U.S. patent application number 15/269143 was filed with the patent office on 2017-01-05 for gel composition for treatment of common acne comprising a combination of benzoyl peroxide and adapalene and/or adapalene salt.
The applicant listed for this patent is Galderma Research & Development. Invention is credited to Sandrine ORSONI-SEGURA, Nathalie WILLCOX.
Application Number | 20170000758 15/269143 |
Document ID | / |
Family ID | 27791899 |
Filed Date | 2017-01-05 |
United States Patent
Application |
20170000758 |
Kind Code |
A1 |
ORSONI-SEGURA; Sandrine ; et
al. |
January 5, 2017 |
GEL COMPOSITION FOR TREATMENT OF COMMON ACNE COMPRISING A
COMBINATION OF BENZOYL PEROXIDE AND ADAPALENE AND/OR ADAPALENE
SALT
Abstract
Dermatological/cosmetic compositions suited for preventing or
treating cell differentiation and/or proliferation and/or
keratinization disorders, including preventing or treating common
acne, comprise, in a physiologically acceptable medium, (i) at
least one dispersed retinoid, (ii) dispersed benzoyl peroxide, in
free or encapsulated form, and (iii) at least one pH-independent
gelling agent, selected from the group consisting of (a)
polyacrylamide gelling agents, (b) gelling agents which are acrylic
polymers coupled to hydrophobic chains, (c) modified starch gelling
agents, and mixture thereof, said composition maintaining good
chemical stability of (i) and (ii) without their degradation over
time at a temperature of between 4.degree. C. and 40.degree. C.
Inventors: |
ORSONI-SEGURA; Sandrine;
(Mandelieu, FR) ; WILLCOX; Nathalie; (Le Rouret,
FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Galderma Research & Development |
Biot |
|
FR |
|
|
Family ID: |
27791899 |
Appl. No.: |
15/269143 |
Filed: |
September 19, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12076860 |
Mar 24, 2008 |
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15269143 |
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10326389 |
Dec 23, 2002 |
7820186 |
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12076860 |
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60351382 |
Jan 28, 2002 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/10 20130101;
A61K 31/07 20130101; A61K 31/20 20130101; A61K 31/19 20130101; A61P
17/14 20180101; A61K 31/327 20130101; A61K 9/0014 20130101; A61K
47/06 20130101; A61P 35/00 20180101; A61K 2300/00 20130101; A61K
31/20 20130101; A61P 17/10 20180101; A61K 31/19 20130101; A61P
17/00 20180101; A61K 31/07 20130101; A61K 2300/00 20130101; A61K
31/192 20130101; A61K 9/06 20130101; A61K 2300/00 20130101; A61K
47/32 20130101 |
International
Class: |
A61K 31/327 20060101
A61K031/327; A61K 31/192 20060101 A61K031/192; A61K 9/00 20060101
A61K009/00; A61K 47/06 20060101 A61K047/06; A61K 47/10 20060101
A61K047/10; A61K 9/06 20060101 A61K009/06; A61K 47/32 20060101
A61K047/32 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 21, 2001 |
FR |
01/16747 |
Claims
1-34. (canceled)
35. A physiologically acceptable aqueous gel composition for
treatment of common acne comprising: (1) anti-acne actives
consisting of: 0.05% to 1% adapalene and/or at least one
pharmaceutically acceptable salt thereof, and 2.5% to 5% dispersed
benzoyl peroxide; and (2) 2% to 5% polyacrylamide/C13-14
isoparaffin/laureth-7 gelling agent, said percentages being based
on the weight of the total aqueous gel composition for treatment of
common acne,
36. The physiologically acceptable aqueous gel composition of claim
35 comprising 3.5% to 4% polyacrylamide/C13-14
isoparaffin/laureth-7 gelling agent, said percentages being based
on the weight of the total aqueous gel composition for treatment of
common acne.
37. The physiologically acceptable aqueous gel composition of claim
35 comprising anti-acne actives consisting of: 0.1% adapalene
and/or at least one pharmaceutically acceptable salt thereof, and
2.5% dispersed benzoyl peroxide said percentages being based on the
weight of the total aqueous gel composition for treatment of common
acne.
38. The physiologically acceptable aqueous gel composition of claim
35 comprising anti-acne actives consisting of: 0.3% adapalene
and/or at least one pharmaceutically acceptable salt thereof, and
2.5% dispersed benzoyl peroxide said percentages being based on the
weight of the total aqueous gel composition for treatment of common
acne.
39. A method for treating common acne comprising administering, to
a subject in need thereof, a physiologically acceptable aqueous gel
composition for treatment of common acne comprising: (1) anti-acne
actives consisting of: 0.05% to 1% adapalene and/or at least one
pharmaceutically acceptable salt thereof, and 2.5% to 5% dispersed
benzoyl peroxide; and (2) 2% to 5% polyacrylamide/C13-14
isoparaffin/laureth-7 gelling agent, said percentages being based
on the weight of the total aqueous gel composition for treatment of
common acne.
40. The method of claim 39, wherein the physiologically acceptable
aqueous gel composition comprises 3.5% to 4% polyacrylamide/C13-14
isoparaffin/laureth-7 gelling agent, said percentages being based
on the weight of the total aqueous gel composition for treatment of
common acne.
41. The method of claim 39, wherein the physiologically acceptable
aqueous gel composition is administered once daily.
42. The method of claim 39, wherein the physiologically acceptable
aqueous gel composition comprises anti-acne actives consisting of:
0.1% adapalene and/or at least one pharmaceutically acceptable salt
thereof, and 2.5% dispersed benzoyl peroxide said percentages being
based on the weight of the total aqueous gel composition for
treatment of common acne.
