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[Not exactly a PK/PD question but a quiet day...maybe formulation answers
could go to the author below or to the PharmPC.-at-.pharm.cpb.uokhsc.edu list,
thanks. PK/PD replies of course would be welcome on this list...db]
Hello everybody
Sometime ago we had a discussion on dermal patches. Does anybody know
whether there are any dermal patches for NSAIDs? If there aren't any, are
there any technical problems in developing patches for NSAIDs? Wouldn't a
dermal patch for NSAID eliminate the gastrointestinal side effects of NSAIDs?
Any input is appreciated.
Chandrani Gunaratna
Chandrani Gunaratna, Ph.D.
Senior Research Chemist
Bioanalytical Systems
2701 Kent Avenue
West Lafayette, IN 47906
Phone: (765)463-4527
E-Mail: prema.aaa.bioanalytical.com
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[A popular topic this morning - db]
From: "Lands, William"
To: "'PharmPK.-a-.pharm.cpb.uokhsc.edu'"
Subject: RE: NSAID patches
Date: Thu, 2 Oct 1997 11:56:28 -0400
X-Priority: 3
An investigator truly interested in the pharmacodynamics of NSAIDS needs
to incorporate aspects of the three different classes of mechanism that
occur; the kinetics for one type will not always fit the others.
1- Reversible competitors at the substrate site (like ibuprofen)
are the "classical" type and are easy to handle.
2- Time-dependent tight ligands at the substrate site (like
indomethacin) are almost irreversible (like aspirin) leaving inhibited
cells after the bulk of the drug has been excreted.
3- Peroxide-sensitive non-competitive inhibitors (like
acetamidophenol) diminish activated intermediates and are more effective
in hyperalgesic sites than in inflammatory sites with high peroxide
tone.
Most of this was described in the literature over 10-20 years ago.
Examples are: Proc.Nat.Acad.Sci.72: 4863-4865 (1975)
Trends in Pharmacol.Sci. March: 78-80 (1981)
Prostaglandins 24: 271-278 (1982)
Biochem.Pharmacol. 31: 3307-3311 (1982)
With the new COX-2 inhibitors, there is a real need to identify more
clearly which mechanism of action pertains for each new agent.
_____________________________________
William E.M. Lands
Voice = (301) 443-0276
FAX = (301) 594-0673
--
Date: Thu, 2 Oct 1997 10:08:43 -0600 (MDT)
From: Keith Anderson
X-Sender: keithand.-at-.gpu5.srv.ualberta.ca
To: PharmPK.-a-.pharm.cpb.uokhsc.edu
cc: Multiple recipients of PharmPK - Sent by
Subject: Re: NSAID patches
MIME-Version: 1.0
> Hello everybody
>
> Sometime ago we had a discussion on dermal patches. Does anybody know
> whether there are any dermal patches for NSAIDs? If there aren't any, are
> there any technical problems in developing patches for NSAIDs? Wouldn't a
> dermal patch for NSAID eliminate the gastrointestinal side effects of NSAIDs?
>
There are both dermal patches and creams/gels for NSAIDs in markets other
than Canada, the U.S., and Austrailia. Pharmetrix in the US developed a
ketoprofen patch (I believe the company is now under a different name),
Hyal Pharmaceuticals has a hyaluronic acid based gel for diclofenac,
Dimethaid Inc. has a diclofenac formulation as well (Pennsaid), and Ciba
Geigy has their Voltaren Emulgel. The arguement goes that transdermal
delivery of NSAIDs is an inefficient system for systemic delivery of
NSAIDs but has many applications for local enhanced therapeutic delivery
(LETD). Epidemiologic studies show that GI adverse events with topical
NSAIDs is rare, however cutaneous adverse events are increased causing
concern for regulatory bodies. Relative bioavailability of diclofenac
generally ranges from 5-10% after topical admin. Topical NSAID therapy
seems to be effective for soft tissue injurys and muscle injurys, as well
as inflammatory dermal conditions, however reports of penetration to
deeper joints and synovial fluid are inconclusive as yet.
--
From: WKRAMER.-at-.qrvl.quintiles.com (William Kramer)
To: PharmPK.-a-.pharm.cpb.uokhsc.edu
Subject: Re: NSAID patches
Date: Thu, 02 Oct 97 12:58:18 -0400
Mime-Version: 1.0
You should look at the current issue of Clinical Pharmacology and
Therapeutics -- page 293 (Volume 62, September 1997).
