Transdermal preparation

Abstract

The purpose of the present invention is to provide a transdermal preparation that makes it possible to enhance the efficacy of an active pharmaceutical ingredient to be transdermally administered.　This transdermal preparation contains an active pharmaceutical ingredient and carbonate apatite and has enhanced efficacy of the active pharmaceutical ingredient.

Description

Transdermal administration preparation

[0001] The present invention relates to a transdermal administration preparation capable of enhancing the medicinal effect of a medicinal ingredient administered transdermally. The present invention also relates to a medicinal effect enhancer and a skin permeability improver for a medicinal ingredient administered transdermally. Furthermore, the present invention relates to an anti-inflammatory drug for transdermal administration.

[0002] Conventionally, as transdermal administration preparations, various dosage forms such as ointments, creams, gels, liquids, lotions, patches, tapes, etc. have been developed. Also, conventionally, various formulation technologies for improving the medicinal effect of a medicinal ingredient contained in a transdermal administration preparation or improving the skin permeability of the medicinal ingredient have been studied.

[0003] On the other hand, it has been reported that carbonated apatite has an effect of enhancing the antitumor effect of an anticancer agent, an effect of promoting the accumulation of a contrast agent in a tumor, etc. (Patent Documents 1 and 2). It has also been reported that composite particles in which miR-29a and / or miR-29b are supported on carbonated apatite particles are effective for the treatment of inflammatory bowel disease (Patent Document 3). However, there has been no report on using carbonated apatite in a transdermal administration preparation, and it has not been clarified what kind of influence carbonated apatite can have on a medicinal ingredient administered transdermally.

[0004] International Publication No. 2015 / 125934, Japanese Unexamined Patent Application Publication No. 2015 - 151377, International Publication No. 2018 / 199121

[0005] One of the objects of the present invention is to provide a transdermal administration preparation capable of enhancing the medicinal effect of a medicinal ingredient administered transdermally. Another object of the present invention is to provide a medicinal effect enhancer or a skin permeability improver for a medicinal ingredient administered transdermally. Furthermore, another object of the present invention is to provide an anti-inflammatory drug for transdermal administration.

[0006] The inventors conducted diligent studies to solve the aforementioned problems and found that a transdermal formulation containing a pharmacoactive ingredient and carbonate apatite enhances the efficacy of the pharmacoactive ingredient. Furthermore, the inventors found that carbonate apatite improves the skin penetration of the pharmacoactive ingredient administered transdermally. In addition, the inventors found that carbonate apatite itself can exert an anti-inflammatory effect through transdermal administration. This invention was completed by further studies based on these findings.

[0007] In other words, the present invention relates to a technology for enhancing the efficacy of a pharmacoactive ingredient, and provides inventions in the following embodiments: 1-1. A transdermal preparation containing a pharmacoactive ingredient and carbonate apatite. 1-2. The transdermal preparation according to 1-1, wherein the pharmacoactive ingredient is an immunosuppressant and / or a plant extract. 1-3. The transdermal preparation according to 1-2, wherein the immunosuppressant is cyclosporine. 1-4. The transdermal preparation according to 1-2, wherein the plant extract is bamboo extract. 1-5. The transdermal preparation according to 1-3 or 1-4, used for the treatment of atopic dermatitis. 1-6. A method for treating a skin disease, comprising transdermally administering a transdermal preparation containing a pharmacoactive ingredient effective for treating the skin disease and carbonate apatite to a person seeking treatment for the skin disease. 1-7. Use of a transdermal preparation containing a pharmacoactive ingredient effective for treating a skin disease and carbonate apatite for the manufacture of a treatment for a skin disease. Item 1-8. A drug efficacy enhancer for transdermally administered drug components, containing carbonate apatite as the active ingredient. Item 1-9. A drug permeability enhancer for transdermally administered drug components, containing carbonate apatite as the active ingredient.

[0008] Furthermore, the present invention provides the following embodiments of a therapeutic technology for inflammatory skin diseases utilizing carbonate apatite: Item 2-1. An anti-inflammatory agent for transdermal administration, comprising carbonate apatite as an active ingredient. Item 2-2. The anti-inflammatory agent according to Item 2-1, used for the treatment of atopic dermatitis. Item 2-3. A method for treating inflammatory skin diseases, comprising transdermally administering a therapeutically effective amount of carbonate apatite to a patient with the inflammatory skin disease. Item 2-4. Carbonate apatite used for transdermal administration to treat inflammatory skin diseases. Item 2-5. Use of carbonate apatite for the manufacture of an anti-inflammatory agent for transdermal administration.

[0009] According to one embodiment of the present invention, the efficacy of a transdermal active ingredient can be significantly enhanced. Furthermore, according to one embodiment of the present invention, the skin penetration of a transdermal active ingredient can be improved. Moreover, according to one embodiment of the present invention, an anti-inflammatory drug exhibiting excellent anti-inflammatory effects is provided.

[0010] This is a photograph of a mouse in the base application group taken on Day 24 in Test Example 1. This is a photograph of a mouse in the cyclosporine-only application group taken on Day 24 in Test Example 1. This is a photograph of a mouse in the cyclosporine and sCA combination application group taken on Day 24 in Test Example 1. This is a photograph of a mouse in the sCA-only application group taken on Day 24 in Test Example 1. This figure shows the results of measuring the time course of the total inflammation score of mice in each group in Test Example 1. This is a photograph of a mouse in each group taken on Day 0 and Day 6 in Test Example 2. This figure shows the results of measuring the time course of the average inflammation score of each group and the average inflammation score on Day 6 in Test Example 2. This is an image of HE stained skin inflamed areas taken from mice in each group on Day 6 in Test Example 2.

