U.S. patent application number 15/456933 was filed with the patent office on 2017-06-29 for method for the treatment of acne using pharmaceutical compositions comprising 0.3% by weight of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid.
The applicant listed for this patent is GALDERMA RESEARCH & DEVELOPMENT. Invention is credited to Janusz CZERNIELEWSKI, Michael GRAEBER.
Application Number | 20170181991 15/456933 |
Document ID | / |
Family ID | 27806678 |
Filed Date | 2017-06-29 |
United States Patent
Application |
20170181991 |
Kind Code |
A1 |
GRAEBER; Michael ; et
al. |
June 29, 2017 |
METHOD FOR THE TREATMENT OF ACNE USING PHARMACEUTICAL COMPOSITIONS
COMPRISING 0.3% BY WEIGHT OF
6-[3-(1-ADAMANTYL)-4-METHOXYPHENYL]-2-NAPHTHOIC ACID
Abstract
Dermatological disorders having an inflammatory or proliferative
component, notably common acne, are treated with topically
applicable pharmaceutical compositions containing about 0.3% by
weight of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid
(adapalene) or salt thereof, formulated into pharmaceutically
acceptable media therefor, advantageously formulated into topically
applicable gels, preferably aqueous gels, creams, lotions or
solutions.
Inventors: |
GRAEBER; Michael;
(Lawrenceville, NJ) ; CZERNIELEWSKI; Janusz;
(Biot, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GALDERMA RESEARCH & DEVELOPMENT |
Biot |
|
FR |
|
|
Family ID: |
27806678 |
Appl. No.: |
15/456933 |
Filed: |
March 13, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14524602 |
Oct 27, 2014 |
9622994 |
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15456933 |
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|
12957882 |
Dec 1, 2010 |
8921423 |
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|
14524602 |
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|
12772861 |
May 3, 2010 |
7868044 |
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12957882 |
|
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|
11494693 |
Jul 28, 2006 |
7737181 |
|
|
12772861 |
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10937612 |
Sep 10, 2004 |
7579377 |
|
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11494693 |
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PCT/EP2003/003246 |
Mar 12, 2003 |
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10937612 |
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60370223 |
Apr 8, 2002 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/08 20130101; A61K
47/22 20130101; A61K 47/26 20130101; A61K 47/10 20130101; C07C
2603/74 20170501; A61Q 19/007 20130101; A61K 8/36 20130101; A61K
31/203 20130101; A61K 31/07 20130101; A61P 17/02 20180101; A61P
17/12 20180101; A61K 47/06 20130101; A61K 9/0014 20130101; A61Q
17/04 20130101; A61K 47/183 20130101; A61P 17/10 20180101; A61K
47/14 20130101; A61K 47/6903 20170801; A61K 31/192 20130101; A61P
17/00 20180101; A61K 8/362 20130101; A61K 47/32 20130101; A61Q
19/008 20130101; A61K 47/34 20130101; A61K 47/02 20130101; Y10S
514/859 20130101; A61K 9/06 20130101; A61P 9/06 20180101; A61K
8/368 20130101; A61P 17/06 20180101; A61P 17/18 20180101 |
International
Class: |
A61K 31/192 20060101
A61K031/192; A61K 9/06 20060101 A61K009/06; A61K 9/08 20060101
A61K009/08; A61K 9/00 20060101 A61K009/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 12, 2002 |
FR |
0203070 |
Claims
1. A method for treating common acne, comedones, polymorphous acne,
nodulocystic acne, acne conglobata, or secondary acne afflicting
the skin of an individual in need of such treatment, comprising
topically administering to said individual a topically applicable
pharmaceutical aqueous gel composition consisting essentially of an
anti-acne effective amount of
6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid (adapalene) of
0.3% by weight thereof, formulated into a topically applicable,
pharmaceutically acceptable aqueous gel medium therefor, wherein
said aqueous gel medium comprises at least one ingredient selected
from the group consisting of carbomers, polymeric emulsifying
agents, polysaccharidic biopolymers, gums, alginates, modified
celluloses, starch derived products, a mix of polysorbate 80 and
isohexadecane and acrylamide/sodium acryloyldimethyltaurate, and
mixtures thereof.