43. The method of claim 39, wherein the physiologically acceptable
aqueous gel composition comprises anti-acne actives consisting of:
0.3% adapalene and/or at least one pharmaceutically acceptable salt
thereof, and 2.5% dispersed benzoyl peroxide said percentages being
based on the weight of the total aqueous gel composition for
treatment of common acne.
44. A product for treatment of common acne comprising: a container;
and a physiologically acceptable aqueous gel composition for
treatment of common acne comprising: (1) anti-acne actives
consisting of: 0.05% to 1% adapalene and/or at least one
pharmaceutically acceptable salt thereof, and 2.5% to 5% dispersed
benzoyl peroxide; and (2) 2% to 5% polyacrylamide/C13-14
isoparaffin/laureth-7 gelling agent, said percentages being based
on the weight of the total aqueous gel composition for treatment of
common acne, wherein the container contains the aqueous gel
composition for treatment of common acne.
45. The product of claim 44, wherein the physiologically acceptable
aqueous gel composition for treatment of common acne comprises
polyacrylamide/C13-14 isoparaffin/laureth-7 gelling agent, said
percentages being based on the weight of the total aqueous gel
composition.
46. The product of claim 44, wherein the physiologically acceptable
aqueous gel composition comprises anti-acne actives consisting of:
0.1% adapalene and/or at least one pharmaceutically acceptable salt
thereof, and 2.5% dispersed benzoyl peroxide said percentages being
based on the weight of the total aqueous gel composition for
treatment of common acne.
47. The product of claim 44, wherein physiologically acceptable
aqueous gel composition comprises anti-acne actives consisting of:
0.3% adapalene and/or at least one pharmaceutically acceptable salt
thereof, and 2.5% dispersed benzoyl peroxide said percentages being
based on the weight of the total aqueous gel composition for
treatment of common acne.
Description
CROSS-REFERENCE TO EARLIER APPLICATIONS
[0001] This application is a continuation of copending U.S. patent
application Ser. No. 10/326,389, filed Dec. 23, 2002 (Attorney
Docket No. 1034227-000478), which claims benefit of U.S.
Provisional Application No. 60/351,382, filed Jan. 28, 2002, and
claims priority under 35 U.S.C. .sctn.119 of Application No.
01/16747, filed in France on Dec. 21, 2001, all of said
applications being hereby expressly incorporated by reference in
their entireties and relied upon.
CROSS-REFERENCE TO RELATED APPLICATION
[0002] This application is related to concurrently filed copending
U.S. application Ser. No. ______ (Attorney Docket No.
1034227-000897), which is also a continuation of U.S. patent
application Ser. No. 10/326,389 and claims the same domestic and
foreign priorities.
BACKGROUND OF THE INVENTION
[0003] Technical Field of the Invention
[0004] The invention relates to a composition comprising, in a
physiologically acceptable medium, at least one retinoid, dispersed
benzoyl peroxide and at least one pH-independent gelling agent.
[0005] Description of the Prior Art
[0006] The use of several classes of active principles is a
therapeutic tool that is frequently employed, especially for
treating dermatological disorders.
[0007] Specifically, it is known practice in the treatment of
dermatitis to use corticosteroids such as, for example,
hydrocortisone, miconazole or betamethasone valerate,
antihistamines (e.g., mizolastine) and/or keratolytic agents, for
instance salicylic acid. Various antifungal agents, for instance
allylamine derivatives, triazoles, antibacterial agents or
antimicrobial agents such as, for example, antibiotics, quinolones
and imidazoles, are also conventionally combined in the treatment
of dermatological diseases. Peroxides, D vitamins and retinoids are
also described for the topical treatment of various pathologies
associated with the skin or mucous membranes, in particular
acne.
[0008] The combination of several local treatments (antibiotics,
retinoids, peroxides and zinc) is also used in dermatology to
increase the efficacy of the active principles and to reduce their
toxicity (Cunliffe W. J., J. Dermatol. Treat., 2000, 11 (suppl2),
pp. 13-14).
[0009] The multiple application of various dermatological products
may be relatively burdensome and restricting for the patient.
[0010] The value in seeking to obtain a novel treatment that is
effective on dermatological complaints in a stable composition
offering good cosmetic utility, allowing a single application and a
utilization that the patient finds pleasant, may thus be
appreciated.
[0011] Among this panoply of treatments proposed to a person
skilled in the art, there was nothing to encourage him to combine,
in the same composition, benzoyl peroxide and a retinoid.
[0012] However, formulating such a composition poses several
problems.
[0013] Firstly, the efficacy of benzoyl peroxide is associated with
its decomposition when it is placed in contact with the skin.
Specifically, it is the oxidizing properties of the free radicals
produced during this decomposition that lead to the desired effect.
Thus, in order to maintain the optimum efficacy of benzoyl
peroxide, it is important to prevent its decomposition before use,
i.e., during storage.
[0014] Benzoyl peroxide is an unstable chemical compound, making it
difficult to formulate it in finished products.
[0015] The solubility and stability of benzoyl peroxide were
studied by Chellquist et al., in ethanol, propylene glycol and
various mixtures of polyethylene glycol 400 (PEG 400) and water
(Chellquist E. M. and Gorman W. G., Pharm. Res., 1992, Vol 9:
1341-1346). Benzoyl peroxide is particularly soluble in PEG 400 and
ethanol, as shown in the following table:
TABLE-US-00001 Benzoyl peroxide Solvent solubility (mg/g) PEG 400
39.6 Ethanol 17.9 Propylene glycol 2.95 Propylene glycol/water
(75:25) 0.36 Glycerol 0.15 Water 0.000155
[0016] The said document moreover states that the stability of
benzoyl peroxide is greatly influenced by the chemical composition
of the formulation and by storage temperature. Benzoyl peroxide is
extremely reactive and degrades in solution at low temperature on
account of the instability of its peroxide bond. The authors thus
state that benzoyl peroxide in solution degrades more or less
quickly in all the solvents studied as a function of the type of
solvent and of its concentration.