[0011] 1. Transdermal formulation The transdermal formulation of the present invention is characterized by containing a pharmacoactive ingredient and carbonate apatite. The transdermal formulation of the present invention will be described in detail below.

[0012] The transdermal formulation of the present invention contains a pharmacoactive ingredient, which is an active ingredient. A pharmacoactive ingredient is a component that exerts pharmacological effects on the skin.

[0013] The types of pharmacoactive ingredients used in the present invention are not particularly limited, as long as they can be administered transdermally, but examples include immunosuppressants, plant extracts, steroidal anti-inflammatory agents, nonsteroidal anti-inflammatory agents, α-adrenergic receptor blockers, adrenergic receptor agonists, angiotensin II receptor antagonists, angiotensin-converting enzyme inhibitors, calcium channel blockers, antifungal agents, antibacterial agents, antiviral agents, local anesthetics, anti-allergic agents, antihistamines, hemostatic agents, antipruritic and anti-inflammatory agents, peripheral vasodilators, retinoids, RNA drugs for dermatitis, peptides, and the like.

[0014] Examples of immunosuppressants include cyclosporine, tacrolimus, sirolimus, and everolimus.

[0015] Plant extracts are extracts obtained from plants through extraction processes such as dry distillation and solvent extraction. Any plant extract that can exert anti-inflammatory and antioxidant effects through transdermal application is acceptable. Specifically, examples include bamboo extract, horse chestnut extract, olive leaf extract, artichoke leaf extract, arnica flower extract, apricot seed extract, Satsuma mandarin peel extract, Coptis japonica root extract, chamomile flower extract, licorice root extract, Phellodendron amurense bark extract, Sasa veitchii leaf extract, Sophora flavescens root extract, Geranium thunbergii flower / leaf / stem extract, pomegranate peel extract, hawthorn extract, Zanthoxylum piperitum peel extract, perilla leaf extract, peony root extract, calamus rhizome extract, and sillago. Examples include birch bark extract, linden flower extract, sage leaf extract, Cnidium officinale rhizome extract, cherry blossom leaf extract, green tea leaf extract, green tea flower extract, clove extract, angelica root extract, Houttuynia cordata extract, linden flower extract, coix seed extract, iris extract, Isodon japonicus leaf / stem extract, loquat leaf extract, grape seed extract, grape leaf extract, linden flower extract, peony extract, mulberry root bark extract, lilac root extract, saxifrage extract, raspberry fruit extract, mugwort leaf extract, and burnet extract. Specific extraction conditions for each type of plant extract are publicly known.

[0016] Among these plant extracts, bamboo extract is a particularly suitable example. Bamboo extract is known to have anti-inflammatory and antibacterial properties. The types of bamboo used for bamboo extract are not particularly limited, but examples include Phyllostachys pubescens, Phyllostachys bambusoides, Phyllostachys nigra, Phyllostachys aurea, Phyllostachys heterocycla, Bambusa multiplex, Semirundinaria fastuosa, Sasa kurilensis, Sinobambusa tootsik, Chimonobambusa quadrangularis, Chimonobambusa marmorea, Pseudosasa japonica, and Pleioblastus simonii. Bamboo extract can be obtained by dry distillation (reduced pressure dry distillation) of the bamboo stem, or by solvent extraction using a solvent such as ethanol, water, or aqueous ethanol. A preferred example of bamboo extract is bamboo extract obtained by dry distillation extraction.

[0017] Steroidal anti-inflammatory agents include, specifically, prednisolone valerate acetate, methylprednisolone, hydrocortisone butyrate, hydrocortisone acetate, hydrocortisone propionate butyrate, fluocinolone acetonide, triamcinolone acetonide, dexamethasone, dexamethasone acetate, dexamethasone propionate, dexamethasone valerate, betamethasone valerate, and betamethasone propionate butyrate. Examples include ion acid esters, diflucortolone valerate, clobetasol propionate, fluocinonide, halcinonide, tetrahydrozoline hydrochloride, amcinonide, alclomethasone propionate, clobetasone butyrate, difluprednate, diflorasone acetate, deprodone propionate, prednisolone, prednisolone acetate, betamethasone dipropionate, mometasone furoate, and the like.

[0018] Nonsteroidal anti-inflammatory drugs include, specifically, salicylic acid, aspirin, sulpyrine, acetaminophen, diclofenac sodium, fenbufen, ibuprofen, aminoprofen, loxoprofen sodium, naproxen, oxaprofen, ketoprofen, tiaprofenic acid, sulindac, aluminum flufenamate, felbinac, mefenamic acid, indomethacin, indomethacin farnesyl, acemetacin, proglutetacin maleate. Examples include diphenhydramine phosphate, bendazac, piroxicam, ampiroxicam, lornoxicam, tenoxicam, meloxicam, flurbiprofen, etodolac, tiaramide hydrochloride, bucolome, flurbiprofen, esflurbiprofen, methyl salicylate, lysozyme hydrochloride, bromelain, diphenhydramine hydrochloride, dibucaine, dimethylisopropylazulene, benzethonium chloride, dipotassium glycyrrhizinate, allantoin, and glycyrrhetinic acid.

[0019] Examples of alpha-adrenergic receptor blockers include urapidil, terazosin hydrochloride, timolol maleate, bunazosin hydrochloride, prazosin hydrochloride, oxprenolol hydrochloride, propranolol hydrochloride, bevantrol hydrochloride, doxazosin mesylate, bisoprolol fumarate, carteolol hydrochloride, bufetrol hydrochloride, bupranolol hydrochloride, alprenolol hydrochloride, nadolol, pindolol, indenolol hydrochloride, nipradilol, bunitrol hydrochloride, penbutrol sulfate, bopindolol malonate, atenolol, tilisolol hydrochloride, metoprolol tartrate, betaxolol hydrochloride, and acebutrol hydrochloride.

