Download Done By: Sanaa Otoom Advanced Technology Lecture#24

Done By: Sanaa Otoom
Advanced Technology
Lecture#24
Evaluation of novel CR-GRDF formulation of levodopa in dogs:
Today, we will see an application on GRDF and we will see how formulation
variables can affect the bioavailability, gastric residence and enhancement of
therapeutic outcomes.
 Model Drug is Levodpa, it’s absorbed by Dipeptide transporter in proximal
small intestine, and it’s hydrophilic.
It has narrow absorption window so it’s logic to go toward GRDF, also from
therapeutic point of view, there’s need to maintain relatively narrow therapeutic
window to control symptoms - we have pharmacokinetic, pharmacodynamic
justification for formulation of GRDF.
- The gastroretentive system used here is folding:
In folding DDS, we have rigid frame which is polylactic acid with ethyl
cellulose in ratio (9:1), note that polylactic acid is rigid polymer not soluble,
but it’s susceptible to gradual hydrolysis for ester bonds in acidic
environment of stomach.
Also since the polymer is not soluble, there’s gradual diffusion of water
inside, and diffusion of drug to the outside  the whole process is
controlled “diffusional controlled release”.
The system has dimensions of 5*2.5 cm  the dimensions will not allow
the gastric emptying through the pylorus.
The CR-GRDFs were folded before insertion into gelatin capsules (000,
which is highest size of capsules).
** The formulations produced have different thickness of drug containing
layers, this allow different release rates but why?
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Done By: Sanaa Otoom
Advanced Technology
Lecture#24
Since when we have insoluble polymer, polymer doesn’t gel in acidic
environment in stomach  the drug on the surface will be exposed
directly to water and released into bulk solution then emptying to proximal
small intestine and then absorbed.
While, the particles of drug that located beneath the outermost layer will
need longer distance to diffuse, therefore the rate of drug release over
time is decreased.
 As general rule: an increase in diffusional path length will
decrease the concentration gradient and flux “it’s the rate of drug
release per unit area”.
As conclusion, when we have thin layer system we expect rapid rate of
drug release. While thicker system “thicker drug containing layer”, the rate
of drug release will decrease.
•
The results of the in vitro drug release test showed that the CR-GRDFs
released levodopa in a controlled manner. Levodopa release rate showed
an inverse correlation to the ethylcellulose membrane thickness, and
different types of the GRDFs were characterized by different release
rates:
The composition were identical, the difference between different formulas
was the thickness of the drug containing layer.
We can notice that fastest release is from the thickness of 0.31mm, and
slowest release was from thickness of 0.61 mm.
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Done By: Sanaa Otoom
Advanced Technology
Lecture#24
We can conclude that the main factor control the drug release here is
thickness of drug containing layer since it’s diffusional drug release.
Now, let’s make comparison between GRDFs and conventional controlled
release tablets:
Controlled release particles composed of drug and shell only “enteric
polymer”, if enteric polymer remains in stomach it will give sustained
release  will control the permeation of water inside and release of drug
to the outside.
BUT, if we have gastric emptying for the enteric polymer it will not give
sustained release but delayed release.

Animal studies, which includes administration of formula into beagle dogs,
and we obtain plasma concentration-time profile:
If we have slower release rate, this means that drug is gradually emptied
into absorptive mechanism into proximal small intestine, which will lead to
more efficient absorption (decrease in rate of drug release  more
efficient absorption).
Formulations that were thicker with slower release rate have extended
absorption for longer period of time, provided that increase in thickness of
the layer is for the same drug BUT different doses.
Now, look on the length of the absorption phase, slow release tablets will
have extended absorption phase.
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Done By: Sanaa Otoom
Advanced Technology
Lecture#24
In comparison with controlled release tablets that have slowest release
rate, the Cmax will decrease and even though they have slowest release
rate, the absorption phase shorter than GRDF C, why?
Since the controlled release particles don’t have mechanism for gastric
retention, it will control the release of drug and not saturate the receptors
which are good, but at the same time, the residence time in proximal
small intestine is limited  low bioavailability since only fraction of drug
will be released before leaving the absorption window.
The previous figure is proof of concept we’ve discussed, it shows the
advantage of using GRDF over CR forms, we can see the rate of release
will control the duration or length of the absorption phase (each increase
in rate of drug release will decrease the length of absorption phase).
Note 1: the arrow
inside the figure represent the length of the
absorption phase on X-axis.
Note 2: if the gastroretentive dosage form has been emptied to the
intestine and contains some particles of drug; this drug will be absorbed
also in controlled manner with no saturation of transporters.
The End 
For any questions, if you don’t understand the sheets properly, you can
ask me at any time  best of luck in your finals and congratulations for
graduates ^_^
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