[0017] The degradation times for benzoyl peroxide in PEG 400 (0.5
mg/g), in ethanol and in propylene glycol are, respectively, 1.4,
29 and 53 days at 40.degree. C.
[0018] Such a degradation does not allow the preparation of a
product intended for sale.
[0019] It is moreover known that benzoyl peroxide is more stable in
water and propylene glycol when it is in suspension (i.e., in
dispersed form), since it is not degraded after storage for 90 days
in these solvents. Thus, in order to limit the problem of rapid
instability of benzoyl peroxide in solution, it has been found to
be advantageous to formulate benzoyl peroxide in dispersed form.
However, this type of formulation is not entirely satisfactory
since degradation of the benzoyl peroxide in the finished product
is still observed.
[0020] Another difficulty to be overcome in preparation of a
composition comprising both benzoyl peroxide and a retinoid is that
most retinoids are particularly sensitive to natural oxidation, to
visible light and to ultraviolet light, and, since benzoyl peroxide
is a strong oxidizing agent, the chemical compatibility of these
compounds in the same formulation poses numerous problems in terms
of physical and chemical stability.
[0021] A study of the stability of two retinoids was performed by
combining two commercial products, one containing a retinoid
(tretinoin or adapalene) and the second based on benzoyl peroxide
(B. Martin et al., Br. J. Dermatol. (1998) 139, (suppl. 52), 8-11).
The presence of the formulation based on benzoyl peroxide results
in very rapid degradation of the oxidation-sensitive retinoids: it
is measured that 50% of the tretinoin is degraded in 2 hours, and
95% in 24 hours. In the composition in which the retinoid is
adapalene, no degradation of the adapalene was measured over 24
hours. This study confirms that benzoyl peroxide becomes degraded
and degrades oxidation-sensitive retinoids over time, gradually
releasing benzoic acid into the finished products. In contrast, no
indication is given regarding the physical stability of the two
compositions placed in contact, or regarding the therapeutic
activity that may finally be obtained by combining the two active
principles in the same composition. There was no encouragement for
combining these two active agents in order to obtain a stable
composition of gel type, given that it was commonly known that the
presence of benzoyl peroxide chemically and physically destabilized
this type of composition.
[0022] Now, it is clear that the degradation of benzoyl peroxide
and retinoids is not desirable since it impairs the efficacy of the
composition containing them.
[0023] Moreover, a finished product, in particular when it is a
pharmaceutical or cosmetic composition, must maintain throughout
its shelf life precise physicochemical criteria for ensuring its
pharmaceutical or cosmetic quality, respectively. Among these
criteria, it is necessary for the rheological properties to be
maintained. They define the behavior and texture of the composition
during application, but also the active principle's release
properties [1998 SFSTP Commission Report] and the homogeneity of
the product when the active principles are present therein in
dispersed form.
[0024] In particular, the formulation of benzoyl peroxide and of a
retinoid in gel form is advantageous for topical treatments, such
as the treatment of acne, since it especially avoids a greasy feel
being left on the skin.
[0025] Another difficulty to be overcome in preparing a composition
especially comprising benzoyl peroxide, when it is in gel form, is
that the gelling agents are destabilized by the benzoic acid
released during the degradation of the benzoyl peroxide.
[0026] Specifically, the thickeners most commonly used for
formulating these compositions with benzoyl peroxide are acrylic
acid polymers (Carbomer) and celluloses alone or combined with
silicates.
[0027] Now, the use of carbomers in compositions of aqueous gel
type does not give good results in terms of chemical stability of
the benzoyl peroxide or in terms of rheological stability. As
described by Bollinger (Bollinger, Journal of Pharmaceutical
Science, 1977, vol 5), it has been observed that from 5% to 20%
benzoyl peroxide is lost after 2 months at 40.degree. C. depending
on the neutralizer of the carbomer used. Furthermore, the release
of benzoic acid results in depolymerization of the carbomers,
leading to a drop in viscosity which may result in phase
separation. In other gels consisting of a mixture of
hydroxypropyl-cellulose and aluminum magnesium silicate, a drop in
viscosity over time is also observed, resulting in sedimentation of
the active agents as a suspension and heterogeneity of the
dispersion in the finished product.
[0028] This instability of benzoyl peroxide gels impairs their
efficacy and their cosmetic utility.
[0029] There is thus still a need for a physically stable gelled
composition containing benzoyl peroxide and a retinoid.
SUMMARY OF THE INVENTION
[0030] The Applicant has now, surprisingly, produced a composition
that satisfies this need, which comprises dispersed, free or
encapsulated benzoyl peroxide, at least one retinoid and a
pH-independent gelling agent with good physical stability, i.e.,
not showing a drop in viscosity over time and at temperatures of
between 4 and 40.degree. C., and maintaining good chemical
stability of the two active agents (benzoyl peroxide and retinoid),
i.e., no degradation of the active agents over time and at
temperature of between 4 and 40.degree. C. is observed. The
Applicant has also discovered, surprisingly, that total dispersion
of the active principles can be obtained by following a particular
preparation process. This preparation process performed without
heat makes it possible to obtain an optimum particle size and
uniform dispersion of the two active agents in the composition,
while at the same time ensuring the physical stability of the
product.
[0031] The invention thus relates to a composition comprising, in a
physiologically acceptable medium, at least one retinoid, dispersed
benzoyl peroxide and at least one pH-independent gelling agent.
DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED
EMBODIMENTS OF THE INVENTION
[0032] The composition according to the invention is preferably in
the form of an aqueous gel.
[0033] The term "aqueous gel" means a composition containing, in an
aqueous phase, a viscoelastic mass formed from colloidal
suspensions (gelling agent).
