Note: Descriptions are shown in the official language in which they were submitted.
W092/0S769 PCT/US91/06934
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PREVENTION OR TREATMENT OF SUNBURN
USING THE S5+) ISOMER OF KETOPROFEN
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to the use of topically
administered S(T) ke'oprofen to prevent or treat erythema
induced by ultraviolet irradiation in mammalian organisms
in need of such prevention or treatment, and to certain
topical pharmaceutical compositions comprising unit dosage
effective amounts of S(+) ketoprofen.
Descri~tion of the Art:
Ketoprofen, also known as DL-2-(3-benzoylphenyl)-
propionic acid, has the structural formula
O
~ 1 ~ CHCOOH
The compound is well-known as a nonsteroidal anti-
inflammatory drug having analgesic and antipyretic
activity. In the United States, ketoprofen is marketed
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under the tradename OrudisR. Other tradenames or
codenames include RP 19583, Alrheumat, Alrheumun,
Capisten, Fastum, Iso-K, Xefenid, Xetopron, Lertus,
Meprofen, Oruvail and Profenid. As OrudisR, the drug
is available by prescription in the U.S. as capsules
containing 25 mg, ~0 mg or 75 mg of ketoprofen,
indicated for the acute or long-term treatment of the
signs and symptoms of rheumatoid arthritis or
osteoarthritis. OrudisR is recommended at a daily dose
of 150 to 300 mg, divided in three or four doses. It
is recommended that drug treatment begin at 75 mg three
times or 50 mg four times a day. Small people may need
smaller doses. Daily dosages should not exceed 300 mg
per day. see also PhYsician's Desk Reference, 41st
edition, 1987, publisher Edward R. Barnhart, Medical
Economics Company, Inc., Oradell, NJ 07649, pp. 2179-
2181. For mild to moderate pain and dysmenorrhea, a
dose of 25 mg to 50 mg every 6 to 8 hours as needed was
recently approved by the Food and Drug Administration
("F.D.A.").
As is apparent from its chemical
nomenclature, ketoprofen is a racemic mixture. It is
only the racemic mixture which has in fact ever been
marketed. There have, however, been a few studies of
the individual S(+) and R(-) isomers reported in the
literature.
The prior art groups the 2-arylpropionic
acids together as a class. These possess a chiral
cent~r at the carbon atoms alpha to the carboxyl
function. According to the prior art, many 2-
arylpropionic zcids are believed to have a metabolic
chiral inversion of their asymmetric center, with
partial or complete conversion in nonhuman mammals of
the R to the S isomer. The rate and extent of that
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conversion has been known to vary as noted by ~utt et
al, J. Pharm. Pharmacol., 35, 693-704 (1983). This
metabolic inversion of the chiral center, with no other
covalent change to the drug, is thus far unique to the
2-arylpropionic acids. Caldwell et al., "The Metabolic
Inversion and Dispositional Enantioselectivity of the
2-Arylpropionic Acids and their Biological
Consequences", Biochem. ~harmacol., 37, 105-114
(1988).
Generally, if an optically active compound
has two isomers, there ~s an argument for resolving
what is believed to be the optically active and
therapeutically desirable isomer. However, many of the
2-arylpropionic non-steroidal anti-inflammatory drugs
(NSAIDs) are unique and run contrary to that argument
because of the teachings of the prior art relating to
the conversion of the R(-) to the S(+) isomer. Thus,
the argument for resolving the 2-arylpropionic acids to
improve their clinical effect is not as clear as with
other classes of racemic drugs. In many instances, the
prior art actually teaches away from such a resolution
by leading one of ordinary skill in the art to believe
that there would be clinical or near clinical
equivalence between the S(+) form and the racemic
mix~ure. That is, the conversion of the R(-) isomer to
the S(+) form is believed to progress at such a rate
and to such an extent that a substantially equivalent
~linical effect would result.
The majority of the prior art was too
inconclusive to yield an accurate estimate of the
extent of the possible conversion of the R(-) to the
S(+) form of ketoprofen in man. Moreover, amang the
members of that class of NSAID's, comparatively few
studies appear to have been conducted on ketoprofen.
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However, conversion in man would be assumed by one of
ordinary skill in the art since in addition to the
ketoprofen specific evidence from studies cited in the
specification, several members of the 2-arylpropionic
acid classes of NSAID's, e.g., ibuprofen, were known to
undergo substantial chiral inversion of the R to the S
enantiomer in man.
Indeed, Hutt et al concluded that there was
no advantage in administering the pure S(+) form of
ketoprofen since a rapid in v vo conversion of the R(-)
in the racemic mixture to the S(+) form would be
expected, based on the fact that ketoprofen has a
chiral center and it is known to be incorporated into
triglycerides.
Ketoprofen, liXe fenoprofen, has
been reported to be incorporated
into triglycerides, and, in
addition, a study using [3H-~-
methyl] drug in man found
increasing quantities of
circulating radioactivity due to
tritiated water. One means of loss
of 3H from the a-methyl group would
be that proposed for the loss of
deuterium from d4-ibuprofen during
the chiral inversion process.
Hutt et al, "Review - The Metabolic Chiral Inversion of
2-Arylpropionic Acids - A Novel Route with
Rharmacological Consequences," J. Pharm. Pharmacol.,
Vol. 351, pp. 693-674 at 703 (1983). Thus, Hutt et al
recognized that evidence existed supporting chiral
inverion of the R(-) to the S(+) isomer for ketoprofen.
