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 edicines 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. 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

4. 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

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

6. Classification of variable factors
Clinical
factors
time of drug application
interaction simultaneously or consistently entered drugs
infringements of functions: stomach, kidneys, intimate 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

7. Classification of variable factors
Pharmaceutical
Physiological
Biochemical
Clinical
Medicinal substance
Dose or concentration of medicinal substance
Factors
Constant
Variable

8. Glossary of BiopharmaceIdutic 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

9. 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
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

10. 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)

11. 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

12. 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)

13. 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

14. 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

15. 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

16. 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.

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

18. 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

19. 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

20. 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.