I Illll IIllllll II Illlll Illll Illll Illll Illll Illll Illll Illll Illll Illll Illll Illlll Illl Illl Illl
`
`US 20110003894A1
`
`(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2011/0003894 A1
`LOUIS et al. (43) Pub. Date: Jan. 6, 2011
`
`(54) DERMATOlOGICAl, COMPOSITIONS
`COMPRIS~G RETINOIDS, DISPERSED
`BENZOYL PEROXIDE AND CARRAGEENANS
`
`(30)
`
`Foreign Application Priority Data
`
`Jan. 10, 2008 (FR) ....................................... 0850131
`
`(75)
`
`Inventors:
`
`Fabienne LOUIS,
`Villencuve-Loubet (FR); Sandrine
`Segura, Biot (FR); Nathalie
`Willcox, Magagnosc (FR)
`
`Correspondence Address:
`BUCHANAN, INGERSOLL & ROONEY PC
`POST OFFICE BOX 1404
`ALEXANDer, VA 22313-1404 (US)
`
`(73) Assignee:
`
`GALDERMA RESEARCH &
`DEVELOPMENT~ BlOT (FR)
`
`(21) Appl. No.:
`
`12/833,335
`
`(22) Filed:
`
`Jul. 9, 2010
`
`Related U.S. Application Data
`
`(63) Continuation of application No. PC’ITFR2~9i
`050040, filed on Jan. 12, 2009.
`
`Publication Classification
`
`(51)
`
`Int. CI.
`A61K 31/192
`A61P 17/10
`A61P 17/14
`A61P 17/16
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(52) U.S. CI ......................................................... 514/569
`
`(57)
`
`ABSTRACT
`
`Dermatological compositions contorting, in a physiologi-
`cally acceptable m~itma, at least one retinoid, dispersed ben-
`zoyl peroxide mid at least one gelling agcalt of the fmnily of
`the carrageenans, are useful for treating dermatological con-
`ditions and afflictions lil~ked to disorders of cell differentia-
`fion and/or proliferation an&/or keratinization, notably for
`treating ache vulg~is.
`
`1 of 14
`
`Almirall EXHIBIT 2049
`Amneal v. Almirall
`IPR2018-00608
`
`

`

`US 2011/0003894 A1
`
`Jan. 6, 2011
`
`1
`
`DERMATOLOGICAL COMPOSITIONS
`COMPRISING RETINOIDS, DISPERSED
`BENZOYL PEROXIDE AND CARRAGEENANS
`
`CROSS-REFERENCE TO PRIORITY/PCT
`APPLICATIONS
`
`[0001] This application claims priority under 35 U.S.C.
`§119 of FR0850131,filed Jan. 10, 2008, andis a continnation
`of PCT/FR 2009/050040, filed Jan. 12, 2009 and designating
`the United States (published in the French language on Jul.
`30, 2009 as WO 2009/092954 A1 ; the title and abstract were
`also published in English), each hereby expressly incorpo-
`rated 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 present invention relates to dermatological
`compositions comprising, formulated into a physiologically
`acceptable medium, at least one retinoid, dispersed benzoyl
`peroxide and at least one carrageenan,
`[0004] 2. Description ofBackgroundand/orRelated and/or
`Prior Art
`[0005] The administration of several categories of active
`principles is a therapeutic tool to which recourse is frequently
`had, in particular in the treatment of demmtological disor-
`ders.
`[0006] Specifically, it is known to administer peroxides,
`vitamins D and retinoids in the topical treatment of various
`pathologies related to the skin or mucous membranes, in
`particular acne.
`[0007] The combination of several local treatments (anti-
`biotics, retinoids, peroxides, zinc) is also employed in der-
`matology to make it possible to enhance the effectiveness of
`the active principles and to reduce their toxicity (Cunlillb W.
`J., J. Demmtol. Treat., 2000, 11 (Suppl. 2), S13-S14).
`[0008] The multiple application of different dermatological
`products may be rather burdensome and demanding for the
`patient,
`[0009] The interest in attempting to obtain a novel treat-
`ment which is effective with regard to dermatological condi-
`tions in a stable composition which offers a good cosmetic
`quality, which makes possible a single application and which
`makes possible adaninistration which is a~eeable to the
`patient is thus understood.