It has recently been noted that contrary to
the expectations of the prior art, there is no
conversion of R(-) to S(+) ketoprofen in man.
Interestingly, the R-enantiomer of
some of these agents (e.g.,
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ibuprofen, fenoprofen, and
benoxaprofen~ may undergo a unique
in vivo irreversible inversion to
the S-enantiomer. This inversion
is not a universal occurrence, as,
at least in humans, it does not
occur to any significant extent
with tiaprofenic acid, indoprofen,
carprofen, and perhaps ketoprofen.
Jamali et al, "Stereoselective Pharmacokinetics of
Flurbiprofen in Humans and Rats," Journal of
Pharmaceutical Sciences, Vol. 77, No. 8, pp. 666-69
(August 1988).
A considerable amount of effort has been
spent in the search for a method to prevent the
occurrence of, or alternatively, to treat sunburn.
Sunburn is caused by certain wavelengths of ultraviolet
(W) radiation striking the skin. The ultraviolet
light alters the keratinocytes in the basal layer of
the epidermis. A slight alteration results in
erythema, and a severe alteration causes bullae to form
from the fluid collected in the epidermis. To produce
a suntan, ultraviolet light stimulates the melanocytes
in the germinating layer to generate more melanin and
oxidizes melanin already in the epidermis. Both of
these processes serve as protective mechanisms by
diffusing and absorbing additional W radiation. The
effects of the sun on the skin usually begin to appear
anywhere from 1 to 24 hours after exposure and range
from mild erythema to tenderness, pain, and edema.
Severe reactions due to excessive exposure involve the
development of vesicles or bullae as well as the
constitutional symptoms of fever, chills, weakness, and
s~oc~ .
3~ Energy emissions from the sun include
radiation wavelengths ranging from 200 nm to more than
.
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18,000 nm. Ultraviolet radiation is in the 200-400 nm
range, and this spectrum is subdivided into three
bands.
W -A (320-400 nm) radiation can cause tanning
of the skin, but is weak in causing mild sunburn of the
skin. Erythemic activity (producing redness) is
relatively weak at this wavelength. The primary action
of W -A is the development of a slow natural tan. At
this W level, radiation produces some immediate
pigment darkening. In addition, W -A represents the
range in which most photosensitizing chemicals are
active. It is also believed that W -A may augment the
effects of W -B.
W -B (290-320 nm) radiation causes sunburn
reaction, which also stimulates pigmentation (tanning)
of the skin. It is the most effective UV radiation
wavelength for producing erythema, which is why it is
called sunburn radiation. It triggers new pigment
formation as well as vitamin D production. In
addition, it is thought to be responsible for inducing
skin cancer.
W -C (200-290 nm) radiation from sunlight
does not reach the earth's surface, but artificial W
sources can emit this radiation. It does not tan the
2~ skin, but it can burn it. W -C radiation from the sun
does not reach the surface of the earth. However, W -C
is emitted by artificial ultraviolet sources. Although
it wil~ not stimulate tanning, it causes some erythema.
Other wavelengths of light also are absorbed
and, if intense enough, produce erythema and burning.
This type of burning differs from sunburn in that it is
due to generated heat rather than a photochemical
reaction.
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Thus, it has been well documented that
excessive exposure to ultraviolet light will cause
erythema, edema, bIister formation and sloughing of the
skin due to cellular damage. Ultraviolet light injury
includes epide~al cell death, increase in mitotic
index, hyperplasia, as well as the vascular responses
of vasodilation, altered permeability and cellular
exudation.
The vascular changes that occur secondary to
exposure to ultraviolet light are biphasic. The
immediate erythema reaction is a faint, transient
reddening o the skin beginning shortly after exposure
to ultraviolet light and fading within 30 minutes after
the exposure ends. A delayed erythema reaction appears
after 2-6 hours and peaks 10-24 hours after
ultraviolet-light exposure. This erythema gradually
subsides over the next 2-4 days. Peeling follows 4-7
days after a moderate to severe s~nburn. The
mechanisms by which these two types of erythema are
produced are not understood completely. Kinins,
histamine, prostaglandins, other vasoactive substances,
hydrolytic enzymes, and free radicals have been
implicated as mediators of the erytnema caused by
sunlight.
Prostaglandins have been shown to increase in
erythematous skin exposed to ultraviolet B radiation.
Aspirin and indomethacin which are nonsteroidal anti-
inflammatory agents have been shown to inhibit the
prostaglandin synthetase system in skin.
Snyder et al, "Intradermal Anti-Prostaglandin
Agents and Sunburn," The Journal of Investiqative
DermatolQoy, Vol. 62, No. 1, 47-50 (1974) discussed the
intradermal administration of indomethacin as well as
W092/05769 PCT/US91/069~
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aspirin to guinea pigs. The administration of each of
those drugs was shown to decrease the intensity and
delay the development of ultraviolet radiation induced
erythema. Snyder et al, "Topical Indomethacin and
Sunburn," British Journal of Dermatoloav, pp. 90-91
(1974), further demonstrated that the topical
application of indomethacin in humans produced a
reduction in redness, skin temperature and pain
perception. It was suggested that indomethacin may be
affecting sunburn by preventing biosynthesis of
prostaglandins.
Likewise, several nonsteroidal anti-
inflammatory drugs have been administered orally to
human subjects and have been demonstrated to be
effective in reducing erythema after exposure to
ultraviolet radiation. In particular, Edwards et al,
"Reduction of the Erythema Response to Ultraviolet
Light by Nonsteroidal Anti-inflammatory Agents," Arch.
