Download Enzymes - ISpatula

Done By: Sanaa Otoom
Advanced Technology
Introduction
 Application of technologies in the area of drug delivery is pharmaceutical technology, it
includes the development, design of drugs, evaluation and performance of dosage forms.
It’s synonym for “Pharmaceutics”.
 In this topic we’ll discuss:
1- Improvement and optimization of bioavailability of pharmaceutical compounds. We
will focus mainly about orally administered compounds; simply because it represent
70-80% of different dosage units that are administered.
2- Barriers against bioavailability of oral dosage forms.
The active ingredient in the orally administered compound must be able to reach the site of
action in different tissues, before this, it must be absorbed because it’s administered
extracellularly; this absorption depends on:
1) Permeation: movement of the compound across the barrier membrane (affected by the
ionization of the compound, molecular structure, functional groups, logP .... Etc ).
2)Solubility: usually when we administer drugs orally we use mainly solid dosage forms
,because if we use liquid system like solution or suspension we will have high risk of
different instabilities (physical instability like changing in the crystal form , chemical
instability like degradation and microbiological instabilities ) so it’s more logic to go toward
solid dosage form. when the drug present in a solid dosage form then we have the drug in a
solid state that need to be in a molecular form in order to be permeated, this process of
converting a matter from a solid state in to molecular (solution) form in a liquid media is
called dissolution.
 We studied before the Biopharmaceutical Classification System (BCS): When we
have a drug that is poorly water soluble then the rate limiting step of the absorption
will be dissolution not permeation, so it’s going to be a major barrier against drug
absorption.
3) Stability : the stability in the GI fluids Or in the brush border of the intestinal membrane or
before reaching systemic circulation like potential metabolism of the drug by hepatic
metabolic machinery ( after passing intestinal wall it will go by the portal vein to the liver
where it will work here as refinery machine for foreign compounds).
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If we have a drug that has instability in GI fluid by its pH or by degradation enzymes
there, or extensively metabolized in the liver, this would be an additional obstacle for
drug absorption, because when we talk about drug absorption we actually talk about
3 steps, if the drug has good dissolution and permeation and has big 1 st pass
metabolism then it won’t be bioavailable i.e. won’t reach the concentration needed at
the site of action. If we have a drug that is extensively metabolized like nitrates, so
they are giving it sublingually because we have extensive hepatic metabolism so
can’t be given orally, or in unstable angina we give patches.
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We could also have instability in the GI fluids, that’s why sometimes we give a drug
in a form of enteric coated tablets or pellets, here actually we improve their
bioavailability by improving their stability because otherwise they will get broken in
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Done By: Sanaa Otoom
Advanced Technology
Introduction
the stomach acids before reaching parietal cells .also one of the approaches that is
used in the administration of the peptides by oral pathway is using protease
inhibitors that will improve their bioavailability, also we can use encapsulation in
cyclodextrin or micelle system improve the stability of the product by shielding the
compound from GI conditions.
 so ... we have 3 issues when talking about drug absorption that are dissolution,
permeability and stability, and we need to overcome these problem in order to reach the
site of action in sufficient concentration and give a response.
Regarding affecting permeation, we can do:
1) prodrug, but it is a chemical modification on the parent drug, if we do this then we are
forming new chemical entity so we need to study everything related to this compound like a
new drug, like starting a new drug discovery trip with a huge bill because we need to prove
that drug A is the same as prodrug A in term of efficacy, binding properties, solubility ...etc,
so start from scratch again! …… so this isn’t the most suitable approach in advanced
stages of drug development or in generic model of pharmaceutical manufacturing.
2) Permeation enhancers, like using of surfactant, they affect biological membranes, they
do solubilization of cholesterol present in cell membrane making it more fluid and decrease
its diffusional resistance in it, this approach lead to inflammation in the membranes when
it’s exposed to a high concentration of surfactant.
3) Permeability Glycoprotein (P-gp) inhibitors, here the problem isn’t with the permeability of
a compound cross membranes but with this protein in the cytoplasm that pump it outside,
but even this will interfere with the defense mechanism like using of cancer drug that work
by this principle, it will destruct the defensive mechanism for the cancerous cell as well as
the normal one because most of them lack specificity.
So using of these issues to improve bioavailability is debatable, it may interfere
with the biological system and defensive mechanism .....
 This leaves us with the solubility and dissolution enhancement by physical methods,
particle size reduction and micronization ...etc. these are formulation approaches
related to our product not to the physiological system, so we don’t have these
concerns about physiological system. What we said till now is that permeability (
intestinal mucosa membrane ) and stability ( 1st pass metabolism , it would be hard
to interfere with them....So the main approach that we work on it is modification of
solubility and dissolution ... Now ...how relevant is this approach ? Are there a lot of
drugs that have problem in their bioavailability due to its dissolution? Around 70-80%
of drugs that has been discovered in the last 10 to 20 years are in Class II , so their
main problem is solubility , Why ? because the change in the way we discover drug
now , the way that our colleagues in medicinal chemistry and drug discovery thinking
:In medicinal chemistry , the main principle to discover drug is having a compound
that bind to a receptor or inhibit an enzyme at very low concentration... like Nanomolar inhibitors / binders ( IC50 for an enzyme is in nanomolar level ).This mean that
we have a compound in very low concentration in a solution that have a higher
affinity to the binding pocket of the enzyme than the solution , then he has low affinity
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Done By: Sanaa Otoom
Advanced Technology
Introduction
to stay in water and higher one to go to the hydrophobic pocket even at low
concentration, this means that we have hydrophobic compound very potent
inhibitor... so if we formulate it in a solid dosage form , will it have this affinity to leave
this solid dosage form and move to the solution to be absorbed? So the rate limiting
step in our sequence is dissolution, and here in our course we will study how we can
work on modification on bioavailabity.
Good Luck ^_^
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