`[0010] There is nothing among this range of therapies pro-
`vided to one skilled in the art which would encourage him to
`combine, in the same composition, benzoyl peroxide, a rot-
`inoid and several gelling agents,
`[0011] This is because the formulation of such a composi-
`tion presents several problems.
`[0012] First of all, the e£tectiveness of the benzoyl peroxide
`is related to its decomposition when it is brought into contact
`with the skin. This is because it is the oxidizing properties of
`the free radicals produced during this decomposition which
`result in the desired effect. Consequently, to maintain the
`optimum effectiveness of the benzoyl peroxide, it is impor-
`tant to prevent it from decomposing before use, that is to say
`during storage. In point of fact, benzoyl peroxide is an
`unstable chemical compound, which makes it difficult to
`formulate it into firfished products,
`[0013] The solubility and the 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). It turns out that benzoyl
`peroxide is particularly soluble in PEG 400 and ethanol.
`[0014] This document furthermore specifies that the stabil-
`ity ofbenzoyl peroxide is strongly influenced by the chemical
`composition of the formulation and by the storage tempera-
`ture. Benzoyl peroxide is highly reactive and decomposes in
`solution at low temperature due to the instability of its per-
`oxide bond.
`[0015] The authors thus determine that benzoyl peroxide in
`solution decomposes more or less rapidly in all the solvents
`studded according to the type of solvent and its concentration.
`[0016] The decomposition times of benzoyl peroxide in
`PEG 400 (0.5 mg/g), in ethanol and in propylene glycol are
`1.4, 29 mad 53 days respectively at 40° C. Such a decompo-
`sition does not make possible the fommlation of a product
`intended for sale.
`[0017] Furthermore, it is known that benzoyl peroxide is
`more stable in water and propylene glycol when it is in sus-
`pension (i.e., in the dispersed form), since it is not decom-
`posed after storing for 90 days in these solvents.
`[0018] Thus, to limit the problem of rapid instability of
`benzoyl peroxide in solution, it has proven to be advanta-
`geous to formulate benzoyl peroxide in the dispersed form.
`[0019] However, this type of formulation is not completely
`satisfactoi3.insofaras the benzoyl peroxide is still foundto be
`decomposed in the finished product.
`[0020] Anotherdifficultytobeovercomeintheformulation
`of a composition comprising both benzoyl peroxide and a
`retinoid is that the majority ofretinoids are particularly sen-
`sitive to natural oxidation, to visible light and ultraviolet
`radiation. As benzoyl peroxide is a strong oxidizing agent, the
`chemical compatibility of these two compounds in one and
`the same formulation presents numerous problems of stabil-
`ity from the physical and chemical viewpoint.
`[0021] Astability studywas carriedout ontwo retinoids by
`combining two commercial products, one comprising a ret-
`inoid (tretinoin or adapalene) and the second based on ben-
`zoyl peroxide (t3. Martin et al., Br. J. Dermatol., (1998) 139,
`(suppl. 52), 8-11).
`[0022] The presence ofbenzoyl peroxide in the formulation
`causes very rapid decomposition of the oxidation-sensitive
`retinoids: 50% of the tretinoin is measured as decomposing in
`2 hours and 95% in 24 hours. In the composition comprising
`adapalene as relinoid, no decomposition of the adapalene was
`measured during 24 hours.
`[0023] This study confirms that benzoyl peroxide is decom-
`posed and decomposes oxidation-sensitive retinoids over
`time by gradually releasing benzoic acidin finishedproducts.
`[0024] In point of fact, it is clear that the decomposition of
`benzoyl peroxide and retinoids is not desirable insothr as it is
`harmful to the effectiveness of the composition in wlfich they
`are present.
`[0025] Nothing thus prompted the combining of these two
`activeagentstoobtaina stablecompositionofgeloremulsion
`type, it being known that it was conventionally recognized
`that the presence of benzoyl peroxide chemically mad physi-
`cally destabilized compositions of these types.
`[0026] In particular, the formulation as a gel of benzoyl
`peroxide and a retinoid is advantageous for topical treat-
`ments, such as that of ache, as it avoids in particular leaving a
`greasy feel remaining on the skin.
