, bromine camphor, iodine, iodoform, essential oils), the content of drugs in the dosage form may change.
Chemical processes occur in the form of reactions of hydrolysis, oxidation-reduction, racemization, and the formation of high-molecular compounds. Biological processes cause changes in drugs under the influence of the vital activity of microorganisms, which leads to a decrease in the stability of drugs and human infection.
Medicines are most often contaminated by saprophytes, which are widespread in the environment. Saprophytes are capable of decomposing organic substances: proteins, lipids, carbohydrates. Yeast and filamentous fungi destroy alkaloids, antipyrine, glycosides, glucose, and various vitamins.
The shelf life of a drug can be sharply reduced due to poor quality packaging. For example, when storing injection solutions in bottles or ampoules made of low-quality glass, sodium and potassium silicate transfer from the glass into the solution. This leads to an increase in the pH value of the medium and the formation of so-called “spangles” (particles of broken glass). With increasing pH, salts of alkaloids and synthetic nitrogen-containing bases decompose with a decrease or loss of therapeutic effect and the formation of toxic products. Alkaline solutions catalyze the oxidation of ascorbic acid, aminazine, ergotal, vikasol, vitamins, antibiotics, and glycosides. In addition, the alkalinity of glass also promotes the development of microflora.
The shelf life of drugs can be increased by stabilization.
Two methods of drug stabilization are used - physical and chemical.
Physical stabilization methods are usually based on protecting medicinal substances from adverse environmental influences. In recent years, a number of physical methods have been proposed to increase the stability of drugs during their preparation and storage. For example, freeze drying of thermolabile substances is used. Thus, an aqueous solution of benzylpenicillin retains its activity for 1 - 2 days, while the dehydrated drug is active for 2 - 3 years. Ampulation of solutions can be carried out in a flow of inert gases. It is possible to apply protective coatings to solid heterogeneous systems (tablets, dragees, granules), as well as microencapsulation.
However, physical stabilization methods are not always effective. Therefore, chemical stabilization methods are more often used, based on the introduction of special auxiliary substances - stabilizers - into drugs. Stabilizers ensure the stability of the physicochemical, microbiological properties, and biological activity of drugs over a certain period of storage. Chemical stabilization is of particular importance for drugs subjected to various types of sterilization, especially thermal. Thus, stabilization of drugs is a complex problem, including the study of the resistance of drugs in the form of true solutions or dispersed systems to chemical transformations and microbial contamination.
2. Clinical trials of medicinal products (GCP). GCP Stages
The process of creating new medicines is carried out in accordance with the international standards of GLP (Good Laboratory Practice), GMP (Good Manufacturing Practice) and GCP (Good Clinical Practice).
Clinical drug trials involve the systematic study of an investigational drug in humans to test its therapeutic effect or detect an adverse reaction, as well as the study of absorption, distribution, metabolism and excretion from the body to determine its effectiveness and safety.
Clinical trials of a drug are a necessary stage in the development of any new drug, or the expansion of indications for the use of a drug already known to doctors. At the initial stages of drug development, chemical, physical, biological, microbiological, pharmacological, toxicological and other studies are carried out on tissues (in vitro) or on laboratory animals. These are so-called preclinical studies, the purpose of which is to obtain scientific estimates and evidence of the effectiveness and safety of drugs. However, these studies cannot provide reliable information about how the drugs being studied will act in humans, since the organism of laboratory animals differs from humans both in pharmacokinetic characteristics and in the response of organs and systems to drugs. Therefore, clinical trials of drugs in humans are necessary.
Clinical study (test) of a medicinal product - is a systemic study of a drug through its use in humans (patient or healthy volunteer) in order to assess its safety and effectiveness, as well as identify or confirm its clinical, pharmacological, pharmacodynamic properties, assess absorption, distribution, metabolism, excretion and interaction with other drugs means. The decision to initiate a clinical trial is made by the customer, who is responsible for organizing, monitoring and financing the trial. Responsibility for the practical conduct of the research rests with the researcher. As a rule, the sponsor is a pharmaceutical company that develops drugs, but a researcher can also act as a sponsor if the study was initiated on his initiative and he bears full responsibility for its conduct.
Clinical trials must be conducted in accordance with the fundamental ethical principles of the Declaration of Helsinki, GСP (Good Clinical Practice) and applicable regulatory requirements. Before the start of a clinical trial, an assessment must be made of the relationship between the foreseeable risk and the expected benefit for the subject and society. The principle of priority of the rights, safety and health of the subject over the interests of science and society is put at the forefront. The subject can be included in the study only on the basis of voluntary informed consent (IS), obtained after a detailed review of the study materials. Patients (volunteers) participating in testing a new drug must receive information about the essence and possible consequences of the tests, the expected effectiveness of the drug, the degree of risk, enter into a life and health insurance agreement in the manner prescribed by law, and during the tests be under constant supervision of qualified personnel. In the event of a threat to the health or life of the patient, as well as at the request of the patient or his legal representative, the head of the clinical trial is obliged to suspend the trial. In addition, clinical trials are suspended if a drug is unavailable or insufficiently effective, or if ethical standards are violated.
The first stage of clinical trials of the drug is carried out on 30 - 50 volunteers. The next stage is expanded trials on the basis of 2 - 5 clinics involving a large number (several thousand) of patients. At the same time, individual patient cards are filled out with a detailed description of the results of various studies - blood tests, urine tests, ultrasound, etc.
Each drug undergoes 4 phases (stages) of clinical trials.
