Back to the Top
I am trying to formulate a compound that has had much difficulty
staying in solution as soon as it comes in contact with an aqueous
solution. I've tried 10% DMSO, 10%PEG 400 in saline and it totally
crashes once I add saline. Are there other ways of formulating
compounds that are highly lipophilic that would be safe for mouse IV
dosing?
This is for very early preclinical, investigational quick study.
Can you lend any sort of insight on other solvents to try?
Any thoughts would be much appreciated.
Thanks much!
Hanna
hanna.kang.-a-.orphagen.com
Back to the Top
Dear Hanna,
One other very effective alternative is the use of one of the
Cremophores. It has been very susccessful solubilizing compounds like
paclitaxel and docetaxel. In fact, the clinical formulation of
paclitaxel contain these kinds of agents.
All Cremopheores do cause some kind of hypersensitivity and depending
on the % you use, these solubilizing agents may alter the
pharmacokinetics of your compound.
I hope this helps.
Murad Melhem, PhD
Assistant Director of PK/PD
Cognigen Corporation
Buffalo, NY
Back to the Top
Dear Hanna,
Regarding solubilization of an insoluble compound for IV
administration, we once several years ago had some success in keeping
a compound in aqueous solution by adding a relatively high level of
albumin to the IV formulation. It was tricky to add (e.g., DMSO
solution added slowly) without denaturing the protein or adding the
spiking solution too fast. It needs to be highly bound to protein for
the method to work.
-Tom
Thomas L. Tarnowski, Ph.D.
Bioanalytical Development
Elan Pharmaceuticals, Inc.
800 Gateway Boulevard
South San Francisco, CA 94080
thomas.tarnowski.-at-.elan.com
Back to the Top
Dear Hanna,
we try to avoid DMSO becasue of altering the PK by CYP-inhibition, but
working with PEG200 up to 50% v/v allows formulation of /at least our
cmpds) of up to 3 -5 mg/mL.
hope this helps
Dirk
--
Dr. Dirk Scharn
Senior Scientist, DMPK
Jerini AG
Invalidenstrasse 130
10115 Berlin, Germany
eMail: scharn.aaa.jerini.com
Back to the Top
The following message was posted to: PharmPK
Dear Hanna,
the trouble you face with DMSO or PEG is that you seem to first
saturate those solvents with the drug. Then you add saline the
solubility dramatically decreases and the drug precipitates. This is
well-known and due to the dynamics of solubilization.
A better method should be to to first prepare the solvent (10% DMSO in
saline) and to determine the max solubility of your drug in such a
vehicle. Then you will be comfortable with preparing solution
concentrated at 80% of the max solubility.
Other solvents to be used could be surfactants (polysorbate 80,
Cremophor, Solutol HS15) or cyclodextrin complexs.
Depending on the kind of study you are performing you could also look
at other routes of administration.
Please let me know if you need additional information.
Best regards,
Frederic DOC
fdoc.aaa.acriter-consulting.com
Back to the Top
The following message was posted to: PharmPK
Hanna,
You can use intra lipid. We routinely use 10% intralipid for IV dosing
of lipophilic chemicals. You can make it yourself (search for my earlier
email under PharmPK group) or buy from commercial source. You will need
to polytron and/or sonicate using a probe sonicator to make homogenous
emulsion.
--
Shakil A. Saghir, M.S.P.H., Ph.D., D.A.B.T.
Senior Toxicology Specialist
The Dow Chemical Co.
1803 Bldg., Midland, MI 48674
Email: ssaghir.aaa.dow.com
Back to the Top
The following message was posted to: PharmPK
Dear Dirk!
did PEG 200 at 50% v/v ever exhibit some precipitation at the
injection point?
I am concerned by this point because if such a massive precipitation
occured it would dramatically compromise PK data, wouldn't it?
I would certainly encourage the use of more "stable" formulations for
PK studies but I would appreciate your point of view on this.
Best regards,
Frederic DOC
Back to the Top
Hi Alan,
sorry we don't use corn oils, but I have some ref. for the CYP
inhibition:
WILLIAM F. BUSBY, JR., JOSEPH M. ACKERMANN, AND CHARLES L. CRESPI;
EFFECT OF METHANOL, ETHANOL, DIMETHYL SULFOXIDE, AND ACETONITRILE ON
IN VITRO ACTIVITIES OF CDNA-EXPRESSED HUMAN CYTOCHROMES P-450 in DMD,
1999, Vol27(2), 246ff
Dirk
--
Dr. Dirk Scharn
Senior Scientist, DMPK
Jerini AG
Invalidenstrase 130
10115 Berlin, Germany
eMail: scharn.at.jerini.com
Back to the Top
Dear Hanna,
Try to combine cyclodextrins with DMSO. I experienced with surprising
results.
Drug precipitation can be substantially sustained or even prevented by
dilution of DMSO stock solution with aqueous/buffered cyclodextrin
solutions with different concentrations. If hydroxypropyl-Beta-
cyclodextrin not effective enough, try the methylated derivatives such
as DIMEB or RAMEB, which prooved to be more effective.
The sequence of the dilution is also important, adding cyclodextin
solution to DMSO stock solution is advised.
Best regards,
Maria Vikmon
Back to the Top
Hello Hanna:
Although vehicle selection for preclinical in vivo studies can be a =20
major hurdle for many of us, several strategies can be adopted to =20
increase the solubility of compounds with low aqueous solubility. If =20=
the compound is ionizable, it may be possible to achieve the target =20
concentration through pH adjustment. If pH adjustment does not give =20
the desired results, a cosolvent can be used. We may consider using =20
more exotic vehicles such as N-methyl-2-pyrrolidone, Labrafil, =20
Cyclodextrins, and vitamin E TPGS in addition to other commonly used =20=
vehicles viz., Dimethylacetamide, Dimethyl sulfoxide, Ethanol, =20
Glycerin, Solutol HS-15, Cremophor EL (non-ionic solubilizer) etc.,
Although diluted plasma or BSA can be used for highly protein bound =20
and lipophilic compounds with limited options, it is hard to predict =20
on-off dynamics and its impact on distribution apart from feasibility, =20=
I guess.
You may refer some of the excellent reviews viz., =93Preclinical =20
formulations for discovery and toxicology; physicochemical challenges=94 =
=20
in Expert Opin. Drug Metab Toxicol (2006) 2(5) and =93Intravenous =20
administration of poorly soluble new drug entities in early drug =20
discovery: the potential impact of formulation on pharmacokinetic =20
parameters=94 in Curr Opin Drug Discov Devel. 2002 Jan; 5(1):59-71, for =20=
better understanding on this topic.
Good Luck.
Cheers,
SYED MUSTAFA,
Advinus Therapeutics Pvt. Ltd.,
International Biotech Park,
Genesis Square, Bio Resource Centre,
2nd Floor, Phase II, Hinjewadi,
Pune- 411 057
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "Mouse IV dosing formulations" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)