`
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`[0027] More specifically, the term "gel" means a system
`comprising at least one themlodynamically stable phase (in
`general one or two phases) resulting from the coagulation as
`a tlaree-dimensional network of a colloidal solution. More
`precisely, an aqueous gel corresponds to a composition corn-
`prising, in an aqueous phase, a viscoelastic mass fomled from
`colloidal suspensions (carrageenan or combination of a car-
`rageenan with another gelling agent).
`In particular, the formulation as a "light" emulsion
`[0028]
`ofbenzoyl peroxide and a retinoid is advantageous for topical
`treatments, such as that of ache, as, in the case of a "light"
`emulsion, it contributes emollience while avoiding leaving an
`excessively greasy feel remaining on the skin.
`[0029] "Light" emulsion means an emulsion comprising a
`low proportion of fatty, phase, the aqueous phase remaining
`predominant. An emulsion is a system comprising two fluids
`which are insoluble or only slightly soluble in one another,
`and in which one of the fluids is dispersed in the other as
`microscopic particles. Preferably, the emulsions used corn-
`prise or do not comprise at least one emulsifier, a polar hydro-
`philic phase, preferably aqneous phase, and a nonpolar fatty
`phase. Prel~rably, they are provided in the lbrm of "oil-in-
`water" (O/W) or "water-in-oil" (W/O) emulsions,
`[0030] In point oflact, another difficult?" to be overcome in
`the formulation of a composition comprising in particular
`benzoyl peroxide, when it occurs in the gel or emulsion form,
`is that the gelling agents of the aqueous phase are destabilized
`by the benzoic acid released during the decomposition of the
`benzoyl peroxide,
`[0031] Specifically, the gelling agents of the aqueous phase
`most commonly used with benzoyl peroxide are acrylic acid
`polymers (carbomer).
`In point of fact, the use of curbomers in composi-
`[0032]
`tions of aqueous gel type does not provide good results in
`terms of chemical stability of the benzoyl peroxide and in
`terms ofrheological stability.As described by Bollinger (Bol-
`linger, Journal of Pharmaceutical Science, 1977, Vol. 5), a
`loss of 5 to 20% ofbenzoyl peroxide after 2 months at 40° C.,
`depending on the neutralizing agent of the carbomer used,
`was observed. Furthernlore, the release of benzoic acid brings
`about depolymerization of the carbomers, giving a lhll in
`viscosity which may bring about phase separation,
`[0033] This instability ofbenzoyl peroxide gels (as such or
`as gelled aqueous phase of an emulsion) is thus harmful to
`their effectiveness and to their cosmetic quality,
`[0034] Furthermore, a finished product, in particular when
`it concerns pharmaceutical or cosmetic compositions, must
`maintain, throughout its lifetime, precise physicochemical
`criteria which make it possible to guarantee its pharmaceuti-
`cal and cosmetic quality. Among these criteria, it is necessary
`for the rheological properties to be retained. They define the
`behavior and the texture of the composition during applica-
`tion but also the properties of release of the active principle
`[SFSTP Commission report 1998] and the homogeneity of
`the product when the active principles are present therein in
`the dispersed state,
`[0035] Need thus exists tbr a physically and chemically
`stable composition of gel or emulsion type comprising ben-
`zoyl peroxide and a retinoid.
`
`SUMMARY OF THE INVENTION
`
`[0036] Dermatological compositions of gel and emulsion
`type have now been developed which meet this need, which
`comprise dispersed benzoyl peroxide in the free or encapsu-
`
`lated form, at least one retinoid and at least one carrageenan,
`whichhave goodphysical stability, that is to saywhichdo not
`exhibit a drop in viscosity over time and in particular at
`ambient temperature, and which maintain good chemical sta-
`bility of the two active principles (benzoyl peroxide and ret-
`inoid). In particular, decomposition of tile active principles
`over time and/or at ambient temperature is not observed.
`[0037] The present invention thus features compositions
`comprising, formulated into the same physiologically accept-
`able medium:
`at least one retinoid,
`[0038]
`[0039] benzoyl peroxide,
`at least one gelling agent of the family of the carra-
`[0040]
`geenmls, the saidbenzoyl peroxide and/or the said at least one
`retinoid preferably being in a form dispersed in the said
`composition.
