Note: Descriptions are shown in the official language in which they were submitted.
1 31 ~827
PR~VENTION AND TREATMENT OF THE DELETERIOUS ~FFECTS OF
EXPOSING SKIN TO THE SUN, AND COMPOSITIONS THEREFOR
Skin cancer now ranks as the number one form of cancer in
the United States today. The increase in the occurrence
of skin cancer ranks second only to the increase of lung
cancer in women.
Some forms of skin cancer, such as basal cell carcinoma
and squamous cell carcinoma, can be attributed to chronic,
year-round exposure to the ultraviolet radiation of the
sun. Malignant melanoma, a dangerous form of skin cancer
because of the speed with which it can spread through the
body, is thought to stem from "severe episodic sunburn".
This type of sunburn is described as a sunburn obtained
intermittently with no base tan. It occurs when people go
out and get burnt once or twice a year; and then repeat
this pattern year after year. It is frequently found in
people who live in cold climates and who vacation in
midwinter in warmer regions. There is no gradual exposure
to the sun. They go into the sun with zero exposure, so
that the skin has no chance to protect itself, and end up
with severe sunburn.
Until now, severe sunburn has been treated in much the
same way as a first or second degree burn with lotions and
creams to soothe the pain and antibiotics, if necessary,
in the most severe cases. Individuals with chronic
exposure to ultraviolet radiation from the sun may or may
not treat themselves.
The exposure to ultraviolet light which causes the sunburn
likewise induces other changes in the skin which are
believed to predispose, or lead, an individual to skin
cancer. Such exposure can cause tumor graft tolerance and
suppress delayed hypersensitivity tDH) [Parrish, J.A., ed.
"The Effect of Ultraviolet Radiation on the Immune
System", Johnson and Johnson 3aby Products Company.].
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Ultraviolet irradiation of mouse skin causes tolerance to
the placing of relatively immunogenic skin tumor grafts,
[Kripke, J. Nat. Cancer Inst. _ , pp. 211-215 (1976)].
The extent of suppression of delayed hypersensitivity (DH)
by ultraviolet light has been used to quantify
immunological tolerance caused by ultraviolet light,
[Noonan, Springer Semin, Immunopathol., _, pp. 293-304
(1981~ and Parrish, cited above]. Irradiated mouse skin
secretes low molecular weight protein that stimulates
suppressor T cells in the spleen [Swartz, J. Invest.
Dermatol. 83, pp. 305-307 (1984) and Schwartz et al., J.
Invest. Dermatol., 87, pp. 289-291 (1986)]. Moreover, the
c isomer of urocanic acid is released from irradiated
mouse skin, presumably a photoproduct of the trans isomer,
lS normally present in the skin [De Fabo et al., J. Exp.
Med., 157, pp. 84-98 (1983)]. Ultraviolet photoproducts
of purified urocanic ac;d also were able to suppress DH to
herpes virus in mice [Ross et al., J. Invest. Dermatol.,
87, pp. 630-633 (1986)], so t~ere may be more than one
inducer or more than one cutaneous step in this process.
Neither the mechanism of action, nor the source of the
active substance, has been identified with certainty.
Also, it is not known what normal physiological function,
if any, is served by the suppressor cells. These cells,
however, prevent rejection of tumor tissue, thus allowing
ultraviolet carcinogenesis [Fisher et al., Science, 216,
pp. 1133-1134 (1981)].
It is obvious that ultraviolet radiation suppression of
delayed hypersensitivity can prevent rejection of
ultraviolet radiation exposed skin, at the risk of the
long-term consequence of elevated skin tumor
susceptibility. It would be advantageous to eliminate
this effect in order to reduce or eliminate the possible
long-term consequence of skin cancer in individuals who
have sustained recent sun exposure.
SUMMARY OF THE INVENTION
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We have now discovered that the 21-oic acid methyl ester
of triamcinolone acetonide (TAme), other compounds
affecting the arachidonic acid cascade and other known
synthesis inhibitors, and topical compositions thereof can
b~ utilized to inhibit ultraviolet radiation suppression
of delayed hypersensitivity in the epidermis of
individuals exposed to ultraviolet radiation, thereby
reducing or obviating the carcinogenic effects of
ultraviolet radiation by administering topically to the
affected area the compound or a composition thereof in an
amount effective to inhibit the ultraviolet radiation
suppression of delayed hypersensitivity without systemic
effects.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the use of triamcinolone
acetonide 21-oic acid methyl ester, compounds affecting
the arachidonic acid cascade and other known synthesis
inhibitors, and topical compositions thereof to reduce or
obviate the carcinogenic effects of ultraviolet radiation.
