AU2008246274B2 - Gel comprising at least a retinoid and benzoyl peroxide - Google Patents
Gel comprising at least a retinoid and benzoyl peroxide Download PDFInfo
- Publication number
- AU2008246274B2 AU2008246274B2 AU2008246274A AU2008246274A AU2008246274B2 AU 2008246274 B2 AU2008246274 B2 AU 2008246274B2 AU 2008246274 A AU2008246274 A AU 2008246274A AU 2008246274 A AU2008246274 A AU 2008246274A AU 2008246274 B2 AU2008246274 B2 AU 2008246274B2
- Authority
- AU
- Australia
- Prior art keywords
- composition
- benzoyl peroxide
- mixture
- retinoid
- agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 239000004342 Benzoyl peroxide Substances 0.000 title claims description 88
- 235000019400 benzoyl peroxide Nutrition 0.000 title claims description 88
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 title claims description 87
- 150000004492 retinoid derivatives Chemical class 0.000 title claims description 40
- 239000000203 mixture Substances 0.000 claims description 160
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 85
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 64
- 239000003349 gelling agent Substances 0.000 claims description 43
- 238000003756 stirring Methods 0.000 claims description 38
- 239000012071 phase Substances 0.000 claims description 25
- 239000003795 chemical substances by application Substances 0.000 claims description 24
- 206010000496 acne Diseases 0.000 claims description 21
- 238000011282 treatment Methods 0.000 claims description 21
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 20
- 239000008346 aqueous phase Substances 0.000 claims description 19
- 230000000149 penetrating effect Effects 0.000 claims description 19
- 229960002916 adapalene Drugs 0.000 claims description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- 239000013543 active substance Substances 0.000 claims description 14
- LZCDAPDGXCYOEH-UHFFFAOYSA-N adapalene Chemical compound C1=C(C(O)=O)C=CC2=CC(C3=CC=C(C(=C3)C34CC5CC(CC(C5)C3)C4)OC)=CC=C21 LZCDAPDGXCYOEH-UHFFFAOYSA-N 0.000 claims description 14
- 239000002537 cosmetic Substances 0.000 claims description 14
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- DWHIUNMOTRUVPG-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCO DWHIUNMOTRUVPG-UHFFFAOYSA-N 0.000 claims description 4
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- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 claims description 4
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- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
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- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 claims 4
- KGRVJHAUYBGFFP-UHFFFAOYSA-N 2,2'-Methylenebis(4-methyl-6-tert-butylphenol) Chemical compound CC(C)(C)C1=CC(C)=CC(CC=2C(=C(C=C(C)C=2)C(C)(C)C)O)=C1O KGRVJHAUYBGFFP-UHFFFAOYSA-N 0.000 claims 1
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- 229920002472 Starch Polymers 0.000 claims 1
- KQWGXHWJMSMDJJ-UHFFFAOYSA-N cyclohexyl isocyanate Chemical compound O=C=NC1CCCCC1 KQWGXHWJMSMDJJ-UHFFFAOYSA-N 0.000 claims 1
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 34
- 239000000499 gel Substances 0.000 description 27
- 239000008213 purified water Substances 0.000 description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 17
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- BANXPJUEBPWEOT-UHFFFAOYSA-N 2-methyl-Pentadecane Chemical compound CCCCCCCCCCCCCC(C)C BANXPJUEBPWEOT-UHFFFAOYSA-N 0.000 description 10
- 229920002125 Sokalan® Polymers 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 9
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 8
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 8
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 8
- 150000002978 peroxides Chemical class 0.000 description 7
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
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- -1 for example Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 229940043268 2,2,4,4,6,8,8-heptamethylnonane Drugs 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- KUVMKLCGXIYSNH-UHFFFAOYSA-N isopentadecane Natural products CCCCCCCCCCCCC(C)C KUVMKLCGXIYSNH-UHFFFAOYSA-N 0.000 description 5
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 3
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- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 2
- POJWUDADGALRAB-UHFFFAOYSA-N allantoin Chemical compound NC(=O)NC1NC(=O)NC1=O POJWUDADGALRAB-UHFFFAOYSA-N 0.000 description 2
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- 229910052708 sodium Inorganic materials 0.000 description 1
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
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Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/07—Retinol compounds, e.g. vitamin A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION Standard Patent Applicant (): GALDERM RESEARCH & DEVELOpMg' Invention Title: GEL COMPRISING AT LEAST A RETrNoCrD AND BENZOYL PEROXIDE The following statement is a gull description of this invention, including the best method for performing it known to me/us: P03O5AU I PI~t~g~g~ 1 2G- ~ 1A GEL COMPRISING AT LEAST ONE RETINOID AND BENZOYL PEROXIDE The invention relates to a composition 5 comprising, in a physiologically acceptable medium, at least one retinoid, dispersed benzoyl peroxide and at least one pH-independent gelling agent. The Use of several classes of active principles is a therapeutic tool that is frequently 10 employed, especially for treating dermatological disorders. specifically, it is known practice in the treatment of dermatitis to use corticosteroids such as, for example, hydrocortisone, miconazole or betamethasone valerate, 15 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, 20 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, 25 The combination of several local treatments (antibiotics, retinoids, peroxides and