`
`DETAILED DESCRIPTION OF BEST MODE
`AND SPECIFIC/PREFERRED EMBODIMENTS
`OF THE INVENTION
`
`[00411 According to a preferred embodiment, the compo-
`sition is a combination, the active principles of which are
`combined at fixed doses within one and the same vehicle
`(single formnlation) which delivers them together. Prefer-
`ably, the pharmaceutical composition in the form of a fixed
`combination is a gel; in this case, the two active principles are
`dispersed and intimately mixed during formulationin one and
`the same vehicle, which delivers them together when the gel
`is applied.
`[0042] The term "physiologically acceptable medium"
`means a medium compatible with the skin, mucous mem-
`branes and superficial body growths.
`[0043] Preferably, the pharmaceutical composition is use-
`ful for a single topical application daily.
`[0044] The term "active prhaciple in the dispersed foml
`according to the invention" means an active principle in the
`form of solid particles suspended in a given vehicle. Such
`particles have in particular a size of greater than 10 Nn.
`[0045] 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 pm and at least 99%
`by number of the particles have a diameter of less than 100
`pm.
`[0046] The compositions according to the invention corn-
`prise at least one retinoid. The term "retinoid" means any
`compound which binds to RAR and/or RXR receptors. Pref-
`erably, the retinoid is a compound selected ti’om the lhmily of
`the benzonaphthalene retinoids (also known as naphthoic
`acid compotmds), such as described in EP-0199636, in par-
`ticular:
`[0047] 6-(3-methylphenyl)-2-naphthoic acid and its
`methyl ester,
`[0048] 6-(4-(tert-butyl)phenyl)-2-naphthoic acid mad its
`met’_nyl ester,
`[00491 6-(3-(tert-butyl)phenyl)-2-1mphthoic acid and its
`methyl ester,
`[0050] 6-(3,4-dimethoxyphenyl)-2-naphthoic acid and its
`methyl ester,
`[00511 6-(p-(1-adamantylthio)phenyl)-2-naphthoic acid
`and its methyl ester,
`[0052] 6-(3-(l-adamantyl)-4-methoxyphenyl)-2-naph-
`thoic acid (adapalene) and its methyl ester,
`
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`3
`
`[0053] the methyl ester of 6-[3-(1-adamantyl)-4-(tert-bu-
`tyldimethylsilyloxy)phenyl]-2-naphthoic acid,
`
`[0077] The tenn "naphthoic acid compound" means the
`compounds of formula (I):
`
`[0054] the methyl ester of 6-[3-(1-adamantyl)-4-hydrox-
`
`yphenyl]-2-naphthoic acid,
`[0055] 6 -[3-(1 -adamantyl)-4 -hydroxyphenyl]-2 -naphthoic
`acid,
`
`[0056] the methyl ester of 6-[3-(1-adamantyl)-4-decylox-
`yphenyl]-2-naphthoic acid,
`
`6 -[3-(1 -adamantyl)-4 -decyloxyphenyl]-2-naph-
`[0057]
`thoic acid,
`
`[0058] the methyl ester of 6-[3-(1-adamantyl)-4-hexylox-
`yphenyl]-2-naphthoic acid,
`
`6 -[3-(1 -adamantyl)-4 -hexyloxyphenyl]-2-naph-
`[0059]
`thole acid,
`[0060] the methyl ester of 6-[3-(1-adamantyl)-4-methox-
`yphenyl]-4-acetoxy-1-methyl-2-naphthoic acid,
`
`6 -[3-(1 -adamant)q)-4 -methoxyphenyl]-4 -hydroxy-
`[0061]
`1-methyl-2-naphthoic acid,
`
`[0062] the methyl ester of 6-[3-(1-adamanlyl)-4-methox-
`yphew1]-4-hydroxy-1 -methyl-2-naphthoic acid,
`
`[0063] the methyl ester of 6-[3-(1-adamantyl)-4-methox-
`yphenyl)-i-methyl-2-naphthoic acid,
`
`[0064] 6-[3-(1-adamant}’l)-4-methoxyphenyl]-l-methyl-
`2-naphthoic acid,
`[0065] 6-[3-(1-adamantyl)-4-methoxyphew1]-2-naphtha-
`lenemethanol,
`
`[0066] the ethyl amide of 6-[3-(1-adamantyl)-4-methox-
`yphenyl]-2-naphthoic acid,
`[0067] the morpholide of 6-[3-(1-adamantyl)-4-methox-
`yphenyl]-2-naphthoic acid,
`[0068] the methyl ester of 6-[3-(tert-butyl)-4-nlethoxyphe-
`nyl]-2-naphthoic acid,
`[0069] 6-[3-(tert-butyl)-4-methoxyphenyl]-2-naphthoic
`acid,
`the methyl ester of 6-[3-(1,1-dimethyldecyl)-4-
`[00701
`methoxyphenyl]-2-naphthoic acid,
`[0071] 6-[3-(1,1-dimethyldecyl)-4-methoxyphenyl]-2-
`naphthoic acid.