Description
CROSS-REFERENCE TO EARLIER APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 14/524,602, filed Oct. 27, 2014, now allowed, which is a
continuation of U.S. application Ser. No. 12/957,882, filed Dec. 1,
2010, now U.S. Pat. No. 8,921,423, which is a continuation of U.S.
application Ser. No. 12/772,861 filed May 3, 2010, now U.S. Pat.
No. 7,868,044, which is a division of U.S. application Ser. No.
11/494,693, filed Jul. 28, 2006, now U.S. Pat. No. 7,737,181, which
is a continuation-in-part of U.S. application Ser. No. 10/937,612,
filed Sep. 10, 2004, now U.S. Pat. No. 7,579,377, which is a
continuation of PCT/EP03/03246 filed Mar. 12, 2003 and designating
the United States (published in English on Sep. 18, 2003 as WO
03/075908 A1), claiming benefit of U.S. Provisional Application No.
60/370,223, filed Apr. 8, 2002, and also claiming foreign priority
under 35 U.S.C. .sctn.119 of Application No. 02/03070 filed in
France on Mar. 12, 2002, each of the above applications being
hereby expressly incorporated by reference in its entirety and each
being assigned to the assignee hereof.
BACKGROUND OF THE INVENTION
[0002] Technical Field of the Invention
[0003] The present invention relates to novel pharmaceutical
compositions comprising about 0.3% by weight of
6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, the chemical
structure of which is as follows:
##STR00001##
[0004] in particular dermatological compositions, for the treatment
of dermatological ailments, disorders, conditions or afflictions
having an inflammatory or proliferative component.
[0005] Description of Background and/or Related and/or Prior
Art
[0006] 6-[3-(1-Adamantyl)-4-methoxyphenyl]-2-naphthoic acid
(hereinafter referred to as adapalene) is a retinoid derived from
naphthoic acid, having anti-inflammatory properties. This molecule
has been the subject of development for the topical treatment of
common acne and dermatoses sensitive to retinoids.
[0007] Adapalene is described in EP-0199636, and a process for
synthesizing same is described in EP-0358574, both assigned to the
assignee hereof.
[0008] The assignee hereof markets adapalene formulated at a weight
concentration of 0.1% in the form of an alcoholic lotion, an
aqueous gel and a cream. These compositions are suited for the
treatment of acne.
SUMMARY OF THE INVENTION
[0009] Novel pharmaceutical compositions have now been developed
containing adapalene at a weight concentration on the order of or
about 0.3%, formulated into pharmaceutically acceptable media
therefor, suited for the treatment (regime or regimen) of
dermatological ailments, conditions or afflictions having an
inflammatory or proliferative component. Specifically, it has now
surprisingly been shown that, in addition to exhibiting better
therapeutic efficacy compared to known compositions, the
compositions according to the invention exhibit good tolerance,
comparable to those of the known compositions with a lower
concentration of active principle.
[0010] The results regarding tolerance observed in trials relating
to photo-damaged skin (indication "photodamage"), obtained on
individuals on average 65 years old, could not be exploited in the
context of the present invention. Specifically, as regards use of
adapalene on young individuals (in particular regarding acne with
populations of teenagers or young adults), the skin exhibits very
different physiopathological characteristics (presence of many
lesions, in particular inflammatory lesions, modifying skin
permeability, hypercornification of the follicular channel, immuno
response, bacterial colonization of the skin (P. acnes), sebaceous
hyperplasia with hyperseborrhea).
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIGS. 1-3 are graphs illustrating the effectiveness of the
dermatological compositions of the present invention versus
comparative compositions and controls.
DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED
EMBODIMENTS OF THE INVENTION
[0012] Thus, the present invention features pharmaceutical
compositions comprising about 0.3% by weight of adapalene
(6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid) relative to
the total weight of the composition, or salts thereof, preferably
in the form of aqueous gels. Such compositions are suited for the
treatment (regime or regimen) of dermatological ailments, disorders
or conditions having an inflammatory or proliferative
component.
[0013] The term "adapalene salts" is intended to mean the salts
formed with a pharmaceutically acceptable base, in particular
organic bases such as sodium hydroxide, potassium hydroxide and
aqueous ammonia, or organic bases such as lysine, arginine or
N-methylglucamine.
[0014] The term "adapalene salts" is also intended to mean the
salts formed with a pharmaceutically acceptable base, in particular
in organic bases such as sodium hydroxide, potassium hydroxide and
aqueous ammonia, or organic bases such as lysine, arginine or
N-methylglucamine.
