1. “Biopharmaceutics as a theoretical base of medicines FOR pharmaceutical technology. The basic terms of biopharmaceutics”
Lecture 1

2. Biopharmaceutics is a science which studies dependence of therapeutic action of medicines on the organism from the different variable factors.
The term “biopharmaceutics” appeared at first in scientific pharmacy of the USA in the beginning of the 60th years of the 20th century and soon got worldwide acknowledgement.

3. Biopharmaceutics as a science appeared after revealing of the facts of biological non-equivalence of medicines. Medicines containing the equal doses of the same medicinal substance, but prepared by different pharmaceutical factories are differed by the degree of pharmacological effect.
It has been proven by biopharmaceutical research that it was caused by the different dispersion degree of medicinal substances, selection of auxiliary substances, peculiarities of technological processes and other variable factors. Later all this was combined under the term «pharmaceutical factors».
A term «pharmaceutical factors» got distribution in connection with confirmation of experimental information about existence of dependence between the effect of medicines and their technology. Researches confirmed as evaluated by biological availability of medicines, that physical and chemical properties were not unique criteria determining pharmacological action of medicines.

4. On a modern stage in pharmacology science the basic considers high quality of medicines, but medication not only must answer the analytical normative document of active substances assay but also to render a maximal therapeutic effect, minimum side effect and to render optimum biological availability.
The results of biopharmaceutical researches appeared so considerable, that new direction reflecting biological estimation of the prepared medicines was designed in the complex of medicinal and biological sciences.
So there was biopharmaceutics studying co-operation of medicines and organism of patient.
In this connection there was the necessity of study of biopharmaceutics at the professional preparation of pharmacists.

5. Aims and tasks of biopharmaceutics as educational discipline:
teaching of students of activity of pharmacist, as technologist-researcher;
studying of theoretical bases, acquisition of professional abilities and skills in the choice of chart of researches at the development of compositions and technology of new medicines and perfection of existing;
using of bases of extemporal in the ground of optimum technology of extemporal medicines;
prognosing of pharmacokinetic processes of biologically active substances in the process of application of ready and extemporal medicines in different medicinal forms.

6. search of new modulators of bioavailability;
As a science the theoretical and experimental ground is the primary objective of biopharmaceutics creations of new medicines and perfection of existing taking into account the increasing of their therapeutic effect and diminishing of side action on an organism.
Scientific researches of biopharmaceutics include the following directions:
studying the influence of pharmaceutical and other variable factors on processes of release and absorption medicinal substances from medicinal forms;
studying the influence of variable factors on pharmacokinetics of medicinal drugs for optimization of their structure;
studying mechanisms of biopharmaceutical processes, which occur during interaction of components of the ready medicinal drug on the organism;
search of new modulators of bioavailability;
creation of new medicinal forms with a set of biopharmaceutical properties, which should provide optimum bioavailability of active the substances;
studying bioequivalence of drugs;
development of high-sensitivity and selective methods of analysis of interaction of active substances and auxiliary substances in medicinal forms in view of specificity of the patient’s organism.

7. Development of biophafraceutics
Founders of
biopharmaceutics
American scientists
Levy and Wagner (1961)
IBN-Sina of
Х century
Scientists
ХIХ century
Empiric supervisions about influence of honey additions and some vegetable medicines on the degree of medicinal substances action
The influence of auxiliary substances on the processes of absorption of medicines was proved
The dependence of absorption speed and efficiency of medicines on the way of introduction was defined experimentally

8. 8th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology was carry out in Some of hot topic lectures were: • Continuous Production • Industrial Scale Production of Smallest Batches • Innovative Parenteral Preparations • Dosage Forms for Paediatrics and Geriatrics • Oral Products for Poorly Water Soluble Drugs • Polymeric Excipients for Oral and Parenteral Applications • Therapeutic Protein Modifications and Biological Relevance • Drug Regulatory Affairs • Solid dosage forms • Dissolution Testing/Quality Control

9. Biopharmaceutics studies influencing of physical and chemical properties of active and auxiliary substances in medicines produced in different medicinal forms, but in identical doses, on their therapeutic action. Since of therapeutically efficiency of medicines is determined by the processes of their absorption (suction), distribution and elimination (bringing out) from microorganism, biopharmacy pays great attention to these processes, as well as the influence of physicochemical properties of medicinal substances. That’s why now all studied medicinal forms are examined in biopharmaceutical aspects. All pharmaceutical factors, which influence on biological effects of drugs, can be divided on 5 groups: - Physical state of the medicinal substance. - Chemical nature of the medicinal substance - Auxiliary substances. - Type of the medicinal form and the ways of introduction it in the organism. - Technological operations, which take place in getting a drug. Pharmaceutical factors play an important role in working out the composition and the technology of new drugs and improving already existed. The study pharmaceutical factors will help pharmacist-technologist to find an optimal technology of preparing drugs, which will guarantee the maximum absorption of medicinal substance from medicinal form, when it's used correctly.