zinc) is also used in dermatology to increase the efficacy of the 2 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 5 products 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 composition offering good cosmetic utility, allowing a 10 single application 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 15 and a 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 20 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 25 decomposition before use, i.e. during storage. Benzoyl peroxide is an unstable chemical compound, making it difficult to formulate it in 3 finished products. The solubility and stability of benzoyl peroxide were studied by Cheliquist et al. in ethanol, propylene glycol and various mixtures of polyethylene 5 glycol 400 (PEG 400) and water (Chalilquist E.M. and Gorman W.G,, Pharm, Res., 1992, Vol 9: 1341-1346). Benzoyl peroxide is particularly soluble in PEG400 and ethanol, as shown in the following table: Solvent Benaoyl peroxide 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 10 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 15 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 20 and of its concentration. The degradation times for benzoyl peroxide in PEG 400 4 (0.5 mg/g), in ethanol and in propylene glycol are, respectively, 1.4, 29 and 53 days at 40 0 C, Such a degradation does not allow the preparation of a product intended for sale. 5 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 10 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 15 product is still observed. 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 20 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. 25 A study of the stability of two retinoids was performed by combining two commercial products, one containing a retinoid (tretinoin or adapalene) and the 5 second based on benzoyl peroxide (B. Martin et al., Br.J.Dermatol, (1998) 139, supply . 52), 8-11). The presence of the formulation based on benzoyl peroxide results in very rapid degradation of the 5 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 10 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 15 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 20 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 25 it impairs the efficacy of the composition containing them. Moreover, a finished product, in particular 6 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 5 these criteria, it is necessary for the rheological properties to be maintained. They define the behaviour and texture of the composition during application, but also the active principle's release properties [1998 SFSTP Commission Report] and the homogeneity of the 10 product when the active principles are present therein in dispersed form. 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, 15 since it especially avoids a greasy feel being left on the skin. 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 20 destabilized by the bensoic acid released during the degradation of the benzoyl peroxide. Specifically, the thickeners most commonly used for formulating these compositions with benzoyl peroxide are acrylic acid polymers (Carbomer) and celluloses 25 alone or combined with silicates. Now, the use of carbomers in compositions of aqueous gel type does not give good results in terms oZ 7 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 201 5 benzoyl peroxide is lost after 2 months at 40 0 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. 10 In other gels consisting of a mixture of hydroxypropyl cellulose and aluminium 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 15 product. This instability of benzoyl peroxide gels impairs their efficacy and their cosmetic utility. There is thus still a need for a physically stable gelled composition containing benzoyl peroxide 20 and a retinoin. 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 25 with good physical stability, i.e. not showing a drop in viscosity over time and at temperatures of between 4 and 40 0 C, and maintaining good chemical stability of -8 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 400C is observed. The Applicant has also discovered, surprisingly, that total 5 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, 10 while at the same time ensuring the physical stability of the product. The invention thus relates to a composition comprising, in a physiologically acceptable medium, at least one retinoid, dispersed benzoyl peroxide and at 15 least one pH-independent gelling agent. More specifically, the present invention provides a dermatological/cosmetic composition comprising, in a physiologically acceptable medium, (i) at least one dispersed retinoid, (ii) dispersed benzoyl peroxide, in 20 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, and (c) modified starch gelling 25 agents, said composition maintaining good chemical stability of (i) and (ii) without their degradation over time at a temperature of between 4GC and 400C. The present invention also provides a process for preparing the composition as described above, comprising 30 successively conducting the following steps: (a) preparing an aqueous phase which comprises water and optionally further comprises a chelating agent and/or a pro-penetrating agent and/or a humectant; (b) preparing an active phase which comprises the mixture 3.5 in water of the retinoid and benzoyl peroxide, said mixture optionally further comprising a liquid wetting surfactant and/or a pro-penetrating agent, Niebue ae\aeW30490P6 SA~tpedmeP53l2AU 1SpnfemeM 20Q5-121 doe21hi,/De -8A with stirring; (c) introducing the active phase into the aqueous phase, with stirring; and (d) introducing the gelling agent into the mixture 5 obtained from step (c), with stirring. The present invention also provides a process for preparing the composition as described above, comprising successively conducting the following steps: (a) preparing