Self-emulsifying compositions intended for administration to the skin, comprising a biosurfactant, a cosurfactant, and an oil phase - Patent Application 20070122997

Abstract

The present invention provides a self-emulsifying composition for administration to the skin, comprising a biosurfactant, a co-surfactant, and an oil phase, wherein the weight ratios of the biosurfactant, the co-surfactant, and the oil phase are 0.01 to 96.99% by weight: 0.01 to 96.99% by weight: 3 to 70% by weight, respectively; the biosurfactant is surfactin or a salt thereof; and the co-surfactant is 2-(2-ethoxyethoxy)ethanol or cocamidopropyl betaine.

Description

[Technical Field]

[0001] An object of the present invention is a self-emulsifying composition intended for administration to the skin, comprising a biosurfactant, a co-surfactant and an oil phase. [Background technology]

[0002] Self-emulsifying systems are isotropic systems consisting of a surfactant, a co-surfactant, and an oil phase, which spontaneously self-emulsify when diluted in the appropriate ratio.

[0003] Biosurfactants are surface tension-reducing compounds that are extracellular metabolites produced by bacteria, yeast, or molds and may be part of their cell walls (Bednarski W., Fiedurek J. (ed.) Podstawy biotechnologii przemyslowej. WNT, Warsaw 2007). These substances are produced by microorganisms and, thanks to their low toxicity, easy availability, and interesting properties, can be used in many industries (Kosaric N., Biosurfactants in industry. Pure Appl. Chem., 64, 1731 (1992)). For example, in the cosmetics industry, biosurfactants can be an excellent alternative to synthetic surfactants in the production of shampoos, powders, and moisturizing and protective creams.

[0004] Surfactants can be widely used to form carriers because they reduce the tension at the phase interface. Their characteristic hydrophilic-hydrophobic structure allows them to encapsulate compounds with poor or very poor water solubility, improving their bioavailability. For systems applied to the skin, improving efficiency and bioavailability is particularly important. Encapsulating hydrophobic substances in specialized carrier systems facilitates their delivery and penetration into the skin. Lipid nanocarriers, such as liposomes, nanocapsules, lipospheres, and other self-assembling nanosystems, enable the encapsulation of highly hydrophobic compounds, enhancing their efficacy after administration.

[0005] Formulations made with this type of surfactant are patent protected, such as PEG-free cosmetic cleansing agents comprising biosurfactants in combination with anionic surfactants and thickeners, which have excellent foaming and cleaning properties (US 20170071835 A1).

[0006] Another application describes a cosmetic cleanser containing a biosurfactant and having prebiotic activity. The prebiotic effect is achieved by combining the biosurfactant with an anionic surfactant. The agent also has excellent foaming and cleaning properties (Cleansing agents containing biosurfactants and having prebiotic activity US 20170071842 A1).

[0007] Further inventions relate to formulations containing, for example, a specific copolymer and at least one surfactant selected from the group consisting of sulfosuccinates and biosurfactants (Cosmetic formulation containing copolymer and sulfosuccinate and / or biosurfactant, US 20160045424 A1).

[0008] Cosmetics used for skin care, particularly for improving rough skin, are known to contain biosurfactants, particularly MEL-A, MEL-B, or MEL-C (Biosurfactant-containing skin care cosmetic and skin roughness-improving agent, US 20110257116 A1).

[0009] Sophorolipids, glycolipid biosurfactants produced by Candida bombicola, can act as natural moisturizers in creams, shampoos, hair gels, and body gels. One aspect of the present invention relates to cosmetic and dermatological compositions containing acidic sophorolipids or sophorolipids combined with monovalent or divalent salts at a concentration of 0.01 to 30% by weight, and their uses. The compositions may be in the form of w / o, oil / w emulsions, or oil / w microemulsions. Sophorolipid-based compositions are useful as anti-free radical and anti-inflammatory agents (Use of sophorolipids in cosmetic and dermatological compositions, EP 0820273 B1).

[0010] Patent WO 2006028996 A2 (Emulsan-alginate microspheres and methods of use thereof) describes emulsion-alginate compositions that can serve as drug carriers. The compositions of the invention make it possible to avoid some of the problems associated with the preparation of microspheres or alginate particles.

[0011] Microencapsulation and nanoencapsulation are increasingly being used in the cosmetics and personal care product markets. This is due to the fact that most of these types of cosmetics act on the superficial layers of the skin without penetrating the deeper layers. It is generally known that the effectiveness of cosmetic products is directly attributable to the ability of their active ingredients to penetrate the stratum corneum and into the skin. This has led to the development of new carrier systems. The advantages of such structures include the protection of active substances from harmful external influences, the controlled release of encapsulated substances, and the ability to encapsulate substances that are poorly soluble in water. Among the most promising systems for achieving improved skin penetration are solid lipid particles, liposomes, microemulsions, and nanoemulsions (Neubert HR. Potentials of new nanocarriers for dermal and transdermal drug delivery. Eur J Pharm Biopharm. 2011;77(1):1-2). Nanoemulsions are widely used in many industries, including pharmaceuticals, due to their many advantages, including ease of preparation and the possibility of industrial-scale production (Campos VEB, Ricci-Junior E, Mansur CRE. Nanoemulsions as delivery systems for lipophilic drugs. J Nanosci Nanotechnol. 2012;12(3): 2881-2890). Nanoemulsions can facilitate skin penetration due to their nanometer size, and their large surface area can also facilitate skin contact (Trommer H, Neubert HR. Overcoming the stratum corneum: the modulation of skin penetration: a review. Skin Pharmacol Physiol. 2006; 19(2):106-121).

