This invention relates to topical compositions consisting of lipids incorporated into lamellar structures preventing crystallisation for optimised bioavailability and application to human skin.
Skin is a highly complex tissue acting as a protector against physical, chemical and biological attacks. It plays a crucial role in the protection against dehydration and the control of body temperature (A Short Textbook of Cosmetology, K F de Polo (Ed.), Verlag für chemische Industrie, H. Ziokowski GmbH, Augsburg (D), 1998). This barrier is provided by the “horny layer” (stratum corneum, SC), representing the outermost layer of the epidermis. The horny layer is a thin inert, water-retaining barrier which both regulates the moisture content of the skin and protects it against external influences.
Due to its structure it is often compared to a brick wall in which the nonviable corneocytes are embedded like bricks in a matrix of lipids (“Mortar”) (Elias P M, J. Invest. Dermatol. 80 (Suppl 1), 44 (1983)). The lipid mixture is assembled into densely packed lamellar structures consisting of ceramides, cholesterol and fatty acids. In the literature different compositions of skin lipids are given depending on extraction and analytical methods exerted and the origin of the skin used for analysis. On a weight basis, these lipids constitute of approximately 47% by weight ceramides, 24% by weight cholesterol, 11% by weight free fatty acids and 18% by weight cholesterol esters (Rawlings A V, Int. J. Cosmet. Sci. 25, 1-33 (2003)).
The lipid environment of the stratum corneum is an essential factor for maintaining the skin's equilibrium. As a result of age, health or environmental conditions, changes in the lipid composition occur, leading to a weakening of the barrier function (Rawlings, A. V. et al., J. Invest. Dermatol. 103, 731-740 (1994); Motta S; Arch Dermatol. 1994; 130, 452-456; Choi et al, J Invest Dermatol. 2005 Mar., 124(3), 587-595). These findings lead to the concept that ceramides in combination with cholesterol and fatty acids are valuable components of skin care products, since the topical application of such products can replenish low levels of stratum corneum lipids.
It is well known in the literature that the topical application of lipid mixtures containing ceramides, fatty acids and cholesterol improves the skin performance under various suboptimal conditions, e.g. barrier recovery in chronologically aged skin (Zettersten et. al., J Am Acad Dermatol. 1997 Sep., 37, 403-408), in psychologically stressed skin (Choi et al, J Invest Dermatol. 2005 March, 124(3), 587-595) or improving the barrier properties and the clinical condition of the skin in contact dermatitis (Beradesca et. al., Contact Dermatitis, 2001, 45, 280-285).
EP 0 644 764 (Elias et. al.) describes specific lipid mixtures consisting of acylceramides, ceramides or glucosylceramides together with cholesterol and/or fatty acids for epidermal moisturization and repair of barrier function. The invention is related to the treatment of skin diseases which display hyperproliferation and disruptions of the barrier function.
The activity of short chain ceramides on keratinocyte proliferation and differentiation has been described in the literature (Pillai et al. J Invest Dermatol. Symp. Proceed. 1, 39-43). U.S. Pat. No. 5,578,641 (Jackson et. al.) described the topical applications of one or more ceramide pathway intermediates or precursors for the supplementation of skins own ceramide production pathways in the epidermis. Listed structures include free sphingoid bases and their N-acyl derived ceramides with a carbon chain length of 1 to 10 atoms. The invention is related to the treatment of dry and/or (photo-)damaged skin for reducing or delaying wrinkle formation.
EP 0 975 325 (Lambers) describes compositions comprising a combination of a free sphingoid base and a ceramide showing a positive synergistic effect on lipid barrier function.
