`
`US 20110135584A1
`
`(19) United States
`(12) Patent Application Publication (lO) Pub. No.: US 2011/0135584 A1
`MALLARD (43) Pub. Date: Jun. 9, 2011
`
`(54) PHARMACEUTICAL/COSMETIC, E.G.,
`ANTI-ACNE COMPOSITIONS COMPRISING
`AT LEAST ONE NAPHTHOICACID
`COMPOUND, BENZOYL PEROXIDE ANDAT
`LEAST ONE FILM-FORMING AGENT
`
`(75)
`
`Inventor:
`
`Claire MALLARD, Mougins (FR)
`
`(73) Assignee:
`
`GALDERMARESEARCH &
`DEVELOPMENT, Biot (FR)
`
`Publication Classification
`
`(51)
`
`Int. C1.
`AglK 8/22
`(2006.01)
`A61K 31/327
`(2006.01)
`A61Q 17/04
`(2006.01)
`AglP 17/10
`(2006.01)
`A61Q 5/00
`(2006.01)
`AglQ 19/08
`(2006.01)
`(52) U.S. C1 ............................................ 424159; 514/714
`
`ABSTRACT
`(57)
`(21) Appl. No.: 121788,865 Stable pharmaceutical/cosmetic compositions for topical
`
`application, notably for the treatment of acne vulgaris
`(22) Filed: May27,2010 include, formulated into a physiologically acceptable
`
`Related U.S. Application Data
`
`(63) Continuation of application No. PCT/FR2008/
`052169, filed on Dec. 1, 2008.
`
`medium, at least one naphthoic acid compound, benzoyl per-
`oxide and at least one film-forming agent, the at least one
`naphthoic acid compound and the benzoyl peroxide advanta-
`geously being in a dispersed form therein.
`
`1 of 20
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`Almirall EXHIBIT 2048
`Amneal v. Almirall
`IPR2018-00608
`
`
`
`US 2011/0135584 A1
`
`Jun. 9, 2011
`
`1
`
`PHARMACEUTICAL/COSMETIC, E.G.,
`ANTI-ACNE COMPOSITIONS COMPRISING
`AT LEAST ONE NAPHTHOIC ACID
`COMPOUND, BENZOYL PEROXIDE AND AT
`LEAST ONE FILM-FORMING AGENT
`
`CROSS-REFERENCE TO PRIORITY
`APPLICATIONS
`
`[0001] This application claims priority under 35 U.S.C.
`§ 120 of U.S. Provisional Application No. 61/004,763, filed
`Nov. 30, 2007 and is a continuation of PCT/FR 2008/052169,
`filed Dec. 1, 2008 and designating the United States (pub-
`lished in the French language on Jun. 25, 2009 as WO 2009/
`077693 A2; the title and abstract were also published in
`English), each hereby expressly incorporated by reference in
`its entirety and each assigned to the assignee hereof,
`
`BACKGROUND OF THE INVENTION
`
`1. Technical Field of the Invention
`[0002]
`[0003] The presenI invention relates to compositions for
`topical application, to processes for preparing such composi-
`tions and to applications thereof as cosmetic or pharmaceu-
`tical products, the compositions being particularly usefill for
`treating ache.
`2. Description of Background and/or Related and/or
`[00041
`Prior Art
`[0005] Ache is a common multi-factor pathology that
`attacks skin rich in sebaceous glands (face, shoulder area,
`arms and intertriginous areas). It is the most commonly
`occurring form of dermatosis. The following five paflmgenic
`factors play a determining role in the development of ache:
`1. genetic predisposition;
`[0006]
`2. overproduction of sebum (seborrhoea);
`[0007]
`[0008]
`3. androgens;
`[0009] 4. follicular keratinization disorders (comedogen-
`esis); and
`5. bacterial colonization and inflammatory factors,
`[0010]
`[0011] There are several forms of ache, the common factor
`of all of them being attack of the pilosebaceous follicles,
`Exemplary are ache conglobata, ache keloid on the nape of
`the neck, ache medicamentosa, recurrent miliary ache, ache
`necrotica, acneneonatorum, premenstrual ache, occupational
`acne, acne rosacea, senile acne, solar acne and acne vulgaris.