Dermatol. Res., Vol. 272, pp. 263-267, studied the
effect of orally administered aspirin, indomethacin and
ibuprofen on ultraviolet B induced erythema in human
subjects. All three drugs were comparable in reducing
the sunburn response to ultraviolet radiation.
Gomez et al, "Effect of Topical Diflumidone
on Ultraviolet-Light-Induced Erythema," Dermatoloqica,
Vol. 162, pp. 175-182 (1981) studied the topical
efficacy of indomethacin and diflumidone for the
suppres~ion of ultraviolet-light-induced erythema in
humans. Both indomethacin and diflumidone were found
to inhibit the development of erythema; however, the
indomethacin treated sites had significantly less
erythema 24 hours after application.
W092/05769 PCT/US91/06934
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Greenberg et al, "Orally Given Indomethacin
and Blood Flow Response to W L," Arch. Dermatol., Vol.
111, pp. 328-330 (March 1975), demonstrated that orally
administered indomethacin reduced the increase in blood
flow produced by ultraviolet light irradiation by one-
third.
Lim et al, "Effect of Indomethacin on
Alteration of ATPase-Positive Langerhans Cell Density
and Cutaneous Sunburn Reaction Induced by Ultraviolet-B
Radiation," Journal of Investiqative Dermatoloqv, Vol.
81, No. 5, pp. 455-458 (1983), showed that indomethacin
topically applied prior to ultraviolet-B irradiation in
humans resulted in protection from the sun. Topical
application of indomethacin after ultraviolet-B
irradiation resulted in a decrease in erythema. The
protective effect of topical indomethacin applied prior
to radiation may be explained by its ln vitro
absorption of ultraviolet-B irradiation. The
application of indomethacin after irradiation resulting
in decreased erythema was probably related to its
effect on prostaglandin synthetase inhibition. The
authors concluded that indomethacin applied topically
could be useful as a sunscreen agent. Its clinical
safety and efficacy, however, remain to be determined.
Flowers et al, "A Comparative Study of the
Effect of Flurbiprofen and Indomethacin on Sunburn,"
Current Thera~eutic Research, Vol. 36, No. 4, pp. 787-
7gl (October 1984), evaluated the efficacy of
ultraviolet-B induced erythema in humans when the
subjects were treated with a test solution containing
2.5% indomethacin, 2.5% flurbiprofen or vehicle alone.
The authors concluded that flurbiprofen showed more
promise than indomethacin in the suppression of early
ultraviolet-B irradiation induced erythema.
W092/05769 PCT/US9l/06934
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Tas et al, "Effect of Topically Applied
Flurbiprofen on Ultraviolet-Induced Erythema," prua
Intelligence and Clinical Pharmacv, Vol. 20, 496-499
(1986), studied the effect of flurbiprofen on
ultraviolet-B induced erythema in humans. The authors
concluded that topical flurbiprofen decreased the
dermal symptoms of sunburn. The optimum maximum
concentration of flurbiprofen appeared to be
approximately 3~ and more than two applications
appeared to have no added advantage.
In summary, the current state of the art now
teaches that there is no conversion of R(-) to S(+)
ketoprofen in humans and that the S(~) form is the
active enantiomer of ketoprofen. However, there do not
appear to be any human experiments on the efficacy of
the separate enantiomers reported in the literature.
The prior art, moreover, is conspicuously silent in
respect to any prevention or alleviation of sunburn
utilizing any particular optical isomer of the
ketoprofen drug species.
SUMMARY OF THE INVENTION
Surprisingly, the present inventors now find
that S(+) ketoprofen can be advantageously topically
administered to mammals, especially humans, to prevent
or treat ultraviolet radiation-induced erythema and to
evoke such prevention or treatment more effectively
t~an possible by administration of the same dose of
ketoprofen in its racemic form. S(+) ketoprofen is
more potent than an equal amount of the racemic
mixture.
This is particularly surprising in light of
the art's failures to attribute any difference in
.
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activity for S(+) ketoprofen versus the racemic
mixture.
In one aspect, the present invention thus
provides a method for preventing ultraviolet radiation-
induced erythema in a mammal, said method comprising
topically administering to a mammal exposed to
ultraviolet radiation an amount effective to prevent
ultraviolet radiation of S(+) ketoprofen substantially
free of R(-) ketoprofen.
In another aspect, the present invention
provides a method for treating ultraviolet radiation-
induced erythema in a mammal, said method comprisin~
topically administering to a mammal in need of such
treatment an amount effective to treat ultraviolet
radiation-induced erythema of S(+) ketoprofen
substantially free of R(-) ketoprofen.
In yet another aspect, the present invention
provides a pharmaceutical composition of matter for use
in preventing or treating ultraviolet radiation-induced
erythema in mammals, especially humans, said
composition comprising an amount effective to prevent
or treat ultraviolet radiation-induced erythema of S(+)
ketoprofen substantially free of R(-) ketoprofen.
Typically, S(+) ketoprofen is associated with a
nontoxic topical pharmaceutically acceptable inert
carrier or diluent therefor.
