WO2006095778A1

WO2006095778A1 - Nanoparticles containing hair growth-stumulating ingredient, method of producing the same and hair growth stimulant using the same

Info

Publication number: WO2006095778A1
Application number: PCT/JP2006/304487
Authority: WO
Inventors: Hiroyuki Tsujimoto; Kaori Hara; Yusuke Tsukada
Original assignee: Hosokawa Powder Technology Research Institute
Priority date: 2005-03-10
Filing date: 2006-03-08
Publication date: 2006-09-14
Also published as: JPWO2006095778A1

Abstract

Nanoparticles containing a hair growth-stimulating ingredient which are prepared by encapsulating a crude drug ingredient within a biocompatible polymer to give particles in a nano-level size. These nanoparticles penetrate from pores and the scalp surface into the deep part of the scalp. Thus, the crude drug ingredient can be delivered to the deep part of the scalp and then gradually released from the nanoparticles in the deep part of the scalp. Thus, these nanoparticles are appropriately usable as a material for a hair growth stimulant.

Description

Specification

Hair-growth component-containing nanoparticles, production method thereof, and hair-growth agent using the same

[0001] The present invention relates to a hair-growth component-containing nanoparticle in which a herbal medicine is encapsulated as a hair-growth component in the nanoparticle.

Background art

[0002] Human hair is replaced with new hair by repeating a cycle of hair growth and hair removal (hair cycle). During this hair cycle, new hair bulbs are created by the division of the hair matrix cells, the hair papilla reaches the subcutaneous tissue, actively absorbs nutrients, and the hair grows in the growth phase, where the hair force extends to the scalp surface. From the regression phase, where the hair cell nipples are stopped and the hair roots are pushed up, and the hair papilla is prepared to move away from the bulbar force. After a quiescent period of 2 months to 1 year, the hair matrix cells divide again and enter the growth phase.

[0003] Alopecia includes male sex and juvenile alopecia (male pattern baldness), alopecia areata due to stress, and the like due to genetics and inheritance. In these alopecias, the hair does not develop sufficiently during the growth period in the above-mentioned hair cycle, and as a result, the hair moves to the regressing stage, resulting in hair loss in a state where the hair is thin and soft and the hair cycle is short. It is thought to occur.

[0004] For example, in the case of androgenetic alopecia, when testosterone, a kind of male hormone, reaches the hair matrix from the blood, it is caused by the action of the 5a reductase, a reductase present in the cell. Testosterone changes to dihydrotestosterone (DHT). This DHT enters the cell nucleus and inhibits the production of adenosine triphosphate (ATP), an essential energy source for cell division. As a result, the hair matrix cells become inactive, and the growing hair changes to resting hair, leading to hair loss. In addition to male hormones, hair loss is thought to have various causes, including blood circulation failure, nutritional disorders, inheritance, abnormal sebum secretion, and the occurrence of dandruff caused by the growth of resident scalp microorganisms. Yes.

[0005] In recent years, new hair growth ingredients have been actively developed, and a number of hair growth agents for the purpose of preventing hair loss and hair growth have been listed. These products are responsible for the causes of hair loss as described above. In order to improve, various combinations of ingredients with different mechanisms of action, such as vasodilators, nutritional supplements, androgen antagonists, anti-inflammatory agents, anti-allergic agents, bactericides, and moisturizers, are included. Some of these components have been proven to have a hair growth effect by animal experiments with mice and the like.

[0006] However, in spite of the use of these hair growth agents, the hair growth / hair growth effect may not appear. This is due to the problem of scalp permeability of the active ingredient, one of which is considered to be due to a number of factors. Conventionally, external medicines are generally applied by direct application with a finger or using an instrument such as absorbent cotton or brush. Such a method is simple and preferred for dosage forms that are absorbed and transferred into the blood after application to the skin.

[0007] With respect to a drug that stays in the application portion and exhibits a medicinal effect, it is necessary to apply a certain amount of the drug to a certain area of skin in order to achieve a certain medicinal effect. However, many people suffering from alopecia may have their scalp soiled with excessive sebum, dandruff, or dust, and in the conventional method, even if an active ingredient that acts on the hair root is applied, Depending on the state of the scalp and the nature of the drug, it is considered that the drug cannot be sufficiently administered because it is repelled by the application part and the drug cannot be administered sufficiently.

[0008] Therefore, various methods have been proposed for reaching the active site to active ingredients that act on the hair roots and blood vessels present in the scalp. For example, Patent Document 1 uses jaundice extract as an active ingredient. Further, a hair nourishing and hair restoration using phospholipid or cyclodextrin as a transdermal absorption enhancer is disclosed. Patent Documents 2 and 3 disclose hair restorers that contain minoxidil and a herbal extract as active ingredients and that contain a polar solvent to improve the skin retention effect. Patent Document 4 discloses a hair restorer composition containing an active ingredient and a water-swellable viscosity mineral and having excellent scalp permeability and usability.

[0009] In Patent Document 5, an active ingredient is contained in an endoplasmic reticulum (ribosome) obtained by mixing phospholipid and water, and a beneficial substance is directly and selectively delivered to hair cells. Patent document 6 discloses a hair-growth and hair-restoring composition comprising a hair-growth and hair-restoring agent held in small-diameter ribosomes produced using cluster-treated water. Furthermore, Patent Document 7 discloses a transdermal absorbent containing a hair-growth agent as a physiologically active ingredient in polymer nanoparticles. Each is disclosed.

[0010] Here, in order to more reliably express the hair growth effect of the hair growth and hair nourishing agent, in addition to the reliable arrival of the active ingredient to the action site, the active ingredient is released over a long period of time. It is desirable to have a sustained release property. However, in the above-mentioned Patent Documents 1 to 4, no consideration is given to the sustained release, and the methods of Patent Documents 5 and 6 hold the drug in the ribosome. Expected but not enough. In addition, since Patent Document 6 uses magnetic field treatment water, expensive equipment is required, and cost increases due to an increase in manufacturing processes are inevitable! /.

[0011] Patent Document 7 includes minoxidil, TGF (cell growth factor), EGF (epidermal growth factor), FGF (fibroblast growth factor), IGF (insulin-like growth factor), testosterone, androgen, etc. Although it is described that the hair-growth and hair-restoring ingredients are contained in the polymer nanoparticles, the hair-growth, such as specific blending amounts and formulation examples of each ingredient, test results for scalp penetration effect and hair-growth effect, etc. The basis of the effectiveness as a hair nourishing agent is not disclosed at all. Minoxidil, which is described as an active ingredient, was originally developed as an antihypertensive agent, and some side effects have been pointed out over long periods of continuous use along with hormones such as testosterone and androgen. RU

[0012] Further, Patent Document 7 describes halogenated alkanes, which are low-boiling and poorly water-soluble organic solvents, as an oil layer for dissolving a polymer and an active ingredient used in the production process of polymer nanoparticles. Ethyl acetate, jetyl ether, cyclohexane, benzene, toluene, etc. are described, but these organic solvents are all concerned about toxicity to the human body and impact on the environment. It was not preferable to use it in the manufacturing process of hair growth and hair nourishing agents.

Patent Document 1: Japanese Patent Laid-Open No. 10-203933

Patent Document 2: JP-A-10-218737

Patent Document 3: Japanese Patent Laid-Open No. 2002-226329

Patent Document 4: Japanese Unexamined Patent Publication No. 2003-26546

Patent Literature 5: Japanese Patent Publication No. 8-511510

Patent Document 6: Japanese Unexamined Patent Publication No. 2000-229815 Patent Document 7: Japanese Patent Application Laid-Open No. 2002-308728

Disclosure of the invention

Problems to be solved by the invention

[0013] In view of the above problems, the present invention provides a hair-restoring ingredient-containing nanoparticle having a penetrating effect inside the scalp and a sustained-release effect of the ingredient and having high safety, and a hair-restoring agent using the same. The purpose is to do. Another object of the present invention is to provide a method for producing hair-growth-component-containing nanoparticles at low cost and with low environmental impact.

Means for solving the problem

[0014] In order to achieve the above object, the present invention encapsulates one or more herbal components in a biocompatible polymer to form hair-growth component-containing nanoparticles.

