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Dear all,
We would like to know a suitable solvent to solubilize a lipophilic
compound and inject it i.v. in canine for a pharmacokinetic experiment.
Sovents like DMSO, propylene glycol, Tween 80, etc. are associated with
toxicity. How about ethanol and polyethylene glycol or their combination.
Any suggestion or reference on this matter will be highly appreciated.
Thanks,
Delwar
********************************************************************************
M. Delwar Hussain, Ph.D.
Assistant Professor of Pharmaceutics
School of Pharmacy
University of Wyoming
Laramie, WY 82071-3375
Tel:(307) 766 6129
Fax: (307) 766 2953
E-mail: delwar.at.uwyo.edu
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Sender: acy62.-a-.pop.dial.pipex.com
Subject: Re: PharmPK IV Solvent
Date: Wed, 9 Sep 98 09:13:14 +0100
x-sender: acy62.aaa.pop.dial.pipex.com
From: Andrew Sutton
To: "Pharm PK"
Mime-Version: 1.0
From ; Andrew Sutton .at. Guildford Clinical Pharmcology,ASutton.-at-.gcpl.co.uk
Solubilising iv anaesthetics has been a difficult issue for many years.
In the 10970's I organised many trials on Glaxo's steroidal anaesthetic
Althesin that was launched on the market only to find that the cremophor
solubiliser caused anaphylaxis in a few patients...so it had to be
abandoned. Right at the beginning of the development programme we
decided not to go for an emulsion because the opaque fluid would make it
difficult for anasethetists to see the dose they were injecting. Then
along came Roche with Daizmuls and proved us wrong. Another possibility
is the type of vehicle used for Zeneca's Diprivan (propofol) which is now
by far the most used IV anaesthetic in the UK at least. The vehicle
contains glycerol, purified egg phosphatide, sodium hydroxide, soybean
oil and water...It would be interesting to know the role of each
ingredient, if Zeneca will let you have the information. The person who
should be able to help you is Dr Ian (I think) Glenn who you should be
able to contact via telephone at the UK HQ: +44 1625 712 712.
Hope this helps.
Andrew Sutton
Andrew Sutton
ASutton.aaa.gcpl.co.uk
Guildford Clinical Pharmacology
Telephone +44 (0) 1483 406886
---
X-Sender: catalin.aaa.rousseau.timone.univ-mrs.fr (Unverified)
Date: Wed, 09 Sep 1998 10:48:58 +0200
To: PharmPK.at.pharm.cpb.uokhsc.edu
From: Catalin Jacques
Subject: Re: PharmPK IV Solvent
Mime-Version: 1.0
Dear Dr. Hussain,
What about trying to solubilize your drug into a mix of alcohol and
Cremophor EL?
This is normaly a suitable solvent for highly lipophilic compounds and as
far as I know it doesn't induce much toxicity (well, modulation of MDR and
hypersensitivity reactions have been described, but it's still much less
toxic than DMSO or methanol!).
We've tried it in our lab recently in 3 hours perfusions in rats and we
were quite pleased with the results.
For your information, the solvent was prepared according to the following:
Solubilize p (g) of CrEL into p*1.55 (ml) of Ethanol 100=B0, mix vigourously=
,
and dilute 1/6 in a 5% solution of glucose.
Because of its viscosity, Cremophor may not be very convenient for a bolus
I.V injection, and you may have to use a 22=B5 filter on the line to remove
the air bubbles.
I hope this helps,
Good luck with your experiments
Pr. Jacques Catalin
Laboratoire de Toxicocin=E9tique et Pharmacocin=E9tique
Facult=E9 de Pharmacie
27, Bd Jean Moulin
13385 Marseille cedex 05
France.
Tel: (33) (0)4 91 83 55 09
Fax: (33) (0)4 91 83 56 67
---
From: james_atherton.-a-.groton.pfizer.com
Posted-Date: Wed, 9 Sep 1998 08:50:14 -0400 (EDT)
Date: Wed, 09 Sep 98 08:36:52 -0500
To:
Subject: Re: PharmPK IV Solvent
MIME-Version: 1.0
Delwar,
I am no expert in formulation, but I have used a number of iv formulations i=
n
the past and present. Ethanol is fine as I understand, but ideally keep its
concentration to 5 - 10% of dose volume. We are presently using a combinati=
on
of Glycerol Formal/Saline (50/50), which according to an internal manual is
well
tolerated. Hope this helps!