DETAILED DESCRIPTTON OF THE PREFERRED
EMBODIMENTS OF THE INVENTION
The term "ketoprofen" or "racemic ketoprofen"
as used herein is intended to encompass not only DL-2-
(3-benzoylphenyl)propionic acid itself but also any
pharmaceutically acceptable salt thereofO
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The term "S(+) ketoprofen" as used herein is
intended to encompass not only the dextrorotatory or
S(~) isomer of 2-(3-ben~oylphenyl)propionic acid but
also any pharmaceutically acceptable,
antierythematously effective salt thereof. The
expression "substantially free of R(-) ~etoprofen" as
used in conjunction with the term "S(+) ketoprofen"
means that the S(+) ketoprofen is sufficiently free of
R(-) ketoprofen [which is the levorotatory form or R(-)
isomer of 2-(3-benzoylphenyl)-propionic acid or salt
thereof] to exert the desired antierythema effect.
Practically speaking, this means that the active
ingredient should contain at least 90% by weight S(+)
ketoprofen and 10% or less by weight R(-) ketoprofen.
Preferably, the weight ratio of S(+) ketoprofen to R(-)
ketoprofen is greater than or equal to 20:1, more
preferably greater than 97:3. Ideally, the S(+) keto-
profen is 99 or more ~ by weight free of R(-)
ketoprofen, i.e., the weight ratio of S to R is
approximately equal to or greater than 99:1. At the
present time, a 20:1 ratio of S(+) to R(-) is readily
obtainable from racemic ketoprofen by literature
methods and eminently useful in the practice of the
present invention.
Where specific amounts of S(+) ketoprofen are
set forth below, it should be understood that, unless
otherwise specified, the amounts are given in mg of the
acid, not of a salt. Moreover, unless otherwise
specified, for simplicity's sake the amounts given
represent total ketoprofen content, most of which is in
the S(+) form. For example, "50 mg S(+) ketoprofen"
means 50 mg total ketoprofen at least 90% of which is
in the S(+) form, preferably at least 95%, more
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preferably at least 97% and most preferably 99% or
more.
Topical S(+) ketoprofen, in accord with the
present invention, produces the following unexpected
results:
(1) the S(+) isomer of ketoprofen is more
potent than racemic ketoprofen for topical
administration on a mam~al since the ketoprofen is
substantially, or in large part, in the active form;
and
(2) in the case of ketoprofen, the R(-)
isomer is not active and would not substantially
overcome the effects of ultraviolet-induced erythema or
sunburn because there would probably be little if any
chiral conversion in the skin.
These unexpected results can be achieved in
the treatment of sunburn responsive to an NSAID (non-
steroidal anti-inflammatory drug).
In a group responsive to a given dose of the
racemate, it is believed that S(+) ketoprofen applied
in the same amount as racemic ketoprofen would provide
a better response for preventing or treating
ultraviolet radiation-induced erythema. S(+)
Xetoprofen would be at least twice as potent.
The precise amount of topical S(+) ketoprofen
for use in accord with the present invention will vary
depending, for example, on the size and kind of the
mammal and the condition for which the drug is
administered. For use in humans, the amount effective
to prevent or treat ultraviolet radiation-induced
erythema of S(~) ketoprofen will typically be from
about 0.5 wt. ~ to about 10 wt. ~ although greater
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amounts (e.g., 15 wt. %) may be employed if needed or
if tolerated by the patient. The preferred composition
contains about 1 wt. % to about 5 wt. %, more
preferably about 2.5 to 3.5 wt. ~ ketoprofen. The most
preferred composition would likely contain about 3.0
wt. % ketoprofen. It should be noted, however, that
lesser amounts may be useful on patients with
particularly sensitive skin and/or on the skin of
children.
The S(+) ketoprofen of the present invention
may be applied in any vehicle or in any fashion
suitable for topical administration. Topical
preparations typically include solutions, e.g., clear
or milky lotions, gels, creams, ointments, sprays, lip
balm, clothwipe, impregnated bandages and other topical
and transdermal delivery devices.
According to the FDA advisory review panel,
'l[a]n ideal sunscreen vehicle would be stable, neutral,
nongreasy, nondegreasing, nonirritating,
nondehydrating, nondrying, odorless, and efficient on
all kinds of human skin. It should also hold at least
50~ water, be easily compounded of known chemicals, and
have infinite stability during storage". Federal
Register, 43, 38218 (1978).
S(+) ketoprofen may be formulated with any
suitable nontoxic topical pharmaceutically acceptable
inert carrier material. Such topical carrier materials
are well known to those skilled in the art of
pharmaceutical formulations. For those not skilled in
the art, reference is made to the text entitled
Remington's Pharmaceutical Sciences, 17th edition,
1985, ed. Alfonso R. Gennaro, Mack Publish:ing Company,
Easton, Pennsylvania 18042.
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Suitable solvents or vehicles, for instance,
for the topical S(+) ketoprofen composition of the
present invention includes methanol, ethanol, propyl
alcohol, acetone, n-butyl alcohol, isobutyl alcohol and
the like.
The primary uses of sunscreens are to prevent
sunburn and aid in the development of a tan.
Secondarily, they serve to protect exposed areas of the
body in susceptible individuals from the long-term
hazards of skin cancer and premature aging. In
addition, sunscreens can be used to protect against
drug-related ultraviolet-induced photosensitivity.
