Patent Application
20110319491
The present invention relates to a novel cosmetic or pharmaceutical depigmenting composition, characterized in that it comprises, as pharmaceutical active agents, a retinoid and a phenolic derivative dissolved in the fatty phase, for topical application, and to the process for preparing it and to its use in dermatology.
Among the therapeutic agents recommended in the treatment of cutaneous hyperpigmentation, phenolic derivatives and more particularly polyphenols for decades among the active agents that are the most effective. The therapeutic use of these agents results from the observation of cutaneous depigmentation in the case of operatives in the rubber industry, in which some of these products are used as antioxidants. Subsequently, numerous studies have confirmed their efficacy, alone or combined with other depigmenting agents [Jorge L. Sanchez, M.D. and Miguel Vazquez, M.D. International Journal of Dermatology January-February 1982 Vol. 21, pp. 55-58]. They are thus found to be active agents that are virtually indispensable in the treatment of hyperpigmentation and are consequently present in many commercial products.
Among the phenolic derivatives, polyphenols such as hydroquinone are the pharmaceutical active agents most commonly used. Hydroquinone has been the subject of filing of various patent applications, and in particular U.S. Pat. No. 3,856,934 in which hydroquinone is in combination with retinoic acid and a corticoid as a depigmenting composition.
Rucinol or lucinol, or 4-butylresorcinol, is also a phenolic-based pharmaceutical active agent, of polyphenol type, sold as an agent for lightening brown marks associated with pigmentation disorders (the product Iklen®).
However, in the majority of cases, hydroquinone, rucinol or salts or derivatives thereof are dissolved in the aqueous phase of the preparation.
It is known that a certain number of active principles with advantageous therapeutic activity are sensitive to oxidation and especially undergo chemical degradation leading to a substantial loss of their activity in the presence of water. The incorporation of a phenolic derivative such as hydroquinone or rucinol is thus a major drawback in this type of aqueous preparation.
Specifically, degradation of formulations containing phenolic derivatives such as hydroquinone or rucinol, alone or in combination with other active principles, is often observed. These active agents are effectively known for their great sensitivity to oxidation and to heat, leading to a reduction in efficacy, rapid browning of the formulations and occasionally even demixing of the formulation.
Furthermore, to accelerate their solubilization, phenolic derivatives such as hydroquinone or rucinol are often exposed to heat during the phase of preparing the composition, especially in standard emulsions, and this phenomenon initiates and accelerates the browning.
In the prior art, reducing agents are used to combat this degradation, in particular sulfites, which are virtually indispensable. However, these antioxidants have a certain number of drawbacks, such as skin irritation problems, odour of the formulations or destabilization of the formula associated with a loss of viscosity.
Another drawback due to the presence of phenolic derivatives such as hydroquinone, alone or in combination with other active agents in the composition, is their strong irritant power.
As a result of its irritant power, hydroquinone at high concentration can give rise to post-inflammatory hypermelanosis and ochronosis phenomena.
Local irritation and dermatitis may develop after a prolonged use of hydroquinone at high concentration [“N-acetyl4S cysteaminylphenol as a new type of depigmenting agent” Jimbow K. Arch. Dermatol. 1991 October; 127 (10): 1528-1534].
Treatment with hydroquinone may be accompanied by irritation that may lead to a post-inflammatory hyperpigmentation. The incidence of the irritation depends on the hydroquinone concentration. This irritation is relatively high for 10% concentrations and reduces greatly for preparations with a 5% dose, and is considered to be virtually nonexistent at a concentration of 2% [“Les agents chimiques dépigmentants (Depigmenting chemical agents)” JP. Ortonne Ann. Dermatol. Venerol. 1986, 113: 733-736].
The chosen galenical form may thus play a predominant role in minimizing these effects.
Consequently, to avoid the presence of sulphites and to limit the use of antioxidants, which are the cause of irritation, it is appropriate to formulate phenolic derivatives and in particular hydroquinone in dissolved form in oils, allowing the formulation of totally anhydrous compositions.
In the anhydrous compositions described in the prior art, hydroquinone is generally dissolved in alcoholic or glycolic solvents before being incorporated into the rest of the anhydrous preparation.