`[0012] Acne vulgaris, also known as polymorphous juve-
`nile acne, is the most common. It comprises four stages, but it
`is not necessary to pass through all the stages:
`[0013] Stage 1 corresponds to comedonal acne, character-
`ized by a large number of open and/or closed comedones and
`of microcysts.
`[0014] Stage 2, or papulopustular acne, is of mild to mod-
`erate seriousness. It is characterized by the presence of open
`and!or closed comedones and microcysts, but also of red
`papules and of pustules. It mainly affects the face and leaves
`few scars.
`[0015] Stage 3, or papulocomedonal ache, is more serious
`and extends to the back, the thorax and the shoulders. It is
`accompanied by a larger number of scars,
`[0016] Stage 4, or nodulocystic acne, is accompanied by
`numerous scars. It exhibits nodules and also has large painfill
`purplish pustules,
`[0017] The various forms of ache described above can be
`treated with active agents, such as antiseborrhoeics and anti-
`infectives, for example benzoyl peroxide (in particular, the
`
`product Eclaran® marketed by Pierre Fabre), with retinoids,
`such as tretinoin (in particular, the product Retacnyl® mar-
`keted by Galderma) or isotretinoin (the product Roaccutane®
`marketed by Laboratoires Roche), or with naphthoic acid
`compounds. Naphflmic acid compounds, such as, in particu-
`lar, 6-[3-(1-adamantyl)-4-metkoxyphenyl]-2-naphthoic acid,
`commonly known as adapalene (file product Differine® mar-
`keted by Galderma), are widely described and recognized as
`active ingredients which are as effective as tretinoin in the
`treatment of ache.
`[0018] The combination of several local treatments (anti-
`biotics, retinoids, peroxides, zinc) is also used in dermatology
`to increase the efficacy of tJae active ingredients and to reduce
`their toxicity (Cunliffe W. J., J. Dermatol. Treat., 2000, 11
`(suppl. 2), S 13-S 14) but the multiple application of various
`dermatological products can be quite laborious and demand-
`ing for the patient.
`[0019] The advantage of providing a new treatment which
`is effective under dermatological conditions, in a stable com-
`position oflbring good cosmeticity, and which can be applied
`just once and is pleasant for the patient to use, is flaerefore
`apparent.
`[0020] Among this panoply of flaerapeutics proposed to
`those skilled in the art, none would enconrage one to corn-
`bine, in the same composition, benzoyl peroxide and a retin-
`oid.
`[0021] However, the tbrmulation of such a composition
`presents several problems.
`[0022] First, the efficacy ofbenzoyl peroxide is linked to its
`decomposition when it is brought into contact with the skin.
`In tact, it is the oxidizing properties of the free radicals
`produced during this decomposition which result in the
`desired effect. Thus, to maintain optimum efficacy of the
`benzoyl peroxide, it is important to prevent it from decom-
`posing before use, i.e., during storage.
`[0023] However, benzoyl peroxide is an unstable chemical
`compound, which makes it difficult to formulate it into final
`products.
`[0024] The solubility and stability of benzoyl peroxide
`have been studied by Chellquist et al. in ethanol, propylene
`glycol and various mixtures of polyethylene glycol 400 (PEG
`400) and water (Chellquist E. M. and Gorman W. G., Pharm.
`Res., 1992, Vol. 9:1341-1346).
`[0025] This prior art specifies, moreover, that the stability
`of benzoyl peroxide is greatly influenced by the chemical
`compo sition of the formulation and by the storage tempera-
`ture thereof. Benzoyl peroxide is extremely reactive and
`degrades in solution at low temperature due to the instability
`of its peroxide bond.
`[0026] The authors thus note that benzoyl peroxide in sohi-
`tion degrades more or less rapidly in all of the solvents stud-
`ied, dependingonthetypeofsolvent andonflaeconcentration
`flaereof.
`[0027] The degradation times of benzoyl peroxide in PEG
`400 (0.5 mg/g), in ethanol and in propylene glycol are,
`respectively, 1.4, 29 and 53 days at 40° C.
`[0028] Such a degradation does not make it possible to
`formulate a product intended for sale.