The physical organization of the membrane bilayer structure is crucial for an effective skin barrier and this is provided by a lipid lamellar assembly in a tightly packed or thorhombic configuration. Detailed research on the assembly of SC lipids has been performed establishing the so-called “Sandwich model” (Bouwstra J et al., Skin Pharmacol. Appl. Skin Physiol. 14, 52-62 (2001)). By electron microscopy and x-ray diffraction the SC lipids are observed as alternating broad/narrow/broad sequences of bilayers representing two broad lipid layers with crystalline structure separated by a narrow central lipid layer with fluid domain. The optimal ratio for the topical application of the stratum corneum lipids ceramides, cholesterol and fatty acids is in the range of 1:1:1 on a molar basis. The structural organisation of the stratum corneum lipids in vivo can be mimicked by lipid mixtures prepared with well-defined synthetic ceramides 1, 2, 3 and 9 (de Jager et al, J. Lipid Res. 2005 Dec., 46(12), 2649-2656). Using the more recent lettering system of Ceramides classification (Motta et al. BBA, 1993, 1182, 147-151) these Ceramides are called Cer(amide) EOS, Cer NS, Cer NP and Cer EOP respectively.
Although the dermatological importance of ceramides is known, it still remains a challenging target to incorporate ceramides in a stable way in cosmetic formulations. Stable in that respect means that not only the formulation is physically stable but also that ceramides do not recrystallize out of these formulations.
There have been publications explaining how ceramides can be included in cosmetic formulations avoiding this crystallization phenomenon (e.g. T. Dietz, P. Hameyer, SOFW-Journal (5), 2-9 (2003)). In these studies it was shown on the example of Ceramide 3 (NS) that up to 1% by weight of this ceramide can be included into cosmetic oil-in-water emulsions without crystallization. As a crucial step in successfully formulating ceramides it was pointed out that the ceramides had to be dissolved in the oil phase in a first processing step. In order to achieve that the oil phases had to be heated to 90° C.
Unfortunately, such a processing is not possible for many types of cosmetic formulations due to limitations in available processing equipment or due to restrictions caused by temperature sensitive ingredients in the formulations. Also for ecological and economical (longer processing, costs for heating) reasons such a way of processing is not optimal.
Moreover, in the Dietz paper it has also been described that all attempts to include Ceramide 3 (Cer NS) in a stable way into water-in-oil emulsions failed. Ceramide 3 (Cer NS) crystals appeared in all formulations after a few days of storage at room temperature even at very low ceramide concentrations of 0.1% by weight in these formulations.
A limitation of stable inclusion of ceramides in formulations just to oil-in-water emulsions is a significant restriction for cosmetic formulators as water-in-oil emulsions are known for their moisturizing benefits especially for dry skin.
Additionally it is even more challenging to include ceramides with N-acyl side chains that are longer than 18 Carbon atoms stable into formulations as these long-chain ceramides tend to crystallize much easier.
However, in order to provide a mixture of ceramides/cholesterol/fatty acids that is able to mimic skin identical lamellar structures, Bouwstra and her group showed that especially such long-chain ceramides are needed (Bouwstra, J. A. et al. J. Lipid Research 1999, 39, 186-196; Bouwstra, J. A. et al. J. Invest. Dermatol. 2002, 118, 606-617; de Jager, M. W. et al. Chem. Phys. Lipids 2003, 124, 123-134)
For all these reasons there is a need to offer the cosmetic and pharmaceutical formulator a composition that is able
Surprisingly, it was found that all three targets can be fulfilled by a suitable design of a skin treatment composition based on nonionic hydrophilic emulsifiers, consistency enhancers, specific ceramide mixtures containing medium and long-chain ceramides, fatty acids and cholesterol. This cholesterol can either be animal derived, be produced by a micro-organism, have a plant origin or be synthetized starting from plant-derived material.
Additionally, it was surprisingly found that inclusion of short chain ceramides (C4 to C8 alkyl chains) did not change the lamellar lipid organization. This inclusion, however, resulted into an increased production of ceramides in the skin.
Therefore the short-chain ceramides surprisingly acted as regulators when the cosmetic composition was applied onto the skin.
The present invention therefore corresponds to liquid and pumpable skin treatment compositions containing (all percentages are given as weight-%):
The main advantages of the inventive mixture are:
In a preferred embodiment of the invention the skin treatment composition contains 0.5 to 5% by weight of the ceramide/cholesterol/free fatty acid mixture A) and 4 to 6% by weight of a nonionic emulsifier or a nonionic emulsifier mixture with a combined HLB value of 12 to 19 and 1 to 5% by weight consistency enhancers like glyceryl stearate or C16 to C22 alkanols and optionally auxiliaries and additives added up to 100% by weight by weight with water.