10. The main cause of biopharmaceutics origin as a science is an determination of therapeutic non-equivalence of medicines .
Bioavailability is the extent to which the active ingredient of a drug dosage form becomes available at the site of the drug action
Differences in bioavailability may result in therapeutic nonequivalence.
The change from a preparation with high bioavailability to one with low bioavailability may result in failure of treatment. The reverse change may lead to an acutely hazardous situation, for example, with an anticoagulant or hypoglycaemic agent.

11. Reasons of therapeutic non-equivalency of medicines are:
The British Pharmaceutical Codex, 1968, states that "when the addition of substances acting as excipients, binders, disintegrants, preservatives, antioxidants, etc., is permitted, the substances used must have no adverse influence on the efficacy of the active ingredients."
Reasons of therapeutic non-equivalency of medicines are:
difference of physical and chemical properties of medicinal substances;
selection of auxiliary substances;
distinction in technological processes
types of medicinal form;
ways of application.

12. Factors are simultaneously working forces, conditions or other circumstances influencing on the result of researches, data or parameters
Pharmaceutical
Physiological
Biochemical
Clinical
Medicinal substance
Dose or concentration of medicinal substance
Factors
Constant
Variable

13. Classification of variable factors
Physiological factors
sex
age
the state of organism
Pharmaceutical factors
the physical state of the medicinal substance
a simple chemical modification of a medicinal substance
auxiliary substances
(their nature, physical state and quantity)
a medicinal form and ways of application in the organism
technological process

14. Classification of variable factors
Clinical
factors
the time of drug application
interaction concomitant or consistent administration of medicines
dysfunctions of the gastrointestinal tract, kidneys, cardiac activity, nervous system etc.
physical activity of the patient
Biochemical factors
peculiarities of biochemical processes in the organism and
metabolism of medicinal substances for the given patient

15. Glossary of Biopharmaceutic terms
Pharmacokinetics (PK)
Is the quantitative study of the course of drug absorption, distribution, metabolism and elimination (ADME)
Pharmacokinetic data is very usefull in optimization of the disage form design and establishing the dosage interval
Pharmacodynamics (PD)
Describes the relationship between the dose and the pharmacological effect at the site of action
Pharmaceutical equivalent
(chemical)
The medicine which containing identical quantity of the substance in the same medicinal form and meeting the requirements which are defined by the technological norms
Clinical
equivalent
Medicine which after application in the same dozes gives the identical therapeutic effect which has been checked up on any symptom or on treatment of illness
Equivalence
Identity of therapeutic effect of the medicine to comparison standard medicine
The state or property of being equivalent

16. Equivalence Non-equivalence
is a term in pharmacokinetics used to assess the expected in vivo biological equivalence of two proprietary preparations of a drug. If two products are said to be bioequivalent it means that they would be expected to be, for all intents and purposes, the same
Equivalence
Non-equivalence
Non equality of therapeutic action of the same medicines in identical dozes and medicinal forms prepared by different manufacturers or the same factory, but different series
Effective substance
Biologically active part of medicine taking responsibility for its therapeutic effect
Efficiency
The production of the desired effects or results with minimum waste of time, effort, or skill
Active ingredient
That which enters into a compound, or is a component part of any combination or mixture; an element; a constituent

17. Absorption rate constant ( ka)
Absolute
availability
The quantity of the medicinal substance entered in the medicinal form intravenously, which acts in blood circulation without influence on the effect of the first passage through the liver (effect «first pass»), and the course of speed this process.
Relative
availability
The quantity of medicinal substances in the biological liquid, which is released from the researched medicinal form, expressed as a Percentage, in comparison with Absolute bioavailability or with the standard medicinal form.
Dosage
The determination and regulation of the size, frequency and number of doses
Absorption
The movement of a substance, such as a liquid or solute, across a cell membrane by means of diffusion or osmosis
The constant for a drug administered by a route other than the intravenous. The rate of absorption of a drug absorbed from its site of application according to first-order kinetics.
A value describing how much drug is absorbed per unit of time
Absorption rate constant ( ka)

18. Distribution coefficient
The process during which the medicinal substance is distributed from blood to the tissues and body organs
Distribution coefficient
The ratio of concentrations of a substance in two immiscible phases at equilibrium
Reabsorption
Process of the opposite absorption of the medicinal substance
Is the area under a plot of drug concentration vs. time.The most common method of estimating AUC is to use the trapezoidal rule where the concentration-time curve is considered as a series of trapezoids and estimate the total area of all the trapezoids
Area under
curve (AUC)
Clearance (Cl)
Is a function of the blood flow rate (Q) to these organs. It depends on the intrinsic ability of the organs such as the liver and kidneys to metabolize or excrete

19. Systemic clearance
Is the sum of all individual organ clearances that contribute to the overall elimination of the drug. It is evaluated from the PK data as shown in following: Cl = Dose/AUC
Is the sum of all individual organ clearances that contribute to the overall elimination of the drug. It is evaluated from the PK data as shown in following:
Cl = Dose/AUC
Elimination
The constant rate is the process during which the effective substance is deduced from the body by the process of biotransformation
Elimination
constant
Tolerance to a drug develops when the response to the same dose of the drug decreases with repeated use
Tolerance
Antagonism is action in which two drugs given together will have an opposite effect on the body
Antagonism

