Note: Descriptions are shown in the official language in which they were submitted.
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FATTY ACIDS AND THEIR SMALL CHAIN
ESTERS AS PENETRATION ENHANCERS
IN AQUEOUS SYST~MS
BACKGROUND OF THE INVENTION
This invention relates to pharmaceutical
compositions which are useful in effecting transdermal
delivery of a therapeutic dose of a therapeutically
active ingredient to the systemic circulation of a
mammal.
As a specific and preferred application,
k~lerapeutically active ingredien-t~ or drugs 5UC~I a5
opioid~ may be ~lngled out a~ pre~rred activ~
lngred.~eIIt~ ln ~uch trall~deLmal sy~tem~.
Many opioid~ are know~ to have poor bioavaila-
bility in the mammalian systemic circulation due to
extensive initial metabolism of the drug by the liver
and intestines. Furthermore, the bioavailability of
orally administered opioids may be unpredictable since
various factors such as changes in acidity and food
content can cause changes in the amount of drug
absorbed from the gastrointestinal tract. Also, oral
administration does not necessarily ensure good
patient compliance.
Parenteral`administration of opioids provides
better bioavailability than oral administration.
However, the various routes of parenteral administra-
tion such as intravenous, intramuscular, and
subcutaneous delivery are not convenient for chronic
therapy. This is particularly true for -those opioids
which exhibit short biological activity half-lives.
Topical formulations of opioids do not
necessarily provide delivery of a therapeutic dose of
the drug to the systemic circulation and thus provide
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poor or unpredictable bioavailability. Natural oils
containing sa-turated or unsaturated fatty acids have
been described in such topical formulations with drugs
used for local anesthetic purposes.
Transdermal delivery of opioid drugs to the
mammalian systemic circulation have been described as
an alternative mode of administration which can
provide the following advantages:
1. Improved and predictable bioavailability of
the opioid as compared to oral administration since
transdermal delivery avoids initial metabolism by the
liver and intestines, and unpredictable absorption
from the gastrointestinal tract.
2. A stable blood serum level of ~he d~rug
re~ulting in a pro].onged phaxmacological eEEect
similar to lntravenou~ ln~u~:lQrl.
3. Easily ~djustable dosing rate whlch prov.ides
maximization o efEicacy and minimization of side
effects.
4. Easily removable drug source which provides
rapid cessation of dosing and elimination of the drug
from the body fluids.
5. Convenience of dosing which provides improved
patient comfort as compared to parenteral adminis-
tration and the possibility of greater patient
compliance as compared to oral adminis-tration.
Transdermal drug delivery is dis-tinguished from
topical drug delivery by the fact that while a
transdermal formulation is specifically designed to
provide a predictable and therapeutically significant
rate of delivery of the drug to the systemic
circulation, a topical formulation is specifically
designed to provide a therapeutic effect only to the
local area to which the drug is applied. Furthermore,
topical formulations are often designed to prevent any
systemic delivery of the drug in order to minimize
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side-effects. However, even if the topical delivery
of a drug does result in systemic absorption, the
amount of drug delivery to the circulation is variable
and uncontrolled.
European Patent Publication 0 171 742 describes
such a sy~tem for the transdermal delivery of opioids
using saturated or unsaturated fatty alcohols as acids
or esters thereof with a carrier or vehicle such as
propylene glycol resulting in an organic system, i.e.
suspension or gel. The disadvantage of this system is
that the use of propylene glycol or other known
organic solvents causes irritation to the skin.
It has now been found that saturated or
unsaturated E~t-t~ acid~ or ~-ter~ thereof, uch as
linolelc acid, 1~ eE~ecti~e as a skin absorpt.lon
enhancer ln pur~ly a~ueou~ ~ys~k~ms thus leading ~o new
and effective tran~dermal compositions without skin
irritation~
SUMMARY OF THE INVENTION
~ccordingly the present invention relates to a
pharmaceutical composition adapted for transdermal
delivery of a therapeutically effective amount of a
drug to the systemic circulation of a mammal
comprising an aqueous suspension containing:
a therapeutically effective amount of a drug or a
pharmaceutically acceptable salt thereof;
an effective amount of a saturated or unsaturated
fatty acid of 8-18 carbon atoms or a Cl-C4 alkyl ester
thereof, and a pharmaceutically acceptable excipient.
Another aspect of the present invention is a
method or the transdermal delivery of a therapeuti-
cally effective amount of a drug to the systemic
circulation of a mammal which comprises administering
to said mammal in an aqueous suspension:
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a therapeutically effective amount of a drug or a
pharmaceutically acceptable salt thereof;
an effective amount of a saturated or unsaturated
fatty acid of C8 -Cl 8 carbon atoms or a C1-C4 alkyl
ester thereof, and a pharmaceutically acceptable
excipient.
