Transcript pharmaceutical factors

“BIOPHARMACEUTICS AS A THEORETICAL BASE
OF MEDICINES FOR PHARMACEUTICAL
TECHNOLOGY.
THE BASIC TERMS OF BIOPHARMACEUTICS”
• Lecture 1
1
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.
2
•
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.
3
•
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.
4
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.
5
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.
6
Development of biophafraceutics
American scientists
Founders of
biopharmaceutics
Scientists
ХIХ century
The influence of
auxiliary
substances on
the processes of
absorption of
medicines was
proved
Levy and Wagner (1961)
IBN-Sina of
Х century
Empiric supervisions about influence of
honey additions and some vegetable
medicines on the degree of medicinal
substances action
The dependence of absorption speed
and efficiency of medicines on the way
of introduction was defined
experimentally
7
8th World Meeting on Pharmaceutics, Biopharmaceutics and
Pharmaceutical Technology was carry out in 2012. 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
8
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.
9
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.
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.
11
Factors are simultaneously working forces, conditions or other
circumstances influencing on the result of researches, data or
parameters
Factors
Constant
Variable
Medicinal substance
Pharmaceutical
Dose or
Physiological
concentration of
Biochemical
medicinal substance
Clinical
12
Classification of variable factors
sex
Physiological
factors
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
13
Classification of variable factors
the time of drug application
Clinical
factors
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
14
Glossary of Biopharmaceutic terms
Pharmacokinetics (PK)
Pharmacodynamics (PD)
Pharmaceutical equivalent
(chemical)
Clinical
equivalent
Equivalence
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
Describes the relationship between the dose and
the pharmacological effect at the site of action
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
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
Identity of therapeutic effect of the medicine to comparison
standard medicine
The state or property of being equivalent
15
Equivalence
Non-equivalence
Effective substance
Efficiency
Active ingredient
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 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
Biologically active part of medicine taking responsibility
for its therapeutic effect
The production of the desired effects or results with minimum
waste of time, effort, or skill
That which enters into a compound, or is a component part
of any combination or mixture; an element; a constituent
16
Absolute
availability
Relative
availability
Dosage
Absorption
Absorption rate constant
( ka)
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.
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.
The determination and regulation of the size,
frequency and number of doses
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
17
Distribution
Distribution
coefficient
Reabsorption
Area under
curve (AUC)
Clearance (Cl)
The process during which the medicinal substance is
distributed from blood to the tissues and body organs
The ratio of concentrations of a substance in
two immiscible phases at equilibrium
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
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
18
Systemic clearance
Elimination
Elimination
constant
Tolerance
Antagonism
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
The constant rate is the process during which the
effective substance is deduced from the body by the
process of biotransformation
Tolerance to a drug develops when the
response to the same dose of the drug decreases
with repeated use
Antagonism is action in which two drugs given
together will have an opposite effect on the body
19
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
20
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.
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.
22
. Interdisciplinary scheme of LADMER system
Rate
Liberation
- in vitro
- in vivo
Discipline
Biopharmaceutics
Absorption
Concentration
-
Distribution
-
Metabolism
-
Elimination
Response
Pharmacokinetics
Pharmacodynamics
23
LADMER system, biopharmaceutics hurdles in drug development,
approaches to overcome them
LADMER
Biopharmaceutic hurdle
Biopharmaceutic class
Drug
Poor Solubility
Class II
Class IV
Liberation
Chemical degradation
Approaches to
overcome the hurdle
Formulation approaches
Chemical modifications
Formulation approaches
All Classes
Chemical modifications
Enzymatic degradation
All Classes
Enzyme inhibitors
Chemical modifications
Poor Permeability
Class III
Class IV
Sorption
Absorption
promoters
Chemical
modifications
First
Distribution
Metabolism
pass
metabolism
All Classes
Alternative route
Prodrug approach
Excretion
Response
24
Biopharmaceutic factors affecting dissolution and/or
absorption
Pharmaceutical
factors
Physicochemical
characteristics of the drug








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
Physiological factors
affecting bioavailability








Permeability
GI transit/motility
Site specific
absorption
Preabsorptive
metabolism
Hepatic metabolism
Biliary excretion
Renal excretion
Protein and tissue
binding
25
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
.
•
•
•
•
•
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.
27