Phase I. First experience of using a new active substance in humans. Most often, studies begin with volunteers (healthy adult men). The main goal of the research is to decide whether to continue working on a new drug and, if possible, to establish the doses that will be used in patients during phase II clinical trials. During this phase, researchers obtain preliminary data on the safety of the new drug and describe its pharmacokinetics and pharmacodynamics in humans for the first time. Sometimes it is impossible to conduct phase I studies in healthy volunteers due to the toxicity of this drug (treatment of cancer, AIDS). In this case, non-therapeutic studies are carried out with the participation of patients with this pathology in specialized institutions.
Phase II. This is usually the first experience of use in patients with the disease for which the drug is intended to be used. The second phase is divided into IIa and IIb. Phase IIa are therapeutic pilot studies because the results obtained from them provide optimal planning for subsequent studies. Phase IIb studies are larger studies in patients with the disease that is the primary indication for the new drug. The main goal is to prove the effectiveness and safety of the drug. The results of these studies (pivotal trial) serve as the basis for planning phase III studies.
Phase III. Multicentre trials involving large (and, if possible, diverse) patient groups (average 1000-3000 people). The main goal is to obtain additional data on the safety and effectiveness of various forms of the drug, the nature of the most common adverse reactions, etc. Most often, clinical studies of this phase are double-blind, controlled, randomized, and the research conditions are as close as possible to normal real routine medical practice. Data obtained in phase III clinical trials are the basis for creating instructions for the use of the drug and for deciding on its registration by the Pharmacological Committee. A recommendation for clinical use in medical practice is considered justified if the new drug:
More effective than known drugs of similar action;
It is better tolerated than known drugs (with the same effectiveness);
Effective in cases where treatment with known drugs is unsuccessful;
It is more economically beneficial, has a simpler treatment method or a more convenient dosage form;
In combination therapy, it increases the effectiveness of existing drugs without increasing their toxicity.
Phase IV. Studies are conducted after the drug is marketed in order to obtain more detailed information about long-term use in various patient groups and with various risk factors, etc. and thus more fully evaluate the drug strategy. The study involves a large number of patients, which makes it possible to identify previously unknown and rare adverse events.
If a drug is going to be used for a new indication that has not yet been registered, then additional studies are conducted, starting with phase II. Most often in practice, an open study is carried out, in which the doctor and the patient know the method of treatment (the study drug or a comparison drug).
When testing with a single-blind method, the patient does not know which drug he is taking (it may be a placebo), and when using a double-blind method, neither the patient nor the doctor is aware of this, but only the leader of the trial (in a modern clinical trial of a new drug, four parties: the sponsor of the study (most often this is a pharmaceutical manufacturing company), the monitor - a contract research organization, a doctor-researcher, a patient). In addition, triple-blind studies are possible, when neither the doctor, nor the patient, nor those who organize the study and process its data know the assigned treatment for a particular patient.
If doctors know which patient is being treated with which drug, they may spontaneously evaluate treatment based on their preferences or explanations. The use of blind methods increases the reliability of the results of a clinical trial, eliminating the influence of subjective factors. If the patient knows that he is receiving a promising new drug, the effect of treatment may be associated with his reassurance, satisfaction that the most desired treatment possible has been achieved.
Placebo (Latin placere - to like, to appreciate) means a drug that obviously does not have any healing properties. The Large Encyclopedic Dictionary defines placebo as “a dosage form containing neutral substances. Used to study the role of suggestion in the therapeutic effect of any medicinal substance, as a control when studying the effectiveness of new drugs.” quality medicine pharmaceutical
Negative placebo effects are called nocebo. If the patient knows what side effects the drug has, then in 77% of cases they occur when he takes a placebo. Belief in a particular effect can cause side effects to occur. According to the commentary of the World Medical Association on Article 29 of the Declaration of Helsinki , “...the use of placebo is justified if it does not lead to an increased risk of causing serious or irreversible damage to health...”, that is, if the patient is not left without effective treatment.
There is a term for “completely blinded studies” when all parties to the study are blinded to the type of treatment being given to a particular patient until the results are analyzed.
Randomized controlled trials serve as the standard of quality for scientific research into the effectiveness of treatments. The study first selects patients from a large population of people with the condition being studied. These patients are then randomly divided into two groups matched according to the main prognostic features. Groups are formed randomly (randomization) using tables of random numbers in which each digit or each combination of digits has an equal probability of selection. This means that patients in one group will, on average, have the same characteristics as patients in another. In addition, before randomization, it should be ensured that disease characteristics known to have a strong influence on outcome occur at equal frequencies in the treatment and control groups. To do this, you must first distribute patients into subgroups with the same prognosis and only then randomize them separately in each subgroup - stratified randomization. The experimental group (treatment group) receives an intervention that is expected to be beneficial. The control group (comparison group) is in exactly the same conditions as the first group, except that its patients are not exposed to the intervention being studied.
3. Quantitative analysis of mixtures without preliminary separation of components by physical and chemical methods
Physicochemical methods are becoming increasingly important for the purpose of objective identification and quantification of medicinal substances. Photometric methods are most accessible for use in pharmaceutical analysis, in particular spectrophotometry in the IR and UV regions, photometry in the visible region of the spectrum and their various modifications. These methods are included in the State Pharmacopoeia, the International Pharmacopoeia and the national pharmacopoeias of many countries, as well as in other regulatory documents. Pharmacopoeial monographs, which are state standards containing a list of indicators and methods used to control the quality of a medicinal product.
Physicochemical methods of analysis have a number of advantages over classical chemical methods. They are based on the use of both physical and chemical properties of substances and in most cases are characterized by rapidity, selectivity, high sensitivity, and the possibility of unification and automation.