[0015] The term "adapalene salts" is also intended to mean the
salts formed with fatty amines such as dioctylamine and
stearylamine.
[0016] The pharmaceutical compositions according to the invention
are preferably applied topically.
[0017] Topically, the pharmaceutical compositions according to the
invention are more particularly suited for treatment of the skin
and the mucous membranes, and may be in the form of ointments,
creams, milks, pomades, powders, impregnated pads, solutions, gels,
sprays, lotions or suspensions. They may also be in the form of
suspensions of microspheres or nanospheres or of lipid or polymeric
vesicles, or of polymeric patches and hydrogels for controlled
release. These compositions for topical application may be in
anhydrous form, in aqueous form or in the form of an emulsion.
[0018] In a preferred embodiment of the invention, the
pharmaceutical compositions according to the invention are in the
form of a gel, preferably aqueous, a cream, a lotion or a
solution.
[0019] Accordingly, this invention also features pharmaceutical
compositions comprising about 0.3% by weight of adapalene
(6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid) relative to
the total weight of the composition, or salt thereof, formulated as
creams.
[0020] This invention also features pharmaceutical compositions
comprising about 0.3% by weight of adapalene
(6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid) relative to
the total weight of the composition, or salt thereof, formulated as
lotions.
[0021] By "lotion" is intended a fluid emulsion of water-in-oil or
oil-in-water type. Preferably, the lotions according to the
invention do not comprise any alcohol, but may comprise at least
one glycol; consequently, they are not alcoholic, but preferably
glycolic.
[0022] Another embodiment of the invention features pharmaceutical
compositions comprising about 0.3% by weight of adapalene
(6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid) relative to
the total weight of the composition, or salt thereof, formulated as
solutions or spray solutions.
[0023] By "solution" is intended a liquid composition at ambient
temperature (20-30.degree.) and comprising a single phase. Such
compositions are preferably alcoholic or may comprise at least one
glycol or lipophilic component.
[0024] In particular, the pharmaceutical composition may be an
aqueous gel comprising at least one ingredient selected from among:
[0025] Carbomers, for example Carbopol 980 NF marketed by NOVEON;
[0026] polymeric emulsifying agents such as PEMULEN (crosspolymers
acrylates/C10-30 alkyl acrylates, for example, PEMULEN TR1, PEMULEN
TR2, CARBOPOL 1342, CARBOPOL 1382, Carbopol 981 or carbopol Ultrez
marketed by the company NOVEON); [0027] polysaccharidic biopolymers
such as xanthan gum (for example, Keltrol T and Xantural 180
marketed by the company Kelco); [0028] gums such as caroub gum,
guar gum; [0029] alginates; [0030] modified celluloses such as
hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose (for
example Natrosol HHX 250 marketed by the company Aqualon),
hydroxypropylmethylcellulose and carboxymethylcellulose; [0031]
starch derived products such as Structure XL marketed by the
company National Starch; [0032] a mix of polysorbate 80 and
isohexadecane and acrylamide/sodium acryloyldimethyltaurate (such
as Simulgel 600); and [0033] humectants or pro-penetrant agents
such as propylene glycol or equivalent, for example, glycerin and
sorbitol, for example, alkylene and polyalkylene glycols (C1 to CE)
such as ethylene glycol, polyethylene glycol (2 to 20 monomers),
propylene glycol, dipropylene glycol, butylene glycol, pentylene
glycol, hexylene glycol. These latter could be oxyethylened or not
(2 to 50 QE). Glycol ethers are also representative such as
ethoxydiglycol, diethylene glycol monoethylether (tradename
transcutol HP by GATTEFOSSE company), dipelargonate propylene
glycol, propylene glycol laurate (tradename Lauroglycol by
GATTEFOSSE company), Propylene glycol dicaprate dicaprylate
(tradename Estol 1526 by UNIQEMA company); and [0034] the
pro-penetrants such as fatty esters family, fatty acids or fatty
alcohols or alcohols, for example, ethanol, dimethyl isosorbide
(tradename Arlasolve DMI by UNIQEMA company), pyrrolidone methyl
(tradename Pharmasolve by ISP company), oleic acid (tradename
Oleine V2 by Stearinerie Dubois company), PEG-8 capric/caprylic
glycerides (tradename LAERASOL by GATTEFOSSE company) and oleic
alcohol (tradename HD EUTANOL V PH by COGNIS company).
