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Hello,
I am wondering if anyone can offer some insights to the pro and cons of
using 20% captisol as the IV and PO vehicle for small molecule drugs in
the rat?
Thanks in advance,
Z. Li
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Dear Li,
The pros of using Captisol is that you obtain up to 25,000 fold
solubility
improvement in some drugs. Moreover, this cyclodextrin has had
approval in
Europe and the US for use Pfizer's IM ziprasidone formulation (2000 and
2001
respectively). If you are working with small molecular weight drugs, my
opinion would be that they tend to be more stable in this type of
formulations than larger molecular weight molecules. The cons would be
scale -up issues, specially when using 20% w/v (I think it can be used
up to
30/ w/v) and cost. Captisol does not come cheap!
The following references may help you further:
Complexation and solubility improvement: J. Control. Rel, 1999, 88,
(10),
967-979
Stability improvement: Int. J. Pharm, 1999, (2), 227-234
Biocompatibility: Oral: J. Pharm and Pharmacol, 49, (1), 43-48, 1997,
parenteral: J. Pharm. Sci, 84, (8), 927-932, 1995
General review: Adv. Drug Del. Rev., 1999, 36(1), 3-16
I hope this helps,
B. Carreņo
Spain
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Hello,
I've got some expertise in this field.
Cyclodextrin in buffer is one of our standard vehicles for preclinical
studies.
The pro is the solubilization power of cyclodextrins, sometimes very
high depending on the chemicals you want to solubilize in.
The cons is the complexation dynamics. You have to perform some
formulation set-up with this vehicle. You have to get a quite good idea
of the complexation of your active with the cyclodextrin. Because this
could become an issue per IV and most likely per oral. If your drug
remains complexed within the cyclodextrin cavity then the fraction
solubilized and available for absorption is underestimated and
bioavailability tends to be poor.
Per IV the problem is the same but probably at some lower extent.
My recommendation is:
1- no use for an oral dosing
2- use as an iv vehicle if you have checked that the calculated
complexation constant remains low enough
I hope this would be of interest.
Cheers,
Frederic Doc
Pfizer Global R&D
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Thanks for offering your expertise. I have some follow-up questions
regarding the use of cyclodextrin. To me overestimation of
bioavailability might occur due to complexation of the compound with
Cyclodextrin. Two possible scenarios:
First, If it is used as an oral vehicle, there is a possibility of
overestimating bioavailability because of enhanced solubility (vs.
suspension formulation)?
Second, if CD is used as an IV vehicle, you may get lower AUC for IV if
the complexation remains in the circulation, which would result in
overestimation of bioavailability.
Thoughts?
Z. Li
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zhaoyang,
I fully agree with your point of view regarding the IV formulation
("Second,
if CD is used as an IV vehicle, you may get lower AUC for IV if the
complexation remains in the circulation, which would result in
overestimation of bioavailability").
But regarding PO dosing the fact is that cyclodextrin is not absorbed
and
entrapped drug molecules won't be as well if the complexation is too
strong.
In this case you cannot say if poor absorption is really due to the low
water solubility or to the cyclodextrin complexation.
does it make sense,
regards
Frederic
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should we not think about the fact that the drug which is entrapped in
the
CD molecules comes in competition with other compounds present as well
in
the GI tract as in the blood . These might due to a higher lipophilic
character chase away the drug out of the complex.
Dr. R. KINGET
Belgium
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Dear Frederic,
What you said about cyclodextrin makes sense. But about the absorption
of
cyclodextrin - It does get absorbed in rodents (Mouse and Rat) to some
extent. We have seen this in our studies and had to develop estimation
methods that could seperate the parent compound from cyclodextrin.
And like zhaoyang, said - We did get the PO (F) more than 200% when we
used
a drug IV by cyclodextrin and oral by Tween suspension. And as soon as
we
shifted to cyclo for PO administration - F came to 90%.
Of course we have observed that cyclo is not absorbed in rabbits, dogs
and
well in humans so !!!.
regards
Yati Chugh
Wockhardt Research Centre.
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"And like zhaoyang, said - We did get the PO (F) more than 200% when we
used
a drug IV by cyclodextrin and oral by Tween suspension.
And as soon as we shifted to cyclo for PO administration - F came to
90%."
Yati,
I would like to take the opportunity of your example to explain my
opinion.
If I consider your experiment: IV with cyclodextrin and PO with Tween
led to
200% oral bioavailability.
This surprising and irrelevant result is the fact of cyclodextrin. Even
if
the polysorbate (Tween) can enhance the absorption (absorption promoter
properties)the bioavailability cannot be higher than 100%. But your
cyclodextrin can remain your drug entrapped at such an extent that the
free
plasma drug is half the amount it should be. This leads to a 200% oral
bioavailability.
If I consider your second experiment: both IV and PO doses made with
cyclodextrin led to 90% bioavailability.
This result sounds relevant. In this case we can only say that the drug
is
absorbed but I would not trust this value of bioavailability as
compared to
the previous experiment.
Regarding the absorption of cyclodextrin administered PO in rodents, I
only
read the bibliography but I did not have any personal experience of
this.
Regards,
Frederic DOC
PFIZER Global R&D
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Dear Frederic,
We have similar experience regarding cyclodextrin formulation.
In a parallel study drug was administered by intravenous route in
cyclodextrin formulation and a formulation containing organic phase
keeping all other parameters (dose, strength of formulation and others)
same. When the study was done in mice we found statistically
significant difference in AUC (lower AUC for cyclodextrin formulation)
but surprisingly, we did not find any difference when similar
experiments were carried out in rat model keeping the parameters same.
Therefore, we concluded that animal model is the key parameter as small
intestinal transit time (SITT) in mice is less than that in rat. As
absorption requires release of drug from cyclodextrin complex SITT in
mice might not be sufficient for complete release which might not the
case in rats. This can be the possible explanation for such an
unexpected result.
Hope this email serves the purpose.
Regards,
Prajakta Dravid
Drug Metabolism and Pharmacokinetics
Discovery Research
Dr. Reddy's Laboratories Ltd.
Hyderabad, INDIA.
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Hi,
I believe it would be wise to study the complexation constant of the
complex
Captisol- drug . The availability of this value could stop all
speculations
??
Kind regards
Prof. Dr. R. KINGET
Dorpsstraat 139
B-3060 BERTEM
Belgium
Tel /Fax 32 - (0)16 - 49 01 49
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