[0034] The expression "pH-independent gelling agent" means a
gelling agent capable of giving the composition a viscosity that is
sufficient to keep the retinoid and the benzoyl peroxide in
suspension, even under the influence of a variation in pH caused by
the release of benzoic acid by the benzoyl peroxide.
[0035] Non-limiting examples that may be mentioned include the
gelling agents of the polyacrylamide family, such as the mixture of
sodium acryloyldimethyltaurate copolymer/isohexadecane/polysorbate
80 sold under the name Simulgel 600 by the company SEPPIC, the
mixture of polyacrylamide/isoparaffin C13-14/laureth-7 such as, for
example, the product sold under the name Sepigel 305 by the company
SEPPIC, the family of acrylic polymers coupled to hydrophobic
chains, such as the PEG-150/decyl/SMDI copolymer sold under the
name Aculyn 44 (polycondensate comprising at least, as components,
a polyethylene glycol containing 150 or 180 mol of ethylene oxide,
decyl alcohol and methylenebis (4-cyclohexyl isocyanate) (SMDI), at
35% by weight in a mixture of propylene glycol (39%) and water
(26%)), the family of modified starches, such as the modified
potato starch sold under the name methylenebis (4-cyclohexyl
isocyanate) (SMDI), Structure Solanace, or mixtures thereof.
[0036] The preferred gelling agents are derived from the
polyacrylamide family, such as Simulgel 600 or Sepigel 305, or
mixtures thereof.
[0037] The gelling agent as described above may be used in
preferential concentrations ranging from 0.1% to 15% and more
preferably ranging from 0.5% to 5%.
[0038] The composition according to the invention contains at least
one retinoid.
[0039] The term "retinoid" means any compound that binds to the RAR
and/or RXR receptors.
[0040] Preferably, the retinoid is a compound chosen from the
family of benzonaphthalene retinoids as described in patent
application EP 0 199 636. In particular, adapalene and also
precursors and/or derivatives thereof will be preferred.
[0041] The expression "retinoid precursors" means the immediate
biological precursors or substrates thereof, and also the chemical
precursors thereof.
[0042] The expression "retinoid derivative" means both their
metabolic derivatives and their chemical derivatives.
[0043] Other retinoids may be chosen from those described in the
following patents or patent applications: U.S. Pat. No. 4,666,941,
U.S. Pat. No. 4,581,380, EP 0 210 929, 15 EP 0 232 199, EP 0 260
162, EP 0 292 348, EP 0 325 540, EP 0 359 621, EP 0 409 728, EP 0
409 740, EP 0 552 282, EP 0 584 191, EP 0 514 264, EP 0 514 269, EP
0 661 260, EP 0 661 258, EP 0 658 553, EP 0 679 628, EP 0 679 631,
EP 0 679 630, EP 0 708 100, EP 0 709 382, EP 0 722 928, EP 0 728
739, EP 0 732 328, EP 0 740 937, EP 0 776 885, EP 0 776 881, EP 0
823 903, EP 0 832 057, EP 0 832 081, EP 0 816 352, EP 0 826 657, EP
0 874 626, EP 0 934 295, EP 0 915 823, EP 0 882 033, EP 0 850 909,
EP 0 879 814, EP 0 952 974, EP 0 905 118, EP 0 947 496, WO
98/56783, WO 99/10322, WO 99/50239, WO 99/65872.
[0044] Needless to say, the amount of the two active agents,
benzoyl peroxide and retinoid, in the composition according to the
invention will depend on the combination chosen and thus
particularly on the retinoid under consideration and the quality of
the desired treatment.
[0045] The preferred retinoid concentrations are between 0.0001%
and 20% by weight relative to the total weight of the
composition.
[0046] Benzoyl peroxide may also be used in free form or in an
encapsulated form in a form adsorbed onto, or absorbed in, any
porous support. It may be, for example, benzoyl peroxide
encapsulated in a polymer system consisting of porous microspheres,
such as, for example, microsponges sold under the name Microsponges
P009A Benzoyl peroxide by the company Advanced Polymer System.
[0047] To give an order of magnitude, the composition according to
the invention advantageously comprises between 0.0001% and 20% by
weight of benzoyl peroxide and between 0.0001% and 20% by weight of
retinoid relative to the total weight of the composition, and
preferably, respectively, between 0.025% and 10% by weight of
benzoyl peroxide and between 0.001% and 10% by weight of retinoid
relative to the total weight of the composition.
[0048] For example, in compositions for treating acne, the benzoyl
peroxide is preferably used at concentrations ranging from 2% to
10% by weight and more particularly from 2.5% to 5% by weight,
relative to the total weight of the composition. As regards the
retinoid, it is used in this type of composition at concentrations
generally ranging from 0.05% to 1% by weight relative to the total
weight of the composition.
[0049] Advantageously, the particle size of the retinoid and of the
benzoyl peroxide is such that at least 80% in numerical terms of
the particles, and preferably at least 90% in numerical terms of
the particles, have a diameter of less than 25 .mu.m and at least
99% in numerical terms of the particles have a diameter of less
than 100 .mu.m.
[0050] According to the invention, the gel containing benzoyl
peroxide and a retinoid advantageously comprises at least water and
may also comprise a pro-penetrating agent and/or a liquid wetting
surfactant.
[0051] The compositions of the invention may contain one or more
pro-penetrating agents in preferential concentrations ranging from
0% to 20% and more preferably ranging from 2% to 6% by weight,
relative to the total weight of the composition. They should
generally not dissolve the active agents at the percentage used,
should not cause any exothermic reactions harmful to the benzoyl
peroxide, should aid in the satisfactory dispersion of the active
agents, and should have antifoaming properties. Among the
pro-penetrating agents preferably used, without this list being
limiting, are compounds such as propylene glycol, dipropylene
glycol, propylene glycol dipelargonate, lauroglycol and
ethoxydiglycol.
[0052] The pro-penetrating agent that is particularly preferred is
propylene glycol.