[0035] In particular, the pharmaceutical composition may be a cream
comprising at least one ingredient selected from among: [0036]
mineral oils such as perhydrosqualene; [0037] silicone oils such as
cyclomethicone; [0038] siliconed oily components such as siliconed
fatty components; [0039] non-siliconed fatty components such as
vegetable, mineral, animal or synthetic oils; [0040] tensioactive
agents or emulsifying agents, preferably such as PEG-20 methyl
glucose sequistearate or Methyl glucose sesquistearate.
[0041] Among the non-siliconed oily components, the common oils are
representative such as paraffin oil, Vaseline (or petroleum jelly),
almond oil, perhydrosqualene, apricot oil, wheat germs oil, sweet
almond oil, calophyllum oil, palm oil, castor oil, avocado oil,
jojoba oil, olive oil or cerales germs oil; fatty acids esters or
fatty alcohols esters such as dodecyl octyl octanoates, alcohols or
polyalcohols decanoates or ricinoleates; fatty acids triglycerides;
glycerides; hydrogenated polyisobutene, solid at 25.degree. C.
hydrogenated oils; lanolines; solid at 25.degree. C. fatty esters;
adipate diisopropyl (tradename Crodamol DA by Croda company), PPG
15 stearyl ether (tradename Arlamol E by UNIQEMA company), octyl
dodecanol (tradename Eutanol G by COGNIS company), Caprilic/capric
triglycerides (tradename Miglyol 812N by SPCI company), C12-C15
alkyl benzoate (tradename Tegosoft TN by Degussa company).
[0042] As tensioactive agents or as emulsifying agents, several
components are representative selected from among PEG-20 methyl
glucose sequistearate (tradename GLUCAMATE SSE 20 by Amerchol
company) or Methyl glucose sesquistearate (tradename GLUCATE SS by
Amerchol company), unsaturated or saturated fatty acids esters,
oleic acid or isostearic acid such as polyglycerin and isostearic
acid esters (tradename LAMEFORM TGI by SIDOBRE-SINNOVA HENKEL
company), sorbitan isostearate (tradename ARLACEL 987 by UNIQEMA
company), sorbitan sesquioleate (tradename ARLACEL 83 by UNIQEMA
company), sorbitan laurate (tradename SPAN 20 by UNIQEMA company),
glycol and isostearic acid esters such as PEG-6 isostearate
(tradename OLEPAL ISOSTEARIQUE by GATTEFOSSE company), sorbitol and
oleic acid esters such as polysorbates (tradename TWEEN by UNIQEMA
company), fatty alcohols ethers such as oleic acid and particularly
glycol and oleic acid esters such as oleths (tradename BRIJ by
UNIQEMA company), oxyethylenated sorbitan monostearate, fatty
alcohols such as stearylic alcohol or cetylic alcohol and
particularly selected from among macrogol 21 stearylether
(tradename BRIJ 721 by UNIQEMA company), macrogol 2 stearylether
(tradename BRIJ 72P by UNIQEMA company), glyceryl/PEG 100 stearate
(tradename Arlacel 165FL by UNIQEMA company), ceteareth 20
(tradename Eumulgin B2 by COGNIS company), PEG-6 and PEG 32
palmitostearate (tradename TEFOSE 1500 by GATTEFOSSE company).
[0043] In particular, the pharmaceutical composition may be a
lotion comprising at least one ingredient selected from among:
[0044] humectant agent or pro-penetrant agent such as propylene
glycol (or equivalent such as glycerin and sorbitol), polyethylene
glycol, PEG400; [0045] mineral oils such as perhydrosqualene as
previously described; [0046] lipophilic components such as
Caprilic/capric triglycerides as previously described; [0047]
emulsifying agents such as described, for example, PEG-20 methyl
glucose sequistearate and methyl glucose sequistearate.
[0048] Also in particular, the pharmaceutical composition may be a
solution or a spray solution comprising alcohol and at least one
ingredient selected from among: [0049] humectant agent or
pro-penetrant agent as described previously and preferably such as
propylene glycol, polyethylene glycol, or PEG400; [0050] a
lipophilic component, such as siliconed or non-siliconed fatty
components or Caprilic/capric triglycerides.
