Note: Descriptions are shown in the official language in which they were submitted.
- 1~635~5 J&J 803
BACKGROU~D OF Tl'E I~ENTION
1. Field of the Invention
The invention relates to a gel formulation of
tretinoin (all trans-retinoic acid, or vitamin A acid).
More particularly, it relates to gel formulations of
tretinoin which are effective when tretinoin is present
in low concentrations. The product is particularly suit-
able for treating such dermatological disorders as acne
vulgaris.
2. ~escriPtion of the Prior Art
Acne vulgaris is a dermatological disorder ~rev
alent in adolescence. It appears most commonly on the
facè and trunk of the patient. mhe basic lesion of acne
is the comedo or 'blackhead" of a pilosebaceous follicle.
In its mildest form, only few comedones are present, but
in its severe form, a multiplicit.v of severe, persistent
c~ones are present. Permanent scarrina is frequently
; a consequence of the severe form of acne.
- ~cne occurs when there is a f-lling up of the
follicle with a rather tough keratinous materl~l. This
impaction of horny material is the whitehead and blac~head.
,: ~
As a result of bacterial growth in these horny impactions,
the fdlicle ruptures, initiating the inflammator~y pllase
` of the disease which takes the form of pustules, papules,
i 25 cysts and nodules.
A variety of methods have been used for the
- treatment of acne, including the use of peeling agents,
hormone therapy for female patients, antibacterial ther-
apy and general surgical sl;in planing.
- 2 -
.- ' . . .
.
1~63515 J&J 803
Although the s,stemic aflministration of hormones
an~ ~ntibacterials have been used with some success, until
recently none of the topical treatments have been parti-
cularly effective
S Vitamin A acid (tretinoin) has been applie~.
topically, (Beer, Von P,, "Untersuchungen uber die Wirkung
der Vitamin A-Saure", Dermatologica, 124: 192-195, March,
.. .
1962 and Stuttgen, G., "Zur Lakal~ehandlung von Keratosen
mit Vitamin A-Saure~, Dermatologica, 124: 65-80, February,
1962) in those hyperkeratotic disorders which are respon-
sive to hi~h oral doses o~ Vitamin A. Among those treated
..
by Beer and Stuttgen were patients with acne; h~wever,
; these investigators reported no effective results with
., Vitamin A acid on acne. 8ritish Patent 906,000 disclosed
a cosmetic preparation containing Vitamin A acid for the
regulation of the corni.~ication processes of human skin,
but no mention is made of the use of such prepa.ration
l for the treatment of acne.
;~ Recently, however, it has been demonstrated
1 20 that prolonged topical application of Vitamin A acid is
. ~ :
effective in the treatment of acne (Kligman, A. M., "Topi-
cal Vitamin A acid in Acne Vulgaris", Arch Derm., 99:
469-476 April 1969). Kligman utilizes a composition in
:
which Vitamin A acid is dispersed in a water-mi~cible
(substantially oil- and fat-free) liqui~ sarrier having
high solvating action. The topical application of this
Vitamin A acid composition causes irritation of the skin
. in the treated areas. ~ee U.S, Patent No. 3,729,568
issued April 24, 1973 to Albert M. Kligman.
More recently, it has been found that acne can
.:
- 3 -
..
.. ..
-
J&J 803
1()635~S
be effectively treated with a cream formulation contain-
inq tretinoin, or Vitamin A acid. A cream formulation is
generally more acceptable to patients than the liquid
: vehicle from the point of view of aesthetics and ease of
; S application. Moreover, another important advantage of
the cream form of tretinoin is that it re~.uces the side
effects normally associate~. with the topical applLcation
of tretinoin. These side effects, erythema, stinging
~; and itching, may be sufficient to cause the patient to
discontinue the application of tretinoin before it can
~" .
.~ be fully effective upon the acne.