DESCRIPTION OF PREFERRED EMBODIMENTS
Although the present aqueous transdermal
composition encompasses the combination with any drug,
the preferred utility of such a composition is wi-th
opioid~.
~ y th~ -term "oploid" ;L~ mean~ any ~atural or
synthetic opio~d aIl~lgcsic ~uch as morphlne,
oxymorphone, Eentanyl, meper.idine, propoxyphene, or
oxycodone; any natural or synthetic narcotic
antagonist such as nalmefene, naloxone or naltrexone;
any natural or synthetic mixed opioid
agonist/antagonist such as nalbuphine, butorphanol,
buprenorphine or pentazocine; or any pharmaceutically
acceptable salt thereof.
By the term "pharmaceutically accep-table salt" is
meant any non-toxic pharmaceutically suitable sal-t of
an opioid which has therapeutic properties in mammals.
Preparation of such salts is well-known to those
skilled in pharmaceuticals. Pharmaceutically
acceptable salts of opioids include acetates,
naphthylates, tosylates, succinates, hydrochlorides,
palmitates, stearates, oleates, pamoates, laurates,
valerates, hydrobromides, sulfates, methane
sulfonates, tartrates, citrates, and maleates.
The term "saturated or unsaturated fatty acid of
8-18 carbon atoms" means any such acid or ester
thereof effective in enhanciny the penetration of a
drug through the mammalian skin. Preferred are
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linoleic and oleic acids and their C1-C4 alkyl esters.
Most preferred is linoleic acid.
Pharmaceutically acceptable excipients are
additional materials used in the compositions to bind
the effective ingredients into a cream or lotion form
suitable for administration on the skin per se or
through known devices such as bandaids, tapes,
patches, and the like. These excipients are, for
example, carbopol 934, carbopol*940, carbopol 941,
(B. F. Goodrich and Co. they are acrylic acid, water
soluble resin polymers, with molecular weights of
3,000,000; 4,000,000; and 1,250,000 respectively);
tween*20, (ICI Americas) polysorbate 20 polyoxy-
ethylene 20 sorbita~ monolaurate, ox other tweerls*such
AS tween*40, tween*60, and tween~80, and other
pharmaceutically acceptable emulsifiexs such as
polyethyleneglycol esters, e.g. polyethyleneglycol
monolaurates, can also be used.
The effectiveness of the present invention is
illustrated by the following examples and results
illustrated in table form which compares the
permeation of oxymorphone through hairless mouse skin
from organic and aqueous enhancer systems containing
linoleic acid.
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Aqueous Systems
Formulations Flux Lag Time
(containing 5% w~w oxymorphone (~ q/cm7 /h) (h)
LA 30% *
(0.3% Carbopol*+ 2.5% Tween 20) 70% 667.45 6.8
LA ~0% ,.
~0.3% Carbopol* + 2.5% Tween*20) 80% 636.11 9.3
LA 10% * *
0.3% Carbopol + 2.S% Tween 20) 90% 672.76 4.3
LA 5% * *
(0.3% Carbopol + 2.5% Tween 20) 95% 543.82 9.5
L~ 20% *
(2.5% Tween 20) 80% ~8~.46 4.4
0.3% Carbopol* 38.31 17
0.3% Carbopol*~ 2.5% Tween*20 19.73 15.61
Leqend
LA = Linoleic Acid
PG = Propylene Glycol
TA = Triacetin
Note: Since the aqueous systems are suspensions, they
are constantly providing maximum availability of
oxymorphone or pe~neation (i.e. maximum flux);
therefore, to compare permeability data with the
organic systems, maximum flux values had to be
calculated. Using the premeability coefficients for
O.5% oxymorphone solutions in the linoleic
acid:propylene glycol:triacetin mixtures, maximum
fluxes were calculated by multiplying the saturation
solubility of oxymorphone in the respective system by
its corresponding permeability coefficient. However,
it should bç noted that the aqueous dispersions (5%
w/w drug) became depleted of drug causing a plateau in
cumulative average concentration versus time graphs,
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therefore, higher flux values may be anticipated with
the aqueous systems.
As shown in the table, aqueous systems containing
the model fatty acid, linoleic acid, effectively
enhanced the permea-tion of a model drug through the
skin. The usual dose of oxymorphone is 6-10 mg per
day which would be adequately provided by any of the
aqueous systems containing linoleic acid from a 10 cm2
patch.