The inclusion of the developed methods in regulatory documents is preceded by extensive research in the field of pharmaceutical analysis. The number of completed and published works on the use of photometric methods is enormous.
To establish the authenticity of medicinal substances, pharmacopoeias use, along with other physical and chemical methods, IR spectroscopy - a method that provides the most objective identification. The IR spectra of the tested medicinal substances are compared either with the spectrum of a standard sample obtained under the same conditions, or with the attached spectrum taken previously for this medicinal substance.
Along with IR spectroscopy, various options for UV spectrophotometry of organic compounds are used in the analysis of medicinal substances. The first works in this direction summarized the state of the art and outlined the prospects for using this method. Approaches to the use of UV spectrophotometry in drug standardization have been formulated, and various methods of performing analysis have been developed. In the authenticity testing methods presented in pharmacopoeias and other regulatory documentation, identification is usually carried out according to generally accepted parameters of UV spectra - the wavelength of the maximum and minimum light absorption and the specific absorption index. For this purpose, parameters such as the position and half-width of the absorption band, asymmetry factor, integral intensity, and oscillator strength can also be used. When controlling for these parameters, the specificity of qualitative analysis increases.
In some cases, the visible region of the spectrum is used for the photometric determination of medicinal substances. The analysis is based on carrying out color reactions followed by measuring optical density using spectrophotometers and photocolorimeters.
In pharmaceutical analysis, UV-visible spectrophotometry is often combined with separation methods (thin layer and other types of chromatography).
As is known, differential methods of photometric measurements carried out using a reference solution containing a certain amount of a standard sample of the test substance have increased accuracy. This technique leads to an expansion of the working area of the instrument scale, allows you to increase the concentration of the analyzed solutions and, ultimately, increases the accuracy of the determination.
4. Quality control system in chemical and pharmaceutical plants and factories
The manufacturer of medicinal products must organize production in such a way that the medicinal products are guaranteed to meet their intended purpose and requirements and do not pose a risk to consumers due to violations of safety, quality or effectiveness. Managers and all employees of the enterprise are responsible for fulfilling these requirements.
To achieve this goal, the manufacturing enterprise must create a quality assurance system, including the organization of work according to GMP, quality control and a risk analysis system.
Quality control includes sampling, testing (analysis) and preparation of relevant documentation.
The purpose of quality control is to prevent materials or products that do not meet quality requirements from being used or sold. Quality control activities are not limited only to laboratory work, but also include conducting research, inspections and participating in any decisions regarding product quality. The fundamental principle of quality control is its independence from production departments.
Basic requirements for quality control:
Availability of the necessary premises and equipment, trained personnel, approved methods for sampling, inspection and testing of starting and packaging materials, intermediate, packaged and finished products;
Conducting tests using certified methods;
Drawing up records confirming that all necessary sampling, inspection and testing have actually been carried out, as well as recording any deviations and investigations in full;
Maintain sufficient samples of raw materials and products for possible inspection if necessary. Product samples should be stored in their final packaging, with the exception of large packages.
Each manufacturing enterprise must have a quality control department, independent from other departments.
For medicinal products, proper microbiological purity is regulated. Microbial contamination can occur at various stages of production. Therefore, tests for microbiological purity are carried out at all stages of drug production. The main sources of microbial contamination are raw materials, water, equipment, air in production premises, packaging of finished products, and personnel. To quantify the content of microorganisms in the air, various sampling methods are used: filtration, deposition in liquids, deposition on solid media. To assess microbiological purity, sterility tests are performed.
When determining the sterility of drugs that have a pronounced antibacterial effect, bacteriostatic, fungistatic properties, as well as drugs containing preservatives or bottled in containers larger than 100 ml, the membrane filtration method is used.
When monitoring the sterility of dosage forms of β-lactam antibiotics, it is possible to use direct inoculation using the penicillinase enzyme in an amount sufficient to completely inactivate the test antibiotic as an alternative method.
The use of the membrane filtration method is based on passing drugs through a polymer membrane. In this case, microorganisms remain on the surface of the membrane. Next, the membrane is placed in an appropriate nutrient medium and the formation of colonies during incubation is observed.
Cellulose ether membranes (nitrocellulose, cellulose acetolate, and mixed cellulose ethers) with a pore size of 0.45 μm are commonly used to count viable microorganisms.
The technique for testing the microbiological purity of medicinal products using the membrane filtration method is given in the addition to the FS “Test for microbiological purity” dated December 28, 1995.
The quality of medicinal products can be confidently guaranteed if at all stages of the life cycle of medicinal products all rules of circulation are strictly observed, in particular the conduct of preclinical and clinical studies, production, wholesale and retail sales of pharmaceutical products.
5. Main tasks and features of biopharmaceutical analysis
Biopharmaceutical analysis is a new promising direction in pharmaceutical chemistry. The objective of biopharmaceutical analysis is to develop methods for the isolation, purification, identification and quantification of drugs and their metabolites in biological fluids such as urine, saliva, blood, plasma or serum, etc. Only on the basis of the use of such methods can biopharmaceutical research be performed, i.e. .e. study issues of absorption, transport and excretion of medicinal substances, its bioavailability, metabolic processes. All this makes it possible to prevent possible toxic effects of drugs, develop optimal pharmacotherapy regimens and monitor the treatment process. It is especially important to determine the concentration of a drug substance in biological fluids when, along with the therapeutic effect, they exhibit toxicity. It is also necessary to monitor the content of medicinal substances in the biological fluids of patients suffering from gastrointestinal diseases and diseases of the liver and kidneys. With such diseases, absorption processes change, metabolic processes are disrupted, and the removal of drugs from the body slows down.