More particularly, this invention provides a method of
inhibiting ultraviolet radiation suppression of delayed
hypersensitivity in the epidermis of individuals exposed
to ultraviolet radiation utilizing triamcinolone acetonide
21-oic acid methyl ester, compounds affecting the
arachidonic acid cascade and other known synthesis
inhibitors, and topical compositions thereof without
systemic effects.
The glucocorticoid utilized in the present invention is
the 21-oic acid methyl est.er of triamcinolone acetonide.
It can be conveniently prepared by the synthetic routes
detailed in Gorsline et al., Endocrinology, 116, pp.
263-273 (1985).
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The active glucocorticoid, triamcinolone acetonide
21-oic acid methyl ester, can be utilized in the method of
the present invention alone, or more conveniently,
f o r m u 1 a t e d i n t o ~ t o p i c ~ 1 c o m p O S i t i o ~ s u i t a b 1 e for
dernlatological use. Suc~ for~nulations comprise the
triamcinolone acetonide ~l-oi~ acid l~thyl esLer in a
vehicle suitable for topical adnlinistration to the
epidermis of an individual in need of therapy for exposure
to ~rlL~aviolet radiation or sunb~rn.
1~ Silnilarly, the co~pounds affecting the arachibonic acid
cascad~ and the prostaglandin synthesis inhibitors that
may be utilized herein include, but are not limited to,
A5pirin, ibuprofen, indornethacin, salicylic acid,
phenylbutdzone, sulfinpyra~on and sulindac. These
compounds raay be formulated into pharrnaceutical
compositions with known pharmaceutically acceptablé
carriers for ther~peutic adminlstration~
Such topical compositions as are useful with the
glucocorticoid of the present invention are exemplified by
ointrnents, cr~dms, lotions, aerosols, gels or soaps.
These compositions will normally be based upon standard
dermatological carriers which are phdrnaceutically
acceptable and cosmetically elegant, such as those
selected from phar~aceut;Cally acceptable polyalkylene
glycols~ isopropanol, gelatin, ben2yl alcohol, gurns,
glycerol and petrolatu~. Optionally, the compositions may
contain preservatives, aerosol propellants, such as
hydrocarbons, and coloring, thickening, suspendin~,
dispersing, emulsifying, ~etting, stabilizing and
buffering agents. These formulations are envisioned to
contain the triamcinolone acetonide 21-oic acid methyl
ester or the other co~pound5 of the present invention in
an amount of from about 0.005 to 1.0% by weight, with a
rdnge of from about 0.01 to 0.2~ by wei~ht being
preferable for topical applicat;on.
* trade-mark
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1 3 1 6827
The compositions of the present invention may be utilized
to treat the epidermis of individuals who have been
exposed to ultraviolet radiation in potentially
carcinogenic quantities. The amount of such exposure may
vary from individual to individual and it is envisioned
that a physician or other treatment administrator will
consider factors such as the individual's age, weight,
complexion and degree of exposure in administering the
proper dosage. Treatment is envisioned to be accomplished
by applying the topical composition to completely cover
the affected area. The dosage of the compounds is
preferably in the range of 0.01 mg/m2 to about 100 mg/m2
skin surface area. The predicted frequency of application
is once or twice daily, but this may of course be varied
depending upon the particular individual involved.
Thus, the method of treatment utilizing the compounds of
this invention to treat individuals exposed to ultraviolet
radiation comprises administering one or rnore of the
compounds or a topical composition thereof to an
individual in need of such therapy in an amount sufficient
to inhibit the ultraviolet radiation suppression of
delayed hypersensitivity in the epidermis thereby reducing
or obviating the carcinogenic effects of the ultraviolet
radiation.
The unique properties of the active ingredient allow
treatment of the epidermis exposed to ultraviolet
radiation without concommitant systemic effects. Since
these compounds act only upon the epidermis in this
therapeutic context, they are uniquely suited to the
method of treatment of the present invention.
