Compositions containing pH-sensitive lipid nanoparticles containing cationic substances

Abstract

The present invention relates to pH-sensitive nanoparticles containing cationic substances, which can stably encapsulate a high content of active ingredients and have significantly improved skin retention and delivery effects of the active ingredients when applied to the skin, and a composition containing the same.

Description

[Technical Field]

[0001] The present invention relates to pH-sensitive nanoparticles containing a cationic substance and compositions containing the same, more particularly to pH-sensitive nanoparticles containing a cationic substance that can stably encapsulate a high amount of an active ingredient and have significantly improved skin retention and delivery effects of the active ingredient when applied to the skin, and compositions containing the same. [Background technology]

[0002] In the fields of cosmetics and pharmaceuticals, there has long been a demand for the development of formulations that can stably capture various skin-active substances within products, allowing them to effectively act on the skin and improve skin condition. However, many bioactive substances are poorly soluble or unstable in aqueous phases, often combining or reacting with other substances, destabilizing the overall system. To overcome this, the use of nanometer- to micrometer-sized emulsion particles to more stably and easily capture active substances within a formulation has been recognized as a key technology. A representative example is a nanoemulsion, which is made by preparing a semi-formulation using a surfactant with a specific hydrophilic-hydrophobic ratio and then processing it in a high-pressure emulsifier to form fine emulsion particles. Liposomes are spherical or other particle structures made from plant- or animal-derived phospholipid materials, forming single or multiple membranes that encapsulate active substances. Also, a technology has been reported for producing nano-sized emulsion particles using a microemulsion formed by optimally concentrating three phases consisting of an emulsifier, oil, and water.

[0003] These emulsion particles have the problem that the active ingredients inside the emulsion are continuously exposed to water, which can lead to denaturation due to oxidation or decomposition. In addition, the emulsion membrane is physicochemically very weak and unstable, and can be destroyed by contamination with salts or charged organic or inorganic substances. It is also very sensitive to heat and light, making it unstable when stored for a long period of time.

[0004] Furthermore, keratin, the main component of the stratum corneum, is a brick-like hard support made up of dead cells, and the intercellular lipid components that bond this support like cement. While keratin plays a vital role in maintaining skin moisture and protecting the skin from harmful external factors, it also poses a significant obstacle to the transdermal absorption of drugs for topical agents used in the cosmetics and pharmaceutical industries. It is generally known in the art that the delivery of drugs through keratin is impossible due to its rigid structure. Therefore, there is a strong demand for a delivery medium that can effectively deliver and penetrate active substances into the skin and retain them in sufficient amounts within the skin. Summary of the Invention [Problem to be solved by the invention]

[0005] Therefore, the inventors have made extensive efforts to produce nanoparticles in which active ingredients can be encapsulated more efficiently and stably, which have excellent particle stability, and which have excellent delivery, penetration, and retention effects on the skin. As a result, they have confirmed that pH-sensitive nanoparticles containing active ingredients using specific cationic lipid materials have excellent encapsulation rate of active ingredients, particle stability, skin penetration effect of active ingredients, and retention amount, unlike existing particles such as liposomes that are known as particles for skin delivery, and have thereby completed the present invention.

[0006] Therefore, an object of the present invention is to provide lipid nanoparticles in which an active ingredient is encapsulated using a cationic substance, and compositions containing the same. [Means for solving the problem]

[0007] To achieve the above object, the present invention provides pH-sensitive lipid nanoparticles comprising a cationic substance, a lipid, and an active ingredient. The present invention also provides a composition comprising the pH-sensitive lipid nanoparticles. [Effects of the Invention]

[0008] The present invention provides lipid nanoparticles that contain a specific cationic substance, lipid, and active ingredient, thereby achieving a high encapsulation rate of the active ingredient, stability of the lipid nanoparticles, and skin penetration, permeability, and retention of the active ingredient, thereby demonstrating excellent effects for use in pharmaceutical compositions or cosmetics for external application to the skin. [Brief explanation of the drawings]

[0009] [Figure 1] FIG. 1 shows the results of a stability confirmation test of the pH-sensitive lipid nanoparticles according to the present invention. [Figure 2] FIG. 1 shows the results of a zeta potential confirmation test of pH-sensitive lipid nanoparticles according to the present invention. [Figure 3] FIG. 1 shows the results of a zeta potential confirmation test of pH-sensitive lipid nanoparticles according to the present invention. [Figure 4a] FIG. 1 shows the results of a test to confirm the skin permeability of pH-sensitive lipid nanoparticles according to the present invention. [Figure 4b] FIG. 1 shows the results of a test to confirm the skin permeability of pH-sensitive lipid nanoparticles according to the present invention. [Figure 4c] FIG. 1 shows the results of a test to confirm the skin permeability of pH-sensitive lipid nanoparticles according to the present invention. [Figure 5a] FIG. 1 shows the results of a test to confirm the skin permeability of pH-sensitive lipid nanoparticles according to the present invention. [Figure 5b] FIG. 1 shows the results of a test to confirm the skin permeability of pH-sensitive lipid nanoparticles according to the present invention. [Figure 5c] FIG. 1 shows the results of a test to confirm the skin permeability of pH-sensitive lipid nanoparticles according to the present invention. [Figure 6a] FIG. 1 shows the results of a test to confirm the amount of pH-sensitive lipid nanoparticles according to the present invention retained in the skin. [Figure 6b] FIG. 1 shows the results of a test to confirm the amount of pH-sensitive lipid nanoparticles according to the present invention retained in the skin. [Figure 7a]FIG. 1 shows the results of a test to confirm the change in zeta potential of the pH-sensitive lipid nanoparticles according to the present invention depending on the pH. [Figure 7b] FIG. 1 shows the results of a test to confirm the change in zeta potential of the pH-sensitive lipid nanoparticles according to the present invention depending on the pH. DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention will be described in detail below.