[0015] Further, according to the present invention, in the hair-growth component-containing nanoparticles having the above-described configuration, the herbal medicine component is one or more selected from a matrix cell activator or an anti-inflammatory agent.

[0016] Further, according to the present invention, in the hair-growth component-containing nanoparticles having the above-described configuration, the hair matrix cell active agent is hinokitiol.

[0017] Further, according to the present invention, in the hair-growth component-containing nanoparticles having the above-described configuration, the anti-inflammatory agent is β-glycyrrhetinic acid.

[0018] Further, the present invention provides the hair-growth component-containing nanoparticles having the above-described configuration,

Furthermore, it was decided to enclose a blood circulation promoter.

[0019] Further, the present invention provides the hair-growth component-containing nanoparticles having the above-described configuration,

Furthermore, it was decided to encapsulate a male hormone antagonist.

[0020] Further, according to the present invention, in the hair-growth component-containing nanoparticles having the above-described configuration, the encapsulation rate of the herbal component in the biocompatible high molecule is 1 wt% or more and 20 wt% or less.

[0021] Further, according to the present invention, in the hair-growth component-containing nanoparticles having the above-described configuration, the biocompatible high molecule is a lactic acid / glycolic acid copolymer.

[0022] Further, according to the present invention, in the hair-growth component-containing nanoparticles having the above-described configuration, the average particle size is 30 nm or more and 300 nm or less.

[0023] Further, according to the present invention, the hair-growth component-containing nanoparticles having the above-described configuration are combined. [0024] Further, according to the present invention, vitamins or vitamin derivatives are combined with the hair-growth component-containing nanoparticles having the above-described configuration.

[0025] Further, according to the present invention, sugar alcohol is complexed with the hair-growth component-containing nanoparticles having the above-described configuration.

[0026] Further, the present invention is a hair restorer obtained by dispersing the hair-growth component-containing nanoparticles having the above-described configuration in a dispersion.

[0027] Further, according to the present invention, in the hair restorer having the above-described configuration, another hair-restoring component is blended in the dispersion.

[0028] Further, according to the present invention, in the hair-restoring agent having the above-described configuration, the hair-restoring component blended in the dispersion is vitamin or a vitamin derivative.

[0029] The present invention also provides nanoparticle formation in which a hair-growth component-containing biocompatible nanoparticle is formed by adding at least a crude drug, a biocompatible polymer and an organic solvent to an aqueous polyvinyl alcohol solution to form a hair-growth component-containing biocompatible nanoparticle. It has a process and the solvent distillation process of distilling off the said organic solvent from the said nanoparticle containing solution, It is a manufacturing method of the hair-growth component containing nanoparticle characterized by the above-mentioned.

[0030] The present invention provides a method of manufacturing hair growing ingredient-containing nanoparticles having the above structure, poly Bulle alcohol concentration in the poly Bulle aqueous alcohol was as this is less than 0.5 wt ^_0/0.

[0031] Further, the present invention provides a method for producing the hair-growth component-containing nanoparticles having the above-described configuration, further comprising a removal step of removing the nanoparticle-containing solution force polybulu alcohol after the solvent distillation step. .

[0032] Furthermore, the present invention provides the method for producing the hair-growth component-containing nanoparticles having the above-described structure, wherein the polybulal alcohol concentration in the aqueous polybulal alcohol is 0.1 wt% or more and 10 wt%

% Or less.

[0033] Further, according to the present invention, in the method for producing hair-growth component-containing nanoparticles having the above-described configuration, the organic solvent is a mixed solution of acetone and ethanol.

[0034] Further, the present invention provides a method for producing a hair-growth component-containing nanoparticle having the above-described structure, wherein the nanoparticle is further combined after the solvent distillation step or the removal step. It was decided to have a degree.

[0035] Further, the present invention provides a method for producing a hair-growth component-containing nanoparticle having the above-described configuration, wherein in the compounding step, at least one of sugar alcohol, vitamin, and vitamin derivative is combined with the nanoparticle. It was decided to make it.

[0036] Further, according to the present invention, in the method for producing the hair-growth component-containing nanoparticles having the above-described configuration, the compounding step is performed by freeze-drying.

Brief Description of Drawings

[0037] [Fig. 1] In Example 11, apply j8-glycyrrhetinic acid PBS dispersion (Fig. 1 (A)) and β-glycyrrhetinic acid encapsulated PLGA nanoparticle aqueous dispersion (Fig. 1 (Β)) of the present invention. 4 is a fluorescence intensity graph and a cross-sectional photograph of the epidermis after 4 hours.

[Fig. 2] Fluorescence intensity graph and cross section of epidermis 4 hours after application of hinokitiol PBS dispersion (Fig. 2 (Α)) and hinokitiol-encapsulated PLG Α nanoparticle aqueous dispersion (Fig. 2 (Β)) of the present invention It is a photograph.

FIG. 3 is a photograph showing the hair growth status of C3H mice in which test solution A of the present invention was applied to the entire shaved area in Example 12.

FIG. 4 is a photograph showing the hair growth of C3H mice in which test solution B of the present invention was applied to the entire shaved area.

FIG. 5 is a photograph showing the hair growth of C3H mice in which hair growth agent R as a comparative control solution was applied to the entire shaved area.

FIG. 6 is a photograph showing the hair growth of C3H mice in which hair growth agent I as a comparative control solution was applied to the entire shaved area.

FIG. 7 is a photograph showing the hair growth of C3H mice in which hair growth agent G as a comparative control solution was applied to the entire shaved area.

BEST MODE FOR CARRYING OUT THE INVENTION

[0038] Herbal medicine mainly refers to medicinal herbs that have been used as natural medicines over the long history of mankind, and the main ingredients of this herbal medicine are herbal ingredients. The hair-growth component-containing nanoparticle according to the present invention is obtained by encapsulating a crude drug component having a hair-growth effect in a biocompatible polymer to form a nano-sized particle. This nanoparticle can also prevent pores and scalp surface force deep in the scalp. It can be suitably used as a hair restorer material because it allows the herbal components to reach the deep scalp and gradually release the hair growth component from the nanoparticles in the deep scalp. .

[0039] The biocompatible polymer used in the present invention is desirably biocompatible with low irritation to the living body and low in toxicity, and is biodegradable after being decomposed and metabolized. Further, it is preferably a particle that continuously and gradually releases the encapsulated drug. As such a material, in particular, polylactic acid / glycolic acid copolymer (PLGA) can be suitably used. It is known that PLGA can contain a drug and can be stored for a long time while retaining the efficacy of the drug. Furthermore, the hydrolysis of PLGA's 'long-term half-life' suggests that it can be sustainedly released in units of several days.

[0040] The molecular weight of PLGA is preferably in the range of 5,000 to 200,000, and more preferably in the range of 15,000 to 25,000. The composition ratio of lactic acid to glycolic acid may be 1:99 to 99: 1, but glycolic acid is preferably 0.333 to lactic acid 1. In addition, PL GA having a content of lactic acid and dalicholic acid in the range of 25% to 65% by weight is preferably used because it is amorphous and soluble in an organic solvent such as acetone. .

[0041] When encapsulating a water-soluble hair-growth component, the surface of PLGA is made of polyethylene glycol.

Modification with (PEG) is preferable because the affinity between the crude drug component and PLGA is improved and encapsulation becomes easy. Other biocompatible polymers include polyglycolic acid (PGA), polylactic acid (PLA), polyaspartic acid, and the like. In addition, these copolymers such as aspartic acid / lactic acid copolymer (PAL) or aspartic acid / lactic acid / glycolic acid copolymer (PALG) may be used. It may have a group to obtain.

[0042] Other biocompatible polymers include polyalkylenes such as polyamide, polycarbonate, and polyethylene, polypropylene, polyethylene glycol, polyethylene oxide, polyethylene terephthalate, polybulal alcohol, polybull ether, and polybull ester. Such polybulu compounds, polymers of acrylic acid and methacrylic acid, cellulose and other polysaccharides, and peptides or proteins, or copolymers thereof. Examples include polymers or mixtures.

