111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US007820 186B2
`
`c12) United States Patent
`Orsoni et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,820,186 B2
`Oct. 26, 2010
`
`(54) GEL COMPOSITION FOR ONCE-DAILY
`TREATMENT OF COMMON ACNE
`COMPRISING A COMBINATION OF
`BENZOYL PEROXIDE AND ADAPALENE
`AND/ORADAPALENE SALT
`
`(75)
`
`Inventors: Sandrine Orsoni, Mandelieu (FR);
`Nathalie Willcox, Le Rouret (FR)
`
`(73) Assignee: Galderma Research & Development
`(FR)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 1066 days.
`
`(21) Appl. No.: 10/326,389
`
`(22) Filed:
`
`Dec. 23, 2002
`
`(65)
`
`Prior Publication Data
`
`US 2003/0170196 AI
`
`Sep. 11, 2003
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/351,382, filed on Jan.
`28,2002.
`
`(30)
`
`Foreign Application Priority Data
`
`Dec. 21, 2001
`
`(FR)
`
`................................... 01 16747
`
`(51)
`
`Int. Cl.
`A61K 8102
`(2006.01)
`A61K 31/07
`(2006.01)
`A61K 31/075
`(2006.01)
`(52) U.S. Cl. ....................... 424/401; 5141717; 514/725;
`514/772
`(58) Field of Classification Search ................... 514/42;
`424/401
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`2/1980 Fulton, Jr.
`4,189,501 A
`111988 Sluoot eta!.
`4,717,720 A
`12/1988 Howard et al.
`4,792,452 A
`10/1990 Sebag eta!.
`4,960,772 A
`5,035,890 A *
`7/1991 Braun ........................ 424/401
`1111993 Sluoot eta!.
`RE34,440 E
`RE34,805 E * 12/1994 Sluoot eta!.
`5,690,946 A
`1111997 Koulbanis eta!.
`5,707,635 A
`111998 Deckner et a!.
`5,733,886 A
`3/1998 Baroody et a!.
`5,824,650 A
`10/1998 De Lacharriere et a!.
`6,106,848 A
`8/2000 Preuilh et a!.
`6,274,151 B1 *
`8/2001 Michel eta!. ............... 424/401
`6,423,324 B1 *
`7/2002 Murphyet a!. .............. 424/401
`2002/0035161 A1
`3/2002 Segura et al.
`2002/0064541 A1 *
`5/2002 Lapidot et a!. .............. 424/401
`2003/0033678 A1
`2/2003 Wiesche et a!.
`2005/0181999 A1
`8/2005 Ferran dis et a!.
`
`2006/0233735 A1
`
`10/2006 Preuilh et al.
`
`FOREIGN PATENT DOCUMENTS
`
`1072843
`CN
`0 335 115 A2
`EP
`2 378 523 A
`FR
`2 618 673
`FR
`2 628 319
`FR
`2 753 626 A1
`FR
`2 833 841
`FR
`1 594 314
`GB
`2 207 353
`GB
`218592
`HU
`218936
`HU
`1 100 134
`JP
`1 268 632
`JP
`7 500 593
`JP
`wo
`93/07856
`wo
`WO 93/07856 A1
`wo 95/31978
`wo
`wo
`99/65456 A1
`wo 00/37027
`wo
`wo 01145647
`wo
`wo 03/055472
`wo
`wo wo 2007/002831
`wo wo 2008/006888
`
`10/1992
`10/1989
`8/1978
`2/1989
`9/1989
`3/1998
`6/2003
`7/1981
`2/1989
`6/1996
`2/1997
`4/1989
`10/1989
`111995
`4/1993
`4/1993
`1111995
`12/1999
`6/2000
`6/2001
`7/2003
`1/2007
`1/2008
`
`OTHER PUBLICATIONS
`
`Mills Jr. et al. Comparing 2.5%, 5% and 10% benzoyl peroxide on
`inflammatory acne vulgaris. Int. J. Dermatology. Dec. 1986,
`25(10);664-667.*
`Caron et al .. "Skin Tolerance ofAdapalene 0.1% Gel in Combination
`with other Topical Antiacne Treatments" Journal of the American
`Academy of Dermatology, vol. 36. No. 6. Part 2, 1997. pp. S113-
`Sll5.