[0020] Examples of adrenergic receptor agonists include epinephrine, norepinephrine, dopamine hydrochloride, isoxuprine hydrochloride, phenylephrine hydrochloride, etilephrine hydrochloride, clonidine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, methamphetamine hydrochloride, salbutamol sulfate, methyldopa, guanfacine hydrochloride, clenbuterol hydrochloride, isoprenaline hydrochloride, methoxyphenamine hydrochloride, orciprenaline sulfate, chlorprenaline hydrochloride, trimethoquinol hydrochloride, methylphenidate hydrochloride, guanabenz acetate, terbutaline sulfate, hexoprenaline sulfate, tulobuterol hydrochloride, fenoterol hydrobromide, procaterol hydrochloride, mabuterol hydrochloride, pemoline, imipramine hydrochloride, and amedinium methylsulfate.

[0021] Examples of angiotensin II receptor antagonists include candesartan, losartan potassium, olmesartan medoxomil, candesartan cilexetil, and irbesartan.

[0022] Examples of angiotensin-converting enzyme inhibitors include captopril, delapril hydrochloride, quinapril hydrochloride, lisinopril, alacepril, cilazapril hydrate, enalapril maleate, benazepril hydrochloride, trandolapril, ramipril-imidapril hydrochloride, perindopril-erbumine, and temocapril hydrochloride.

[0023] Examples of calcium channel blockers include diltiazem hydrochloride, clenthem, nifedipine, cilnidipine, aranidipine, nicardipine hydrochloride, bepridil hydrochloride, verapamil hydrochloride, felodipine, nisoldipine, nitrendipine, benidipine hydrochloride, manidipine hydrochloride, barnidipine hydrochloride, nilvadipine, and efonidipine hydrochloride.

[0024] Examples of antifungal drugs include miconazole nitrate, sulconazole nitrate, oxiconazole nitrate, bifonazole, ketoconazole, lanoconazole, luliconazole, amorolfine hydrochloride, terbinafine hydrochloride, butenafine hydrochloride, efinaconazole, nystatin, flucytosine, thioconazole, fluconazole, itraconazole, fosfluconazole, voriconazole, terbinafine, micafagin sodium, caspofagin, undecylenate, zinc undecylenate, griseofulvin, hinokitiol, rebrucin, iodine tincture, trichomycin, and pyrrolnitrin.

[0025] Examples of antibacterial agents include cephalosporin antibiotics, carbapenem antibiotics, fluoroquinolone antibiotics, penem antibiotics, penicillin antibiotics, chloramphenicol antibiotics, monobactam antibiotics, aminoglycoside antibiotics, fosfomycin antibiotics, macrolide antibiotics, glycopeptide antibiotics, quinolone antibiotics, fradiomycin sulfate, gentamicin sulfate, and pentamidine isethionate.

[0026] Examples of antiviral drugs include vidarabine, acyclovir, valacyclovir, famciclovir, and amenamevir.

[0027] Examples of local anesthetics include lidocaine, bupivacaine, mepivacaine, ropivacaine, and levopipivacaine.

[0028] Examples of anti-allergic drugs include pemirolast, tranilast, sodium cromoglycate, olopatadine, pitramaralast, rastine, anlexanox, mequitazine, azelastine, ketotifen, cetirizine, loratadine, fexofenadine, epinastine, levocetirizine, bepotastine, emedastine, epastine, suplatastotosylate, desloratadine, pranlukast, and montelukast.

[0029] Examples of antihistamines include diphenhydramine, diphenhydramine hydrochloride, diphenhydramine tannate, ketotifen fumarate, chlorpheniramine, lorpheniramine maleate, promethazine, hydroxyazine, cyproheptadine, clemastine fumarate, cudiphenylpyraline hydrochloride, ebastine, clemastine, diphenylpyraline theoclate, azelastine hydrochloride, epinastine hydrochloride, oxatomide, olopatadine hydrochloride, riboflavin phosphate sodium, cyproheptadine hydrochloride hydrate, fexofenadine hydrochloride, bepotastine besylate, alimazine tartrate, triprolidine hydrochloride hydrate, homochlorcyclidine hydrochloride, cetirizine hydrochloride, levocetirizine hydrochloride, and emedastine fumarate.

[0030] Examples of hemostatic agents include tranexamic acid, warfarin potassium, argatroban, carbazochrome, and heparin sodium.

[0031] Examples of antipruritic and anti-inflammatory drugs include crotamiton, cortisone acetate, glycol salicylate, isotipendyl hydrochloride, and calamine.

[0032] Examples of peripheral vasodilators include hydralazine hydrochloride, budralazine, todralazine hydrochloride hydrate, cadralazine, and sodium nitroprusside.

[0033] Examples of retinoids include tretinoin tocopheryl, isotretinoin, and etretinate.

[0034] These medicinal ingredients may be used individually or in combination of two or more.

[0035] In one embodiment of the transdermal formulation of the present invention, the pharmacoactive ingredient is preferably an immunosuppressant, more preferably cyclosporine.

[0036] In another embodiment of the transdermal formulation of the present invention, the pharmacoactive ingredient is preferably a plant extract, more preferably a bamboo extract, and even more preferably a moso bamboo extract.

