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The following message was posted to: PharmPK
Dear all,
I have generated data in the past that suggested that a
hydroxypropyl-beta-cyclodextrin IV formulation gave different PK than
did a
more conventional formulation. I was wondering if anyone out there had
similar experiences and if there was literature to back this up.
Thanks
Dale Sharp
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The following message was posted to: PharmPK
It is very much probable at times to have the scenario that "a
hydroxypropyl-beta-cyclodextrin IV formulation may give different PK
than
did a more conventional formulation" but needs to be evalauted on a
case by
case basis. It is related to the binding constant of the drug/active in
question with HPbCD and its subsequent mode of release in systemic
circulation (dilution, protein binding, displacement or a combination
thereof).
The drug may have more or less affinity with HPbCD and that along with
protein binding and/or dilution may essentially drive the PK.
Therefore, an
early indication could be the binding constant of drug with HPbCD and a
higher value infers to a probable impact on dispostion kinetics.
Literature
is abound in this regard and volumes of ADDR (advanced drug delivery
reviews) can be referred to get more cross references.
V. Sihorkar
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The following message was posted to: PharmPK
We also have an experience where we had seen that cyclodextrin in
iv formulation in rat had different PK than conventional formulation.
Dr. Tausif Ahmed
Ranbaxy Research Laboratories, India
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Dear Dale Sharp,
In case of a HP-beta-CD formulated drug substance, performing
comparative studies with a real conventional formulation which ideally
would be a pure aqueous solution- is hindered by the very hydrophobic
nature of the drugs which finally have to be formulated with the aid
of cyclodextrins.
Numerous studies have shown that aqueous cyclodextrin vehicles does
not or only slightly alter the intrinsic pharmacokinetics of a drug .
After intravenous injection, the drug rapidly and quantitatively
released from the cyclodextrin cavity upon dilution, competitive
replacement, binding to plasma proteins, e.t.c.
The hypothesis that a drug substance in-cyclodextrin formulation would
exhibit no substantially different pharmacokinetic/pharmacodynamic
behavior was confirmed. Let me to cite three recently published
examples:
HP-beta-CD did not alter the kinetic profile of 13-cis-retinoic acid
after intravenous administration on rats in comparison with 13-cis-
retinoic acid sodium salt formulation (Lin HS et al, Int J. Pharm.
341 (1-2) 238-245, 2007.)
The pharmacokinetic profile of a microemulsion formulation of
itraconazole was compared with HP-beta-cyclodextrin formulated
itraconazole and PEG 400 solution. No substantial difference have been
found between the three very different formulations. (Rhee YS, Arch
Pharm Res. 2007 30(1):114-23.)
Sulfobutyl ether-b-cyclodextrin (Captisol) based formulation of
propofol was compared to the conventional lipid emulsion
formulation. Study in a pig model showed that the formulations were
substantially similar. There was no significant difference in the
pharmacokinetics or pharmacodynamics of the two formulations.(Talmage
D. Egan, et al: Anesth Analg . 97:72-79 2003).
Best regards,
Maria vikmon
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Hello Dale:
Cyclodextrins have been used extensively in =20
pharmaceutical R&D, and there are currently over 30 marketed CD-=20
containing pharmaceutical products worldwide and am in agreement with =20=
Sihorkar in this regard. The ionized state of the active compound and =20=
the presence of counterions are likely to affect the drug=92s binding =20=
constant with ionization of drug is often observed. Salt form of a =20
compound can exhibit a greater binding constant with CD than the free =20=
base drug. A lower binding constant due to charge does not necessarily =20=
mean that CD cannot be used to solubilize a compound. In fact, a =20
combination of pH adjustment and complexation with CD has been used to =20=
successfully solubilize compounds
It also appears that as the binding constant increases, there may be a =20=
decrease in the maximum AUC increase that can be achieved. If a =20
complex with a very high binding constant is dosed, the complex may =20
not dissociate appreciably, and may affect the disposition kinetics of =20=
drug. On the other hand, CD when administered orally may enhance free =20=
drug concentration by slowing the precipitation of free drug. =20
Precipitation kinetics are proportional to the drug concentration and =20=
thus are reduced when some of the drug is bound to CD. Binding of CD =20
can reduce the reactivity of a drug by shielding the drug molecule =20
from attack. Thus if a compound is prone to hydrolysis at intestinal =20
pH or intestinal enzymatic degradation, Complexation with CD can aid =20
in maintaining intestinal drug concentrations and thus absorption =20
through the intestinal membrane
Therefore we must understand the physicochemical properties of drug =20
viz., Log P, pKa, etc prior deciding to employ it and use CD: drug =20
ratio of 2:1 or less.
Hope this helps.
Regds,
SYED MUSTAFA,
Advinus Therapeutics Pvt. Ltd.,
International Biotech Park,
Genesis Square, Bio Resource Centre,
2nd Floor, Phase II, Hinjewadi,
Pune- 411 057
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