`Martin et a!., "Chemical Stability of Adapalene and Tretinoin when
`combined with Benzoyl Peroxide in Presence and in Absence of
`Visible Light and Ultraviolet Radiation", British Journal of Derma(cid:173)
`tology, vol. 139. No. S52. 1998. pp. 8-11.
`
`(Continued)
`
`Primary Examiner-Lakshmi S Channavajjala
`(74) Attorney, Agent, or Firm-Finnegan, Henderson,
`Farabow, Garrett & Dunner, LLP
`
`(57)
`
`ABSTRACT
`
`Dermatological/cosmetic gel compositions suited for pre(cid:173)
`venting or treating cell differentiation and/or proliferation
`and/or keratinization disorders, including preventing or treat(cid:173)
`ing common acne, comprise (i) at least one retinoid, (ii)
`dispersed benzoyl peroxide and (iii) at least one pH-indepen(cid:173)
`dent gelling agent, formulated into (iv) a physiologically
`acceptable medium therefor.
`
`1 Claim, No Drawings
`
`1
`
`AMN1011
`
`

`

`US 7,820,186 B2
`Page 2
`
`OTHER PUBLICATIONS
`
`Hurwitz. "The Combined Effect of Vitamin A Acid and Benzoyl
`Peroxide inthe Treatment of Acne". vol. 17. No.3 Mar. 1976. pp.
`5S5-590.
`Search Report issued for FR 011016747 on Sep. 4, 2002. 3 pages.
`Chellquist et al., "Benzoyl Peroxide Solubility and Stability in
`Hydric Solvents," Pharmaceutical Research, vol. 9, No.IO, 1992, pp.
`1341-1346, published by Springer, The Netherlands.
`Seppic Personal Care Ingredients Catalog, pp. 1-26 and endnotes,
`2004/rev. 2006, published by SEPPIC S.A., Lyon, France.
`Bershard, S. V., "The modem age of acne therapy: a review of current
`treatment options," Mt Sinai J Med Sep.-Oct. 2001; 6S(4-5); 279-S6.
`Bikowski, "Clinical Experience Results with Clindamycin I%
`Benzoyl Peroxide 5% Gel (Duac®) as Monotherapy and in Combi(cid:173)
`nation", Journal of Drugs in Dermatology, Mar. 2005, pp. 164-171,
`vol. 4, No.2.
`Brand et al., "Cumulative irritancy comparison of adapalene gel 0 .I%
`versus other retinoid products when applied in combination with
`topical antimicrobial agents", J. Am. Acad. Dermatol., Sep. 2003, pp.
`S227-S232, vol. 49, No.3, Cranbury, NJ.
`Capizzi, et a!., "Efficacy and Safety of Combination Therapy of
`Hydrogen Peroxide Cream and Adapalene Gel in Comparison with
`Benzoyl Peroxide Cream andAdapalene in Common Acne," Journal
`of the American Academy of Dermatology, vol. 50, Issue 3, Supple(cid:173)
`ment I, p. PIS (Mar. 2004).
`Capizzi eta!., "Skin tolerability and efficacy of combination therapy
`with hydrogen peroxide stabilized cream and adapalene gel in com(cid:173)
`parison with benzoyl peroxide cream and adapalene gel in common
`acne. A randomized, investigator-masked, controlled trial", British
`Journal of Dermatology, 2004, pp. 4SI-4S4, vol. 151, No.2.
`Clucas eta!., "Adapalene 0.1% gel has low skin irritation potential",
`Journal of the European Academy of Dermatology and Venereology,
`Sep. 199S, p. S27 5, vol. 11, Elsevier Science Publisher.
