EUTECTIC COMPOSITIONS, METHODS AND USES THEREOF

Abstract

The present disclosure relates to a natural deep eutectic mixture for extraction of biocomponents comprising two different solvents, wherein a first solvent is selected from a list consisting of: lactic acid, and glycerol, citric acid, maleic acid, and tetrabutylammonium bromide and a second solvent is selected from a list consisting of: sodium lactate, sodium citrate, transcutol, glycine, glycerol, oleic acid, sodium lactate, decanoic acid; further comprising up to 90% (w/w) in water. The disclosure also relates to a method to obtain an extract from a natural source material using the NADES, as well as compositions comprising the NADES, the obtained extract and/or a topical active compound. The use of said compositions as cosmetic formulations is also described.

Claims

1. Natural deep eutectic mixture for extraction of biocomponents comprising two different solvents, wherein a first solvent is selected from a list consisting of: lactic acid, and glycerol, citric acid, maleic acid, and tetrabutylammonium bromide; and a second solvent is selected from a list consisting of: sodium lactate, sodium citrate, transcutol, glycine, glycerol, oleic acid, sodium lactate, decanoic acid; further comprising up to 90% (w/w) in water.

2. Natural deep eutectic mixture according to claim 1 comprising: 20-90% (mol/mol) of the first solvent; preferably 30-80% (mol/mol); 10-80% (mol/mol) of the second solvent, preferably 12-50% (mol/mol).

3. Natural deep eutectic mixture according to claim 1 wherein the natural deep eutectic mixture is selected from the following list: lactic acid and glycerol; lactic acid and sodium citrate; glycerol and sodium lactate; glycerol and transcutol; lactic acid and transcutol; transcutol and sodium lactate; lactic acid and glycine; tetrabutylammonium bromide and oleic acid; tetrabutylammonium bromide and decanoic acid; preferably the natural deep eutectic mixture is a combination of: glycerol and transcutol, or lactic acid and transcutol, glycerol and maleic acid.

4. Natural deep eutectic mixture according to claim 1 comprising the equivalent molar ratio between the first and the second solvent ranges from 1:4 to 4:1, preferably (1:4 to 1:3); more preferably 1:1.

5. Natural deep eutectic mixture according to claim 1 comprising lactic acid and glycerol in an equivalent molar ratio of 1:4 to 4:1; preferably (1:4-1:3).

6. Natural deep eutectic mixture according to claim 1 comprising 4:1; lactic acid and sodium citrate in an equivalent molar ratio of 2:1 to 8:1.

7. Natural deep eutectic mixture according to claim 1 comprising 2:1; glycerol and sodium lactate, in an equivalent molar ratio of 1:2 to 2:1.

8. Natural deep eutectic mixture according to claim 1 comprising 1:2; citric acid and sodium lactate in an equivalent molar ratio of 1:4 to 1:3.

9. Natural deep eutectic mixture according to claim 1 comprising lactic acid and glycine in an equivalent molar ratio of 5:1.

10. Natural deep eutectic mixture according to claim 1 comprising tetrabutylammonium bromide and oleic acid, or tetrabutylammonium bromide and decanoic acid, or maleic acid and ethylene glycol, equivalent molar ratio of 1:2.

11. Natural deep eutectic mixture according to claim 1 comprising 6 to 20% (w/w) in water.

12. Natural deep eutectic mixture according to claim 1 wherein the mixture is clear and liquid at a temperature ranging from 15 to 30 C. and the melting point ranges from 55 to 15 C., preferably from 52 to 20 C.

13. Natural deep eutectic mixture according to claim 1 wherein the is adjustable by changing the molar ratio between the two different solvents and/or by the addition of sodium hydroxide, preferably 10 to 30% (w/w) (weight of sodium hydroxide/weight of mixture).

14. Natural deep eutectic mixture according to claim 1 wherein the density of the mixture ranges from 1.2 to 1.4 g.Math.ml.sup.1, and/or the viscosity ranges from 0.015 to 1700 Pa.Math.s at 25 C.