[0012] Application KR100452165 relates to a nanoemulsion containing a phospholipid and a peptide surfactant. The phospholipid used is lecithin or a lecithin derivative, sterol-1 or a sterol derivative.

[0013] Application KR101837433 relates to an oil-in-water (o / w) nanoemulsion having the properties of a low-viscosity liquid or paste, containing 1-10% by weight of lauryl carbamate inulin and 0.01-3% by weight of sodium surfactin as surfactants based on the total weight of the nanoemulsion. The oil phase used includes silicone oil, ester oil, hydrocarbon oil, vegetable oil, wax, sunscreen, etc. The oil phase accounts for 10-60% by weight of the nanoemulsion. The nanoemulsion contains 0.001-30% by weight of at least one active substance selected from the group including water-soluble vitamins.

[0014] Application No. CN107661287 relates to a self-emulsifying saponin delivery system characterized by containing the following components in weight percentages: oil phase (labrafil M 1944CS): 0.05%-0.25%; surfactant (ziyuglycoside): 0.45%-0.65%; surfactant (Tween-20, transcutol P): 0.1%-0.3%.

[0015] Application No. CN107049945 relates to an ivermectin nanoemulsion formulation aimed at solving the problems of ivermectin's low water solubility and poor storage stability. This formulation is characterized by containing 0.5-2% ivermectin, 0.5-5% ethyl oleate as the oil phase, 8-30% hydrogenated castor oil (RH-40) as a polyoxyethylene emulsifier, 1-10% water as an emulsifier, and Transcutol (diethylene glycol monoethyl ether).

[0016] Application WO2016141098 relates to a non-aqueous topical ophthalmic composition comprising an oil, a poorly water-soluble drug, and one or more surfactants, which can self-emulsify when mixed with an aqueous solution after instillation into the eye, and the composition is composed of about 5% to about 60% by weight of oil. The composition contains less than 1% by weight of water. The composition further contains one or more cosolvents. The nanometric emulsion contains dispersed oil droplets after self-emulsification ranging in size from 10 to 200 nm.

[0017] Application KR101440726 relates to a drug delivery system (oral formulation) to the lymphatic system, in which the solubilizer is selected from the group comprising Transcutol (Transcutol HP) (diethylene glycol monoethyl ether), ethanol and propylene glycol.

[0018] Application CN204307112U relates to a method for purifying biosurfactants from fermentation broth, which can be used to produce cosmetic emulsifier systems. The formula describes an apparatus for separating surfactin from the fermentation product.

[0019] Application CN105213210 relates to the delivery of a surfactant (surfactin) in the preparation of an anti-aging (or anti-wrinkle) treatment in a cosmetic composition, the composition comprising a surfactant and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, etc. Preferably, the surfactant is cyclolipidin, which comprises a heptapeptide consisting of seven amino acids (L-aspartic acid, L-leucine, glutamic acid, L-leucine, L-two D-valines, and leucine).

[0020] US Patent Application No. 2012280261 (EP3391872) relates to an oil-in-water emulsion composition useful as an external preparation for skin application, and a method for preparing the same. The present invention relates to a method for preparing an oil-in-water emulsion composition, comprising the steps of: mixing a first surfactant, a second surfactant, and water to form an intermediate phase; adding an oil phase component to the intermediate phase; and further adding an aqueous phase component. The first surfactant forms a first phase in at least one aqueous solution at a concentration of 40 to 80% by weight, and the second surfactant forms a second phase in at least one aqueous solution at a concentration of 40 to 80% by weight. In an embodiment, the first surfactant preferably comprises at least one surfactant selected from surfactin and its salts, mannosylerythritol lipid, polyglycerin fatty acid ester, sophorolipid, polyoxyethyleneglyceryl fatty acid, polyethylene glycol fatty acid, and phospholipid, preferably polyglycerin ester fatty acid or phospholipid. In this embodiment, the second surfactant preferably contains at least one compound selected from alkyl glycosides having the following formula (1), acylamino acid lysine and / or salts thereof, esters of sucrose and fatty acids, alkyl polyglycerol ethers, fatty acid glycosides, monoalkyl phosphates and salts thereof, and preferably contains alkyl glycosides or monoalkyl phosphates and salts thereof:

[0021] US2016030322A relates to an anti-aging treatment that involves administering a cosmetic composition containing surfactin at a concentration of 25-100 μM and a pharmaceutically acceptable carrier, excipient, diluent, or adjuvant, and that the anti-aging effect of the cosmetic composition is related to the enhancement of sirtuins. Surfactin is a cycloaliphatic peptide containing the heptapeptide (L)Glu-(L)Leu-(D)Leu-(L)Val-(L)Asp-(D)Leu-(L)Leu, which is related to β-hydroxy fatty acids. The fatty acid distribution of surfactin is as follows: (1) iso-C13>3%, (2) C13>0.65%, (3) iso-C14>17%, (4) C14<41%, and (5) iso-C15<11%. The preferred distribution of surfactin fatty acids is as follows: (1) iso-C13>10%; (2) C13>25%; (3) iso-C14>35%; (4) C14<25%; and (5) iso-C15<3%. In the method of the anti-aging cosmetic composition, the anti-aging cosmetic composition further contains at least one of the following ingredients: alcohol, ester, complex polysaccharide, peanut oil, and vitamin.