`Gollnick et a!., "Evaluation of a maintenance treatment of acne
`vulgaris with adapalene gel 0.1 %", Journal of the American Acad(cid:173)
`emy of Dermatology, Mar. 2005, p. PIS, vol. 52, No.3.
`Korkut eta!., "Benzoyl Peroxide, Adapalene, and their Combination
`in the Treatment of Acne Vulgaris", The Journal of Dermatology,
`2005, pp. 169-173, vol. 32, No.3, Edirne, Turkey.
`
`Leyden, James J., "A Review of the Use of Combination Therapies
`for the Treatment of Acne Vulgaris," Journal of the American Acad(cid:173)
`emy of Dermatology, vol. 49, No.3, pp. S200-S210 (Sep. 2003).
`Leyden, et a!., "Photographic Review of Results From a Clinical
`Study Comparing Benzoyl Peroxide 5%/Clindamycin I% Topical
`Gel with Vehicle in the Treatment of Rosacea," Topical Treatment for
`the Inflamed Lesion in Acne, Rosacea, and Pseudofolliculitis Barbae,
`Jun. 2004, vol. 73, p. 3.
`Relyveld eta!., "Benzoyl peroxide/clindamycin/UV A is more effec(cid:173)
`tive than fluticasone/UV A in progressive macular hypomelanosis: A
`randomized study," J. Am. Acad. Dermatol., Nov. 2006, vol. 55, No.
`5, pp. S36-S43.
`Van Zuuren, eta!., "Systematic review of rosacea treatments," J. Am.
`Acad. Dermatol., Jan. 2007, vol. 56, No. I, pp. 107-115.
`Weiss eta!., "Adapalene for the treatment of acne vulgaris", Journal
`of the American Academy of Dermatology, Aug. 199S, pp. S50-S54,
`vol. 39, No. 2.
`Wen-Wen eta!., "Clinical efficacy and safety of 5% benzoyl peroxide
`gel combined with 0.1% adapalene gel in the treatment of acne
`vulgaris: a multicenter randomized study", Database Biosis,
`Biosciences Information Service, Jun. 2003, Database accession No.
`PREV200300514701, pp. 310-312, vol. 36, No.6.
`Co-pending U.S. Appl. No. 111S26,364, filed Jul. 13, 2007.
`Co-pending U.S. Appl. No. 12/31S,937, filed Jan. 13, 2009, continu(cid:173)
`ation of Application No. PCT/EP2007 /057207, filed on Jul. 12, 2007.
`Co-pending U.S.Appl. No. 12/473,9SI, filed May 2S, 2009, continu(cid:173)
`ation-in-part of U.S. Appl. No. 12/31S,937.
`Office Action dated Dec. 29, 2009, in co-pending U.S. Appl. No.
`111S26,364.
`Office Action dated Oct. 21, 2009, in co-pending U.S. Appl. No.
`12/31S,937.
`English language abstract ofFR 2 S33 S41, Jun. 27, 2003.
`International Search Report for PCT/EP2007/057207, dated Sep. 24,
`2007.
`International Search Report for EP 02799797, dated Mar. 24, 2003.
`Walker, Susan J., M.D., "Summary Review" dated Dec. I, 200S,
`NDA No. 22-320 (6 pages).
`FDA label for Differin 0.1% gel, NDANo. 0203SO (3 pages), Dec. S,
`2008.
`* cited by examiner
`
`2
`
`

`

`US 7,820,186 B2
`
`1
`GEL COMPOSITION FOR ONCE-DAILY
`TREATMENT OF COMMON ACNE
`COMPRISING A COMBINATION OF
`BENZOYL PEROXIDE AND ADAPALENE
`AND/ORADAPALENE SALT
`
`CROSS-REFERENCE TO
`PRIORITY /PROVISIONAL APPLICATIONS
`
`2
`The solubility and stability of benzoyl peroxide were stud(cid:173)
`ied by Chellquist et a!., 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:
`
`This application claims priority under 35 U.S.C. §119 of 10
`FR-01/16747, filed Dec. 21, 2001, and of provisional appli(cid:173)
`cation Ser. No. 60/351,382, filed Jan. 28, 2002, both hereby
`expressly incorporated by reference. This application is also
`a continuation of said '382 provisional.