Notwithstanding these advantages, cream formu-
lations containing tretinoin possess some un~esirable
;~ attributes. One of these un~esirable attributes is the
.. 15 difficulty in unifor~.ly applyin~ sufficient amounts of
the active ingredient to the lesion of acne to be effec-
tive and at the same tLme avoid local excesses, surface
spread or pooling into facial creases, the nasolabial
.1
folds and corners of the mouth where the cream may cause
erythema. stinging and. itching. Another undesirable attri-
~; bute of cream formulations of tretinoin is their relative
. ~ instability, often necessitating the use of refrigeration
or antimicrobial preservatives to prevent microbiological
contamination, as well as special additives to maintain
physical stability.
It is, therefore, an object of the present in-
vention to provide a vehicle for tretinoin rom which
~-~` tretinoin is readily available for absorption by the skin.
It is a further object to provide an acne treat-
~-~` 30 ment cQmposition which is effective at low concentrations
. .
- 4 -
,
. ..
,, , , ~ :
1~163515
of tretinoin, so as to avoid side effects associated with the
use of acne treatment formulations having high concentrations
of tretinoin.
It is another object of the invention to provide gel
formulations of tretinoin which possess good physical and
chemical stability without refrigeration and without special
additives or antimicrobial preservatives.
; It is still another object to provide gel formulations
having such other desirable ~ualities as being cosmetically
e~egant, having a perceptible drying effect or at least
~ ma~ing no contributions to the oiliness of acne patients'
; ~ skin, and allowing accurate applicatio~ of effective amounts of
,
tretinoin to the acne lesion.
These and other objects of the present invention will
be more fully understood in the light of the specific examples
and description set forth hereinafter.
SUMMARY OF T~E INVENTION
Thus, in accordance with the present teachings, a gel
` formulation for topical application is provided which comprises
from about 0.001% to about 0.025% by weight of tretinoin
, .
~ together with a vehicle system which comprises essentially
,', !, of from about 84% to about 99% by wéight of an organic solvent
; selected from the group consisting of ethanol, isopropanol,
` propylene glycol and mixtures thereof with the remainder of
the system comprising an effective amount of a pharmaceutically
acceptable antioxidant soluble in the organic solvent and an
effective amount of a pharmaceutically acceptable gelling
agent solvated in the organic solvent.
In accordance with a preferred embodiment of the
~ . .
.. ..
present teachings, a gel formulation for topical treatment of
acne vulgaris is provided which consists essentially of from `
about 0.005~ to about 0.025% by weight of tretinoin, from about
5 -
-,'''''. ' .; '
:. .. , , . .. . .. . : . ~ ~ . . .
~0635~5
-
84 to about 99~ by weight of an organic solvent selected fromthe group consisting of ethanol, isopropanol, propylene glycol
and mixtures thereof, from about 0.025 to about 0.075~ by ~;
weight of an antioxidant selected from the group consisting of -
: butylated hydroxytoluene, butylated hydroxyanisole, ascorbic
acid, propyl gallate, and ~-tocopherol, and from about 0.5 to
about 3.05% of a gelling agent which is selected from the group
. consisting of hydroxy-ethylcellulose, hydroxypropyl cellulose,
and an acidic carboxy polymer which is neutralized with an
;i 10 organic amine selected from the group consisting of ~-alanine .
and diisopropanol amine. .
;:,
s In general, my invention comprises a gel formulation
.,.,~,
;~ containing a therapeutically effective amount of tretinoin :~
:;~ (all trans-vitamin A acid; retinoic acid); an organic solvent
. for the tretinoin selected from the group consisting of ethanol
i (absolute or 95~ by volume ethyl alcohol), isopropanol, propy-
. .
.~ lene glycol and combinations thereof; an antioxidant selected .
.
.:j; from the group consisting of butylated hydroxytoluene (BHT), ~ :
.; butylated hydroxyanisole (BHA), ascorbic acid (Vitamin C), propyl
~ . ,,,
' 20 gallate, and ~-tocopherol (Vitamin E); and a gelling agent
~;f' selected from the group consisting of (1) an acidic carboxy
~ polymer, such as those available under the trade names Carbopol
;, ; 934 and Carbopol 940, nèutralized with an organic amine,
~;'' . '~ '
: ' ~ .