`[0029] AnotJaerdifficultytobeovercomeintheformulation
`of a composition comprising both benzoyl peroxide and a
`retinoid is that most retinoids are particularly sensitive to
`natural oxidation, to visible light and to ultraviolet radiation,
`and since benzoyl peroxide is a strong oxidizing agent, the
`chemical compatibility of these compounds in the same for-
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`said naphthoic acid compound and said benzoyl peroxide
`being in a dispersed form in said composition.
`
`mulation poses numerous problems of stability from the
`physical and chemical point of view.
`[0030] A study of the stability of two retinoids was carried
`out by combining two commercially available products, one
`containing a retinoid (tretinoin or adapalene) and the second
`being benzoyl peroxide-based (B. Martin et al., Br. J. Derma-
`tol. (1998) 139 (suppl. 52), 8-11).
`[0031] The presence of the benzoylperoxide-based formu-
`lation causes very rapid degradation of the oxidation-sensi-
`tive retinoids: it is measured that 50% of the tretinoin
`degrades in 2 hours, and 95% in 24 hours. In the composition
`in which the retinoid is adapalene, no degradation of the
`adapalene was measured for 24 hours. This study confirms
`that benzoyl peroxide is degraded and degrades oxidation-
`sensitive retinoids overtime, gradually releasing benzoic acid
`into final products,
`[0032] However, it is apparent that the degradation of ben-
`zoyl peroxide and ofretinoids is undesirable since it is detri-
`mental to the effectiveness of the composition containing
`them.
`[0033] Nothing would prompt the combination of these two
`active agents to obtain a stable composition, given that it was
`customarily known that the presence of benzoyl peroxide
`chemically and physically destabilized this type of composi-
`tion. [0046] Finally, this invention also features the formulation
`ofacompositionasdescribedabove, intomedicamentsuseful
`[0034] Furthermore, those skilled in the art are constantly
`for the treatment and/or prevention of dermatological condi-
`seeking to improve the efficacy and tolerance of compositions
`tions/afftictions associated with a keratinization disorder
`containing benzoyl peroxide and a naphthoic acid compound,
`relating to cell differentiation and proliferation, and in par-
`One of the solutions for improving the efficacy is to increase
`ticular for preventing and/or treating comedonal acne, acne
`the amounts of active agents present in the composition or to
`vulgaris, papulocomedonal ache, nodulocystic ache, poly-
`increase the treatment times. Such modifications generally
`result in an increase in the induced irritation. For this reason,
`morphic ache, ache rosacea, ache conglobata, senile ache, or
`it is necessary to provide compositions that can further
`else secondary ache such as solar ache, acne medicamentosa
`improve the tolerance of the active ingredients,
`or occupational acne.
`
`[0043] According to the invention, the term "active agent in
`dispersed tbrm" means an active ingredient in the form of
`solid particles, suspended in a given carrier. Such particles are
`in particular greater than 10 ~tm in size.
`
`[0044] Advantageously, the particle size of the retinoid and
`of the benzoyl peroxide is such that at least 80% by number of
`the particles, and preferably at least 90% by number of the
`particles, have a diameter of less than 25 Nn, and at least 99%
`by number of the particles have a diameter of less than 100
`
`Nn"
`[0045] The present invention also features a process for
`formulating a composition for topical application, compris-
`ing the step of mixing a physiologically acceptable carrier
`including at least one naphthoic acid derivative and benzoyl
`peroxide with at least one film-forming agent, saidnaphthoic
`acid compound and the benzoyl peroxide being in a dispersed
`form in said composition. The term "physiologically accept-
`able carrier" means a carrier compatible with the skin, the
`mucous membranes and/or the integuments.
`
`[0047] When a composition comprises, in a physiologi-
`cally acceptable medium, at least one naphthoic acid com-
`pound, benzoyl peroxide and at least one film-forming agent,
`said naphthoic acid compound and the benzoyl peroxide
`being in a dispersed form in said compo sition, it shows very
`good tolerance without modifying the amount of active agent
`that has penetrated into the skin.
`
`DETAILED DESCRIPTION OF BEST MODE
`AND SPECIFIC/PREFERRED EMBODIMENTS
`OF THE INVENTION
`
`[0048] The compositions according to the invention com-
`prise at least one naphthoic acid compound, benzoyl peroxide
`and at least one film-forming agent.
`[0049] Naphthoic acid is a compound having the formula:
`
`SUMMARY OF THE INVENTION
`
`[0035] The present invention provides compositions that
`are stable and less irritant than those of the prior art. Such
`compositions furthermore promote the topical penetration of
`the active ingredients in dispersed form.