Bill Kramer
_______________________________
William G. Kramer, Ph.D.
Senior Technical Adviser
Quintiles Strategic Regulatory Division
15825 Shady Grove Road, Suite 90
Rockville, MD 20850-4008
Phone: 301-548-1534 (Direct)
301-548-0500 (Switchboard)
Pager: 800-721-2769
FAX: 301-548-1548
Email: wkramer.-at-.qrvl.quintiles.com
--
From: "rxcdr"
To:,
"Multiple recipients of PharmPK - Sent by"
Subject: Re: NSAID patches
Date: Thu, 2 Oct 1997 19:30:18 -0400
X-MSMail-Priority: Normal
X-Priority: 3
MIME-Version: 1.0
A good question with many answers,
First of all there are topical NSAID creams available in Europe for topical
application. They are only indicated for local action (i.e. at an affected
joint) as the plasma levels never reach therapeutic levels. If you had to
apply the cream to each of the affected joints in a case of arthritis it
would get very messy and would possibly produce the same side effects as
the amount absorbed would necessarily increase with the increasing surface
area.
NSAID patches are for the most part not feasible. If one looks at the
doses required for anti-inflammatory activity for most of the NSAIDs you
are talking about hundred's of mg per day. Given their usually poor degree
of lipophilicity the size of the patch would quickly get very large.
Although adjuvant agents and solvents could be used the effect of driving a
large amount of drug through the skin will cause skin irriation and most
likely long term damage If you look at those products that are available
transdermally you will notice that they are all relatively potent compounds
(i.e., fentanyl, scopolamine, testosterone, estrogen, etc.) where 1-2mg per
day or less is an effective dose. Nicotine is probably the largest dose
that we deliver topically now at 21mg/24hrs, so with the exception of
possibly some drugs like piroxicam or maybe ketoprofen the doses required
exceed the capacity and delivery.
Finally, there is the great debate on side effects, true drugs such as
naproxen and ibuprofen can cause direct gastric irritation, but so can
nabumetone (a non-acidic NSAID). Gastric irritation is due both to direct
action by drug in gastric fluid and by the effect of systemic levels on
prostaglandin production. This explains the severe GI effects of keterolac
injection, a drug that by bypassing the stomach should have minimal impact
on the gastric mucosa.
Dennis Bashaw, Pharm.D.
Http://www.netcom.com/~rxcdr/dbcp.html
--
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There were some good insights into NSAID patches, but the patches may
have been dispatched too hastily with regard to possible antithrombotic
therapy using an "irreversible, time-dependent" NSAID. Low doses can be
effective for such an application, as shown by McAdam et al J.
Pharmacol. Exp. Therap. 277: 559-564; 1996). With platelets having no
nucleus for inducing expression of new cyclooxygenase, a little
inhibition goes a long ways. Of course, a baby aspirin every other day
is simpler for some people.
_____________________________________
William E.M. Lands
Voice = (301) 443-0276
FAX = (301) 594-0673
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Regarding NSAID patches:
As far as I know there are no such patches on the market. On the other hand
there are several topical gels and onitments available. I have seen data
showing that topically applied substance were active only when systemic
effects reached the same level as when administered P.O!!!. I have also
seen one study with another NSAID that did show local effects and
relatively high concentrations in Synovial fluid after topical application.
In light of the quite different structures among NSAIDs (Physiocochemically
its hardly to be regarded as a group at all) this difference among NSAIDS
with regard to their potential topical use is not surprising.
It is also very much to be remembered that the GI side effects largely are
caused by systemic NSAID, and not as one previousely suggested by their
local effect on the Gastric mucosa.The effort to "package" NSAIDS in
"gastric proof formulations" have to my knowledge not showed in a
convincing manner that this scheeme actually results in a significantly
decreased degree of GI-side effects. In my view many of those strategies do
more resemble filling old wine in new bottles e.g making a higher price
possible for an old product.
If one succeds in applying NSAIDS locally in a way that results in local
terapeutic concentrations while maintaining the systemic concentration low
or negligible, then that might off course be a real clinical benefit.
Nils Ove Hoem, Ph.D
Assoc. Professor
Dept. of Pharmacology, School of Pharmacy,
University of Oslo,
POB 1068 Blindern
N-0316 Oslo
NORWAY
Phone: +47 22 856561
Fax: +47 22 857511
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