[0053] Advantageously, the compositions according to the invention
may also contain one or more liquid wetting surfactants in
preferential concentrations ranging from 0% to 10% and more
preferably ranging from 0.1% to 2%. The wetting power is the
tendency of a liquid to spread over a surface.
[0054] They are preferably surfactants with an HLB
(Hydrophilic-Lipophilic Balance) value from 7 to 9, or nonionic
surfactants such as polyoxyethylenated and/or polyoxypropylenated
copolymers. They should be liquid so as to be readily incorporated
into the composition without it being necessary to heat them.
[0055] Among the wetting agents that are preferably used, without
this list being limiting, are compounds of the Poloxamer family and
more particularly Poloxamer 124 and/or Poloxamer 182.
[0056] The liquid wetting surfactant that is particularly preferred
is Poloxamer 124.
[0057] The composition may also comprise any additive usually used
in the cosmetics or pharmaceutical field, such as sequestering
agents, antioxidants, sunscreens, preserving agents, fillers,
electrolytes, humectants, colorants, common mineral or organic
acids or bases, fragrances, essential oils, cosmetic active agents,
moisturizers, vitamins, essential fatty acids, sphingolipids,
self-tanning compounds such as DHA, and calmants and protective
agents for the skin such as allantoin. Needless to say, a person
skilled in the art will take care to select this or these optional
additional compound(s), and/or the amount thereof, such that the
advantageous properties of the composition according to the
invention are not, or are not substantially, adversely
affected.
[0058] These additives may be present in the composition in a
proportion of from 0% to 20% by weight relative to the total weight
of the composition.
[0059] Examples of sequestering agents that may be mentioned
include ethylenediaminetetraacetic acid (EDTA), and also
derivatives or salts thereof, dihydroxyethylglycine, citric acid
and tartaric acid, or mixtures thereof.
[0060] Examples of preserving agents that may be mentioned include
benzalkonium chloride, phenoxy-ethanol, benzyl alcohol,
diazolidinylurea and parabens, or mixtures thereof.
[0061] Examples of humectants that may be mentioned include
glycerol and sorbitol.
[0062] In particular, the invention also relates to a
pharmaceutical or cosmetic composition for topical application to
the skin, the integuments or mucous membranes, in the form of an
aqueous gel, characterized in that it contains, in a
physiologically acceptable medium that is compatible with topical
application to the skin, the integuments or mucous membranes, an
active phase comprising (expressed in percentages by weight):
[0063] 0% to 90%, preferably 5% to 25% and especially 10% to 20%,
of water; [0064] 0% to 10%, preferably 0 to 2% and especially 0% to
0.5%, of liquid wetting surfactant; [0065] 0% to 20%, preferably 0%
to 10% and especially 2% to 5%, of pro-penetrating agent; [0066]
0.0001% to 20% and preferably 0.025% to 10%, of benzoyl peroxide;
[0067] 0.0001% to 20% and preferably 0.001% to 10%, of retinoid;
and [0068] an aqueous phase comprising a pH-independent gelling
agent, and water.
[0069] The aqueous phase of the emulsion according to the invention
may comprise water, a floral water such as cornflower water, or
natural mineral or spring water chosen, for example, from eau de
Vittel, waters of the Vichy basin, eau d'Uriage, eau de la Roche
Posay, eau de la Bourboule, eau d'Enghien-les-Bains, eau de Saint
Gervais-les-Bains, eau de Neris-les-Bains, eau
d'Allevard-les-Bains, eau de Digne, eau de Maizieres, eau de
Neyrac-les-Bains, eau de Lons-le-Saunier, les Eaux Bonnes, eau de
Rochefort, eau de Saint Christau, eau des Fumades, eau de
Tercis-les-bains, eau d'Avene or eau d'Aix les Bains.
[0070] The said aqueous phase may be present in a content of
between 10% and 90% by weight and preferably between 20% and 80% by
weight, relative to the total weight of the composition.
[0071] A composition that is preferred according to the invention
comprises in water: [0072] 2.50% benzoyl peroxide, [0073] 0.10%
adapalene, [0074] 0.10% disodium EDTA, [0075] 4.00% glycerol,
[0076] 4.00% propylene glycol, [0077] 0.05% sodium docusate, [0078]
0.20% Poloxamer 124, [0079] 4.00% sodium acryloyldimethyltaurate
copolymer & isohexadecane & polysorbate 80, [0080] sodium
hydroxide, qs pH 5.
[0081] A subject of the present invention is also the composition
as described above, as a medicinal product.
[0082] The invention also relates to the use of the novel
composition as described above in cosmetics and dermatology.
[0083] A subject of the invention is also a process for preparing a
composition of aqueous gel type, comprising the production of an
active phase, of an aqueous phase and of a gelling phase, at room
temperature (RT), i.e., between 20 and 25.degree. C., and
successively comprising the following steps: [0084] a) the
preparation of an aqueous phase comprising water and optionally a
chelating agent and/or a pro-penetrating agent and/or a humectant;
[0085] b) the preparation of an active phase comprising the mixture
in water of the retinoid, of benzoyl peroxide and, optionally, of a
liquid wetting surfactant and/or of a pro-penetrating agent, with
stirring; [0086] c) the introduction of the active phase into the
aqueous phase, with stirring; and [0087] d) the introduction of the
gelling agent into the mixture obtained from step c), with
stirring.
[0088] In one embodiment, the process for preparing the aqueous gel
composition, comprising the production of an active phase, of an
aqueous phase and of a gelling phase, at room temperature,
successively comprises the following steps: [0089] a) the
preparation of an aqueous phase comprising water and optionally a
chelating agent and/or a pro-penetrating agent and/or a humectant;
[0090] b) the preparation of two active agents, one comprising the
mixture in water of the retinoid, the other comprising the mixture
in water of benzoyl peroxide and, optionally, of a liquid wetting
surfactant and/or of a pro-penetrating agent, with stirring; [0091]
c) the introduction of the active phases into the aqueous phase,
with stirring; and [0092] d) the introduction of the gelling agent
into the mixture obtained from step c), with stirring.