[0051] Preferably in the form of gel, the composition has of
following formula:
TABLE-US-00001 Adapalene 3 mg Carbomer 940 (Carbopol 980 NF) 11 mg
Disodium edetate 1 mg Methyl paraben 2 mg Poloxamer 124 2 mg
Propylene glycol 40 mg Sodium hydroxide: amount required to obtain
a pH 5.0 +/- 0.3 Purified water q.s. 1 g
[0052] The pharmaceutical compositions according to the invention
may also comprise inert additives or combinations thereof, such
as:
[0053] wetting agents;
[0054] flavor enhancers;
[0055] preservatives such as para-hydroxybenzoic acid esters;
[0056] stabilizers;
[0057] moisture regulators;
[0058] pH regulators;
[0059] osmotic pressure modifiers;
[0060] emulsifiers; UV-A and UV-B screening agents; and
[0061] antioxidants, such as .alpha.-tocopherol,
butylhydroxyanisole or butylhydroxytoluene, superoxide dismutase,
ubiquinol or certain metal chelating agents.
[0062] Of course, those skilled in the art will take care to select
the optional compound(s) to be added to these compositions in such
a way that the advantageous properties intrinsically associated
with the present invention are not, or are not substantially,
adversely affected by the envisaged addition.
[0063] The pharmaceutical compositions according to the invention
are suited for the treatment of dermatological ailments, conditions
and afflictions having an inflammatory or proliferative component,
selected from the group consisting of: [0064] common acne,
comedones, polymorphous acne, nodulocystic acne, acne conglobata,
secondary acne such as solar, drug-related or occupational acne;
[0065] widespread and/or severe forms of psoriasis, ichtyoses and
ichtyosiform states; [0066] Darier's disease; [0067] actinic
keratoses; [0068] palmo plantar keratoderma and keratosis pilaris;
[0069] leucoplasias and leucoplasiform states, lichen planus;
[0070] any benign or malignant, severe and extensive dermatological
preparations.
[0071] The compositions according to the invention are particularly
suitable for the treatment of acne, such as common acne, and in
particular for the treatment of common acne of moderate to
moderately severe intensity.
[0072] Various formulations of compositions comprising 0.3% of
adapalene will now be given, it being understood that same are
intended only as illustrative and in nowise limitative. Also given
are results showing the therapeutic effects of the compositions
according to the invention and the good tolerance to same by the
treated patients.
[0073] In said examples to follow, all parts and percentages are
given by weight, unless otherwise indicated.
Example 1--Formulation for Topical Administration
[0074] In this example, various specific topical formulations
comprising 0.3% of adapalene are illustrated.
[0075] The adapalene of the present example was obtained from the
company Sylachim.
[0076] (a) Cream:
TABLE-US-00002 Adapalene 3 mg Carbomer 934 (BF Goodrich Carbopol
974) 4.5 mg Disodium edetate 1 mg PEG 20 methyl glucose
sesquistearate 35 mg Methyl glucose sesquistearate 35 mg Glycerol
30 mg Methyl paraben 2 mg Cyclomethicone 130 mg Perhydrosqualene 60
mg Phenoxyethanol 5 mg Propyl paraben 1 mg Sodium hydroxide
quantity required for pH 6.5 +/- 0.3 Purified water q.s. 1 g
[0077] (b) Alcoholic solution:
TABLE-US-00003 Adapalene 3 mg PEG 400 700 mg Ethanol q.s. 1 g
TABLE-US-00004 (c) Lotion: (% w/w) Adapalene 0.30 Methyl paraben
0.15 Simulgel 600 PHA 1.00 Steareth 21 3.00 Glyceryl and PEG 100
stearate 3.00 Disodium edetate 0.10 Propyl paraben 0.05
Perhydrosqualene 5.00 Cetearyl isononanoate 5.00 Sodium Hydroxide