`
`BACKGROUND OF THE INVENTION
`
`15
`
`Solvent
`
`PEG400
`Etbanol
`Propylene glycol
`Propylene glycol/water (75:25)
`Glycerol
`Water
`
`Benzoyl peroxide
`solubility (mg/g)
`
`39.6
`17.9
`2.95
`0.36
`0.15
`0.000155
`
`1. Technical Field of the Invention
`The invention relates to a composition comprising, in a
`physiologically acceptable medium, at least one retinoid, dis- 20
`persed benzoyl peroxide and at least one pH-independent
`gelling agent.
`2. Description of the Prior Art
`The use of several classes of active principles is a thera(cid:173)
`peutic tool that is frequently employed, especially for treating 25
`dermatological disorders.
`Specifically, it is known practice in the treatment of der(cid:173)
`matitis to use corticosteroids such as, for example, hydrocor(cid:173)
`tisone, miconazole or betamethasone valerate, antihistamines
`(e.g., mizolastine) and/or keratolytic agents, for instance sali- 30
`cylic acid. Various antifungal agents, for instance allylamine
`derivatives, triazoles, antibacterial agents or antimicrobial
`agents such as, for example, antibiotics, quinolones and imi(cid:173)
`dazoles, are also conventionally combined in the treatment of
`dermatological diseases. Peroxides, D vitamins and retinoids 35
`are also described for the topical treatment of various patholo(cid:173)
`gies associated with the skin or mucous membranes, in par(cid:173)
`ticular acne.
`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).
`The multiple application of various dermatological prod-
`ucts may be relatively burdensome and restricting for the
`patient.
`The value in seeking to obtain a novel treatment that is
`effective on dermatological complaints in a stable composi(cid:173)
`tion offering good cosmetic utility, allowing a single applica-
`tion and a utilization that the patient finds pleasant, may thus
`be appreciated.
`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 55
`retinoid.
`However, formulating such a composition poses several
`problems.
`Firstly, the efficacy of benzoyl peroxide is associated with
`its decomposition when it is placed in contact with the skin. 60
`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.
`Benzoyl peroxide is an unstable chemical compound, mak(cid:173)
`ing it difficult to formulate it in finished products.
`
`The said document moreover states that the stability of
`benzoyl peroxide is greatly influenced by the chemical com(cid:173)
`position of the formulation and by storage temperature. Ben(cid:173)
`zoyl 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.
`The degradation times for benzoyl peroxide in PEG 400
`(0.5 mg/g), in ethanol and in propylene glycol are, respec(cid:173)
`tively, 1.4, 29 and 53 days at 40° C.
`Such a degradation does not allow the preparation of a
`product intended for sale.
`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 perox(cid:173)
`ide in the finished product is still observed.
`Another difficulty to be overcome in preparation of a com-
`position comprising both benzoyl peroxide and a retinoid is
`that most retinoids are particularly sensitive to natural oxida(cid:173)
`tion, to visible light and to ultraviolet light, and, since benzoyl
`peroxide is a strong oxidizing agent, the chemical compat-
`ibility of these compounds in the same formulation poses
`numerous problems in terms of physical and chemical stabil(cid:173)
`ity.
`A study of the stability of two retinoids was performed by
`combining two commercial products, one containing a retin(cid:173)
`oid ( tretinoin or adapalene) and the second based on benzoy I
`peroxide (B. Martinetal.,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(cid:173)
`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 oxi(cid:173)
`dation-sensitive retinoids over time, gradually releasing ben-
`zoic acid into the finished products. In contrast, no indication
`is given regarding the physical stability of the two composi(cid:173)
`tions placed in contact, or regarding the therapeutic activity
`65 that may finally be obtained by combining the two active
`principles in the same composition. There was no encourage(cid:173)
`ment for combining these two active agents in order to obtain
`
`40
`
`45
`
`50
`
`3
`
`

`

`10
`
`15
`
`45
`
`50
`
`SUMMARY OF THE INVENTION
`
`US 7,820,186 B2
`
`4
`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
`
`3
`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.