[0022] Publication: Kural FH, Gursoy RN. Formulation and characterization of surfactin-containing self-microemulsifying drug delivery systems (SF-SMEDDS). Hacettepe University Journal of the Faculty of Pharmacy, 2010, 30(2): 171-186. This study is the first to describe the implementation of surfactin in a dosage form. The goal of the study was to design and characterize stable SMEDDS formulations containing surfactin as a bioactive compound. In the initial phase of the study, SMEDDS formulations with various excipient compositions were prepared using a ternary phase diagram.

[0023] Series F1: PEG3000, Gelucire 44 / 14, Labrasol, Vitamin E Series F2: PEG3000, Gelucire 44 / 14, Tyloxapol, Vitamin E Series F3: PEG3000, Tyloxapol, Labrasol, Vitamin E Series F4: Propylene Glycol, Gelucire 44 / 14, Labrasol, Vitamin E

[0024] The physical stability of the tested formulations was then monitored to select the most advantageous proposal. No melting endotherm of surfactin was observed in the thermograms of surfactin-SMEDDS formulations, suggesting the existence of strong interactions between surfactin and excipients in oil-in-water emulsions.

[0025] The results showed that the SMEDDS formulation containing vitamin E, Labrasol, Gelucire 44 / 14, and PEG 3000 in a 1:1:8:0.5 (% w / w) ratio had the highest physical stability. In conclusion, the authors point out that the biological activity of surfactin should be investigated in newly developed SMEDDS (self-emulsifying drug delivery systems) formulations.

[0026] The paper, Wu YS, Ngai SC, Goh BH, Chan KG, Lee LH, and Chuah LH. Anticancer activities of surfactin and potential application of nanotechnology-assisted surfactin delivery. Frontiers in Pharmacology; 2017; 8:761. doi: 10.3389 / fphar.2017.00761, demonstrates that the amphiphilic nature of surfactin allows for the formation of nanoparticles such as polymer nanoparticles, micelles, microemulsions, and liposomes. According to the authors, the use of nanoformulations will optimize surfactin delivery in anticancer drug therapy. This paper reviews the current literature on the anticancer activity of surfactin and the potential application of nanotechnology-assisted surfactin delivery. The objective of this study was to analyze and summarize the current knowledge regarding surfactin, its properties, biosynthetic methods, anticancer activity, and the potential application of nanoformulations for optimal surfactin delivery.

[0027] The authors of the study, "Development of surfactin-based nanoemulsion formulation from selected cooking oils: Evaluation for antimicrobial activity against selected food-associated microorganisms." Journal of The Taiwan Institute of Chemical Engineers 2012; 43: 172-180, developed surfactant-based nanoemulsions using edible oils, including sunflower oil, castor oil, coconut oil, peanut oil, and sesame oil. The oil phase of the O / W nanoemulsion consisted of 14% selected edible oil, 3% ethanol, and 3% surfactant. The mean droplet sizes of the various surfactant-based emulsions ranged from 72.52 to 875.22 nm, with the smallest size obtained with the sunflower oil formulation. Further studies have shown that surfactant-based sunflower oil nanoemulsions exert antibacterial effects against Salmonella typhi, Listeria monocytogenes, and Staphylococcus aureus. They also exhibit strong antifungal activity against Rhizopus nigricans, Aspergillus niger, and Penicillium sp., and have sporicidal activity against Bacillus cereus and Bacillus circulans. These results suggest the potential of surfactin as a food preservative. Summary of the Invention [Problem to be solved by the invention]

[0028] The object of the present invention is to create novel self-emulsifying compositions containing biosurfactants intended for administration to the skin. [Means for solving the problem]

[0029] The gist of the present invention is a self-emulsifying composition intended for administration to the skin, comprising a biosurfactant, a cosurfactant, and an oil phase, wherein the weight ratios of the biosurfactant, the cosurfactant, and the oil phase are 0.01 to 96.99% by weight: 0.01 to 96.99% by weight: 3 to 70% by weight, respectively, the biosurfactant is surfactin or a salt thereof, and the cosurfactant is 2-(2-ethoxyethoxy)ethanol or cocamidopropyl betaine. and the oil phase is at least one compound selected from the group consisting of glyceryl caprylate, cananga flower oil, verbena (litsea asiatica) oil, tamanu oil, oleic acid, tocopherol from sunflower seed (helianthus annuus) oil, ascorbyl tetrahexyldecanoate, rapeseed oil, and fatty acid esters. It is characterized by the following.

[0030] The preferred weight ratio of the biosurfactant, the co-surfactant, and the oil phase is 10 to 50% by weight: 20 to 50% by weight: 10 to 50% by weight.

[0031] The preferred weight ratio of the biosurfactant, the co-surfactant, and the oil phase is 50%:30%:20% by weight.

[0032] Preferably, said surfactin is produced by Bacillus subtilis.

[0033] Preferably, the surfactin salt is sodium surfactin.

[0034] The composition is preferably diluted with water.

[0035] The preferred dilution is 10 to 5000 w / w. [Effects of the Invention]

[0036] The present invention provides the following advantages:

[0037] The nanoemulsions produced by mixing the compositions according to the invention with water exhibit good skin penetration capabilities.

