Samenvatting
Summary Pharmaceutical Technology and Biopharmacy
This is a very extensive summary that belongs to the course Pharmaceutical Technology and Biopharmacy. The summary is written in English.
[Meer zien]Voorbeeld 4 van de 124 pagina's
Voorbeeld 4 van de 124 pagina's
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Voorbeeld van de inhoud
Therapeutically active Excipientssubstance Formulation
Form, qualitatively
quantitatively
Biopharmaceutical Technological
objectives: objectives:
Samenvatting -Release profile
-Route of administration
-Process control
-Stability
Pharmaceutical Technology and Biopharmacy
-Targeting -Reproducibility
quality production
2 december 2019 Therapeutic
developments Dosage form
Technological
developments
Administration to patient Devices
Biopharmacy Therapeutic effect
Biopharmaceutical aspects of drug administration.
The design of a dosage form 2
excipients -> hulpstoffen
Technology: You have to formulate that specific pharmaceutical ingredient into a dosage form -> a
drug product (Tablets, ear drop, injection, inhalation etc. those are typically forms of
administration). The composition or the intern structure of a drug product is determined by two
different aspects The technology -> how can we in a reproducible and true-liable way administer
the drug of a appropriate quality to the patient. The technological objectives (doelen) are Process
control, stability and reproducibility.
The other aspect is the Biopharmaceutical -> the drug product will all end up in a patient and there
will be an interaction of the dosage form containing the drug with the living organism. It is important
of the product will deliver it in a propriety way. There are three biopharmaceutical objectives: The
release profile, the route of administration and targeting. Based on these two objectives you design
a dosage form -> a form which means a structure which consist of the active pharmaceutical
agreement and other forms. After production it will lead to the dosage form which can be
administer to the patients either directly or via a device and this leads to a therapeutic effect.
Drug therapy and Biopharmacy
The therapeutic effect of the drug is determined first of all by the intrinsic pharmacologic activity of
the active pharmaceutical ingredient. That can be the positive side which is the therapeutic effect
but there can also be a negative effect which are the side effects (toxicological) of the drug.
The drug often has a therapeutic effect but does also have often some side effects.
The therapeutic efficacy of a ’’drug substance’’ (active pharmaceutical ingredient) is determined by:
- The intrinsic (innerlijk) pharmacological and toxicological (side effects) properties of the
substance (receptor interaction).
- The extend and rate of delivery of the substance to the site of action (transport rate). Determined
by:
1. The extend and rate of drug release from the dosage form.
2. The site of release of the drug substance from the dosage form.
3. The transport of the drug substance from its site of absorption (drug is taken up by the blood)
to site of action.
The points 1, 2 and 3 are determined by:
- The physics-chemical properties of the drug substance. (solubility->oplosbaarheid, log P->
whether it dissolves (oplost) in an oil or in a water.
- The physics-chemical properties of dosage form. (Putting a drug in an oily or in a aquas (water)
base)
- The structure of dosage from. (put a polymer around a tablet it will prevent drug release or
increase the drug release and if you put the polymers dispersed (verspreid) in the tablet there
will be no difference and there will hardly be an effect.
- The site of drug release from the dosage form.
- The route of drug administration.
Pagina 1 van 124
, A simplified approach for systemically
acting drugs
A simplified approach for
systemically acting drugs.
Dissolution Before a drug can be taken up in the
body the drug first has to release
Dissolved drug from the dosage form. A drug in a
Drug in dosage
form
Site of action
Target with receptor dosage form has no effect. The
(Membrane) transport into
the systemic circulation: Distribution, metabolism
(e.g.organ) major reason that drugs in a dosage
Ab orp ion and elimination form has no effect is that the drug is
Exceptions: not dissolved. Only dissolved drugs
can pass membranes and only
intravenously
dissolved drugs can injected
have adrugs
therapeutic action. Only a dissolved drug can have an interaction with
a receptor
targetedand drugs non dissolved drugs can not.
Locally applied
In a solution and locally
the solute acting
should be drugs
mixed and a solution has a molecular dispersion.
Solution -> Theorsolvent
e.g. dermal nasal is surrounding the molecules of the solute.
drugs
5
Solution -> the solute is dispersed in the solvent at the molecular level and that it is stable.