[0011] In one aspect, the present invention relates to pH-sensitive lipid nanoparticles comprising a cationic substance, a lipid, and an active ingredient.

[0012] The present invention is characterized by the inclusion of a unique cationic lipid material to achieve high encapsulation rate of the active ingredient, stability of the lipid nanoparticles, and skin penetration and permeability and retention of the active ingredient.

[0013] In a specific embodiment, the cationic substance used in the present invention may be a naturally occurring cationic substance or a synthetic cationic substance.Preferably, the cationic substance used in the present invention may be a water-insoluble lipophilic surfactant.Since the core of the pH-sensitive lipid nanoparticle composition of the present invention formed by this lipophilic surfactant is lipid, it may be preferable to use a surfactant that is highly compatible with lipids in order to ensure stable cationic particles.

[0014] The naturally-derived cationic substance used in the present invention may be a cationic surfactant derived from beets. Examples of such naturally-derived cationic substances include, but are not limited to, one or more selected from the group consisting of cetearyl betainate mesylate, arachidyl / behenyl betainate esylate, and stearyl / behenyl betainate mesylate. These naturally-derived cationic substances have been confirmed to be 94% biodegradable according to the OECD 301B test method and have a natural origin index of 0.99 according to the ISO 16128 calculation method, providing the advantage of ensuring safety, particularly when applied to the skin.

[0015] In addition, the synthetic cationic substance used in the present invention may be one or more selected from the group consisting of distearoylethyl hydroxyethylmonium methosulfate, behentrimonium methosulfate, distearoylethyl dimonium chloride, and amodimethicone, but is not limited thereto.

[0016] In the present invention, the content of the cationic substance in the lipid nanoparticles may be, but is not limited to, 0.001 to 10 wt %, 0.01 to 5 wt %, or 0.1 to 2 wt % based on the total weight of the lipid nanoparticles.

[0017] The lipids contained in the pH-sensitive lipid nanoparticles of the present invention can include a combination of cetyl palmitate, a naturally occurring oil selected from the group consisting of cocoglycerides, sunflower seed oil, caprylic / capric triglycerides, and olive oil, and a polar oil selected from octyldodecanol.

[0018] Cetyl palmitate has excellent compatibility with most lipids and emulsifiers, including natural oils, synthetic oils, and waxes. It is a solid lipid with a melting point of 46-51°C, and it can better form stable spherical structures with appropriate hardness inside and outside the pH-sensitive lipid nanoparticles, thereby maintaining the nanoparticle shape well and improving the formulation stability of the composition.

[0019] In the present invention, the lipid content in the lipid nanoparticles may be, but is not limited to, 0.1 to 40 wt % or 5 to 30 wt % based on the total weight of the lipid nanoparticles. The cetyl palmitate content may be, but is not limited to, 0.1 to 40 wt % or 5 to 30 wt % based on the total weight of the lipid nanoparticles. The polar oil content may be, but is not limited to, 0.01 to 20 wt % or 0.1 to 10 wt % based on the total weight of the lipid nanoparticles.

[0020] The active ingredient contained in the pH-sensitive lipid nanoparticles according to the present invention may be any active ingredient that can be applied to the skin, preferably a hydrophobic ingredient or an electrically charged ingredient. In a specific embodiment, the active ingredient may be one or more selected from the group consisting of retinoids such as tretinoin, retinal, retinol, retinyl palmitate, retinyl retinoate, or hydroxypinacolone retinoate; heparin or a pharmaceutically acceptable salt of heparin such as sodium heparin; taurine; ubiquinone (coenzyme Q10); hydroxydecylubiquinone (idebenone); tocopherol; tocopherol acetate; niacinamide; adenosine; ascorbic acid and its derivatives, but is not limited thereto.

[0021] In the present invention, the content of the active ingredient in the lipid nanoparticles may be, but is not limited to, 0.001 to 20% by weight, or 0.01 to 10% by weight based on the total weight of the lipid nanoparticles.