Jim Atherton
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Dear Delwar,
In our lab, we do many PK experiments of investigational compounds in dogs.
The preferred solvent for IV administration is ethanol 96% for injection.
We use up to 2.0 ml for dogs weighing 20-30 kg. Side effects you can expect
are drowsiness and vomiting. Repetitive administrations to the same vein
will cause destruction of normal venous tone. Another solvent we use
instead of ethanol is DMSO up to 2-3 ml. Higher doses will produce toxicity
(cyanosis).
I would like to ask the group if anyone has seen constant (steady state?)
drug concentrations after IV dosing? We have encountered constant drug
concentrations up to 2 hours post administration of the drug to dogs, and
only then drug levels declined over time. We think this may be due to
salting out of the drug in blood, thus creating a drug reservoir. Any
information and references will be appreciated.
*************************************************************
Ofer Spiegelstein
Department of Pharmaceutics
The Hebrew University of Jerusalem
P.O.Box 12065, Jerusalem 91120
Israel
ofersp.at.cc.huji.ac.il
*************************************************************
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[Two replies - db]
From: "Van Der Geest, Ronald [JanBe]"
To: "'PharmPK.-at-.pharm.cpb.uokhsc.edu'"
Subject: RE: PharmPK Re: IV Solvent
Date: Tue, 15 Sep 1998 09:22:44 +0200
MIME-Version: 1.0
Dear Delwar,
What about cyclodextrins?
Ronald van der Geest
Department of Clinical Pharmacokinetics
Janssen Research Foundation
---
Date: Tue, 15 Sep 1998 7:04:36 -0400
X-Priority: 3 (Normal)
To:
From: "James Peggins"
Reply-To:
Subject: re: PharmPK Re: IV Solvent
X-Incognito-SN: 239
X-Incognito-Version: 4.25.254
MIME-Version: 1.0
Hello Ofer,
Regarding your question about constant drug concentrations. Wouldn't this
be more indicative of zero order kinetics rather than a depot effect? How
was the iv dose given (as a bolus or over a short period, i.e. 2-3 min.).
When was your first blood sample taken? Maybe there is a rapid
distribution into peripheral tissues which would act as a reservoir.
Doesn't Lidocain do this (although that might be a pharmacodynamic not a
pharmacokinetic effect, I can't remember)?
My limited experience with ethanol is you don't want to inject it too fast
or the sedative effects are more pronounced, it can also inhibit the
hepatic drug metabolizing system acutely, which might decrease drug
clearance.
Hope this is helpful.
Regards,
Jim Peggins
************
James O. Peggins, Ph.D.
US Food & Drug Administration
Center for Veterinary Medicine
Division of Residue Chemistry
8401 Muirkirk Rd
Laurel, MD 20708
Voice: (301) 827-8092
Fax: (301) 827-8170
*************
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Hello all,
Our lab carries out many Pk studies to support discovery efforts. We
use a
number of formulations to support these studies and there is no single
formulation that could do the job. To state the obvious, it all depends
on
molecule solubility and stability. However, I have devised the following
guidelines and I am no formulation expert:-))
1. check to see if there is pH dependent solubility
2. Check to see if the drug forms inclusion complex with Cyclodextrins.
I
find sulfobutyl ether cyclodextrin(5%) and HPCD(50%) very useful for IV
formulations.
2. Keep the use of cosolvents (DMSO,ethanol, and DMF) in a formulation
below
10%
3. PEG400 or glycerol could be used upto 50 to 60% if the drug is
soluble in
them.
4.use of surfactants such as cremophor el or emulphor upto 10%
Typical dose volumes are upto 2 ml/kg and they are given as slow iv.
Many of
the formulation additives cause adverse reactions, for example ethanol
causes
CNS effects and inhibits CYP450 enzymes, and PEG 400 causes
cardiovascular
effects. Please refer "adverse reactions to drug formulation agents"
published by Marcel Dekker.
I have had a similar experience as the one described by Ofer about
constant
drug concentrations following IV. In my case, it was due to the
bolus(depot
effect) and changing it to slow iv (over 2 min) has taken care of that
problem.
A factoid: valium and dilantin contain 40% propylene glycol and 10%
alcohol
in IV formulation.
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