For purposes of the present invention, the
term "sunscreen agent" shall refer to the use of S(+)-
ketoprofen as a sunscreen-sunburn preventive agent, a
sunscreen-suntanning agent and/or a sunscreen-opaque
sunblock agent. Each of those type of agents has been
defined by the FDA advisory review panel as
nonprescription topical analgesic, antirheumatic, otic,
burn and sunburn prevention and treatment drug products
as follows:
A sunscreen-sunburn preventive agent contains
an active ingredient that absorbs 95% or more of the
radiation in the ultraviolet range at wavelengths from
290-320 nm and thereby removes the sunburning rays;
A sunscreen-suntanning agent contains an
active ingredient that absorbs at least 85% of the
radiation in the ultra-violet range at wavelengths from
290-3Z0 nm, ~ut transmits ultraviolet wavelengths
longer than 320 nm (such agents permit tanning in the
average individual and also permits some erythema
without pain);
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A sunscreen-opaque sunblock agent has an
opaque agent that reflects or scatters all radiation in
the ultraviolet and visible range from 290-777 nm and
thereby prevents or minimizes suntan and sunburn.
The following pharmaceutically acceptable
topical ingredients are present in commercial
sunscreens or sunblocks:
titanium dioxide, petrolatum, red petrolatum,
benzophenone-3, isopropyl myristate, aloe vera extract,
synthetic beeswax, cetyl palmitate, ceresin, lanolin,
cetyl alcohol, alcohol, oleth-3 phosphate, synthetic
spermaceti, glycerin, mineral oil, lanolin alcohol,
cetyl stearyl glycol, lanolin oil, triethanolamine,
carbomer 934, benzyl alcohol, menthol, camphor,
essential oils, acrylic-acrylate copolymer, ammonium
hydroxide, carbomer 934P, dimethicone, quaternium-15,
stearic acid, stearyl alcohol, water, xanthan gum, SD
alcohol 40, animal protein derivative, hydroxyethyl
cellulose, choleth-24, hydroxypropyl cellulose, PPG-15
stearyl ether, propylene glycol dioctanoate, stearic
acid, ozokerite, PEG-4 dilaurate, propylparaben,
dihydroxyacetone, hydrocarbon oil, ointment base zinc
oxide, opaque base, water-repellent cream base,
caramel, perfume and flavors.
It would be advantageous for the topical
composition of the present invention to have sufficient
substantivi~y to withstand exposure of the skin to
swi~ming, high humidity and s~eating.
Generally, sunscreens should be applied
approximately 30 minutes before exposure to the sun.
However, there are exceptions, for instance,
aminobenzoic acid and its esters are more effective if
applied two hours before exposure. Pre-application of
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the topical S(+) ketoprofen composition prior to sun
exposure to the skin is advantageous because it allows
the S(+) ketoprofen to penetrate and perhaps bind with
the skin.
The amount of S~+) ketoprofen useful in the
topical preparations of the present invention is an
amount sufficient to prevent or treat ultraviolet
radiation-induced erythema.
Typical unit dosage forms for topical
administration will contain about 0.~ wt. % to about
10 wt. %, preferably about 1 wt. % to about 5 wt. %,
most preferably about 2.5 wt. % to about ~.5 wt. %,
S(+) ketoprofen based on the entire weight of the
composition per topical unit dose application. If the
composition is intended for sustained release such as
by using micxocapsules or microspheres, much larger
amounts of the active ingredient would of course be
incorporated into an individual unit. As noted
earlier, the composition and the method of the present
invention is "substantially free of the R(-)
ketoprofen."
The topical S(+) ketoprofen composition of
the present invention may f~rther be combined with
other types of sun-protective and/or antierythema
topical agents. Such agents may absorb 95 percent or
more of the ultravio~.et B radiation and thereby prevent
or minimize the deleterious effects on human skin
caused by excessive exposure to ultraviolet B (290 to
320 nm) and ultraviolet A (320 to 400 nm) radiation.
Protection is afforded by the active chemical
ingredients of a sunscreen through absorption,
reflection and scattering of solar radiation impinging
on the skin.
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~opical sunscreens can fall within one of
two categories: (1) chemical, and (2) physical
sunscreens. Chemical sunscreens contain one or more
W -absorbing chemicals, and upon application of a thin
and invisible film, act as filters and do not allow the
penetration of ultraviolet radiation to the viable
cells of the epidermis. Chemical sunscreens are
usually colorless because they do not contain any
visible light-absorbing chemicals and are, therefore,
cosmetically acceptable to most persons provided they
are a nonirritant to the skin and eyes,
nonphotosensitizing, stable, nonvolatile, and
nonstaining to skin and clothes. Most of the
commercial topical sunscreens contain one or more
ultraviolet B absorbing chemicals in a moisturizing
base. More recently, many leading brand-name
sunscreens also contain ultraviolet A absorbing
chemicals, especially the different benzophenones. The
most widely used chemical sunscreens contain para-
aminobenzoic acid (PABA), PABA esters (amyldimethyl
PABA and octyldimethyl PABA), benzophenones (oxybenzone
and sulisobenzone), cinnamates (octylmethoxy cinnamate
and cinoxate), salicylates (homomenthyl salicylate),
and anthranilates. To date, more than 21 such
chemicals have been declared by the U.S. FDA as safe,
effective agents in protecting skin against sunburn
(see Table 1), and are listed under Category I (safe
and approved).