[0022] In the present invention, the encapsulation rate of the active ingredient in the lipid nanoparticles may be 70% or more, 75% or more, 80% or more; or 85% or more.

[0023] In the present invention, the lipid nanoparticles are characterized by having a zeta potential of 20 mV or more, exhibiting a positive charge of 20 to 60 mV. It has been confirmed that the zeta potential of the pH-sensitive lipid nanoparticles according to the present invention changes with changes in pH, and in particular, it converts to a positive charge under weakly acidic conditions of less than pH 7, which has the advantage that the active ingredients in the nanoparticles are not only well retained in the skin, which is negatively charged, but also well penetrated.

[0024] In an additional embodiment, the pH-sensitive lipid nanoparticles according to the present invention may further comprise a co-lipid in addition to the above components.

[0025] Such auxiliary lipids are further included to improve particle formation and stability of the pH-sensitive lipid nanoparticles according to the present invention.

[0026] As used herein, the term "lipid" refers to a group of organic compounds, including, but not limited to, esters of fatty acids, that are characterized by being insoluble in water but soluble in many organic solvents. These are generally divided into at least three categories: (1) "simple lipids," which include fats and oils as well as waxes; (2) "complex lipids," which include phospholipids and glycolipids; and (3) "derived lipids," such as steroids.

[0027] The co-lipid of the present invention may be a non-cationic lipid, such as an amphoteric lipid, a phospholipid, a neutral lipid, a non-cationic lipid, an anionic lipid, a hydrophobic lipid, or the like.

[0028] The term "amphoteric lipid" refers to any suitable lipid material in which the hydrophobic portion of the lipid material is directed toward the hydrophobic phase, while the hydrophilic portion is directed toward the aqueous phase. The hydrophilic character is derived from the presence of polar or charged groups such as carbohydrates, phosphate, carboxyl, sulfato, amino, sulfhydryl, nitro, hydroxyl, and other similar groups. Hydrophobicity can be imparted by the inclusion of nonpolar groups, including, but not limited to, long-chain saturated and unsaturated aliphatic hydrocarbon groups and such groups substituted with one or more aromatic, cycloaliphatic, or heterocyclic groups. Examples of amphoteric compounds include, but are not limited to, phospholipids, aminolipids, and sphingolipids.

[0029] Representative examples of phospholipids include, but are not limited to, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, palmitoyloleoylphosphatidylcholine, lysophosphatidylcholine, lysophosphatidylethanolamine, dipalmitoylphosphatidylcholine, dioleoylphosphatidylcholine, distearoylphosphatidylcholine, and dilinoleoylphosphatidylcholine. Other phosphorus-free compounds, such as sphingolipids, glycosphingolipid families, diacylglycerols, and β-acyloxyacids, are also included in the group designated as amphoteric lipids. Additionally, the amphoteric lipids can be mixed with other lipids, including triglycerides and sterols.

[0030] The neutral lipid refers to any of several lipid species that exist in uncharged or neutral zwitterionic form at a selected pH. At physiological pH, such lipids include, for example, diacylphosphatidylcholine, diacylphosphatidylethanolamine, ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides, and diacylglycerol.

[0031] The anionic lipid refers to any lipid that is negatively charged at physiological pH, including, but not limited to, phosphatidylglycerol, cardiolipin, diacylphosphatidylserine, diacylphosphatidic acid, N-dodecanoylphosphatidylethanolamine, N-succinylphosphatidylethanolamine, N-glutarylphosphatidylethanolamine, lysylphosphatidylglycerol, palmitoyloleoylphosphatidylglycerol (POPG), and other anionic variants attached to neutral lipids.

[0032] The hydrophobic lipid refers to a compound having a non-polar group, including, but not limited to, long-chain saturated and unsaturated aliphatic hydrocarbon groups and such groups optionally substituted with one or more aromatic, cycloaliphatic, or heterocyclic groups. Suitable examples include, but are not limited to, diacylglycerol, dialkylglycerol, N-N-dialkylamino, 1,2-diacyloxy-3-aminopropane, and 1,2-dialkyl-3-aminopropane.

[0033] In other embodiments, the non-cationic lipid can include, for example, one or more anionic lipids and / or neutral lipids. In preferred embodiments, the non-cationic lipid includes one of the following neutral lipid components: (1) cholesterol or a derivative thereof, (2) a phospholipid; or (3) a mixture of a phospholipid and cholesterol or a derivative thereof.

[0034] Examples of such cholesterol derivatives include, but are not limited to, cholestanol, cholestanone, cholestenone, coprostanol, cholesteryl-2'-hydroxyethyl ether, cholesteryl-4'-hydroxybutyl ether, and mixtures thereof.