[0038] The compositions according to the invention for administration to the skin can be used in the cosmetics industry. [Brief explanation of the drawings]

[0039] [Figure 1] Figure 1 shows the chemical formula of sodium surfactin. [Figure 2] Figure 2 shows the size distribution of nanoemulsions formed by diluting a concentrate containing glyceryl caprylate, sodium surfactin, and 2-(2-ethoxyethoxy)ethanol (40:10:50 w / w) with water in a ratio of 1:100 w / v. [Figure 3] Figure 3 shows the zeta potential distribution of nanoemulsions formed after dilution of a concentrate containing glyceryl caprylate, surfactant sodium, and 2-(2-ethoxyethoxy)ethanol (40:10:50 w / w) with water in a ratio of 1:100 w / v. [Figure 4] Figure 4 shows the size distribution of nanoemulsions formed after dilution of a concentrate containing glyceryl caprylate, surfactant sodium, and 2-(2-ethoxyethoxy)ethanol (50:30:20 w / w) with water in a ratio of 1:100 w / v. [Figure 5] Figure 5 shows the zeta potential distribution of nanoemulsions formed after dilution of a concentrate containing rapeseed oil, surfactant sodium, and 2-(2-ethoxyethoxy)ethanol (20:50:30 w / w) with water in a ratio of 1:200 w / v. [Figure 6] FIG. 6 shows the morphology of the nanoemulsion produced in embodiment 17 by TEM photography, where A) is an enlarged view at 500 nm and B) is an enlarged view at 200 nm. [Figure 7] FIG. 7 shows the permeability of a fluorescent dye (coumarin) suspended in an oil phase (A) and encapsulated in a nanoemulsion according to the invention (B). DETAILED DESCRIPTION OF THE INVENTION

[0040] The present invention is illustrated by the following non-limiting embodiments, whereby the individual components of the compositions according to the invention are known and have been tested for toxicity, available test results indicate that none of the components are toxic to humans, and each of them can be used to manufacture a composition to be applied to human skin. [Example]

[0041] [Embodiment 1.] Preparation of self-emulsifying (spontaneous) nanoemulsion formulations co-formed with surfactin (a bacterial biosurfactant that reduces interphase tension, resulting in nanocarriers)

[0042] Glyceryl Caprylate Sodium surfactin (Figure 1) and 2-(2-ethoxyethoxy)ethanol were thoroughly mixed in a ratio of 40:10:50 w / w to form a concentrate, which is a composition according to the present invention for administration to the skin. 50 mg of this composition was then mixed with 10 ml of water at 37°C. The whole was stirred with a stirrer to obtain an o / w nanoemulsion with a size of 125.2 ± 1.6 nm, a polydispersity index (PdI) of 0.182 ± 0.009, and a zeta potential of -87.86 ± 1.42 mV.

[0043] The concentrate with the composition defined above, after dilution with water at 1:100 w / v, allows obtaining an o / w type nanoemulsion with a size of 116.8 ± 0.7 nm, a polydispersity index (PdI) of 0.162 ± 0.014 (Figure 2), and a zeta potential of -87.63 ± 0.98 mV (Figure 3).

[0044] The resulting nanoemulsion can be rediluted 1:1000 w / v with water to a final dilution with the following parameters: size 129.5±0.4 nm, polydispersity index (PdI) 0.153±0.012, zeta potential -61.2±3.03 mV.

[0045] Parameters such as size (hydrodynamic diameter of nanoemulsion droplets), polydispersity index (PdI), and zeta potential were obtained by appropriate dynamic light scattering (DLS) and electrophoretic light scattering (ELS) techniques.

[0046] [Embodiment 2.] In preparing self-emulsifying (spontaneous) nanoemulsion formulations co-formed with surfactants, Glyceryl Caprylate The surfactant sodium and 2-(2-ethoxyethoxy)ethanol were thoroughly mixed in a ratio of 50:10:40 w / w to form a concentrate, which is the composition of the present invention. Next, 50 mg of this composition was mixed with 10 ml of water at 37°C. The whole was stirred with a stirrer to obtain an oil-in-water nanoemulsion with a size of 161.3±4 nm, a polydispersity index (PdI) of 0.362±0.021, and a zeta potential of -94.23±4.96 mV.

[0047] The concentrate of the composition described above, after dilution with water at 1:100 w / v, yields an oil-in-water nanoemulsion with a size of 166.7 ± 4.5 nm, a polydispersity index (PdI) of 0.402 ± 0.014, and a zeta potential of -92.6 ± 0.86. The resulting nanoemulsion can be diluted again with water at 1:1000 w / v to obtain the final dilution, which has the following parameters: size 161.7 ± 1.7 nm, polydispersity index (PdI) 0.291 ± 0.023, and zeta potential -63.33 ± 0.66 mV.

[0048] [Embodiment 3.] In preparing self-emulsifying (spontaneous) nanoemulsion formulations co-formed with surfactants, Glyceryl Caprylate The surfactant sodium and 2-(2-ethoxyethoxy)ethanol were thoroughly mixed in a 50:30:20 w / w ratio to form a concentrate, which is the composition of the present invention. Next, 50 mg of this composition was mixed with 10 ml of water at 37°C. The whole was stirred with a stirrer, resulting in an o / w nanoemulsion with a size of 82.85 ± 0.9 nm, a polydispersity index (PdI) of 0.159 ± 0.009 (Figure 4), and a zeta potential of -90.93 ± 3.09 mV.

[0049] The concentrate of the composition described above, after dilution with water at 1:100 w / v, yields an o / w nanoemulsion with a size of 67.2 ± 1.2 nm, a polydispersity index (PdI) of 0.201 ± 0.005, and a zeta potential of -87.60 ± 1.05 mV. The resulting nanoemulsion can be diluted again with water at 1:1000 w / v to obtain the final dilution, which has the following parameters: size 105.8 ± 0.5 nm, polydispersity index (PdI) 0.071 ± 0.014, and zeta potential -67.93 ± 8.07 mV.