an aqueous phase which comprises water and 10 optionally further comprises a chelating agent and/or a pro-penetrating agent and/or a humectant; (b) preparing two active agents, one comprising the mixture in water of the retinoid, the other comprising the mixture in water of benzoyl peroxide 15 and optionally further comprising a liquid wetting surfactant and/or a pro-penetrating agent, with stirring; (c) introducing the active phases into the aqueous phase, with stirring; and 20 (d) introducing the gelling agent into the mixture obtained from step (c), with stirring. The present invention also provides a regime or regimen for inhibiting or treating dermatological afflictions associated with cell differentiation and/or 25 proliferation disorders and/or keratinization disorders, or common acne, or for treating acne-prone skin, for regrowth of the hair or for inhibiting hair loss, for combating the greasy appearance of the skin or the hair, in protecting against the harmful effects of sunlight or 30 in the treatment of physiologically dry skin, or for inhibiting and/or combating signs of photo-induced or chronological aging, comprising administering to an individual subject in need of such treatment, an effective amount of the composition as described above. NA~eD01rri~emg\Puen15000.5990453WA~m aIPM WAIJ.1 5pananduon 2008-11-*21.de 211iJ08i - 8B The present invention also provides a dermatological/cosmetic composition comprising, in a physiologically acceptable medium, (i) at lest one dispersed retinoid, (ii) dispersed benzoyl peroxide, in 5 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, and (c) modified starch gelling 10 agents, said composition having good physical stability without loss of viscosity over time at a temperature ranging from 4 0 C to 40 0 C, said composition having a stable flow threshold over time as measured by viscosity measurements for rheograms which measure a shear stress T 15 for a given rate gradient y and which measure a rate gradient y for a given shear stress T, the yield value (TO) being extrapolated visually or by calculation. The composition according to the invention is preferably in the form of an aqueous gel. 20 The term "aqueous gel" means a composition containing, in an aqueous phase, a viscoelastic mass formed from colloidal suspensions (gelling agent). The expression "pH-independent gelling agent" means a gelling agent capable of giving the composition a 25 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. Non-limiting examples that may be mentioned 2653026_1 (GHMatters) P53025.AU.1 27/04/11 include the gelling agents of the polyacrylamide family, such as the mixture of sodium acryloyldimethyltaurate copolymer/isohexadecane/polysorbate 80 sold under the 5 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 10 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 15 mixture of propylene glycol (39%) and water (26%)), the family of modified starches, such as the modified potato starch sold under the name Structure Solanace, or mixtures thereof. The preferred gelling agents are derived from 20 the polyacrylamide family, such as Simulgel 600 or Sepigel 305, or mixtures thereof. The gelling agent as described above may be used in preferential concentrations ranging from 0.1* to 15% and more preferably ranging from 0.5W to 5t. 25 The composition according to the invention contains at least one retinoid. The term "retinoid" means any compound that 10 binds to the RAR and/or RXR receptors. Preferably, the retinoid is a compound chosen from the family of benzonaphthalene retinoids as described in patent application EP 0 199 636. In 5 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. 10 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 15 applications, US 4,666,941, US 4,581,380, EP 0 210 929, EP 0 232 199, EP 0 260 162, EP 0 292 348, EP 0 325 540, EP 0 359 521, EP 0 409 728, EP 0 409 740, EP 0 552 282, EP 0 584 191, EP 0 514 264, EP 0 514 269, BP 0 661 260, EP 0 661 258, HP 0 658 553, EP 0 679 628, EP 0 679 631, 20 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, HP 0 915 823, EP 0 882 033, EP 0 850 909, EP 0 879 814, 25 EP 0 952 974, EP 0 905 118, EP 0 947 496, WO 98/56783, WO 99/10322, WO 99/50239, WO 99/65872. Needless to say, the amount of the'two active 11 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 5 desired treatment. The preferred retinoid concentrations are between 0.0001% and 205 by weight relative to the total weight of the composition. Benzoyl peroxide may also be used in free 10 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 15 POO9A Benzoyl peroxide by the company 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 ben2oyl 20 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 25 to the total weight of the composition. For example, in compositions for treating acne, the benzoyl peroxide is preferably used at 12 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 5 concentrations generally ranging from 0.05% to 1% by weight relative to the total weight of the composition. 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 10 preferably at least 90% in numerical terms of the particles, have a diameter of less than 25 pm and at least 99% in numerical terms of the particles have a diameter of less than 100 pm. According to the invention, the gel 15 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 20 one or more pro-penetrating agents in preferential concentrations ranging from a 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 25 percentage used, should not cause any exothermic reactions harmful to the benzoyl peroxide, should aid in the satisfactory dispersion of the active agents, 13 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, 5 lauroglycol and ethoxydiglycol. The pro-penetrating agent that is particularly preferred is propylene glycol. Advantageously, the compositions according to the invention may also contain one or more liquid 1o 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 15 (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. 