Preparation of botanical nano-particles having excellent percutaneous absorption properties, and cos

专利摘要:
The present invention relates to the production and application of nanoparticles having a size (diameter) of 10 to 300 nm while collecting physiologically active ingredients therein using phospholipids or derivatives thereof. The nanoparticles are produced in the form of liposomes or oil-in-water emulsifiers according to the physical properties of the physiologically active ingredient using phospholipids or derivatives thereof derived from plants as main surfactants, alcohol, diols, polyols, More preferably, it contains 4-10 carbon atoms. Nanoparticles provided by the present invention is excellent in long-term stability and biocompatibility, in particular, excellent in promoting the percutaneous absorption, can be used as an effective carrier to penetrate the active ingredient into the skin, by using this cosmetic and excellent efficacy A pharmaceutical external preparation composition can be comprised.
公开号:KR20030062492A
申请号:KR1020020002701
申请日:2002-01-17
公开日:2003-07-28
发明作者:김진한；박지은；이영하；유병희；강병영；김한곤；강학희
申请人:주식회사 태평양；
IPC主号:

专利说明:

Preparation of botanical nano-particles having excellent percutaneous absorption properties, and cosmetic and medical composition comprising the nano-particles
[1] The present invention relates to nanoparticles having a size (diameter) of 10 to 300 nm in which a physiologically active substance or derivative thereof is used to collect a physiologically active ingredient. More specifically, as phospholipids or derivatives thereof, lecithin extracted from plants, especially soybeans; Hydrogenated lecithin from which the unsaturated double bond is removed by hydrogenation of the lecithin; Or as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, or mixtures thereof as purified phospholipids, and using liposomes or oil-in-water emulsification according to the physical properties of the biologically active active ingredients collected therein. A particle size (diameter), produced in the form of particles, relates to a nanoparticle having a particle size of 10 to 300 nm, more preferably 30 to 60 nm. The nanoparticles are prepared in a dispersed form in an aqueous phase, and are characterized in that they contain alcohols, diols or polyols, more preferably 4 to 10 carbon atoms in the formulation of the nanoparticles.
[2] The present invention also relates to cosmetic and pharmaceutical external preparation compositions containing the nanoparticles. Nanoparticles provided by the present invention is excellent in long-term stability and biocompatibility, in particular, excellent in promoting the percutaneous absorption can be used as an effective carrier to penetrate the active ingredient into the skin.
[3] The skin is composed of three parts, stratum corneum, epidermis and dermis, and the stratum corneum is present at the outermost part of the skin. The skin is the body's primary protective layer that protects the organs of the body from temperature and humidity changes and external environmental stimuli such as ultraviolet rays and pollutants.The barrier function of the skin is mainly due to the stratum corneum in the outermost part of the skin. It depends on the physicochemical properties. The stratum corneum consists of keratinocytes, the main component of which is a protein called keratin, and a lipid layer that fills the cells. Absorption through the keratinocytes is very difficult in the skin absorption of the substance, and the path through the lipid layer between keratinocytes is common.
[4] Phospholipids are generally known to increase the fluidity of stratum corneum lipids to increase skin absorption of drugs or active ingredients (Journal of controlled release, 58 (1999), 207-214).
[5] Generally, in order to promote transdermal absorption, a method of adding an organic solvent, a surfactant, or a lower fatty acid, which is known as a transdermal absorption accelerator, is known, but the type and content of the organic solvent that can be applied to cosmetic and pharmaceutical external preparations Most of the organic solvents, surfactants, lower fatty acids, etc., which are regulated and have a transdermal absorption promoting effect, often cause skin irritation by destroying the structure of the stratum corneum. Lecithin or phospholipids, however, have very little skin irritation and are emerging as a new transdermal absorption system (PSIT Vol. 3, No. 12 (2000) 417-425).
[6] Liposomes and oil-in-water emulsifier types with phospholipids, in particular lecithin, are known in the art. However, the lecithin or phospholipid alone may easily destroy the interface membrane due to contamination by salts or charge-containing organic and inorganic substances, and may be easily hydrolyzed by heat, pH conditions, or microorganisms. It is difficult to obtain a sufficiently stable formulation at. In order to compensate for these disadvantages, a method of improving stability by adding cholesterol in lecithin or phospholipid formulations is known, but in general, when cholesterol is added, the particle size of liposomes or emulsifiers tends to increase, and when applied to skin There is a drawback that it is not smooth and stiff.
