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Dear All,
I am working in a colloborative work on transdermal Drug Delivery.
Today I
came across an interesting discussion with my colleague.
Compound is Hydrophobic, so the drug was solubilized using suitable
solvents. We performed two transdermal deliery experiments.
1. The solution was applied directly on the skin
2. In the second case the drug was applied and rubbed on the skin.
Obviously we noticed elevated levels in the second case. My argument
is that,
the elevated levels are due to the raise in minor temperature increase
created during rubbing, which led to the enlargement of aqueous spaces
and
ultimately the increase in delivery and/or else due to diruption of
superficial stratum corneum.
Please let me know if there are any other reasons or if you come
across any
suitable literature.
Regards
Shankar Lanke
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Shankar,
If the effects were observed in healthy skin, rubbing is not only
expected
to increase permeation, but also cutaneous blood flow and perfusion,
which
can increase absorption... especially rubbing of an organic solvent.
Best regards,
Shawn D. Spencer, Ph.D., R.Ph.
Assistant Professor of Biopharmaceutics
Florida A&M College of Pharmacy
Tallahassee, FL 32307
shawn.spencer.-a-.famu.edu
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Shankar
Permeation of therapeutic agents across the skin would strongly depend
upon the following physiological factors:
* selection of skin site (skin from different areas of the body
may demonstrate different degree of skin permeation). was the skin
site same for 1 and 2?
* presence of significant amount of hair at the application site
could affect drug permeation.
* compromised skin (like shaved or depilated skin, cuts, wounds,
or tattoo's) would also affect permeation and thus absorption into
systemic circulation
* increased skin temperature has also been reported to show
increase in drug absorption for some drugs. excessive rubbing of the
skin site is normally not practiced clinically unless you are studying
the effect of the rubbing action on drug permeation.
When you say "In the second case the drug was applied and rubbed on
the skin", in what form was the drug applied and in what solvent was
the drug dissolved, if any? Was the solvent same for 1 and 2?
If you provide answers to the asked Q's then i may be able to
elaborate further.
best wishes
Manish Issar, Ph.D
Applied Biopharmaceutics
Corona, CA, USA
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Assuming, for the time being, that Mr. Lanke's hypothesis is correct
and that, in fact, rubbing or friction causes an increase in surface
temperature of the skin, which opens up the aqueous pores and thereby,
increasing permeability. The questions that come to one's mind are
1. Why would a rise in surface temperature lead to an expansion
only of the hydrophilic or aqueous pathways and not the hydrophobic or
lipid pathway?
2. Even if temperature on the skin surface is raised, whether this
increases will be felt or translated throughout the stratum corneum,
because it will depend on the thermal conductivity (and the specific
heat capacity) of the stratum corneum.
3. The compound is hydrophobic, so if it is solubilized does it
become extremely hydrophilic, such that it only chooses the
hydrophilic aqueous pathway for permeation?
The reason seems more mechanical or chemical. Rubbing could mean
forcing the formulation to get through the pores in the stratum
corneum. It could also mean that rubbing destroys any concentration
gradient in the liquid layer on top of the skin (vehicle) which leads
to higher source concentration at the vehicle-skin interface and
increasing permeability. At this point these are, at best, guesses.
When I was a member of the percutaneous absorption research group with
Prof Gerald B. Kasting (University of Cincinnati, James L. Winkle
College of Pharmacy), our group did thermal studies with volatile
compounds. In those studies, rapid evaporation of volatile compounds
left the surface colder and even with a decrease in surface
temperature of over 2 degrees (as measured by an infrared
thermometer), there was no appreciable decrease in permeability. One
also needs to keep in mind that a lot of heat is required to change
the surface temperature and mere rubbing will only at best probably
increase it by thousands of a degree.
At this point, one needs to assert that
1. The experiment was uniformly reproducible.
2. The application areas in both cases (application and no rubbing
vs. application with rubbing) were identical or not. If they weren't
then there is another answer.
Kind regards,
Ray
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Hi Shankar,
I am new to TDDS.
Would there be any increase in exposed surface area (for absorption)
in the second case?
Thanks
Ravi
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Dear Shankar,
A lot of research in the area of cutaneous drug delivery has been done
using microdialysis. As an example, please have a look at the
following two review articles, which may help to clarify your question
or point you to respective original research papers.