20 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. The liquid wetting surfactant that is 25 particularly preferred is Poloxamer 124. The composition may also comprise any additive usually used in the cosmetics or 14 pharmaceutical field, such as sequestering agents, antioxidants, sunscreens, preserving agents, fillers, electrolytes, humectants, colorants, common mineral or organic acids or bases, fragrances, essential oils, 5 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 10 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, 15 These additives may be present in the composition in a proportion of from 0 to 201 by weight relative to the total weight of the composition. Examples of sequestering agents that may be mentioned include ethylenediaminetetraacetic acid 20 (EDTA), and also 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 25 ethanol, benzyl alcohol, diazolidinylurea and parabens, or mixtures thereof. Examples of humectants that may be mentioned 15 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 5 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 10 weight): - 0 to 901, preferably 5% to 251 and especially 101 to 201, of water; - 0 to 101, preferably 0 to 2% and especially 0 to 0.5%, of liquid wetting surfactant; 15 - 0 to 20%, preferably 0 to 10% and especially 21 to 51, of pro-penetrating agent; - 0.0001% to 20% and preferably 0.025% to 10%, of benzoyl peroxide; - 0.0001 to 20% and preferably 0,001% to 101, of 20 retinoid; and - an aqueous phase comprising a pM-independent gelling agent, and water. The aqueous phase of the emulsion according to the invention may comprise water, a floral water 25 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 16 Posay, eau de la Bourboule, eau d'Enghien-les-Bains, eau de Saint Gervais-les-Bains, eau de Ndris-les-Baine, eau d'Allevard-les-Bains, eau de Digne, eau de Maizieres, eau de Neyrac-les-Bains, eau de Lons-le 5 Saunier, les Eaux Bonnes, eau de Rochefort, eau de Saint Christau, eau des Fumades, eau de Tercis-les bains, eau d'Avine 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 10 between 20% and 80% by weight, relative to the total weight of-the composition. A composition that is preferred according to the invention comprises in water: 2.50% benzoyl peroxide, 15 - 0.10% adapalene, - 0.10% disodium EDTA, - 4.00% glycerol, - 4.00% propylene glycol, - 0.05% sodium docusate, 20 - 0.20% Poloxamer 124, - 4.00% sodium acryloyldimethyltaurate copolymer & isohexadecane & polysorbate 80, - sodium hydroxide, gs pH 5. A subject of the present invention is also 25 the composition as described above, as a medicinal product. The invention also relates to the use of the 17 novel composition as described above in cosmetics and dermatology. A subject of the invention is also a process for preparing a composition of aqueous gel type, 5 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: a) the preparation of an aqueous phase comprising 10 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 15 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 galling agent into the mixture obtained from step c), with stirring. 20 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; 25 a) the preparation of an aqueous phase comprising water and optionally a chelating agent and/or a pro penetrating agent and/or a humectant; 18 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 5 and/or of a pro-penetrating agent, with stirring; c) the introduction of the active phases into the aqueous phase, with stirring; and d) the introduction of the gelling agent into the mixture obtained from step c), with stirring, 10 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 15 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 20 diameter of less than 25 pm and at least 99% in numerical terms of the particles have a diameter of less than 100 pm in the composition. On account of the keratolytic, bactericidal and antiinflammatory activity of benzoyl peroxide and 25 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: 1) for treating dermatological complaints associated with a keratinization disorder relating to differentiation and proliferation, especially for 5 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, 10 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, 15 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 20 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, 25 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, 20 molluscum contagiosum and verruciform epidermodysplasia, oral or florid papillomatoses and proliferation that may be induced by ultraviolet radiation, especially in the case of actinic keratosis, 5 5) for repairing or combating ageing of the skin, whether photoinduced or chronological ageing, or for reducing pigmentation, or any pathology associated with chronological or actinic ageing, 6) for preventively or curatively treating 10 cicatrization disorders and skin ulcers, for preventing or repairing stretch marks, or for promoting cicatrization, 7) for combating sebaceous function disorders such as the hyperseborrhoea of acne or simple seborrhoea, 15 8) in the treatment of any complaint of fungal origin on the skin, such as tinea pedis and tinea versicolor, 9) in the treatment of dermatological complaints with an immunological component, 10) in the treatment of skin disorders caused by 20 exposure to UV rays, and 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, 25 especially impetigo, seborrhoeic dermatitis, folliculitis or sycosis barbae, or involving any other bacterial or fungal agent.