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Table 1
SUNSCREEN AGENTS
Dose
Com~ound limits
p-aminobenzoic acid 5.0-15.0
glyceryl aminobenzoate 3.0-5.0
amyl p-dimethylamino benzoate (Padimate A) 1.0-5.0
2-ethylhexyl-p-dimethylamino benzoate
(Padimate O) 1.4-8.0
2-ethoxy-ethylhexyl-p-~ethoxy cinnamate
(cinnoxate) 1.0-3.0
diethanolamine-p-methoxycinnamate 8.0-10.0
ethylhexyl-p-methoxycinnamate 2.0-7.5
2,2-dihydroxy-4-methoxybenzophenone
(dioxybenzone) 3.0
2-hydroxy-4-methoxybenzophenone
(oxybenzone) 2.0-6.0
2-hydroxy-4-methoxybenzophenone-5-sulfonic
acid (sulisobenzone) 5.0-lO.0
2-ethyl-hexyl-2-cyano-3,3-diphenylacrylate 7.0-10.0
ethyl-4-bis-(hydroxypropyl)-amino benzoate 1.0-5.0
digalloyl trioleate 1.0-5.0
2-ethylhexyl-salicylate 3.0-5.0
lawsone + dihydroxyacetone 0.25-3.0
3,3,5-trimethylcyclohexyl salicylate
(homosalate) 4.0-15.0
methylanthranilate 3.5-4.0
2-phenyl-benzimidazole-5-sulfonic acid 1.0-4.0
triethanolamine salicylate 5.0-12.0
red veterinary petrolatum 30.0-100
titanium dioxide 2.0-25.0
Several European sunscreen manufacturers
often use p-methoxy-2-ethylhexylcinnamate,
2-phenylbenzimidazole-5-sulfonic acid, 2-phenyl-5-
me~oxybenzophenone, and 4-tert-butyl-4'-methoxy-
dibenzoylmethane as ultraviolet A and B absorbing
filters. The recommended concentration for each
chemical may vary and is based on not only the
solubility of the chemical in a given vehicle, but also
- 40 the anticipated use of the sunscreen product as a total
or partial block for the prevention of sunburn or
acquisition of suntan responses. The formulation base
(vehicle) used include alcohol plus glycerol or glycol,
W092~05769 PCT/US91/06934
t
2o933s9
- 20 -
oil-in~water or water-in-oil lotion, cream, or
ointment. The vehicle in which the ultraviolet
radiation absorbing chemical is incorporated can
determine whether a sunscreen remains effective under
the general use condition involving prolonged
sunbathing, sweating (sport1ng activities), and
swimming. This adherent property to skin, known as
"substantivity," varies considerably among commercially
available sunscreen formulations, some of which are
retained on the skin and others of which are washed off
easily after sweating or swimming.
Table 2 identifies several commercial
chemical sunscreen preparations along with their
ingredients and type of composition.
Table 2
Type of
Trade name Inaredients sunscreen
PABA sunscreens:
PreSun-15 Clear lotion
Pabanol 5% PABA in 50%-70~ Clear lotion
Sunbrella ethyl alcohol Clear lotion
PreSun-15 Gel
P~BA ester sunscreens:
Block out 3.3~ isoamyl-p-N,N- Lotion/gel
dimethyl amino-
benzoate (padimate-A)
PABAFILM 3~3% isoamyl-p-N,N- Lotion/gel
dimethyl amino-
benzoate (padimate-A)
Sundown 3.3% isoamyl-p-N,N- Lotion
dimethyl amino-
benzoate (padimate-A)
Original 3.5% padimate-A + 3.0% Lotion
Eclipse octyldimethyl PABA
Aztec 5.0% homomenthyl Lotion
salicylate + 2.5%
amyl-p-dimethyl
aminobenzoate
Sea ~ Ski 3.3% octyldimethyl Cream
PABA
W092/05769 PCT/US91/06934
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j:,
20933~9
- 2} -
Marbert Sun benzyliden-camphor Cream
- Creme phenylbenzimidazole-
5-sulfonic acid +
isopropyl dibenzoyl
: 5 methane
PABA-ester combination ~unscreens:
Copper~one 7% octyldimethyl PABA Milky lotion
Super Shade-15 + 3% oxybenzone
Total Eclipse- 2.5% glyceryl PABA Milky lotion
15 + 2.5% octyldimethyl
PABA + 2.5% oxybenzone
MMM-What-A-Tan! 3.0% octyldimethyl Milky lotion
PABA+ 2.5%
benzophenone-3
15PreSun-15 8% padimate-0 + Milky lotion
(water- 3% oxybenzone
resistant)
Clinique-l9 phenyl-benzimidazole- Milky lotion
5-sulfonic acid +
2.5% octyldimethyl
PABA
Sundown-15 7% padimate-0 + 5% MilXy lotion
(sunblock) octylsalicylate +
4% oxybenzone
Bain de Soleil 7.0% padimate-0 + White crea~
2.5% oxybenzone +
0.5% dioxybenzone
Elizabeth Arden padimate-0 + oxy- White cream
Suncare benzone
Creme-15
Estee Lauder-15 phenyl-benzimidazole- White cream
5-sulfonic acid +
: dimethyl PABA
. Rubenstein Gold ethyl-hexyl-p- Yellow gel
35Beauty-15 methoxycinnamate
+ octyldimethyI PABA
810ck Out-15 7% octyldimethyl PABA Creamy lotion
+ 3% oxybenzone
Shiseido-15 ~.5% titanium dioxide Lotion
+ 2.5% octyldimethyl
PABA + 0.3%
benzophenone-3
Non PABA sunscreens:
Piz Buin-8 5% ethyl-hexyl-p- Cream
methoxycinnamate +
3% 2-hydroxy-4-
methoxybenzophenone +
4S 2-phenyl-benzimidazole
- sulfonic acid
-
W O 92/05769 PCT/US91/06934
2~93359
- 22 -
Piz Buin-8 5~ ethyl-hexyl-p- Milky lotion
TIScreen-15 methoxycinnamate +
3% 2-hydroxy-4-
methoxybenzophenone
Piz Buin-4 4.5% ethyl-hexyl-p- Milky lotion
methoxycinnamate
W AL 10% 2-hydroxy-4- Milky lotion
methoxybenzophenone-
5-sulfonic acid
Coppertone 8% homomenthyl- Lotion
salicylate
Ultra Vera-20 octylmethoxycinnamate Milky lotion
(Cheesebrough- + 2-hydroxy-4-
Ponds) methoxybenzophenone
Piz Buin cinnamide + dibenzoyl- Yellow lotion
Gletscher methane
Creme-15
Piz Buin-12 4.5~ octyl-methoxy- Milky lotion
cinnamate + 4.5%
zinc oxide + 4.5%
talc + 2.2%
benzophenone-3
Physical sunscreens are usually opaque
formulations and contain ingredients particulate in
nature that do not selectively absorb ultraviolet
radiation, but, when applied as a thin film, primarily
reflect and scatter ultraviolet and visible radiation
because of the size of the particles and the thickr.ess of
the film. These include titanium dioxide (5% to 20%),
talc tmagnesium silicate), magnesium oxide, zinc oxide,
~aolin, ferric chloride, and ichthyol (ichthammol). Zinc
oxide appears to be the most effective. These
formulations are cosmetically unpleasing, unacceptable to
~any patients, and are often occlusive and messy to use.