`[0072] The presem invention thns features compositions
`comprising, formulated into the same physiologically accept-
`able medimla:
`at least one naphthoic acid componnd,
`[0073]
`[0074] benzoyl pevaxide, and
`at least one gelling agent of the family of the carra-
`[0075]
`geenans,
`[0076] The naphthoic acid is a compound of formula:
`
`o
`
`(I)
`
`wherein
`[0078] Risahydrogenatom, ahydroxylradical, abranched
`or unbranched alkyl radical having from 1 to 4 carbon atoms,
`an alkoxy radical having from 1 to 10 carbon atoms or a
`cycloaliphatic radical which is substituted or unsubstituted.
`[0079] The term "linear or branched alkyl radical having
`from 1 to 4 carbon atoms" means the methyl, ethyl, propyl
`and butyl radicals.
`[0080] The term"alkoxy radical having from 1 to 10 carbon
`atoms" is preferably understood to mean the methoxy,
`ethoxy, propoxy, butoxy, hexyloxy and decyloxy radicals.
`[0081] The term "cycloaliphatic radical" is preferably
`understood to mean mono- or polycyclic radicals, such as the
`1 -methylcyclohexyl radical or the 1 -adamantyl radical.
`[0082] The selection will advantageously be made, among
`the naphthoic acid compounds suitable lbr inclusion in the
`compositions according to the invention, of 6-[3-(1-adaman-
`tyl)-4-methoxyphenyl]-2-naphthoic acid (adapalene), 6-[3-
`(1-adamantyl)-4-hydroxyphenyl]-2-naphthoic acid, 6-[3-(1-
`adamantyl)-4-decyloxyphenyl]-2-naphthoic acid and 6-[3-
`(1-adamantyl)-4-hexyloxyphenyl]-2-naphthoic acid.
`[0083] The abovementionednaphthoic acid compounds are
`generally provided in a dispersed form in the composition
`according to the invention. Insoluble naphthoic acid com-
`pounds arc thus homogeneously distributed in the composi-
`tion according to the invention.
`[0084] In particular, preference will be given to adapalene
`and its salts.
`[0085] The term "salts of adapalene" means the salts
`formed with a pharmaceutically acceptable base, in particular
`inorganic bases, such as sodium hydroxide, potassium
`hydroxide and aqueous ammonia, or organic bases, such as
`lysine, arginine or N-methylglucamine.
`[0086] The term "salts of adapalene" is also tmderstood to
`mean the salts formed with laW amines, such as dioctylamine
`and stearylamine.
`[0087] Other retinoids can be selected from tretinoin,
`isotretinoin, retinoic acid, retinal, retinol or retinyl palmitate,
`in particular tho se described in the following patents or patent
`applications: U.S. Pat. Nos. 4,666,941, 4,581,380,
`EP-0210929, EP-0232199, EP-0260162, EP-0292348,
`EP-0325540, EP-0359621, EP-0409728, EP-0409740,
`EP-0552282, EP-0584191, EP-0514264, EP-0514269,
`EP-0661260, EP-0661258, EP-0658553, EP-0679628,
`
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`EP-0679631, EP-0679630, EP-0708100, EP-0709382
`EP-0722928, EP-0728739, EP-0732328, EP-0740937
`EP-0776885, EP-0776881, EP-0823903, EP-0832057
`EP-0832081, EP-0816352, EP-0826657, EP-0874626
`EP-0934295, EP-0915823, EP-0882033, EP-0850909
`EP-0879814, EP-0952974, EP-0905118, EP-0947496
`WO98/56783, WO99/10322, WO99150239 and WO99/
`65872.