`[0036] Thus, it has now surprisingly, been demonstrated
`that ingredients that are known for providing a composition a
`film-forming effect may also improve the tolerance of the
`combination of two irritant active ingredients, such as anti-
`ache active ingredients, and in particular benzoyl peroxide
`and naphthoic acid compounds, such as adapalene.
`[0037] Thus, the present invention provides compositions
`tbr topical application that are particularly efl~ctive, compris-
`ing at least one naphthoic acid compound and benzoyl per-
`oxide, devoid of an obviously irritant effect that would pre-
`vent same from being used over a relatively long term by the
`individual.
`[0038] This invention thus features compositions for topi-
`cal application, comprising, in a physiologically acceptable
`medium, at least one naphthoic acid compound and benzoyl
`peroxide and at least one film-forming agent, said naphthoic
`acid compound being in a dispersed form in said composition.
`[0039] Thus, the present invention features compositions,
`preferably pharmaceutical compositions, in particular for
`topical application, comprising, tbrmulated into a physiologi-
`cally acceptable medium, at least:
`(i) one naphthoic acid compound,
`[00401
`(ii) benzoyl peroxide, and
`[00411
`(iii) a film-forming agent,
`[0042]
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`[0050] The term "naphthoic acid compound" means those
`compounds of formula (I):
`
`o
`
`(i)
`
`in which R is a hydxogen atom, ahydxoxylradical, abranched
`or unbranched alkyl radical having from 1 to 4 carbon atoms,
`an alkoxy radical having from 1 to 10 carbon atoms or a
`substituted or unsubstituted cycloaliphatic radical,
`[0051] The term "linear or branched alkyl radical having
`from 1 to 4 carbon atoms" means, preferably, methyl, ethyl,
`propyl and butyl radicals.
`[0052] The term "alkoxy radical having from 1 to 10 carbon
`atoms" means, preferably, methoxy, ethoxy, propoxy, bntoxy,
`hexyloxy and decyloxy radicals,
`[0053] The term "cycloaliphatic radical" means, prefer-
`ably, monocyclic or polycyclic radicals such as the 1-meth-
`ylcyclohexyl radical or the 1-adamantyl radical.
`[0054] Among the naphthoic acid compounds that may be
`formulated into the compositions according to the invention,
`6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid
`(adapalene), 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naph-
`thoic acid, 6-[3-(1-adamantyl)-4-decyloxyphenyl]-2-naph-
`thoic acid and 6-[3-(1-adamantyl)-4-hexyloxyphenyl]-2-
`naphthoic acid will advantageously be selected,
`[0055] The abovementionednaphthoic acidcompounds are
`generally in a dispersed form in the composition according to
`the invention. The insoluble naphthoic acid compounds are
`thus uniformly distributed in the compositions according to
`the invention,
`In the compositions according to the invention, the
`[0056]
`naphthoic acid compounds are used at concentrations of less
`than or equal to 10% by weight relative to the total weight of
`the composition, and are preferably from 0.001% to 10% by
`weight relative to the total weight of the composition, and
`preferentially from 0.01% to 5%, more preferentially from
`0.05% to 2%, and most preferentially from 0.1% to 0.3% by
`weight relative to the total weight of the composition,
`[0057] Throughontthepresenttext, unless otherwise speci-
`fled, it is understood that, when concentration ranges are
`given, they include the upper and lower limits of said range,
`[0058] Advantageously, the naphthoic acid compound in
`the compositions according to the invention is 6-[3-(1-ada-
`mantyl)-4-methoxyphenyl]-2-naphthoic acid (adapalene).
`Preferably, in the case ofadapalene, the compositions accord-
`ing to the invention comprise from 0.001% to 5%, and advan-
`tageously from 0.01% to 1% by weight of adapalene, relative
`to the total weight of the composition, preferentially from
`
`0.01% to 0.5%, preferably from 0.1% to 0.4% by weight of
`adapalene, more preferentially still at 0.1% or at 0.3% by
`weight of adapalene.
`[0059] The subject compositions also comprise benzoyl
`peroxide (BPO).
