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The following message was posted to: PharmPK
I have a high log P compound that I would like to study in an oral
proof of concept study in mice. The compound prepared in 10% DMSO/
90% PEG 400 solvent precipitated when injected ip.
I have seen some reports on dissolving lipophilic drugs in DMSO then
mixing with corn oil for oral delivery. Does anyone have any
experience with preparing drugs for delivery in this way? Would
adding a surfactant to the DMSO/corn oil assist in preventing drug
precipitation?
Any advice or guidance is appreciated.
Steve
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Hi Steve,
I think for proof of concept, you have the right idea. I strongly
recommend Labrafil MS2125 from Gattefosse. It is derived from corn
oil by transesterification with PEG300. It is a much better solvent
than corn oil. It is totally absorbed and seems to carry lipid
soluble drugs with it. You can generally get a sample (up to 500mL)
from the supplier - otherwise the smallest purchase is 25kg! You
might need to warm it up to clarify it first.
After absorption, Labrafil is hydrolysed, which creates a lot of
lipid in the plasma and the PEG can interfere with LCMS assays,
though it is not nearly as bad as PEG itself. Mice tolerate 5mL/kg ok.
I usually find for drugs with poor aqueous solubility that Labrafil
2125 is the best that can be achieved. As you say, dissolve in 10%
DMSO (or NMP if you can't stand the smell) and mix with Labrafil.
Another approach for poorly solule drugs in longer term studies is to
make a fine suspension and go sub-cut. Sometimes you get a sustained
release; the Css depends on the ratio of rate of dissolution and
clearance. To get a fine suspension, dissolve the drug in DMSO, let
it stand, then add the solution to water for injection thickened with
MC or CMC while vortexing. The viscosity prevents the growth of
large particles.
Regards.
Ted
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The following message was posted to: PharmPK
I have some PD experience with fibrates dissolved in corn oil and
administered to rats. As much as I know corn oil is not an inert
vehicle since poliunsaturated fatty acid act as PPAR alpha agonist in
animals fed with 4-8% fat in the diet. Moreover a fat bolus may cause
the release of enteric hormones such as CCK.
I don't known if may alter PK but it will be not surprising.
Regards
Roberto
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The following message was posted to: PharmPK
Dear Steve,
Greetings.Why don't you go ahead and try any of the surfactants such as
sodium lauryl sulphate and see what happens.
All the best.
its Akpa A.P
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)