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I'm currently working on a formulation for parenteral delivery of a highly lipophilic compound. My initial attempts with cosolvents have generated reasonable plasma levels, but one formulation in particular is puzzling me. Although toxic when delivered IP, 40% EtOH/40%PEG400/20% DI water gave plasma levels that were 50-60 times higher than other formulations (e.g. HPBCD, various other cosolvents (including varying levels of EtOH), and pH adjustment). I'm curious as to how others might interpret this result.
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Dear AJ,
Not sure if this is the case but as a bioanalytical chemist the first thing I would be concerned about is the PEG.
Have you run a CTRL study for this formulation (no drug)?
I'm thinking that the PEG could be causing analytical issues. I've seen that PEG hits a lot of masses for small molecules - polymeric additives tend to interfere. CD's as well.
Hope this helps,
Ken
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Did you see an unexpectedly higher levels at all or few time points?
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Dear Beaupre,
Never recommended to use that much high levels of
ethanol concentration. According to me, there will be a problem of
onsite precipitation with drugs administered IP, may be you are facing
this problem with remaning formulations that you had tried with. So to
confirm whether you are losing compound due to onsite precipitation try to
make your formulation in much amount of normal saline/DI. The two
factors you have to consider is solubility and onsite precipitation.
Hope I answered your query, any doubts do revert back.
With regards,
Veeravalli Vijaya Bhaskar,
GVK BIO
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AJ,
More information is needed, and clarification of some;
What species are we talking about?
Are the higher plasma concentrations seen when administered IP, or by
some other route?
What happens when you adminiser vehicle alone? (i.e. wrt toxicity and/or
"apparent" plasma concentrations?)
What assay method are you using? - HPLC-MS/MS?
Ross N.
ACPP.
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Dear Dr Beaupre
There is some discussion of alcohol and precipitation issues
in the following article:
Fadda et al 2008 Impairment of the in vitro release behaviour
of oral MR preparations in the presence of alcohol. Int J
Pharmaceut 360 171.
Regards
David
David Turner, PhD
Principal Scientist
Simcyp Limited
Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK
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Thanks for all of the replies, here are some answers to your questions:
All formulation trials at this point have been performed in mice. IV dosing was performed with this formulation, but not with others. All plasma concentration comparisons have been made from IP dosing, and all of the timepoints (8) from the 40%EtOH/40%PEG400/20% H2O showed a higher plasma concentration compared to other formulations. Vehicle only dosing showed effects attributable to ethanol intoxication, but not overt toxicity noted when dosed with drug. Regarding the PEG concentration, similar formulations were tested with the same PEG but lower ethanol concentrations, however, they did not achieve comparable drug levels. All analysis is performed via LC/MS/MS. Given the quantity of organic solvent in the formulations I've also been concerned with precipitation, but have yet to find/optimize a formulation that both solubilizes the compound to an acceptable concentration, and reduces the number of solvents. I am open to suggestions.
Thanks again
AJ
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AJ,
Given that you have assayed samples after dosing at lower dose with the
same vehicle and not seen the high concentrations, it seems unlikely to
be assay interference from the vehicle. Just a couple of further (very
basic) questions for you to consider.
(1) Are the results repeatable? That is, have you repeated the
experiment and found the same results?
(2) How experienced is the person administering the dose IP? That is, is
the dose going into the IP cavity, or maybe into the GI tract by mistake
sometimes?
Have you tried "injecting" the formulations into a beaker of isotonic pH
7.4 buffer to mimic what happens when injected into the IP cavity? This
may let you know what is happening wrt precipitation.
Regards,
Ross N
ACPP
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