[0050] [Embodiment 4.] In preparing self-emulsifying (spontaneous) nanoemulsion formulations co-formed with surfactants, Glyceryl Caprylate The surfactant sodium and 2-(2-ethoxyethoxy)ethanol were thoroughly mixed in a 10:50:40 w / w ratio to form a concentrate, which is the composition of the present invention. Next, 50 mg of this composition was mixed with 10 ml of water at 37°C. The whole was stirred with a stirrer to obtain an o / w nanoemulsion with a size of 69.6 ± 1.5 nm, a polydispersity index (PdI) of 0.287 ± 0.025, and a zeta potential of -87.46 ± 2.20 mV.

[0051] The concentrate with the composition defined above, after dilution with water at 1:100 w / v, yields an o / w nanoemulsion with a size of 59.8 ± 0.9 nm, a polydispersity index (PdI) of 0.293 ± 0.037, and a zeta potential of -74.23 ± 0.30 mV. The resulting nanoemulsion can be diluted again with water at 1:1000 w / v to obtain the final dilution, which has the following parameters: size 100.1 ± 0.8 nm, a polydispersity index (PdI) of 0.139 ± 0.008, and a zeta potential of -71.86 ± 5.44 mV.

[0052] [Embodiment 5.] In preparing self-emulsifying (spontaneous) nanoemulsion formulations co-formed with surfactants, Glyceryl CaprylateA concentrate, the composition of the present invention, was formed by mixing surfactant sodium and 2-(2-ethoxyethoxy)ethanol in a ratio of 20:50:30 w / w. 50 mg of this composition was then mixed with 10 ml of water at 37°C. The mixture was stirred with a stirrer to obtain an o / w nanoemulsion with a size of 69.3 ± 1.4 nm, a polydispersity index (PdI) of 0.084 ± 0.019, and a zeta potential of -77.36 ± 1.61 mV (Figure 5).

[0053] After diluting the concentrate with the composition defined above with water to 1:100 w / v, an o / w type nanoemulsion is obtained with a size of 67.9 ± 0.2 nm, a polydispersity index (PdI) of 0.054 ± 0.015, and a zeta potential of -75.93 ± 2.10 mV. The resulting nanoemulsion can be diluted again with water to 1:1000 w / v to obtain the final dilution, which has the following parameters: size 97.4 ± 0.5 nm, polydispersity index (PdI) 0.027 ± 0.015, and zeta potential -54 ± 6.60 mV.

[0054] [Embodiment 6.] In preparing a self-emulsifying (spontaneous) nanoemulsion formulation co-formed with a surfactant, similar to embodiment 1, Glyceryl Caprylate A concentrate, which is the composition of the present invention, was formed by mixing surfactant sodium and 2-(2-ethoxyethoxy)ethanol in a ratio of 3:96.99:0.01 w / w. 50 mg of this composition was then mixed with 5 ml of water at 37°C. The mixture was stirred with a stirrer to obtain an oil-in-water nanoemulsion with a particle size of 536.63±302.77 nm, a polydispersity index (PdI) of 0.684±0.277, and a zeta potential of -99.13±6.16.

[0055] [Embodiment 7.] In preparing a self-emulsifying (spontaneous) nanoemulsion formulation co-formed with a surfactant, similar to embodiment 1, Glyceryl CaprylateThe surfactant sodium and 2-(2-ethoxyethoxy)ethanol were thoroughly mixed in a ratio of 3:0.01:96.99 w / w to form a concentrate, which is the composition of the present invention. Next, 50 mg of this composition was mixed with 5 ml of water at 37°C. The whole was stirred with a stirrer to obtain an o / w nanoemulsion with a particle size of 216.86 ± 5.74 nm, a polydispersity index (PdI) of 0.439 ± 0.023, and a zeta potential of -69.66 ± 2.85.

[0056] [Embodiment 8.] In preparing a self-emulsifying (spontaneous) nanoemulsion formulation co-formed with a surfactant, similar to embodiment 1, Glyceryl Caprylate A concentrate, which is the composition of the present invention, was formed by mixing surfactant sodium and 2-(2-ethoxyethoxy)ethanol in a ratio of 95:2:3 w / w. 50 mg of this composition was then mixed with 5 ml of water at 37°C. The mixture was stirred with a stirrer to obtain an o / w nanoemulsion with a particle size of 570.56 ± 7.39 nm, a polydispersity index (PdI) of 0.991 ± 0.014, and a zeta potential of -63.06 ± 1.45.

[0057] In this embodiment, surfactin produced by Bacillus subtilis is used to prepare a self-emulsifying emulsion.

[0058] In this non-limiting embodiment, surfactin produced by Bacillus subtilis was used, but surfactin produced by other species of the genus Bacillus, such as B. mojavensis, B. amyloliquefaciens, B. circulans, and B. licheniformis, can also be used.

[0059] [Embodiment 9.] Preparation of self-emulsifying (spontaneous) nanoemulsion formulations co-formed by surfactin using cananga oil as the oil phase. Cananga oil, sodium surfactin, and 2-(2-ethoxyethoxy)ethanol were thoroughly mixed in a 20:50:30 w / w ratio to form a concentrate. 50 mg of this composition was then mixed with 10 ml of water at 37°C. The whole was stirred with a stirrer to obtain an o / w nanoemulsion with a particle size of 174.2 ± 2.3 nm, a polydispersity index (PdI) of 0.076 ± 0.010, and a zeta potential of -73.5 ± 1.8 mV.