15. Method to obtain an extract from a natural source material, comprising the following steps: contacting, preferably dipping, the natural source material with a natural deep eutectic mixture described in claim 1; incubating the natural deep eutectic mixture and the natural source material at a temperature ranging from 25 C. to 150 C. during 1 min to 24 hours, preferably 25 to 100 C.; replacing the used natural source material by a new natural source material; repeating the previous steps for 0 to 30 times; optionally wherein the natural source material is selected from a list comprising: cork, agricultural wastes, tomato, olive oil, grape seeds, grape peels, plants, teas, eucalyptus, lavender, fish skin or bones, or mixtures thereof.

16. Method according to claim 15 wherein the natural source material is cork.

17. Method according to claim 15 further comprising a step of increasing the viscosity of the natural deep eutectic mixture by reaction with a lipase, esterase or protease.

18. Extract obtainable by the method described in claim 15 comprising fatty acids and oils, preferably oleic acid, palmitic acid, stearic acid, 1-docosanol; alcohols and small acids, such as 2-hydroxymalonic acid, 2,3-Butanediol; phenolics and aromatics, such as ferulic acid and derivatives, diisooctyl phthalate or analogues; terpenoids, such as borneol or pantolactone; sugars, such as D-sorbitol, D-mannonic acid; steroids, such as friedelin, stigmasterol, or mixtures thereof.

19. Composition comprising a natural deep eutectic mixture as described in claim 1 and at least one of the following: an extract comprising fatty acids and oils, preferably oleic acid, palmitic acid, stearic, acid, 1-docosanol, alcohols and small acids, such as 2-hydroxymalonic acid, 2,3-Butanediol, phenolics and aromatics, such as ferulic acid and derivatives, diisooctyl phthalate or analogues: terpenoids, such as borneol or pantolactone, sugars, such as D-sorbitol, D-mannonic acid; steroids, such as friedelin, stigmasterol: or mixtures thereof, or up to 1% (w/w) of topical active compound.

20. Composition according to claim 19 comprising 0.01-1% (w/w) of the topical active compound, preferably 0.1-0.5 (w/w) of the topical active compound.

21. Composition according to claim 20 comprising up to 90% (w/w) of the natural deep eutectic mixture, up to 10% (w/w) of the extract and up to 1% (w/w) of the topical active compound. ##STR00027## ##STR00028## ##STR00029## ##STR00030##

22. Composition according to claim 19 further comprising a component selected from a list consisting of: hyaluronic acid, niacinamide, folic acid, D-panthenol, tocopherol, ceramide NP (3), ceramide AP (6 II), ceramide FOP (1), apigenin, quercitin, luteolin, ursolic acid, rosmarinic acid, thymol, carvacrol, cooper peptide, K18 peptide, retinol, urea, xylitol, or mixtures thereof.

23. Use of the composition as described in claim 19 as a cosmetic formulation or in hair treatment, namely hair products, preferably in hair conditioners, hair curling agents, hair straightening agents, hair masks, or hair shampoos; or in skin care treatment, namely skin care products, preferably in skin balms, skin creams, skin soap, skin masks, or skin moisturizers.

24. Composition according to claim 19 wherein the topical active compound is selected from a list comprising: opioid peptide, secretory leukocyte protease inhibitor; ##STR00031## ##STR00032## ##STR00033## ##STR00034## or mixtures thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0061] The following figures provide preferred embodiments for illustrating the disclosure and should not be seen as limiting the scope of invention.

[0062] FIG. 1: Representation of an embodiment of the coloration of the extracts obtained after extraction using NADES as extraction media. AFormulation NADES 2 before the extraction process; BEnfleurage method extraction using the formulation NADES 2; CUltrasound assisted extraction using the formulation NADES 2; DSealed system extraction using the formulation NADES 2.

[0063] FIG. 2: Representation of an embodiment of the extraction of cork using NADES as extraction media; at the left side is represented the raw material and at the right side the liquid and the remaining material after extraction.

[0064] FIG. 3: Representation of an embodiment of the extraction of tomato using NADES as extraction media; at the left side is represented the raw material and at the right side the liquid and the remaining material after extraction.

[0065] FIG. 4: Representation of an embodiment of the extraction of fish skin using NADES as extraction media; at the left side is represented the raw material and at the right side the liquid and the remaining material after extraction.

[0066] FIG. 5: Representation of an embodiment of the extraction of grape bunch using NADES as extraction media; at the left side is represented the raw material and at the right side the liquid and the remaining material after extraction.