This is the case especially in patent application US and 2006/0 120 979, describes a composition comprising hydroquinone and an anhydrous base formed from an anhydrous solvent and a high molecular weight silicone vehicle. In this case, the hydroquinone is dissolved in a solvent preferably selected from the group of monohydric alcohols (such as isopropanol), dihydric alcohols (such as glycols) and trihydric alcohols (such as glycerol). These compositions do not contain any sulfites, but require lipophilic anti-oxidants in relatively large amount. The reason for this is that, in such a medium, hydroquinone nevertheless undergoes degradation, which is less pronounced than in water but substantial enough to require the presence of lipophilic antioxidants in proportions ranging up to 1% by weight relative to the weight of the composition.
U.S. Pat. No. 4,466,955 also discloses compositions of anhydrous type containing hydroquinone. The solvents used are only solvents of polyalkoxylated fatty acid ether type (PPO or PEO derivatives). Moreover, these solvents must be used at a large concentration of between 30-60% (preferably 40-45%) and not lower under any circumstances, in order to manage to dissolve between 2-10% of hydroquinone. Moreover, despite the choice of these solvents, degradation of the hydroquinone is observed if rapid cooling is not performed. Moreover, it is pointed out that the heating temperature of the phase containing the hydroquinone should not be greater than 45° C. This thus places considerable constraints on the manufacturing processes.
One of the aims of the present invention here is to dissolve the phenolic derivative in an oily solvent in which the active agent is both soluble and stable and in which it is then possible to envisage the incorporation of the active agent into manufacturing processes that require heating steps without having any impact on the stability of the active agent.
Another aim of the present invention is to propose an anhydrous pharmaceutical composition for topical application that has prolonged stability, allowing optimized release of the active agents while at the same time being very well tolerated.
The present invention thus relates to a novel anhydrous stable composition, especially for topical application, comprising a dissolved phenolic derivative of polyphenol type and a retinoid in the fatty phase.
By virtue of its anhydrous composition, the composition according to the invention ensures both excellent stability and harmlessness of the composition.
One subject of the present invention is an anhydrous pharmaceutical composition comprising a pharmaceutical active agent of phenolic derivative type, and especially of polyphenol type, and characterized in that the said phenolic derivative is dissolved in the fatty phase.
As pharmaceutical active agents of phenolic derivative type according to the invention, mention may be made in a non-limiting manner of polyphenols and more particularly hydroquinone, rucinol or lucinol and salts thereof, 4-hydroxyanisole, hydroquinone monoethyl ether and hydroquinone monobenzyl ether. Hydroquinone, or rucinol and salts thereof, is preferably used. The term “rucinol salts” especially means salts formed with a pharmaceutically acceptable base, especially a mineral base such as sodium hydroxide, potassium hydroxide and aqueous ammonia, or an organic base such as lysine, arginine or N-methylglucamine, but also the salts formed with fatty amines such as dioctylamine, aminomethylpropanol and stearylamine.
Preferably, hydroquinone or rucinol is used.
Advantageously, the amount of phenolic derivative is from 0.01% to 10% by weight, preferably from 0.1% to 6% by weight and more particularly from 0.1% to 5% by weight relative to the total weight of the composition.
The composition according to the invention comprises, as second pharmaceutical active agent, a retinoid.
The term “retinoid” means any compound that binds to the receptors (retinoic acid receptors (RARs) and/or retinoic X receptors (RXRs)) and also precursors and derivatives thereof.