Treatment of the epidermis of individuals suffering from
ultraviolet radiation exposure (sunburn) the method of the
present invention will inhibit the ultraviolet suppression
of delayed hypersensitivity in the epidermis. Thus, for
example, the adminstration of the triamcinolone acetonide
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21-oic methyl ester will prevent the induction of
suppressor T lymphocytes which lymphocytes are responsible
for the prevention of rejection of tumor tissue. By
prevention of such a response, the epidermis will thus
continue in a normal fashion which would thus allow the
rejection of tumor tissue and prevent the carcinogenic
effects of the ultraviolet radiation exposure. The
elicited response to treatment with the compounds of the
present invention in the individual's epidermis will be
rejection of the sunburned skin. This rejection will
result in intense infiltration, hyperproliferation and
purulent crusting in the epidermis of the individual.
This is a manifestation of a normal immune system which is
indicative of the fact that the ultraviolet radiation
suppression of delayed hypersensitivity has been
successfully blocked. Thus, the so-treated individual
will have increased his chances of rejecting to neoplasm
and thus reduce or obviate his chances of sustaining
ultraviolet radiation carcinogenesis.
While not wishing to be absolutely bound by a scientific
explanation, it appears that when applied to irradiated
skin, TAme and the other compounds of the present
invention prevent the UV suppression of delayed
hypersensitivity at the site of irradiation. TAme may
block all cell responses by poisoning cell machinery or by
vasoconstriction. One would thus expect less change in
irradiated, treated skin than in irradiated skin not
treated with compound, and atrophy or other abnormalities
in the epidermis of unirradiated, compound-treated
animals.
However, as to rAme, it has been noted as having no
discernible effect on unirradiated skin, but enhanced
markedly neutrophilic infiltration and epidermal
hyperplasia in UV-irradiated skin. Thus, TAme directly
prevents an epidermal signal inducing ultraviolet
radiation suppression of delayed hypersensitivity. The
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nature of this signal remains obscure. Possible sources
include the Langerhans cell, whose functional properties
appear to be altered substantially by glucocorticoids; the
keratinocyte; or arachidonic acid metabolism to
prostaglandin in the skin, of which the last appears to be
confirmed to date. Other explanations are possible.
While there is no evidence that a steroid applied after
irradiation would influence photocatalyzed conversion of
urocanic acid to a suppressing substance, possible effects
on its release or subsequent metabolism cannot be
excluded.
Cell surface antigen changes following ultraviolet
radiation should lead to immune recognition of the
epidermis as foreign, but ultraviolet radiation
suppression of delayed hypersensitivity can prevent
rejection of sunburned skin, at the risk of the long-term
consequence of elevated skin tumor susceptability. The
intense infiltration, hyperproliferation, and purulent
crusting in the test ultraviolet radiation + TAme group
may reveal the epidermal response to ultraviolet radiation
damaged skin in the absence of normal immune suppression
or else some ancillary effect of the steroid.
Since the infiltrate and hyperplasia were absent in the
TAme only group, these were not caused by simple drug
effects such as irritation. However, the response did not
resemble microscopically either graft rejection or delayed
hypersensitivity, in that mononuclear cels were not
abundant. The polymorphonuclear infiltrate could be a
response to cell breakdown products or to bacterial
antigens. Conceivably, the neutrophils or irradiated
epidermal cells secrete a growth factor. Gamma interferon
secretion from macrophages or T-lymphocytes has been
implicated in acanthotic changes during delayed
hypersensitivity reactions, see Kaplan et al., Proc. Nat.
Acad. Sci. USA, 83, pp 3469-3473 (1986). This data
evidences acanthosis with little or no T-lymphocyte or
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macrophage infiltrate. In view of the above, as well as
the observation that TAme at the site of application can
prevent sensitization and also response to challenge in
DH, it seems likely that several cutaneous mechanisms were
affected by TAme, including the stimulation of helper T
cells potentially responsive to UV-modified skin. It
should be emphasized, however, that no glucocorticoid
effects beyond the site of TAme application are detected,
yet TAme abolished UV suppression of DH in unirradiated
skin. The simplest explanation is that TAme prevents
synthesis of a suppressor substance or its release from
the irradiated skin to which TAme was applied.