[7] It is known that the width of the lipid layer between keratinocytes, ie, the gap between keratinocytes, is about 40-60 nm to be used as a transdermal absorption pathway of the active ingredient (Journal of controlled release, 32 (1994), 249). Therefore, when the nanoparticles are to be used as a carrier for promoting percutaneous absorption, it may be expected to produce the same or smaller size than this gap to achieve a better effect. However, in order to prepare nanoparticles of such a size by the conventional technology, due to the excessive use of a surfactant, there is a disadvantage in that a sticky feeling appears when applied to the skin.
[8] In order to solve the above problems, the present inventors improve the physicochemical stability of nanoparticles using phospholipids or derivatives thereof, in particular lecithin, and at the same time, to obtain an excellent transdermal absorption promoting effect when the nanoparticles are applied to the skin. They have studied how to make the particle size smaller than the gap between the skin keratinocytes.
[9] As a result, the present inventors improved the physicochemical stability of nanoparticles by promoting the percutaneous absorption by adding an appropriate amount of alcohols, diols or polyols, more preferably 4 to 10 carbon atoms in the formulation when preparing the nanoparticles. It has been found that particles of an effective size can be prepared and the present invention has been completed.
[10] Accordingly, an object of the present invention is to add a suitable content of alcohol, diol or polyols, more preferably diols having 4 to 10 carbon atoms, phospholipids excellent in promoting the percutaneous absorption of the active ingredient and improved physical and chemical stability It is to provide a method for producing nanoparticles using the derivative. In particular, it is an object to provide a method for producing nanoparticles using lecithin or derivatives thereof.
[11] It is also an object of the present invention to provide a cosmetic and pharmaceutical external preparation composition containing the nanoparticles.
[12] Accordingly, the present invention provides a method for producing nanoparticles composed of phospholipids or derivatives thereof, containing a bioactive active ingredient therein and having an excellent transdermal absorption promoting effect. Preferably composed of lecithin or a derivative thereof, it provides a method for producing a nanoparticle containing a physiologically active ingredient therein and excellent in the percutaneous absorption promoting effect.
[13] In other words, in the present invention, the physiologically active active ingredient is trapped inside, and the nanoparticles having a particle size (diameter) of 10 to 300 nm prepared using phospholipids or derivatives thereof, in particular lecithin, for controlling the particle size Provided are nanoparticles having an effect of promoting transdermal absorption using monoalcohols, diols or polyols as alcohols in the preparation of the particles, and methods for producing the same. Preferably, the alcohol is a diols having 4 to 10 carbon atoms.
[14] The size of the nanoparticles according to the present invention is more preferably 30 to 60 nm. The nanoparticles are generally obtained in a translucent aqueous dispersion formulation.
[15] Phospholipids or derivatives thereof used in the present invention are not particularly limited in their physicochemical properties, but are derived from vegetable origin. Preferably, the phospholipid is preferably lecithin, and the lecithin or its derivative is also preferably derived from a plant. In addition, since lecithin is commercially available, those skilled in the art may select and purchase lecithin suitable for the needs.
[16] In addition, the present invention provides a cosmetic and pharmaceutical external preparation composition containing the nanoparticles.
[17] By adding the alcohols according to the present invention, not only the particle size can be easily controlled but also the stability of the nanoparticles is improved. According to the composition of the present invention, the size of the nanoparticles can be adjusted to about 10 to 300 nm, preferably about 40 to 60 nm.
[18] On the other hand, lecithin generally refers to phosphatidyl choline, and such lecithin is a kind of phospholipid. In the present invention, a preferred example of phospholipid is lecithin, and a representative example of lecithin is phosphatidyl choline.
[19] In general, commercially available vegetable phospholipids may be used lecithin extracted from plants, in particular soybean, the commercially available lecithin has a fatty acid chain of 12 to 24 carbon atoms, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine It consists of a mixture of phospholipids and other fatty acids, such as phosphatitylglycerol and phosphatidylinositol. Meanwhile, in some cases, hydrogenated lecithin may be used in which unsaturated double bonds of fatty acid chains are removed by a hydrogenation reaction, and purified lecithin may be used to further refine the lecithin to use purified phospholipids having a higher content of specific components.
[20] In addition, lysocithin prepared by partially hydrolyzing a fatty acid chain of phospholipid, hydroxylated lecithin which introduces a hydroxyl group into lecithin, and the like can be used.
[21] The content of the phospholipid used in the present invention or its derivative in the overall formulation is preferably 0.1 to 20% by weight, more preferably 0.5 to 8.0% by weight.