[0060] [Embodiment 10.] Verbena ( Litsea cubeba ) Preparation of self-emulsifying (spontaneous) nanoemulsion formulations co-formed with surfactin, with oil as the oil phase. Verbena ( Litsea cubeba ) Oil, sodium surfactin, and 2-(2-ethoxyethoxy)ethanol were thoroughly mixed in a 20:50:30 w / w ratio to form a concentrate. 50 mg of this composition was then mixed with 10 ml of water at 37°C. The whole was stirred with a stirrer to obtain an o / w nanoemulsion with a particle size of 86.78 ± 4.58 nm, a polydispersity index (PdI) of 0.408 ± 0.034, and a zeta potential of -56.83 ± 8.32 mV.

[0061] [Embodiment 11.] Preparation of self-emulsifying (spontaneous) nanoemulsion formulations co-formed by surfactin with tocopherol as the oil phase. Tocopherol, sodium surfactin, and 2-(2-ethoxyethoxy)ethanol were thoroughly mixed in a 20:50:30 w / w ratio to form a concentrate. 50 mg of this composition was then mixed with 10 ml of water at 37°C. The whole was stirred with a stirrer to obtain an oil-in-water nanoemulsion with a particle size of 150.25 ± 52.85 nm, a polydispersity index (PdI) of 0.656 ± 0.248, and a zeta potential of -58.83 ± 3.44 mV.

[0062] [Embodiment 12.] Preparation of a self-emulsifying (spontaneous) nanoemulsion formulation co-formed with surfactin using sunflower (Helianthus annuus) seed oil as the oil phase. Tocopherol accounts for 70% and sunflower oil for 30%. Tocopherol, sodium surfactin, and 2-(2-ethoxyethoxy)ethanol in sunflower (Helianthus annuus) seed oil were carefully mixed in a 20:50:30 w / w ratio to form a concentrate. 50 mg of this composition was then mixed with 10 ml of water at 37°C. The mixture was stirred with a stirrer, resulting in an o / w nanoemulsion with a particle size of 183.9 ± 7.64 nm, a polydispersity index (PdI) of 0.328 ± 0.01, and a zeta potential of -95.03 ± 5.11 mV.

[0063] [Embodiment 13.] Preparation of a self-emulsifying (spontaneous) nanoemulsion formulation co-formed by surfactin using ascorbyl tetraisopalmitate as the oil phase. Ascorbyl tetraisopalmitate, sodium surfactin, and 2-(2-ethoxyethoxy)ethanol were thoroughly mixed in a 20:50:30 w / w ratio to form a concentrate. 50 mg of this composition was then mixed with 10 ml of water at 37°C. The whole was stirred with a stirrer to obtain an oil-in-water nanoemulsion with a particle size of 176.46 ± 0.50 nm, a polydispersity index (PdI) of 0.108 ± 0.014, and a zeta potential of -82.7 ± 1.9 mV.

[0064] [Embodiment 14.] Self-emulsifying surfactants co-formed by surfactin using oleic acid as the oil phase Preparation of nanoemulsion formulations. Oleic acid, sodium surfactin, and 2-(2-ethoxyethoxy)ethanol were thoroughly mixed in a 20:50:30 w / w ratio to form a concentrate. 50 mg of this composition was then mixed with 10 ml of water at 37°C. The whole was stirred with a stirrer to obtain an o / w nanoemulsion with a particle size of 147.96 ± 2.89 nm, a polydispersity index (PdI) of 0.255 ± 0.013, and a zeta potential of -87.63 ± 2.19 mV.

[0065] [Embodiment 15.] Preparation of self-emulsifying (spontaneous) nanoemulsion formulations co-formed by surfactin using rapeseed oil as the oil phase. Rapeseed oil, sodium surfactin, and 2-(2-ethoxyethoxy)ethanol were thoroughly mixed in a 20:50:30 w / w ratio to form a concentrate. 50 mg of this composition was then mixed with 10 ml of water at 37°C. The mixture was stirred with a stirrer to obtain an o / w nanoemulsion with a particle size of 780.36 ± 117.67 nm, a polydispersity index (PdI) of 0.680 ± 0.033, and a zeta potential of -103.33 ± 1.52 mV.

[0066] [Embodiment 16.] Preparation of self-emulsifying (spontaneous) nanoemulsion formulations co-formed by surfactin using fatty acid esters as the oil phase. A fatty acid ester, sodium surfactin, and 2-(2-ethoxyethoxy)ethanol were thoroughly mixed in a 20:50:30 w / w ratio to form a concentrate. Next, 50 mg of this composition was mixed with 10 ml of water at 37°C. The whole was stirred with a stirrer to obtain an o / w nanoemulsion with a particle size of 164.9 ± 2.98 nm, a polydispersity index (PdI) of 0.235 ± 0.008, and a zeta potential of -93.46 ± 5.33 mV.

[0067] [Embodiment 17.] In the preparation of self-emulsifying (spontaneous) nanoemulsion formulations co-formed with surfactin, Glyceryl CaprylateA concentrate, which is the composition of the present invention, was formed by thoroughly mixing sodium surfactin and 2-(2-ethoxyethoxy)ethanol in a ratio of 20:50:30 w / w. This concentrate contained dissolved curcumin. Next, 50 mg of this composition was mixed with 10 ml of water at 37°C. The whole was stirred with a stirrer, resulting in an o / w nanoemulsion with a particle size of 68.03 ± 0.91 nm, a polydispersity index (PdI) of 0.271 ± 0.017, and a zeta potential of -73.40 ± 4.71 mV.