`Now, it is clear that the degradation of benzoyl peroxide
`and retinoids is not desirable since it impairs the efficacy of 5
`the composition containing them.
`Moreover, a finished product, in particular when it is a
`pharmaceutical or cosmetic composition, must maintain
`throughout its shelflife precise physicochemical criteria for
`The composition according to the invention is preferably in
`ensuring its pharmaceutical or cosmetic quality, respectively.
`the form of an aqueous gel.
`Among these criteria, it is necessary for the rheological prop(cid:173)
`The term "aqueous gel" means a composition containing,
`erties to be maintained. They define the behavior and texture
`in an aqueous phase, a viscoelastic mass formed from colloi(cid:173)
`of the composition during application, but also the active
`dal suspensions (gelling agent).
`principle's release properties [1998 SFSTP Commission
`The expression "pH-independent gelling agent" means a
`Report] and the homogeneity of the product when the active
`gelling agent capable of giving the composition a viscosity
`principles are present therein in dispersed form.
`that is sufficient to keep the retinoid and the benzoyl peroxide
`In particular, the formulation of benzoyl peroxide and of a
`in suspension, even under the influence of a variation in pH
`retinoid in gel form is advantageous for topical treatments,
`caused by the release ofbenzoic acid by the benzoyl peroxide.
`such as the treatment of acne, since it especially avoids a 20
`Non-limiting examples that may be mentioned include the
`greasy feel being left on the skin.
`gelling agents of the polyacrylamide family, such as the mix-
`ture of sodium acryloyldimethyltaurate copolymer/isohexa-
`Another difficulty to be overcome in preparing a composi-
`tion especially comprising benzoyl peroxide, when it is in gel
`decane/polysorbate 80 sold under the name Simulgel 600 by
`form, is that the gelling agents are destabilized by the benzoic
`the company SEPPIC, the mixture of polyacrylamide/isopar-
`acid released during the degradation of the benzoyl peroxide. 25 affin C13-14/laureth-7 such as, for example, the product sold
`under the name Sepigel 305 by the company SEPPIC, the
`Specifically, the thickeners most commonly used for for-
`mulating these compositions with benzoyl peroxide are
`family of acrylic polymers coupled to hydrophobic chains,
`acrylic acid polymers (Carbomer) and celluloses alone or
`such as the PEG-150/decyl/SMDI copolymer sold under the
`combined with silicates.
`nameAculyn44 (polycondensate comprising at least, as com-
`Now, the use of carbomers in compositions of aqueous gel 30 ponents, a polyethylene glycol containing 150 or 180 mol of
`type does not give good results in terms of chemical stability
`ethylene oxide, decyl alcohol and methylenebis ( 4-cyclo-
`ofthe benzoyl peroxide orin terms of rheological stability. As
`hexyl isocyanate) (SMDI), at 35% by weight in a mixture of
`described by Bollinger (Bollinger, Journal of Pharmaceutical
`propylene glycol (39%) and water (26% )), the family of
`Science, 1977, vol 5), it has been observed that from 5% to
`modified starches, such as the modified potato starch sold
`20% benzoyl peroxide is lost after 2 months at 40o c. depend- 35 under the name Structure So Ianace, or mixtures thereof.
`ing on the neutralizer of the carbomer used. Furthermore, the
`The preferred gelling agents are derived from the polyacry-
`release of benzoic acid results in depolymerization of the
`!amide family, such as Simulgel 600 or Sepigel 305, or mix-
`tures thereof.
`carbomers, leading to a drop in viscosity which may result in
`phase separation. In other gels consisting of a mixture of
`The gelling agent as described above may be used in pref-
`hydroxypropyl-cellulose and aluminum magnesium silicate, 40 erential concentrations ranging from 0.1% to 15% and more
`preferably ranging from 0.5% to 5%.