[22] There is no particular limitation on the physiologically active ingredients used in the nanoparticles provided by the present invention, for example, gentamycin, dibekacin, canendomycin, libidomycin, and the like. (lividomycin), tobramycin, tomimycin, amikacin, pradiomycin, sisomicin, tetracycline hydrochloride, oxytetracycline hydrochloride, lolly Tetracycline, oxycycline hydrochloride, ampicillin, piperacillin, ticarcillin, cephalothin, cephalothin, cephaloridine, cephatidine (cefotiam), cefsulodin, cefmenoxime, cefmetazole, cefazolin, cefotaxime, ce Antibiotics such as piperacillin zone (cefoperazone), three Petit joksim (ceftizoxime), moksol lactam (moxolactam), lactase capillary loop (latamoxef), thienyl or neomycin (thienamycin), sulfonamides Shin (sulfazecin), Az Tire Onam (azthreonam); Bleomycin hydrochloride, methotrexate, actinomycin D, mitomycin C, vinblastine sulfate, vincristine sulfate, Daunorubicin hydrochloride, adriamycin neocarcinostatin, cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil 5-fluorouracil, krestin, picibanil, lentinan, levamisole, levamisole, bestatin, azimexon, glycyrrhizin, poly I Antitumor agents, such as: C, poly A: U, and poly ICLC; Sodium salicylate, sulfyrine, sodium flufenamate, sodium diclofenac, sodium indomethacin, morphine hydrochloride, petidine Anti-inflammatory, antipyretic, analgesic, anti-edema agents such as pethidine hydrochloride, levophanol tartrate, oxymorphone; Ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, allochloramide hydrochloride ), Clophedianol hydrochloride, picoperidamine hydrochloride, cloperastine, protokylol hydrochloride, isoproterenol hydrochloride, flesh Antitussive expectorants such as butamol sulfate and terbutaline sulfate; Sedatives, such as chlorpromazine hydrochloride, prochlorperazine, trifluoperazine, atropine sulfate, scopolamine methylbromide, and the like; Muscle relaxants such as pyridinol methanesulfonate, tubocurarine chloride and pancuronium bromide; Antiepileptic agents such as sodium phenytoin, ethosuximide, sodium acetazolamide, chlordiazepoxide hydrochloride and the like; Anti-ulcer agents such as metoclopramide and L-histidine monohydrochloride; Antidepressants such as imipramine, clomipramine, noxiptiline, phenelzine sulfate; Diphenhydramine hydrochloride, chlorpheniramine maleate, triprenamine hydrochloride, metdilazine hydrochloride, clemizole hydrochloride, diphenyl Anti-allergic agents such as diphenylpyraline hydrochloride and methoxyphenamine hydrochloride; Cardiac agents such as trans-p-oxocamphor, theophyllol (theophyllol), aminophylline (aminophylline), and ethyleneprine hydrochloride; Antiarrhythmic agents such as propranolol hydrochloride, alprenolol hydrochloride, bufetolol hydrochloride and oxyprenolol hydrochloride; Vasodilators such as oxyfedrine hydrochloride, diltiazem hydrochloride, tolazoline hydrochloride, hexobendine, bamethan sulfate, and the like; Blood pressure lowering agents such as hexamethonium bromide, pentolinium, mecamlamine hydrochloride, ecarazine hydrochloride, clonidine hydrochloride, etc .; Diabetes treatment agents such as sodium glymidine, glypizide, phenformin hydrochloride, buformin hydrochloride, metformin, etc .; Anti-precipitation agents such as sodium heparin and sodium citrate; Thromboplastin, thrombin, menadione sodium bisulfite, acetomenaphthone, e-amino-caproic acid (e-amino-caproic acid), tranexamic acid homeostatic agents such as (tranexamic acid), carbazochrome sodium sulfonate, and adrenochrome monoaminoguanidine methanesulfonate; Anti-tuberculosis agents such as isoniazid, ethambutol and sodium p-aminosalicylate; Insulin, somatostatin, somatostatin derivative, growth hormone, prolactin, adrenocorticotropic hormone (ACTH), melanocyte stimulating hormone (MSH), thyroid hormone releasing hormone (TRH)) and salt forms and derivatives thereof; Thyroid stimulating hormone (TSH), luteinizing hormone (LH), follicle stimulating hormone (FSH), vasopressin, vasopressin derivatives, oxytocin, calcitonin (calcitonin), parathyroid hormone, glucagon, gastrin, secretin, pancreozymin, cholecystokinin, angiotensin, angiotensin stimulating hormone (human placental lactogen), human chorionic gonadotropin (HCG), enkephalin, enkephalin derivatives, endorphin, endotorhin, kyotorphin, interferon (a, b, g), Interleukin