The retinoids that may be used in the context of the invention especially comprise all-trans-retinoic acid or tretinoin, 13-cis-retinoic acid or isotretinoin, acitretin, arotinoic acid, retinol, tazarotene, retinaldehyde, etretinate and the protected compounds in patent applications EP 0 199 636, U.S. Pat. No. 4,666,941, U.S. Pat. No. 4,581,380, EP 0 210 929, EP 0 232 199, EP 0 260 162, EP 0 292 348, EP 0 325 540, EP 0 359 621, EP 0 409 728, EP 0 409 740, EP 0 552 282, EP 0 584 191, EP 0 514 264, EP 0 514 269, EP 0 661 260, EP 0 661 258, EP 0 658 553, EP 0 679 628, EP 0 679 631, EP 0 679 630, EP 0 708 100, EP 0 709 382, EP 0 722 928, EP 0 728 739, EP 0 732 328, EP 0 740 937, EP 0 776 885, EP 0 776 881, EP 0 823 903, EP 0 832 057, EP 0 832 081, EP 0 816 352, EP 0 826 657, EP 0 874 626, EP 0 934 295, EP 0 915 823, EP 0 882 033, EP 0 850 909, EP 0 879 814, EP 0 952 974, EP 0 905 118, EP 0 947 496, WO 98/56783, WO 99/10322, WO 99/50239, WO 99/65872 and WO 2006/066 978, and especially 6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthoic acid (adapalene) and the methyl ester thereof, the protected compounds in patent application WO 2006/066 978 such as 3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl-[1,1′; 3′,1″]ter-phenyl-4-carboxylic acid, the compounds of patent application WO 2007/066 041, including 2-hydroxy-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid or an enantiomer thereof, the Compounds of patent application WO 05/56516, including 4′-(4-isopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthen-2-yl)-biphenyl-4-carboxylic acid, the compounds of patent application WO 2005/056 510, including 4-{3-hydroxy-3-[4-(2-ethoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronapthen-2-yl]prop-1-ynyl}benzoic acid, and the compounds of patent application WO 2005/037 772, including 4-[2-(3-tert-butyl-4-diethylaminophenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoic acid.
In particular, adapalene and salts thereof, and 3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′; 3′,1″]terphenyl-4-carboxylic acid will be preferred.
The term “adapalene salts” especially means the salts formed with a pharmaceutically acceptable base, especially mineral bases such as sodium hydroxide, potassium hydroxide and aqueous ammonia or organic bases such as lysine, arginine, N-methylglucamine, and the salts formed with fatty amines such as dioctylamine and stearylamine.
The term “retinoid precursors” means the immediate biological precursors or substrates thereof, and also the chemical precursors thereof.
The term “retinoid derivatives” means both the metabolic derivatives thereof and the chemical derivatives thereof.
Preferably, the composition comprises an amount of retinoid agent of between 0.0001% and 1% by weight, preferably between 0.001% and 0.3% and even more preferentially between 0.01% and 0.1% by weight relative to the total weight of the composition.
The present invention thus relates to a novel anhydrous stable composition, especially for topical application, comprising, in a fatty phase, a retinoid and a dissolved phenolic derivative.
On account of its anhydrous nature, the composition according to the invention ensures both excellent stability and harmlessness of the composition.
The term “anhydrous composition” means a composition comprising an amount of water of less than or equal to 5% by weight relative to the total weight of the composition.
In one preferred mode according to the invention, the composition does not contain any water.
The term “stable composition” means a chemically and physically stable composition.
The term “chemical stability” especially means that no degradation of the active agent is observed over time and at temperatures between 4 and 40° C.
The term “physical stability” especially means that the compositions do not show any changes in macroscopic appearance, in particular of colour, or in microscopic appearance, and no change in viscosity over time and at temperatures of between 4 and 40° C.
Optionally, a flow threshold measurement may be taken in order to characterize the finished product.
For the flow threshold measurement, a Haake VT550 rheometer with an SVDIN measuring spindle was used.
The rheograms are produced at 25° C. and at an imposed speed of 0 to 100 s−1. The viscosity values are given at the shear values of 4 s−1, 20 s−1 and 100 s−1 (γ). The term “flow threshold” (τ0 expressed in pascals) means the force necessary (minimum shear force) to overcome the cohesion forces of Van der Waals type and to bring about flow.
Throughout the present patent application, the term “room temperature” means a temperature between 20 and 30° C.
The anhydrous nature of the composition according to the invention makes it possible to avoid the instability of the phenolic derivative, in particular its oxidation in aqueous medium. In such a formulation, the use of sulfites, which are indispensable for stabilizing hydroquinone in aqueous medium, is thus no longer necessary. Consequently, in one preferred mode according to the invention, the composition does not contain any sulfites and contains an amount of antioxidants strictly less than 0.3% and preferentially less than 0.2% by weight relative to the total weight of the composition. The antioxidants that may be used according to the invention are preferably antioxidants such as vitamin E and derivatives thereof, for instance DL-α-tocopherol or tocopheryl acetate from Roche; vitamin C and derivatives thereof, for instance ascorbyl palmitate from Roche, and the butylhydroxy-toluene sold under the name Nipanox BHT by Clariant.
The composition according to the invention comprises at least one solvent fatty phase, or solvent oily phase, for the compound of the phenolic derivative family, and preferably hydroquinone or rucinol.