;:
., .
~,. . ,,~
'~' `' ''
','' .
.~:. 30
,~ ' `,'
` - 5a -
~, :
B
.. i
-
J&J ~03
1~)63515
(2) hydroxyethylcellulose and (3) hydroxypropyl cellulose.
other conventionally used ingredients may be aclded ! if
desired, such as dyes, nerfumes, sunscreens, antimicrobials
and topical corticosteroids.
A general formula encompassina tretinoin gel
- formulations within the scope of my invention is set forth
below. (Unless otherwise indicated herein, all amounts
are in weight percent.)
General Gel Formula in ~ w/w
Tretinoin . . . . . . . . . . . . . . . 0.001 - n. 500
Antioxidant(s). . . . . . . . . . . . . 0,010 ~ 0.100
Gelling agent(s). . . . . . . . . . . . 0.5 -- 5.000
Dye(s) and/or perfume oil(s). , . . . . O.O - O.750
Sunscreen(s). . . . . . . . . . . . . . 0,0 - 2.500
Topical corticosteroid. . . . . . . . , 0,0 - 2.000
Antimicroblal(s). . . . . . . . . . . . 0.0 - 3,000
Organic solvent . . . . . . . . . . . q.s. to 100,000
It has been unexpectedly found that tretinoin
gel formulations of the present invention are more effec-
tive in the treatment of acne conditions than tretinoin
cream formulations of similar tretinoin concentration.
It also has been found that cream formulations havina low
: concentrations of tretinoin may have little or no efficacy
a~ainst acne when compared to the same vehicle with no
tretinoin, whereas, gel formulations having the same low
concentrations of tretinoin exhibit high efficacy against
acne, the efficacy le~el often being almost the same as
exhibited by gels with higher tretinoin concentrations.
This is a surprising and unexpected discovery and the
reason for i. is not fully understood. However, without
-- 6 -
J~J 80~
63~5
the intention of being bound by it, the following explan-
ation is provided.
It is known in the healing art that solid drugs
intended ror absorption by the skin are not absorbed
;~ 5 directly but must be dissolvefl hy a vehicle or by skin
fluids. It is also well known that drugs in the micro-
fine form are more readily available for absorption.
Upon evaporation of the solvent carrier drugs are depos-
ited on the skin in different forms, such as, for example
large crystals or a film. Tretinoin is not soluble in
common vehicles such as, for example, water. It is
; soluble in several vehicles if the vehicles are made
alkaline. However, in alkaline solutions tretinoin is
very unstable. The only vehicles in which tretinoin is
both soluble and at the same time stable are the organic
solvents. Most of these organic solvents quickly evapor-
ate and leave behind the large crystalline deposit of
tretinoin. It is then u~ to the skin fluids to solvate
the crystalline tretinoin for absorption by the skin.
The rate of absorption mainly depends on the solubility
of tretinoin in skin fluids. Obviously, the larger the
crystals, the lower their solubility in ski.n fluids and
the slower their absorption through the skin. It is be-
lieved that the tretinoin is de~osited on the skin from
~5 the gel formulations of the present invention in a micro-
fine form, thus promoting the penetration of tretinoin
; through the skin by virtue of its relative ease of solu-
bility in skin fluids as compared to that of a larqer
crystal form. This would enable a lower strength treti-
noin gel to deliver subcutaneously an effective quantity
~:
~ 7 -
:~ 1063SlS J&J 803
', .
- of the tretinoin that is equivalent to that delivered
-~ b~ a preparation of higher strength from which the treti-
noin is not deposited on the skin in a micro-fine form.
Tretinoin gel formulations in accordance with
the present invention have been found to have good chemi-
cal and physical stability for at least 18 months at
.... .
100F.
.
;- DETAILED DESCRIPTION OF THE INYENTION
.