I, II, III, tuftsin, thymopoietin, thymosin, thymostimulin, thymic humoral factor (THF), serum thymus factor ( serum thymic factor (FT S)) and derivatives thereof and other thymic factors; Tumor necrosis factor (TNF), colony stimulating factor (CSF), motilin, dinorphin, bombesin, neurotensin, cerulein, bra Bradykinin, urokinase, asparaginase kallikrein, substance P analogs and antagonists, nerve growth factor, blood coagulation factors VIII and IX, lysozyme chloride, polymyxin B (polymixin B), colistin, gramicidin, bacitracin, protein synthesis stimulating peptide, gastric inhibitory polypeptide (GIP), vascular small intestine polypeptide ( vasoactive intestinal polypeptide (VIP), platelet-derived growth factor (PDGF), growth hormone release factor (GRF, somatocrinin), bone morphogenetic protein (BMP), epidermal growth factor ( polypeptides such as epidermal growth factor (EGF) Prednisolone and its derivatives, dexamethasone and its derivatives, betamethasone and its derivatives, hexstrol phosphate, hexstrol acetate, methiazole, Hormonal drugs such as hydrocortisone; Coenzyme Q10 (coenzyme-Q10), vineatrol, resveratrol, butylated hydroxytoluene (BHT), ascorbic acid (vitamin C) and derivatives thereof, tocopherol (vitamin E) and derivatives thereof, etc. Antioxidants; Antibacterial agents such as triclosan, chlorohexidine, cetylpyridinium chloride and natural essential oils; Hair growth agents such as minoxidil; Growth hormones such as transforming growth factor (TGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), and insuline-like growth factor (IGF); Anti-wrinkle agents such as whitening materials such as arbutin and kojic acid, collagen synthesis promoters, retinol (vitamin A) and derivatives thereof; Skin barrier strengthening and skin moisturizing agents such as ceramide, sphingosine, and faresol; Etc. can be contained. In addition, natural extracts widely used in cosmetics, such as saponaria extract, willow extract, papaya extract, green tea extract, pine bird sprout extract, rice bran extract, rosemary extract, wild pansy extract, kiwi extract, gentian extract, White iris extract, witch hazel extract, ivy extract, carrot extract, licorice extract, clove extract, white lotus extract, mulberry extract, chamomile extract and the like can be collected and used. The type and content of the active ingredient collected inside the nanoparticles can be adjusted depending on the purpose and case.
[23] If the active ingredient used in the present invention is water-soluble nanoparticles are prepared in the form of liposomes, if the active ingredient is fat-soluble can be used in itself or in a form dissolved in an appropriate solvent, in this case, the nanoparticles are liposomes or It is prepared in oil-in-water emulsion. The amount of phospholipids or derivatives thereof for the active ingredient varies depending on the physicochemical properties of the active ingredient, but is used in a weight ratio of 0.1 to 10 times, more preferably in a weight ratio of 0.5 to 5 times.
[24] In order to increase the strength of the interfacial membrane of the nanoparticles provided in the present invention, cholesterol and derivatives thereof, phytosterol and derivatives thereof may be added and used. These components are attached between the interfacial membranes made of phospholipids or derivatives thereof to keep the interfacial membranes in the liquid crystal phase, and can prevent a sudden phase transition phenomenon due to temperature, so that they can be stored at a normal storage temperature, that is, at 0 to 40 ° C. There is a function to improve the stability.
[25] There are no particular limitations on the components, purity, and physicochemical properties of cholesterol and its derivatives, phytosterol and its derivatives used in the present invention, but only those derived from plants should be used. For example, PEG-25 phytosterol sold by Nikko (trade name Nikkol BPSH-25), phytosterol sold by Carotech (trade name Steromax), rapeseed sterol sold by Cognis or its polyoxyethylenated derivatives (trade name Generol R). , Generol R E5, Generol R E10), soy sterol or polyoxyethylenated derivatives thereof (trade names Generol 122N, Generol 122N E 5D, Generol 122N E 10D, Generol 122N E 16, Generol 122N E25), canola sold by Flytochem Sterol (trade name Flytosterol-85) and the like can be used.