`[0060] In the compositions according to the invention, the
`benzoyl peroxide is included at concentrations ranging from
`1% to 10% by weight, more particularly from 2% to 7% by
`weight, more preferentially still from 2.5% to 5% by weight,
`relative to the total weight of the composition.
`[0061] The benzoyl peroxide may equally be in the free
`form or else in an encapsulated form in a form adsorbed onto,
`or absorbed into, any porous support.
`[0062] It may, fbr example, be benzoyl peroxide encapsu-
`lated in a polymeric system composed of porous micro-
`spheres, for instance microsponges marketed under the trade-
`mark Microsponges P009A benzoyl peroxide by Cardinal
`Health.
`[0063] The compositions according to the invention also
`comprise at least one film-forming agent.
`[0064] The term "film-forming agent" means an ionic or
`nonionic hydrophilic polymer having a molecular mass at
`least greater than 10,000, which, during application to the
`skin, forms a continuous film. The applicant has demon-
`strated that these film-forming agents provide the composi-
`tions comprised thereof better tolerance.
`[0065] Examples of film-forming agents, include the poly-
`vinylpyrrolidones, which are preferably water-soluble, and
`soluble copolymers thereof, polysaccharides, with the exclu-
`sion of cellulose and derivatives thereof, in particular hydrox-
`ypropyl cellulose and xanthan gum, polyvinyl alcohols,
`acrylic copolymers and polyquaterniums.
`[0066] Among the polyvinylpyrrolidones and derivatives
`thereof, exemplary are poly- 1-vinyl-2-pyrrolidone, also
`known as povidone, or the polyvinylpyrrolidone/vinyl
`acetate copolymer, also known as copovidone, for instance
`Kollidon® VA64, Kollidon® 30, Kollidon® 90F or Kolli-
`don® K17PF.
`[0067] Examples ofpolysaccharides include the celluloses
`and derivatives, for instance carboxymethyl cellulose, and
`also exemplary are the pectins, gums such as karaya gum, and
`sodium hyaluronate marketed by Contipro.
`[0068] Examples of polyvinyl alcohols are polyvinyl alco-
`hols having a degree of polymerization from 500 to 5,000, a
`degree ofhydxolysis from 85 to 89% to a viscosity from 20 to
`65 mPa-s (4% (w/w) in water at 20° C.). More specifically,
`exemplary is Mowiol 40-88 marketed by Sigma Aldrich
`which has a degree of polymerization of 4200, a degree of
`hydrolysis from 86.7 to 88.7% to a viscosity from 38 to 42
`mPa-s (4% (w/w) in water at 20° C.).
`[0069] Among the acrylic copolymers, exemplary are the
`acrylates/dimethylaminoethyl methacrylate copolymer mar-
`keted under the trademark Eudragit E 100 by Rohm & Haas,
`the acrylates/ammonium methacrylate copolymer marketed
`under the trademark Eudragit RS100 or Eudxagit S100 by
`Rohm & Haas, the acrylates/octylacrylamide copolymer
`marketed under the trademark Dermacryl 79 by National
`Starch.
`[0070] Among the polyquaterninms, exemplary are
`polyquaternium 1, 7 and 10, more particularly the polyquater-
`ninm-10 marketed under the trademark Celquat SC240C by
`National Starch.
`[0071] Preferably, the film-forming agent is selected from
`among polyvinylpyrrolidones, which are preferably water-
`
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`soluble, polysaccharides such as sodium hyaluronate, poly-
`vinyl alcohols, acrylic copolymers and polyquaterninms,
`[0072] Preferentially, the water-soluble film-forming
`agents according to the invention are selected from among
`polyvinylpyrrolidones, which are preferably water-soluble
`such as, for example Kollidon VA64, Kollidon 30 and Kolli-
`don 90F marketed by BASF, from polysaccharides such as the
`sodium hyaluronate marketed under the trademark high
`molecular weight sodium hyaluronate by Contipro, from
`polyvinyl alcohols such as, for example, Mowio140-88 mar-
`keted by Sigma-Aldxich, from polyacrylamides such as, for
`example, Dermacryl 79 marketed by National Starch, from
`polyquaterniums such as, for example, polyquatemium 10
`marketed under the trademark Celquat SC240C by National
`Starch.