A tretinoin gel formulation of the present in-
vention, in yeneral, comprises from about 0.001 weight
% to about 0.500 weight % of tretinoin; from about 0.01
weight % to about 0.10 weight ~ of an antioxidant selected
; ~rom the group consisting of butylated hydroxytoluene
; ~BHI3), butylated hydroxyanisole (8HA), ascorbic acid
' 15 (Vitamin C), propyl gallate and d-tocopherol (Vitamin E);
.,
from about 0.5 to about 5.0 weight ~3 of a gelling agent
selècted from the group consisting of hydroxyethylcellulose,
',!, hydroxypropyl cellulose, and an acidic carboxy polymer
; such as the ones available under the trade name Carbopol
20 934 and Carbopol 940, which are neutralized with an or-
ganic amine, such as, ~33-alanine and diisopropanol amine;
and from about 84 to 99 weight % of a solvent selected
from the group consisting of ethanol, isopropanol, pro-
pylene glycol and combinations thereof. Optionally,
. 25 minor amounts of such agents as dyes, perfumes, and
sunscreens which are commonly used in topical pharmaceu-
tical compositions may be added. Furthermore, such
topically active medicaments as the anti-inflammatory
corticosteroids and antimicrobials may also be incorporated.
.
.~
~,. ,'
J&J 803
~ ~063~S
; While the tretinoin gel composi~ions of the
~' present invention have been described herein primarily
as suitable for use in treating acne, it will be under-
stood that these compositions are effective generally
for treating dermatological conditions where tretinoin
is indicated. The concentration of tretinoin in the
gel compositions of the present invention may be as
low as 0.001 or 0.0025 weight ~. The preferred range
for the concentration of tretinoin in the gel formulation
i8 from about 0.005 to about 0.05 weight ~, from about
0.01 to about 0.025 weight % being particularly pre~-
ferred. Besides being effective and safe on application
to the ~kin, concentrations within these preferred ranges
offer ~ubstantial costs savin~s.
The antioxidants which may be used in the com
r!, ~
positions of the present invention are those which are
soluble in ethanol, isopropyl alcohol, propylene glycol
and mixtures thereo~; are non reactive to the gelling
t~ agents, tretinoin, and other components o~ the formu-
20~ lat~lons; and are safe for human topical use. I prefer
to empioy from about 0.025 to about 0.075 weight % of an anti-
oxidant~selected from the ~roup consistin~ of butylated
hydroxytoluene (~HT), butylated hyd.roxyanisole (BP~),
ascorbic acid (Vitamin C), propyl gallate, and d-tocopherol
25~ (Vitamin E), although other antioxidants may be used
provided they satisfy the above criteria.
The gelling agents employed in the compositions
of the present invention are those capable of being sol-
vated or those which can be ~.odified to be capable of
` i.l ~
i~ 30 being solvated in the solvents utilized in these composi--
. g _
,.`~.:
: .
. . , . : .
~ ~~~ J~J 803
1063S~S
tions and which are commonly used in pharmaceutical pre- ~
... . . . .
parations for topical applications. ~7hile there are
numerous pharmaceutically acceptable gelling agents for
-~ topical use, they are either only marginally acceptable
i 5 such as, for example, ethyl cellulose or they are not
; suitable for the purposes of the present invention such
as, for example, methylcellulose and the salts and deri-
vatives of alginic acid because they do not form a satis
' .
factory gel. I prefer to use amounts of from about 0.5
to about 3.0 weight ~ of a gellin~ agent selected from
` the group consistina of hydroxyethylcellulose,
havina a viscosity of fro~. about 3,500 to about 50,000
. ~, .
~, cps. when a 2 percent aqueous solution is measured at
20C using Brookfield Viscometer, Model LVF, with Spindle
. ;i ~
~30 at 30 ~PM., available under the trademark ~atrosol
from ~ercule~ Pow~.er Co. Inc., l~ilmington, Delaware;
.;~ .
hvdroxypropyl cellulose havin~ a molecular wei~ht from
about 100,000 to about 1,000,000, available unAer the
.,',,,! .