Biological fluids are very difficult objects to analyze. They are multicomponent mixtures, including a large number of inorganic and organic compounds of various chemical structures: trace elements, amino acids, polypeptides, proteins, enzymes, etc. Their concentration ranges from 10 mg/ml to several nanograms. Even in such a relatively simple physiological fluid as urine, several hundred organic compounds have been identified. Any biological object is a very dynamic system. Its condition and chemical composition depend on the individual characteristics of the body, the influence of environmental factors (food composition, physical and mental stress, etc.). All this further complicates the performance of biopharmaceutical analysis, since against the background of such a large number of organic substances with a complex chemical structure, it is often necessary to determine very small concentrations of drugs. Drugs introduced into biological fluids during the process of biological transformation form metabolites, the number of which often amounts to several dozen. Isolating these substances from complex mixtures, separating them into individual components and establishing their chemical composition is an extremely difficult task.
Thus, the following features of biopharmaceutical analysis can be distinguished:
1. The objects of study are multicomponent mixtures of compounds.
2. The quantities of the substances being determined are usually calculated in micrograms and even nanograms.
3. The studied medicinal substances and their metabolites are located in an environment consisting of a large number of natural compounds (proteins, enzymes, etc.).
4. The conditions for isolation, purification and analysis of the substances under study depend on the type of biological fluid being studied.
In addition to the theoretical significance that research in the field of biopharmaceutical analysis has for the study of newly created medicinal substances, the practical role of this branch of knowledge is also undoubted.
Therefore, biopharmaceutical analysis is a unique tool necessary for conducting not only biopharmaceutical, but also pharmacokinetic studies.
6. Types of state standards. Requirements of general standards for dosage forms
Product quality standardization refers to the process of establishing and applying standards. A standard is a standard or sample taken as the initial one for comparison of other similar objects with it. A standard as a normative document establishes a set of norms or requirements for the object of standardization. The application of standards helps to improve product quality.
In the Russian Federation, the following categories of regulatory documents have been established: State standards (GOST), industry standards (OST), republican standards (RS.T) and technical conditions (TU). The standards for drugs are FS, technical specifications that regulate their quality, as well as production regulations that normalize their technology. FS - regulatory documents defining a set of quality standards and methods for their determination. These documents ensure the same effectiveness and safety of drugs, as well as the consistency and uniformity of their production, regardless of the series. The main document regulating the quality of drugs produced in our country is the State Pharmacopoeia (SP). Regulatory documents reflecting additional technical requirements for the production, control, storage, labeling, packaging, and transportation of drugs are industry standards (OST).
Since June 2000, the industry standard “Rules for organizing production and quality control of drugs” has been put into effect in Russia. This is a standard identical to the international GMP rules.
In addition to the specified standard, which ensures the production of high-quality drugs, a standard has been introduced that normalizes the quality of drugs, regulating the procedure for creating new and improving existing regulatory documentation for drugs. It was approved by the Ministry of Health of the Russian Federation on November 1, 2001 (order No. 388), registered by the Ministry of Justice of the Russian Federation on November 16, 2001 and is an industry standard OST 91500.05.001-00 “Quality Standards for Medicines. Basic provisions". The previously existing standard OST 42-506-96 has lost its force. The purpose of creating an industry standard is to establish categories and a unified procedure for the development, presentation, execution, examination, coordination, designation and approval of drug quality standards. The requirements of this standard are mandatory for development organizations, drug manufacturing enterprises, organizations and institutions that carry out examination of quality standards of domestic drugs, regardless of departmental affiliation, legal status and forms of ownership.
In the newly approved OST, the categories of drug quality standards have been changed. A medicinal product quality standard is a normative document (ND) containing a list of standardized indicators and methods for drug quality control. It must ensure the development of effective and safe drugs.
The new OST provides for two categories of quality standards:
State quality standards for medicines (GSKLS), which include: general pharmacopoeial monograph (GPM) and pharmacopoeial monograph (PS);
Quality Standard (SKLS); pharmacopoeial monograph of the enterprise (FSP).
The General Pharmacopoeia Monograph contains the basic general requirements for the dosage form or a description of standard methods for drug control. The General Pharmacopoeia Monograph includes a list of standardized indicators and test methods for a specific drug or a description of drug analysis methods, requirements for reagents, titrated solutions, and indicators.
The FS contains a mandatory list of indicators and methods for quality control of a medicinal product (taking into account its DF), which meet the requirements of leading foreign pharmacopoeias.
Drug treatment is inextricably linked with the dosage form. Due to the fact that the effectiveness of treatment depends on the dosage form, the following general requirements are imposed on it:
Compliance with the therapeutic purpose, bioavailability of the drug substance in this dosage form and corresponding pharmacokinetics;
Uniformity of distribution of medicinal substances in the mass of auxiliary ingredients and hence dosing accuracy;
Stability during shelf life;
Compliance with microbial contamination standards, if necessary, preservation;
Ease of administration, possibility of correcting unpleasant taste;
Compactness.
The General Pharmacopoeia Monograph and the FS are developed and revised after 5 years by the Scientific Center for Expertise and State Control of Medicines, and for immunobiological drugs - by the National MIBP Control Authority.
OFS and FS constitute the State Pharmacopoeia (SP), which is published by the Ministry of Health of the Russian Federation and is subject to reissue every 5 years. The State Pharmacopoeia is a collection of state drug quality standards that has a legislative nature.