21 The compositions according to the invention are particularly suitable for preventively or creatively treating common acne. A subject of the invention also relates to 5 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 10 pharmaceutical preparation for preventing or treating common acne. The compositions according to the invention also find an application in cosmetics, in particular for treating acne-prone skin, for regrowth of the hair, 15 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 photoinduced or 20 chronological ageing. The compositions according to the invention also find an application in body and hair hygiene. The present invention thus relates also to the cosmetic use of a composition according to the invention 25 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 22 against harmful effects of sunlight or in treating physiologically dry skin, or for preventing and/or controlling photoinduced or chronological ageing. The formulation examples below illustrate the 5 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 10 compositions, are also described. I. FORMKULATION EXAMPLES In the compositions below (Examples 1 to 5), the proportions of the various constituents are 15 expressed as percentages by weight relative to the total weight of the composition. Example .: phase Components Active ENZOYL PEROXIDE 5.00% ADAPALENE 0.10% DIPROPYLENE GLYCOL 4.00% PURIFIED WATER 101 POLOXAMER 182 0. 20% Aqueous PURIFIED WATER qs 100% SILICA 0. 02% GLYCEROL 2.00% MICROSPONGES 4.00% Gelling POLYACRYLAMIDE (and) C13-14 3.50% _____S AFFIN (and) LAURETH-7 23 Example 2 Phase Components % Active BENZOYL PEROXIDE S% ADAPALENE 0.101 PURIFIED WATER 10.00% PROPYLENE GLYCOL 2.00% POLOXAMER 124 0.20-% Aqueous PURIFIED WATER qs 100% DISODIUM RDTA 0.10% GLYCEROL 4.00% PROPYLENE GLYCOL 2.00% SODIUM DOCUSATE 0.05% Gelling SODIUM ACRYLOYLDIMETHYLTAURATE 4.00% COPOLYMER & ISOHEXADECANE & POLYSORBATE 80 Example 3: Phase Components % Active BENZOYL PEROXIDE 2.50% ADAPALENE 0.10% PURIFIED WATER 10.00% PROPYLENE GLYCOL 2.00% POLOXAMER 124 0.20% Aqueous PURIFIED WATER qe 100% DISODIUM EDTA 0.10% GLYCEROL 4.00% PROPYLENE GLYCOL 2.00% SODIUM DOCUSATE 0.05% Gelling SODIUM ACRYLOYLDIMETHYLTAURATE 4.00% COPOLYMER & ISOHEXADECANE & POLYSORBATE 80 pH modifier SODIUM HYDROXIDE qs pH 5.00 24 Example 4; 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% DISODIUM EDTA 0.10% GLYCEROL 4.00% PROPYLENE GLYCOL 2.001 SODIUM C14-16 OLEFIN SULFONATE 0.05% Gelling PEG-150/decyj/SMDI copolymer 3.50% Examle 5: Phase Components % Active 1 BENZOYL PEROXIDE 2.50% 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 g8 100% DISODIUM EDTA 0.10% GLYCEROL 4.00% PROPYLENE GLYCOL 2.00% SODIUM DOCUSATE 0.05% Gelling SODIUM ACRYLOYLDIMETHYLTAURATE 4 .00% COPOLYMER & ISOHEXADECANE & POLYSORBATE 80 pH modifier SODIUM HYDROXIDE qs pH 500 25 II. EXAMPLES OF A PREPARATION PROCESS Example 6: The examples of a preparation process are 5 given in a non-limiting manner, The preparation presented is that of the composition that is the subject of Example 3: PROCEDURE PARAMETERS Introduce the following into T*: RT 0 C beaker (Phase 1): STIRRER: Rayneri - purified water PADDLE: deflocculating - disodium EDTA STIRRING: 350 rpm - glycerol TIME: 10 min Introduce the following into a TO: RT *C related beaker: STIRRER: stirring plate - propylene glycol PADDLE: magnetic bar - sodium docusate TURBOMIXER: N.A. Place under magnetic stirring TIME: 45 min until the sodium docusate is fully dissolved Active phase: Introduce the T 6 : RT + cold water bath following into a related beaker STIRRER: dispersed of suitable size: PADDLE: Polytron - propylene glycol (PG) STIRRING: 9 000 rpm - Poloxamer 124 TIME: 30 mi - purified water - benaoyl peroxide - adapalene Stir using a Polytrcn stirrer until the active agents are fully dispersed, in a bath of cold water to avoid overheating of the active agents.
26 When .the mixture of sodium TO: RT 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: TO: RT 0 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 TO: RT C S.00 1 0.3 with: STIRRER: Rayneri 10% sodium hydroxide, qs PADDLE: deflocculating STIRRING: 1 000-1 200 rpm TIME: 25 min The preparation given is that of the composition that is the subject of Example 5: PROCEDURE PARAMETERS Introduce the following into a TO: RT '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 27 Next, introduce the following: TO: RT "C - glycerol STIRRER: stirring plate PADDLE: deflocculating STIRRING: 350 rpm TIME: 5 min Active phase 1: Introduce the TO: 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 TO: RT + cold water bath following into a related beaker PADDLE: Ultra-Turrax of suitable size: STIRRING: 9 500 rpm - propylene glycol (PG) TIME: 15 mir - Poloxamer 124 - adapalene. Incorporate the active phase 2 T": RT "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: TO: RT "C - Simulgel 600 STIRRER: Rayneri Stir using a Rayneri stirrer for PADDLE: deflocculating the time required for good STIRRING: 680 rpm homogeneity of the finished TIME: 35 min product.
28 Neutralization: Adjust the pH to TO: RT OC 5.00 1 0.3 with: STIRRER: Rayneri 10% sodium hydroxide, qs PADDLE: deflocculating STIRRING: 680 rpm TIME: 25 min III. STABILITY STUDY 5 Example 6: Physical stability of the composition by measuring the flow threshold (in Pa.s 1 ) The tests performed are viscosity measurements for plotting curves known as rheograms, which make it possible, for a given rate gradient y, to 10 measure a shear stress T, and for a given shear stress T, to measure a rate gradient y ("Initiation & la rheologie" [Introduction to rheology Gouarraze Grossiord 1991; "La viscosity et sa mesure dans les pharmacop6es" [Viscosity and its measurement in 15 pharmacopoeias]; L. Molle, Journal Pharma Belg. 1975, 30, 5-6, 597-619). The term "yield value" means the force required (minimum shear stress) to overcome the cohesion forces of Van der Waals type and to bring 20 about flow. The yield value (TO) is extrapolated either visually (y-axis at the origin of the rheograms) or by calculation (application of mathematical models).