DETAILED DESCRIPTION

[0067] The present disclosure relates to natural deep eutectic mixtures (NADES) comprising two different solvents, wherein a first solvent is selected from a list consisting of: lactic acid, ethylene glycol, glycerol, caprylic acid, enanthic acid, glucose, transcutol, citric acid, menthol, sodium lactate, sodium acetate, xylitol, sorbitol, decanoic acid, maleic acid, malic acid, oxalic acid, tartaric acid, oleic acid, palmitic acid, and tetrabutylammonium bromide; and a second solvent is selected from a list consisting of: ethylene glycol, sodium lactate, sodium citrate, caprylic acid, enanthic acid, transcutol, glycine, glycerol, glucose, oleic acid, formic acid, sodium acetate and decanoic acid. The disclosure also relates to a method to obtain an extract from a natural source material using the NADES, as well as compositions comprising the NADES, the obtained extract and/or a topical active compound. The use of said compositions as cosmetic formulations is also described.

[0068] The present disclosure relates to the use of natural deep eutectic solvents (NADES) in the extraction of bioactive compounds from Quercus suber (cork), agricultural wastes like grape peels and seeds, tomato, olive oil, and plants (teas, eucalyptus, lavender) and fish skin and bones. Extracts of natural products are often used in the cosmetic and pharmaceutical industry. In an embodiment, all the components used to prepare the NADES are approved to be incorporated in cosmetic formulations. The extracts obtained can be use directly in cosmetic formulations without any purification step.

[0069] In an embodiment, the biomaterial chosen for the application of NADES as extraction solvents was Quercus suber cork (Cork oak). This natural material is constituted by suberin (=42%), lignin (=22%), polysaccharides (=20%), some extractives compounds (=15%) and ash (=1%). Suberin is a complex lipophilic biopolymer mainly composed of long chain fatty acids called suberin acids, some alcohols like glycerol and polyaromatic compounds [18-20]. All these components can be found in cosmetic and/or pharmaceutical formulations, which is why the scientific community is interested in extracting this type of natural compounds from cork.

[0070] In an embodiment, new NADES were formed by the mixing of at least two compatible natural compounds at proper ratios (Table 1). These compounds strongly interact by hydrogen bonds interactions to form the liquid. The combination of all the constituents results in a high melting point depression that gives the new NADES. The formation temperatures of these solvents do not exceed 100 C.

TABLE-US-00001 TABLE 1 NADES composition. NADES Ratio Composition Eutectic mixture (molar ratio) 1 Lactic Acid Ethylene glycol 1:1 2 Lactic Acid Glycerol 4:1; 2:1; 1:1; 1:2; 1:4 3 Lactic Acid Sodium Citrate 2:1; 4:1; (monobasic to 6:1; 8:1 tribasic) 4 Ethylene glycol Sodium Lactate 2:1; 1:1; 1:2 5 Glycerol Sodium Lactate 2:1; 1:1; 1:2 6 Caprylic acid Ethylene glycol 1:1; 2:1 7 Lactic Acid Caprylic acid 1:1; 2:1 8 Enanthic acid Ethylene glycol 1:1 9 Enanthic acid Glycerol 1:1 10 Lactic Acid Enanthic acid 1:1 11 Glucose Ethylene glycol 1:1 12 Glucose Glycerol 1:1 13 Glucose Sodium Lactate 1:1 14 Ethylene glycol Transcutol 1:1 15 Glycerol Transcutol 1:1 16 Lactic Acid Transcutol 1:1 17 Transcutol Sodium Lactate 1:1 18 Citric acid Sodium Lactate 1:3; 1:4 19 Lactic acid Glycine 5:1 20 Tetrabutylammonium Oleic acid 1:2 bromide 21 Tetrabutylammonium Decanoic acid 1:2 bromide 22 Menthol Transcutol 1:1 23 Glycerol Formic Acid 1:1 24 Ethylene glycol Formic Acid 1:1 25 Lactic Acid Formic Acid 1:1 26 Sodium Lactate Formic Acid 1:1 27 Transcutol Formic Acid 1:1 28 Sodium Acetate Formic Acid 1:1 29 Xylitol Formic Acid 1:1 30 Xylitol Sodium Acetate 1:1 32 Sorbitol Formic Acid 1:1 33 Sorbitol Sodium Acetate 1:1 33 Ethylene glycol Sodium Acetate 1:1 34 Transcutol Sodium Acetate 1:1 35 Lactic Acid Sodium Acetate 1:1 36 Sodium Lactate Sodium Acetate 1:1 37 Citric Acid Glycerol 1:1; 1:2; 1:3 38 Citric Acid Ethylene glycol 1:1; 1:2; 1:3 39 Citric Acid Transcutol 1:1; 1:2; 1:3 40 Caprylic Acid Transcutol 1:1 41 Decanoic Acid Transcutol 1:1 42 Enanthic Acid Transcutol 1:1 43 Oleic Acid Transcutol 1:1 44 Decanoic Acid Ethylene glycol 1:1; 2:1 45 Maleic Acid Ethylene glycol 1:1; 1:2 46 Malic Acid Ethylene glycol 1:1 47 Malic Acid Glycerol 1:1 48 Oxalic Acid Glycerol 1:1 49 Oxalic Acid Ethylene glycol 1:1 50 Tartaric Acid Glycerol 1:1 51 Tartaric Acid Ethylene glycol 1:1