[0035] Examples of the phospholipid include dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylethanolamine (DOPE), palmitoyloleoyl-phosphatidylcholine (POPC), palmitoyloleoyl-phosphatidylethanolamine (POPE), palmitoyloleoyl-phosphatidylglycerol (POPG), dipalmitoyl-phosphatidylethanolamine (DPPE), dimyristoyl-phosphatidylethanolamine (DPPE), and palmitoyloleoyl-phosphatidylethanolamine (POPG). The phospholipid may be a neutral lipid, including, but not limited to, distearoyl-phosphatidylethanolamine (DMPE), distearoyl-phosphatidylethanolamine (DSPE), monomethyl-phosphatidylethanolamine, dimethyl-phosphatidylethanolamine, dielaidoyl-phosphatidylethanolamine (DEPE), stearoyloleoyl-phosphatidylethanolamine (SOPE), egg phosphatidylcholine (EPC), soybean phosphatidylcholine (SPC), sunflower seed phosphatidylcholine, and mixtures thereof. In a preferred embodiment, the phospholipid is SPC, EPC, or a mixture thereof.

[0036] The amphoteric phospholipids include phosphatidyl choline (PC) [e.g., egg phosphatidylcholine (EPC) and soybean phosphatidylcholine (SPC)], hydrogenated phosphatidyl choline [e.g., hydrogenated soybean phosphatidyl choline (HSPC)], dioleoyl phosphatidyl choline [e.g., 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)], dimyristoyl phosphatidyl choline) [e.g., 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)], dipalmitoyl phosphatidyl choline [e.g., 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)], distearoyl phosphatidyl choline [e.g., 1,2-distearoyl-sn-glycero-3-phosphocholine (1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)], myristoyl palmitoyl phosphatidyl choline (e.g., 1-myristoyl-palmitoyl-sn-glycero-3-phosphocholine (MPPC)), myristoyl stearoyl phosphatidyl choline (e.g., 1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine (MSPC)), and stearoyl palmitoyl phosphatidyl choline (stearoyl palmitoyl phosphatidyl choline (e.g., 1-stearoyl-2-palmitoyl-sn-glycero-3-phosphocholine (SPPC)), phosphatidylethanolamine, dioleoyl phosphatidylethanolamine (e.g., 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)), dimyristoyl phosphatidylethanolamine (dioleoyl phosphatidylethanolamine), phosphatidylethanolamine) [e.g., 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE)], dipalmitoyl phosphatidylethanolamine [e.g., 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (1,The amphoteric phospholipid may be one or more selected from the group consisting of phospholipids such as 2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), and distearoyl phosphatidylethanolamine (e.g., 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)). Preferably, the amphoteric phospholipid may be hydrogenated soybean phosphatidyl choline (HSPC).

[0037] Preferred examples of such auxiliary lipids include, but are not limited to, one or more selected from the group consisting of phosphatidylcholine, ceramide EPI, ceramide API, cholesterol, and cetearyl alcohol.

[0038] The phosphatidylcholine (PC) used in the present invention may be derived from plants (beans, sunflower) rather than animals (egg yolk lecithin), but is not limited thereto, and may be preferably included to ensure formulation stability (particle formation).

[0039] In addition, Ceramide NP is known to be an essential component of the skin (stratum corneum) structure, and along with improving particle formation and stability, it can strengthen the skin barrier and improve sensitive skin.

[0040] In addition to improving particle formation and stability, Ceramide AP has a long-chain lipid structure, which can enhance stability and moisturizing power when used together with Ceramide AP.

[0041] Cholesterol is also known to be an essential component of the skin (stratum corneum) structure and can enhance the skin barrier and formulation stability.

[0042] In addition, cetearyl alcohol is a higher alcohol derived from natural sources (coconut, palm), and can be used as a solid lipid to enhance the stability of the lipid nanoparticles according to the present invention.

[0043] The content of the co-lipid in such lipid nanoparticles may be, but is not limited to, 0.001 to 5% by weight, or 0.01 to 3% by weight, based on the total weight of the lipid nanoparticles.

[0044] The pH-sensitive lipid nanoparticles according to the present invention may further comprise an emulsifier in addition to the above ingredients. Non-limiting examples of such emulsifiers include glyceryl-based emulsifiers such as glyceryl stearate, olivate-based emulsifiers such as cetearyl olivate, sorbitan olivate, and ethylhexyl olivate, polyglyceryl stearate-based emulsifiers such as polyglyceryl-10 laurate, polyglyceryl-10 stearate, and polyglyceryl-3 alkyl glucose distearate (e.g., polyglyceryl-3 methyl glucose distearate), olive-derived emulsifiers such as sorbitan olivate and cetearyl olivate, glyceryl-based emulsifiers such as glyceryl stearate, phosphate-based emulsifiers such as potassium cetyl phosphate, glucose-based emulsifiers such as methyl glucose dioleate, and inulin lauryl carbamate emulsifier.

[0045] The lipid nanoparticles of the present invention may further contain a solvent. Such a solvent must contain a hydroxyl group (-OH) to completely dissolve most water-insoluble lipids and increase their efficiency. Preferred examples include those commonly used in the art, such as ethanol, 1,3-butylene glycol, 2,3-butylene glycol, propylene glycol, glycerin, 1,2-pentanediol, D-panthenol, dipropylene glycol, and mixtures of two or more of these. It is preferable to use a solvent in a commonly known amount depending on the lipid content. Glycerin may be more preferred.