[0037] The content of the pharmacoactive ingredient in the transdermal formulation of the present invention may be appropriately set depending on the type of pharmacoactive ingredient used, the dosage form of the transdermal formulation, etc., but examples include 0.01 to 50% by weight; preferably 0.05 to 40% by weight; more preferably 0.05 to 30% by weight, 0.05 to 20% by weight, 0.05 to 10% by weight, 0.05 to 5% by weight, 0.05 to 1% by weight, 0.1 to 30% by weight, 0.1 to 20% by weight, 0.1 to 10% by weight, 0.1 to 5% by weight, 0.1 to 1% by weight, 1 to 30% by weight, 1 to 20% by weight, 1 to 10% by weight, or 1 to 5% by weight. When the pharmacoactive ingredient is a plant extract, the content of the pharmacoactive ingredient is the value converted to the weight of plant-derived components in the plant extract. In other words, when using a plant extract containing solvents, excipients, etc., as the medicinal component, the content of the medicinal component is the value converted to the weight excluding the solvents, excipients, etc. contained in the plant extract.

[0038] Carbonated Apatite The transdermal formulation of the present invention contains carbonated apatite together with the pharmacoactive ingredient. In the transdermal formulation of the present invention, the coexistence of the pharmacoactive ingredient and carbonated apatite in the formulation enhances the efficacy of the pharmacoactive ingredient, resulting in superior efficacy compared to when the pharmacoactive ingredient is used alone.

[0039] Carbonate apatite is hydroxyapatite (Ca 10 It has a structure in which some of the hydroxyl groups of (PO4)6(OH)2 are replaced with CO3, and the general formula is Ca 10-m X m (PO4)6(CO3) 1-n Y nIt is a compound represented by [formula]. Here, X is an element that can partially substitute Ca in carbonated apatite, and examples include Sr, Mn, rare earth elements, etc. m is usually a positive number of 0 or more and 1 or less, preferably 0 or more and 0.1 or less, more preferably 0 or more and 0.01 or less, and still more preferably 0 or more and 0.001 or less. Y is a group or element that can partially substitute CO3 in carbonated apatite, and examples include OH, F, Cl, etc. n is usually a positive number of 0 or more and 0.1 or less, preferably 0 or more and 0.01 or less, more preferably 0 or more and 0.001 or less, and still more preferably 0 or more and 0.0001 or less.

[0040] Regarding the average particle diameter of the carbonated apatite used in the present invention, as long as it is large enough to be administered in vivo and migrate into cells, it is not particularly limited, but it is usually more than 50 nm (for example, more than 50 nm and 3000 nm or less), preferably 100 to 3000 nm, more preferably 100 to 2000 nm, still more preferably 200 to 2000 nm or 400 to 3000 nm, and particularly preferably 400 to 2000 nm.

[0041] Incidentally, the average particle diameter of the carbonated apatite is a value measured by dynamic light scattering particle measurement (DLS). When there are huge particles (for example, particle size of 5 μm or more) that are not suitable for measurement using DLS, they are removed from the measurement target range. Also, in this specification, the particle diameter means the particle diameter of an independent particle that can be recognized as a separate particle when measured with a scanning probe microscope. Therefore, when a plurality of particles are aggregated, their aggregate is judged as one particle.

[0042] In the transdermal administration preparation of the present invention, a part or all of the active ingredient may be contained as a composite supported on carbonated apatite, but the active ingredient and carbonated apatite may be contained in a state of separate dispersion or dissolution without being complexed.

[0043] Carbonated apatite can be obtained according to known methods. For example, it can be obtained by preparing in an aqueous solution by coexisting calcium ions, phosphate ions and hydrogen carbonate ions. The concentration of each ion in the aqueous solution is not particularly limited as long as carbonated apatite is formed, and can be appropriately set referring to the following.

[0044] The calcium ion concentration in the aqueous solution is usually 0.1 to 1000 mM, preferably 0.5 to 100 mM, more preferably 1 to 10 mM.

[0045] The phosphate ion concentration in the aqueous solution is usually 0.1 to 1000 mM, preferably 0.5 to 100 mM, more preferably 1 to 10 mM.

[0046] The hydrogen carbonate ion concentration in the aqueous solution is usually 1.0 to 10000 mM, preferably 5 to 1000 mM, more preferably 10 to 100 mM.

[0047] As the sources of calcium ions, phosphate ions and hydrogen carbonate ions, there is no particular limitation as long as these ions can be supplied into the aqueous solution. For example, water-soluble salts of these ions can be mentioned. Specifically, CaCl2 can be used as the calcium ion source, NaH2PO4·2H2O can be used as the phosphate ion source, and NaHCO3 can be used as the carbonate ion source.

[0048] The aqueous solution for preparing carbonated apatite may contain components other than the above-mentioned ion sources and other substances as long as carbonated apatite is formed. For example, by adding fluoride ions, chloride ions, Sr, Mn, polyethylene glycol (PEG), etc. to the above composition in the aqueous solution, Ca or CO3 in the carbonated apatite may be partially substituted or modified. However, the addition amounts of fluoride ions, chloride ions, Sr, Mn, PEG, etc. are preferably within a range that does not significantly affect the pH solubility and particle size range of the formed composite particles. Also, water can be used as the base for the aqueous solution for preparing carbonated apatite, but various media and buffers for cell culture can also be used.

[0049] In preparing the carbonate apatite used in the present invention, the mixing order of each ion source and other substances into the aqueous solution is not particularly limited, and the aqueous solution may be prepared in any mixing order as long as the desired carbonate apatite is obtained. For example, a first solution containing calcium ions and other substances may be prepared, and a second solution containing phosphate ions and bicarbonate ions may be prepared separately, and the first solution and the second solution may be mixed to prepare the aqueous solution.