Kreilgard M., Assessment of cutaneous drug delivery using
microdialysis, Adv Drug Deliv Rev. 2002 Nov 1;54 Suppl 1:S99-121
Schmidt et al., Clinical microdialysis in skin and soft tissues: an
update, J Clin Pharmacol. 2008 Mar;48(3):351-64
Best Regards,
Stephan
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Shankar: Here is another consideration that may apply. If the drug
under consideration for T/D delivery is too soluble in the solvent you
are using, then the "activity" of the drug on the skin surface may
decrease leading to less uptake by the skin.
Angus McLean
BioPharm Global Inc.
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Shankar wrote:
>>"...My argument is that,
the elevated levels are due to the raise in minor temperature increase
created during rubbing, which led to the enlargement of aqueous spaces
and
ultimately the increase in delivery and/or else due to diruption of
superficial stratum corneum.
Please let me know if there are any other reasons...">>
First of all, the increased bioavailability (but not necessarily
physical bioaccessibility) from the skin after rubbing the agent on -
is due to the local increase of blood perfusion (make an experiment
yourself: rub your hand for a while - and you will notice the redness
of the skin at this site. It is caused by the increased blood flow).
Hope it helps.
Best wishes.
Janusz Z. Byczkowski, Ph.D., D.Sc., DABT
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The following message was posted to: PharmPK
Dear Ray,
Thank you very much for your explanation.
I appreciate your time and consideration. In both the cases each and
every
parameter is same, in one experiment we used rubbing to enhance the
delivery. I agree with your answer and at the same time I believe as
Shawn
mentioned rubbing increases cutaneous blood flow and perfusion, which
ultimately results in increased absorption.
Regards,
Shankar Lanke
PhD Candidate
Department of Pharmaceutical Sciences
Mercer University
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Is it an in vivo or in vitro transdermal experiment?
Thanks,
Jin
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Hi Shankar,
You are welcome. My only concern ... even if you rub vigorously on the
surface, its effect will be felt by the stratum corneum, which is
devoid of
blood vessels. I wouldn't think that it is easy for that mechanical
action
to penetrate well into the dermis and affect cutaneous blood flow
considerably. I still think the difference you are observing is
increased
absorption into the stratum corneum and not particularly increased
systemic
uptake from the skin compartments owing to higher perfusion rates.
Kind regards,
Ray
Siladitya Ray Chaudhuri, PhD
Senior Scientist - Simulation Technologies
Simulations Plus, Inc.
42505 10th Street West, Lancaster, CA 93534
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I would agree with you as the Stratum Corneum is the major rate
limiting mechanism for drug absorption. Unless the drug causes
vasoconstriction (like corticosteroids), otherwise the drug
concentration in the blood flow is negligible compared to the drug
solution.
Thanks,
Jin
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The following message was posted to: PharmPK
Hello Ray,
It is surprising that you said that vigorous rubbing will only effect
the
stratum corneum ... however there is data that indicates rubbing can
indeed
increase skin perfusion.
"In all the normal subjects, rubbing stimulus was followed by an
increase in
blood flow from 5.2+-SEM 0.6 to 24.4+-SEM 3.1 ml/100g/min (p < 0.001)"
(From: Cutaneous Blood Flow during White Dermographism in Patients with
Atopic Dermatitis, Journal of Investigative Dermatology (1982) 79,
243-245)
There are likely other Laser Doppler studies that report the influence
of
blood flow on percutaneous absorption. Such data does not negate the
desquaming effect of rubbing on stratum corneum cells, but in
particular for
lipophilic drugs, a potential 5-fold increase in organ perfusion should
perhaps not be readily discounted, and proposes an interesting research
hypothesis on which is more influential in most cases.
Best regards,
-Shawn
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Dear Shankar,
Lot of good discussion. Is the difference significant? In my
experience, in vivo transdermal data can be highly variable. Are you
talkiing about a systematic trend after rubbing? As everybody said,
rubbing can increase blood flow and also temperature. Temperature
increases the diffusion of drugs as it increases the thermodynamic
activity. Are you trying to use rubbing as a major mode of delivery
enhancement? If yes, it is probably unlikely you get a successful
product. Ultrosonic delivery also increases permeation by increasing
temperature as one of the mechanisms of action. I am not sure what
exactly you are trying to answer? Do you have any safety issues
around drug, that rubbing can be a potential safety issue?
Temperature increases diffusion is a well established fact.
Ayyappa Chaturvedula
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The following message was posted to: PharmPK
Hi Shawn,
Nice point. Perhaps I should have been more careful before choosing
the word
'vigorous'. Rubbing the liquid formulation on the skin surface and
vigorous
rubbing of the skin (like a massage) are different. While I see the
possibility of changes in cutaneous blood flow with massage and vigorous
rubbing, I don't think it's applicable to the former. I do not know what
Shankar adopted, but I am guessing the former as well.
