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(12) Patent Application Publication (10) Pub. No.: US 2004/0219123 A1 Astruc Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2004/0219123 A1 Astruc Et Al US 2004O219 123A1. (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0219123 A1 Astruc et al. (43) Pub. Date: Nov. 4, 2004 (54) INVERT EMULSIONS COMPRISING DHEA Related U.S. Application Data (75) Inventors: Fanny Astruc, Mougins Le Haut (FR); (63) Continuation of application No. PCT/FR02/02569, Sandrine Orsoni, Mandelieu (FR); filed on Jul. 18, 2002. Laurent Fredon, Roquefort Les Pins (FR); Jean-Thierry Simonnet, Paris (30) Foreign Application Priority Data (FR); Pascal Richart, Paris (FR) Aug. 2, 2001 (FR)............................................ O1/10398 Publication Classification Correspondence Address: BURNS DOANE SWECKER & MATHIS LLP (51) Int. Cl. ............................... A61K 7/06; A61K 7/11 POST OFFICE BOX 1404 (52) U.S. Cl. .......................................................... 424/70.12 ALEXANDRIA, VA 22313-1404 (US) (57) ABSTRACT Stable, recrystallization-resistant invert emulsions, Suited, (73) Assignee: GALDERMARESEARCH & DEVEL e.g., for preventing/treating the Signs of chronological or OPMENT, S.N.C., VALBONNE (FR) actinic skin aging and for preventing/treating atrophy of the skin or mucous membranes, comprise a cosmetically/thera peutically effective amount of DHEA and/or chemical and/ (21) Appl. No.: 10/767,814 or biological precursor or derivative thereof, Such invert emulsions also comprising a glycolic or hydroglycolic dis persed hydrophilic phase, a lipophilic continuous phase and (22) Filed: Jan. 30, 2004 an emulsifier having an HLB ranging from 2 to 7. US 2004/0219123 A1 Nov. 4, 2004 INVERT EMULSIONS COMPRISING DHEA proliferation in the living layers, will result in an increase in the epidermal content of phospholipids (sphingomyelin/ CROSS-REFERENCE TO PRIORITY/PCT phosphatidylinositol or phospholipids of the membranes, APPLICATIONS respectively) and will result in an increase in the size or in the number of living cells, that is to Say in a thickening of 0001. This application claims priority under 35 U.S.C. S the epidermis. 119 of FR 01/10398, filed Aug. 2, 2001, and is a continuation of PCT/FR 02/02569, filed Jul.18, 2002 and designating the 0012. This physiological activation will thus make it United States (published in the French language on Feb. 13, possible to prevent or to combat the Signs of chronological 2003 as WO 03/011243 A1; the title and abstract were also or actinic aging and certain skin pathologies. published in English), both hereby expressly incorporated 0013 Indeed, it is known that during chronobiological by reference and both assigned to the assignee hereof. aging, in particular during the menopause, atrophy of the epidermis is observed which results from a general slowing BACKGROUND OF THE INVENTION of cellular metabolism and which is partly responsible for 0002) 1. Technical Field of the Invention the appearance of wrinkles and fine lines. Atrophy of the 0003. The invention relates to novel invert emulsion-type epidermis has also been identified as one of the histological compositions containing DHEA and/or its chemical and/or Signs of photoaging (Gilchrest B. A., Skin and Aging Pro biological precursors or derivatives thereof, and to the cesses, 1989, CRC Press). applications therefor in the fields of cosmetics and derma 0014. This process is also present in other mucous mem tology. branes, in particular during Vulvar or vaginal atrophy. 0004 2. Description of Background and/or Related and/ 0015. It can therefore be understood why it is important or Prior Art to have a means for facilitating cell multiplication or 0005 Human skin consists of two compartments, namely metabolism, in particular of the living cells of the epidermis, a deep compartment, the dermis, and a top compartment, the for preventing or combating atrophy of the epidermis and epidermis. thus giving the skin a young appearance again. 0016 DHEA or dehydroepiandrosterone, also known as 0006 The dermis provides the epidermis with a solid 3-beta-hydroxyandrosteron-5-en-17-one or dehydroisoan Support. It is also its feeder component. It is mainly com drosterone or trans-dehydroandrosterone or prasterone, is a posed of fibroblasts and an extracellular matrix which is natural Steroid essentially produced by the adrenocortical itself mainly composed of collagen, elastin and a Substance, glands. called ground Substance. Leukocytes, mastocytes or tissue macrophages are also present therein. It also contains blood 0017 Exogenous DHEA, administered by the topical or vessels and nerve fibers. oral route, is known for its capacity to promote keratiniza tion of the epidermis (JP-0-7,196,467) and to treat dry skins 0007. The epidermis is in contact with the external envi by increasing the endogenous production and the Secretion ronment. Its role consists in protecting the body from of sebum and by thereby reinforcing the barrier effect of the dehydration and from external attacks, whether they are skin (U.S. Pat. No. 4,496.556). There has also been chemical, mechanical, physical or infectious. described in U.S. Pat. No. 