[0043] The herbal components included in the hair-growth component-containing nanoparticles of the present invention include hair matrix cell activators, anti-inflammatory agents, androgen antagonists, blood circulation promoters, bactericidal and antibacterial agents, and the like. And various herbal medicine components. The hair matrix active agent acts directly on hair matrix cells and hair root cells, or increases ATP, which is an energy source for cell division, to activate cell division. Such hair matrix activators include panthenol, pantothenic acid lucum, pantothenic acid ethyl, pantothel ether, and other panthenol derivatives, hinokitiol, potassium aspartate, pentadecanoic acid glyceride, photosensitizer 301, N Acetyl-L-methionine, 5-mono-trogoiacol, mono-trogoiacol sodium, chlorhexidine dalconate, biotin, netacanal, chixenin ginseng, taisou extract, placenta extract, carrot extract, royal jelly extract, garlic component, etc. Is mentioned.

[0044] An anti-inflammatory agent suppresses inflammation of the scalp and suppresses dandruff and itching. Such anti-inflammatory agents include β-glycyrrhetinic acid and its derivatives, fat-soluble glycyrrhetinic acids, glycyrrhizic acid derivatives such as glycyrrhizic acid and dipotassium glycyrrhizinate, monoammoyl glycyrrhizinate, diphenhydramine hydrochloride, hydrocortisone acetate, brednisolone, salicylic acid , Azulene, guaiazulene, licorice extract, age extract, argon extract, shikon extract, power walnut extract, kikiyou extract, kiyonin extract, gardenia extract, kumana extract, gentian extract, comfrey extract, hawthorn extract, birch extract, cicada mushroom extract, Examples include zeaoi extract, tounin extract, bamboo leaf extract, and bi bamboo leaf extract.

[0045] A male hormone antagonist, like a 5a reductase inhibitor, suppresses the activity of male hormones that slow down the division of hair matrix cells. Examples of such male hormone antagonists include estradiol, ethynyl estradiol, spironolatatone, oxendron, jetinorestino lestrone, epitestosterone, estrone, cyproterone acetate, 11 α-hydroxyprogesterone, flutamide, 3 deoxyadenosine , Magnumone acetate, hop extract, peppermint extract, thiodi extract, quina extract, aloe extract, salamander extract, ginseng extract and the like. [0046] The blood circulation promoter increases blood flow by dilating capillaries and promotes nutrient supply to the hair papilla. Such blood circulation promoters include nicotinic acid derivatives such as nicotinic acid and -cotinamide, benzil nicotinate, cephalanthin, carbamine chloride, acetylcholine, _Ί oryzanol, cerretin, cromakalim, nicorandil, pinacidil , Phthalides, dialkylmonoamine derivatives, yew extract, force honey kiss, toki extract, citrus extract, rosemary extract, assembly extract, bevana extract, pepper tincture, chimpi extract, ginger tincture, carrot extract, ginger root extract, Examples include medicinal extract and juice extract.

[0047] The bactericidal agent prevents the growth of various germs that have an adverse effect on hair growth. Examples of such fungicides include hinokitiol, isopropylmethylphenol, menthol, salicylic acid, benzalkonium chloride, otatovilox, black mouth hexidine, zinc pyrithione, potassium sorbate, biosol, kudin extract, muclojekis, ovata extract, etc. It is

[0048] Among the herbal medicine components, it is preferable to encapsulate a hair matrix cell active agent or an anti-inflammatory agent that acts directly on hair matrix cells or hair papilla present in the deep part of the scalp. In particular, hinokitiol and β-glycyrrhetinic acid are suitable as herbal components to be encapsulated in nanoparticles because their effects are improved by supplying them to the deep part of the scalp as described later. Hinokitiol is a substance contained in Aomori Hiba, Taiwan Hinoki, etc., and has both bactericidal and antibacterial effects in addition to cell activity. β-Dalicyrrhetinic acid is one of the representative components of licorice, a kind of herbal medicine, and is known to have a wide range of physiological activities such as anti-ulcer activity and detoxification activity in addition to anti-inflammatory activity.

[0049] The higher the encapsulation rate of these herbal medicine components in the nanoparticles, the higher the content of the herbal medicine components, which is preferable. However, the reason for manufacturing is increased in proportion to the encapsulation rate. Therefore, it becomes difficult for the nanoparticles to reach the deep part of the scalp. Therefore, the encapsulation rate of the crude drug component is preferably 1% by weight to 20% by weight with respect to the biocompatible polymer, and more preferably 5% by weight to 20% by weight. In addition, it is possible to obtain a sufficient hair-growth effect even if only one of the above herbal medicine ingredients is encapsulated, but if multiple ingredients with different efficacy and action mechanism are encapsulated in particular, the synergistic effect of each ingredient Promotion of hair growth effect can be expected. In addition, herbal medicine Along with this, it is possible to seal hair-growth ingredients other than herbal ingredients, such as minoxidil-vitamin derivatives.

[0050] Generally, since the pore diameter is about 200 m, the hair-growth component-containing nanoparticle of the present invention is not particularly limited as long as it has an average particle size of less than lOOOnm, but it penetrates deep into the scalp. In order to enhance the effect, it is preferable to have an average particle size of 300 nm or less. Also, the skin cell size is 15, OOOnm, and the skin cell spacing is fluctuating between shallow and deep skin, but it is considered to be around 70nm, so the average particle size of nanoparticles is 200nm or less. By doing so, it becomes a nanoparticle that penetrates from the part other than the pores to the deep part of the scalp. On the other hand, as described above, the smaller the particle size of the nanoparticles, the lower the encapsulation rate. Therefore, the average particle size is preferably 30 nm or more.

[0051] The nanoparticles obtained as described above can be formed into aggregated particles that can be redispersed when powdered by freeze-drying or the like (can be composited). In addition, even when combined by applying compressive force and shearing force by fluidized bed dry granulation method or dry mechanical particle compositing method (for example, Mechano-Fusion System AMS (manufactured by Hosokawa Micron Co., Ltd.)) Can be integrated in a separable state. This makes it easy to handle agglomerated particles in which nanoparticles are collected before use, and it becomes composite particles that return to the nanoparticles and restore properties such as high reactivity when exposed to moisture during use.

[0052] When the encapsulated hair-growth component is water-soluble, once the encapsulated hair-growth component leaks to the surface of the nanoparticle, it is dissolved again in the surrounding water. If this water is removed by lyophilization or the like, the hair-growth component is reduced by that amount, and the encapsulation rate varies. Therefore, it is preferable to combine organic or inorganic substances so that they can be redispersed, and to dry them with the nanoparticles as they are without removing the water in which the hair-growth ingredients are dissolved. For example, by applying sugar alcohol or sucrose, it is possible to effectively prevent variation in the encapsulation rate, and sugar alcohol or the like can be used as an excipient to improve the handleability of the nanoparticles. Examples of the sugar alcohol include mannitol, trenorose, sorbitol, erythritol, manolecitose, xylitol, etc. Among them, trehalose is particularly preferable. Trehalose is also preferable from the viewpoint of improving the hair-growth effect by moisturizing action.

[0053] Further, during the compounding, vitamins and prosthesis are further added to the surface of the composite particle (nanocomposite). By attaching a drug such as a vitamin, a fast-acting drug that dissolves the composite particle surface force immediately after permeation of the scalp can be applied, in addition to the hair-growth component that is released gradually from the nanoparticle force. With such a configuration, PLGA composite particles can be given even quicker permeability (fast-acting penetrating action). In addition, if the drug to be combined is water-soluble, it is preferable because it dissolves quickly and exhibits a fast-acting effect.

[0054] Such drugs include vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, vitamin, vitamin K, vitamin ビタミン, vitamin U, carcin, ferulic acid, y-oryzanol, a-ribo. Acid, orotic acid and their components or derivatives retinol acetate, riboflavin acetate, pyridoxine dioctanoate, L-ascorbic acid dipalmitate, L-ascorbic acid-2-sodium sulfate, L-ascorbic acid phosphate, DL—Tocopherol L Ascorbic acid phosphoric acid diester dipotassium, pantotulletil etherenore, D pantoteninorenoreconole, acetinorepantoteninorenoinoatenore, enoregonoreciferronore, colecanoreciferonore, acetic acid dl—a—tocopheronole, -cotic acid One α- tocopherol, succinate monobasic _alpha - vitamin or vitamin derivatives such as tocopherol, or a water-soluble pro-vitamins, e.g., VC- PMG (Asuko ascorbyl Mg water soluble phosphate), AA2G (Asukorubin acid Darukoshido), panthenol (Water-soluble vitamin B),

Five

L Cystein and the like.