The composition according to the invention comprises at least one fatty phase, or oily phase, which is solubilizing or dispersing for the retinoid.
Specifically, the majority of retinoids are soluble in various solvents, including oily solvents. However, the preferred retinoid according to the invention, adapalene, has the particular feature of being insoluble in all the solvents that may be used for retinoids. In any composition and especially in the present invention, adapalene must thus be dispersed, and more particularly in the fatty phase of the present invention.
The solvent oily phase for the phenolic derivative and the solvent or dispersant oily phase for the retinoid may be, but are not mandatorily, formed from the same fatty substances.
In one preferred mode according to the invention, the composition comprises at least one solvent oily phase for the phenolic-based pharmaceutical active agent, especially hydroquinone or rucinol, and at least one dispersant oily phase for adapalene.
The term “constituents of the oily solvent and/or dispersant phase” especially refers to:
PPG-15 stearyl ether or any other ether or derivatives, diisopropyl adipate or any other ester of derivatives, or alternatively triglycerides such as caprylic/capric triglycerides or derivatives thereof, or a mixture of these compounds, will preferably be chosen as oily solvents for the phenolic derivative, and more particularly for hydroquinone or rucinol. The composition according to the invention more particularly comprises a mixture of solvents.
Preferentially, the mixture of solvents will be formed from a maximum of 15% (by weight relative to the total weight of the composition) of solvent of ether derivative type. In the composition according to the invention, this amount of solvent, combined with the other novel solvents present, is sufficient to dissolve the desired concentrations of active agent and to obtain stable preparations.
Preferably, triglycerides such as caprylic/capric triglycerides or derivatives thereof will be chosen as oily dispersants for the retinoid and more particularly for adapalene.
The oily phase that is a solvent and/or dispersant for the active agent comprises at least one oily solvent and/or dispersant for the active agent and/or a lipophilic surfactant.
The term “lipophilic surfactant” more particularly means:
The amount of solvent and/or dispersant fatty phase in the composition according to the invention is generally between 5% and 99% and preferentially from 10% to 98% by weight relative to the total weight of the composition.
According to one particular embodiment, the compositions according to the invention do not contain any alcoholic or glycolic solvents.
The composition according to the invention may also comprise at least one lipophilic gelling agent or thickener depending on the desired viscosity. Specifically, these compounds are used in the present invention as “viscosity regulators”.
According to the invention, the term “lipophilic thickeners or gelling agents” means compounds chosen especially from waxes, hydrogenated oils and fatty acid esters.
The term “wax” generally means a lipophilic compound, which is solid at room temperature (25° C.), with a reversible solid/liquid change of state, which has a melting point of greater than or equal to 30° C., which may be up to 200° C. and especially up to 120° C. As waxes that may be used, mention may be made of carnauba wax, microcrystalline waxes, beeswax, sold under the name Cerabeil blanche by Barlocher, glyceryl behenate, derivatives thereof such as glyceryl monobehenate, glyceryl dibehenate, tribehenine or a mixture thereof, such as that sold under the name Compritol 888 by Gattefossé, or candelilla wax.
The term “hydrogenated oil” means oils obtained by catalytic hydrogenation of animal or plant oils containing linear or branched C8-C32 fatty chains. Among these oils, mention may be made especially of hydrogenated jojoba oil, isomerized jojoba oil such as partially hydrogenated trans-isomerized jojoba oil manufactured or sold by the company Desert Whale under the commercial reference Iso-Jojoba-50®, hydrogenated sunflower oil, the hydrogenated castor oil sold especially under the name Cutina HR by Cognis, the polyoxyethylenated castor oil sold especially under the name Cremophor EL by BASF, hydrogenated coconut oil and hydrogenated lanolin oil; hydrogenated castor oil will preferably be used.
As fatty acid esters that may be used, mention may be made of lanolin sold especially under the name Medilan by Croda, the fatty acid esters of glycerol sold under the name Gelucire by Gattefosse, the hydrogenated coconut glycerides sold under the name Akosoft 36 by Karlshamns, or the diethylene glycol or propylene glycol monostearate sold, respectively, under the names Hydrine or Monostéol by Gattefossé.
The amount of lipophilic thickeners or gelling agents in the composition according to the invention is generally between 1% and 40% and preferably between 5% and 30% by weight relative to the total weight of the composition.