[0071] In an embodiment, the NADES presented in table 1 were prepared by mixing the constituents at temperatures ranging from 25 C. to 100 C., under vigorous stirring. After 1 hour, a clear solution was formed, and the eutectic mixture was kept at room temperature for further use. Depending on the application, it is possible to add some amount of water (0-90% (w/w)) to modulate the properties of the eutectic mixtures.

[0072] For the scope and interpretation of the present disclosure it is defined that room temperature should be regarded as a temperature between 15-30 C., preferably between 18-25 C., more preferably between 20-22 C.

[0073] In an embodiment, the components of the eutectic mixture include ethylene glycol, lactic acid, glycerol, sodium citrate, sodium lactate, caprylic acid, enanthic acid, glucose and transcutol, among others. All of these components are non-toxic and biocompatible, being therefore suitable for the future applications in the cosmetic or pharmaceutical fields.

[0074] Some physical-chemical properties of the eutectic mixtures where measured, such as the melting point, pH, density, conductivity and refractive index (table 2). These new NADES have a lower melting point than the isolated constituents; the pH can be modulated by changing the ratio between NADES components; and the NADES physicochemical properties can also be slightly modulated by changing the ratio between the components.

TABLE-US-00002 TABLE 2 Physical/chemical properties of the NADES used in examples. Eutectic Melting Density Conductivity Refractive NADES mixture Ratio point ( C.) pH (g .Math. mL.sup.1) (mS .Math. cm.sup.1) index 2 Glycerol:Lactic 1:1 52 1 1.2424 0.00295 1.45727 acid (6.6% H.sub.2O) 3 Sodium 4:1 15 5 1.3920 1.58 1.43809 citrate tribasic (12.6% (30% dihydrate:Lactic H.sub.2O) H.sub.2O) acid 4 Ethylene 1:1 19 7.6 1.3433 0.722 1.45507 glycol:Sodium (20% lactate H.sub.2O) 5 Glycerol:Sodium 1:1 21 7.9 1.3658 0.0487 1.46670 lactate (20% H.sub.2O)

[0075] In an embodiment, the mixtures developed have a lower melting point than the isolated constituents. All NADES presented in this work are liquid at room temperature. With the addition of sodium hydroxide (NaOH), it was possible to increase the pH of NADES and these remained liquid at room temperature. As an example, the addition of granules of 24% NaOH (mass of NaOH/mass of NADES), the pH of NADES 2 increases from 1 to 7 without changing its physical state.

[0076] An aspect of the present disclosure focuses on the application of NADES in the extraction of chemical compounds from natural sources. NADES were used as solvents for the extraction of these compounds following the same methodology principle designated as enfleurage replacing the fat by NADES [21]. Other extraction techniques, like Ultrasound assisted extraction and sealed system extraction, were also used.

[0077] In an embodiment, the NADES were used to extract chemical compounds from cork, agricultural wastes and plants, preferably to extract alcohols, fatty acids, phenolics, steroids, terpenoids, or sugars.

[0078] In an embodiment, the enfleurage method was performed using cork from Quercus suber (0.1 g-1 Kg). The cork was placed in a recipient and submerged with the eutectic solvent (0.1 mL to 25 L) and with/without a water percentage (0-90% (w/w)). The system was covered and left at room temperature for 1-30 days. After this process, the old cork was removed and a new one was added. The same process was repeated for 0 to 30 times.

