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Dear all,
in case of poorly soluble drugs, is the use of a cosolvent generally
accepted for an iv administration to rats? which are the most common
cosolvent used? and which are the max acceptable percentages?
Thanks to all.
Federica
University of Parma
Italy
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Dear Federica,
Common cosolvents used for formulating an intravenous formulation are
DMSO, Cremophor ELP, PEG 400, Ethanol, dimethyl formamide etc. In my
earlier company I used the following formulation
DMSO : 20 %
ELP : 20 %
PEG 400 : 10 %
Ethanol : 10 %
Milli Q : 40 %
This formulation was used for a compound which was having very poor
solubility. Depending on the solubility characteristics of your
compound you can optimize the above formulation to suite your needs.
One more alternative is using complexation phenomenon by including beta
cyclodextrins. One point that is to be considered in this case is
volume expansion. Dextrin addition leads to increase in the volume of
the solution which you need to consider while preparing your final
formulation.
Note: Usage of dextrin formulations will sometimes lead to drastic
change in the PK parameters of the compound.
Regards,
Ravi
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Dear Federica,
We have used 10%(v/v) DMSO (Dimethyl sulfoxide) in normal saline for i.v
administrations in rats for some insoluble drugs. i think you can try
this
formulation for your drugs. another important thing here is dose volume,
we have administered from 1-5 ml/kg body wt. for i.v. and 5-10 ml/kg for
i.p.
i hope this information is useful to you,
thanks,
krishna
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Dear Federica,
We used plasma from the donor rat to adsorb the poorly soluble drug
Meloxicam for administering the drug by i.v. (bolus) route. As most of
the excipients have some influence on the PK of the drug. This paper
was accepted for publication with excellent remarks from the reviewers.
We appreciate comments from the Group about the validity of this
concept.
Best regards,
jagdish
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Dear Federica,
First of all I would like to thank Frederic Doc, ex-Pfizer, ACRITER
consulting for guiding me making the intravenous formulations for very
poor water soluble compounds in our lab. Now we are highly comfortable
for making any intravenous formulations for any compound.
We are using several combinations of co-solvents for intravenous
formulations depending upon the solubility of the drug.
General co-solvents we use are
Cosolvents Max.(v/v)
N-methyl 2-Pyrrolidine (Pharmasolve) 20%
Ethanol 25%
Propylene glycol 50%
PEG 200 50%
PEG 300 40%
PEG 400 40%
DMSO 10%
5% Na2CO3 or saturated bicarbonate, dilute with saline 1:49, v/v or
adjust with HCl
N-Dimethyl Acetamide
Acid Phosphate buffer: 0.1 M Na2HPO4 and HCl to put pH 2.6 to 2.9
0.1 N NaOH and saline
Complexation with 1.8% hydroxypropyl-beta-cyclodextrin and dissolve in
1M NaOH, adjust pH with 1M HCl to acidic side
Regards,
KANTHI KIRAN
Drug Metabolism and Pharmacokinetics Department,
Glenmark Pharmaceuticals LTD.
INDIA.
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Dear Federica,
Yes, one could use co-solvent formulations for IV dosing of poorly
soluble
drugs. But before using co-solvents I suggest you to try solubilizing
the
drug by pH modifications based on its PKa.
If this doesnt work then,
you could use the following co-solvent formulations in rats with
indicated
max doses( mL/kg)
1. DMA: water = 50:50
2. PEG400 :water = 80:20
3. PEG400:DMA:water = 40:40:20
Max recommended doses for DMA = 1 mL/kg and for PEG400 = 3 mL/kg
Good luck
Ramesh
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Dear Krishna,
With 10% DMSO as a formulation don't you fear precipitation after
injection?
Dario
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Hi Ravi
Is there a reference (or guidelines) for using 10% ethanol as a
cosolvent for insoluble drugs? We have the same issue.
thanks
satheesh
Sorry this paper could not be attached in Pubmed format with my reply.Back to the Top
jags
J Chromatogr B Biomed Sci Appl. 2000 Feb 11;738(2):431-6. Development
and validation of a new high-performance liquid
chromatographicestimation method of meloxicam in biological samples.
Velpandian T, Jaiswal J, Bhardwaj RK, Gupta SK. Department of
Pharmacology, All India Institute of Medical Sciences, New Delhi.
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)