' trademark Klucel from Yercules Powder Co. Inc.; an acidic
': 'I ,
,~
20~ carboxy polymer, such as those available under the trade
mark Carbopol 934 and Ci~rbopol 940 from B. F. Goodrich
.~,. . .
~; Chemical Co., Cleveland, Ohio, neutralized with an oraanic
amine, such as ~-alanine and diisoDroPanol amine. ~he
neutralization of the acidic carboxy polymer with an or-
,
ganic amine enables the acidic carboxy polymer to be
solvated by the organic solvent utilized in practicing
f the invention. rhile partial neutralization is suf~icient
to affect solvation, preferably the amount of or~anic
; amine used to neutralize the acidic carboxy polymer will
"., : . I
~;~ 30 generally be approximately eouivalent by moles to the acidic
.~, . ...
.
.~ ,:
1 0 - .
,. , :
r~
1(~63515 J6J 803
,
carboxy polymer present in the formulation, and may even
be in excess of the molar equivalent amount~
While many organic solvents could be used to
s solubilize tretinoin, ethanol, isoproparol, propylene
glycol nd mixtures thereof are particularly preferred
for reasons related to toxicity, irritation and quality
i~ ; of product made therewith. As indicated previously, the
solvents form the largest part by weight of the composi-
tions of the present invention and are generally present
in amounts of from about 84 weight % to about 99 weight ~.
The compositions of the invention may be pre-
pared by various methods practiced and well known in the
art. In general, the formula amount of antioxidant is
dissolved in the solvent, followed by the addition and
subsequent solvation of the formula amount of tretinoin.
The formula amount of gèlling agent is added in small
I ~; qu-ntities under low shear agitation until solvation
occurs and the mixture gels. When an acidic carboxy poly-
mer such as Carbopol 934 or Carbopol 940 i8 used as the
20 ~ gelling agent, the neutralization with an organic amine
is accomplished by adding the desired amount o~ an organic
amine after the last portion of the acidic carbo~y poly-
mer is -dded to the mixture and sufficient amount of time
allowed for its dispersion. ~ow shear agitation continues
~25;~ until sol-vation occurs and the gel is formed.
The procedure preferably should take place
at room temperature, i.e. at about 25C. If desired,
additional materials, such as dyes, perfumes, sunscreens,
and corticosteroids may be incorporated into the formula-
tions by adding and mixing them with the solvent prior
to the addition of the gelling agent.
: ~
-- 11 --
::
635~5
. J&J 803
.~
. . .
The following examples are presented to further
illustrate compositions of the invention withollt thereby
. limiting the scope thereof.
, ~
.~: EXAMPLE 1
% w/w
S Tretinoin 0,001
Butylated hydroxytoluene 0.01
~:, Hydroxypropyl cellulose 2,0
Propylene glycol a.s. to 100.0
~:~"
i EXAMPLE 2 ~w/w
Tretinoin 0,S
Butylated ~!ydroxyanisole 0.10
Hydroxypropyl cellulose 5.00
::,
Propylene glycol q. 9. to 100,0
. . :, .. .