Physical sunscreens are, however, essential for those
patients who are unusually sensitive to ultraviolet
radiation as well as visible radiation; these are usually
applied to limited areas such as the nose, lips, or helix
of the ear.
,
W O 92t05769 P ~ /US91/06934
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2~93'~
- 23 -
Table 3 identifies several commercial physical
sunscreen preparations along with their ingredients and
type of composition.
Table 3
Physical sunscreens
Tradename Inaredlents TY~e of Sunscreen
A-Fil titanium dioxide + Cream
RV Paque oxide + talc, Cream
Shadow kaolin, iron oxide, Cream
Reflecta or red veterinary cream
Covermark petrolatum Cream
Clinique Cream
- S(+) ketoprofen may be combin~d along with
any of the compounds identified in any of the Tables
15 identified above as a topical vehicle for
administration.
For cosmetic rather than therapeutic needs,
the patient may desire a suntan product. In many
cases, suntan products differ from sunscreens only by
20 having a lower concentration of the sunscreen agent.
The concentration of the activP ingredient is an
important factor in judging the use and effectiveness
of a product. For example, SunDare Lotion, a suntan
product, contains 1.75% cinoxate, while Maxafil Cream,
25 a sunscreen product, contains 4% (about twice as much
as the suntan product) and 5~ menthyl anthranilate, a
second sunscreen.
Further, the sunburn/sunscreen product of the
present invention may include a burn or sunburn
30 treatment component such as an anesthetic,
antimicrobial or another ingredient.
The anesthetic component of commercial
products presently include:
W092/05769 PCT/US91/06934
~933~9
- 24 -
benzocaine, lidocaine hydrochloride, butamben
picrate, dibucaine, tetracaine hydrochloride,
tripelennamine, and menthol benzocaine.
The antimicrobial component of commercial
products currently include:
benzethonium chloride, benzalkonium chloride,
povidone-iodine, chloroxylenol, chlorobutanol,
8-hydroxyquinoline, phenol, 8-hydroxyquinoline sulfate,
cresol-camphor complex, chlorothymol,
methylbenzethonium chloride, triclosan, benzyl alcohol,
and parahydracin.
The S(+) ketoprofen for use in the method and
compositions of the present invention can be prepared
by a variety of methods, such as by resolution of
racemic ketoprofen.
Farge et al, United States Patent No.
3,641,127 describes the preparation of racemic
ketoprofen and related compounds; see, in particular,
Example V thereof. The Farge et al patent also
describes a method for preparing the individual D- and
L-isomers by oxidation of the corresponding optically
active (3-benzylphenyl)alkanoic acids; see column 3,
lines 22-40.
Abas et al, J. Pharmacol. Ex~. Ther. 240(2),
637-641 (19873, have resolved racemic ketoprofen using
a modification of the method of Blazevic et al, Acta
Pharmacol. Juaoslav. 25, 155-164 (1975). Abas et al
prepared the diastereoisomeric amides of R(-) and S(+)
ketoprofen with (+)-R-l-methylbenzylamide from racemic
ketoprofen, via the acid chlorides using thionyl
chloride. The diastereoisomeric amides were separated
by the HPLC (high performance liquid chromatographic)
method of Sallustio et al, Journal of ChromatoaramhY
-: W092/05769 PCT/US91/069~
~ . .
. ( ...... ~
2~33~9
. .
- 25 -
374, 329-337 (1986), but using a 7.8 mm x 300 mm
preparative column. The pure amides were then
separately converted to nitroso derivatives with
dinitrogen tetroxide, and the nitroso derivatives were
thermally decomposed to the respective ketoprofen
enantiomers as described by Balzevic et al.
Purification of the R and S enantiomers by silica gel
chromatography, recrystallization from diethyl
ether/cyclohexane and HPLC analysis according to
Sallustio et al's method afforded the R and S
enantiomers with enantiomeric purities of 98% and 95%,
respectively.
HPLC methods other than Sallustio et al's for
- resolving enantiomers of NSAID's such as ketoprofen and
fenoprofen, and liXely adaptable to resolution of
ketoprofen, include the method of Doyle et al, Pharm.