The Ceramide(s) present in mixture A1) consist of:
wherein
Preferably R is either a straight chain alkyl group having 12 to 18 carbon atoms or C(H)OH coupled to a straight chain alkyl group having 11 to 17 carbon atoms.
Most preferred A and R combinations are Phytosphingosine (P), Sphingosine (S), 6-hydroxysphingosine (H) and Sphinganine (Sa).
The above Sphingoid base is coupled via an amide linkage to a fatty acid (both hydroxy and non hydroxy fatty acids) according to formula 2
wherein
The alkyl chain may be interrupted by an Oxygen atom or by an internal ester group; may eventually contain one or more double bonds and may eventually be substituted by one or more hydroxyl groups,
or
skinidentical Ceramide(s). These are Ceramides with a composition as above but with a stereochemical configuration, that is identical to the natural ceramides present in the mammalian skin,
or
natural Ceramide(s). These are Ceramides with a composition as above, which are extracted from the mammalian skin and have maintained their original steriochemical configuration during the extraction process,
or
combinations thereof.
In a preferred embodiment of the invention the ceramide/cholesterol/free fatty acid mixture A contains a combination of natural or skin identical ceramides A1) consisting of:
Mixture A1) present in the composition according to the invention consists preferably of:
In a more preferred embodiment of the invention the ceramides/cholesterol/free fatty acid mixture A contains specific combinations of natural or skin identical ceramides A1, that are able to mimic skin identical lamellar structures (in the following referred to as A1 lam). For this aim Ceramides mixture A1lam, should consist of at least 3, but preferably 4 natural or skin-identical ceramides:
Most preferred compositions of Mixture A1lam. being able to mimic skin identical lamellar structures consist of:
The free fatty acids A3) present in the composition according to the invention consists preferably of fatty acids with an alkyl, alkenyl-, alkadienyl-, alkatrienyl-, alkapolyenyl-chain of C12 to C30, most preferably of C18 to C26, or combinations thereof. In a preferred embodiment of the invention behenic acid (C22) is used as free fatty acid component A3).
The nonionic emulsifier or emulsifier mixture B) present in the composition according to the invention include compounds from at least one of the following groups:
The nonionic emulsifier or emulsifier mixture B) present in the composition according to the invention consists preferably of a nonionic ethoxylated emulsifier or a mixture of nonionic ethoxylated emulsifiers with a total HLB value of 12 to 19, most preferably with a HLB value of 14 to 18.
The HLB value for an ethoxylated emulsifier Ei is typically calculated by the formula (1)
with Ei being the weight percentage of ethylene oxide groups in the ethoxylated emulsifier i. When an emulsifier mixture is used, the total HLB value (HLBmixture) is calculated as the simple linear mass weighted average as given by formula (2)
with (mi/mtotal) being the mass fraction of the emulsifier i.
This type of calculation of the HLB value of nonionic emulsifiers and emulsifier mixtures is based on empirical equations derived by Griffins (W. C. Griffin, J. Soc. Cosmet. Chem., 1949, 1, 311 and W. C. Griffin, J. Soc. Cosmet. Chem., 1954, 5, 249). Alternative calculations of the HLB value are summarized in several text books on emulsion science (e.g. B. P. Binks (edt.), Modern Aspects of Emulsion Science, The Royal Society of Chemistry, Cambridge, 1998).
In a preferred embodiment of the invention Ceteareth-25 (HLB=16.2) is used as hydrophilic nonionic emulsifier component B).
As auxiliaries and additives G according to the invention all auxiliaries and additives customary in cosmetic and pharmaceutical applications and known to the person skilled in the art can be used. These include, for example, additional consistency regulators, thickeners, waxes, UV photoprotective filters, antioxidants, hydrotropes, preservatives, perfume oils, dyes and additional biogenic active ingredients as described for example in DE 10 2005 011 785.6.