[26] In the present invention, alcohols, ie mono alcohols, diols and polyols, are used to stabilize the nanoparticles and control the particle size. For example, ethanol, glycerol, 1,2-propanediol, 1,2-butanediol, 1,2-pentanediol, 1,2-hexanediol, 1,2-octanediol, 1,3-propanediol, 1 , 3-butanediol, 1,5-pentanediol, 2,4-pentanediol, 1,6-hexanediol, 2,5-hexanediol, 3,6-octanediol, 3-methyl-1,3-butanediol, 2-methyl-2,4-pentanediol, ethoxydiglycol, dipropylene glycol and polyoxyethylene of a wide range of molecular weights such as PEG-400, PEG-4000 and the like can be used. More preferably, diols having 4 to 10 carbon atoms are preferably used.
[27] Such diols include 1,3-butanediol, 1,2-pentanediol, 1,2-hexanediol, 1,2-octanediol, 2-ethyl-1,3-hexanediol, 1,6-hexanediol, 2 -Methyl-2,4-pentanethiol and the like. 2-ethyl-1,3-hexanediol is a substance used as a solvent in cosmetics, such as ethoxydiglycol and dipropylene glycol, but has higher biocompatibility because it has better skin safety than ethoxydiglycol and dipropylene glycol. There is an excellent effect in controlling the particle size of the nanoparticles small.
[28] The above alcohol, diol and polyol materials may be used alone or in combination, and may be used at a concentration of 0.01 to 20% by weight, more preferably 0.1 to 15% by weight, based on the total weight of the nanoparticle formulation. When the material is used at an appropriate concentration, it is possible to produce nanoparticles of a size, preferably 60 nm or less, that can pass through the keratinocyte gap in the stratum corneum.
[29] In addition, by adding such alcohols, diols and polyols, the size distribution of the nanoparticles to be produced is uniform, thereby preventing the Ostwald life phenomenon in which small particles are absorbed / fused to large particles. This can increase the physical stability during use and storage / storage.
[30] In the present invention, in the preparation of nanoparticles, an auxiliary surfactant may be used to assist in emulsifying power of phospholipids or derivatives thereof. Although there is no restriction | limiting in the kind and structure of auxiliary surfactant, For example, Anionic surfactant, such as a higher fatty acid soap, alkyl sulfate ester salt, polyoxyethylene alkyl ether sulfate, alkyl ether phosphate ester salt, and N-acylamino acid salt; Cationic surfactants such as alkyltrimethylammonium chloride, dialkyldimethylammonium chloride and benzalkonium chloride; Amphoteric surfactants such as alkyl dimethylamino acetic acid betaine, alkylamide dimethylamino acetic acid betaine and 2-alkyl-N-carboxy-N-hydroxyimidazolinium betaine; Nonionic surfactants, such as a polyoxyethylene form, a polyhydric-alcohol ester form, an ethylene oxide / propylene oxide block copolymer, can be added.
[31] In a preferred embodiment of the invention, suitable thickeners may be added in the formulation to enhance the water dispersion stability of the prepared nanoparticles. For example, natural polymers such as acacia gum, xanthan gum, gellan gum, locust bean gum and starch, cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose and carboxymethyl cellulose, polyacrylic acid, polyacrylamide, polyacrylamide Synthetic polymers such as vinylpyrrolidone, polyvinyl alcohol, copolymers thereof and materials in crosslinked form can be used.
[32] Still another object of the present invention is to provide a cosmetic and pharmaceutical external preparation composition containing the nanoparticles. The formulation of the composition is not particularly limited, but is used in the skin, mucous membranes, oral cavity, scalp or hair, and the like, for example, basic cosmetics such as supple cosmetics, nourishing cosmetics, creams, packs, gels, patches, lipsticks, makeup bases, Color cosmetics such as foundation, shampoo, rinse, cleaning agent such as body cleanser, oral composition such as toothpaste, mouthwash, hair tonic, gel, mousse and other hair composition, wool, hair dye, etc. It is widely applicable to medicines and quasi-drugs such as ointments, gels, creams, patches or sprays.
[33] In the case of the material constituting the interfacial membrane of the nanoparticles provided in the present invention, that is, phospholipid or derivative thereof, interfacial film reinforcing agent, and cosurfactant, it is most preferable to use a plant-derived material, and to replace some components with a synthetic material. However, it is not preferable to use substances derived from animals. The inventors call the nanoparticles prepared from these plant raw materials Phytonanosphere (PNS).
[34] The reason why the vegetable raw material is particularly preferable is that lecithin derived from cows and the like has problems such as mad cow disease infection, which is a problem recently, and vegetable lecithin is preferable in consideration of the safety of the product to the human body. Vegetable lecithin or hydrogenated lecithin according to the present invention may be prepared as needed, but commercially available products may be used. Those skilled in the art can select and use appropriate vegetable lecithin corresponding to the purpose as needed.