7. Hydrochloric acid: physical properties, authenticity, quantitative determination, application, storage
Diluted hydrochloric acid (Acidum hydrochloridum dilutum) is a colorless transparent liquid of an acidic reaction. density, solution density 1.038-1.039 g/cm3, volume fraction 8.2-8.4%
Hydrochloric acid (Acidum hydrochloridum) is a colorless, transparent, volatile liquid with a peculiar odor. Density 1.122-1.124 g/cm3, volume fraction 24.8-25.2%.
Medicinal preparations of hydrochloric acid are mixed with water and ethanol in all proportions. They differ only in the content of hydrogen chloride and, accordingly, in density.
Chloride ion can be detected with the help of silver nitrate by the formation of a silver chloride precipitate, insoluble in water and in nitric acid solution, but soluble in ammonia solution:
HCl+H2O->AgClv+HNO3
AgCl+2NH3*H2O->2Cl+2H2O
Another method for detecting chloride ion is based on the release of free chlorine when heating drugs from manganese dioxide:
4HCl+MnO2->Cl2?+MnCl2+2H2O
Chlorine is detected by smell.
The content of hydrogen chloride in medicinal preparations of hydrochloric acid is determined by the acid-base titration method, titrating with a solution of sodium hydroxide in the presence of the methyl orange indicator:
HCl+NaOH->NaCl+H2O
Purity tests. Hydrochloric acid may contain impurities of heavy metals, mainly in the form of iron (II) and iron (III) salts. These impurities can enter the drug from the material of the apparatus in which the acid is produced. The presence of iron salts can be detected by the following reactions:
FeCl3 + K4>KFeFe(CN)6v + 3KCl
FeCl2 + K3>KFeFe(CN)6v + 2KCl
From the last two reactions it is clear that the composition of the resulting sediments is identical. This was established relatively recently. Previously, it was believed that two individual compounds were formed - Prussian blue and Turnbull blue.
If hydrogen chloride is produced by the reaction between hydrogen and chlorine, then chlorine may be detected as an impurity. Its determination in solution is carried out by adding potassium iodide in the presence of chloroform, which acquires a purple color as a result of concentrating the released iodine in it:
Cl2 + 2KI > I2 + 2 KCl
When producing hydrogen chloride by the reaction:
2NaCl(TS) + H2SO4(END) > Na2SO4(TS) + 2 HCl^
The drug may contain impurities of sulfites and sulfates. An admixture of sulfurous acid can be detected by adding iodine and starch solution. In this case, iodine is reduced: H2SO3 + I2 + H2O > H2SO4 + 2HI and the blue color of the starch iodine complex disappears.
When barium chloride solution is added, a white precipitate of barium sulfate is formed:
H2SO4 + BaCl2 > BaSO4 + HCl
If hydrochloric acid was produced using sulfuric acid, arsenic may also be present as a very undesirable impurity.
Quantitation. The concentration of hydrochloric acid can be determined by two methods:
1). neutralization method (titration with alkali using methyl orange - pharmacopoeial method):
HCl + NaOH > NaCl + H2O
2) argentometric method for chloride ion:
HCl + AgNO3> AgClv + HNO3
Hydrochloric acid was previously used as a medicine for insufficient acidity of gastric juice. Prescribed orally 2-4 times a day during meals, 10-15 drops (per? -1/2 glass of water).
Titrated solutions of hydrochloric acid with a molar concentration of 0.01 - 1 mol/l are used in pharmaceutical analysis. Storage: in closed containers made of glass or other inert material at temperatures below 30 °C.
Use diluted hydrochloric acid when gastric juice is insufficiently acidic. Prescribed orally 2-4 times a day during meals, 10-15 drops (per? -1/2 glass of water). If it is prescribed without indicating the concentration, diluted hydrochloric acid is always dispensed; A 6% acid solution is used in the treatment of scabies according to Demyanovich.
Storage conditions:
List B. In a dry place. In bottles with ground stoppers. For medical purposes, diluted hydrochloric acid is used.
8. Oxygen: physical properties, authenticity, quality, quantification, application, storage
Oxygen - Oxygenium. The simple substance oxygen consists of non-polar O2 molecules (dioxygen) with a y, p-bond, a stable allotropic form of the element existing in a free form.
A colorless gas, in the liquid state it is light blue, in the solid state it is blue.
Component of air: 20.94% by volume, 23.13% by mass. Oxygen boils away from liquid air after nitrogen N2.
Supports combustion in air
Slightly soluble in water (31 ml/1 l H2O at 20 °C), but somewhat better than N2.
The authenticity of oxygen is determined by introducing a smoldering splinter into the gas stream, which flares up and burns with a bright flame.
It is necessary to occasionally bring a smoldering splinter to the hole of the gas outlet tube, and as soon as it begins to flare up, you should lift the tube, then lower it into the crystallizer with water and bring it under the cylinder. Incoming oxygen fills the cylinder, displacing water.
A smoldering splinter is brought into one of the cylinders with N2O, it flares up and burns with a bright flame.
To distinguish oxygen from another gaseous drug - nitrous oxide (dianitrogen oxide), equal volumes of oxygen and nitric oxide are mixed. The mixture of gases turns orange-red due to the formation of nitrogen dioxide: 2NO+O2-> 2NO2
Nitrous oxide does not give the indicated reaction. During industrial production, oxygen can become contaminated with impurities of other gases.
Purity assessment: In all purity tests, the admixture of other gases is determined by passing a certain amount of oxygen (at a rate of 4 l/h) through 100 ml of a reagent solution.