EXAMPLE 3
, ~: ~ w/w
. : ~15 ~ Tretinoin 0,OS
; ~
~ tocopherol 0~05
~; ,,
~ : Hydroxyethylcellulose 2.5
,1 .~
: Ethanol q.s. to 100.0
EXAMPLE 4 ~ w/w
Tretinoin 0 005
utylated hydroxytoluene O OS
: Carbopol 940 3,0
alanine 3,0
Ethanol q.s. to 100.0
1:: ' ,
. ~ - 12 -
:
:
~ -- J&J 803 `
1063515
EXAMPLE 5
W/W
Tretinoin 0.025
8utylated hydroxytoluene 0.05
Hydroxypropyl cellulose 3~0 -
S Ethanol q.s. to 100.0
EXAMPLE 6
~ W/W
Tretinoin 0.025
Butylated hydroxytoluene 0.05
Carbopol 940 3,00
Diisopropanol amine 3,00
Isopropanol q~s. to 100.0
EXAYPLE 7
~ w/w
Tretinoin 0.1
Butyla~ed ~ydroxyanisole 0,05
Hydroxyethylcellulose 4.0
Perfume Oil 0.25
~ye 0.25
Ethanol - Isopropanol
. 50/50 mixture by weight q.s. to 100.0
EXAMPLE 8
~ w/w
Tretinoin O.lS
d-tocopherol 0.05
Hydroxypropyl cellulose 0.5
Hydrocortisone 0.5
Ethanol - Propylene glycol
50/50 mixture by weight q.s. to 100.0
- 13 -
.,. , , .~ .
: . . ~ . - . ~ . .. .
~,
: 1~63SlS J&J ~03
EXA~PLE 9
% w/w
Tretinoin 0.05
Butylated hydroxytoluene 0.05
Hydroxypropyl cellulose 3~00
Propylene glycol/isopropanol
50/50 mixture by ~eight q.s. to lO0.0
. .
EXAMPLE 1 0
' % W/W
Tretinoin o,oS
Butylated hydroxytoluene 0,OS
Hydroxypropyl cellulose 3.00
Propylene glycol/ethanol
50/50 mixture by weight q,s. to 100.0
EXAMPLE 1i
% w/w
Tretinoin O.OS
Butylated hydroxytoluene 0.05
Hydroxypropyl cellulose 3,00
Ethanol/Lsopropanol
S0/50 mixture by weight q. 8. to lO0.0
EXAMPLE 12
- ~ w/w
Tretinoin O.OS
Butylated hydroxytoluene O.OS
Carbopol 934 1.5
~-alanine 1.5
Propylene glycol/ethanol
50/50 mixture by weight q.s. to 100Ø
EXAMPLE 13
% w/w
Tretinoin 0,02
Butylated Hydroxytoluene 0,05
Carbopol 934 1.5
Diisopropanol amine 1.5
Propylene glycol/isopropanol
S0/50 mixture by weight q.s. to 100 0
1063515
l vo ~ 1 ~
~ o U : ~ ~ ~ ~ V U ~ U U
., ~ ~ ~ C ~ ~ o ~ ~ , o o .
~ ~ + ''~
~;`' ~
1~ ~ , . 1 S
~ 10 ~ 3 5 1S J~J 803
In use, the tretinoin gel composition of the
present invention is generally applied daily until the
desired relief is obtained. The number of daily appli-
cations depends on the severity of the acne condition
that the patient has, and may vary between one and three
applications. Normally the treatment requires at least
8-12 wee~s. However, acne in its mildest form i,e.,
only a small nu~ber of comedones, may be substantially
cleared in four to six weeks. More seYere cases may
require two to three months or longer.
It has been observed in use that the gel
formulations of the present invention were easy to
apply, remaining on the areas that were treated with
little tendency to run and pool or to produce dis-
turbing irritation at the angles of the mouth or
nasolabial fold~. Furthermore, and quite unexpectedly,
only momentary stinging rather than prolonged discom-
fort, following application, was generally experienced
as compared to previously used dosage forms.
ClLnical studies have been conducted by
i:
different investigators on the relative effectiveness
of the gel formulations of the present invention con-
tainLng tretinoin in combination with butylated hydroxy-
toluene, hydroxypropyl cellulose and ethanol in com-
parison to cream formulations containing tretinoin in
combination with stearic acid, isopropyl myristate,
polyoxy 40 stearate, stearyl alcohol, xanthan gum,
sorbic acid, and butylated hydroxytoluene. The studies
were double-blind, parallel clinical studies comparing
gels and creams having the same concentrations of treti-
16 -
3~1S
J~J 803
noin, against each other and against their respective con-
trol vehicle or placebo without tretinoin~ Tables I through
III summarize the combined results of these studies~
Table I compares overall effectiveness data of
S the identified cream and gel formulations on the treatment
of acne whether it be in the form of camedones, pustules,
papules, cysts or nodules. Table II compares effectiveness
data of creams and gels in reducing comedones. Table III
compares effecti~eness of creams and gels in reducing papules.