10% m/m q.s. pH 5.5 .+-. 0.5 Purified water q.s. 100
TABLE-US-00005 (d) Lotion: (% w/w) Disodium EDTA 0.1 Methyl paraben
0.2 Glycerine 7.0 Carbopol 981 NF 0.15 Propyl paraben 0.1 Ceteareth
20 3.0 Stearyl alcohol 2.0 Caprilic/capric triglycerides 7 Glyceryl
and PEG 100 stearate 3.0 Cyclomethicone 5 6 Poloxamer 124 0.2
Propylene glycol 4.0 Adapalene 0.3 Simulgel 600 PHA 1.0 Solution
aq. De NaOH 10% 0.4 Purified water q.s. 100
TABLE-US-00006 (e) Lotion: (% w/w) EDTA disodium 0.1 Methyl paraben
0.2 Carbopol 980 NF 0.15 Carbapol 981 NF 0.3 Glycerine 3.0
Phenoxyethanol 1.0 Propyl paraben 0.2 Methyl glucose sesquistearate
1.0 PEG 20 methyl glucose sesquistearate 5.0 Caprilic/capric
triglycerides 6.0 Dimethicone 20 cst 1.0 Poloxamer 124 0.2
Propylene glycol 4 Adapalene 0.3 Sodium hydroxide 10% (w/w) 0.8
Purified water q.s. 100
[0078] (f) Aqueous Gel:
TABLE-US-00007 Adapalene 3 mg Carbomer 940 (Carbapol 980) 11 mg
Disodium edetate 1 mg Methyl paraben 2 mg Poloxamer 124 2 mg
Propylene glycol 40 mg Sodium hydroxide: amount required to obtain
a pH 5.0 +/- 0.3 Purified water q.s. 1 g
[0079] (g) Aqueous Gel:
TABLE-US-00008 Adapalene 3 mg Xanthan gum 8 mg Hydroxypropylethyl
cellulose 10 mg Disodium edetate 1 mg Methyl paraben 2 mg
Phenoxyethanol 10 mg Poloxamer 124 2 mg Propylene glycol 40 mg
Purified water q.s. 1 g
[0080] (h) Cream Gel:
TABLE-US-00009 Adapalene 3 mg Simulgel 600 PHA 20 mg Cetearyl
isononanoate 100 mg Disodium edetate 1 mg Methyl paraben 2 mg
Poloxamer 124 2 mg Propylene glycol 40 mg Purified water q.s. 1
g
[0081] (i) Cream gel:
TABLE-US-00010 Adapalene 3 mg Pemulen TR1 5 mg Mineral oil 120 mg
Disodium edetate 1 mg Methyl paraben 2 mg Propyl paraben 1 mg
Poloxamer 124 2 mg Propylene glycol 40 mg Sodium hydroxide: amount
required to obtain a pH 5.0 +/- 0.3 Purified water q.s. 1 g
TABLE-US-00011 (j) Spray solution: (% w/w) Adapalene 0.3
Caprilic/capric triglycerides 50 N-methyl pyrrolidone 3 Ethanol
q.s. 100
Example 2--Effectiveness of 0.3% Adapalene Gel and Comparison with
0.1% Adapalene Gel
[0082] Tests were carried out on a population consisting of
patients suffering from acne. In this population, three groups were
differentiated; the first received a daily topical application of
the 0.3% adapalene gel, the second a daily topical application of
the 0.1% adapalene gel in the same vehicle, and the third is a
control group which receives a daily topical application of the gel
corresponding to the composition of the first two gels but
containing no active agent.
[0083] FIGS. 1 to 3 provide the results obtained in terms of
regression of the number of lesions according to their nature.
[0084] These observations lead to the following conclusions:
[0085] the 0.3% adapalene gel acts more rapidly than the 0.1%
adapalene gel; specifically, from the fourth week of treatment, a
difference is noted between the effectiveness of the 0.1% adapalene
gel and the 0.3% adapalene gel;
[0086] the 0.3% adapalene gel produces a clearly greater
therapeutic effect after 8 weeks of treatment.
Example 3--Tolerance Regarding the 0.3% Adapalene Gel
[0087] 1. Measurement of the Plasma Concentration of Adapalene:
[0088] Eight individuals suffering from common acne of medium to
moderately severe intensity are treated for 10 days with 2 g of
0.3% adapalene gel applied daily over 1000 cm.sup.2 of skin to be
treated (face, chest and back).
[0089] Blood samples are taken on the days 1, 2, 4, 6, 8 and 10.
During day 10, and following the final application, samples are
taken at 1, 2, 6, 8, 10, 12, 16 and 24 hours.