The data as a whole indicate that TAme-treated epidermis
was ineffective at provoking or suppressing cell-mediated
immunity when untreated epidermis was effective. TAme did
not cause direct toxicity nor did it affect sensitization
or challenge at a distal site.
The following examples describe in detail the methods and
compositions illustrative of the present invention. It
will be apparent to those skilled in the art that many
modifications, both of materials and methods, may be
practiced without departing from the purpose and intent of
this disclosure.
EXAMPLE I
Materials: Mice aged about 4 months are secured from the
Rockefeller University colony established in December,
1983, from NIH Balb/CAnN stock. DNCB
(1-chloro-2,4-dinitrobenzene) and TA (triamcinoone
acetonide) are purchased from Sigma; TAme (triamcinolone
acetonide 21-oic methyl ester) is synthesized as described
by Gorsline, Bradlow and Sherman [Endocrinology, 116, pp.
263-273 (1985)].
1 3 1 6827
Irradiation: To handle the irradiation of mice in groups,
holes 2 cm on a side are cut in a cardboard mask which is
then set above a bank of two GEG15T8 high pressure Hg
lamps emitting primarily at 254 nm. This lamp minimizs
possible systemic effects of irradiation. 254 nm light
penetrates the epidermis less deeply than sunlamp
radiation, which is more commonly used to study UV
supression of delayed hypersensitivity. Incident dose is
12 W/m2 as measured by an actinometrically calibrated
Black Ray model J-225 shortwave UV monitor. Mice
anesthetized with nembutal injected i.p., 2 mg/kg in 0.5
ml saline, are fastened gently to the mask with tape for
the 30 - 40 minute exposure. The cumulative exposure, 6
J/cm2 (total 24 J per mouse), is applied from below the
mask to clipper-shaved skin on the lower abdomen.
Steroid treatment: Forty micrograms of TA or TAme,
dissolved at a concentration of 0.2% in absolute USP
ethànol, is spread over the UV-irradiated site and spread
with a microliter pipette (Rainin Pipetman P-20); the same
dosage being used for both compounds since they differ
only by a methyl group. (TA is used to compare results
with a glucocorticoid having undesirable systemic
effects).
DNCB Applications: Animals are shaved on the lower back
to expose about 4 cm2 skin. For experimental
sensitization, 20 microliters of a 2% solution of DNCB in
ethanol are applied to this shaved site. To ascertain the
degree of delayed hypersensitivity; four days after the
first sensitizing application, 5 microliters of DNCB
freshly dissolved to 2% in ethanol are applied to the
inner and outer aspects of each animal's left ear (total
200 micrograms). Ear thickness is measured just prior to
this challenge and at 24 hour intervals thereafter with
the aid of a dissecting microscope and a dial engineer's
caliper.
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Histology: Abdominal skin, fixed in formalin9 is embedded
in paraffin; microtome sections is stained with
hematoxylin-eosin.
Procedure: Male mice from a colony are caged in six
groups. Three of the groups of mice are exposed to 4
kJ/m2 254 nm light; others are shaved but not irradiated.
Immediately following ultraviolet exposure (day 0), mice
are painted with steroid or with vehicle (ethanol) at the
site of irradiation. This treatment is repeated 3 times
at approximately 24 hour intervals, then discontinued. On
- day 5, the lower back of each animal is shaved to expose
about 4 cm2 skin. Animals to be sensitized are painted at
this site with 1-chloro-2, 4-dinitrobenzene (DNCB) in
ethanol, and this treatment is repeated 24 hours later
(day 6). The test for delayed hypersensitivity response
is maximal four days after the first sensitizing tratment
(not shown). Day 9 is chosen to challenge for contact
sensitivity by application to the left ear of 1-chloro-2,-
4-dinitrobenzene in ethanol. Ear swelling is measurable
on day 10, but it peaks on day 11, 48 hours following
challenge.
The data for this experiment are summarized in Table I,
where the average for each group of mice is shown as the
ratio of left and right ear thicknesses. The average
thickness of the left and right ears for most groups was
0.24 mm on day 9. The sensitization causes the
1-chloro-2,4-dinitrobenzene treated skin to thicken and
become indurated. This response is most pronounced in the
controls, the TAme only, and the ultraviolet radiation +
3Q TAme groups.