[0093] The aqueous gel prepared according to one of these
procedures was found to provide many advantages over the
preparation of other already-known aqueous gels, especially since
it is simpler, and, since the incorporation of the gelling agent
into the end of the process makes it possible to obtain better
dispersion of the particles by enclosure, these gels may also be
film-forming and may thus limit perspiration. At least 80% in
numerical terms of the particles and preferably at least 90% in
numerical terms of the particles have a diameter of less than 25
.mu.m and at least 99% in numerical terms of the particles have a
diameter of less than 100 .mu.m in the composition.
[0094] On account of the keratolytic, bactericidal and
antiinflammatory activity of benzoyl peroxide and the pronounced
activity of retinoids in the fields of cell differentiation and
proliferation, the compositions of the invention are particularly
suitable in the following therapeutic fields: [0095] 1) for
treating dermatological complaints associated with a keratinization
disorder relating to differentiation and proliferation, especially
for treating common acne, comedones, polymorphonuclear leukocytes,
acne rosacea, nodulocystic acne, acne conglobata, senile acne,
secondary acnes such as solar acne, medication-related acne or
occupational acne, and suppurative hydradenitis, [0096] 2) for
treating other types of keratinization disorder, especially
ichtyosis, ichtyosiform conditions, Darier's disease, palmoplantar
keratoderma, leukoplakia and leukoplakiform conditions, and
cutaneous or mucous (buccal) lichen, [0097] 3) for treating other
dermatological complaints associated with a keratinization disorder
with an inflammatory and/or immunoallergic component, and
especially all forms of psoriasis, whether cutaneous, mucous or
ungual psoriasis, and even psoriatic rheumatism, or cutaneous
atopy, such as eczema, or respiratory atopy, or even gingival
hypertrophy; the compounds may also be used in certain inflammatory
complaints not exhibiting a keratinization disorder, such as
folliculitis, [0098] 4) for treating all dermal or epidermal
proliferations, whether benign or malignant, and whether of viral
origin or otherwise, such as common warts, flat warts, molluscum
contagiosum and verruciform epidermodysplasia, oral or florid
papillomatoses and proliferations that may be induced by
ultraviolet radiation, especially in the case of actinic keratosis,
[0099] 5) for repairing or combating aging of the skin, whether
photo induced or chronological aging, or for reducing pigmentation,
or any pathology associated with chronological or actinic aging,
[0100] 6) for preventively or curatively treating cicatrization
disorders and skin ulcers, for preventing or repairing stretch
marks, or for promoting cicatrization, [0101] 7) for combating
sebaceous function disorders such as the hyperseborrhoea of acne or
simple seborrhoea, [0102] 8) in the treatment of any complaint of
fungal origin on the skin, such as tinea pedis and tinea
versicolor, [0103] 9) in the treatment of dermatological complaints
with an immunological component, [0104] 10) in the treatment of
skin disorders caused by exposure to UV rays, and [0105] 11) in the
treatment of dermatological complaints associated with inflammation
or infection of the tissues surrounding the hair follicles, caused
especially by microbial colonization or infection, especially
impetigo, seborrhoeic dermatitis, folliculitis or sycosis barbae,
or involving any other bacterial or fungal agent.
[0106] The compositions according to the invention are particularly
suitable for preventively or curatively treating common acne.
[0107] A subject of the invention also relates to the manufacture
of a pharmaceutical preparation for preventing or treating
dermatological complaints associated with cell differentiation
and/or proliferation disorders and/or keratinization disorders, and
also to the manufacture of a pharmaceutical preparation for
preventing or treating common acne.
[0108] The compositions according to the invention also find an
application in cosmetics, in particular for treating acne-prone
skin, for regrowth of the hair, for preventing hair loss, for
combating the greasy appearance of the skin or the hair, in
protecting against the harmful effects of sunlight or in the
treatment of physiologically dry skin, or for preventing and/or
combating photo induced or chronological aging.
[0109] The compositions according to the invention also find an
application in body and hair hygiene.
[0110] The present invention thus relates also to the cosmetic use
of a composition according to the invention for treating acne-prone
skin, for regrowth of the hair or for preventing hair loss, for
combating the greasy appearance of the skin or the hair, in
protecting against harmful effects of sunlight or in treating
physiologically dry skin, or for preventing and/or controlling
photo induced or chronological aging.
[0111] The formulation examples below illustrate the compositions
according to the invention without, however, limiting its scope.
Examples of processes for preparing the compositions according to
the invention, mentioned in a non-limiting manner, and also
examples illustrating the physical and chemical stability of the
compositions, are also described.
I. FORMULATION EXAMPLES
[0112] In the compositions below (Examples 1 to 5), the proportions
of the various constituents are expressed as percentages by weight
relative to the total weight of the composition.
Example 1
TABLE-US-00002 [0113] Phase Components % Active BENZOYL PEROXIDE
5.00% ADAPALENE 0.10% DIPROPYLENE GLYCOL 4.00% PURIFIED WATER .sup.