Technol. 9f2~, 28-32 (1985), which utilizes conversion
of the racemate to its amide derivatives for effective
resolution; and that of Wainer et al, J. Chromatoar.
284tl), 117-124 (1984), which utilizes conversion of
the drug to l-naphthalenemethylamide derivatives.
A method for derivatizing ketoprofen,
fenoprofen and other nonsteroidal anti-inflammatory
drugs with optically active amphetamine (~-
methylbenzeneethanamide) has been described by Singh et
al, J. Chromatoar! 8iomed. A~ln., 378, 125-135 (1986).
Those a~thors also provide a summary of the usual
methods for resolving enantiomers, i.e. (1) by direct
separation or chiral HPLC or ~C (gas chromatographic)
columns, or (2) by diastereoisomer formation, by
reaction with an optically pure resolving agent,
- fo~lowed by chromatographic separation on an optically
inactive column. Singh et al's method is a new version
of the second approach, using optically active
. .
W092/05769 PCT/US91/06934
2ag335~
- 26 -
amphetamine as the resolving agent, followed by
separation of the diastereoisomers by capillary gas
chromatography with nitrogen-phosphorus detection.
(~he acid, now in optically pure form, could of course
then be regenerated from the salt as is well-known.)
The usual method in the art utilizes optically active
~-methylbenzylamine and involves preparation of the
diastereoisomeric NSAID-a-methylbenzylamide directly by
~eans of a coupling agent (e.g. 1,1'-
carbonyldiimidazole) or via the NSAID acid chloride
(prepared with thionyl chloride).
More generally speaXing, the S(+) isomer can
be separated from racemic ketoprofen by preparing a
salt of ketoprofen with an alkaloid or similar
resolving agent such as cinchonidine, then separating
the products by fractional crystallization from a
solvent in which the dextrorotatory isomer is least
soluble. The d-salt can then be acid cleaved to yield
S(+) ketoprofen. Compare, for example, Alvarez,
United States Patent No. 3,637,767, issued January 25,
1972, which relates to resolution of naproxen and
related compounds; and Kaiser et al, J. Pharm. Sci.
65(2), 269-273 (1976), which relates to resolution of
ketoprofen.
While S(+) ketoprofen may be conveniently
obtained by resolution of racemic ketoprofen, it may
also be possible to utilize a chemical or
microbiological synthetic process which will provide
the S(+) enantiomer directly. One such chemical
process is described in Farge et al, United States
Patent No. 3,641,127, as already mentioned hereinabove.
Another chemical process is provided by Schloemer,
United States Patent No. 4,542,237, which describes a
process for preparing ~-arylalkanoic acids utilizing
W092/05769 PCT/US91/06934
2~3~
- 27 -
novel ~-hydroxy alkyl aryl ketals as intermediates. As
taught in column 9 of the Schloemer patent, the process
is advantageous in that the ~-hydroxy ketal can be
resolved by well-known methods and the optically active
~-hydroxy ketal thus obtained can then be used in the
subject process to ultimately afford the desired acid
in optically pure form.
Alternatively, a microbiological process such
as that described in SHELL INTERNATIONALE RESEARCH
MAATSCHAPPIJ B.V.'s European Patent Appln. No. 86
200987.5, published under No. 0 205215 on Decem~er 17,
1986, may be employed. According to the European
application, a pharmaceutically active compound of the
type
lS ______CH3
Rl - Cl{~
COOH
or a pharmaceutically active salt or ester thereof,
which most preferably is naproxen or ketoprofen but
which may be ketoprofen or various other NSAIDs, is
prepared in stereospecific form by subjecting a
compound of the formula
_____CH3
Rl-CH~
CH3
to the action of an appropriate microorganism. The
desired acid i8 obtai~ed having at least 70% by weight
in the S-configuration. Preferably, a microorganism is
selected such that the acid which is formed is at least
90% by weight in the S-configuration. Use of this
method has afforded naproxen with enantiomeric
distributions of 98.9% S and 1.1% R in one instance,
and distributions of 99.5% S and 0.5% R in another.
Processes of this type may be utilized to prepare S(+)
W092/05769 PCT/US91/06934
~ .,
'~0933~ 28 -
ketoprofen for use in the present invention if the S(+)
isomer can be obtained in sufficient purity [ideally,
at least 90% by weight S(+) isomer.]
When S(+) ketoprofen is to be employed in the
form of a pharmaceutically acceptable,
antierythematously active salt thereof, such salt may
be conveniently prepared by direct salification of
S(+) ketoprofen by known methods. See, for example,
deVincentiis, United States Patent No. 4,440,787, which
describes salts of (2l,4'-difluoro-4-biphenyl)oxypro-
pionic acid with metallic ions, such as sodium,
potassium, magnesium and calcium, or with
pharmaceutically acceptable organic bases, such as
lysine, arginine and diethanolamine. Compare also
Armitage et al, United states Patent No. 4,501,727,
issued February 26, 1985, which describes the N-methyl-
D-glucamine salt of flurbiprofen. Such a salt may not
only be used in oral or rectal compositions, but, if
sufficiently soluble in water, may be useful in the
preparation of aqueous solutions of S(+) ketoprofen for
parenteral injection.
From the foregoing description, one of
ordinary skill in the art can easily ascertain the
essential characteristics of the instant invention, and
without departing from the spirit and scope thereof,
can make various changes and/or modifications of the
invention to adapt it to various usages and conditions.
As such, these changes and/or modifications are
properly, equitably and intended to be within the full
range of equivalents of the following claims.