Following challenge, ears swell according to group. The
swelling is accompanied by a mild erythema, and a visual
estimate of the extent of the erythema and swelling
correlates well with the caliper measurements: Ears of
sensitized controls swell to about twice their normal
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thickness. Ears of unsensitized mice do not swell. The
response measured here is therefore a consequence of
delayed hypersensitivity rather than primary irritation,
which, at higher 1-chloro-2,4-dinitrobenzene
concentrations than those used here, also produces ear
swelling. For instance, 1-chloro-2,4-dinitrobenzene
irritation is measurable in the controls.
The ultraviolet suppression of sensitization is readily
apparent when columns 3 and 4 of Table I are compared for
the sensitized control and ultraviolet radiation only
groups. Ultraviolet radiation on day O suppressed the
swelling for all but one animal in which the response was
delayed but about normal in magnitude. In sharp contrast,
mice treated with TAme either following ultraviolet
radiation or without ultraviolet radiation responded like
the control mice, showing normal delayed hypersensitivity.
This shows that treatment with TAme immediately following
ultraviolet irradiation prevents ultraviolet radiation
suppression of delayed hypersensitivity.
Mice that were treated with triamcinolone acetonide after
ultraviolet radiation like those treated with
triamcinolone acetonide alone on days 1-3, had ears 0.18
mm thick on day 9, about 0.06 mm thinner than those of
other mice. When the right ear is taken as the baseline,
the triamcinolone acetonide only group was strongly
suppressed for delayed hypersensitivity. The UV + TA
group exhibited a weak degree of delayed hypersensitivity
comparable to that in the UV only group. Mice treated
with triamcinolone acetonide 21-oic acid methyl ester but
not with UV, on the other hand, exhibited normal delayed
hypersensitivity. Triamcinolone acetonide gains access to
the circulation and thus may act at a distance. In this
experiment, triamcinolone acetonide could act at the
spleen or at the skin to prevent delayed hypersensitivity.
Testing for the effect of TAme on delayed hypersensitivity
at the site of sensitization is as follows: On day 0, the
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shaved back skin of C57B1/K65 mice are painted with
1-chloro-294-dinitrobenzene; with TAme; or with both
compounds. On day 6, the animals are tested for delayed
hypersensitivity by application of
1-chloro-2,4-dinitrobenzene or of TAme + DNCB. The data
obtained shows that TAme prevents delayed hypersensitivity
when applied to the back at the time of sensitization and
also prevents ear swelling when applied to the ear at the
time of challenge.
Some animals of the experiment shown in Table I are killed
on day 3 or 12 for histological examination of the
UV-exposed portion of their abdominal skin. The
evaluation is summarized in Table II. The skin of UV only
mice on day 3 contained a diffuse dermal infiltrate,
consisting of about 90% neutrophils and 10% monocytes and
macrophages. The inflammatory changes were not
accompanied by erythema and were in other ways
characteristic of UV-exposed mouse skin [Photobiol. 37, pp
623~631 (1983)]. The dermis of TAme-treated,
UV-irradiated mice was infiltrated by polymorphonuclear
leukocytes. Macroscopically, there was induration and
purulent crusting. The infiltrate persisted for at least
12 days in the TAme plus UV-treated mice, when it had
subsided in the ultraviolet radiation only group. There
was no apparent influx or mononuclear cells in the UV +
TAme infiltrate, suggesting that the cellular immune
system was unresponsive to the ultraviolet radiation
damaged skin. The other striking histological finding in
UV + TAme treated animals was the intense epidermal
3~ hyperplasia, accompanied by acanthosis and hyperkeratosis.
In many places, the epidermal thickness exceeded 20
nucleated cells. Normal mouse belly skin is 1 - 3
nucleated cells thick. This prolonged, exaggerated
response was not noted in the ultraviolet radiation only
group, or in the triamcinolone acetonide 21-oic acid
methyl ester only group, so it is the result of an
interaction of the two treatmentsO The triamcinolone
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acetonide 21-oic acid methyl ester only group, in
contrast, had a normal epidermis, accompanied by mild
follicular hyperplasia.