29 Composition of the gels used: Aqueous gel based on carbomer Constituents% PURIFIED WATER ga 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 MICROSPONGES qs 2.5% BPO ADAPALENE 0.10 10% SODIUM HYDROXIDE 2.00 qs pH 5 Aqueous gel based on hydroxypropylcellulose 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) 0.50 HYDROXYPROPYLCELLULOSE (NATROSOL HHX) 1.50 PROPYLENE GLYCOL 4.00 SODIUM DOCUSATE 0.05 POLOXAMER 124 0.20 BENZOYL PEROXIDE MICROSPONGES qs 2.5% BPO ADAPALRNE 0.10 30 Example 2 in Aqueous gel Aqueous gel based accordance based on on hydroxypropyl with the carbomer cellulose and invention aluminium magnesium silicate Temperature RT T40 0 C RT T40 0 C RT T40 0 C T initial 137 / 111 / 170 T 1 month 139 137 135 111 183 93 T 2 months 147 121 159 65 T 3 months 149 127 100 76 147 34 RT: room temperature T40*C: storage at 40 0 C The yield value of the composition according to the 5 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 0 C. These results demonstrate the very good physical stability of the composition 10 according to the invention over time, unlike the standard compositions of aqueous gels. Example 7: Stability of benzoyl peroxide over time and as a function of the storage temperature by measuring 15 the amount of benzoyl peroxide in the composition (in percentages) The percentages of benzoyl peroxide (BPO) presented in the table below were obtained by measuring 31 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. 5 When the potassium iodide is added, a colour 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: 10 12 + 2 Na 2
S
2 03 -- > 2 Nal + NaaS 4 0 6 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. Example 2 in Aqueous gel Aqueous gel based accordance with based on on hydroxypropyl the invention carbomer cellulose and aluminium magnesium silicate Temperature RT T40*C RT T40*C RT T40OC k BPO at T 100 / 94,3 / 101.7 initial % BPO at T Not 102.5 95.7 90,3 / 94.9 1 month performed t BPO at T Not 99.1 94.3 95.5 / 87.3 2 months performed % BPO at T 102.4 100.3 94 78.3 99.7 85.6 3 months - 32 In the composition of Example 2, the percentage of benzoyl peroxide over time remains stable and equivalent to 100k both at room temperature and at 400C. The benzoyl peroxide present in the other two examples of 5 prior-art aqueous gels degrades significantly over time. After 3 months, a loss of benzoyl peroxide that is up to 6k at room temperature and at least 141 at T40 0 C may be observed. These results demonstrate that the compositions according to the invention allow very good stability of 10 benzoyl peroxide over time, even at 40 0 C, unlike standard compositions. It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part is of the common general knowledge in the art, in Australia or any other country. In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary 20 implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention. 25 N:WibOumen sjeg003BBP32 AU.j\E~p6 5 ANi Specnhanoln 2005.-1121,doc gi(1 i/Og
Claims (30)
1. A dermatological/cosmetic composition comprising, in a physiologically acceptable medium, (i) at least one s 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 10 hydrophobic chains, and (c) modified starch gelling agents, said composition maintaining good chemical stability of (i) and (ii) without their degradation over time at a temperature of between 40C and 40*C. 15
2. The composition as defined by claim 1, wherein the at least one pH-independent gelling agent is selected from the group consisting of (a) polyacrylamide gelling agents selected from the group consisting of a mixture of sodium acryloyldimethyltaurate copolymer/isohexane/polysorbate 20 80, a mixture of polyacrylamide/isoparaffin C13 14/laureth-7 and a mixture of said mixtures; (b) gelling agents which are acrylic polymers coupled to hydrophobic chains selected from the group consisting of PEG 150/decyl/SMDI copolymers; (c) modified potato starch 25 gelling agents; and mixtures thereof.
3. The composition as defined by claim 2, wherein the at least one pH-independent gelling agent is selected from the group consisting of: 30 (1) a mixture of sodium acryloyldimethyltaurate copolymer/isohexane/polysorbate 80, (2) a mixture of a mixture of polyacrylamide/isoparaffin C13-14/laureth-7, (3) a PEG-150/decyl/SMDI copolymer which is 35 polycondensate comprising at least, as components, a polyethylene glycol containing 150 or 180 mol of ethylene oxide, decyl alcohol and methylenebis(4 2615121_1 (GHMatter) P53025 AU.1 - 34 cyclohexyl isocyanate) (SMDI), and (4) mixtures thereof.
4. The composition as defined by any one of claims 1 to 5 3, wherein the retinoid is adapalene.
5. The composition as defined by claim 4, comprising between 0.1% and 1% by weight of adapalene and between 2% and 10% by weight of benzoyl peroxide. 10
6. The composition as defined by claim 5, comprising between 2.5% and 5% by weight of benzoyl peroxide.
7. The composition as defined by any one of claims 1 to 15 6, wherein good chemical stability of (i) and (ii) without their degradation is maintained over a period of time of at least 3 months.
8. The composition as defined by any one of claims 1 to 20 7, comprising from 0.1% to 15% of said pH-independent gelling agent.
9. The composition as defined by any one of claims 1 to 8, further comprising at least one pro-penetrating agent. 25
10. The composition as defined by claim 9, said at least one pro-penetrating agent comprising propylene glycol.
11. The composition as defined by any one of claims 1 to 30 10, further comprising at least one liquid wetting surfactant.