[0046] In a specific embodiment, the pH-sensitive lipid nanoparticles of the present invention may be 50 to 200 nm, 50 to 150 nm, 50 to 120 nm, 70 to 200 nm, 70 to 150 nm, 70 to 120 nm, 90 to 200 nm, 90 to 150 nm, 90 to 120 nm, 100 to 120 nm, 100 to 130 nm, 100 to 140 nm, 100 to 150 nm, or 110 nm, but are not limited to these.

[0047] The pH-sensitive lipid nanoparticles of the present invention exhibit the following excellent effects compared to conventional particulate substances for skin delivery, such as liposomes.

[0048] While conventional liposomes have an aqueous interior, the pH-sensitive lipid nanoparticles of the present invention have an oily interior, which allows a relatively large amount of lipid-soluble particles to be encapsulated, thereby providing the advantage of ensuring a high encapsulation rate.

[0049] In contrast to conventional liposomes, which have a flexible exterior and are therefore likely to undergo deformation during manufacturing, the pH-sensitive lipid nanoparticles of the present invention have a relatively hard exterior, which allows the nanoparticle shape to be well maintained and provides a stable formulation.

[0050] Furthermore, when the pH-sensitive lipid nanoparticles of the present invention are applied to the skin, they suddenly encounter a low pH, and the nanoparticles take on a higher positive charge. This increases the negative charge of the skin and the electrostatic attraction, allowing more of the active ingredient to remain on the skin, ensuring high skin retention and penetration at the same time.

[0051] Furthermore, the pH-sensitive lipid nanoparticles of the present invention have the advantage of being easily homogenized with a constant viscosity due to their high phase stability, even when the same active ingredient is used.

[0052] Due to the high stability of the pH-sensitive lipid nanoparticles of the present invention, when they are formulated into external skin preparations such as cosmetics, it is possible to produce stable formulations ranging from creams to low viscosity formulations.

[0053] In another aspect, the present invention provides a pharmaceutical composition comprising the pH-sensitive lipid nanoparticles. Preferably, the pharmaceutical composition is for parenteral administration, more particularly, for dermal administration.

[0054] Pharmaceutically acceptable carriers can additionally include, for example, carriers for parenteral administration. Also, carriers for parenteral administration can include water, suitable oils, saline, aqueous glucose, glycols, etc., and can additionally include stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

[0055] The composition of the present invention can be administered to mammals, including humans, by any method. For example, it can be administered orally or parenterally. Parenteral administration can also be via transdermal administration. The pharmaceutical composition of the present invention can be formulated into a preparation for parenteral administration by the administration route described above.

[0056] Parenteral formulations can be formulated into injections, creams, lotions, topical ointments, oils, moisturizers, gels, aerosols, and nasal inhalants by methods known in the art. The total effective amount of the composition of the present invention can be administered to a patient in a single dose, or in a fractionated treatment protocol in which multiple doses are administered over a long period of time. The effective dose of the pharmaceutical composition is determined by taking into account various factors, such as the formulation method, administration route, and number of treatments, as well as the patient's age, weight, health condition, sex, disease severity, diet, and excretion rate. Taking these factors into consideration, a person skilled in the art should be able to determine the appropriate effective dose of the composition of the present invention. The present invention may be a pharmaceutical composition for preventing, improving, or treating skin aging, wrinkles, and skin sensitivity, comprising the pH-sensitive lipid nanoparticles.

[0057] In another aspect, the present invention provides a cosmetic composition comprising the pH-sensitive lipid nanoparticles.

[0058] In addition to the pH-sensitive lipid nanoparticles, the components contained in the cosmetic composition of the present invention include components commonly used in cosmetic compositions, such as conventional adjuvants such as antioxidants, stabilizers, solubilizers, vitamins, pigments, and fragrances, and carriers.

[0059] The cosmetic composition of the present invention can be prepared in any dosage form commonly used in the art, including, but not limited to, a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleanser, oil, powder foundation, emulsion foundation, wax foundation, spray, etc. More specifically, it can be prepared in the form of a softening lotion (skin), nourishing lotion (milk lotion), nourishing cream, massage cream, essence, eye cream, cleansing cream, cleansing foam, cleansing water, pack, spray, or powder.

[0060] Preferably, the cosmetic composition of the present invention can be characterized as being in the form of a W / O cream, an O / W cream, an O / W essence, or a hydrogel, and most preferably, the cosmetic composition of the present invention can be in the form of a hydrogel, but is not limited thereto.

[0061] When the dosage form of the present invention is a paste, cream, or gel, the carrier component may be an animal oil, a vegetable oil, a wax, a paraffin, a starch, tragacanth, a cellulose derivative, a polyethylene glycol, a silicone, a bentonite, silica, talc, or zinc oxide.