As explained above, the liquid and pumpable skin treatment composition can easily be incorporated in cosmetic, dermatological or pharmaceutical formulations in a cold process.
The cosmetic or dermatological formulation can be an aqueous solution, a water-in-oil (W/O) emulsion, an oil-in-water (O/W) emulsion, an aqueous or a water-alcohol gel, a wet-wipe or an aerosol. In case a hot process is needed to prepare the desired formulation type, e.g. solid sticks or wax containing emulsions, the liquid and pumpable skin treatment composition can also be used for such type of hot processing.
The cosmetic or dermatogical formulation is preferably a W/O or an O/W emulsion that contains 1 to 50% by weight of an oil phase and 47 to <99% by weight water, with respect to the weight of the whole formulation. The oil phase can contain all types of cosmetic emollients known to the person skilled in the art. The emulsions are stabilized by all types of emulsifiers, stabilizing polymers and thickeners known to the person skilled in the art. Examples for such emollients, emulsifiers, stabilizing polymers and thickeners are described in DE 10 2005 011 785.6.
Therefore, the invention further provides cosmetic, dermatological or pharmaceutical preparations which comprise a ceramide containing skin treatment composition according to the invention.
In an embodiment of the invention the skin treatment composition is included in a topical skin treatment formulation with an effective amount between 0.001 and 20% by weight.
In a preferred embodiment of the invention the skin treatment composition is included in a topical skin treatment formulation with an effective amount between 0.05 and 10% by weight in order to maximize benefits at minimum costs.
Besides the skin treatment composition other specific skin-benefit actives such as anti-ageing actives, moisturizers, sunscreens, skin lightening agents, skin tanning agents may also be included.
Typical additional bioactive compounds are:
In addition, auxiliaries and additives customary in cosmetic and pharmaceutical applications and known to the person skilled in the art can be used. These include, for example, co-emulsifiers, consistency regulators, thickeners, waxes, organic and inorganic UV filters, pigments, buffers, hydrotropes, deodorant and antiperspirant active ingredients, insect repellents, antioxidants, self-tanning agents, preservatives, perfume oils and dyes (as described for example in DE 10 2005 011 785.6).
In addition to topical skin treatment formulations the skin treatment composition can also be incorporated into hair care formulations such as, for example, shampoos and conditioners, where it can show a stimulating effect on the scalp performance.
Another embodiment of the invention is therefore the use of the liquid and pumpaple skin treatment composition for hair care applications.
The liquid and pumpable skin treatment compositions according to the invention can also be used in so-called “wash-off” products, e.g., body wash formulations or bath or shower gels.
Therefore, another embodiment of the invention is the use of the liquid an pumpable skin care treatment in “wash-off” applications.
To prepare formulations containing the liquid and pumpable skin treatment composition according to the present invention, the usual manner for preparing such formulations may be employed. The formulations containing the inventive skin treatment composition may be packaged in any suitable manner such as in a jar, a bottle, tube, roll-ball, or the like, in the conventional manner.
Skin is subject to deterioration through environmental abuse (wind, air conditioning, central heating, pollution, sun exposure etc.) accompanied by the passage of time (chronological ageing, dermatological disorders, hormonal changes). These factors lead to decreased skin performance that manifest themselves among others by dry, rough and rigid skin. These effects are observable in vivo by parameters like skin moisture (corneometer measurement), barrier function (transepidermal waterloss measurement) or elasticity (cutometer measurement). Concomitantly to the physiologically observable parameters, there are also processes involved on a molecular level:
Cosmetic products which treat or delay the visible signs of ageing and improve the environmental protection should increase the expression marker of genes mentioned above leading to a measurable improvement of classical skin performance parameters.
Dermatological studies revealed that the application of cosmetic formulations containing the skin treatment compositions showed such significant increase of these expression markers.
The following example emulsions serve to illustrate the subject-matter of the invention in more detail without limiting it to these examples. The concentration data in all examples are given as % by weight.