Oxygen must be neutral. The presence of gaseous impurities of an acidic and basic nature is determined by the colorimetric method (change in color of the methyl red indicator solution)
The admixture of carbon (II) is detected by the passage of oxygen through an ammonia solution of silver nitrate. Darkening indicates the reduction of silver to carbon monoxide:
CO+2[ Ag(NH3)2]NO3+2H2O -> 2Agv+(NH4)CO3+2NH4NO3
The presence of carbon dioxide impurities is determined by the formation of opalescence when oxygen is passed through a solution of barium hydroxide:
CO2+Ba(OH)2 -> BaCO3v+H2O
The absence of ozone and other oxidizing substances is determined by passing oxygen through a solution of potassium iodide, to which a solution of starch and a drop of glacial acetic acid have been added. The solution should remain colorless. The appearance of a blue color indicates the presence of ozone impurities:
2KI+O3+H2O -> I2+2KOH+O2 ?
Quantitation. All methods for the quantitative determination of oxygen are based on interaction with easily oxidized substances. Copper can be used for this. Oxygen is passed through a solution containing a mixture of ammonium chloride and ammonia solutions (ammonia buffer solution, pH = 9.25 ± 1). Pieces of copper wire with a diameter of about 1 mm are also placed there. Copper is oxidized by oxygen:
The resulting copper(II) oxide reacts with ammonia to form bright blue copper(II) ammonia:
CuO + 2 NH3 + 2 NH4CI > Cl2 + H2O
Application. In medicine, oxygen is used to prepare oxygen water and air baths, and “medical gas” is used for inhalation by patients. For general anesthesia in the form of inhalation anesthesia, a mixture of oxygen and low-toxic cyclopropane is used.
Oxygen is used for diseases accompanied by oxygen deficiency (hypoxia). Oxygen inhalations are used for diseases of the respiratory system (pneumonia, pulmonary edema), cardiovascular system (heart failure, coronary insufficiency), poisoning with carbon monoxide (II), hydrocyanic acid, asphyxiants (chlorine C12, phosgene COC12). A mixture of 40-60% oxygen and air is prescribed for inhalation at a rate of 4-5 l/min. Carbogen is also used - a mixture of 95% oxygen and 5% carbon dioxide.
In hyperbaric oxygenation, oxygen is used at a pressure of 1.2-2 atm in special pressure chambers. This method has been established to be highly effective in surgery, intensive care of severe diseases, and in cases of poisoning. This improves oxygen saturation of tissues and hemodynamics. Usually one session is performed a day (40-60 minutes), the duration of treatment is 8 - 10 sessions.
The method of enteral oxygen therapy is also used by introducing oxygen foam into the stomach, used in the form of an oxygen cocktail. The cocktail is prepared by passing oxygen under low pressure through the white of a chicken egg, to which is added rosehip infusion, glucose, vitamins B and C, and infusions of medicinal plants. Fruit juices and bread kvass concentrate can be used as a foaming agent. The cocktail is used to improve metabolic processes in the complex therapy of cardiovascular diseases.
Storage. In pharmacies, oxygen is stored in blue cylinders with a volume of 27-50 liters, containing 4-7.5 m3 of gas under a pressure of 100-150 atm. The threads of the cylinder reducer must not be lubricated with grease or organic oils (spontaneous combustion is possible). Only talc (“soapstone” is a mineral belonging to layered silicates) serves as a lubricant. Oxygen is dispensed from pharmacies in special pillows equipped with a funnel-shaped mouthpiece for inhalation.
Similar documents
Stability as a factor in the quality of medicines. Physical, chemical and biological processes occurring during their storage. The influence of production conditions on the stability of drugs. Classification of drug groups. Expiration date and re-control period.
presentation, added 10/26/2016
The purpose of epidemiological experimental studies. Stages of creating a medicine. Standards according to which clinical trials are conducted and their results are reported. Multicenter clinical drug trial.
presentation, added 03/16/2015
Stages of drug development. The purpose of conducting clinical trials. Their main indicators. Typical clinical trial designs. Testing of pharmacological and medicinal products. Bioavailability and bioequivalence study.
presentation, added 03/27/2015
Premises and storage conditions for pharmaceutical products. Features of quality control of medicines, rules of Good Storage Practice. Ensuring the quality of medicines and products in pharmacy organizations, their selective control.
abstract, added 09/16/2010
Physical and chemical processes occurring during storage of medicines. The influence of production conditions, degree of purity and chemical composition of packaging material on the stability of medicines. Storage of dosage forms manufactured in pharmacies.
abstract, added 11/16/2010
State regulation in the field of circulation of medicines. Counterfeiting of drugs is an important problem in today's pharmaceutical market. Analysis of the state of quality control of medicinal products at the present stage.
course work, added 04/07/2016
Microflora of finished dosage forms. Microbial contamination of drugs. Methods for preventing microbial spoilage of finished medicinal substances. Norms of microbes in non-sterile dosage forms. Sterile and aseptic preparations.
presentation, added 10/06/2017
Standardization of medicines. Regulatory requirements for the quality of drugs. Determining the authenticity of raw materials as a task of practical pharmacognosy. Levels of control of medicinal plant raw materials. Study of the drug "Dentos".
presentation, added 01/29/2017
The problem of counterfeit medicines. Classification of counterfeit medicines. Distribution of counterfeit products in Ukraine. Tramadol and its properties. Study of the drug using NIR spectroscopy and UV spectrophotometry.
course work, added 11/10/2011
State guarantee of the quality of medicines, its social significance for protecting public health. Physico-chemical properties of pharmaceutical products and materials; organizational, legal and technological conditions and standards for their storage.