[0062] When the dosage form of the present invention is a powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, or polyamide powder can be used as a carrier component, and particularly when it is a spray, it can additionally contain a propellant such as chlorofluorohydrocarbon, propane / butane, or dimethyl ether.

[0063] When the dosage form of the present invention is a solution or emulsion, a solvent, solubilizer, or emulsifier is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, aliphatic esters of glycerol, polyethylene glycol, or a fatty acid ester of sorbitan.

[0064] When the dosage form of the present invention is a suspension, the carrier component may be a liquid diluent such as water, ethanol, or propylene glycol; a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester, or polyoxyethylene sorbitan ester; microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, or tragacanth.

[0065] When the dosage form of the present invention is a surfactant-containing cleanser, the carrier component may be a fatty alcohol sulfate, a fatty alcohol ether sulfate, a sulfosuccinic acid monoester, an isethionate, an imidazolinium derivative, a methyl taurate, a sarcosinate, a fatty acid amide ether sulfate, an alkylamidobetaine, a fatty alcohol, a fatty acid glyceride, a fatty acid diethanolamide, a vegetable oil, a lanolin derivative, or an ethoxylated glycerol fatty acid ester.

[0066] In another aspect, the present invention relates to a method for preparing pH-sensitive lipid nanoparticles according to the present invention, comprising the steps of: a) weighing water, an aqueous solvent, and an aqueous component as an aqueous phase and a cationic substance and a co-lipid as an oil phase, respectively, and then heating to dissolve them; b) adding and dissolving an active ingredient in the oil phase; c) adding the aqueous phase of step a) to the oil phase of step b) and stirring to emulsify; d) filtering the emulsified reaction product of step c), adjusting the temperature, and then feeding the filtered product into a microfluidizer to perform high-pressure emulsification; e) cooling the reaction mixture after the high-pressure emulsification in step d). The aqueous solvent used in step a) may be at least one selected from the group consisting of raw materials used in the manufacture of cosmetics in the art, including, but not limited to, water (e.g., purified water), alcohol (e.g., ethanol, isopropyl alcohol, glycerin, propylene glycol, polyhydric alcohols such as sorbitol, and higher alcohols such as cetanol. In step a), heating may be performed at 75 to 90°C, but is not limited thereto, and may be adjusted to a temperature at which the aqueous phase and oil phase are both dissolved and transparent.

[0067] The aqueous component means a component dissolved in water and an aqueous solvent among the components contained in the lipid nanoparticles, and may be, for example, an emulsifier.

[0068] In step b), after confirming that the oil phase is dissolved transparently, the active ingredient is added and completely dissolved.

[0069] In steps a) and b), components contained in the previous nanoparticles other than the aqueous and oil phase components are introduced into the aqueous or oil phase according to their respective hydrophilicity and lipophilicity.

[0070] In step c), the oil phase may be gradually added to the aqueous phase and emulsified using a homogenizer while maintaining the temperature at 70-75° C. In a specific embodiment, the emulsification may be performed by homogenizing at 6,000 rpm for 5 minutes, although this is not intended to be limiting.

[0071] In step d), the emulsified formulation can be filtered by a method well known in the art. For example, it can be filtered through a 120 mesh sieve. After that, the temperature is adjusted to 60-65°C, and the emulsified formulation can be placed in a microfluidizer and subjected to high-pressure emulsification at 1,000 bar for about three cycles.

[0072] The preparation after high pressure emulsification is cooled at 30 to 35°C to finally prepare the pH-sensitive lipid nanoparticles according to the present invention.

[0073] The present invention will be described in more detail below through examples.

[0074] These examples are intended to more specifically illustrate the present invention, and the scope of the present invention is not limited to these examples. [Example]

[0075] <Examples 1-7 and Comparative Examples 1 and 2: Production of lipid nanoparticles and liposomes> pH-sensitive lipid nanoparticles according to the present invention and comparative examples were prepared using the compositions shown in Tables 1 and 2 below. More specifically, the components contained in the aqueous phase and the components contained in the oil phase in Tables 1 and 2 below were weighed and mixed, and then heated to 75-80°C for dissolution. After confirming that all of the oil phase components were dissolved and transparent, the active ingredient was added to the oil phase and completely dissolved. The oil phase containing the active ingredient was then gradually added to the aqueous phase and emulsified at 70-75°C under homogenization conditions at 6,000 rpm for 5 minutes. For preparations of 1 kg or more, the emulsification was continued for 8 minutes. The emulsified formulation was filtered through a 120-mesh filter, the temperature was adjusted to 60-65°C, and then placed in a high-pressure emulsifier (Microfluidics, LM20, DIXC diamond interaction chamber) and subjected to high-pressure emulsification at 1,000 bar for 3 cycles.

[0076] After that, the preparation after high-pressure emulsification was cooled to 30 to 35°C, and then stored in a sealed state, protected from light.