`[0088] Of course, the amount of the two active agents,
`benzoyl peroxide and retinoid, in the composition according
`to the invention would depend on the combination selected
`and thus in particular on the retinoid under consideration and
`on the quality of the desired treatment,
`[0089[ The preferred concentrations of retinoid are ti’om
`0.0001 to 20% by weight, with respect to the total weight of
`the composition,
`[0090] In the compositions according to the invention, the
`naphthoic acid compounds are included at concentrations of
`less than or equal to 10% by weight, with respect to the total
`weight of the composition, and preferably from 0.001 to 10%
`byweight, withrespecttothetotalweightofthecomposition,
`and preferably from 0.01 to 5% by weight, more preferably
`from 0.05 to 2% by weight and most preferably from 0.1 to
`0.3% by weight, with respect to the total weight of the corn-
`position.
`[0091] Throughoutthe present text, anless otherwise speci-
`fled, it is understood that. when ranges of concentrations are
`given, they include the upper and lower limits of the said
`range,
`[0092] Advantageously, the naphthoic acid compound for-
`mulated in the compositions according to the invention is
`6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid
`(adapalene). Preferably, in the case ofadapalene, the compo-
`sitions according to the invention comprise from 0.001 to 5%
`by weight and advantageously from 0.01 to 1% by weight of
`adapalene, with respect to the total weight of the composition,
`preferentially from 0.01 to 0.5% by weight, preferably ti’om
`0.1 to 0.4% by weight of adapalene, more preferably still
`0.1% by weight or 0.3% by weight ofadapalene.
`In the compositions according to the invention, ben-
`[0093]
`zoyl peroxide is formulated at concentrations ranging from
`0.5 to 10% by weight, more particularly from 1 to 7% by
`weight and more preferably still from 2.5 to 5% by weight,
`with respect to the total weight of the composition,
`[0094] The benzoyl peroxide can just as easily be formu-
`lated in the free form or else in an encapsulated form, in a
`form adsorbed on or absorbed in any porous support,
`It can, for example, be beazoyl peroxide encapsu-
`[0095]
`lated in a polymeric system composed of porous micro-
`spheres, such as, for example, microsponges marketed under
`the trademark Microsponges P009A Benzoyl Peroxide by
`Cardinal Healthcare.
`[0096] To provide an order of magnitude, the compositions
`according to the invention advantageously comprise from
`0.0001 and 20% by weight of benzoyl peroxide and from
`0.0001 to 20% by weight ofretinoid, with respect to flae total
`weight of the composition, and prelerably fi:om 0.025 to 10%
`by weight of benzoyl peroxide and li’om 0.001 to 10% by
`weight of retinoid respectively, with respect to the total
`weight of the composition,
`[0097] For example, in the compositions for the treatment
`of acne, the benzoyl peroxide is preferably formulated at
`concentrations ranging from 0.5 to 10% by weight and more
`particularly froln 1.0to 5%byweight, withrespect to thetotal
`
`weight of the composition; forits part, the retinoid is formu-
`latedintlffs type of composition at concentrations generally
`ranging from 0.05 to 1% by weight, with respect to the total
`weight ofthe composition.
`
`[0098] Advantageously, thcparticlesizeoftherctinoidand
`ofthebenzoyl peroxideis suchthat at least 80% bynumber of
`the particles and preferably at least 90% by number of the
`particles have a diameter of less than 25 ~tm and at least 99%
`by number of the particles have a diameter of less than 100
`gm.
`[0099] The compositions according to the invention addi-
`tionally comprise at least one gelling agent of the family of
`the carrageenans.
`
`[0100] Carragecnans arc polysaccharides constituting the
`cell walls of various red algae (Rhodophyceae) belonging to
`the Gigartinacae, Hypneaceae, Furcellariaceae and Polyide-
`aceae families. They are generally obtained by aqueous
`extraction starting from natural strains of the said algae. They
`comprise long anionic polyelectrolyte galactane chains.
`These linear polymers, lbrmed of disaccharide units, are
`composed of two D-galactopyranose units alternatively
`bonded via ct and 13 bonds. These arc highly sulfated (20-
`50%) polysaccharides mad the ct-D-galactopyranosyl resi-
`dues can be in the 3’,6’-anhydro form.
`[0101] Initially, the carrageenans were subdivided into two
`families according to their solubility in KC1. The fractions
`soluble in KC1 were denoted by the prefixes "kappa" while
`the "lanthda" terms were reserved for the insoluble fractions.