Algorithm for creating a new drug
Typically, the development of a new drug includes the following stages:
1. idea;
2. laboratory synthesis;
3. bioscreening;
4. clinical trials;
The search for new drugs is developing in the following areas:
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 waste products of fungi and microorganisms; biotechnology (cell and genetic engineering)
Currently, drugs are produced mainly through chemical synthesis. One of the important ways of directed synthesis is the reproduction of nutrients formed in living organisms or their antagonists. For example, adrenaline, norepinephrine, γ-aminobutyric acid, prostaglandins, a number of hormones and other physiologically active compounds were synthesized. One of the most common ways to find new drugs is chemical modification of compounds with known biological activity. Recently, computer modeling of the interaction of a substance with a substrate such as receptors, enzymes, and so on has been actively used, since the structure of various molecules in the body is well established. 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. In addition to directed synthesis, the empirical route for obtaining drugs still retains a certain importance. One type of empirical search is screening (a rather labor-intensive test of the effect of a drug on rats and then on humans).
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.
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.
Clinical trial is a scientific study of the effectiveness, safety and tolerability of medical products (including drugs) in humans. There is an international standard for Good Clinical Practice. The National Standard of the Russian Federation GOSTR 52379-2005 “Good Clinical Practice” specifies a full synonym for this term - clinical trial, which, however, is less preferable due to ethical considerations.
The basis for conducting clinical studies (tests) is the document of the international organization “International Conference on Harmonization” (ICH). This document is called the "Guideline for Good Clinical Practice" ("Description of the GCP standard"; Good Clinical Practice is translated as "Good Clinical Practice").
Typically, there are other clinical research specialists working in clinical research in addition to physicians.
Clinical trials must be conducted in accordance with the fundamental ethical principles of the Declaration of Helsinki, GCP standard and applicable regulatory requirements. Before the start of a clinical trial, an assessment must be made of the relationship between the foreseeable risk and the expected benefit for the subject and society. The principle of priority of the rights, safety and health of the subject over the interests of science and society is put at the forefront. The subject can be included in the study only on the basis of voluntary informed consent (IS), obtained after a detailed review of the study materials. This consent is certified by the signature of the patient (subject, volunteer).
The clinical trial must be scientifically justified and described in detail and clearly in the study protocol. The assessment of the balance of risks and benefits, as well as the review and approval of the study protocol and other documentation related to the conduct of clinical trials, are the responsibilities of the Institutional Review Board/Independent Ethics Committee (IRB/IEC). Once approval has been received from the IRB/IEC, the clinical trial can begin.
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 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.
4th phase. Extensive study of the drug on the largest possible number of patients. The most important data are on side effects and toxicity, which require particularly long-term, careful and extensive monitoring. In addition, long-term treatment results are assessed. The data obtained is compiled in the form of a special report, which is sent to the organization that gave permission to release the drug. This information is important for the future fate of the drug (its use in widespread medical practice).
The quality of drugs produced by the chemical-pharmaceutical industry is usually assessed using chemical and physical-chemical methods specified in the State Pharmacopoeia. In some cases, if the structure of the active substances is unknown or chemical methods are not sensitive enough, biological standardization is resorted to. This refers to the determination of the activity of drugs on biological objects (based on the most typical effects).
According to the internationally recognized information resource Wikipedia, in Russia currently new drugs are mainly being studied in the field of cancer treatment, with treatment of endocrine system diseases in second place. Thus, in our time, the creation of new drugs is completely controlled by the state and the institutions it controls.
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, and 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 the international standards of GLP (Good Laboratory Practice), GMP (Good Manufacturing 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.
GENERAL RECIPE."
1. Definition of the subject of pharmacology and its tasks.
2. Stages of development of pharmacology.
3.Methods of studying pharmacology in Russia.
4. Ways to find medicines.
5.Prospects for the development of pharmacology.
7. The concept of drugs, medicinal substances and dosage forms.
8. Classification of drugs by strength,
by consistency and application.
9. The concept of galenic and new-galenic preparations.
10. The concept of state pharmacology.
Pharmacology studies the effect of drugs on the body.
1. Finding new medicines and bringing them to practical medicine.
2.Improving existing drugs (obtaining drugs with less pronounced side effects)
3.Search for drugs with new therapeutic effects.
4. Study of traditional medicine.
The medicine must be: effective, harmless and have an advantage over drugs of this group.
STAGES OF PHARMACOLOGY DEVELOPMENT.
Stage 1- empiric (primitive communal)
Random discoveries are random finds.
2nd stage- emperico-mystical (slave-owning)
The appearance of the first dosage forms
(fragrant waters,)
Hippocrates, Paracelsus, Galen.
3rd stage- religious - scholastic or feudal.
4th stage- scientific pharmacology, end of U111 beginning of the 1st century.
Stage 1- pre-Petrine
In 1672, a second pharmacy was opened, where there was a tax (payment was collected).
Under Peter 1, 8 pharmacies were opened.
2nd stage- pre-revolutionary
3rd stage- modern
Scientific pharmacology is being formed. The end of the 16th century and this stage is associated with the opening of medical faculties at universities.
STUDY METHODS.
1.Descriptive. Nestor Maksimovich
2. Experimental: the first laboratory was opened in Tartu.
Founders: Nelyubin, Iovsky, Dybkovsky, Dogel.
3. Experimental-clinical. The first clinics appear.
Botkin, Pavlov, Kravkov.
4. Experimental - clinical. On pathologically altered organs.
Academician Pavlov and Kravkov, they are also the founders
Russian pharmacology.
Academician Pavlov - study of digestion, ANS, CVS.
Kravkov - (Pavlov's student) - published the first textbook on pharmacology,
which was reprinted 14 times.
5. Experimental - clinical on pathologically changed organs
taking into account the dose.
Nikolaev and Likhachev - introduced the concept of dose.
In 1920, VNIHFI was opened.
In 1930, VILR was opened.
