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Hi
Has anybody used microcapsules for oral dosing in mice? If so, please
provide details. I have a compound I would like to use for pk studies
but is not suitable for oral dosing due to intrinsic pungency and I
cant use rats due to limited supply.
Sunita
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Sunita:
There is another option. We use intragastric catheters for mice. The
catheter can be implanted several days in advance of the study so that
the mouse has fully recovered from the surgery. The catheter is
externalized to the back (between the shoulder blades) and plugged with
a small pin. There is no need to flush it or use any filling or locking
solutions prior to dose. When it's time to dose, you remove the pin,
insert a syringe and deliver the dosing solution, plus a flushing
volume, before returning the pin. If the volume of the dose + the flush
is < 20 mL/kg, and you've fasted the mouse, you should be able to dose
an adult mouse by this method. Alternately, the catheter can be
installed in the duodenum if you want to bypass the stomach.
Candice Kissinger
Senior VP Research
BASi
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Dear Sunita,
I am quite concerned that the use of microcapsules will interfere in
the determination of some pk parameters. How do you take into account
the modified biopharmaceutics due to the microcapsules?
Is the intrinsic pungency that high that it is not easy to dose in mice?
Regards,
Frederic Doc
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Dear Sunita,
Dosing delivery systems like microcapsules in mice for NCE may not be
the most preferred strategy however it could well be part of
developing a value added delivery system for pre-exisiting drugs
(specially off-patent). If your development pertains to an NCE, you
can better look for other options (like drug nanoparticles) as polymer
(s) used to prepare microcapsules may influece the disposition
kinetices of your drug. If it is not possible, you can disperse your
microcapsules in a suitable vehicle and ensure integirty of system
and homogeneity of the formulation before dosing in rodent species.
regards,
Vaibhav Sihorkar, Ph.D
Senior Scientist, Formulations R&D
Discovery Research,
Dr. Reddy's Laboratories Ltd.
sihorkarv.-at-.drreddys.com
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Dear Vaibhav,
don't you think that the use of nanoparticles would certainly
interfere in the drug kinetics too?
I am quite concerned that whatever you choose between micro- and
nano- particles the confidence in PK data is not ensured. Using drug
nanoparticles for such PK studies in mice will give PK data of the
drug nanoparticles and nothing else ...and certainly not PK data of
the drug itself!
Dear Sunita,
I would be very happy to help and find alternatives if you give more
information about what you really want to do and what your
expectations are with those studies.
Best regards,
Frederic Doc
fdoc.aaa.acriter-consulting.com
www.acriter-consulting.com
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Dear Frederic,
Indeed your opinion is quite valid if micro or nano-systems are being
prepared using a polymer/polysaccharide or any other carrier where
drug is either encapsulated or adsorbed (or entrapped). In these
cases, the disposition of drug in most probability get influenced by
the disposition kinetics of carrier.
However, when I referred drug nanoparticles, I meant micro/nanosizing
of the drug itself without using any carrier or polymeric matrix.
These strategies are very common (micronization, in situ
micronization, nanocrystal, nanosuspension etc.) and are being
explored to addess solubility or dissolution rate limited
bioavailability issues even at preclinical and clinical stages of
drug development. They will mainly influence the bio-pharmaceutics
and not necessarily affect the PK profile. Having said that,
probability exist for rare events like lymphatic uptake of intact
nanosized drug particles (which is still under investigation and have
not been forseen as predominating mechansim of absorption to date).
regards,
Vaibhav
Vaibhav Sihorkar, Ph.D
Senior Scientist, Formulations R&D
Discovery Research,
Dr. Reddy's Laboratories Ltd.
Miyapur, Hyderabad 500 049, India
sihorkarv.-at-.drreddys.com
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The following message was posted to: PharmPK
Dear Vaibhav,
I fully agree with you regarding micro or nanosizing of drug particles.
This is the way I used to address dissolution rate limited absorption
issues for oral dosing.
I would recommend a suspension of the micronized drug for oral dosing
for PK studies if we focus on dissolution issues. But in this case
there is also the pungency issue that was raised by Sunita, isn't it?
If this is a key issue I am concerned that taste-masking will
interfere with pk parameters determination.
Best regards,
Frederic
Frederic Doc
fdoc.-at-.acriter-consulting.com
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