Verschil solvent, solute en solution.
The drug has to dissolve because otherwise the drug is too big to pass the
membrane. After the drug is taken up by the blood it enters your blood flow/
circulation either directly or via the lymfe and the drug is distributed over the
body and when the drug is at the site of action it can work either directly or
via a receptor depending on the type of action of the drug.
There are some exceptions if you take a drug which is intravenously
injected drugs it will be directly in the blood circulation. The drug you inject
intravenously should be in a solution because non-dissolved drugs would
leas the embolism which is deadly.
Exceptions: will not be taken up by the blood but directly injected ->
intravenously injected drugs, targeted drugs, locally applied and locally
acting drugs (dermal->huid or nasal->neus drugs) -> don’t need a blood
flow.
Pharmacokinetics: What happens with a drug in the body?
Pharmacokinetics: What does the body with the drug after the drug is administered? How good is
the drug absorbed? How well will the drug after administration get into the blood circulation and be
distributed over the body and can act in their. After the drug is taken up it will be distributed over
the body and depending on the physical properties of a drug this distribution may be different.
There are two steps to get rid of the drug which is first metabolism -> chemical processes mostly
catalyzed by enzymes that will inactivate the drug and the second step is excretion -> How are the
drugs or the metabolites excreted from the body. There are more pathways of excretion for
example via the urine or bile… etc.
ADME:
-Absorption: Uptake of the drug in the systemic blood circulation
-Distribution: The distribution of the drug to the different
compartments (fluids, organs) in the body
-Metabolism: The chemical conversion of drug substance by the body
(often by enzymes) to different active or inactive substances
(metabolites).
-Excretion: The removal of the drug or its metabolites from the body,
via urine, bile (gal), sweat or breath.
These steps determines the behavior of the drug in the body.
Pagina 2 van 124
, Administration of the drug via the intravenous injection: ‘’most direct route’'
-> the complete dose of the drug is injected (by injection or infusion) in the systemic blood
circulation. Pharmacokinetics after intravenous
In this case the bioavailability = 100% -> Everything that we administer will get into the blood flow.
injection
This is the only way of getting this high percentage.
Distribution of drug over the body Metabolism and excretion
Bioavailability is the fraction of drug that enter the blood flow.
(fluids, tissues and organs may eliminate (e) the drug from the
This administration is generally the fastest way to gethave a different
therapeutic effect.
concentrations) body
If you inject a drug intravenous in a vein -> The drug is going
Volume to he heart
of distribution: Vd and is spread furtherClfirst
Clearance:
to the lung and then further to the rest of the body byThe theapparent
small volume
and the large circulation.
in which the The blood or plasma volume
drug is dissolved (L/kg) after which is cleared from all drug per
Pharmacokinetics after intravenous administration unit of time (ml/min)
injection. First order elimination process:
- Distribution of drug over the body (fluids, Vd (1 compartment kinetics)
tissues and organs may have different D0
concentrations) Cp exp ket
Vd
- Volume of distribution: Vd -> The apparent Cp: concentration in blood (or plasma)
volume in which the drug is dissolved (L/kg) D0: dose
after administration ke: elimination rate constant
- Metabolism and excretion eliminate the ke= Cl/Vd
drugs from the body 9 Log. scale
t: time
- Clearance: Cl -> The blood or plasma
volume which is cleared from all drug per
unit of time (ml/min)
Pharmacokinetics after intravenous injection.
There is a distribution phase and at that point there are high concentration in the blood because
the drug has not been completely distributed over the entire body. At a certain moment the blood
has been pumped to the entire body and the drug is been distributed over the entire body. The
drug is distributed in the blood vessels, veins and also in the tissues. After that we see a
logarithmic decrease in concentration of the drug in the blood. That is because there is metabolism
or excretion. It is a first order elimination process. The decrease of drug concentration is fast so the
half time is short.
For most drug activities you need a certain plasma or blood level of the drug in the blood otherwise
The volume of distribution there is no effect. The distribution phase is were the decreasing
in drug concentration starts. This distribution may vary some
drugs are for all of the body but some drugs are concentrated
No concentration of for the brain and the liver etc. Than you get variations in
the drug in organs,
fluids or tissues volume of distribution.
dV not larger than In the first (above) situation the drug in the body is equal to the
body volume administer dose -> no concentration of the drug in organs,
fluids or tissues. Vd not larger than body volume.