[0079] In another embodiment, the extraction was performed using the ultrasonic bath assisted extraction. Cork from Quercus suber (0.1 g-1 Kg) was placed in a recipient, and the eutectic solvent (0.1 mL-25 L) was added with or without a water percentage (0-90% (w/w)). The system was covered and put in the ultrasonic bath for 1 minute to 24 hours and at temperatures ranging from 25 C. to 80 C. After this process, the old cork was removed and a new one was added. The same process was repeated for 0 to 30 times.

[0080] In a yet further embodiment, the extraction was performed using the sealed system extraction. Cork from Quercus suber (0.1 g-1 Kg) was placed in amber flask and was added 5 mL of the NADES extraction solvent (0.1 mL-25 L) and with/without a water percentage (0-90% (w/w)). The flask was sealed with an aluminium seal cap and put in an oil bath, under magnetic agitation, at temperatures ranging from 25 C. to 150 C. for 1 minute to 24 hours. After this process, the old cork was removed and a new one was added. The same process was repeated for 0 to 30 times.

[0081] In an embodiment, at the end of each extraction process, all remaining cork was washed with water to extract the solvent that may be adsorbed by the biomaterial by a natural extract treatment. The remaining water content in the extract was removed by evaporation under pressure. The extract containing the eutectic mixture was obtained for further application.

[0082] The extraction yields increased when NADES were used as solvents instead of water. From the applied methods, the sealed system is the most efficient extraction method, followed by extraction assisted by ultrasound and, finally, the enfleurage method showed lower extraction efficiency. In an embodiment, when NADES 2 was used as a solvent, the extraction yields were 12% for sealed system, 6.9% for ultrasound assisted method, and 3.3% for the enfleurage method. Additionally, when NADES 2 was used as solvent in the enfleurage method, the extraction yield was 4 times higher when compared to water under the same conditions. For the ultrasound-assisted method, the yield was 2 times higher and, for the sealed system, it was 3 times. Table 3 lists a comparison of extraction yields obtained in three different extraction methods when using water or NADES 2 as solvent.

TABLE-US-00003 TABLE 3 Extraction yields for the three extraction methods using formulation NADES 2 or water as solvent; the yield of extraction was obtained by the difference between the total initial cork mass and the mass obtained after extraction. Ultrasound Sealed Eutectic Eutectic Enfleurage* assisted** system*** Solvent compounds Ratio Yield Yield Yield H.sub.2O 0.7% 3.2% 4.2% NADES Lactic acid: 1:1 3.3% 6.9% 18.6% 2 Glycerol NADES Ethylene 1:1 3.5% 8.5% 23.0% 4 glycol: Sodium Lactate NADES Glycerol: 1:1 3.9% 9.0% 25.8% 5 Sodium Lactate *Enfleurage method: Cork 0.7 g; Solvent 15 mL; 0% of water in NADES; room temperature; 3 days; 3 cycles. **Ultrasound assisted: Cork 0.7 g; Solvent 10 mL; 0% of water in NADES; 50 C.; 6 hours; 3 cycles. ***Sealed system: Cork 0.7 g; Solvent 5 mL; 0% of water in NADES; 100 C. 6 hours; 3 cycles.

[0083] FIG. 1 shows a representation of an embodiment of the coloration of the extracts obtained after extraction using NADES as extraction media. Formulation of NADES 2 (FIG. 1-A) were used to perform the extraction process, using different methods. FIG. 1-B shows the extract obtained from the enfleurage method extraction using the formulation NADES 2, using 0.7 g of cork; 15 mL of the natural deep eutectic mixture without the addition of water in the mixture. The extraction was performed at room temperature, for 3 days in 3 cycles. FIG. 1-C shows an embodiment of an ultrasound assisted extraction using the formulation NADES 2, 0.7 g of cork; 10 mL of the natural deep eutectic mixture, without the addition of water in the mixture, at 50 C.; for 6 hours in 3 cycles. FIG. 1-D shows the extract obtained after sealed system extraction using the formulation NADES 2, 0.7 g of cork, 5 mL of the natural deep eutectic mixture, without the addition of water in the mixture, at 100 C. for 6 hours, in 3 cycles.