Considering that this is a poorly soluble compound, which has been made
soluble through formulation changes, I think absorption through SC is
the
key here. Changes in cutaneous blood flow affecting systemic uptake
can only
follow absorption and so, may not be the rate-determining step. Also,
even
if it does change blood flow, the actual systemic uptake will depend
on the
skin-blood partition coefficient for the drug.
As I indicated earlier ... these are at best guesses at this point.
Thanks for your comment.
Kind regards,
Ray
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The following message was posted to: PharmPK
Dear All,
I would like to thank you all again for your time and consideration. I
appreciate your comments on my question.
These in vivo experiments were performed on male CD hairless rats. The
difference between the Experiment 1 and 2 is significant, it is 3 fold
higher when it was rubbed on the skin compared to normal application.
It was
rubbed on to the skin normally, it was not vigorously performed which
may
lead to abrasion of stratum corneum. Moreover we are not trying the
mode of
rubbing as a major enhancement technique. It was an experiment to
identify
whether the patch application is better or an ointment to rub on the
skin is
best way?
Thank you very much.
Regards,
Shankar Lanke
PhD Candidate
Department of Pharmaceutical Sciences
Mercer University
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The following message was posted to: PharmPK
Ray,
Indeed, I fully agree that SC permeation is expected to be a primary
rate-limiting process, however once the drug is in the epidermal and
dermal
regions, then flow or perfusion-limited vascular uptake predominates,
especially for nonpolar compounds (however there is an "optimum"
lipophilicity above which we will begin to see the opposite effect
when the
drug enters deeper dermal regions).
You stated that "Changes in cutaneous blood flow affecting systemic
uptake
can only follow absorption and so, may not be the rate-determining
step",
however, transdermal absorption is complete upon entering the vascular
lumen, not crossing the SC. Perhaps you are thinking primarily of
dermatologicals.
Also, the apparent rate of uptake depends on the (inverse) ratio of the
skin-blood partition coefficient AND the perfusion rate (or else
depends on
the skin-blood concentration gradient).
H. Maibach co-authored a book chapter titled "Does rubbing enhance in
vivo
dermal absorption?" in Percutaneous Absorption /Marcel Dekker 1985,
and I am
curious if some older studies looked at compartmental vs PBPK
mechanisms of
enhanced dermal absorption, however I only have access to the 4th ed.,
so
perhaps someone on the boards can offer insights from that chapter.
Best regards!
-Shawn
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The following message was posted to: PharmPK
Shawn,
Perhaps the world of dermal delivery is different than oral in terms of
definitions, but the old-fashioned definition of oral absorption was
actually referring to bioavailability - the drug that reached the
systemic
circulation. The modern definition says absorption takes place when
the drug
first enters the body (I believe this would be when it first enters
living
cells), which in the case of oral delivery via the gastrointestinal
tract,
is when the drug enters the apical membrane of the enterocytes.
If the same logic is applied to dermal absorption, it would seem that
the
drug has been "absorbed" as soon as it enters the first lipid bilayer
of the
first living cells it encounters. The amount that makes it through to
the
bloodstream is another matter - first pass extraction in the intervening
cells could reduce the amount of drug that makes it into the blood,
just as
first pass extraction in the enterocytes reduces the amount absorbed
in the
gut.
I would be very interested to know if the dermal community does not
consider
drug to be absorbed when it has entered living cells.
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
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Patch application is for sustain action (1-7 days) of drug while
ointment delivery is used for topical action /immediate systemic action.
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The following message was posted to: PharmPK
Hello Walt,
That's an excellent point. Systemic uptake does follow "absorption",
and any
debate on the mechanisms of rubbing effects should keep the terms,
absorption, dermal, transdermal and bioavailability in their proper
(or at
least biopharmaceutically accepted) context. Thank you for correcting
me.
I understood Shankar's discussion to center on the likely effects of
rubbing
on (what may be) the rate and/or extent of "systemic uptake".
Ray offered that increases in local perfusion (my suggestion) are not
likely
to influence absorption (and perhaps systemic levels) because the SC
is the
rate limiting barrier. I suppose the question remains, is there an
oct/water drug partition coefficient and/or molecular weight range, at
which
the SC may not be rate limiting?
Indeed, comments from the dermal community would be very interesting.
Thanks again,
-Shawn
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The following message was posted to: PharmPK
Dear Shankar,
You wrote:
1. The solution was applied directly on the skin
2. In the second case the drug was applied and rubbed on the skin.
Obviously we noticed elevated levels in the second case.