[0068] Curcumin was chosen as a model for bioactive compounds used in cosmetics and pharmaceuticals. The morphology of the resulting curcumin-encapsulated emulsion was demonstrated using transmission electron microscopy (TEM) (Figure 6). The prepared nanoemulsion was applied to a mesh, dried, and then introduced into a transmission electron microscope and imaged at an accelerating voltage of 80 eV.

[0069] [Embodiment 18.] Preparation of self-emulsifying (spontaneous) nanoemulsion formulations co-formed with surfactin as a carrier for the active substance. In this non-limiting embodiment, lidocaine was used as the active agent. In the preparation of self-emulsifying (spontaneous) nanoemulsion formulations co-formed with surfactin, Glyceryl Caprylate The oil, surfactant sodium, and 2-(2-ethoxyethoxy)ethanol were thoroughly mixed in a 20:50:30 w / w ratio to form a concentrate, which is the composition of the present invention. The active ingredient, lidocaine, was then dissolved in the concentrate in an amount of 10 mg per 1 g of oil. 50 mg of this composition was then mixed with 10 ml of water at 37°C. The mixture was stirred with a stirrer to obtain an oil-in-water nanoemulsion with a particle size of 60.92 ± 0.11 nm, a polydispersity index (PdI) of 0.157 ± 0.021, and a zeta potential of -70.06 ± 4.21 mV.

[0070] [Embodiment 19.] The skin penetration of the compositions of the present invention was analyzed microscopically. A self-emulsifying (spontaneous) nanoemulsion formulation system was prepared by co-forming sodium surfactin, ascorbyl tetraisopalmitate, and 2-(2-ethoxyethoxy)ethanol in a 20:50:30 w / w ratio and thoroughly mixing to form a concentrate, the composition of the present invention. Furthermore, the fluorescent dye coumarin was dissolved in the concentrate. Next, 50 mg of this composition was mixed with 10 ml of water at 37°C. The entire mixture was stirred with a stirrer to obtain an oil-in-water nanoemulsion. A control sample was prepared by dissolving coumarin in ascorbyl tetraisopalmitate at the same concentration as the nanoemulsion. Samples of the preparation were applied to pig skin prepared from pig ears. The experiment was performed in a Franz chamber for 1 hour. Then, tissue imaging was performed using a confocal microscope according to standard procedures. The results are shown in Figure 7, which demonstrates that the nanoemulsion containing the fluorescent dye (coumarin) penetrated the skin better after 1 hour (Figure 7B) compared to the control sample (Figure 7A).

[0071] [Embodiment 20] To prepare a surfactant-coformed self-emulsifying (spontaneous) nanoemulsion formulation, oleic acid, surfactant sodium, and cocamidopropyl betaine were thoroughly mixed in a 10:20:70 w / w ratio to form a concentrate, which is the composition of the present invention. 50 mg of this composition was then mixed with 10 ml of water at 37°C. The mixture was stirred with a stirrer to obtain an o / w nanoemulsion with a size of 143.2±0.5 nm, a polydispersity index (PdI) of 0.267±0.025, and a zeta potential of -42.4±5.03 mV.

[0072] [Embodiment 21] To prepare a surfactant-coformed self-emulsifying (spontaneous) nanoemulsion formulation, oleic acid, surfactant sodium, and cocamidopropyl betaine were thoroughly mixed in a 10:20:70 w / w ratio to form a concentrate, which is the composition of the present invention. 50 mg of this composition was then mixed with 30 ml of water at 37°C. The mixture was stirred with a stirrer to obtain an o / w nanoemulsion with a particle size of 121.32±0.6 nm, a polydispersity index (PdI) of 0.198±0.022, and a zeta potential of -74.5±3.03 mV.

[0073] [Embodiment 22] To prepare a surfactant-coformed self-emulsifying (spontaneous) nanoemulsion formulation, oleic acid, surfactant sodium, and cocamidopropyl betaine were thoroughly mixed in a 0.5:25:70 w / w ratio to form a concentrate, which is the composition of the present invention. 50 mg of this composition was then mixed with 10 ml of water at 37°C. The mixture was stirred with a stirrer to obtain an o / w nanoemulsion with a size of 91.2 ± 0.2 nm, a polydispersity index (PdI) of 0.266 ± 0.014, and a zeta potential of -50.4 ± 4.03 mV.

[0074] [Embodiment 23] To prepare a surfactant-coformed self-emulsifying (spontaneous) nanoemulsion formulation, oleic acid, surfactant sodium, and cocamidopropyl betaine were thoroughly mixed in a 0.5:25:70 w / w ratio to form a concentrate, which is the composition of the present invention. 50 mg of this composition was then mixed with 30 ml of water at 37°C. The mixture was stirred with a stirrer to obtain an o / w nanoemulsion with a particle size of 80.45±0.6 nm, a polydispersity index (PdI) of 0.210±0.021, and a zeta potential of -61.5±2.03 mV.

[0075] [Embodiment 24] To prepare a surfactant-coformed self-emulsifying (spontaneous) nanoemulsion formulation, oleic acid, surfactant sodium, and cocamidopropyl betaine were thoroughly mixed in a 10:30:60 w / w ratio to form a concentrate, which is the composition of the present invention. 50 mg of this composition was then mixed with 20 ml of water at 37°C. The mixture was stirred with a stirrer to obtain an o / w nanoemulsion with a particle size of 152.41 ± 0.8 nm, a polydispersity index (PdI) of 0.216 ± 0.014, and a zeta potential of -52.01 ± 5.16 mV.