[0055] Alternatively, chitosan that enhances mucoadhesion may be combined on the surface of the nanoparticles, or phospholipids (lecithin / phosphatidylcholine) may be combined to increase scalp affinity. In addition, by combining polyethylene glycol (PEG), it becomes easier to dissolve in water and enhances the permeability to the scalp. Furthermore, by combining talc, the slipperiness of the particles can be improved and the feeling on the skin can be enhanced.

[0056] The hair-growth component-containing nanoparticles produced in this way produce an effective hair-growth effect when used as a hair-growth agent dispersed in a dispersion. However, PLGA is hydrolyzed when mixed with moisture, and the nanoparticle transport performance is lost in a short period of time. Therefore, when using as such a hair restorer, it is possible to store the dispersion and powder in separate containers and store them in a predetermined amount immediately before use. preferable [0057] As the dispersion, it is necessary to use hair-grown component-containing nanoparticles that are uniformly dispersed in a short time and highly safe to the human body, and a mixture of water and ethanol is preferably used. In addition, since the aggregation of nanoparticles occurs when the volume ratio of ethanol to water is 1Z2 or more, it is preferably in the range of 1/10 to 3/10.

[0058] In addition, in order to promote the hair growth and hair growth effects, it is necessary to use a combination of hair growth ingredients having various action mechanisms. Therefore, by combining one or more of the above-mentioned herbal medicine components in the dispersion, the hair-growth component in the dispersion adsorbed on the surface of the nanoparticles is simultaneously absorbed in the deep scalp as the nanoparticles penetrate into the deep scalp. Therefore, more hair-growth ingredients can be supplied to the hair matrix cells and hair papilla. Among the hair-growth ingredients, anti-inflammatory agents, bactericidal and antibacterial agents that also act on the scalp surface, moisturizers, local stimulants, antiseborrheic agents that act on the scalp to further enhance the hair-growth effect, or as described above When vitamins and vitamin derivatives are added, the immediate effect of these drugs on the scalp surface is ensured, and in the deep scalp, the effect of hair growth over a long period of time can be achieved by gradual release of herbal components from hair-growth component-containing nanoparticles. Can be expected.

[0059] The moisturizing agent adjusts the hair growth environment by making the scalp dry and soft. Such moisturizers include trehalose, mayifa, sorbitol, soluble collagen, glycerin, chondroitin sulfate, tuberose polysaccharides, cordyceps, trisaccharide, urea, biohyaluronic acid, hyaluronic acid, vitamin C phosphate calcium Salt, Sodium pyrrolidone carboxylate, Propylene glycol, Buttonpi extract, Aroche extract, Placenta extract, Enmeiso extract, Hypericum extract, Oat extract, Barley extract, Orange extract, Seaweed extract, Cucumber extract, Gobouex , Shiitake extract, zio extract, duke extract, bean extract, grape leaf extract, prune extract, loofah extract, maikai extract, mini sasanishiki, lily extract, apple extract, etc. I can get lost.

[0060] The local stimulant has effects such as activation of scalp metabolism, strengthening of the scalp, and prevention of itching. Examples of such local stimulants include camphor, capsicum tincture, norcolic acid-lylamide, menthol, pepper tincture, Dutch power rachi extract, cantharis tincture, salamander extract, chili oil, and radish radish extract. . [0061] The antiseborrheic agent excludes excessively secreted sebum that promotes hair loss, or suppresses sebaceous gland activity. Examples of such antiseborrheic agents include cashew extract, odoricosou extract, iow, thixolone, vanside, polysorbates, and lecithin.

[0062] In the dispersion, any component other than the hair-growth component, for example, alcohols such as ethanol and polyhydric alcohol, celluloses, surfactants, fats and oils, water-soluble polymers, colorants, and fragrances In addition, ultraviolet absorbers, preservatives and the like can be blended within a range that does not hinder the effects of the present invention.

[0063] When the hair growth agent thus obtained is applied to the scalp, the nanoparticles efficiently penetrate into the hair roots inside the pores where the hair matrix cells and hair papilla are present. That is, a droplet containing nanoparticles applied to the scalp is likely to move in a direction in which the interfacial energy decreases (direction of penetrating into the scalp) because the surface tension is reduced by the nanoparticles. Furthermore, adsorption from the inside of the scalp occurs with respect to the nanoparticles or water in the droplets, so that the nanoparticles are efficiently delivered to the hair root. The herbal medicine components encapsulated in the nanoparticles are gradually released over a long period at the hair root.

[0064] The method for producing the hair-growth component-containing nanoparticles of the present invention is not particularly limited as long as the target substance can be processed into particles having a particle diameter less than lOOOnm. It is highly preferred to use a crystallization method. Spherical crystallization is a method in which spherical crystal grains can be designed and processed by directly controlling their physical properties by controlling the crystal formation and growth process in the final process of compound synthesis. Spherical crystallization methods can be divided into spherical granulation method (SA method) and emulsion solvent diffusion method (ESD method) according to the difference in the formation of crystallized crystals' aggregation mechanism.

[0065] The SA method is a method of forming a spherical granulated crystal by precipitating drug crystals using two kinds of solvents. Specifically, first, a poor solvent that hardly dissolves the target drug and a good solvent that can dissolve the drug well and can be mixed and diffused in the poor solvent are prepared. Then, the drug solution dissolved in the good solvent is dropped into the poor solvent with stirring. At this time, drug crystals are precipitated in the system by utilizing the transition from a good solvent to a poor solvent and a decrease in solubility due to temperature effects. [0066] Further, when a small amount of liquid (liquid cross-linking agent) that has affinity for the drug and is not miscible with the poor solvent is added to the system, the liquid cross-linking agent is liberated. And a bridge | crosslinking is formed between crystals and a crystal | crystallization begins to aggregate non-randomly by interface tension and capillary force. This state is called “Fanikiyura one state”.

[0067] When a mechanical shearing force is further applied to the system in the Fanikiyura state, the aggregated crystals are consolidated into a substantially spherical granulated product. This state is referred to as a “quickly one state”. The final spherical granulated crystals are formed by randomly coalescing the granules in the capillary state (nanoparticle formation process).

[0068] Unlike the force SA method, which is a method using two types of solvents, the ESD method forms an emulsion and then crystallizes the drug into a spherical shape by utilizing the mutual diffusion between the good solvent and the poor solvent. Is the method. Specifically, first, a drug solution dissolved in a good solvent is dropped into the poor solvent with stirring. At this time, since the drug and the good solvent have an affinity, the transfer of the good solvent to the poor solvent is delayed, and emulsion droplets are formed. Then, due to cooling of the emulsion droplets and mutual diffusion of the good solvent and the poor solvent, the solubility of the drug in the emulsion droplets decreases, and the spherical crystal particles of the drug precipitate and grow while maintaining the shape of the emulsion droplets. Do

[0069] In the above spherical crystallization method, nanoparticles can be formed by a physicochemical method, and the resulting nanoparticles are almost spherical. Can be formed as easily as necessary. Thereafter, the organic solvent, which is a good solvent, is distilled off under reduced pressure (solvent distillation step) to obtain a hair-growth component-containing nanoparticle powder. Then, the obtained powder is composited as it is or by freeze-drying as necessary (composite step) to form composite particles, which are then filled into a container to obtain hair-growth component-containing nanoparticles.

[0070] The types of the good solvent and the poor solvent, and the type of the liquid crosslinking agent are determined according to the type of the target drug and the like, and are not particularly limited. Since it is used as a raw material for hair growth agents that are applied directly to the scalp, it is necessary to use a material that is highly safe for the human body and has a low environmental impact. As such a poor solvent, for example, a polybulal alcohol aqueous solution is preferably used, and as a good solvent, for example, a mixed solution of acetone and ethanol is preferably used. Surplus polyvinyl alcohol When the alcohol remains, a step (removal step) of removing polyvinyl alcohol by centrifugation or the like is provided after the solvent distillation step.