5,843,932 the use of DHEA for 0008. The natural human epidermis is mainly composed remedying the atrophy of the dermis by inhibiting the loss of of three types of cell which are the keratinocytes, which are collagen and of connective tissue. Finally, the assignee highly predominant, the melanocytes and the Langerhans hereof has demonstrated the capacity of DHEA to combat cells. Each of these cell types contributes, by its specific the weathered appearance of the skin (FR-2,803.513), to functions, to the essential role played in the body by the skin. modulate the pigmentation of the Skin and of the hair 0009. The cells constituting the epidermis are delimited (EP-1,092,423) and to combat the atrophy of the epidermis. by a lipid domain. The epidermal lipids are mainly Synthe These properties of DHEA make it a candidate of choice as sized in the living epidermis. They are essentially composed anti-aging active agent. of phospholipids, Sphingolipids, cholesterol, free fatty acids, 0018. However, DHEA exhibits the difficulty of being triglycerides, esters of cholesterol and alkanes. During cell very sparingly Soluble in commonly used cosmetic or phar differentiation, the phospholipids, whose role consists in maceutical Solvents Such as water, polar or apolar oils. producing the fluid Structure of the cell membranes of the 0019. It is indeed known that DHEA is only soluble with living layers of the epidermis, are gradually replaced by a difficulty in aqueous media, which limits its formulation in mixture which is predominantly composed of fatty acids, cosmetic or dermatological compositions applied by the cholesterol and Sphingolipids, which are essential constitu ents of the horny layer of the epidermis (stratum corneum). topical or oral route. It thus has a tendency to recrystallize. 0020 DHEA indeed has several polymorphic forms of 0.010 The lipids of the intercorneocyte cement of the which the type and the distribution can be poorly controlled, skin, and in particular the ceramides, are organized into these being dependent on environmental conditions and the lamellar bilayerS or sheets and participate in the cohesion of manner of preparing the active ingredient (Chang et al., J. the Stratum corneum in order to maintain the integrity of the Pharm. Sci., 84: 1169-1179 (1995)). There are between three barrier and its protective, antipenetration and in particular and five anhydrous polymorphic forms and at least three anti-irritation role. hydrated forms. These polymorphic forms can only be 0011. It can be understood why activation of the metabo distinguished by analytical techniques Such as X ray dif lism in the living cells of the epidermis, or an increase in cell fraction, infrared spectroscopy and DSC (differential scan US 2004/0219123 A1 Nov. 4, 2004 ning calorimetry) (WO 00/54763). Depending on the source 0030 Finally, a use of a water-in-oil type composition of Supply of DHEA, there may be a variable polymorphic had been mentioned in the prior art. Thus, FR-2,777,194 distribution of the raw material, which can potentially cause describes a water-in-oil type cosmetic or dermatological Significant variations in therapeutic bioavailability and in composition containing 10% to 50% of a Co to Co efficacy. branched Saturated liquid hydrocarbon or of a mixture of 0021. The result is a loss of efficacy and an uncertainty as such hydrocarbons, 1% to 47% of a natural phospholipid or regards the more or less large dose of DHEA present in these of a mixture of natural phospholipids and 50% to 80% of compositions, depending on the degree of recrystallization, water. However, although DHEA is generically mentioned which runs counter to the desired objective. In addition, this in an extensive list of active compounds, no concrete data is recrystallization can modify the overall stability of these provided. In addition to the absence of an effective embodi compositions and their appearance, which can put the user ment in this prior art, perSons skilled in the art were not inclined to follow this formulation route given the high off these compositions. percentage of water taught in FR-2,777,194 (50% to 80%) 0022. Moreover, controlling the stability of a particulate and the low solubility of DHEA in water (maximum solu dispersion can prove difficult to achieve. bility of 0.02 mg/ml), in which DHEA precipitates very 0023. In Table 1 are various examples showing the low rapidly. solubility of DHEA in a lipophilic phase: 0031. In addition, this prior art is mainly centered on the use of phospholipids and not on the production of formu TABLE 1. lations which can be used for complex derivatives Such as INCINAME Solubility (% w/w) DHEA, and/or its chemical and/or biological precursors or derivatives. Caprylic?capric triglycerides 1.77% Sesame oil 1.40% 0032 Too, phospholipids exhibit limited chemical stabil Isopropyl palmitate 1.37% ity in relation to the phenomena of oxidation, which does not Mineral oil 1.00% Octyl palmitate 1.00% encourage those skilled in this art to rely on this document Cetearyl isononanoate O.83% in their search for stable formulations based on DHEA or Dimethicone O.17% analogs.
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