12. The composition as defined by claim 11, said at least one liquid wetting surfactant comprising a poloxamer. 35
13. A process for preparing the composition as defined by any one of claims 1 to 12, comprising successively 2615121_1 (GHMatters) P53025.AU 1 - 35 conducting the following steps: (a) preparing an aqueous phase which comprises water and optionally further comprises a chelating agent and/or a pro-penetrating agent and/or a humectant; s (b) preparing an active phase which comprises the mixture in water of the retinoid and benzoyl peroxide, said mixture optionally further comprising a liquid wetting surfactant and/or a pro-penetrating agent, with stirring; 10 (c) introducing the active phase into the aqueous phase, with stirring; and (d) introducing the gelling agent into the mixture obtained from step (c), with stirring. is
14. A process for preparing the composition as defined by any one of claims 1 to 12, comprising successively conducting the following steps: (a) preparing an aqueous phase which comprises water and optionally further comprises a chelating agent and/or 20 a pro-penetrating agent and/or a humectant; (b) preparing two active agents, one comprising the mixture in water of the retinoid, the other comprising the mixture in water of benzoyl peroxide and optionally further comprising a liquid wetting 25 surfactant and/or a pro-penetrating agent, with stirring; (c) introducing the active phases into the aqueous phase, with stirring; and (d) introducing the gelling agent into the mixture 30 obtained from step (c), with stirring.
15. A regime or regimen for inhibiting or treating dermatological afflictions associated with cell differentiation and/or proliferation disorders and/or 35 keratinization disorders, comprising administering to an individual subject in need of such treatment, an effective amount of the composition as defined by any one of claims 26151211 (GHMatters) P53025.AU.1 - 36 1 to 12.
16. A regime or regimen for inhibiting or treating common acne, comprising administering to an individual subject in 5 need of such treatment, an effective amount of the composition as defined by any one of claims 1 to 12.
17. A regime or regimen for treating acne-prone skin, for regrowth of the hair or for inhibiting hair loss, for 10 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 inhibiting and/or combating signs of photo-induced or chronological aging, comprising administering to an is individual subject in need of such treatment, an effective amount of the composition as defined by any one of claims 1 to 12.
18. Use of (i) at least one dispersed retinoid, (ii) 20 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, and (c) modified 25 starch gelling agents in the manufacture of a composition for inhibiting or treating dermatological afflictions associated with cell differentiation and/or proliferation disorders and/or keratinization disorders, or for inhibiting or treating common acne, or for treating acne 30 prone skin, for regrowth of the hair or for inhibiting 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 inhibiting and/or combating signs of photo-induced 35 or chronological aging, said composition maintaining good chemical stability of (i) and (ii) without their degradation over time at a temperature of between 4 0 C and 26151211 (GHMatsHM) P53025.AU.1 - 37 40*C.
19. A dermatological/cosmetic composition comprising, in a physiologically acceptable medium, (i) at least one 5 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 io hydrophobic chains, and (c) modified starch gelling agents, said composition having good physical stability without loss of viscosity over time at a temperature ranging from 4 0 C to 400C, said composition having a stable flow threshold over time as measured by viscosity is measurements for rheograms which measure a shear stress T for a given rate gradient y and which measure a rate gradient y for a given shear stress T, the yield value (TO) being extrapolated visually or by calculation.
20 20. The composition as defined by claim 19, having good physical stability without loss of viscosity over a period of time of at least 3 months.
21. The composition as defined by claim 19 or 20, having 25 a stable flow threshold greater than 100% for a period of time of at least 3 months.
22. The composition as defined by any one of claims 19 to 21, wherein (i) and (ii) are homogenously dispersed. 30
23. The composition as defined by claim 22, wherein at least 80% in numerical terms of the particles have a diameter of less than 25 pm and at least 99% in numerical terms of the particles have a diameter of less than 100 35 pm.
24. The composition as defined by claim 23, wherein at 2615121_1 (GHMatters) P53025 AU.1 - 38 least 90% in numerical terms of the particles have a diameter of less than 25 pm.
25. The composition as defined by any one of claims 19 to 5 24, comprising from 0.1% to 15% of said pH-independent gelling agent.
26. The composition as defined by claim 25, said pH independent gelling agent comprising a polyacrylamide. 10
27. The composition as defined by any one of claims 19 to 26, comprising from 0.0001% to 20% of said at least one retinoid. 15
28. The composition as defined by claim 27, wherein the retinoid is adapalene.
29. The composition as defined by any one of claims 19 to 28, comprising 0.0001% to 20% of benzoyl peroxide. 20
30. A composition as defined in claim 1 or claim 19, a process for preparing the composition, a use or method involving the composition, or a regime or regimen comprising the composition, substantially as herein 25 described with reference to the accompanying Examples.