[0071] The concentration of the polyvinyl alcohol aqueous solution, the mixing ratio of acetone and ethanol, the conditions at the time of crystal precipitation, and the method of applying mechanical shear force are not particularly limited. If determined appropriately according to the particle size of the granulated crystals (in the nano-order case in the present invention), the concentration of the polyvinyl alcohol aqueous solution is higher! On the other hand, the redispersibility in water after drying is improved, but when the concentration of the polyvinyl alcohol aqueous solution exceeds a predetermined level, the viscosity of the poor solvent is increased, which adversely affects the diffusibility of the good solvent. Therefore, although depending on the degree of polymerization and saponification of polyvinyl alcohol, when a removal step is provided after the nanoparticle formation step, 0.1% to 10% by weight is preferable, and about 2% is more preferable. If no removal process is provided, it is preferable to use 0.5% by weight or less.

[0072] It should be noted that the present invention is not limited to the above-described embodiments, and various modifications are possible within the scope of the claims, and the technical means disclosed in different embodiments are appropriately combined. Embodiments obtained in this manner are also included in the technical scope of the present invention. Example 1

[0073] The method for producing the hair-growth component-containing nanoparticles of the present invention was studied. A 2% by weight aqueous solution of polyvinyl alcohol (PVA: manufactured by Kuraray Co., Ltd.) was prepared and used as a poor solvent. A biocompatible polymer, lactic acid / glycolic acid copolymer (PLGA: PLGA7520, manufactured by Wako Pure Chemical Industries, Ltd.) j8-glycyrrhetinic acid (manufactured by Alps Pharmaceutical Co., Ltd.) dissolved in 20 mL of acetone and then dissolved in 10 mL of ethanol lOOmg was added and mixed to make a good solvent. This good solvent was added dropwise to the previous poor solvent at 40 ° C and 400 rpm at a constant speed (4 mLZ), and β-darlicylretinic acid-encapsulated PLGA nanosphere was suspended by diffusion of the good solvent into the poor solvent. A liquid was obtained.

[0074] Subsequently, stirring was continued at 40 ° C and lOOrpm under reduced pressure. After distilling off the organic solvent for 1 hour, excess polybutyl alcohol was removed by centrifugation (20,000 rpm, 20 ° C, 20 minutes). Removed. After removing the supernatant, the precipitate was resuspended in purified water and lyophilized. One day later, the average particle size is 200ηπ! PLGA composite nanoparticle dry powder with good redispersibility in water of ~ 300nm was obtained. Encapsulation rate of | 8-glycyrrhetinic acid in PLGA nanoparticles using a spectrophotometer The quantitative amount was 8.5%.

Example 2

[0075] 5 wt ^_0/0 of poly Bulle alcohol (PVA: Kurarene made earth) aqueous solution was prepared and a poor solvent.

Lactic acid / glycolic acid copolymer (PLGA: PLGA7 520, manufactured by Wako Pure Chemical Industries), a biocompatible polymer, is dissolved in 20 mL of acetone, and then 300 mg of hinokitiol (manufactured by Takasago Fragrance) dissolved in 10 mL of ethanol is added and mixed. A good solvent was used. This good solvent is added dropwise to the previous poor solvent at 40 ° C and 400 rpm at a constant speed (4 mLZ), and a suspension of hinokitiol-encapsulated PLGA nanospheres is obtained by diffusion of the good solvent into the poor solvent. It was.

[0076] Subsequently, stirring was continued under reduced pressure at 40 ° C and lOOrpm, and after distilling off the organic solvent for 40 minutes, an excess of polybutyl alcohol was removed by centrifugation (20,000 rpm, 20 ° C, 20 minutes). Was removed. After removing the supernatant, the precipitate was resuspended in purified water and centrifuged, and then the supernatant was removed again, and the resulting precipitate was resuspended in about 50 mL of purified water. Thereafter, a previously prepared trehalose aqueous solution (prepared by dissolving 2 g of trehalose (manufactured by Hayashibara) in 8 mL of purified water) was added, mixed uniformly, and then lyophilized. One day later, a dry powder of PLGA composite nanoparticles having an average particle size of 200 nm to 300 nm and good redispersibility in water was obtained. Using a spectrophotometer, the entrapment ratio of hinokitiol in PLG A nanoparticles was determined to be 6.6%.

Example 3

[0077] 7 wt ^_0/0 of poly Bulle alcohol (PVA: Kurarene made earth) aqueous solution was prepared and a poor solvent.

Lactic acid / glycolic acid copolymer (PLGA: PLGA7 520, manufactured by Wako Pure Chemical Industries, Ltd.), a biocompatible polymer, is dissolved in 20 mL of acetone, and then 9.5 mL of capsicum tincture (manufactured by Maruzen Pharmaceutical) is added. Solvent was used. This good solvent is added dropwise to the previous poor solvent at 40 ° C and 400 rpm at a constant speed (4 mLZ), and the suspension of PLGA nanospheres filled with red pepper tincture by diffusion of the good solvent into the poor solvent. Got.

[0078] Subsequently, stirring was continued under reduced pressure at 40 ° C and lOOrpm, and after distilling off the organic solvent for 40 minutes, an excess of polybutyl alcohol was removed by centrifugation (20,000 rpm, 20 ° C, 20 minutes). Was removed. After removing the supernatant, the precipitate was resuspended in purified water and centrifuged, and then the supernatant was removed again, and the resulting precipitate was resuspended in about 50 mL of purified water. Then, add a pre-prepared trehalose aqueous solution (prepared by dissolving 2 g of trehalose (manufactured by Hayashibara) in 8 mL of purified water) And then lyophilized. One day later, a dry powder of PLGA composite nanoparticles having an average particle size of 200 nm to 300 nm and good redispersibility in water was obtained. Using a spectrophotometer, the encapsulation rate of red pepper tincture in PLG A nanoparticles was determined to be 1.8%.

Example 4

[0079] 10 weight ^_0/0 of poly Bulle alcohol (PVA: Kurarene made earth) aqueous solution was prepared and a poor solvent. Lactic acid / glycolic acid copolymer which is a biocompatible polymer (PLGA: PLGA 7520 manufactured by Wako Pure Chemical Industries, Ltd.) After dissolving 1 g in acetone 20 mL, benzoyl nicotinate (manufactured by Sakai Chemical) 0.13 mL, ethanol 10 mL The mixture was added and mixed to make a good solvent. This good solvent is added dropwise to the previous poor solvent at 40 ° C and 400 rpm at a constant speed (4 mLZ), and benzil nicotinate-encapsulated PLGA nanosphere is suspended by diffusion of the good solvent into the poor solvent. A liquid was obtained.

[0080] Subsequently, stirring was continued under reduced pressure at 40 ° C and lOOrpm, and after distilling off the organic solvent for 40 minutes, excess polybuty alcohol was removed by centrifugation (20,000 rpm, 20 ° C, 20 minutes). Was removed. After removing the supernatant, the precipitate was resuspended in purified water and centrifuged, and then the supernatant was removed again, and the resulting precipitate was resuspended in about 50 mL of purified water. Thereafter, a previously prepared trehalose aqueous solution (prepared by dissolving 2 g of trehalose (manufactured by Hayashibara) in 8 mL of purified water) was added, mixed uniformly, and then lyophilized. One day later, a dry powder of PLGA composite nanoparticles having an average particle size of 200 nm to 300 nm and good redispersibility in water was obtained. Using a spectrophotometer, the encapsulation rate of benzyl nicotinate in PLGA nanoparticles was quantified and found to be 8.9%. Example 5

[0081] 0.5 wt ^_0/0 less than poly Bulle alcohol (PVA: Kurarene made earth) into an aqueous solution was prepared poor solvent medium. Lactic acid 'glycolic acid copolymer (PLGA: PLGA7520 manufactured by Wako Pure Chemical Industries, Ltd.), a biocompatible polymer, is dissolved in 20 mL of acetone, and then dissolved in 10 mL of ethanol. J8 —Darityrrhetinic acid (manufactured by Alps Pharmaceutical Industries) Were mixed to make a good solvent. This good solvent was dropped into the above poor solvent at 40 ° C and 400 rpm at a constant speed (4 mLZ), and the good solvent was diffused into the poor solvent, and j8-glycyrrhetinic acid-encapsulated PLGA nanospheres were added. A suspension of was obtained.