In 1954, the Research Institute of Pharmacology and Chemistry of Therapy was opened at the Academy of Medical Sciences.
The “golden age” of pharmacology began in 1954.
In 1978, at our Medpreparatov plant - NIIA. (Biosynthesis)
PRINCIPLES OF CREATION OF NEW MEDICINES.
The resulting drugs are similar to those that exist in life
body (for example, adrenaline).
2.Creation of new drugs based on known biologically
active substances.
3.Imperial path. Random discoveries, finds.
4. Obtaining drugs from products of fungi and microorganisms
(antibiotics).
5. Obtaining drugs from medicinal plants.
PROSPECTS FOR THE DEVELOPMENT OF PHARMACOLOGY.
1.Increase the level and efficiency of clinical examination.
2.Raise the level and quality of medical care.
3. Create and increase the production of new medicines for the treatment of cancer patients, patients with diabetes mellitus, and cardiovascular disease.
4.Improve the quality of training for mid- and senior-level personnel.
General recipe –
This is a branch of pharmacology that studies the rules for prescribing, preparing and dispensing medications to patients.
RECIPE- this is a written request from a doctor with a request to prepare
and dispensing medication to the patient.
According to Order No. 110 of the Ministry of Health of Russia of 2007 No. 148-1 U/-88, there are three forms of prescription forms.
FORM 107/U- You can prescribe: one poisonous or no more than two simple or potent ones.
For simple and potent ones, the prescription is valid for two months, and for potent and alcohol-containing ones - for 10 days.
FORM 148/U- It is written out in two copies with mandatory completion as a carbon copy, for dispensing medications free of charge or on preferential terms.
The difference between form No. 2 and form No. 3
FORM No. 1. 1. Clinic stamp or code.
2.Date of prescription.
3.F.I.O. patient, age.
4.F.I.O. doctor
5. The drug is prescribed.
6.Stamp and signature.
A recipe is a legal document
FORM No. 2. 1.Stamp and code.
2.Indicated: free.
3.These recipes have their own number.
4.Indicate the number of the pension certificate.
5.Only one drug is prescribed.
FORM No. 3. The recipe is written out on special forms made of moire paper, pink in color, waves are visible in the light, i.e. This form cannot be faked.
This is a special accounting form, has a pink color, watermarks and a series
Difference from form No. 3 from other forms of the corresponding forms.
1.Each form has its own series and number (for example, ХГ - No. 5030)
2. The number of the medical history or outpatient history is indicated on the prescription form
3. The forms are stored in safes, they are closed and stamped, i.e. are sealed. A record of prescription forms is kept in a special journal, which is numbered, laced and sealed.
4. The person responsible for storage is carried out by order to the hospital or clinic.
5.Only one substance is prescribed for drugs, prescribed only by the doctor himself and certified by the chief physician or manager. department.
RULES FOR WRITING PRESCRIPTIONS:
The prescription is written out only with a ballpoint pen; corrections and crossing-outs are not allowed. Issued only in Latin.
Solid medicinal substances are prescribed in grams (for example: 15.0),
liquid substances are indicated in ml.,
· ethyl alcohol in its pure form is sold from the pharmacy warehouse angro i.e. by weight. and therefore, for accounting purposes, it is written out in prescriptions by weight, i.e. in grams
Conventional abbreviations are permitted. (see order)
The signature is written in Russian or in the national language. The method of application is indicated.
IT IS FORBIDDEN: in the signature write expressions such as:
internally
or the use is known.
Every pharmacy has a log of incorrect prescriptions.
DRUG SUBSTANCE is a substance used for treatment,
prevention and diagnosis of diseases.
MEDICINE is a drug (l.f.) containing one or more medicinal substances and produced in a specific dosage form.
DOSAGE FORM - This is a form of a drug that makes it convenient to use.
Topic: CLASSIFICATION OF DRUGS BY
POWER OF ACTION.
1. Poisonous and narcotic. (list A. powders)
They are designated (Venena “A”), stored in standglasses, the label is black,
The name of the drug is written in white letters. Stored in accordance with Order No. 328 of 08/23/1999 in safes, under lock and key, equipped with sound or light alarms, sealed at night. The key is held by the person responsible for registering narcotic substances.
On the inside of the safe door there is a list of A - toxic drugs, indicating the highest single dose and the highest daily dose.. Inside the safe there is a separate place where especially toxic substances (sublimate, arsenic) are stored.
2.Potent
(Heroica "B")
The label on the rods is white, the names of the substances are written in red letters, and are stored in ordinary cabinets.
3. General action drugs.
They can also be placed in regular cabinets.
The label is white, written in black letters.
CLASSIFICATION BY CONSISTENCY.
Are divided into:
1.Solid.
CLASSIFICATION BY METHOD OF APPLICATION:
1.For external use.
2.For internal use.
3.For injections.
According to the method of manufacturing liquid dosage forms medicines are classified into a special group, which are called galenic
GALENIC PREPARATIONS- these are alcohol extracts from medicinal raw materials, containing ballast substances along with active ingredients. - (substances do not have a therapeutic effect and are also not harmful to the body)
NEW GALENIC PREPARATIONS:- these drugs are as purified as possible
from ballast substances. They mainly contain pure active ingredients.
ACTIVE SUBSTANCES- these are chemically pure substances with a specific therapeutic effect.
BALLAST SUBSTANCES- reduce or increase the effect of therapeutic action without causing harm to health
STATE PHARMACOPOEIA is a collection of general state standards that determine the quality, effectiveness and safety of medicines. It contains articles on determining the qualitative and quantitative content of substances in dosage forms.
Loading...