[0050] Carbonate apatite can be obtained by adjusting the pH of an aqueous solution containing the above-mentioned ions to a range of 6.0 to 9.0 and allowing it to stand (incubate) for a certain period of time. Examples of the pH of the aqueous solution used to form carbonate apatite include 7.0 to 8.5, preferably 7.1 to 8.5, more preferably 7.2 to 8.5, even more preferably 7.3 to 8.5, particularly preferably 7.4 to 8.5, and most preferably 7.5 to 8.0.

[0051] The temperature conditions of the aqueous solution used to form carbonate apatite are not particularly limited as long as carbonate apatite is formed, but are usually 4°C or higher, preferably 25 to 80°C, and more preferably 37 to 70°C or higher.

[0052] The incubation time for the aqueous solution to form carbonate apatite is not particularly limited as long as carbonate apatite is formed, but is usually 1 minute to 24 hours, preferably 5 minutes to 1 hour. The presence or absence of particle formation can be confirmed, for example, by observation under a microscope.

[0053] Furthermore, there are no particular limitations on the method for controlling the average particle size of carbonate apatite to the aforementioned range, but one example is to treat carbonate apatite formed in the aqueous solution with ultrasonic vibration. Specifically, ultrasonic vibration treatment can include a process in which an ultrasonic transducer, such as that of an ultrasonic crusher, is brought into direct contact with the sample and ultrasonic waves are applied; or a process using an ultrasonic cleaner equipped with an ultrasonic transducer and a water tank (cleaning tank), in which a liquid (e.g., water) is placed in the water tank, a container (e.g., a plastic tube) containing carbonate apatite is floated in it, and ultrasonic waves are applied to the aqueous solution containing carbonate apatite through the liquid. By such ultrasonic vibration treatment, the particle size of carbonate apatite can be easily and efficiently reduced to the aforementioned range. Furthermore, after ultrasonic treatment, the particle size of carbonate apatite can also be adjusted to the aforementioned range by separating carbonate apatite of a desired particle size using a filter with a predetermined pore size.

[0054] The above ultrasonic vibration treatment conditions are not particularly limited as long as the particle size can be controlled within a predetermined range. For example, when using an ultrasonic cleaner equipped with an ultrasonic transducer and a water tank (cleaning tank), the following conditions are exemplified: Water tank temperature: for example, 5 to 45°C, preferably 10 to 35°C, more preferably 20 to 30°C. High-frequency output: for example, 10 to 500 W, preferably 20 to 400 W, more preferably 30 to 300 W, more preferably 40 to 100 W. Oscillation frequency: for example, 10 to 60 Hz, preferably 20 to 50 Hz, more preferably 30 to 40 Hz. Treatment time: for example, 30 seconds to 30 minutes, preferably 1 to 20 minutes, more preferably 3 to 10 minutes.

[0055] The type of container used to enclose carbonate apatite during ultrasonic vibration treatment is not limited as long as it is possible to refine the particles to a predetermined particle size range, and can be appropriately selected according to the volume of the aqueous solution and the intended use. For example, a plastic tube with a capacity of 1 to 1000 ml can be used.

[0056] Furthermore, ultrasonic vibration treatment is preferably performed in the presence of a dispersant (i.e., with the dispersant added to an aqueous solution containing carbonate apatite). This is because performing ultrasonic vibration treatment in an environment where the dispersant and carbonate apatite coexist allows for the production of carbonate apatite nanoparticles with finer particle sizes and also suppresses particle re-aggregation. The type of dispersant is not particularly limited, as long as it can disperse carbonate apatite, and any dispersant commonly added to pharmaceuticals is acceptable, although albumin is one example. The dispersant may be used alone or in combination of two or more types. The concentration of the dispersant in the aqueous solution containing carbonate apatite is not particularly limited as long as the effect of particle refinement and / or suppression of re-aggregation is obtained, but examples include 0.1 to 500 mg / ml, preferably 1 to 100 mg / ml, more preferably 1 to 10 mg / ml; or about 0.001 to 10% by weight.

[0057] The carbonate apatite thus prepared may be incorporated into the transdermal formulation of the present invention either in the form of a dispersion or as a concentrated solution. Alternatively, it may be subjected to a drying treatment such as freeze-drying to obtain a dried product before being incorporated into the transdermal formulation of the present invention.

[0058] The content of carbonate apatite in the transdermal formulation of the present invention can be appropriately set according to the dosage form of the transdermal formulation, but examples include 0.01 to 50% by weight; preferably 0.05 to 40% by weight; more preferably 0.1 to 20% by weight, 0.1 to 10% by weight, 0.1 to 8% by weight, 0.1 to 6% by weight, 0.5 to 20% by weight, 0.5 to 10% by weight, 0.5 to 8% by weight, 0.5 to 6% by weight, 1 to 20% by weight, 1 to 10% by weight, 1 to 8% by weight, or 1 to 6% by weight.

[0059] In the transdermal formulation of the present invention, the ratio of the pharmacoactive ingredient to carbonate apatite is not particularly limited, but for example, per 100 parts by weight of the pharmacoactive ingredient, carbonate apatite may be 0.1 to 2500 parts by weight; preferably 0.5 to 2000 parts by weight; more preferably 0.5 to 1500 parts by weight, 0.5 to 1000 parts by weight, 0.5 to 800 parts by weight, 1 to 1500 parts by weight, 1 to 1000 parts by weight, 1 to 800 parts by weight, 5 to 1500 parts by weight, 5 to 1000 parts by weight, and 5 to 800 parts by weight.

