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Dear all,
I am doing pharmacokinetic studies for new NCE's.
I wanted to know is dosing with 30% NMP + 70% PEG200 at a dose volume
of 5ml/kg for intravenous bolus dose, and 10% NMP + 90% PEG200 at a
dose volume of 10ml/kg for per oral dose is OK for mice species?
What is the maxiumum percentage of NMP and PEG200 and what is the
maxiumum dose volume that can be injected with the above said
formulation ingredients to mice. Any comments/references would be of
great help.
Thanks,
Suresh.B.L
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The following message was posted to: PharmPK
Dear Suresh,
do you really want to dose mice with NMP and PEG 200 ? Don't you plan
to dilute in water ?
I'm concerned about the relevance of such ingredients in a
formulation strategy for early PK studies.
As an expert in the design of drug formulations for preclinical
studies I would like to take this opportunity to convince PK
scientists of the importance of the drug formulation in PK studies.
Suresh, the kind of formulation you suggest to use is not relevant
for preclinical PK studies. What will happen when you dose your NCE
(solubilized in NMP and PEG) per IV ? You will face a massive
precipitation at the injection point ...and as a consequence your PK
parameters will vary as compared to the intrinsic values.
Hope this helps,
best regards,
Frederic Doc
PharmD, MS in Pharmaceutical Sciences
www.acriter-consulting.com
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Dear Suresh,
I have a couple of experiences with NMP and PEG 300. From animal
safety point, PEG is safe even with high doses and it is well
recommended in IV formulations. However, NMP is not very safe to the
animals (mice and rat).
When we administered 25% NMP in NS by IV bolus (2min infusion), mice
could tolerate only upto 2.5ml/kg of final solution (i.e. 0.675ml/kg
NMP). After that dose we observed sudden depression in mice although
they completely recovered in 2 hr.
With 10% NMP in NS, mice tolerated upto 5ml/kg of final solution,
while rat tolerated upto 2.5ml/kg. FOllowing 5ml/kg of this solun
resulted in 50% mortality in rats.
And of course, we need to ensure that the drug do not precepitate out
on dilution of formulation (at least upto 20fold). Precipitation of
drug may kill the subject and also will give wrong Pk parameters.
These issues become complicated in tox studies when you have to load
high amounts of drug. However for PK studies, you may go for less
dose if you have a sensitive analystical method.
Hope this will help
Regards
Varma
Dr. Manthena VS Varma
NDDS-Pharmaceutical R&D,
Nicholas Piramal Research Center,
1, Nirlon Complex, Off Western Express Highway,
Near NSE Complex, Goregaon (E),
Mumbai-400 063, INDIA.
email: varma_mvs.-a-.yahoo.com or vmanthena.-a-.nicholaspiramal.co.in
Phone: +91 22 3081 8914; +91 932 426 9193
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Dear Dr. Fredric and Dr. Varma
The IV formulation of water insoluble drugs for preclinical PK
studies has always been a topic of concern and there is no unanimity
over this issue. One may find some references where people from
Industry have used 50% DMSO, 20-30 dimethylacetamide along with
saline with some surfactants added to it. And again mortality of an
animal may be a chance factor. I have personally injected 100% DMSO
to adult rats and found the mortality rate very low.
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The following message was posted to: PharmPK
Dear Satya,
you should not only consider the mortality rate of the vehicle.
When using such ingredients you cannot ensure that the PK profile you
get from your studies is not affected by the presence of DMSO. Did
you ever face some massive precipitation when dosing a drug dissolved
in 100% DMSO in the blood circulation ?
How do you justify the use of such a vehicle as you already know that
you will not be able to use it in humans in clinical trials ?
If a drug is so much insoluble that you have to use such "exotic"
vehicles to get an IV formulation do you really think that it is a
promising compound ?
Best regards,
Frederic Doc
ACRITER - drug discovery consulting
www.acriter-consulting.com
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The following message was posted to: PharmPK
This is just a suggestion, for what it's worth, BUT...
I have previously suggested to people to use an in vitro test to
check for
precipitation before hand. The test set-up is cheap, and it may prevent
much unnecessary expenditure at a later date.
James Ladd
James Ladd
Scientist Erimos Pharmaceuticals
840 main campus Drive suite 3700
Raleigh, NC 27606
jladd.-a-.erimos.com tel: +1 (9198215204) EXT2816
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The following message was posted to: PharmPK
Dear James,
your suggestion regarding the use of an in vitro test to prevent the
drug precipitation from a dosage form is very useful. I personally
used to perform such tests when setting up formulations for
preclinical studies. This is definitely a key part of the work of
formulation scientists involved in preclinical research.
In the present case where 100% DMSO or PEG/DMSO formulations are
suggested my personal background shows that there is no need for
precipitation studies. This is a waste of time as all formulation
scientists know that these kinds of formulations ALWAYS lead to
massive precipitation. But I fully agree that there is a real need
for such studies when setting up PEG/saline, PEG/EtOH/water, x%DMSO/
water formulations for instance.
However it seems that early preclinical formulation issues are more
and more taken into account. I actually work with clients to support
their efforts in setting up a relevant formulation strategy in early
preclinical studies. This is a key point as it participates in
reducing late attrition by providing preclinical scientists with
smarter formulations to be dosed in animals.
Best regards,
Frederic Doc
ACRITER - drug discovery consulting
www.acriter-consulting.com
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The following message was posted to: PharmPK
Another alternative to having DMSO is any percentage is the use of
Cremophores (e.g. Ceremophor EL). Although DMSO pauses a reasonable
threat to the survival of lab. animals. Cremophor in high percentages
has been proven to cause anaphylaxis in both pre-clinical and
clinical experiments. Liposomal formulations represent a reasonable
alternative for IV administration of water-insoluble drugs; but the
characetrization of drug loadinga nd release from liposomes is of
critical importance regarding both techniques and interpretation of
response.
Murad
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