The examples STC 1 to 10 illustrate liquid and pumpable skin treatment compositions according to the invention. The skin treatment compositions are prepared by heating the oil phase to 90 to 120° C. depending on the Ceramides present (in order to be above the melting point of the dosed ceramides) and heating the water phase to 90° C. Then both phases are combined and homogenized for a short time. Liquid and pumpable skin treatment compositions are obtained that can easily be incorporated into e.g. cosmetic formulations.
1)Oxynex ® LM (Merck): or alternative antioxidant mixture
2)Euxyl ® K 300 (Schulke & Mayr): preservative mixture
3) Cholesterol either animal or plant based
4)C27-32 means with a fatty acid side chain length of 27 to 32 Carbon atoms
5)Cn means with a fatty acid chain length of about n Carbon atoms
All compositions are stable for at least one year at temperatures from −5 to 40° C. No ceramide crystals can be found in this period for all tested temperatures. This illustrates the excellent storage stability of the skin treatment compositions.
All methods used in the SAXD diffraction studies were derived from the work of Prof. Bouwstra and her group. (de Jager et al., J. Lipid Res. 2004, 45, 923-932; de Jager et al., J. Lipid Res. 2005, 46, 2649-2656).
Pig CER (1-6) mixture, composition conform Bouwstra et al., J. Lipid Res., 1998, 39, 186 to 196. (Please Note: Composition in % mol instead of % by weight)
Human Cer mixture, conposition conform: Bouwstra et al., J. Invest. Dermatol., 2002, 118, 606-617. (Please Note: Composition in % mol instead of % by weight)
Ceramide 1 (C30) 15; Ceramide 2 (C24) 51; Ceramide 3 (C24) 16; Ceramide 3 (C16) 9; Ceramide 4 (C24) 4; Ceramide 6 (C24) 5
Ceramide 1 (C30) 10; Ceramide 9 (C30) 5; Ceramide 2 (C24) 51; Ceramide 3 (C24) 16; Ceramide 3 (C16) 9; Ceramide 4 (C24) 4; Ceramide 6 (C24) 5
Scer6A=STC, This patent
4)C27-32 means with a fatty acid side chain length of 27 to 32 Carbon atoms
5)Cn means with a fatty acid chain length of about n Carbon atoms
If not mentioned specifically otherwise, animal based cholesterol HP was used, which was supplied by Solvay. Pharmaceuticals, Veenendaal.
Plant cholesterol provided by Degussa Care Specialties or Syntechol supplied by Sigma.
FFA mix, composition conform (de Jager et al., J. Lipid Res. 2004, 45, 923-932;
Fatty acids C16:0, C18:0, C20:0, C22:0, C23:0, C24:0 and C26:0 were mixed at molar ratios of respectively 1.3, 3.3, 6.7, 41.7, 5.4, 36.8 and 4.7% by weight respectively;
FFA, linoleic acid As above but C23:0 replaced by linoleic acid;
FFA, arachidonic acid As above but C23:0 replaced by Arachidonic acid.
Plant derived free fatty acid mixture containing mainly of Behenic acid' (±85% mol). Further C16:0, C18:0, C20:0, C21:0, C23:0 and C24:0 are present.
Samples were prepared with the ceramide mixture described above. The CER mixture was mixed with cholesterol and free fatty acids in equimolar ratio, if not specifically mentioned otherwise. Appropriate amounts of individual lipids dissolved in chloroform:methanol (2:1) were combined to yield mixtures of approximately 1.5 mg total weight at the desired composition with a total lipid concentration of 7 mg/ml. A Camag Linomat IV was used to apply the lipid mixtures on mica. This was done at a rate of 4.3 μl/min under a continuous nitrogen stream. The samples were equilibrated for 10 minutes at the appropriate temperature of 65° C. and subsequently hydrated with an acetate buffer of pH 5.0. Finally, the samples were homogenized by 10 successive freeze-thawing cycles between −20° C. and room temperature, during which the samples were stored under gaseous argon.