[0077] [Table 1]

[0078] [Table 2]

[0079] <Experimental Example 1: Stability study of pH-sensitive lipid nanoparticles> To confirm the stability of the pH-sensitive lipid nanoparticles according to the present invention, an experiment was conducted using the following method. Specifically, the formulations of Examples 1 and 2 and Comparative Examples 1 and 2 were prepared, and the stability of the active ingredients in the nanoparticles was confirmed by liquid chromatography analysis (HPLC, UV 325 nm (retinol), 340 nm (tretinoin), UV 368 nm (retinal), 4.6 x 150 mm; 5 μm column, injection volume 20 μl). The results are shown in Table 3 and Figure 1.

[0080] [Table 3]

[0081] As can be seen from Table 3 and FIG. 1, the lipid nanoparticles according to the present invention are superior to liposomes in terms of properties, encapsulation rate, and stability of the active ingredient.

[0082] <Experimental Example 2: Particle size and zeta potential analysis> Particle size and zeta potential values ​​were analyzed by dynamic light scattering using a Zetasizer Ultra instrument (Malvern Instrument, Worcestershire, UK), and the results are shown in Table 4 and Figures 2 and 3.

[0083] [Table 4]

[0084] As can be seen from Table 4, the particle size of the lipid nanoparticles according to the present invention was measured to be about 111-116 nm. In addition, it was confirmed that the zeta potential was 31-36 mV, which indicates cationicity, due to the application of a cationic substance.

[0085] <Experimental Example 3: Skin permeability study of pH-sensitive lipid nanoparticles> To confirm the skin permeability of the pH-sensitive lipid nanoparticles according to the present invention, an experiment was conducted using the following method. Specifically, a skin permeation test of the lipid nanoparticles prepared in the above examples and comparative examples was conducted using the Franz diffusion cell method. This experiment was conducted using human cadaver skin (Hans Biomed, Gyeonggi-do, South Korea). The cadaver skin was placed on a receptor chamber with the stratum corneum facing upward, and the donor chamber was then fastened, after which the Franz diffusion cell test was conducted. The Franz diffusion cell method is a test method that can measure skin absorption in vitro to evaluate the permeation characteristics of drugs, and has the advantage of allowing repeated measurements of test substances.

[0086] Specifically, the skin was hydrated with PBS, placed on the receptor chamber with the stratum corneum facing upward, and the donor chamber was fastened and mounted in a Franz diffusion cell. PBS (pH 7.4) containing ethanol (50%, v / v) was used as the receptor phase. 200 mg of each composition sample prepared in Example and Comparative Example 1 was applied to the entire skin, and the content of the active ingredient permeated after 0, 18, 24, and 48 hours was measured by liquid chromatography.

[0087] The results are shown in Figures 4 and 5.

[0088] As can be seen from the results of Figures 4 and 5, the lipid nanoparticles according to the present invention exhibited superior skin permeability compared to liposomes. In particular, the lipid nanoparticles using a naturally occurring cationic substance exhibited the highest skin permeability.

[0089] Furthermore, retinoids showed excellent skin permeability when encapsulated in the lipid nanoparticles according to the present invention, regardless of the type.

[0090] <Experimental Example 4: Examination of the amount of pH-sensitive lipid nanoparticles retained in the skin> In order to confirm the skin retention of the pH-sensitive lipid nanoparticles according to the present invention, the following experiment was carried out. Specifically, the lipid nanoparticles and liposomes prepared in the examples and comparative examples were confirmed by the following test method.

[0091] First, the cadaver skin was activated in PBS for over 30 minutes, then removed and wiped with PBS. The skin was then placed on a frame with the skin surface facing up, and the lipid nanoparticles and liposomes prepared in Experimental Example 3 and 1% olive oil were applied, with the bottom filled with PBS to prevent drying. 24 hours after application, the lipid nanoparticles, liposomes, and 1% olive oil were wiped off, washed three times with PBS, and then minimized moisture with Kimtech.

[0092] The specimen was immediately immersed in a mixed solvent of dichloromethane and methanol (2:1) and cut into pieces as small as possible with scissors. After that, the specimen was shielded from light, immersed in ice, and subjected to sonic treatment for 30 minutes, followed by filtration to obtain the test solution.

[0093] The test solution was measured by liquid chromatography, and the results are shown in Figure 6.

[0094] As can be seen from the results in Figure 6, the lipid nanoparticles according to the present invention showed superior skin retention compared to liposomes. In particular, the lipid nanoparticles using a naturally occurring cationic substance showed the highest skin permeability.

[0095] Furthermore, there was no significant difference between the types of retinoids, and when encapsulated in the lipid nanoparticles according to the present invention, excellent skin retention was observed.

[0096] <Experimental Example 5: Study of zeta potential changes in pH-sensitive lipid nanoparticles> The change in zeta potential of the pH-sensitive lipid nanoparticles according to the present invention with respect to pH was confirmed. Specifically, a test was conducted in the same manner as in Experimental Example 2, and the zeta potential was measured at different pH values ​​as shown in Table 5. The results are shown in Table 5 and Figure 6. As can be seen from Table 5 and Figure 6, the zeta potential of the lipid nanoparticles according to the present invention changes with changes in pH, and in particular, when changing from a neutral pH to a weakly acidic pH, the charge rapidly changes from negative to positive.