10% POLOXAMER 182 0.20% Aqueous PURIFIED WATER qs 100% .sup. SILICA
0.02% GLYCEROL 2.00% MICROSPONGES 4.00% Gelling POLYACRYLAMIDE
(and) C13-14 3.50% ISOPARAFFIN (and) LAURETH-7
Example 2
TABLE-US-00003 [0114] Phase Components % Active BENZOYL PEROXIDE 5%
ADAPALENE 0.10% PURIFIED WATER 10.00% PROPYLENE GLYCOL 2.00%
POLOXAMER 124 0.20% Aqueous PURIFIED WATER qs 100% .sup. DISODIUM
EDTA 0.10% GLYCEROL 4.00% PROPYLENE GLYCOL 2.00% SODIUM DOCUSATE
0.05% Gelling SODIUM 4.00% ACRYLOYLDIMETHYLTAURATE COPOLYMER &
ISOHEXADECANE & POLYSORBATE 80
Example 3
TABLE-US-00004 [0115] Phase Components % Active BENZOYL PEROXIDE
2.5% ADAPALENE 0.10% PURIFIED WATER 10.00% PROPYLENE GLYCOL 2.00%
POLOXAMER 124 0.20% Aqueous PURIFIED WATER qs 100% .sup. DISODIUM
EDTA 0.10% GLYCEROL 4.00% PROPYLENE GLYCOL 2.00% SODIUM DOCUSATE
0.05% Gelling SODIUM 4.00% ACRYLOYLDIMETHYLTAURATE COPOLYMER &
ISOHEXADECANE & POLYSORBATE 80 pH modifier SODIUM HYDROXIDE qs
pH 5.00
Example 4
TABLE-US-00005 [0116] Phase Components % Active BENZOYL PEROXIDE
5.00% ADAPALENE 0.10% PURIFIED WATER 10.00% PROPYLENE GLYCOL 2.00%
POLOXAMER 124 0.20% Aqueous PURIFIED WATER qs 100% .sup. DISODIUM
EDTA 0.10% GLYCEROL 4.00% PROPYLENE GLYCOL 2.00% SODIUM C14-16
OLEFIN 0.05% SULFONATE Gelling PEG-150/decyl/SMDI copolymer
3.5%
Example 5
TABLE-US-00006 [0117] Phase Components % Active 1 BENZOYL PEROXIDE
2.5% PURIFIED WATER 20.00% PROPYLENE GLYCOL 1.00% POLOXAMER 124
0.10% Phase ADAPALENE 0.10% Active 2 PROPYLENE GLYCOL 1.00%
POLOXAMER 124 0.10% Aqueous PURIFIED WATER qs 100% .sup. DISODIUM
EDTA 0.10% GLYCEROL 4.00% PROPYLENE GLYCOL 2.00% SODIUM DOCUSATE
0.05% Gelling SODIUM 4.00% ACRYLOYLDIMETHYLTAURATE COPOLYMER &
ISOHEXADECANE & POLYSORBATE 80 pH modifier SODIUM HYDROXIDE qs
pH 5.00
II. EXAMPLES OF A PREPARATION PROCESS
Example 6
[0118] The examples of a preparation process are given in a
non-limiting manner. The preparation presented is that of the
composition that is the subject of Example 3:
TABLE-US-00007 PROCEDURE PARAMETERS Introduce the following into
T.degree.: RT .degree. C. beaker (Phase 1): STIRRER: Rayneri
purified water PADDLE: deflocculating disodium EDTA STIRRING: 350
rmp glycerol TIME: 10 min Introduce the following into a T.degree.:
RT .degree. C. related beaker: STIRRER: stirring plate propylene
glycol PADDLE: magnetic br sodium docusate TURBOMIXER: N.A. Place
under magnetic stirring TIME: 45 min until the sodium docusate is
fully dissolved Active phase: Introduce the T.degree.: RT .degree.
C. following into a related beaker STIRRER: disperser of suitable
size: PADDLE: Polytron propylene glycol (PG) STIRRING: 9 000 rpm
Poloxamer 124 TIME: 30 min purified water benzoyl peroxide
adapalene Stir using a Polytron stirrer until the active agents are
fully dispersed, in a bath of cold water to avoid overheating of
the active agents. When the mixture of sodium T.degree.: RT.degree.
C. docusate + PG is fully dissolved, STIRRER: Rayneri incorporate
it into Phase 1. PADDLE: deflocculating Next, add the active phase.
STIRRING: 400-500 rpm Stir with a Rayneri stirrer until TIME: 20
min a homogeneous mixture is obtained. Finally, add the following:
T.degree.: RT .degree. C. Simulgel 600 STIRRER: Rayneri Stir with a
Rayneri stirrer for PADDLE: deflocculating the time required for
good STIRRING: 1 000-1 200 rpm homogeneity of the finished TIME: 25
min product. Neutralisation: Adjust the pH to T.degree.: RT
.degree. C. 5.00 .+-. 0.3 with: STIRRER: Rayneri 10% sodium
hydroxide, qs PADDLE: deflocculating STIRRING: 1 000-1 200 rpm
TIME: 25 min
[0119] The preparation given is that of the composition that is the
subject of Example 5:
TABLE-US-00008 PROCEDURE PARAMETERS Introduce the following into a
T.degree.: RT .degree. C. beaker: STIRRER: Rayneri purified water
PADDLE: deflocculating disodium EDTA STIRRING: 350 rpm sodium
docusate TIME: 50 min propylene glycol Place under magnetic
stirring until the sodium docusate is fully dissolved Next,
introduce the following: T.degree.: RT .degree. C. glycerol
STIRRER: stirring plate PADDLE: deflocculating STIRRING: 350 rpm
TIME: 5 min Active phase 1: Introduce the T.degree.: RT + cold
water bath following into a related beaker PADDLE: Ultra-Turrax of
suitable size: STIRRING: 13 500 rpm propylene glycol (PG) TIME: 30
min Poloxamer 124 purified water benzoyl peroxide Stir until the
active agent is fully dispersed, in a cold water bath to avoid
overheating. Active phase 2: Introduce the T.degree.: RT + cold
water bath following into a related beaker PADDLE: Ultra-Turrax of
suitable size: STIRRING: 9 500 rpm propylene glycol (PG) TIME: 15
min Poloxamer 124 adapalene. Incorporate the active phase 2
T.degree.: RT .degree. C. into the aqueous phase. STIRRER: Rayneri
Next, add the active phase 1. PADDLE: deflocculating Stir using a
Rayneri stirrer STIRRING: 300 rpm until a homogeneous mixture is
TIME: 20 min obtained Finally, add the following: T.degree.: RT
.degree. C. Simulgel 600 STIRRER: Rayneri Stir using a Rayneri
stirrer for the PADDLE: deflocculating time required for good
homogeneity STIRRING: 680 rpm of the finished product TIME: 35 min
Neutralization: Adjust the pH to T.degree.: RT .degree. C. 5.00
.+-. 0.3 with: STIRRER: Rayneri 10% sodium hydroxide, qs PADDLE:
deflocculating STIRRING: 680 rpm TIME: 25 min
III. STABILITY STUDY
Example 6
[0120] Physical stability of the composition by measuring the flow
threshold (in Pas.sup.-1)
[0121] The tests performed are viscosity measurements for plotting
curves known as rheograms, which make it possible, for a given rate
gradient .gamma., to measure a shear stress .tau., and for a given
shear stress .tau., to measure a rate gradient .gamma. ("Initiation
a la rheologie" [Introduction to rheology] Gouarraze-Grossiord
1991; "La viscosite et sa mesure dans les pharmacopees" [Viscosity
and its measurement in pharmacopoeias]; L. Molle, Journal Pharma
Belg. 1975, 30, 5-6, 597-619).