All measurements were performed at the European Synchrotron Radiation Facility ESRF, Grenoble) using station BM26B. The X-ray wavelength and the sample-to-detector distance were 1.24 Å and 1.7 m, respectively. Diffraction data were collected with a two-dimensional multiwire gas-filled area detector. The spatial calibration of this detector was performed using silver behenate. The samples were mounted in a temperature-controlled sample holder with mica windows. The diffraction patterns of the lipid mixtures were obtained at room temperature for a period of 10 minutes.
Small angle X-ray diffraction provides information about the larger structural units in the sample, namely the repeat distance of a lamellar phase. The scattering intensity I (in arbitrary units) was measured as a function of the scattering vector q (in reciprocal nm). The latter is defined as q=(4π sin θ)/λ, in which θ is the scattering angle and λ is the wavelength. From the positions of a series of equidistant peaks (qn), the periodicity, or d-spacing, of a lamellar phase was calculated using the equation d=2nπ/qn, n being the order number of the diffraction peak.
Just as published by Prof. Bouwstra and her group SynthCerIII and Scer6 show SAXD patterns similar to human Cer mixture and pig Cer [1-6] mixture. Compare
The SAXD patterns show that the formation of the lamellar LPP and SPP structures are not affected by the addition of short chain Ceramides.
Despite the presence of Linoleic acid in the fatty acid mixture the LPP and SPP structures are still formed. The same is true for Arachidonic acid (not shown).
These examples illustrate the easy use of the skin treatment compositions (STC 1, STC 2 and STC 4) in the preparation of cosmetic skin treatment formulations. The skin treatment compositions can be added to the water phase at room temperature. Depending on the processing the water phase can be processed at room temperature or it can be heated, e.g. to 80° C. Therefore the skin treatment compositions can be used in cold and hot processing of 0/W emulsions (formulations 1 to 4 and 5 to 8) and for the processing of W/O emulsions (formulations 9 to 12).
All formulations have been successfully tested on stability for at least six months at temperatures from −5° C. to 40° C., additionally for 3 months at 45° C. Freeze stability was successfully tested in 3 freeze-thaw cycles between room temperature and −15° C.
Processing: Phases A and B are combined at room temperature, the emulsion is homogenized. Additional phases are added afterwards.
3)ABIL ® Care 85 (Degusssa)
4)TEGO ® Care LTP (Degussa)
5)Carbomer dispersion 1 consists of 10% TEGO ® Carbomer 140 (Degussa) and 10% TEGO ® Carbomer 141 (Degussa) dispersed in Ethylhexyl Palmitate
6)Carbomer dispersion 2 consists of 15% TEGO ® Carbomer 141 (Degussa) dispersed in Ethylhexyl Stearate
7)Carbomer dispersion 3 consists of 10% TEGO ® Carbomer 140 (Degussa) and 10% TEGO ® Carbomer 341 ER (Degussa) dispersed in Ethylhexyl Palmitate
8)Sepigel ® 305 (Seppic)
Processing: Phases A) and B) are heated separately to approx. 80° C. Phase A) is added to phase B) with stirring, a homogenization step follows. The emulsions are cooled to 60° C. and phase C) is added, the emulsion is homogenized for a short time. All other phases are added below 40° C.
9)TEGO ® Care 450 (Degusssa)
10)AXOL ® C 62 (Degussa)
11)TEGO ® Care 215 (Degusssa)
12)Carbomer dispersion 4 consists of 20% TEGO ® Carbomer 134 (Degussa) dispersed in Isopropyl Palmitate
13)Carbomer dispersion 5 consists of 20% TEGO ® Carbomer 141 (Degussa) dispersed in Ethylhexyl Palmitate
Processing: Heat phase A) to approx. 80° C. Phase B) is added while stirring, a homogenization step follows. The emulsions are cooled to 30° C. and phase C) is homogenized again for a short time.
13)ISOLAN ® GPS (Degusssa)
14)ISOLAN ® PDI (Degusssa)
15)ABIL ® EM 90 (Degusssa)
Filing Document | Filing Date | Country | Kind | 371c Date |
---|---|---|---|---|
PCT/EP2006/009919 | 10/13/2006 | WO | 00 | 3/19/2010 |