[35] Hereinafter, an Example and a test example are given and this invention is demonstrated more concretely. However, the scope of the present invention is not limited to the following examples, test examples and the like.
[36] <Example 1>
[37] 4g soy hydrogenated lecithin, 1g canola sterol, 1g PEG-5 rapeseed sterol, 10g sunflower seed oil, 6g farnesol, 16g propylene glycol, 8g 2-ethyl-1,3-hexanediol After heating and dissolving at 60 ° C., the mixture was added to distilled water, which was pre-heated to 200 g in total, and then emulsified at 3,000 to 6,000 rpm for 3 minutes with a homogenizer, followed by a microfluidizer. ) Was recycled three times at 1,000 bar, and then 10 g of a 1% by weight solution of hydroxyethyl cellulose was added and stirred uniformly. The obtained nanoparticles were prepared in a bluish translucent suspension. The active ingredient used in the present embodiment is farnesol, which has the effect of promoting the differentiation of keratinocytes, promoting the expression of filaggrin protein in keratinocytes and consequently enhancing the skin moisturizing function. to be.
[38] <Example 2>
[39] Except that 8g of 1,2-pentanediol instead of 8g of 2-ethyl-1,3-hexanediol in Example 1 was the same as in Example 1.
[40] Comparative Example 1
[41] Proceed in the same manner as in Example 1 except that 10g of propylene glycol is used and 2-ethyl-1,3-hexanediol is not added.
[42] <Example 3>
[43] 4 g of soy lecithin, 1 g of soy sterol, 1 g of hydrocortisone, 10 g of ethanol, and 5 g of 2-ethyl-1,3-hexanediol were mixed and heated to 50 ° C., and then dissolved in 40 ° C. of distilled water, and adjusted to 200 g in total. Then, the mixture was stirred uniformly and then recycled twice at 1000 bar using a Microfluidizer (High Pressure Homogenizer). The obtained nanoparticles were prepared in a pale yellow translucent suspension. The active ingredient used in the present embodiment is hydrocortisone and is a substance widely used for the treatment of skin inflammation and erythema.
[44] <Example 4>
[45] Except that 5g of 1,3-butanediol instead of 5g of 2-ethyl-1,3-hexanediol in Example 3 was prepared in the same manner as in Example 3.
[46] Comparative Example 2
[47] Except that 2-ethyl-1,3-hexanediol was not added in Example 3 is the same as in Example 3.
[48] <Test Example 1>
[49] In order to measure the average particle size of the nanoparticles obtained in Examples 1 to 4 was measured using dynamic light scattering (Dynamic light scattering, instrument model Zetasizer 3000HS, Malvern, UK), the scattering angle is fixed to 90 degrees, The temperature was measured while maintaining 25 degrees. Hydrodynamic particle diameter and polydispersity were calculated according to the CONTIN method, and the average particle size (diameter) was based on the Z-average value. In addition, in order to test the storage stability, not only the particle size at the time of manufacture, but also the particle size after 2 weeks and 4 weeks were observed to determine the particle size change.
[50] The results are shown in Table 1 below.
[51] Average size (diameter) of nanoparticles obtained in Examples 1-4Particle size (diameter; nm) Example 153 Example 287 Comparative Example 1131 Example 346 Example 472 Comparative Example 2109
[52] Looking at the above results, it can be seen that the size of the nanoparticles prepared by the addition of 2-ethyl-1,3-hexanediol is generally smaller, and the particle size is larger in Comparative Examples 1 and 2 with less diol content. You can see that it is large.
[53] Test Example 2 Storage Stability Test
[54] When the size of the nanoparticles obtained in Examples 1, 2, 3, 4 and Comparative Examples 1, 2 was stored at 30 ° C., the change in particle size was measured.
[55] Immediately after manufactureafter 2 weeks4 weeks later Example 153 nm55 nm58 nm Example 287 nm91 nm94 nm Comparative Example 1131 nm143 nm159 nm Example 346 nm48 nm50 nm Example 472 nm78 nm84 nm Comparative Example 2109 nm117 nm132 nm
[56] As shown in Table 2, in Comparative Examples 1 and 2 having a small diol content, an increase in particle size was greater than that of other examples, and it was confirmed visually. This increase in particle size means that Ostwald life is progressing, where small particles are fused to large particles.