`In the compositions according to the invention, the
`[0073]
`film-forming agents are included at concentrations of less
`thanorequalto20%,preferablyfrom0.5%to 20% by weight,
`relative to the total weight of the composition, and more
`preferentially from 0.5% to 10%, and preferably from 0.5% to
`6%, and in particular 0.5%, 1%, 2%, 3%, 4% or 6%.
`[0074] The presence of at least one film-forming agent
`allows the tolerance to be improved and is p articularly advan-
`tageous in the case of formulations comprising adapalene and
`benzoyl peroxide. The reason for this is that naphthoic acid
`derivatives may be irritant and may have a dehydrating action
`on the skin. It is therefore advantageous to reduce the irrita-
`tion induced to be able to increase the doses.
`[0075] Thecompositionsofthepresentinventionmaybein
`any galenic form normally employed for topical application,
`in particular in the form of aqueous, aqueous-alcoholic or oily
`dispersions, suspensions, aqueous, anhydrous or lipophilic
`gels, emulsions (lotions, creams, ointments) of liquid, semi-
`solid or solid consistency obtained by dispersing a fattyphase
`in an aqueous phase (O/W) or vice versa (W/O) in the pres-
`ence or absence of emulsifier, or else microemulsions, micro-
`capsules, microparticles or vesicular dispersions of ionic and/
`or nonionic type.
`[0076] Preferably, the compositions according to the inven-
`tion are in the form of emulsions (lotions, creams or emulsi-
`tier-free creams), suspensions or gels, and more preferen-
`tially in the form of gels and emulsions,
`[0077] Those skilled in the art will take care to select the
`excipients constituting the compositions according to file
`invention according to the desired galenic form and such that
`the advantageous properties of the composition according to
`the invention are respected.
`[0078] The compositions of gel type according to the inven-
`tion may also in particular comprise one or more of the
`following ingredients:
`[0079] a) one or more gelling agents and/or suspending
`agents and/or pH-independent gelling agents;
`[0080] b) optionally, one or more chelating agents;
`c) optionally, one or more emollients and/or humec-
`[0081]
`tants;
`d) one or more wetting agents;
`[0082]
`e) one or more additives,
`[0083]
`[0084] The compositions of emulsion (cream, lotion, emul-
`sifter-free cream) type according to the invention may also in
`particular comprise one or more of the following ingredients:
`[0085] a) one or more gelling agents and/or suspending
`agents and/or pH-independent gelling agents;
`[0086] b) optionally, one or more chelating agents;
`
`[0087] c) optionally, one or more emollients and/or humec-
`tams;
`[0088] d) one or more lipophilic excipients making up the
`fatty phase;
`e) optionally, one or more emulsifiers;
`[0089]
`f) one or more wetting agents;
`[0090]
`[0091] g) one or more additives.
`[0092] Representative gelling agents and/or suspending
`agents and/or pH-independent gelling agents that may be
`included in the compositions according to the invention,
`exemplary are the acrylates/C10-30 alkyl acrylate crosspoly-
`mermarketedunder thetrademarkPemulenTR-1 orPemulen
`TR-2 by Noveon, the "electrolyte-insensitive" carbomers
`marketed under the trademark Ultrez 20®, Ultrez 10~, Car-
`bopol 1382®, Carbopol ETD2020NF®, Carbopol 980® or
`Carbopol 981® by Noveon, polysaccharides, non-limiting
`examples of which include xanthan gum such as Xantural
`180® marketed by Kelco, gellan gum marketed under the
`trademark Kelcogel® by Kelco, guar gum, cellulose and
`derivatives thereof such as the microcrystalline cellulose and
`sodium carboxymethyl cellulose marketed under the trade-
`mark Avicel CL-611 by FMC Biopolymer, hydroxypropyl
`methyl cellulo se, in particular the product marketed under the
`trademark Methocel E4M premium by Dow Chemical, or
`hydxoxyethyl cellulose, in particular the product marketed
`under the trademark Natrosol IIIIX 250® by Aqualon, the
`family ofmagnesinm aluminum silicates, such as theVeegum
`K marketed by Vanderbilt, the family of acrylic polymers
`coupledto hydxophobic chains, such as the PEG-150/decyl/
`SMDI copolymer marketed under the trademark Aculyn 44
`(polycondensate comprising, as elements, at least one poly-
`ethylene glycol containing 150 or 180 mol of ethylene oxide,
`decyl alcohol and methylenebis(4-cyclohexylisocyanate)
`(SMDI), at 35% by weight in a mixture of propylene glycol
`(39%) and water (26%)), the family of modified starches such
`as the modified potato starch marketed under the trademark
`Structure Solanace, or else mixtures thereof, and the gelling
`agents of the polyacrylamide family, such as the sodium
`acryloyldimethyltanrate copolymer/isohexadecane/polysor-
`bate 80 mixture marketed under the trademark Sepineo P
`600® (or Simulgel 600 PHA®) by Seppic, the polyacryla-
`mide/C 13-14 isoparaffin/laureth-7 mixture, for instance that
`marketed under the trademark Sepigel 305 by Seppic, the
`family of carrageenans, in particular divided up into four
`main families: ~c, )~, [3, ~), such as Viscarin® and Gelcarin®
`marketed by IMCD.
