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We are working on a project where we must administer drug for >100
days to mice PO. The drug is quite insoluble (< 1uM pH 7 and does not
have ionizable groups) so we cannot put it in drinking water, thus it
must be mixed with solid or liquid diet. We are exploring some liquid
diet options where the drug is first disolve the drug into PEG and
then addd the PEG solution to the liquid diet but it is not clear if
the drug will precipitate in the liquid diet.
We'd like to find a way to mix drug w/ solid food in a way that the
food does get wasted. We have provided mice with finely ground food
+drug in small petri dishes but the food spills (or gets played with)
so that we must provide 75% more food (and drug) than usual. This is
an early program so we do not have excess amounts of drug.
Has anyone had success preparing small scale semi-solid food or food-
blocks with drug that are less likely to be spilled/wasted? Are there
any recommended mouse feeders that can better handle finely ground food?
Thank you,
tt1_chemistry.at.hotmail.com
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In my opion, why do not try oral gavage using these syringe and
special needle? I meant that first, you could disolve the drug into
PEG, and then you could quantitatively adminstrate these solution to
mice.
Feng
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The one probable way to work it out is to make a liquid concentrate of
your compound (use cosolvent or lipid) and then mix it with finely
ground solid food (and not with another liquid or water). This should
result a granular or at the worst a semi-solid consistency but should
be consumed by animals within 12 h time. In case you want to extend
the time of usage, you may need to use an anti-oxindant to avoid
rancidification of liquid-lipid.
Hope this will work.
Vaibhav
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The following message was posted to: PharmPK
In my opinion, I doubt there is any way to prevent wastage of the drug
when mixed with feed. Since it is said that the drug is in the early
developmental stage, one option could be exposing the animals to the
drug mixed feed only to a limited period within a day. This could be
worked as follows,
As we know that the rats are nocturnal and they are more active during
the night time. You may have to find out the amount of feed intake by
rats in each cage by having paired-fed control group and give only half
of the required feed for each day mixed with drug and the rest of the
feed could be a normal feed. But the feed exposure time should be at the
same time everyday after giving a fixed period of fasting. For examples,
as the animals are nocturnal, the feed could be removed during the
light/day period (for 12 hours) and drug mixed feed, could be given in
the next 2-3 hours and once they complete consuming the feed mixed with
drug, the rest of the dark/night period could be exposed with normal
feed. The light and dark cycle could be reversed, if feasible, for the
convenience of the scientists to expose the animals with feed and
no-feed cycle.
There could be a problem here that the drug exposure would be acute but
not distributed through out the 24 hour period with feed. This would
reduce the wastage of drug to a greater extent, I believe. This is just
my wild thought and may be useful to you if it works.
Thanks and Regards
Dr.Srinivasan M. Rajaram
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The following message was posted to: PharmPK
Dear All,
I fully agree with Feng on the use of oral gavage.
Why do you only try and get a solution of your active drug?
I used to set up and prepare formulations for preclinical studies and
we always used "micronised suspensions" in methylcellulose 0.5% with
very significant results. The protocol used to prepare those
suspensions ensured efficient wetting and dispersion of the drug
particles and led to homogenous suspensions to be dosed PO by gavage.
Do not hesitate to get in touch for additional information.
Best regards,
Frederic DOC
fdoc.at.acriter-consulting.com
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The following message was posted to: PharmPK
Tarra,
The study that you describe is more akin to a Tox study than a PK
study. A 3 month study would most often be conducted using oral
gavage administration. Longer studies such as the 2 year
carcinogenicity study may also be conducted using oral gavage but
could also be conducted using administration in the feed or drinking
water. Administration of the drug in feed or in the water will
inevitably require large amounts of drug since there will be a large
wastage. When the drug is formulated in the feed it is advisable to
confirm the homogeneity of the drug in the food in order to ensure
that the doses are consistently administered across days/groups.
Another important factor to consider when administering drug in feed
is the food effect. Exposures may be lower than by oral gavage and
lead to increased compound needs. For both administration in feed and
water, confirmation of the stability of the test article in the dose
formulation will also be important. It should be noted that when
compound is administered in the feed or drinking water you are not in
control of how much drug is administered. If the drug is toxic this
will most likely lead to decreased food consumption which will lead to
lower dose being administered. That will confound your data.
One approach that has been used for poorly soluble drugs is to use a
SEDDS (self-emulsifying drug delivery system) formulation. This will
allow for oral gavage administration. Although administering the drug
daily by oral gavage for 100 days is very labor intensive, that is the
approach that I would recommend since it will give the cleanest data
and require the least additional support in terms of stability
assessments and require the least amount of chemical.
Regards
Mark Milton
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