[0084] In an embodiment, the colour increment (FIG. 1) of the extracts obtained from cork using NADES is related to the increase of the extract concentration. The sealed system method provides the most effective extraction of natural cork compounds. As an example, for the extraction using the sealed system at 100 C., 5 mL of NADES 2 were used to extract from 2.1 g of cork (3 cycles of 0.700 g of renewal of cork). From this extraction, the final extract concentration obtained was 0.07812 g/mL (m.sub.extract/v.sub.solvent) (Table 4). Other examples for the extraction of compounds of interest from other natural sources (tomato, grape bunch and fish skin) using NADES 2 combined with the sealed system are also presented in Table 4. The resulting extracts, as well as remaining material, are depicted in FIGS. 2-5.

[0085] In an embodiment, the extract obtained from cork using NADES comprises fatty acids and oils (oleic acid, palmitic acid and stearic acid; 1-docosanol); alcohols and small acids (2-hydroxymalonic acid; 2,3-Butanediol); phenolics and aromatics (ferulic acid and derivatives, diisooctyl phthalate and analogues); terpenoids (borneol and pantolactone); sugars (D-sorbitol, D-mannonic acid) and steroids (friedelin, stigmasterol).

TABLE-US-00004 TABLE 4 Extracts concentration (g/mL (m.sub.extract/v.sub.solvent)) after extraction with NADES 2 or water as solvent, using the sealed system. Concentration of extract (g/ml) Eutectic Eutectic Grape Fish Solvent compounds Ratio Cork.sup.a) bunch.sup.b) Tomato.sup.c) skin.sup.d) H.sub.2O 0.0178 0.0455 0.079 0.1301 NADES Glyc- 1:1 0.07812 0.0653 0.1161 0.2000 2 erol:Lactic acid .sup.a)Cork 0.7 g; Solvent 5 mL; 100 C. 6 hours; 3 cycles. .sup.b)Grape Bunch 0.7 g; Solvent 5 mL; 100 C. 6 hours; 1 cycle. .sup.c)Tomato 0.7 g; Solvent 5 mL; 100 C. 6 hours; 1 cycle. .sup.d)Fish skin 1.0 g; Solvent 5 mL; 100 C. 6 hours; 1 cycle.

[0086] When the sealed system is used as an extraction method, the extract obtained is more concentrated than the other techniques, namely the enfleurage technique and ultrasound assisted extraction (Table 4). The efficiency of the sealed system is related to the creation of pressure inside the vessel which translates into an improvement in the extraction of natural cork compounds. The enfleurage method is static, which is why the extract obtained is the least concentrated of the three extraction techniques presented in this work. The ultrasound assisted extraction have an intermediate performance in terms of extract concentration.

[0087] The present disclosure also relates to the use of a composition comprising the NADES formulations and the natural extract in cosmetic applications. Since the NADES formulations used are compatible with cosmetic application, there is no need to further purify the extract obtained.

[0088] NADES containing chemical compounds from naturals sources could be further enriched with active components for skin topical applications for sensations of warm, cold, freshness, relaxing, pain relive, lightness and well-being. In an embodiment, the composition may further comprise a topical active compound, such as icilin, menthol, carboxylated icilin, among others. These topical active compounds can induce different sensations on the skin where the composition is applied, such as listed in Table 5.

[0089] In an embodiment, the composition comprises up to 1% (w/w) of the natural deep eutectic mixture, 0.1% (w/w) of the natural extract and 97.9% (w/w) of excipients, including up to 1% (w/w) of the topical active compound.

[0090] In an embodiment, the composition can be applied in atopic skin by the inclusion of one or further components as: Hyaluronic acid, Niacinamide, Folic acid, D-Panthenol, Tocopherol, Ceramide NP (3), Ceramide AP (6 II), Ceramide EOP (1), Apigenin, Quercitin, Luteolin, Ursolic acid, Rosmarinic acid, Thymol, Carvacrol, Cooper peptide, K18 peptide, Retinol, Urea and Xylitol, or mixtures thereof.