`[0093] The gelling agents as described above may be incor-
`porated at the preferred concentrations ranging from 0.001%
`to 15%, and more preferentially ranging from 0.15% to 5%.
`[0094] Preferred gelling agents, include the tamily of car-
`bomers and in particular Carbopol Ultrez-20® and Carbopol
`ETD 2020®, the family of polyacrylamides and in particular
`the sodium acryloyldimethyltanrate copolymer/isohexade-
`cane/polysorbate 80 mixture marketed under the trademark
`Sepineo P 600® (or Simulgel 600 PHA®), the tamily of
`polysaccharides and in particular the xanthan gum marketed
`under the trademark Xantural 180®, the family of celluloses
`and derivatives thereof and in particular the hydroxyethyl
`cellulose marketed under the trademark Natroso1250HHX®
`and the hydroxypropyl methyl cellulo se marketed under the
`trademark Methocel E4M Premium®, the tamily of acrylic
`polymers coupled to hydrophobic chains and in particular the
`PEG-150/decyl/SMDI copolymer marketed under the trade-
`mark Aculyn 44®.
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`[0095] Preferred gelling agents include carbomers, poly-
`acrylamides, acrylic polymers coupled to hydrophobic
`chains, cellulose and derivatives thereof such as hydroxypro-
`pyl methyl cellulose or hydroxyethyl cellulose, polysaccha-
`rides and especially xanthan gum, and in particular those
`especially marketed under the trademarks Sepineo P 600®
`(or Shnulge1600 PHA®), PEG- 150/decyl!SMDI copolymer,
`Methocel E4M premium®, Natrosol HHX 250®, Xantural
`180~ and Carbopol Ultrez 20®.
`[0096] Preferred suspending agents include microcrystal-
`line cellulose and sodium carboxymethyl cellulose marketed
`under the trademark Avicel CL-611 by FMC Biopolymer.
`[0097] Exemplary chelating agents, include ethylenedi-
`anfinetetraacetic acid (EDTA), diethylenetrimninepentaace-
`tic acid (DTPA), ethylenedimninebis(O-hydroxyphenylace-
`tic acid) (EDDHA), hydroxyl-2-ethylenedimninetriacetic
`acid (HEDTA), ethyldimninebis(O -hydroxy-p-methylphe-
`nyl)acetic acid (EDDHMA) and ethylenediaminebis(5-car-
`boxy-2-hydroxyphenyl)acetic acid (EDDCHA).
`[0098] A preferred chelating agent is ethylenedimninetet-
`raacetic acid (EDTA) marketed in particular under the trade-
`mark Titriplex III®.
`[0099] Among the humectants and/or emollients, the role
`of which is to hydrate the skin and to thcilitate the application
`of the formulation, use is optionally made, without this list
`being limiting, of compounds such as glycerol and sorbitol,
`sugars (by way of exmnple, glucose, lactose) polyethylene
`glycols (PEG) (by way of exmnple, Lutrol E400), urea or
`mnino acids (by way of exmnple, serine, citrulline, arginine,
`asparagine, alanine),
`[0100] A preferred humectant and/or emollient is glycerol,
`[0101] Among the wetting agents, the role of which is to
`reduce the surthce tension and to allow greater spreading of
`the liquid, use is preferentially made, without this list being
`limiting, of a wetting agent which may have pret~rentially an
`HLB of 10 to 14, compounds from the fmnily of Poloxmners
`and/or glycols and more particularly Synperonic PE/IA4 and/
`or Synperonic PE/L62 and/or compounds such as propylene
`glycol, dipropylene glycol, propylene glycol dipelargonate,
`lanroglycol, ethoxydiglycol. Preferably, the wetting agents
`are in liquid form so as to be easily incorporated into the
`composition without it being necessary to heat it.