[0082] Subsequently, the organic solvent was distilled off while continuing to stir at 40 ° C and lOOrpm under reduced pressure. At the same time as the evaporation of the solvent was started, 40 mL of purified water was added dropwise to this suspension over 4 mLZ. About 1 After evaporating the solvent for a time, the suspension was filtered. Thereafter, a pre-prepared trehalose aqueous solution (prepared by dissolving 2 g of trehalose (manufactured by Hayashibara) in 8 mL of purified water) was added, mixed uniformly, and lyophilized. One day later, the average particle size is 200ηπ! A PLGA composite nanoparticle dry powder having a good redispersibility in water of ˜300 nm was obtained.

Example 6

[0083] 0.5 wt ^_0/0 less than polyvinyl alcohol (PVA: Kurarene made earth) into an aqueous solution was prepared poor solvent medium. Lactic acid 'glycolic acid copolymer (PLGA: Wako Pure Chemicals PLGA7520) lg, which is a biocompatible polymer, is dissolved in 20 mL of acetone, and then 300 mg of hinokitiol (manufactured by Takasago Fragrance) dissolved in 10 mL of ethanol is added and mixed. A good solvent was used. This good solvent is dropped into the above poor solvent at 40 ° C and 400 rpm at a constant speed (4 mLZ), and a suspension of hinokitiol-encapsulated PLGA nanospheres is obtained by diffusion of the good solvent into the poor solvent. It was.

[0084] Subsequently, the organic solvent was distilled off while continuing to stir at 40 ° C and lOOrpm under reduced pressure. At the same time as the evaporation of the solvent was started, 40 mL of purified water was added dropwise to this suspension over 4 mLZ. After the solvent was distilled off for about 1 hour, the suspension was filtered. Thereafter, a pre-prepared trehalose aqueous solution (prepared by dissolving 2 g of trehalose (manufactured by Hayashibara) in 8 mL of purified water) was added, mixed uniformly, and lyophilized. One day later, the average particle size is 200ηπ! A PLGA composite nanoparticle dry powder having a good redispersibility in water of ˜300 nm was obtained.

Example 7

[0085] 0.5 wt ^_0/0 less than polyvinyl alcohol (PVA: Kurarene made earth) into an aqueous solution was prepared poor solvent medium. Lactic acid 'glycolic acid copolymer (PLGA: Wako Pure Chemicals PLGA7520) lg, which is a biocompatible polymer, is dissolved in 20 mL of acetone, and then 9.5 mL of chili pepper tincture (manufactured by Maruzen Pharmaceutical) is added and mixed with a good solvent. did. This good solvent is added dropwise to the previous poor solvent at 40 ° C and 400 rpm at a constant rate (4 mLZ), and a suspension of pepper tincture-encapsulated PLGA nanospheres is formed by diffusion of the good solvent into the poor solvent. Obtained.

[0086] Subsequently, the organic solvent was distilled off while stirring at 40 ° C under reduced pressure at lOOrpm. At the same time as the evaporation of the solvent was started, 40 mL of purified water was added dropwise to this suspension over 4 mLZ. After the solvent was distilled off for about 1 hour, the suspension was filtered. Then, add a pre-prepared trehalose aqueous solution (prepared by dissolving 2 g of trehalose (produced by Hayashibara) in 8 mL of purified water) After uniform mixing, it was lyophilized. One day later, the average particle size is 200ηπ! A PLGA composite nanoparticle dry powder having a good redispersibility in water of ˜300 nm was obtained.

Example 8

[0087] 0.5 wt ^_0/0 less than polyvinyl alcohol (PVA: Kurarene made earth) into an aqueous solution was prepared poor solvent medium. Lactic acid 'glycolic acid copolymer (PLGA: Wako Pure Chemicals PLGA7520) lg, which is a biocompatible polymer, is dissolved in acetone 20mL, then benzoyl nicotinate (manufactured by Sakai Chemical) 0.13mL and ethanol 10mL are added. Mixed to make a good solvent. This good solvent was added dropwise to the previous poor solvent at 40 ° C and 400 rpm with a constant speed (4 mLZ), and benzil nicotinate-encapsulated PLGA nanosphere was suspended by diffusion of the good solvent into the poor solvent. I got a turbid liquid

[0088] Subsequently, the organic solvent was distilled off while continuing to stir at 40 ° C and lOOrpm under reduced pressure. At the same time as the evaporation of the solvent was started, 40 mL of purified water was added dropwise to this suspension over 4 mLZ. After the solvent was distilled off for about 1 hour, the suspension was filtered. Thereafter, a pre-prepared trehalose aqueous solution (prepared by dissolving 2 g of trehalose (manufactured by Hayashibara) in 8 mL of purified water) was added, mixed uniformly, and lyophilized. One day later, the average particle size is 200ηπ! A PLGA composite nanoparticle dry powder having a good redispersibility in water of ˜300 nm was obtained.

Example 9

[0089] 0.5 wt ^_0/0 less than poly Bulle alcohol (PVA: Kurarene made earth) into an aqueous solution was prepared poor solvent medium. Lactic acid 'glycolic acid copolymer (PLGA: PLGA7520 manufactured by Wako Pure Chemical Industries, Ltd.), a biocompatible polymer, is dissolved in 20 mL of acetone, and then dissolved in 10 mL of ethanol. J8 —Darityrrhetinic acid (manufactured by Alps Pharmaceutical Industries) Were mixed to make a good solvent. This good solvent was dropped into the above poor solvent at 40 ° C and 400 rpm at a constant speed (4 mLZ), and the good solvent was diffused into the poor solvent, and j8-glycyrrhetinic acid-encapsulated PLGA nanospheres were added. A suspension of was obtained.

[0090] Subsequently, the organic solvent was distilled off while continuing to stir at 40 ° C and lOOrpm under reduced pressure. At the same time as the evaporation of the solvent was started, 40 mL of purified water was added dropwise to this suspension over 4 mLZ. After the solvent was distilled off for about 1 hour, the suspension was filtered. Then, dl-α-tocopherol lg acetate and 2 g of trehalose (produced by Hayashibara) as an excipient are dissolved in 10 ml of purified water. And the beaker was pre-frozen under ultrasound (ie, cooled at 40 ° C. for 15 minutes) and then lyophilized at −80 ° C. at lOtorr. As a result, β-darlicylretinic acid-encapsulated PLGA composite nanoparticles having dl-a tocopherol acetate on the surface were obtained.

Example 10

[0091] By using the same biocompatible polymer polymer (polyethylene glycol-modified PLGA, polylactic acid (PLA)) other than the above-mentioned PLGA by the same operation as in Examples 1 to 9, 13 darityl retinoic acid, hinokitiol, red pepper When tincture and benzil nicotinate encapsulated nanoparticles were prepared, a nanoparticle dry powder with an average particle size of 200 nm to 300 nm and good redispersibility in water could be prepared.

Example 11

[0092] A scalp penetration test was carried out by the modified Bronoff diffusion chamber method using the hair-growth component-containing PLGA nanoparticles prepared according to the methods of Examples 1 and 2 above. The test solution was an aqueous dispersion of β-glycyrrhetinic acid-encapsulated PLGA nanoparticles (nanoparticle concentration = 0.4%, β-daritylretinoic acid concentration = 0.036%), an aqueous dispersion of hinokitiol-encapsulated PLGA nanoparticles (nano A particle dispersion = 0.6%, hinokitiol concentration = 0.036%) was used, and a buffer dispersion (concentration 0.036%) of j8-glycyrrhetinic acid and hinokitiol was used as a comparative control solution.

[0093] The steps of the modified Bronov diffusion chamber method will be described below.