Was the dose applied in both cases? Did you apply the drug to the same
surface area? I found that often for lipophilic compound, increasing
application surface area is more effective than increasing dose for
achieving higher systemic levels. Also what was the veichle in the 2nd
case, it seems to me that you did not use any? Is this correct? Please
also verify that you are talking about blood levels and systemic
exposure. What species are you using for the two experiments?
One minor note and request for clarification from dermal experts:
According to one dernal expert that I consulted two years ago (I am
new to this area myself), what you are reffering to as transdermal
delivery is indeed dermal delivery. Apparently, when a patch or
occlusion mans are used then the term transdermal is proper.
Rostam
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The following message was posted to: PharmPK
Hi Shawn,
Thanks for continuing the interesting discussion. As Walt pointed out
earlier, by "absorption" I meant the amount of drug getting through SC
into
the viable epidermis and dermis. That will, obviously, not be affected
by
perfusion rate down in the dermis. What perfusion rate may significantly
affect is systemic uptake or "bioavailability", provided the blood-to-
tissue
partition coefficient is high and there is sufficient amount of drug
that
penetrated the SC (high absorption).
Now, the question is what is happening in Shankar's case. Without
reading
about his experimental protocol in detail, ensuring that the effect is
reproducible not only for this set of drug/formulation but perhaps
another
one, we can only speculate without being able to converge on a
definitive
mechanistic reasoning.
At high values of LogKoct/w, it is the viable epidermis or dermis that
serves at the rate-limiting barrier. I vaguely recall the value of 3.0
but I
can confirm that later on. I am not aware of any MW cutoffs. Our group
published predictive correlations for both SC diffusivity and VE/DE
diffusivities and I can quickly run it through an excel spreadsheet to
come
up with a cut-off for both logKoct/w and MW. Alternatively, I can use
Potts-Guy SC diffusivity instead of the correlation that we developed
for
the same analysis.
Shall keep you posted.
Ray
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The predominant route of percutaneous drug absorption is through the
SC for most passive diffusion drugs. Skin has extensive vasculature,
which can efficiently remove the drug permeated into the skin.
Theoretically blood flow change could result in drug permeation
enhancement, for rapidly permeating molecules (for example, gases).
But for a lipophilic molecule, increasing the blood perfusion would
not help enhancing the drug permeation as much as altering the barrier
function of the SC.
For large polar molecules and also drugs used in electrophoresis,
transfollicular route plays an important role so the SC is not the
major rate limiting mechanism in the permeation process. However, for
most permeants, the transfollicular route is only responsible for a
very small fraction of the drug permeation.
Thanks,
Jin
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The following message was posted to: PharmPK
Interesting discussion! = Amazing how complex assessing
dermal-transdermal delivery is. - Not only blood levels but also
deposition and binding to target tissues would need to be determined at
different time intervals.
We followed the local routes for 3H-estradiol and 3H-vitamin D with
cellular autoradiography. Here are three references related topical
application, in case somebody is interested:
Bidmon H-J, Pitts JD, Solomon HF, Bondi JV, Stumpf WE (1990)Estradiol
distribution and penetration in rat skin after topical application,
studied by high resolution autoradiography. Histochemistry 95:43-54
Hayakawa N, Kubota N, Imai N, Stumpf WE (2004). Receptor Microscopic
Autoradiography for the study of percutaneous absorption, in vivo skin
penetration, and cellular-intercellular deposition. Journal of
Pharmacological and Toxicological Methods 50:131-137
Stumpf WE, Hayakawa N, Bidmon HJ (2008). Skin research and drug
localization with receptor microscopic autoradiography.Exp Dermatol
17(2):133-8. Review.
--
Walter E Stumpf
University of North Carolina
2612 Damascus Church Rd
Chapel Hill, NC 27516
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The following message was posted to: PharmPK
Hello Jin,
Not sure why you stated that a lipophilic drug molecule is not likely to
experience a perfusion limitation. Here's an interesting study of a
drug
with Log Kow ~ 1.20: "Intravenous nicotine retards transdermal
absorption
of nicotine: evidence of blood flow--limited percutaneous
absorption"(Clin
Pharmacol Ther. 1992 Sep;52(3):223-30)
Best regards,
-Shawn
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Dear Shawn,
In this case, the result could be biased by the non-sink condition
from the iv dose. So it's not very convincing to me. It would be very
interesting if the iv was done with other vasoconstriction other than
nicotine or in comparison also with a vasodilator. I think what Jin
refered to is in the normal sink condition.
Cheers,
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