The composition according to the invention may contain an elastomer. The term “elastomer” means any polyorganosiloxane elastomer, i.e. any chemically crosslinked siloxane polymer that has viscoelastic properties especially such as, preferably, the Elastomer 10 sold by Dow Corning. The amount of high molecular weight elastomer in the composition according to the invention is generally between 0% and 40% and preferentially from 0 to 20% by weight relative to the total weight of the composition.
Optionally, the composition according to the invention may also comprise another surfactant and/or at least one binder.
The surfactants used are preferably nonionic surfactants, which are used for example, but not exclusively, to facilitate the incorporation of certain constituents such as glycols into the oily phase of the composition.
Among the surfactants that may be used according to the invention, mention may be made of esters of glycerol and optionally of polyethylene glycol, such as the mixture of glyceryl stearate and of PEG-100 stearate, sold under the name Arlacel 165 by Uniqema, the mixture of glyceryl stearate and of PEG-75 stearate sold under the name Gelot 64 by Gattefosse, the glyceryl stearate sold under the name Cutina GMSV by Cognis; emulsifying waxes, such as the self-emulsifying wax sold under the name Polawax NF by Croda or the PEG-8 beeswax sold under the name Apifil by Gattefossé; the polysorbate 80 sold under the name Tween 80 by Uniqema; castor oil and derivatives such as the polyoxyethylenated castor oil from BASF sold under the trade name Cremophor EL, or the mixture of glyceryl stearate and PEG-2 stearate, sold under the name Sedefos 75 by Gattefosse. Preferably, polysorbate 80 will be used. The amount of surfactants is between 0.1% and 10% by weight and preferably between 1% and 10% by weight.
The composition may optionally comprise at least one binder. Among the binders that may be used, mention may be made of the magnesium stearate sold by Brenntag, the corn starch sold by Roquette, the talc sold by WCD, the cholesterol sold by Croda or the silica sold by Degussa.
The binders may be used in an amount of between 0.1% and 30% by weight and preferably between 1% and 20% by weight.
The composition according to the invention may also contain additives, which a person skilled in the art will select as a function of the desired effect.
Among the additives, examples that may be mentioned include, taken alone or in combination:
Preferentially, the composition according to the invention comprises, on a weight basis relative to the total weight:
More preferentially, the composition according to the invention comprises, on a weight basis relative to the total weight:
Even more preferentially, the composition according to the invention comprises, on a weight basis relative to the total weight:
The anhydrous composition according to the invention may be in the various known galenical forms, which a person skilled in the art will adapt to the particular use of the composition.
The compositions according to the invention are preferably formulated for topical application.
The term “topical application” means external application to the skin or mucous membranes.
The compositions may be in any galenical form normally used for topical administration. As non-limiting examples of compositions as described in the American pharmacopoeias (USP32-NF27—Chap 1151—Pharmaceutical Dosage Forms) or European pharmacopoeias (Edition 6.3—in the chapter: Préparations semi-solides pour application cutanée [Semi-solid preparations for cutaneous application]) or as defined in the decision trees of the American Food and Drug Administration (FDA) (CDER Data Standards Manual Definitions for topical dosage Forms). The compositions according to the invention may thus be in liquid, semi-solid, pasty or solid form, and more particularly in the form of ointments, oily solutions, dispersions of the lotion type, which may be two-phase lotions, serum, anhydrous or lipophilic gels, powders, impregnated pads, syndets, wipes, sprays, mousses, sticks, shampoos, compresses, washing bases, emulsions of liquid or semi-liquid consistency of the oil-in-glycol or glycol-in-oil type, a microemulsion, semi-liquid or solid suspensions or emulsions of the white or coloured cream type, inverse or multiple emulsions, gel or pomade, suspensions of microspheres or nanospheres or of lipid or polymeric vesicles, or microcapsules, microparticles or nanoparticles, or polymeric or gelled patches for controlled release.
The anhydrous composition according to the invention is preferably an ointment. According to the invention, the term “ointment” means a composition especially as defined in the US or European pharmacopoeias mentioned above. The FDA thus defines an ointment as being a semi-solid composition comprising, as vehicle, less than 20% water and volatile compounds and more than 50%'hydrocarbons, waxes or polyols. In certain cases, when the content of volatiles is high, such compositions may be referred to as creams (decision tree of the American Food and Drug Administration (FDA)). The American Pharmacopoeia defines an ointment as being a product whose base is a vehicle that may belong to the following four classes: hydrocarbon base or absorbent base or water-washable base or water-soluble base. Preferably, the ointment, according to the invention and the US Pharmacopoeia belongs to the class of hydrocarbon-based ointments. The European Pharmacopoeia defines an ointment as being a one-phase composition in which liquids or solids may be dispersed.
