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

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.

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

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

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

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

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

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

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

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)

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

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)

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

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

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

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.

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

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

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

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.