`Later, the classifications were based on the number and the
`position of sulfate groups and on the presence of the 3’,6’-
`anhydro bridge on the 13-D-galactopyranosyl residues. This
`resulted in the 1bur main lhmilies: K, L, [3, co and t.
`[0102] Carrageenans are essentially composed of potas-
`slum, sodium, magnesium, triethanolamine and/or calcium
`salts and sulfate esters of polysaccharides.
`[0103] Thus, carrageenans are capable of conferring a vis-
`cosity on the composition sufficient to keep the retinoid and
`the benzoyl peroxide in suspension, even under the influence
`in particular of a variation in pH due to the release of benzoic
`acid by the benzoyl peroxide. For the kappa and iota forms,
`the contribution of potassium ions or of calcium ions is nec-
`essary to ensure gelling and thus to have an impact on the
`viscosity. This is because the gelling mechanism exhibits two
`major stages (Selim Kara, "Photon transmission study on
`swelli!g ofkappa-carrageenan gelsprepared in various con-
`centrations", InternationalJournalqfBiolog;icalMacromol-
`ecules, 33 (2003), 235-243)(Tommasina Coviello, "Polysac-
`charide 1Lvdrogels ,for roo!!fled release formulations",
`Journal qf Controlled Release, 119 (2007), 5-24):
`[0104] the formation of helices;
`[0105] the action of the cations causes the hclices to come
`together and brings about the formation of aggregates.
`[0106] The gelling mechanism thus takes place.
`[0107] The amount ofcarrageenan can vary to a large extent
`and depends in particular on the viscosity desired, on the
`carrageenan used and optionally on the other gelling agents
`present in the composition. To provide an order of magnitude,
`the carrageenan can be formulated at concentrations of 0.1 to
`20% by weight, with respect to the total weight of the coin-
`position, and more preferably from 0.1 to 10% to preferably
`from 0.5 to 2%, in particular 0.5%, 1% to 2%.
`
`5 of 14
`
`

`

`US 2011/0003894 A1
`
`Jan. 6, 2011
`
`5
`
`[0108] The carrageenans are marketed in particular by
`IMCD under the Gelcarin® and Viscarin® names (for
`example: Gelcarin GP812N®, Gelcarin GP379NF® or Vis-
`carin GP209NF®).
`[0109] The compositions of the present invention can be
`provided in all the formulation forms normally used for a
`topical application, in particular in the form of aqueous or oily
`dispersions, of suspensions, of gels, whichare aqueous, mflay-
`drous or lipophilic, or of emulsions (lotions, creams or emul-
`sifter-free creams) with a liquid, semi-solid or solid consis-
`tency obtained by dispersion of a fatty phase in an aqueous
`phase (O/W) or vice-versa (W/O), with or without emulsifier,
`[0110] Preferably, the compositions according to the inven-
`tion are provided in the lbrm of emulsions (creams, lotions,
`emulsifier-fi’ee creams), o1 suspensions or of gels and more
`prelbrably in the lbrm of gels and o1 emulsions,
`[0111] One skilled in the art will take care to select the
`excipients constituting the compositions according to the
`invention in terms of the formulation form desired and such
`that the advantageous properties of the compositions accord-
`ing to the invention are respected,
`[0112] The compositions of gel type according to the inven-
`tioncanadditionallyconapriseinparticularoneornmreoffiae
`following ingrediems:
`[0113] a) one or nmre additional gelling agents and/or sus-
`pending agents and/or pH-independent gelling agents,
`[0114] b) optionally, a cation,
`[0115]
`c) one or more emollients and/or hnmectants,
`[0116] d) one or more wetting agents,
`e) optionally, one or more additives,
`[0117]
`[0118] The compositions of emulsion type (cream, lotion,
`emulsifier-free cream) according to the invention can addi-
`tionally comprise in particular one or more of the following
`ingredients:
`[0119] a) one or more additional gelling agents and/or sus-
`pending agents and, or pH-independent gelling agents,
`[0120] b) optionally, a cation,
`c) one or more emollients and/or hmnectants,
`[0121]
`[0122] d) one or more wetting agents,
`e) one or more lipophilic excipients composing the
`[0123]
`fatty phase,
`f) optionally, one or more emulsifiers,
`[0124]
`[0125] g) optionally, one or more additives,
`[0126] The compositions according to the invention can
`compriseatleastoneadditional gelling agent and/or suspend-
`ing agent and/or pH-independent gelling agent other than fire
`carrageenans. The other additional gelling agent and/or sus-
`pending agent and/or pH-independent gelling agent can in
`particular be selected from the group formed by celluloses
`and their derivatives, polysaccharide gums, silicates and gel-
`ling agents of the family of polyacrylamides, the family of
`acrylic polymers coupled to hydrophobic chains and the fam-
`ily of modified starches.