`a drop in viscosity over time is also observed, resulting in
`sedimentation of the active agents as a suspension and het-
`The composition according to the invention contains at
`least one retinoid.
`erogeneity of the dispersion in the finished product.
`The term "retinoid" means any compound that binds to the
`This instability of benzoyl peroxide gels impairs their effi-
`RAR and/or RXR receptors.
`cacy and their cosmetic utility.
`Preferably, the retinoid is a compound chosen from the
`There is thus still a need for a physically stable gelled
`family of benzonaphthalene retinoids as described in patent
`composition containing benzoyl peroxide and a retinoin.
`application EP 0 199 636. In particular, adapalene and also
`precursors and/or derivatives thereof will be preferred.
`The expression "retinoid precursors" means the immediate
`biological precursors or substrates thereof, and also the
`chemical precursors thereof.
`The expression "retinoid derivative" means both their
`metabolic derivatives and their chemical derivatives.
`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
`60 514 264, EP 0 514 269, EP 0 661 260, EP 0 661 258, EP 0 658
`553, EPO 679 628, EPO 679 631, EPO 679 630, EP0708100,
`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
`65 626, EPO 934 295, EPO 915 823, EPO 882033, EP0850909,
`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.
`
`The Applicant has now, surprisingly, produced a composi(cid:173)
`tion 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, 55
`i.e., not showing a drop in viscosity overtime and at tempera(cid:173)
`tures ofbetween 4 and 40° C., and maintaining good chemical
`stability of the two active agents (benzoyl peroxide and ret(cid:173)
`inoid), i.e., no degradation of the active agents over time and
`at temperature of between 4 and 40° C. is observed. The
`Applicant has also discovered, surprisingly, that total disper(cid:173)
`sion of the active principles can be obtained by following a
`particular preparation process. This preparation process per(cid:173)
`formed 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 physi(cid:173)
`cal stability of the product.
`
`4
`
`

`

`US 7,820,186 B2
`
`15
`
`20
`
`5
`Needless to say, the amount of the two active agents, ben(cid:173)
`zoyl 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 qual(cid:173)
`ity of the desired treatment.
`The preferred retinoid concentrations are between
`0.0001% and 20% by weight relative to the total weight of the
`composition.
`Benzoyl peroxide may also be used in free form or in an
`encapsulated form in a form adsorbed onto, or absorbed in, 10
`any porous support. It may be, for example, benzoyl peroxide
`encapsulated in a polymer system consisting of porous micro(cid:173)
`spheres, such as, for example, microsponges sold under the
`name Microsponges P009A Benzoyl peroxide by the com-
`pany Advanced Polymer System.
`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 ofbenzoyl peroxide and
`between 0.001% and 10% by weight of retinoid relative to the
`total weight of the composition.
`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 30
`weight relative to the total weight of the composition.
`Advantageously, the particle size of the retinoid and of the
`benzoy I 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 ofless than 25 f.Ull and
`at least 99% in numerical terms of the particles have a diam(cid:173)
`eter ofless than 100 f.tm.
`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.
`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 com(cid:173)
`position. 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 com(cid:173)
`pounds such as propylene glycol, dipropylene glycol, propy(cid:173)
`lene glycol dipelargonate, lauroglycol and ethoxydiglycol.
`The pro-penetrating agent that is particularly preferred is
`propylene glycol.
`Advantageously, the compositions according to the inven(cid:173)
`tion 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.
`They are preferably surfactants with an HLB (Hydrophilic(cid:173)
`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 incor- 65
`porated into the composition without it being necessary to
`heat them.
`
`6
`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 Polox(cid:173)
`amer 182.
`The liquid wetting surfactant that is particularly preferred
`is Poloxamer 124.
`The composition may also comprise any additive usually
`used in the cosmetics or pharmaceutical field, such as seques(cid:173)
`tering 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-tauning 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.
`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.
`Examples of sequestering agents that may be mentioned
`include ethylenediaminetetraacetic acid (EDTA), and also
`25 derivatives or salts thereof, dihydroxyethylglycine, citric acid
`and tartaric acid, or mixtures thereof.