1) Subject (40-year-old woman's forehead) Remove scalp and remove lmm of subcutaneous tissue.

2) Divide the scalp piece into 8 pieces in the vertical direction.

3) Wrap the cut side of the scalp piece with biocompatible TG polymer.

4) Install in the sterilized modified Bronov diffusion chamber housing.

5) Place the chamber in a 24-well microplate and place serum-free DMEM medium.

6) Aerate 5% carbon dioxide to maintain the pH at 7.2-7.3.

7) Add the test solution and control solution to the surface side of 20 μLZcm ² scalp.

8) After 4 hours of application, a scalp piece is removed.

9) Cut the pore cross section of the scalp piece into 4 m thin (vertical direction). 10) Photograph the scalp permeability of the hair growth component with a fluorescence microscope (excitation wavelength: 480 nm) and scan the fluorescence intensity.

The results are shown in FIG. 1 and FIG.

[0095] Figure 1 shows the fluorescence intensity dull of the scalp 4 hours after application of β-glycyrrhetinic acid PBS dispersion (Figure 1 (Α)) or β-glycyrrhetinic acid-encapsulated PLGA nanoparticle aqueous dispersion (Figure 1 (Β)). FIG. As is apparent from FIG. 1, when the aqueous dispersion of PL8 nanoparticles encapsulated with j8-glycyrrhetinic acid of the present invention was applied, the scalp surface was thin, and deep fluorescence was observed toward the deep part of the scalp, and the fluorescence intensity was also observed. Was also observed deep in the scalp. On the other hand, when a comparative control solution in which | 8-glycyrrhetinic acid was simply dispersed was applied, fluorescence was observed only on the scalp surface, and the fluorescence intensity was weak. From the above, it was confirmed that by encapsulating β-darlicyl retinoic acid in PLGA nanoparticles, it penetrates to a high concentration of human scalp pore depths of 0.47-0.88 mm.

[0096] Fig. 2 is a cross-sectional photograph of the scalp 4 hours after application of hinokitiol PBS dispersion (Fig. 2 (A)) or hinokitiol-encapsulated PLGA nanoparticle aqueous dispersion (Fig. 2 (B)). In FIG. 2, as in FIG. 1, when the aqueous dispersion of hinokitiol-encapsulated PLGA nanoparticles of the present invention was applied, the scalp surface was thin, but deep fluorescence was observed toward the deep part of the scalp, and the fluorescence intensity was also observed. Also strongly observed over the scalp. On the other hand, when a comparative solution in which hinokitiol was simply dispersed was applied, fluorescence was observed only on the scalp surface, and the fluorescence intensity was weak. From the above, it was confirmed that encapsulating hinokitiol in PLGA nanoparticles penetrates into human scalp with a high concentration from 0.666 to L 39mm.

Example 12

[0097] In Example 11, the hair growth effect of β-daricylretinoic acid-encapsulated PLGA nanoparticles and hinokitiol-encapsulated PLGA nanoparticles that had good scalp permeability was evaluated using C3H mice. This C3H mouse is characterized by the fact that the hair cycle enters a resting state when the hair is cut, and it has been shown that hair does not grow for 15 days after cutting.

[0098] The procedure for evaluating the hair growth effect using C3H mice is shown below. The test solution is an aqueous dispersion of β-gallic retinoic acid-encapsulated PLGA nanoparticles (test solution A; nano-particle concentration = 0.5%, β-glycyrrhetinic acid concentration = 0.045%), water of hinokitiol-encapsulated PLGA nanoparticles. Dispersion liquid (test solution B; nanoparticle concentration = 0.5%, hinokitiol concentration = 0.03%) was used as a comparative control solution, 0.045% β-glycyrrhetinic acid aqueous solution, 0.03% hinokitiol aqueous solution, Commercially available hair restorer R (Taisho Pharmaceutical Co., Ltd.), hair restorer 1 (Lion Corp.), and hair restorer G (Daiichi Pharmaceutical Co., Ltd.) were used.

1) Cut the lower half of C3H mice with clippers.

2) Shaving with a shaver.

3) Apply 20 LZcm ^{2 of} test solution or control solution to the entire shaved area.

4) Apply once a day at a fixed time every day.

5) Observe hair growth every few days.

The observation results are shown in Figs.

[table 1]

Figures 3 to 7 are photographs showing the hair growth of C3H mice with test solutions A and B and hair growth agents R, I, and G applied to the entire shaved area. Table 1 shows the observation of hair growth. The results are summarized. In Table 1, X represents a state in which hair growth has not occurred, Δ represents a state in which hair has grown from a very small amount to a slight amount, and ◯ represents a state in which hair growth can be clearly confirmed. As is clear from FIGS. 3 and 4 and Table 1, the mice to which the test solutions A and B containing the hair-growth component-containing nanoparticles of the present invention were applied were applied. After a few days, hair began to grow, although only in a small amount, and hair growth was clearly confirmed 15 days after application. On the other hand, when a comparative control solution in which j8-glycyrrhetinic acid or hinokitiol is dispersed is applied, However, no hair growth was observed.

[0100] In addition, as is apparent from FIGS. 5 to 7 and Table 1, hair growth agent R showed no hair growth after 13 days of application, and only had further hair growth after 15 days of application. It was. In addition, hair growth agent I began to shine thinly 13 days after application, and hair growth was clearly confirmed 15 days after application. In addition, hair growth agent G showed no hair growth even after 15 days of application. As described above, β-glycyrrhetinic acid and hinokitiol are markedly enhanced in hair growth effect by encapsulating in PLGA nanoparticles, and the effect is superior to that of commercially available hair restorer R and hair restorer G. It was confirmed that they were almost equivalent.

[0101] Hair growth agent I is a combination of several types of hair growth components, whereas test solutions A and B are | 8-daricylretinoic acid or hinokitiol alone, respectively. Nevertheless, it is considered that the rapid hair growth effect as described above was obtained as a result of promoting penetration into the pores by forming nanoparticles.

[0102] The difference in hair growth effect between j8-darlicylretinoic acid and hinokitiol was significant when encapsulated in nanoparticles and when encapsulated in non-encapsulated cases. , Β Glycyrrhetinic acid and hinokitiol stay near the scalp surface and do not reach the deep scalp and are metabolized and decomposed soon after application. This is thought to be due to the fact that j8-glycyrrhetinic acid and hinokitiol are gradually released from the nanoparticles that have reached the depth of the scalp, resulting in long-term hair growth effects. In addition, the sebum decomposition effect of lactic acid produced by hydrolyzing PLGA is considered to have a positive effect.

[0103] Establishing a formulation of a dispersion containing other hair-growth ingredients (vitamins, anti-inflammatory, bactericidal, blood circulation promoting ingredients, etc.) that can fully utilize the hair-growth and hair-growth effects of the above-mentioned hair-growth ingredient-encapsulated nanoparticles It was. Examples of prescriptions are shown in Tables 2 and 3.

Example 13

[0104] [Table 2]

Example 14

[0105] [Table 3]

[0106] As a method for producing the dispersion, ethanol-soluble components are gradually added and dissolved at room temperature with stirring, and purified water is added to the solution to make it uniform, followed by filtration. In this dispersion, the β-glycyrrhetinic acid-encapsulated PLGA nanoparticles and hinokitiol-encapsulated PLGA nanoparticles described above can be well dispersed. This makes it possible to apply it as a dissolving hair restorer. In addition, blended in the dispersion The types and blending amounts of the hair-growth components to be applied are merely examples, and may be appropriately set according to the herbal components encapsulated in the nanoparticles and the type of target alopecia.

Industrial applicability

[0107] The hair-growth component-containing nanoparticles of the present invention include a highly safe herbicide component with little side effects as a hair-growth component in a biocompatible polymer. The component-containing nanoparticles penetrate into the pores and deep into the scalp where the surface of the scalp has hair roots, so that the herbal components can reach the deep part of the scalp (hair roots) and the deep part of the scalp (hair roots). Part)), it is possible to obtain highly safe hair-growth component-containing nanoparticles capable of maintaining an excellent hair-growth effect over a long period of time. In particular, it is suitable when a hair matrix active agent such as hinokitiol that acts directly on hair matrix cells and hair papilla present in the deep part of the scalp or an anti-inflammatory agent such as β-glycyrrhetinic acid is used as a crude drug component. Furthermore, if other herbal ingredients such as blood circulation promoters and male hormone antagonists are encapsulated together, it is expected that the hair-growth effect will be improved by the synergistic effect of the components having different action mechanisms.