[0090] The plasma concentration of total adapalene (free and
conjugated) in these samples is determined using the following
protocol:
[0091] enzymatic hydrolysis with a mixture of .beta.-glucurodinase
and arylsulfatase;
[0092] liquid-liquid extraction;
[0093] passage through HPLC (high performance liquid
chromatography); and
[0094] then fluorometric detection.
[0095] This method makes it possible to detect a minimum
concentration of 0.15 ng/ml and permits quantification of the
adapalene for a minimum concentration of 0.25 ng/ml.
CONCLUSION
[0096] The plasma concentrations of adapalene measured after 10
days of treatment are very low and confirm the safety of daily use
of the 0.3% adapalene gel.
[0097] 2 a) Clinical Observation of the Side Effects Caused by
Topical Administration of the 0.3% Adapalene Gel:
[0098] Two types of observation could be made:
[0099] firstly, monitoring of the patients treated within the
framework of point 1 of the present example 3 made it possible to
note that tolerance to the 0.3% adapalene gel was good for all
patients. They all showed signs of dryness of the skin and of
desquamation with a maximum on the seventh day of treatment, these
symptoms then decrease up to the end of the treatment.
[0100] 2 b) Furthermore, Reference May Also be Made to the Tests
Described in Example 2 Above:
[0101] In parallel to the measurements of effectiveness, the
experimenters recorded the possible side effects caused, firstly,
by topical application of the 0.3% adapalene gel and those caused,
secondly, by application of the 0.1% adapalene gel; finally, the
same observations were made on a control population to which a gel
without active principle was administered.
[0102] These observations are reported in the table below.
TABLE-US-00012 Local undesirable 0.3% adapalene 0.1% adapalene
Vehicle gel effects gel (N = 70) gel (N = 70) (N = 74) Skin and
secondary 31 (44.3%) 28 (40.0%) 5 (6.8%) structures (nails, hair)
Dry skin 16 (22.9%) 13 (18.6%) 2 (2.7%) Erythema 8 (11.4%) 3 (4.3%)
0 (0.0%) Skin discomfort 8 (11.4%) 7 (10.0%) 0 (0.0%) Desquamation
6 (8.6%) 5 (7.1%) 0 (0.0%) Dermatitis 3 (4.3%) 1 (1.4%) 0 (0.0%)
Pruritus 3 (4.3%) 1 1.4%) 1 (1.4%) Irritant dermatitis 2 (2.9%) 7
(10.0%) 0 (0.0%) Local allergic reactions 1 (1.4%) 0 (0.0%) 0
(0.0%) Pediculosis 1 (1.4%) 0 (0.0%) 0 (0.0%) Contact dermatitis 1
(1.4%) 0 (0.0%) 0 (0.0%) Insolation 1 (1.4%) 3 (4.3%) 1 (1.4%)
Burning sensation 1 (1.4%) 0 (0.0%) 0 (0.0%) Urticaria 1 1.4%) 0
(0.0%) 0 (0.0%) Infection 1 (1.4%) 0 (0.0%) 0 (0.0%) Excoriation 0
(0.0%) 0 (0.0%) 1 (1.4%) Eczema 0 (0.0%) 0 (0.0%) 1 (1.4%) Oedema 0
(0.0%) 1. (1.4%) 0 (0.0%)
[0103] From this table, it is noted that the occurrence of
undesirable side effects is statistically the same for the two gels
with the different concentrations of active agent. The intensity of
the undesirable side effects is average, which leads to the
conclusion that the two gels are well-tolerated by the
patients.
[0104] On the basis of these observations, it may be concluded that
patients suffering from common acne can be treated with 0.3%
adapalene gel, such an exposure to adapalene being described as
weak or very weak under clinical conditions.
[0105] It therefore ensues from these various studies that a
pharmaceutical composition containing 0.3% of adapalene exhibits a
benefit/risk ratio which makes it particularly suitable for the
treatment of dermatological maladies having an inflammatory or
proliferative component, and in particular, common acne.
[0106] Each patent, patent application, publication and literature
article/report cited or indicated herein is hereby expressly
incorporated by reference.
[0107] While the invention has been described in terms of various
specific and preferred embodiments, the skilled artisan will
appreciate that various modifications, substitutions, omissions,
and changes may be made without departing from the spirit thereof.
Accordingly, it is intended that the scope of the present invention
be limited solely by the scope of the following claims, including
equivalents thereof.
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