[57] <Prescription 1>
[58] Formulation of nutrient cosmetics containing nanoparticles prepared in Examples 1 and 2 is shown in Table 3 below. The content of each component was based on the weight percentage.
[59] Nutrition Ingredient NameFormulation Example 1Formulation Example 2Comparative Formulation Example 1Comparative Formulation Example 2 Cetostearyl alcohol1.01.01.01.0 Squalane7.07.07.07.0 Polysorbate 601.01.01.01.0 Sorbitan monostearate0.30.30.30.3 Example 15.0--- Example 2-5.0-- Comparative Example 1--5.0- Panesol---0.15 glycerin3.03.03.03.0 Triethanolamine0.20.20.20.2 Carboxy Vinyl Polymer0.20.20.20.2 antiseptica very small amounta very small amounta very small amounta very small amount incensea very small amounta very small amounta very small amounta very small amount Distilled waterto 100to 100to 100to 100
[60] In Table 3, Formulation Examples 1 and 2 are formulations containing the nanoparticles of Examples 1 and 2, Comparative Formulation Example 1 contains the nanoparticles of Comparative Example 1, and 2 in Formulation Formulations 1 and 2 And the same amount of farnesol as included in Comparative Formulation Example 1.
[61] <Prescription 2>
[62] The ointment containing the nanoparticles prepared in Examples 3 and 4 is shown in Table 4 below. The content of each component was based on the weight percentage.
[63] Ointment prescription Ingredient NameFormulation Example 3Formulation Example 4Comparative Formulation Example 3Comparative Formulation Example 4 Beeswax2.02.02.02.0 Glyceryl Stearate2.52.52.52.5 Cetostearyl alcohol1.51.51.51.5 Polysorbate 600.50.50.50.5 Solbitan Sesquioleate5.05.05.05.0 3,7 hexanoate5.05.05.05.0 Squalane8.08.08.08.0 Liquid paraffin8.08.08.08.0 glycerin4.04.04.04.0 Propylene glycol5.05.05.05.0 Example 310.0--- Example 4-10.0-- Comparative Example 2--10.0- Hydrocortisone 0.1 antiseptica very small amounta very small amounta very small amounta very small amount incensea very small amounta very small amounta very small amounta very small amount Distilled waterto 100to 100to 100to 100
[64] In Table 4, Formulation Examples 3 and 4 are formulations containing the nanoparticles of Examples 3 and 4, Comparative Formulation Example 3 contains the nanoparticles of Comparative Example 2, and in Comparative Formulation 4, Formulation Examples 3 and 4 And hydrocortisone in the same amount as those included in Comparative Formulation Example 3 were simply added.
[65] Test Example 3 Transdermal Absorption Measurement Experiment
[66] Percutaneous absorption test was performed using Formulation Examples 1, 2, 3, 4 and Comparative Formulation Examples 1, 2, 3, and 4 prepared in Formulation Examples 1 and 2. Transdermal absorption was measured using Franz permeable cells in hairless guinea pig skin. Immediately before the test, the abdominal skin of the hairless guinea pig was taken, cut into square 1 cm 2 areas, and then mounted in a transmission cell having a diameter of 0.9 cm in a transmission diameter, and fixed with a clamp. 0.5 ml of Formulation Examples 1-4 and Comparative Formulation Examples 1-4 were added to one side of the skin (donor container). The other side (receptor vessel) was to contact the solvent mixed with purified water and ethanol in a 4: 1 weight ratio, the temperature was maintained at 32 ℃ the actual skin temperature during the test. After the start of the test, a portion of the solvent was collected at regular time intervals, and then the amount of absorbed Panesol and hydrocortisone was measured and expressed as the amount of skin absorption (μg / cm 2 / wt%) per application concentration. Table 5 shows.
[67] The quantitative analysis of Panesol is carried out by gas chromatography method, the conditions are as follows.
[68] Injector: Split Ratio 1:50
[69] Detector: Flame Ionization Detector
[70] Column: 30 m DBWAX 0.25 mm LD
[71] Column pressure: 10psi
[72] Injector Temperature: 250 ℃
[73] Detector temperature: 250 ℃
[74] Oven temperature program
[75] Start: 200 ℃
[76] Heating rate: 4 ℃ / min to 250 ℃
[77] Hydrocortisone is measured by high performance liquid chromatography, and the conditions are as follows.