[0108] In addition, the reason for manufacturing The particle diameter of the nanoparticles increases in proportion to the encapsulation rate of the crude drug component, but the average particle diameter of the nanoparticles is 30 nm or more and 300 nm or less, and hair growth for a biocompatible polymer is performed. Contains 1% to 20% by weight of ingredients, so the average particle size of nanoparticles is limited to the ability to penetrate the pores of the scalp cells other than the pores and pores, while containing hair-growth ingredients It becomes the hair-growth component containing nanoparticle which raised the quantity.

[0109] In addition, as a material for forming nanoparticles, a biocompatible polymer that can be incorporated into a hair-growth component with low irritation to a living organism and is metabolized by being decomposed after administration is used. Can be ensured, and the sustained release of the hair-growth component can be achieved. In particular, when PLGA is used, hydrolysis of PLGA's long-term half-life makes it possible to release it on a monthly basis for several days.

[0110] If the hair-growth component-containing nanoparticles are composited by freeze-drying or the like, they become agglomerated particles that are easy to handle when filled into a container. In addition, if sugar alcohol and vitamins are combined with nanoparticles, the dispersibility and heat resistance of the combined nanoparticles are improved, and even if the hair-restoring ingredient to be encapsulated is water-soluble, it is encapsulated once. Of grown hair growth ingredients Leakage to the particle surface can be prevented, and especially when trehalose is combined with sugar alcohol, the hair-growth effect can be improved by moisturizing action. In addition, when vitamins and vitamin derivatives are combined, the hair-growth effect of herbal ingredients and the hair-growth effect of vitamins act synergistically, and a more remarkable hair-growth effect can be expected.

[0111] Then, the hair-growth component-containing nanoparticles are mixed and dispersed in a predetermined amount with the dispersion immediately before use, and used as a hair-growth agent to produce an effective hair-growth effect. In addition, if a hair-growth component is also added to the dispersion, it is adsorbed on the nanoparticle surface and delivered to the deep scalp together with the nanoparticle, so that more hair-growth components with different mechanisms of action are transferred to the hair matrix cells and hair. Can be supplied to the nipple. On the other hand, if ingredients that act on the surface of the scalp are formulated, the immediate effect of these drugs on the surface of the scalp is ensured, and in the deep part of the scalp, the herbal medicine components are gradually released from the nanoparticles for a longer period of time. A wide range of hair growth effects can be expected.

[0112] Further, the hair-growth component-containing nanoparticles of the present invention that form nanoparticles by using a spherical crystallization method can be easily used. And it can manufacture at low cost. Here, the concentration of the polybulal alcohol aqueous solution to which the drug, the biocompatible polymer and the organic solvent are added is 0.5% by weight or less, so that the nanobulb polyhydric alcohol aqueous solution is used as in the case of using the high concentration polybulal alcohol aqueous solution. Since there is no need for a removal step of removing excess polyvinyl alcohol by washing the particles by centrifuge separation, labor and time can be reduced, which is advantageous in production.

[0113] On the other hand, when nanoparticles are formed using a high-concentration polybulualcohol aqueous solution and then the nanoparticles are washed by centrifugation or the like to remove excess polybulualcohol, The encapsulation rate of the hair-growth component to be encapsulated can be stabilized. At this time, by setting the concentration of the polyvinyl alcohol aqueous solution to 0.1 wt% or more and 10 wt% or less, the viscosity of the poor solvent can be suppressed to an appropriate range that does not affect the diffusion of the good solvent.

[0114] In addition, since a mixed solution of acetone and ethanol, which has little influence on the human body and the environment, is used as a good solvent, it is highly safe as a raw material for a hair restorer applied directly to the scalp. In addition, in the compounding process, by combining sugar alcohol, vitamins or vitamin derivatives with the nanoparticles, the dispersibility, heat resistance and hair growth effect of the combined nanoparticles can be improved. This can be further improved. Moreover, if the composite coating process is performed by freeze-drying, the composite coating of nanoparticles can be performed satisfactorily and efficiently.

Claims

The scope of the claims

[I] Hair-growth component-containing nanoparticles comprising one or more herbal components encapsulated in a biocompatible polymer

[2] The hair-growth component-containing nanoparticles according to claim 1, wherein

The herbal medicine component is at least one selected from hair matrix cell activators or anti-inflammatory agents.

[3] In the hair-growth component-containing nanoparticles according to claim 2,

The hair matrix cell active agent is hinokitiol.

[4] In the hair-growth component-containing nanoparticles according to claim 2,

The anti-inflammatory agent is β-glycyrrhetinic acid.

[5] The hair-growth component-containing nanoparticles according to any one of claims 2 to 4, wherein a blood circulation promoter is further encapsulated as the herbal medicine component.

[6] The hair-growth component-containing nanoparticle according to any one of claims 2 to 4, wherein a male hormone antagonist is further encapsulated as the herbal component.

[7] The hair-growth component-containing nanoparticle according to any one of claims 1 to 4, wherein the herbicide component is encapsulated in the biocompatible polymer in an encapsulation rate of 1 wt% or more and 20 wt% or less.

[8] The hair-growth component-containing nanoparticles according to any one of claims 1 to 4, wherein the biocompatible polymer is a lactic acid / glycolic acid copolymer.

[9] The hair-growth component-containing nanoparticles according to any one of claims 1 to 4, wherein the average particle size is 30 nm or more and 300 nm or less.

[10] A hair-growth component-containing nanoparticle obtained by combining the hair-growth component-containing nanoparticle according to any one of claims 1 to 4.

[II] In the hair-growth component-containing nanoparticles according to claim 10,

A sugar alcohol is complexed with the hair-growth component-containing nanoparticles.

[12] The hair-growth component-containing nanoparticles according to claim 10,

Vitamins or vitamin derivatives are complexed with the hair-growth component-containing nanoparticles.

[13] A hair restorer obtained by dispersing the hair-growth component-containing nanoparticles according to any one of claims 1 to 4 in a dispersion.

[14] In the hair restorer according to claim 13,

Other hair-growth ingredients are blended in the dispersion.

[15] The hair restorer according to claim 14,

The hair-growth component blended in the dispersion is a vitamin or vitamin derivative.

[16] A nanoparticle forming step of adding at least a crude drug, a biocompatible polymer, and an organic solvent to an aqueous polyvinyl alcohol solution to form a hair-growth component-containing biocompatible nanoparticle to form a nanoparticle-containing solution;

A method for producing hair-growth component-containing nanoparticles, comprising: a solvent distillation step of distilling off the organic solvent from the nanoparticle-containing solution.

[17] In the method for producing the hair-growth component-containing nanoparticles according to claim 16,

The concentration of polybulal alcohol in the polybulal alcohol aqueous solution is less than 0.5% by weight.

[18] In the method for producing the hair-growth component-containing nanoparticles according to claim 16,

After the solvent distillation step, the method further includes a removal step of removing the nanoparticle-containing solution force polybulal alcohol.

[19] In the method for producing hair-growth component-containing nanoparticles according to claim 18,

The polybulal alcohol concentration in the polybulal alcohol aqueous solution is 0.1% by weight or more.

10% by weight or less.

[20] In the method for producing hair-growth component-containing nanoparticles according to any one of claims 16 to 19,

The organic solvent is a mixture of acetone and ethanol.

[21] In the method for producing hair-growth component-containing nanoparticles according to any one of claims 16 to 19,

After the solvent distillation step or the removal step, the method further includes a compounding step for compounding the nanoparticles.

[22] The method for producing the hair-growth component-containing nanoparticles according to claim 21, wherein

In the complexing step, one or more of sugar alcohol, vitamins and vitamin derivatives are complexed with the nanoparticles. The method for producing hair-growth component-containing nanoparticles according to claim 21, wherein the complexing step is performed by lyophilization.