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Table I
Group ~er3Be ear thickne~s
(hundredths of a ~illimeter)
GROUP DAY left ~td rlght std l/r l-r
(t~t) (control)
Sensitized 924.2 1.324.4 1.4 0.99 -0.2
control 1042.6 3.626.9 1.5 1.58 15.6
1148.8 2.026.4 1.2 1.84 22.4
UV only 923.9 1.4 25 0.9 0.95 -1.0
1~32.0 1.328.2 1.5 1.13 3.~3
11 37 2.0 - 30 1.7 1.~3 7
TAme only 925.5 3.124.8 0.7 1.02 0.66
1041.3 2.223.6 2.3 1.74 17.6
114501 3.824.8 1.1 1.81 20.3
TA only 918.6 2.417.5 2.5 1.06 1.16
1033.3 2 22.5 2 1.48 10.8
1126.1 1.122.5 2.0 1.16 3.66
UY I TAme 924.7 1.324.5 1.2 1.00 0.2
1042.4 2.226.6 1.0 1.59 15.7
1145.2 2.7 25 0.9 1.81 20.2
UV ~ TA 917.6 1.816.4 1.7 1.07 1.2
10Z9.6 1.722.6 1.5 1.30 7
1131.4 2.121.4 1.5 1.46 10
Un~en~ltlzed 9 25.4 0.825.8 2.3 0.98 -0.4
control 1027.1 1.626.7 1.8 1.01 0.41
1127.5 0.727.6 1.4 o.gg _o.o
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TABLE II.
SUMMMARY OF HISTOLOGICAL DATA
DAY 3 DAY 12
S Ih~ UV TmTA TA Tm UV
UV UY UV
INFLAMMATCRY
CHANGES
Spongiosis ~+l + +~
Infiltrate
~!eutroph~lic
De~mal I + + I ++
Epidermal +~ ,+
Mononuclear ~ +
_.
HYPERPLASTIC
CHA~JCES
,~ Der~21 +
Epidermal
Hyperkeratosis ~ + +
Hypergranuloai~ + . ~+ +
Acanthosls ~++
~ . . .. ..
ATROPHIC
CHUNGES
Dermal ~+ I+
; 25 Epidermal ++
- .
~ NECROSIS +~ +~ ~
: :
KEY
S = shaved control
; ~m~ triamcinolone ~oetonide 21-oic bcid methyl ester
TA = tria~cinolone sc~onide
UV = uItr~Yiolet ~a~;~o~
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Example 2
Cream Formulation mg~
Triamcinolone acetonide
,21-oic acid methyl ester 0.5
Cetyl Esters Wax 20.0
Cetyl Stearyl Alcohol 100.0
Sorbitan Monostearate 25.0
Polysorbitan 60 20.0
Cetyl Dodecanol 100.0
Propylene Glycol 100.0
Benzyl Alcohol 10.0
Purified Water To make 19
_xample 3
Cream Formulation mg/g
Triamcinolone acetonide
21-oic acid methyl ester 2.0
Stearic Acid 60.0
Propylene Glycol Monostearate 100.0
Isopropyl myristate . 50.0
Propylene Glycol 100.0
Polyoxyethylene 20 Sorbitan Monopalmitate 60.0
Methylparaben 1.0
Butylparaben 4.0
Purified Water To make 19
Example 4
Gel Formulation
Triamcinolone acetonide
21-oic acid methyl ester 1.0
Propylene Glycol 50.0
Hydroxylppropyl Cellulose 20.0
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.'
, Alcohol To make 1g
.
~, Example 5
:
, Gel Formulation
, ,
Triamcinolone acetonide
21-oic acid methyl ester 2.0
Propylene Glycol 350.0
Alcohol 350.0
B Carbomer 940 20.0
Monoamylamine 2.0
Purified Water To make 19
Example 6
Lotion Formulation ~Q
Triamincinolone acetonide
21-oic acid methyl ester 1.0
Ethyl Alcohol 400.0
Polyethylene Glycol 400 300.0
Hydroxypropyl Cellulose 5.0
Propylene Glycol To make 19
This invention may be embodied in other forms or carried
out in other ways without departing form the spirit or
; essential characteristics thereof. The present disclosure
is therefore to be considered as in all respects
illustrative and not restrictive, the scope of the
invention being indicated by the appended Claims~ and all
changes which come within the meaning and range of
equivalency are intended to be embraced therein.
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