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The following message was posted to: PharmPK
Hi,
I'm initiating a collaboration with a group who have an NCE they wish
to dose by an oral and IV route. Ultimately, the goal is to develop
two forms of this NCE - one that is bioavailable and one which is
not. This compound will be used in mouse and rabbit efficacy models,
but all preliminary PK work will be done in mice and rats. The
compound appears to go into solution in a formulation of
5% DMSO
5% Tween 80
20% PEG400
70% Na Bicarbonate, pH 9
and upon dilution in pH 7 PBS (to mimic dissolution in blood) remains
quite soluble. The Tween 80 is essential for this part. Are there
any problems with using this particular combination of excipients in
the three species I mentioned (mouse, rat, rabbit)? Will there be
any dramatic effects on absorption at the concentrations I am using?
I think I have heard that all three will act to increase absorption -
I was just wondering if their effects will be additive? Also, does
anyone have any suggestions for replacing the DMSO ultimately?
Thanks so much,
Noelle
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Dear Noelle
I don't think there will be any need to replace DMSO as you are using
only 5% w/w which is within the limits. I am doubtful for Tween 80
for IV. If possible try to keep it below 2% for IV route.
I think the following excellent review may be of helpful to you.
http://www.expertopin.com/doi/pdfplus/10.1517/17425255.2.5.715
[Not free? - db]
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The following message was posted to: PharmPK
Hi,
Shayne C Glad paper" Nonclinical vehicle use in
studies by multiple routes in mutiple species" is
also a good reference (not free).
Page 509, Table 67 (Tween 80)
Rat by oral and iv route could well tolerate 1 % Tween
80. I too feel 5% will be a lot. It is always better
to develop a formulation at preclinical stage devoid
of these exotic blends of vehicle listed by you. Like
DMSO is just a "no no" in a clinical dose, PEG will
interfere in LC-MS/MS analysis.
My feeling is that if your drug goes in Na Bicarbonate
and on dilution in PBS pH 7.4 is stable then go for it
otherwise intelligently select a vehicle or approved
permeation enhancer which can be used in clinical
study.
Good luck,
J
Jagdish Jaiswal, PhD
ADME Pharmacologist
Auckland Cancer Research Centre
University of Auckland
Auckland
New Zealand
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Dear Noelle,
It seems that your drug compound is ionizable, in situ sodium salt
formation occurs in sodium bicarbonate., however the salt
remains in solution at high pH even in the presence co-
solvent(s)/surfactant. For the preparation of formulation with
not interfering dosing vehicle, please consider cyclodextrin
application. In case of acidic drugs, simultaneous salt formation
and complexation results in well soluble complexes remained
dissolved in the physiological pH range. (shifting of pka). Solid
products prepared from such solutions can easily be reconstituted
at higher dissolved drug concentration than it was in the starting
solution. In addition in vivo absorption of such drugs can be
improved to overcome the pH dependency of solubility/
dissolution. By the determination of drug loading, you could
simply to reconstitute the calculated amout in aqueous vehicle to
adjust the desired dose. If you decide to continue towards
cyclodextrin applications, do not hesitate to contact with
me.
Best regards, Maria Vikmon
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