The ointment according to the invention is preferentially a composition that is thick at room temperature, which comprises between 80% and 98% by weight, relative to the total weight of the composition, of hydrophobic compounds other than petroleum jelly. Such compounds are chosen especially from liquid oils alone or as a mixture, the said oils possibly being hydrocarbons, esters, plant oils and/or silicone oils, which are volatile or non-volatile, which may be gelled with lipophilic compounds that are solid at room temperature such as waxes, butters or fatty acid esters.
Optionally, a measurement of the flow threshold may be performed in order to characterize the finished product.
For the measurement of the flow threshold, a VT550 Haake rheometer with an SVDIN measuring spindle was used.
The rheograms are produced at 25° C. at an imposed speed of 0 to 100 s−1. The viscosity values are given at shear values of 4 s−1, 20 s−1, 100 s−1 (γ). The term “flow threshold” (τ0 expressed in Pascals) means the force (minimum shear stress) required to overcome the cohesion forces of Van der Waals type and to bring about flow.
In one preferred mode according to the invention, the composition is an anhydrous pharmaceutical or cosmetic composition of ointment type comprising:
In a more particularly preferred mode according to the invention, the composition comprises:
A subject of the invention is also the use of the composition thus obtained, as a medicament.
More particularly, the composition may be used for preparing a medicament intended for treating and preventing hyperpigmentary disorders such as melasma, chloasma, lentigo, senile lentigo, vitiligo, freckles, post-inflammatory hyperpigmentations caused by an abrasion, a burn, a scar, a dermatosis or a contact allergy; naevi, genetically determined hyper-pigmentations, hyperpigmentations of metabolic or medicinal origin, melanomas or any other hyperpigmentary lesions.
The compositions according to the invention also find an application in the cosmetics field, in particular in protecting against the harmful effects of sunlight, for preventing and/or combating light-induced or chronological ageing of the skin and the integuments.
The invention also relates to a non-therapeutic cosmetic treatment process for beautifying the skin and/or for improving its surface appearance, characterized in that a composition comprising adapalene and at least one depigmenting agent is applied to the skin and/or its integuments.
In one preferred mode according to the invention, the depigmenting composition characterized in that it comprises hydroquinone or rucinol and adapalene in a fatty phase has improved depigmenting efficacy when compared with a composition containing the same active agents incorporated in the aqueous and/or alcoholic and/or glycolic phase of the composition.
The examples below illustrate the efficacy of particular compositions according to the invention.
The anhydrous compositions according to the invention are obtained by a person skilled in the art using a known standard process for mixing phases.
The preparation process may especially include the following steps:
A person skilled in the art will adapt the manufacturing processes to the types of compositions and ingredients chosen.
The formulation examples below illustrate the compositions according to the invention without, however, limiting the scope thereof. The amounts of the constituents are expressed as weight percentages relative to the total weight of the composition.
a) Solubilities and Stabilities of Hydroquinone in Solvent Oils and Lipophilic Surfactants
Hydroquinone Solubilities
The above table makes it possible to identify which solvents are the most solubilizing for the active agent, for optimum selection of the ingredients of the composition. However, the choice of solvent will also be made on the basis of the results of the stability of hydroquinone in these solvents.
A compromise between solubility and stability must be obtained, if necessary by means of a mixture of solvents.
Stability of Hydroquinone in Solvent Oils and Lipophilic Surfactants
Assay technique by HPLC against reference substance.
The initial time (T0) is considered as 100%.
The above table makes it possible to evaluate the stability of hydroquinone in the various solubilizing agents identified previously.
Thus, it may be deduced therefrom that the preferred solvents are Crodamol DA, Arlamol E and Labrasol, which give the hydroquinone good chemical and physical stability (macroscopic observation of the colour), coupled with a good solubilizing effect.
The use of such solvents may thus make it possible to dispense with any use of antioxidants.
