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The following message was posted to: PharmPK
Hello,
I wondered whether anyone could tell me whether Pharmasolve (N-
methyl-2-pyrrolidone) is ever used for oral delivery for preclinical
studies (tox or PK)? I have seen that it is used IV but didn't know if
it had the same absorption promoting properties as DMSO. I know DMSO
is generally not used for oral delivery for that reason. Also, is
Pharmasolve/NMP ever used in man?
Thanks,
Noelle
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Noelle,
I already used NMP for oral PK/PD rat study (single administration) at
the dose of 330 mg/Kg and the animals were fine. The active compound
bioavailability was lower than the one obtained with more complex drug
delivery systems. Therefore, I wouldn't state that the NMP promote any
oral absorption if the compound of interest shows good membrane
permeability by itself... However as it is a very good solvent and
solubilizer, it probably modulates tight junction integrity.
I won't use this solvent for human (except topically at very low dose)
even if some clinical study with vit B12 or human volunteer study on
the inhalational and dermal absorption from the vapour phase of NMP
have been carried out. Embryotoxic and teratogenic effect have been
found in rats.
The acute oral LD50 is 4.2 g/kg in rats (Lee KP, Chromey NC, Culik R,
Barnes JR, Schneider PW. Toxicity of N-methyl-2-pyrrolidone (NMP):
Teratogenic, subchronic, and two-year inhalation studies. Fundam Appl
Toxicol 1987;9:222-235.)
NOAEL of 0.25 g/kg following 90-day subchronic administration of NMP
in dogs. (Becci PL, Gephart LA, Koschier FJ, Johnson WD, Burnette LW.
Subchronic feeding study in beagle dogs of N-methyl-2- pyrrolidone. J
Appl Toxicol 1983;3:83-86.)
More tox data from one of the supplier:
http://online1.ispcorp.com/Brochures/Pharma/Pharmasolve%20ver98.pdf
Hope this reply may be of your interest.
Fanny
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The following message was posted to: PharmPK
Dear Noelle,
NMP like other co-solvents demonstrates log-linear solubility profile
(non-linear on normal scale) and offer the potential of a massive
crash out upon dilution. Moreover, it does not offer a safety profile
needed to cover higher dose needed for safety margin. We have used and
recommended it very rarely. It also does not provide any confidence as
an excipient/vehicle towards oral safety/tox support over a wide dose
range. So I advise use it only for IV (and that too in early
discovery; pivotal development studies needs to be repeated for IVPK
with an optimized preferably aqueous formulation).
regards,
--
Dr. Vaibhav Sihorkar
Head (Pharmaceutical Development)
Aurigene Discovery Technologies Ltd.
Hyderabad, India
vaibhav_s.aaa.aurigene.com
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The following message was posted to: PharmPK
Hi Noelle,
As already pointed out by few others, we generally avoid using NMP for
oral formulations, due to the toxicities observed at higher doses.
We generally use it in iv formulations to get a solublized
formulation. In fact, we have used it in initial pilot studies and try
to avoid it as the molecule moves into development stage.
Some papers have reported use of upto 40% NMP in iv formulations.
Ref: "Preclinical formulations for discovery and toxicology:
physicochemical challenges; Expert opinion Drug Metab Toxicol; 2006; 2
(5); 715-731.
Regards
Tausif
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