2615121.1 (GHMatters) P53025 AU 1
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2008246274A AU2008246274B2 (en) | 2001-12-21 | 2008-11-21 | Gel comprising at least a retinoid and benzoyl peroxide |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0116747A FR2833841B1 (en) | 2001-12-21 | 2001-12-21 | GEL COMPRISING AT LEAST ONE RETINOID AND BENZOYL PEROXIDE |
| FR0116747 | 2001-12-21 | ||
| PCT/FR2002/004233 WO2003055472A1 (en) | 2001-12-21 | 2002-12-09 | Gel comprising at least a retinoid and benzoyl peroxide |
| AU2002364437A AU2002364437B2 (en) | 2001-12-21 | 2002-12-09 | Gel comprising at least a retinoid and benzoyl peroxide |
| AU2008246274A AU2008246274B2 (en) | 2001-12-21 | 2008-11-21 | Gel comprising at least a retinoid and benzoyl peroxide |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2002364437A Division AU2002364437B2 (en) | 2001-12-21 | 2002-12-09 | Gel comprising at least a retinoid and benzoyl peroxide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2008246274A1 AU2008246274A1 (en) | 2008-12-11 |
| AU2008246274B2 true AU2008246274B2 (en) | 2011-05-19 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2002364437A Expired AU2002364437B2 (en) | 2001-12-21 | 2002-12-09 | Gel comprising at least a retinoid and benzoyl peroxide |
| AU2008246274A Expired AU2008246274B2 (en) | 2001-12-21 | 2008-11-21 | Gel comprising at least a retinoid and benzoyl peroxide |
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| Application Number | Title | Priority Date | Filing Date |
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| AU2002364437A Expired AU2002364437B2 (en) | 2001-12-21 | 2002-12-09 | Gel comprising at least a retinoid and benzoyl peroxide |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP1458369B1 (en) |
| JP (2) | JP4889922B2 (en) |
| KR (1) | KR101014586B1 (en) |
| CN (1) | CN1329025C (en) |
| AR (1) | AR038026A1 (en) |
| AT (1) | ATE347354T1 (en) |
| AU (2) | AU2002364437B2 (en) |
| BR (1) | BRPI0214264B8 (en) |
| CA (1) | CA2466321C (en) |
| CY (1) | CY1107583T1 (en) |
| DE (2) | DE122008000041I1 (en) |
| DK (1) | DK1458369T3 (en) |
| ES (1) | ES2275948T3 (en) |
| FR (2) | FR2833841B1 (en) |
| HU (1) | HU230439B1 (en) |
| MX (1) | MXPA04005918A (en) |
| PL (1) | PL220838B1 (en) |
| PT (1) | PT1458369E (en) |
| RU (1) | RU2320327C2 (en) |
| SI (1) | SI1458369T1 (en) |
| WO (1) | WO2003055472A1 (en) |
| ZA (1) | ZA200403759B (en) |
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| FR2833841B1 (en) * | 2001-12-21 | 2005-07-22 | Galderma Res & Dev | GEL COMPRISING AT LEAST ONE RETINOID AND BENZOYL PEROXIDE |
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| FR2916966B1 (en) * | 2007-06-11 | 2011-01-14 | Galderma Res & Dev | COMPOSITIONS COMPRISING AT LEAST ONE RETINOID COMPOUND, ANTI-IRRITANT COMPOUND AND BENZOYL PEROXIDE, AND USES THEREOF |
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| FR2969492B1 (en) * | 2010-12-23 | 2013-07-05 | Galderma Res & Dev | DERMATOLOGICAL FOAMS OBTAINED FROM GEL OR SUSPENSION CONTAINING ADAPALENE |
| US8563535B2 (en) | 2011-03-29 | 2013-10-22 | Kamal Mehta | Combination composition comprising benzoyl peroxide and adapalene |
| EP2854791A1 (en) | 2012-05-25 | 2015-04-08 | Galderma Research & Development | Treatment of preadolescent moderate acne vulgaris |
| US10610594B2 (en) * | 2012-11-13 | 2020-04-07 | Galderma S.A. | BPO wash gel composition |
| US9687465B2 (en) | 2012-11-27 | 2017-06-27 | Sol-Gel Technologies Ltd. | Compositions for the treatment of rosacea |
| EP3082785A1 (en) | 2013-12-19 | 2016-10-26 | Galderma Research & Development | Therapy regimen for treating severe acne related diseases |
| AU2015239688B2 (en) | 2014-04-01 | 2020-06-25 | Galderma Research & Development | Combination of adapalene and benzoyl peroxide for treating acne scars |
| MA40179B1 (en) | 2014-07-25 | 2020-10-28 | Galderma Res & Dev | Combination of adapalene and benzoyl peroxide for the treatment of severe acne |
| MX2018002176A (en) * | 2015-08-20 | 2018-06-15 | Sol Gel Tech Ltd | Compositions for topical application comprising benzoyl peroxide and adapalene. |
| WO2018080284A1 (en) * | 2016-10-31 | 2018-05-03 | (주)동구바이오제약 | Pharmaceutical composition for enhancing bioavailability of drug for treatment of acne |
| CN106729722B (en) * | 2016-11-21 | 2020-05-12 | 成都山信药业有限公司 | Method for preparing stable compound preparation and compound preparation |
| SG11202111028YA (en) * | 2019-04-04 | 2021-11-29 | Galderma Hoding Sa | Isopropylcarbonate benzoyl peroxide compositions and methods of use |
| WO2023112664A1 (en) * | 2021-12-14 | 2023-06-22 | ロート製薬株式会社 | Pharmaceutical composition for external application which contains benzoyl peroxide |
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| FR2628319B1 (en) * | 1988-03-09 | 1990-12-07 | Oreal | PHARMACEUTICAL AND COSMETIC COMPOSITIONS BASED ON BENZOYL PEROXIDE AND QUATERNARY AMMONIUM SALTS |
| US5470884A (en) * | 1994-05-19 | 1995-11-28 | Procter & Gamble | Anti-acne compositions |
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