[0122] The term "yield value" means the force required (minimum
shear stress) to overcome the cohesion forces of Van der Waals type
and to bring about flow.
[0123] The yield value (.tau.O) is extrapolated either visually
(y-axis at the origin of the rheograms) or by calculation
(application of mathematical models).
Composition of the gels used:
Aqueous Gel Based Carbomer
TABLE-US-00009 [0124] Constituents % PURIFIED WATER qs 100%
DISODIUM EDTA 0.10 SODIUM DOCUSATE 0.05 SILICA (AEROSIL 200) 0.02
CARBOMER (CARBOPOL 980) 0.85 GLYCEROL 4.00 PROPYLENE GLYCOL 4.00
POLOXAMER 124 0.20 BENZOYL PEROXIDE qs 2.5% BPO MICROSPONGES
ADAPALENE 0.10 10% SODIUM HYDROXIDE 2.00 qs pH 5
Aqueous Gel Based on hydroxypropycellulose
TABLE-US-00010 [0125] Constituents % PURIFIED WATER qs 100%
DISODIUM EDTA 0.10 SILICA (AEROSIL 200) 0.02 GLYCEROL 4.00 CLAY
(VEEGUM K) 2.00 XANTHAN GUM (KELTROL T) 0.5 HYDROXYPROPYLCELLULOSE
1.5 (NATROSOL HHX) PROPYLENE GLYCOL 4.0 SODIUM DOCUSATE 0.05
POLOXAMER 124 0.2 BENZOYL PEROXIDE MICROSPONGES qs 2.5% BPO
ADAPALENE 0.10
TABLE-US-00011 Aqueous gel based on hydroxypropyl- Example 2 in
cellulose and accordance Aqueous gel aluminum with the based on
magnesium invention carbomer silicate Temperature RT T40.degree. C.
RT T40.degree. C. RT T40.degree. C. T initial 137 / 111 / 170 T 1
month 139 137 135 111 183 93 T 2 months 147 121 / / 158 65 T 3
months 149 127 100 76 147 34 RT: room temperature T40.degree. C.:
storage at 40.degree. C.
[0126] The yield value of the composition according to the
invention is stable over time and with temperature, unlike the
other two examples of aqueous gel, whose viscosity falls rapidly
over time, both at room temperature and at 40.degree. C. These
results demonstrate the very good physical stability of the
composition according to the invention over time, unlike the
standard compositions of aqueous gels.
Example 7
[0127] Stability of benzoyl peroxide over time and as a function of
the storage temperature by measuring the amount of benzoyl peroxide
in the composition (in percentages)
[0128] The percentages of benzoyl peroxide (BPO) presented in the
table below were obtained by measuring the benzoyl peroxide
concentration by iodometry. A suitable amount of composition is
first dissolved in purified water and then in acetonitrile, and
subjected to the action of a potassium iodide solution. When the
potassium iodide is added, a color change from white to brown takes
place,
indicating the presence of benzoyl peroxide in the composition. The
iodine released is titrated using 0.1N sodium thiosulphate
solution:
I.sub.2+2 N.sub.2S.sub.2O.sub.3.fwdarw.2
NaI+Na.sub.2S.sub.4O.sub.6
[0129] The percentages of benzoyl peroxide given in the table below
correspond to the percentage of benzoyl peroxide measured in the
product relative to the theoretical amount introduced.
TABLE-US-00012 Aqueous gel based on hydroxypropyl- cellulose and
Example 2 in Aqueous gel aluminum accordance with based on
magnesium the invention carbomer silicate Temperature RT
T40.degree. C. RT T40.degree. C. RT T40.degree. C. % BPO at T 100 /
94.3 / 101.7 initial % BPO at T Not 102.5 95.7 90.3 / 94.9 1 month
performed % BPO at T Not 99.1 94.3 85.5 / 87.3 2 months performed %
BPO at T 102.4 100.3 94 78.3 99.7 85.8 3 months
[0130] In the composition of Example 2, the percentage of benzoyl
peroxide over time remains stable and equivalent to 100% both at
room temperature and at 40.degree. C. The benzoyl peroxide present
in the other two examples of prior-art aqueous gels degrades
significantly over time. After 3 months, a loss of benzoyl peroxide
that is up to 6% at room temperature and at least 14% at
T40.degree. C. may be observed. These results demonstrate that the
compositions according to the invention allow very good stability
of benzoyl peroxide over time, even at 40.degree. C., unlike
standard compositions.
* * * * *