It i~ to be noted that the result should be interpreted in
an order-of-magnitude sense and not an absolute sense. The
reason for this is the variables affecting the outcome of
the result, such as, different in~estigators, different
groups of patients, time, and geographic or climatic factors.
TABLE I
Percent of Patients Having a Good
or Excellent Clinical Evaluation
Tretinoin Number of Patients* Percent
Strength Cream Gel Cream Gel
.000% 121 66 28 39
, .010% 59 41 31 ~3
.025% 65 67 46 83
.050% 125 64 62 80
.100% 63 --** 70 --**
TABLE II
Percent Reduction of Comedones
Tretinoin Number of Patients* Percent
Strength Cream Gel Cream Gel
.000% 122 60 35 48
.010% 62 38 44 67
.025~ 67 65 44 77
.050% 126 62 61 7
.100~ 63 ~ s4 -_~
- 17 -
~ J~J ~03
1()63S15
TAB~E III
Percent Reduction of Papules
j TretinoinNumber of Patients* Percent
Strength Cream Gel Cream Gel
.000% 122 60 23 34
.010~ 62 38 13 62
.025% 67 65 52 60
.050% 126 62 53 62
.100~ 63 --** 64 --**
Referring to Tables I, II and III, it is apparent
that there is a higher percent improvement in acne con-
ditions when treating patients with a zero strength or
placebo gel than with a zero strength or placebo cream.
The reason for this difference: no doubt, is in the clean-
sing or disinfecting nature of the carriers: while both
carriers effect reduction of acne conditions due to the
cleansing capabilities of some of their components, the
gel carrier, having an alcohol, propylene glycol or mix-
tures of alcohols and propylene glycol therein, exhibit
i -
¦~ 20 higher antibacterial or cleansing properties.
~ `~
*Some of the patients in the studies had only comedones and
some had only papules, although most patients had both.
~`~ Therefore, Table I, which summarizes the investiqators'
evaluation of overall effectiveness, would be expected
to show somewhat greater total number of patients than
either of Tables II and III, and does so with respect to
the "gel" patients. However, one of the investigators,
omitted overall evaluation for the "cream" patients,
providing only separate evaluation with respect to
~ ~ comedonesand pustules. Hence the lower number of total
.4 ~ patients in the cream column in Table I as compared to
Tables II and III.
**No test was run.
.
~ - 18 -
,
.~ .
1 .
~ - 1~3~1S J&J 803
.,
It is also apparent from Tables I, II an~ III
: thiat the gel formulations of various tretinoin concen-
tration effect unexpectedly greater improvement in reducing
acne conditions than do the cream formulations of the same
tretinoin concentration. In fact, a ten fold increase
.
,~ in tretinoin concentration is necessary in the cream for-
' mulatLons to achieve the effect of the 0.01% gel formu-
`,~ Iation~ both in the reduction of comedones and papules and
in overall clinical improvement. As explained previously
herein, this is thought to be due to the availability of
tretinoin in micro-fine forms for absorption through the
: skin.
'~ .
As will be obvious to those skilled in the
art, many variations and modifications may be made with-
1`~
,~ 15 out departing from the spirit and scope of the invention.
~' ' .
l ~.
,, .
~,
, ~ .. .
"~
~,,
,~
, :
: ~
: .
,::
: .
, ,i , : .- ...... .: ., . , : : . , .. , .. . . - ,., . .. , .. .. . . , ,.. : . , ~ .. .. . - ..
.. .... . ... .. -.. .. ... .: -. . , . . , . ~ . . . ... -. . ~ . . . .. . .....