[0076] [Embodiment 25] To prepare a surfactant-coformed self-emulsifying (spontaneous) nanoemulsion formulation, oleic acid, surfactant sodium, and cocamidopropyl betaine were thoroughly mixed in a 10:30:60 w / w ratio to form a concentrate, which is a composition according to the present invention. Next, 50 mg of this composition was mixed with 10 ml of water at 37°C. The mixture was stirred with a stirrer to obtain an o / w nanoemulsion with a size of 162.72 ± 0.5 nm, a polydispersity index (PdI) of 0.254 ± 0.039, and a zeta potential of -43.01 ± 3.19 mV.

[0077] [Embodiment 26] To prepare a surfactant-coformed self-emulsifying (spontaneous) nanoemulsion formulation, oleic acid, surfactant sodium, and cocamidopropyl betaine were thoroughly mixed in a 10:30:60 w / w ratio to form a concentrate, which is the composition of the present invention. Next, 50 mg of this composition was mixed with 10 ml of water at 37°C, and the whole was stirred with a magnetic stirrer. Preferably, the resulting nanoemulsion was diluted 2.5 times with water to a final dilution of 1:2500 w / v, resulting in an o / w formulation with a size of 65.65±0.4 nm, a polydispersity index (PdI) of 0.169±0.053, and a zeta potential of -63.54±2.18 mV.

[0078] [Embodiment 27] To prepare a surfactant-coformed self-emulsifying (spontaneous) nanoemulsion formulation, oleic acid, surfactant sodium, and cocamidopropyl betaine were thoroughly mixed in a 0.5:25:70 w / w ratio to form a concentrate, which is the composition of the present invention. 50 mg of this composition was then mixed with 10 ml of water at 37°C. The resulting nanoemulsion was preferably diluted 2.5 times with water to a final dilution of 1:5000 w / v, resulting in an o / w formulation with a size of 68.75±0.3 nm, a polydispersity index (PdI) of 0.124±0.036, and a zeta potential of 69.32±1.88 mV.

[0079] [Embodiment 28] In preparing self-emulsifying (spontaneous) nanoemulsion formulations co-formed with surfactants, Glyceryl Caprylate The surfactant sodium and cocamidopropyl betaine were thoroughly mixed in a ratio of 5:25:70 w / w to form a concentrate, which is the composition of the present invention. Next, 50 mg of this composition was mixed with 10 ml of water at 37°C. The whole was stirred with a stirrer to obtain an oil-in-water nanoemulsion with a particle size of 80.45±0.6 nm, a polydispersity index (PdI) of 0.210±0.021, and a zeta potential of -61.5±2.03 mV.

[0080] [Embodiment 29] In preparing self-emulsifying (spontaneous) nanoemulsion formulations co-formed with surfactants, Glyceryl Caprylate The surfactant sodium and cocamidopropyl betaine were thoroughly mixed in a ratio of 5:25:70 w / w to form a concentrate, which is the composition of the present invention. Next, 50 mg of this composition was mixed with 20 ml of water at 37°C. The whole was stirred with a stirrer to obtain an o / w nanoemulsion with a particle size of 105.83±0.7 nm, a polydispersity index (PdI) of 0.289±0.072, and a zeta potential of -53.5±4.02 mV.

[0081] [Embodiment 30] In preparing self-emulsifying (spontaneous) nanoemulsion formulations co-formed with surfactants, Glyceryl CaprylateThe surfactant sodium and cocamidopropyl betaine were thoroughly mixed in a ratio of 5:25:70 w / w to form a concentrate, which is the composition of the present invention. Next, 50 mg of this composition was mixed with 30 ml of water at 37°C. The whole was stirred with a stirrer to obtain an oil-in-water nanoemulsion with a particle size of 110.03±0.7 nm, a polydispersity index (PdI) of 0.235±0.024, and a zeta potential of -75.6±2.14 mV.

Claims

1. A self-emulsifying composition intended for administration to the skin and having enhanced skin permeability, comprising a biosurfactant, a co-surfactant and an oil phase, wherein the weight ratios of the biosurfactant, the co-surfactant and the oil phase are 0.01 to 96.99% by weight of the total composition: 0.01 to 96.99% by weight of the total composition: 3 to 70% by weight of the total composition, respectively; the biosurfactant is surfactin or a salt thereof; the co-surfactant is 2-(2-ethoxyethoxy)ethanol or cocamidopropyl betaine; and the oil phase is at least one compound selected from the group consisting of glyceryl caprylate, cananga flower oil, verbena (litsea asiatica) oil, tamanu oil, oleic acid, tocopherol from sunflower seed (helianthus annuus) oil, ascorbyl tetrahexyldecanoate, rapeseed oil and fatty acid esters.

2. 2. The composition according to claim 1, wherein the weight ratio of the biosurfactant, the co-surfactant and the oil phase is 10-50% by weight of the total composition: 20-50% by weight of the total composition: 10-50% by weight of the total composition.

3. 3. The composition of claim 1, wherein the weight ratio of the biosurfactant, the cosurfactant and the oil phase is 50% by weight of the total composition: 30% by weight of the total composition: 20% by weight of the total composition.

4. The composition according to any one of claims 1 to 3, wherein the surfactin is produced by Bacillus subtilis.

5. The composition according to any one of claims 1 to 4, wherein the surfactin is sodium surfactin.

6. The composition according to any one of claims 1 to 5, characterized in that it is diluted with water.

7. 7. The composition according to claim 6, characterized in that a dilution of 10 to 5000 w / w is used.

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