It may be noted that despite a high solubility of hydroquinone in Cremophor EL, it shows macroscopic instability demonstrated by browning that becomes pronounced over time and with temperature. Cremophor EL may be used in limited amount to aid the dissolution of the hydroquinone, but preferably along with a hydroquinone-stabilizing solvent, for instance medium-chain triglycerides such as Miglyol® 218N.
Moreover, it may be noted that in the solvents used in the prior art US 2006/0 120 979, such as glycols, a colouration is observed at RT and at 40° C., which is evidence of instability of the hydroquinone in these solvents in the absence of antioxidants.
b) Solubilities and Stabilities of Rucinol in Solvent Oils and Lipophilic Surfactants
Rucinol Solubilities
The solubility study performed showed that rucinol shows very good solubility in all the solvents tested. However, the optimum choice of solvent will also be made on the basis of the results of the stability of rucinol in these solvents.
Stability of Rucinol in Solvent Oils and Lipophlic Surfactants
Assay technique by HPLC against reference substance.
The initial time (T0) is considered as 100%.
The table above makes it possible to evaluate the stability of rucinol in the solubilizing agents identified previously.
On the basis of these results, the following compositions according to the invention were prepared.
For all the formulations, the physical stability is measured by macroscopic and microscopic observation of the formulation at room temperature, at 4° C. and at 40° C. after 1 month, 2 months and optionally 3 months and 6 months.
At room temperature, the macroscopic observation makes it possible to ensure the physical integrity of the products and the microscopic observation makes it possible to check that there is no recrystallization of the dissolved active agent.
At 4° C., microscopic observation verifies the non-recrystallization of the dissolved active agents.
At 40° C., macroscopic observation verifies the integrity of the finished product.
The chemical stability is measured by assaying the active agents by external calibration in HPLC and the results are expressed as a % of duplication relative to the theoretical value.
Phase A:
Introduce the glyceryl behenate and the cetearyl isononanoate into the formulation beaker. Bring the mixture to 85° C. with slow stirring. Maintain the stirring and heating until fully homogeneous.
Stop the heating and maintain the stirring.
Phase B:
In a separate beaker, dissolve the minor part of hydroquinone or rucinol in the caprylic/capric triglycerides with magnetic stirring while heating at about 75° C. Disperse the adapalene in the above mixture, with stirring.
Phase C:
In a separate beaker, dissolve the DL-α-tocopherol and the ascorbyl palmitate and the second part of hydroquinone or rucinol in PPG-15 stearyl ether with magnetic stirring while heating at about 75° C.
Phase D:
In a separate beaker, dissolve the third part of hydroquinone or rucinol in PEG-8 caprylic/capric triglycerides with magnetic stirring while heating at about 75° C.
Phase E:
In a separate beaker, disperse the adapalene in one part of caprylic/capric triglycerides with stirring.
Phase F:
In a separate container, weigh out the ST Elastomer 10.
Mixing:
At about 75° C., add the fully homogenized phase B with stirring.
At about 55° C., add phases C and D and homogenize fully with stirring.
At 40° C. maximum, add phase E with continued stirring.
Then add phase F.
Leave to cool with stirring to about 35° C.
Specifications at T0:
Macroscopic appearance: firm white ointment
Microscopic appearance: absence of crystals of hydroquinone−adapalene in dispersion (observed by fluorescence), crystals <2.5 to 5 μm
Physical Stability:
Chemical Stability:
Hydroquinone
Adapalene
Specifications at T0:
Macroscopic Appearance: Glossy White Ointment
Microscopic appearance: absence of crystals of rucinol—adapalene in dispersion (observed by fluorescence), crystals <2.5 to 5 μm.
Haake profile (4 s−1/20 s−1/100 s−1): 126/84/109
Physical Stability:
Chemical Stability:
Rucinol:
Adapalene:
The composition of Example 2 is compared, in a test for measuring depigmenting activity on the tail of a mouse, with the composition below:
Results:
FIG. 1 shows that, at the same concentrations of active agents, the composition according to Example 2 of the present invention with adapalene dispersed in the fatty phase and hydroquinone dissolved in the fatty phase shows greater depigmenting activity than the composition in which the adapalene and the hydroquinone are dissolved and/or dispersed in the aqueous/alcoholic phase of a gel.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/FR2009/051040 | 6/2/2009 | WO | 00 | 3/9/2011 |