`[0127] The celluloses and their derivatives include, by way
`of examples, the microcrystalline cellulose and sodimn car-
`boxymethyl cellulose marketed under the trademarl, Avicel
`CL-611® by FMC Biopolymer, the ethylcellulose marketed
`under the trademark Ethocel® by Dow Chemical, the hydrox-
`yprepylmethylcellulose marketed under the trademark
`Methocel E4M® by Dow Chemical, the hydroxyethylcellu-
`lose marketed under the trademark Natrosol 250ItHX~!~ by
`Aqualon or the carboxymethylcellulose marketed under the
`131anose® name by Aqualon.
`
`[0128] The polysaccharide gums are complex mixtures of
`severalpolysaccharidesofhighmolecularweightobtainedby
`exudation from certain plants. The various types ofpolysac-
`charide gums include, by way of non-limiting examples, gum
`arabic, gellan gmn, gum tragacanth and xanthan gum, inter
`alia marketed by CP Kelco under the Xantural® name (for
`example: Xantural® 180).
`[0129] The term "’silicate" is understood in particular to
`mean clay derivatives, more specifically magnesium alumi-
`num silicates. These compounds are marketed in particular by
`R.T.Vanderbilt under theVeegum® name (for example: Vee-
`gum® HV or Veegum’,l~ K).
`[0130] Particularly exemplar>" gelling agents are of poly-
`aerylamide type, of the sodimn aeryloyldimethyltaurate
`copolymeriisohexadecaneipolysorbate 80 mixture marketed
`under the trademark Sepineo P600® (or Simulgel
`600PHA®) by Seppic or the polyacrylamide/C13-14 isopar-
`affin/laureth-7 mixture, such as, for example, marketed under
`the trademark Sepigel 305® by Seppic.
`[0131] Particularly exemplary acrylic polymers coupled to
`hydrophobic chains are the PEG- 150/decyl/SMDI copolymer
`marketed under the trademark Aculyn 44® (polycondensate
`comprising at least, as components, a polyethylene glycol
`comprising 150 or 180 mol of ethylene oxide, decyl alcohol
`and nlethylenebis(4-cyclohexyl isocyanate) (SMD1), at 35%
`by weight in a mixture of propylene glycol (39%) mad water
`(26%)) by R6bala & ttaas.
`[0132] Particularly exemplary gelling agents of tim family
`of modified starches are the modified potato starch marketed
`under the trademark Structure Solanace®, or else their mix-
`tures, by National Starch.
`[0133] The amount of additional gelling agent is generally
`from 0.01 to 20% by weight, with respect to the total weight
`of the composition.
`[0134] Prelerence is given to combinations ofcarrageenans
`with polyacrylamides, prelbrably the sodium aculoyldim-
`ethyltaurate copolymeffisohexadecane/polysorbate 80 mix-
`turemarketedunder the trademark Simulge1600PHA®, orof
`carrageenans with celluloses mad their derivatives, preferably
`hydroxyethylcellulose marketed under the trademark Natro-
`sol 250HHX®, or ofcarmgeenans with polysaccharide gums.
`[0135] According to a specific embodiment, the composi-
`tion can comprise a carrageenan in combination with at least
`one polyacrylanfide and at least one cellulose gelling agent
`aM its derivatives.
`[0136] The amount ofpolyacrylmnide can vary to a large
`extent and depends in particular on the viscosity desired, on
`the carrageenanusedandoptionally ontheothergelling agent
`and/or agents present in the composition. To provide an order
`of magnitude, Simulgel 600PHA can be present in the corn-
`position according to theinvention in amounts offrom 0.01 to
`10% by weight, preferably ranging from 0.05 to 6% by
`weight, with respect to the total weight of the composition.
`Advantageously, the amo