Concentration of drug in organs, In the second (under) situation there are concentration of drug
tissues or fluids (compartments)
in organs, tissues or fluids. Vd is larger than body volume. In
Vd > body volume this case the concentration of drug in the blood are lower. The
volume of distribution will be in this situation higher and will be
10
larger than the volume of the body.
The drug absorption process
Absorption: only dissolved drugs may be able to pass the absorption membranes. Only dissolved
drugs pass the membrane other drugs not.
Pagina 3 van 124
, administration
Sublingual dissolution
Intramuscular
subcutaneous
oral
The absorption model used for systemic
administration.
The oral route The drug has to be dissolved and absorption
liver
Drugs administered via
than the dissolved drug may pass the intestinal Pulmonary heart
Dermal
(darm) membrane. This membrane is the barrier
non-intravenous routes
in the process. There are multiple ways to
Portal vein
first pass effect
i.v. injection
administer drugs. By the oral route the drug1first infusion
The goes
drugtomust enter
the liver wherethea lot of the drug already
will be metabolized.
blood flo : absorp ion Sometimes there will rectal
already be 80% lost of the drug because of the
process
metabolism. of the liver you may have than too
0,1 12
The little
blood effect
orofplasma
the drug. Sublingual -> drug is put under the tongue -> the drug dissolves there and
c (mg/l)
will be taken up by blood vessels.
concentration
Dermal route -> versus
drug viatime
skin inject the drug0,01 in the skin (subcutaneous) or in the muscles
s administered via curve will have another
(intramuscular). Pulmonary -> inhaling via longs. These are all possible routes for entree of drugs
into the body.
ntravenous routes profile.
0,001
1 Drugs administered
0 via
1 non-intravenous
2 3 4 routes
the -The drug must enter the blood
time (hr) flow: absorption process.
on -The blood or plasma concentration versus time curve will have
another profile.
0,1
c (mg/l) Drugs administered via non-intravenous routes
(Maximum tolerable
concentration)
There is an absorption phase during this phase the drug is passing a
time 0,01 membrane and goes through the membrane in the blood circulation.
er There is a rise of drug in the plasma concentration. The moment a
drug gets into the blood the elimination phase and the excretion or
0,001
metabolism starts too. So at a certain moment when the majority of
13 0 1 2 drug
3 is4 absorbed we see a elimination again which is similar to the
time (hr) plasma curve we saw after the intravenous injection. The uptake
(absorption fast) goes faster than the outtake
(elimination phase). Cmax is the same for the
absorption and the elimination. So the absorption rate
(Maximum tolerable and the elimination rate are the same.
concentration) The minimal effective concentration (Cmin) this is the
minimum concentration at which an effect of the drug
occurs. When we are above that concentration we
may expect an effect of the drug. However we can not
go endless up in the drug concentration because there
are no drugs without side effects. There is also a
maximal tolerable concentration and you should stay
below that level otherwise there occur side-effects.
Pharmaceutical availability
Pharmaceutical availability and bioavailability. and Bioavailability
How can we manipulate the absorption of the drug Driving force dissolution and diffusion partition, diffusion
that determines how the plasma profile of a drug will for transport: diffusion (partition) convection active transport
be. Within pharmaceutical technology there are two
defined parameters and that are the pharmaceutical
availability and the bioavailability. The pharmaceutical
availability is the amount of drugs that dissolves from
a dosage form. Bioavailability is the amount of drug
that enters the systemic circulation. The difference Release of drug from
Dosage form
Drug dissolved
aqueous fluids
Transport over
the membrane
Uptake in
in blood
between these two parameters is the amount of drug Pharmaceutical availability metabolism
that we loose when a drug has to be transported over
the absorbed membrane so not all drugs can pass the Bioavailability (incl. metabolism in gut and liver)
membrane. Metabolism can also creates a decrease dissolution diffusion and convection membrane passage metabolism
of bioavailability by enzymes. The pharmaceutical 15
availability at maximum will always be larger or equal
to you bioavailability.
Pagina 4 van 124
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