`Examples of preserving agents that may be mentioned
`include benzalkonium chloride, phenoxy-ethanol, benzyl
`alcohol, diazolidinylurea and parabens, or mixtures thereof.
`Examples of humectants that may be mentioned include
`glycerol and sorbitol.
`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
`35 aqueous gel, characterized in that it contains, in a physiologi(cid:173)
`cally acceptable medium that is compatible with topical
`application to the skin, the integuments or mucous mem(cid:173)
`branes, an active phase comprising (expressed in percentages
`by weight):
`0% to 90%, preferably 5% to 25% and especially 10% to
`20%, of water;
`0% to 10%, preferably 0 to 2% and especially 0% to 0.5%,
`ofliquid wetting surfactant;
`0% to 20%, preferably 0% to 10% and especially 2% to
`5%, of pro-penetrating agent;
`0.0001% to 20% and preferably 0.025% to 10%, of ben(cid:173)
`zoyl peroxide;
`0.0001% to 20% and preferably 0.001% to 10%, ofretin-
`50 oid; and
`an aqueous phase comprising a pH-independent gelling
`agent, and water.
`The aqueous phase of the emulsion according to the inven(cid:173)
`tion 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 Ia Roche Posay, eau de Ia Bourboule, eau d'Enghien(cid:173)
`les-Bains, eau de Saint Gervais-les-Bains, eau de Neris-les(cid:173)
`Bains, eau d'Allevard-les-Bains, eau de Digne, eau de Mai-
`60 zieres, eau de Neyrac-les-Bains, eau de Lons-le-Saunier, les
`Eaux Bounes, eau de Rochefort, eau de Saint Christau, eau
`des Fumades, eau de Tercis-les-bains, eau d' Avene or eau
`d' Aix les Bains.
`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.
`
`40
`
`45
`
`55
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`5
`
`

`

`US 7,820,186 B2
`
`7
`A composition that is preferred according to the invention
`comprises in water:
`2.50% benzoyl peroxide,
`0.10% adapalene,
`0.10% disodium EDTA,
`4.00% glycerol,
`4.00% propylene glycol,
`0.05% sodium docusate,
`0.20% Poloxamer 124,
`4.00% sodium acryloyldimethyltaurate copolymer & iso- 10
`hexadecane & polysorbate 80,
`sodium hydroxide, qs pH 5.
`A subject of the present invention is also the composition as
`described above, as a medicinal product.
`The invention also relates to the use of the novel composi(cid:173)
`tion as described above in cosmetics and dermatology.
`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° C., and
`successively comprising the following steps:
`
`20
`
`15
`
`8
`proliferation, the compositions of the invention are particu(cid:173)
`larly suitable in the following therapeutic fields:
`
`1) for treating dermatological complaints associated with a
`keratinization disorder relating to differentiation and prolif(cid:173)
`eration, 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,
`
`2) for treating other types of keratinization disorder, espe(cid:173)
`cially ichtyosis, ichtyosiform conditions, Darier's disease,
`palmoplantar keratoderma, leukoplakia and leukoplakiform
`conditions, and cutaneous or mucous (buccal) lichen,
`
`3) for treating other dermatological complaints associated
`with a keratinization disorder with an inflammatory and/or
`immunoallergic component, and especially all forms of pso(cid:173)
`riasis, 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,
`
`a) the preparation of an aqueous phase comprising water and
`optionally a chelating agent and/or a pro-penetrating agent
`and/or a humectant;
`
`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;
`
`c) the introduction of the active phase into the aqueous phase,
`with stirring; and
`
`d) the introduction of the gelling agent into the mixture
`obtained from step c), with stirring.
`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:
`
`a) the preparation of an aqueous phase comprising water and
`optionally a chelating agent and/or a pro-penetrating agent
`and/or a humectant;
`
`b) the preparation of two active agents, one comprising the
`mixture in water of the retinoid, t