[78] Column: MightySil ODS (4.6X250mm, 5mm)
[79] Mobile phase: Acetonitrile / 10 mM phosphate buffer (35/65)
[80] Flow rate: 1ml / min
[81] Detector: UV 254nm
[82] Percutaneous absorption measurement resultElapsed time Elapsed time 0481204812 Formulation Example 108.1518.9833.13Formulation Example 3014.3026.5949.99 Formulation Example 206.7215.8428.21Formulation Example 4013.2526.7348.35 Comparative Formulation Example 104.8611.5820.93Comparative Formulation Example 3010.3818.0634.81 Comparative Formulation Example 202.596.2512.32Comparative Formulation Example 405.2311.6523.06
[83] Looking at the test results, it can be seen that the formulation containing the nanoparticles according to the present invention is more effective in the percutaneous absorption of the active ingredient than the formulation that is not.
[84] As described above, the nanoparticles provided by the present invention can be manufactured in a smaller size than the gap of the skin keratinocytes, thereby promoting the percutaneous absorption of the bioactive active ingredients trapped inside the nanoparticles. It is available. That is, by using the nanoparticles trapping the biologically active active ingredient therein, by providing improved percutaneous absorption ability, it is possible to provide a cosmetic and pharmaceutical external preparation composition excellent in the desired effect on the skin.

权利要求:
Claims (11)
[1" claim-type="Currently amended] As nanoparticles trapping physiologically active ingredients inside,
Prepared using phospholipids or derivatives thereof;
The particle size (diameter) of the nanoparticles is adjusted to 10-300 nm;
Nanoparticles, characterized in that prepared by adding monoalcohol, diol or polyols as alcohol when the nanoparticles are prepared.
[2" claim-type="Currently amended] The nanoparticles of claim 1, wherein the nanoparticles have a size of 30 to 60 nm.
[3" claim-type="Currently amended] The nanoparticle of claim 1, wherein the phospholipid or a derivative thereof is derived from lecithin and is a lecithin or a derivative thereof.
[4" claim-type="Currently amended] According to claim 3, wherein the lecithin or a derivative thereof is a phospholipid having a fatty acid chain having 12 to 24 carbon atoms, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatitylglycerol, phosphatidylinositol or mixtures thereof Nanoparticles characterized by.
[5" claim-type="Currently amended] The nanoparticle according to claim 1, further comprising soy sterol, rapeseed sterol, canola sterol or derivatives thereof in order to strengthen the interfacial film of the nanoparticle.
[6" claim-type="Currently amended] The nanoparticles of claim 1, wherein the alcohol is diol having 4 to 10 carbon atoms.
[7" claim-type="Currently amended] The method of claim 6, wherein the diol is 1,3-butanediol, 1,2-pentanediol, 1,2-hexanediol, 1,2-octanediol, 2-ethyl-1,3-hexanediol, 1,6 -Nanoparticles, characterized in that hexanediol, 2-methyl-2,4-pentanethiol or 2-ethyl-1,3-hexanediol.
[8" claim-type="Currently amended] According to claim 1, wherein the physiologically active ingredient is an antibiotic, anti-tumor, anti-inflammatory, antipyretic, analgesic, anti-edema, antitussive expectorant, sedative, muscle relaxant, antiepileptic, anti-ulcer, antidepressant, antiallergic, cardiovascular, Antiarrhythmic, vasodilator, antihypertensive, diabetic, homeostatic, hormonal, antioxidant, hair restorer, wool, antibacterial, whitening, collagen synthesis accelerator, wrinkle remover, emollient, skin barrier enhancer, skin moisturizer or skin cosmetic Nanoparticles, characterized in that.
[9" claim-type="Currently amended] The nanoparticles of claim 1, wherein the phospholipids or derivatives thereof are derived from plants.
[10" claim-type="Currently amended] The external preparation composition containing the nanoparticle in any one of Claims 1-9.
[11" claim-type="Currently amended] In the method of producing nanoparticles using a lecithin or derivatives thereof,
A monoalcohol, a diol or a polyol is added as an alcohol in the preparation of the nanoparticles, and the particle size (diameter) is adjusted to 10 to 300 nm.

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同族专利:

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公开号 | 公开日

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KR100422763B1|2004-03-12|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2002-01-17|Application filed by 주식회사 태평양

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2002-01-17|Priority to KR10-2002-0002701A

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2003-07-28|Publication of KR20030062492A

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2004-03-12|Application granted

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2004-03-12|Publication of KR100422763B1

优先权:

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申请号 | 申请日 | 专利标题

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KR10-2002-0002701A|KR100422763B1|2002-01-17|2002-01-17|Preparation of botanical nano-particles having excellent percutaneous absorption properties, and cosmetic and medical composition comprising the nano-particles|