[0060] Other Components: In addition to the components described above, the transdermal formulation of the present invention may contain additives commonly used in transdermal formulations, as needed. Examples of such additives include aqueous bases (water, buffer solutions, monohydric lower alcohols, polyhydric alcohols, etc.), surfactants, solubilizers, oily bases, oils (petrolatum, animal oils, vegetable oils, mineral oils, waxes, waxes, ester oils, fatty acid alkyl esters, higher fatty acids, monohydric higher alcohols, silicone oils, cholesterol, etc.), thickeners, chelating agents, preservatives, antioxidants, stabilizers, and chelating agents. When these additives are included in the transdermal formulation of the present invention, their content may be appropriately determined depending on the type of additive used, the dosage form of the transdermal formulation, etc.

[0061] Dosage Form The dosage form of the transdermal formulation of the present invention is not particularly limited, as long as it can be used as a topical medicine, and may be liquid, solid, semi-solid, etc. Specific examples of dosage forms of the transdermal formulation of the present invention include ointments, sprays, creams, lotions, gels, emulsions, liquids, poultices, patches, liniments, aerosols, packs, etc.

[0062] Method of Use: The transdermal formulation of the present invention is administered by applying or spraying it onto the skin. The amount of the transdermal formulation of the present invention administered to the skin should be appropriately determined depending on the type of active ingredient used, the disease to be treated, the dosage form of the transdermal formulation, etc.

[0063] The diseases targeted by the transdermal formulation of the present invention are appropriately determined according to the type of pharmacoactive ingredient used. Examples of diseases targeted by the transdermal formulation of the present invention include inflammatory skin diseases such as atopic dermatitis, psoriasis, eczema, prurigo, palmoplantar pustulosis, pressure ulcers, drug eruptions, erythroderma, lichen, herpes simplex, herpes zoster, acne, impetigo, seborrheic dermatitis, and lichen planus; scars, keloids, scleroderma, mycosis fungoides, xerosis, tinea, vitiligo, molluscum contagiosum, alopecia, pemphigus, bullous pemphigoid, pigment disorders, arthritis, and bullous diseases.

[0064] In the transdermal formulation of the present invention, when an immunosuppressant (particularly cyclosporine) or bamboo extract is used as the pharmacoactive ingredient, a remarkably superior therapeutic effect can be achieved against inflammatory skin diseases such as atopic dermatitis. In view of the effects of the present invention, a preferred embodiment of the transdermal formulation of the present invention is one in which an immunosuppressant and / or bamboo extract, preferably cyclosporine and / or Moso bamboo extract, is used for the treatment of inflammatory skin diseases such as atopic dermatitis.

[0065] The dosage of the transdermal formulation of the present invention will vary depending on the active ingredient used and the type of target disease, but for example, it is sufficient to set the daily dosage to approximately 5 to 200 mg in terms of carbonate apatite content. Furthermore, the transdermal formulation of the present invention can be used by applying or spraying it onto the skin area where the skin disease is present, once to several times a day.

[0066] 2. Drug efficacy enhancer The drug efficacy enhancer of the present invention is used for the purpose of enhancing the efficacy of a drug active ingredient administered transdermally, and is characterized by having carbonate apatite as the active ingredient.

[0067] The carbonate apatite used in the drug efficacy enhancer of the present invention is as described in section "1. Transdermal administration preparations" above.

[0068] The drug efficacy enhancer of the present invention is used by being incorporated into a transdermal preparation containing a pharmacokinetic ingredient for the purpose of enhancing the efficacy of the pharmacokinetic ingredient administered transdermally. The type of pharmacokinetic ingredient whose efficacy is to be enhanced, the dosage form of the transdermal preparation, the amount of the drug efficacy enhancer of the present invention incorporated into the transdermal preparation, and the method of use of the transdermal preparation containing the drug efficacy enhancer of the present invention are as described in section "1. Transdermal Preparation" above.

[0069] 3. Skin Penetration Enhancer The skin penetration enhancer of the present invention is used for the purpose of improving the skin penetration of a pharmacoactive ingredient administered transdermally, and is characterized by containing carbonate apatite as an active ingredient.

[0070] The carbonate apatite used in the skin penetration enhancer of the present invention is as described in section "1. Transdermal administration preparations" above.

[0071] The skin penetration enhancer of the present invention is used by being incorporated into a transdermal formulation containing a pharmacoactive ingredient for the purpose of improving skin penetration when administered transdermally. The type of pharmacoactive ingredient that improves skin penetration, the dosage form of the transdermal formulation, the amount of the skin penetration enhancer of the present invention incorporated into the transdermal formulation, and the method of use of the transdermal formulation containing the skin penetration enhancer of the present invention are as described in section "1. Transdermal Formulation" above.

[0072] 4. Anti-inflammatory drug The anti-inflammatory drug of the present invention is characterized by containing carbonate apatite as an active ingredient and being administered transdermally. The inventors have found that carbonate apatite itself has anti-inflammatory properties, and therefore, carbonate apatite itself is used as the active ingredient in the anti-inflammatory drug of the present invention.

[0073] The carbonate apatite used in the anti-inflammatory agent of the present invention is as described in section "1. Transdermal administration preparations" above.