`[0102] A particularly preferred wetting agent is propylene
`glycol and Syperonic PE/L44 marketed by Uniqema.
`[0103] The compositions according to the invention may
`comprise one or more emulsifiers,
`[0104] Emulsifiers are mnphiphilic compounds which con-
`tain a hydxophobic portion with affinity tbr oil and a hydro-
`philic portion with affinity tbr water, thus creating a link from
`the two phases. Ionic or nonionic emulsifiers thus stabilize
`oil!water emulsions by becoming adsorbed at the interface
`and by forming lamellar liquid crystal layers.
`[0105] The emulsifying power of nonionic surtactants is
`closely linked to the polarity of the molecule. This polarity is
`defined by the HLB (hydrophilic/lipophilic balance).
`[0106] A high HLB indicates that the hydrophilic fraction
`is predominant and, conversely, a low HLB indicates that the
`lipophilic portion is predominant. For exmnple, HLB values
`of greater than approximately 10 correspond to hydrophilic
`surthctants.
`[0107] Emulsifiers may be classified, according to their
`structure, under the generic terms "ionic" (anionic, cationic
`or mnphoteric) or "nonionic". Nonionic emulsifiers are emul-
`
`sifters that do not dissociate into ions in water and are there-
`tbre insensitive to variations in pH.
`[0108] Exemplary nonionic emulsifiers exhibiting a high
`HLB are sorbitan esters, such as POE(20) sorbitan
`monooleate, marketed under the trademark of Tween 80®
`(HLB 15), or POE(20) sorbitan monostearate, marketed
`under the trademark of Tween 60® (HLB 14.9), tatty alcohol
`ethers, such as POE(21) stearyl ether (HLB 15.5), marketed
`under the trademark Brij 721 ® by Uniqema, or ceteareth-20,
`marketed under the trademark Eumulgin B2® (HLB of 15.5)
`by Cognis, polyoxyethylene glycol esters, such as glyceryl
`stearate and PEG 100 stearate, marketed under the trademark
`Arlacel 165 FL® (HLB 11) by Uniqema, or PEG 6 stearate
`and PEG 32 stearate, marketed under the trademark Tefose
`1500® (HLB 10) by Gatefoss~, or sugar esters with a high
`HLB, such as PEG 20 methyl glucose sesquistearate, mar-
`keted under the trademark glucmnate SSE20® (HLB 15) by
`Amerchol, and sucrose laurate, marketed under the trademark
`Surf hope C-1216® (HLB 16), and sucrose stearate, mar-
`keted under the trademark Snrthope C-1811 ® (HLB 11) and
`Surthope SE Pharma D-1816® and sucrose pahnitostearate
`marketed under the trademark Surf hope SE Pharma
`D-1616® by Gattefoss~ and polyglycerol esters. Preferably,
`said nonionic emulsifiers with a high HLB exhibit an HLB of
`from 10 and 18.
`[0109] Exemplary nonionic emulsifiers exhibiting a low
`HLB (lipophilic emulsifiers) are sorbitan esters, such as sor-
`bitan monostearate (HLB 4.7), marketed under the trade-
`mark Span 60 by Uniqema, glycerol esters, such as glycerol
`monostearate, marketed under the trademark Cutina GMS-
`VPH (HLB=3.8) by Cognis, polyethylene glycol esters, such
`as PEG-6 isostearate, marketed under the trademark Olepal
`isostearique® (HLB 8) by Gattetbss~, or sugar esters with a
`low HLB, such as methyl glucose sesquistearate, marketed
`under the trademark of Glucate S S® (HLB 6) by Amerchol,
`and sucrose dilanrate, marketed under the trademark of Surf
`hope C-1205® (HLB 5), and sucrose tristearate, marketed
`under the trademark of Surthope C-1803® (HLB=3), by Gat-
`tefoss~.
`[0110] Also exemplary nonionic emulsifiers are self-e