[0097] This indicates that the lipid nanoparticles according to the present invention change their charge in response to changes in pH, which has a significant effect on the degree to which they remain on the skin.

[0098] Specifically, the skin surface is weakly acidic and has a relatively low pH, and the lipid nanoparticles according to the present invention are weakly acidic in the formulation, but when applied to the skin surface, they encounter a relatively low pH and acquire a higher positive charge. As a result, they form an electrostatic attraction with the negative charge of the skin, remaining on the skin surface in greater amounts and for longer periods, and even after washing the skin, allowing the active ingredients to be effectively delivered.

[0099] [Table 5]

Claims

1. A pH-sensitive lipid nanoparticle comprising a cationic substance, a lipid, and an active ingredient, wherein the active ingredient is in a form encapsulated by the cationic substance and the lipid.

2. The pH-sensitive lipid nanoparticle of claim 1, wherein the cationic substance exhibits lipophilicity.

3. the cationic material is one or more naturally occurring cationic materials selected from the group consisting of cetearyl betainate mesylate, arachidyl / behenyl betainate esylate, and stearyl / behenyl betainate mesylate; and The pH-sensitive lipid nanoparticles according to claim 1, wherein the pH-sensitive lipid nanoparticles are one or more selected from the group consisting of one or more synthetic cationic substances selected from the group consisting of distearoylethyl hydroxyethylmonium methosulfate and amodimethicone.

4. The pH-sensitive lipid nanoparticles according to claim 1, wherein the content of the cationic substance in the lipid nanoparticles is 0.1 to 2% by weight based on the total weight of the lipid nanoparticles.

5. 2. The pH-sensitive lipid nanoparticle of claim 1, wherein the lipid is a combination of cetyl palmitate; and an oil selected from cocoglycerides, sunflower seed oil, caprylic / capric triglycerides, olive oil, and octyldodecanol.

6. The pH-sensitive lipid nanoparticles according to claim 1, wherein the lipid content in the lipid nanoparticles is 0.1 to 30% by weight based on the total weight of the lipid nanoparticles.

7. The pH-sensitive lipid nanoparticles of claim 1, wherein the active ingredient is one or more selected from the group consisting of retinoid substances such as tretinoin, retinal, retinol, retinyl palmitate, retinyl retinoate, or hydroxypinacolone retinoate; heparin or a pharmaceutically acceptable salt of heparin such as sodium heparin; taurine; ubiquinone; hydroxydecyl ubiquinone; tocopherol; tocopherol acetate; niacinamide; adenosine; ascorbic acid, and derivatives thereof.

8. The pH-sensitive lipid nanoparticles according to claim 1, wherein the content of the active ingredient in the lipid nanoparticles is 0.01 to 10% by weight based on the total weight of the lipid nanoparticles.

9. The pH-sensitive lipid nanoparticles according to claim 1, wherein the lipid nanoparticles exhibit a zeta potential of 20 to 60 mV.

10. The pH-sensitive lipid nanoparticles of claim 1, further comprising one or more co-lipids selected from the group consisting of phosphatidylcholine, ceramide enpy, ceramide api, cholesterol, and cetearyl alcohol.

11. The pH-sensitive lipid nanoparticles according to claim 1, wherein the content of the co-lipid in the lipid nanoparticles is 0.01 to 3% by weight based on the total weight of the lipid nanoparticles.

12. The pH-sensitive lipid nanoparticles of claim 1, further comprising one or more emulsifiers selected from the group consisting of glyceryl-based, olivate-based, polyglyceryl-10 laurate, and polyglyceryl-3 alkyl glucose distearate.

13. The pH-sensitive lipid nanoparticles according to claim 1, wherein the pH-sensitive lipid nanoparticles have a particle size of 50 to 200 nm.

14. A pharmaceutical composition for preventing, improving, or treating skin aging, wrinkles, and skin sensitivity, comprising the pH-sensitive lipid nanoparticles according to claim 1.

15. A cosmetic composition comprising the pH-sensitive lipid nanoparticles according to claim 1.

16. a) weighing water, an aqueous solvent, and an aqueous component as an aqueous phase, and a cationic substance and a co-lipid as an oil phase, and then heating to dissolve them; b) adding and dissolving an active ingredient in the oil phase; c) adding the aqueous phase of step a) to the oil phase of step b) and stirring to emulsify; d) filtering the emulsified reaction product of step c), adjusting the temperature, and then feeding the filtered product into a microfluidizer to perform high-pressure emulsification; The method for producing pH-sensitive lipid nanoparticles according to claim 1, further comprising the step of: e) cooling the reaction mixture after the completion of the high-pressure emulsification in step d).

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