TABLE-US-00005 TABLE 5 Molecular formula and chemical structure of the topical active compounds to incorporate in NADES formulations and the respective skin sensations induced. Skin Molecular Compound Feeling formula Chemical Structure Icilin Freshness C.sub.16H.sub.13N.sub.3O.sub.4 [00002] Menthol Freshness C.sub.10H.sub.20O [00003] Carboxylated Icilin Freshness C.sub.17H.sub.13N.sub.3O.sub.6 [00004] Carboxylated Menthol Freshness C.sub.11H.sub.20O.sub.2 [00005] 2,6- dimethylaniline Antipain C.sub.8H.sub.11N [00006] Carboxyiciline- 2,6 dimethylaniline conjugate Antipain/ Freshness C.sub.25H.sub.22N.sub.4O.sub.5 [00007] Carboxymenthol- 2,6- dimethylaniline conjugate Antipain/ Freshness C.sub.19H.sub.29NO [00008] Dermorphin- derived tetrapeptide (Dmt1) DALDA Antipain/ Relaxing C.sub.32H.sub.49N.sub.9O.sub.5 [00009] Carboxymenthol- DALDA Antipain/ Relaxing/ Freshness C.sub.43H.sub.67N.sub.9O.sub.6 [00010] Carboxyicilin- DALDA Antipain/ Relaxing/ Freshness C.sub.49H.sub.60N.sub.12O.sub.10 [00011] Opioid peptides Relaxing YGGFL: C.sub.28H.sub.37N.sub.5O.sub.7 [00012] YPWF-NH.sub.2: C.sub.34H.sub.38N.sub.6O.sub.5 [00013] YGGFM: C.sub.27H.sub.35N.sub.5O.sub.7S [00014] YPFF-NH.sub.2: C.sub.32H.sub.37N.sub.5O.sub.5 [00015] Carboxymenthol- YGGFL conjugate Freshness/ Relaxing C.sub.39H.sub.55N.sub.5O.sub.8 [00016] Carboxymenthol- YGGFM conjugate Freshness/ Relaxing C.sub.38H.sub.53N.sub.5O.sub.8S [00017] Carboxymenthol- YPWF-NH2 conjugate Freshness/ Relaxing C.sub.45H.sub.56N.sub.6O.sub.6 [00018] Carboxymenthol- YPFF-NH.sub.2 conjugate Freshness/ Relaxing C.sub.43H.sub.55N.sub.5O.sub.6 [00019] Carboxyicilin- YGGFL conjugate Freshness/ Relaxing C.sub.45H.sub.48N.sub.8O.sub.12 [00020] Carboxyicilin- YGGFM conjugate Freshness/ Relaxing C.sub.44H.sub.46N.sub.8O.sub.12S [00021] Carboxyicilin- YPWF-NH.sub.2 conjugate Freshness/ Relaxing C.sub.51H.sub.49N.sub.9O.sub.10 [00022] Carbocyicilin- YPFF- NH.sub.2 conjugate Freshness/ Relaxing C.sub.49H.sub.48N.sub.8O.sub.10 [00023] Sivelestat Anti- wrinkle/ Anti-aging C.sub.20H.sub.22N.sub.2O.sub.7S [00024] Argireline Ac- EEMQRR- NH2 Anti- wrinkle/ Anti-aging C.sub.46H.sub.56N.sub.12O.sub.6 [00025] Sivelestate- argireline Ac- EEMQRR- NH2 Anti- wrinkle/ Anti-aging C.sub.52H.sub.78N.sub.16O.sub.17S.sub.2 [00026]

[0091] Sequence List: [0092] SEQ ID No 1: Tyr-Gly-Gly-Phe-Leu (YGGFL); [0093] SED ID No 2: Tyr-Pro-Trp-Phe (YPWF); [0094] SEQ ID No 3: Tyr-Gly-Gly-Phe-Met (YGGFM); [0095] SEQ ID No 4: Tyr-Pro-Phe-Phe (YPFF); [0096] SEQ ID No 5: Glu-Glu-Met-Gln-Arg-Arg (EEMQRR); [0097] SEQ ID No 6: Xaa Arg Phe Lys (XRFK) wherein Xaa=Tyr(2,6-dimethyl)

[0098] The term comprising whenever used in this document is intended to indicate the presence of stated features, integers, steps, components, but not to preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

[0099] The disclosure should not be seen in any way restricted to the embodiments described and a person with ordinary skill in the art will foresee many possibilities to modifications thereof. The above described embodiments are combinable.

[0100] The following claims further set out particular embodiments of the disclosure.

REFERENCES

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