[0074] The anti-inflammatory drug of the present invention is formulated and used as a transdermal formulation. When formulating the anti-inflammatory drug of the present invention as a transdermal formulation, additives commonly used in transdermal formulations should be added. Examples of such additives include aqueous bases (water, buffer, monohydric lower alcohol, polyhydric alcohol, etc.), surfactants, solubilizers, oily bases, oils (petrolatum, animal oil, vegetable oil, mineral oil, wax, wax, ester oil, fatty acid alkyl ester, higher fatty acid, monohydric higher alcohol, silicone oil, cholesterol, etc.), thickeners, chelating agents, preservatives, antioxidants, stabilizers, chelating agents, fragrances, colorants, etc. When formulating the anti-inflammatory drug of the present invention and including these additives, the amount should be appropriately set according to the type of additive used, the dosage form of the transdermal formulation, etc.

[0075] In one embodiment of the anti-inflammatory agent of the present invention, the active ingredient may consist solely of carbonate apatite. In another embodiment of the anti-inflammatory agent of the present invention, it may be formulated as a transdermal administration preparation in combination with other pharmacoactive ingredients. Examples of such pharmacoactive ingredients include immunosuppressants, plant extracts, steroidal anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs, α-adrenergic receptor blockers, adrenergic receptor agonists, angiotensin II receptor antagonists, angiotensin-converting enzyme inhibitors, calcium channel blockers, antifungal agents, antibacterial agents, antiviral agents, local anesthetics, anti-allergic agents, antihistamines, hemostatic agents, antipruritic and anti-inflammatory agents, peripheral vasodilators, retinoids, RNA drugs for dermatitis, peptides, and the like.

[0076] When the anti-inflammatory drug of the present invention is formulated into a transdermal administration formulation, the content of carbonate apatite in the transdermal administration formulation can be appropriately set according to the type of inflammatory skin disease to be treated, the dosage form of the transdermal administration formulation, etc., but for example, 10 to 50% by weight, preferably 1 to 10% by weight, and more preferably 0.01 to 1% by weight are given.

[0077] The anti-inflammatory agent of the present invention is used for the treatment of inflammatory skin diseases. The types of inflammatory skin diseases to which the anti-inflammatory agent of the present invention can be applied are not particularly limited, but examples include atopic dermatitis, psoriasis, eczema, prurigo, palmoplantar pustulosis, drug eruption, erythroderma, scarring, keloids, scleroderma, lichen, herpes zoster, acne, tinea, seborrheic dermatitis, arthritis, lichen planus, and bullous diseases. Among these inflammatory skin diseases, the anti-inflammatory agent of the present invention is particularly suitable for the treatment of atopic dermatitis.

[0078] The dosage of the anti-inflammatory agent of the present invention varies depending on the type of disease, but for example, it is sufficient to set the daily dose of carbonate apatite to approximately 5 to 200 mg. Furthermore, the anti-inflammatory agent of the present invention may be applied or sprayed once to several times a day to the skin area where the inflammatory skin disease is occurring.

[0079] The present invention will be described below with reference to examples. However, the present invention is not limited to the following examples.

[0080] Reference Example: Production of sonicated carbonate apatite (sCA) First, an inorganic aqueous solution (NaHCO3; 44 mM, NaH2PO4; 0.9 mM, CaCl2; 1.8 mM, pH 7.5) was prepared and incubated at 37°C for 30 minutes. Then, it was centrifuged at 12,000 rpm for 3 minutes to obtain a pellet of sonicated carbonate apatite (sCA). Physiological saline (containing 0.5 wt% albumin) was added to the obtained pellet to a volume of 200 μL and dispersed. This was then subjected to ultrasonic vibration treatment (38 kHz, 80 W) for 10 minutes and freeze-dried. The obtained freeze-dried sCA was confirmed to have an average particle size of 400–2000 nm by dynamic light scattering particle measurement (DLS) using a Zetasizer Nano ZS (Malvern).

[0081] Test Example 1: Verification of Pharmacological Efficacy Using an Atopic Dermatitis Mouse Model 1. Preparation of an Atopic Dermatitis Mouse Model An atopic dermatitis mouse model was prepared using 10-week-old NC / NgaTndCrlj mice (female) according to the standard protocol for inducing atopic dermatitis with an ointment containing mite body components (Biosta AD ointment). Specifically, the atopic dermatitis mouse model was prepared by inducing the condition with Biosta AD ointment twice a week for a total of 14 times using the method described below. Conditions for the first induction treatment: The mice were anesthetized, and the hair on their backs and ears was removed with clippers. Biosta AD ointment, an atopic dermatitis inducing ointment, was then applied uniformly to the backs and ears. Conditions for subsequent induction treatments: If hair growth was observed in the depilated areas during the second and subsequent induction treatments, the hair was always shaved with clippers or an electric shaver. First, 150 μl of an aqueous solution containing 4% by weight of SDS (sodium dodecyl sulfate) was applied evenly to the back and auricles using a micropipette. Then, the mice were returned to their cages and left for approximately 2-3 hours to dry naturally. After that, Biosta AD ointment was applied evenly to the back and auricles.

[0082] Forty-six days after the initial induction treatment, abrasions and tissue loss symptoms (erosions and ulcers) of the auricle were observed in a mouse model of atopic dermatitis, and the degree of inflammation of the auricle was scored according to the following criteria: <Inflammation Score> 0: Asymptomatic; no abrasions or tissue loss symptoms were observed on the auricle. 1: Mild; non-continuous abrasions were observed on the auricle, but no tissue loss was observed. 2: Moderate; small, continuous abrasions were observed on the auricle, but no tissue loss was observed. 3: Severe; continuous abrasions were observed on the auricle, and tissue loss was observed.

[0083] 2. Preparation of the ointment: An ointment with the composition shown in Table 1 was prepared.

[0084] 3. Verification of the therapeutic effect on dermatitis Atopic dermatitis mouse models were divided into four groups (n=3 in each group) as shown in Table 1, and ointment was administered under each condition, with day 0 being 46 days after the initial induction treatment.