20. Influensing of variable factors on the medical effect of medicines
LADMER
General term characterizing the separate areas of co-operation of medicine with an organism (Liberation, Absorption, Distribution, Metabolism, Elimination, Response), i.e. includes biopharmaceutics, pharmaсokinetics and pharmaсodynamiсs
Therapeutic efficiency of medicines determined by processes:
absorption (suction)
distribution
elimination

21. Many factors are responsible for the entry of a drug into the body and then into biophase. These factors include the route of administration; the dosage form; the liberation rate of the drug from the dosage form; dissolution; penetration and permeation of the drug through biomembranes; its distribution within the body fluids and tissues; the type, amount and rate of biotransformation; and recycling processes and elimination.
In addition to these factors, pharmacogenetics and certain pathophysiological conditions also affect the above process. The entire process can be described as the LADMER (liberation, absorption, distribution, metabolism, elimination and response) system showing that liberation, absorption, distribution, metabolism and elimination are involved to elicit the response. One can subdivided this approach according to the scheme shown in fig.

22. Biopharmaceutics is a major branch of the pharmaceutical sciences concerned with the relationship between the physicochemical properties of a drug in dosage form and the pharmacologic, toxicologic, or clinical response observed after its administration. Biopharmaceutics mainly involves drug absorption process. Systemic absorption of most drug products consists of a succession of rate processes viz.: (i) disintegration of the product; (ii) dissolution of the drug in an aqueous environment; and (iii) absorption across cell membranes into the systemic circulation and, ultimately, to its site of action.

23. . Interdisciplinary scheme of LADMER system
Rate
Discipline
Liberation
in vitro
in vivo
Absorption
Concentration
Distribution
Metabolism
Elimination
Response
Biopharmaceutics
Pharmacokinetics
Pharmacodynamics

24. LADMER system, biopharmaceutics hurdles in drug development, approaches to overcome them
Biopharmaceutic hurdle
Biopharmaceutic class
Approaches to overcome the hurdle
Drug
Poor Solubility
Liberation
Chemical degradation
Class II
Class IV
Formulation approaches
Chemical modifications
All Classes
Enzymatic degradation
Poor Permeability
Enzyme inhibitors
Class III
Sorption
promoters
First
pass
metabolism
Alternative route
Prodrug approach
Absorption
Distribution
Metabolism
Excretion
Response

25. Biopharmaceutic factors affecting dissolution and/or absorption
Physicochemical characteristics of the drug
Pharmaceutical
factors
Physiological factors affecting bioavailability
Solubility
Partition coefficient, pKa
Dissolution rate
Salt formation
Prodrugs
Particle size, surface area and shape
Crystallinity, polymorphism
Stereochemical factors
Factors related to formulation (excipients)
Galenical:dosage form
Manufacturing process
Stability and storage of drug and drug product
Permeability
GI transit/motility
Site specific absorption
Preabsorptive metabolism
Hepatic metabolism
Biliary excretion
Renal excretion
Protein and tissue binding

26. The quantitative side of medicinal substances absorption is limited, foremost, by efficiency (by kinetics) of their releasing on the initial stage of absorption. Efficiency of medicinal substances releasing is in direct dependence on pharmaceutical factors and their successive use for advancement of active substances by following chart: - choice of the chemical state; - choice of bodily condition; - influencing of auxiliary substances; - influencing of the simultaneously accepted medicines; - choice of medicinal form; - choice of way of introduction; - establishment of exact dosage; - influencing of pharmaceutical factors; - determination of role of physiological factors enorganic this.

27.   Thus, on the basis of numerous laboratory researches and experimental information confirmation is got about dependence of medicines on physical and chemical properties of medicinal substances, methods of their obtaining, correlation of active and auxiliary substances in a medicinal form. Biopharmaceutic succeeded to be successfully decided row of tasks of applied pharmacy and medicine and to render substantial influence on further development of theory of modern pharmacology science.
Consumption and efficiency of drugs production can be described from quantitative and high-quality sides. So, a quantitative side appears by annual pharmacy and factory production of medicines. With respect to high-quality estimation, it has both positive and negative sides. Estimating positive sides, we must remember always, that to the high level of the medicinal providing of population (and it is determined how accepted, above all things by an amount, assortment of medications and analytical normative document) must correspond and high level of pharmacotherapy. From this point of view presently efficiency is estimated not only on an amount but also in quality treatments by medicinal preparations. It means, it is necessary to estimate, as far as the applied medications are effective for renewal of ability to work patients and making healthy of population.
Therefore presently all more frequent in the special literature is associated the word «technology» and «bio-efficiency» of medicines, as production must produce high-quality medicines.
Biopharmaceutics is scientific discipline without development of which it is impossible to represent modern pharmacology science.