[0085] On Day 0, Day 7, Day 10, Day 14, and Day 24, the inflammation score of the auricle of each mouse was determined according to the aforementioned criteria, and the total inflammation score for each group (the sum of the inflammation scores of the right and left ears of three mice) was calculated.

[0086] The results are shown in Figures 1-5. Figures 1-4 show photographs of each group of mice taken on Day 24, and Figure 5 shows the change in the total inflammation score of each group over time.

[0087] In the group treated with the base agent, the inflammation score continued to increase over time, reaching 12 on Day 24. At the next visit, continuous abrasions were observed, and tissue loss (erosions, ulcers) was present.

[0088] In the cyclosporine monotherapy group, the inflammation score decreased from 5 to 3 by day 7. However, after reducing the cyclosporine dosage to 1 / 5 from day 8 onwards, the inflammation score increased to 6 by day 14. Furthermore, after the drug-free period, the inflammation score increased to 9 by day 24, indicating a worsening of inflammation.

[0089] In the group treated with cyclosporine and sCA, the inflammation score significantly decreased to 2 by Day 7. Furthermore, even after reducing the cyclosporine dose to 1 / 5 from Day 8 onwards, the inflammation score remained at 3, and remained at 3 even after the drug-free period on Day 24.

[0090] In the sCA monotherapy group, the inflammation score remained at 5 until Day 7, and although it increased slightly along the way, it remained at 5 even on Day 24. This indicates that inflammation was suppressed compared to the base-based application group and the cyclosporine monotherapy group.

[0091] The results above clearly show that sCA, when applied transdermally in combination with other active ingredients such as cyclosporine, can enhance the skin penetration of the drug and increase its therapeutic effect. Furthermore, it was also found that sCA, when applied transdermally alone, exhibits a certain degree of anti-inflammatory effect and can suppress the worsening of inflammation.

[0092] Test Example 2: Verification of Pharmacological Efficacy Using a DNCB-Induced Dermatitis Mouse Model 1. Preparation of a DNCB-Induced Dermatitis Mouse Model A DNCB-induced dermatitis mouse model was prepared using 6-week-old C57BL / 6 mice (male). Specifically, the DNCB-induced dermatitis mouse model was prepared by performing induction treatment with DNCB (2,4-dinitrochlorobenzene) a total of 11 times using the method described below. Conditions for the first induction treatment: On day 1, the mice were anesthetized, and the hair on their backs and ears was removed with clippers, and 150 μl of 2% DNCB solution was uniformly applied to the backs. Conditions for subsequent induction treatments: If hair growth was observed in the removed areas during the second and subsequent induction treatments, the hair was always shaved with clippers or an electric shaver. On days 5, 7, 9, 11, 13, 16, 18, 20, 22, and 24, 150 μl of 0.5% DNCB solution was uniformly applied to the backs.

[0093] On day 25, abrasions and tissue loss symptoms (erosions and ulcers) of the auricle were observed in the DNCB-induced dermatitis mouse model, and the degree of inflammation of the auricle was scored according to the criteria shown in Test Example 1 above.

[0094] 2. Preparation of the spray agent A spray agent with the composition shown in Table 3 was prepared.

[0095] 3. Verification of the therapeutic effect on dermatitis The DNCB-induced dermatitis mouse model was divided into three groups (n=3 in each group) as shown in Table 4, and administration was carried out under each condition, with Day 0 being defined as 24 days after the initial induction treatment.

[0096] On Day 0 and Day 6, the inflammation score of the auricle of each mouse was determined according to the aforementioned criteria, and the average inflammation score for each group was calculated. Furthermore, on Day 6, after determining the inflammation score, the mice were sacrificed, the inflamed skin was sampled, and HE (hematoxylin eosin) pathological staining was performed.

[0097] The results are shown in Figures 6-8. Figure 6 shows photographs of each group of mice taken on Day 0 and Day 6, Figure 7 shows the time course of the mean inflammation score for each group and the mean inflammation score on Day 6, and Figure 8 shows the results of HE staining of the inflamed skin on Day 6.

[0098] Bamboo extract is known to contain components that exhibit anti-inflammatory effects. On Day 6, the group administered sCA alone showed a reduction in inflammation scores comparable to that of the group administered bamboo extract alone. In other words, this result confirms that sCA, even when applied transdermally alone, has an anti-inflammatory effect and can suppress the worsening of inflammation.

[0099] Furthermore, on Day 6, the inflammation score was significantly lower in the group administered with both bamboo extract and sCA compared to the groups administered with sCA alone and the groups administered with bamboo extract alone, demonstrating a remarkably superior anti-inflammatory effect. In other words, it was confirmed that sCA, when applied transdermally in combination with bamboo extract, can enhance the therapeutic effect of bamboo extract.

Claims

1. A transdermal preparation containing a medicinal ingredient and carbonate apatite.

2. The transdermal formulation according to claim 1, wherein the pharmacoactive ingredient is an immunosuppressant and / or a plant extract.

3. The transdermal formulation according to claim 2, wherein the immunosuppressant is cyclosporine.

4. The transdermal formulation according to claim 2, wherein the plant extract is bamboo extract.

5. A transdermal formulation according to claim 3 or 4, used for the treatment of inflammatory skin diseases.

6. A method for treating a skin disease, comprising administering a transdermal preparation containing a pharmacologically active ingredient effective in treating the skin disease and carbonate apatite to a person in need of treatment for the skin disease.

7. Use of a transdermal preparation containing a medicinal ingredient effective in treating skin diseases and carbonate apatite for the manufacture of a treatment for skin diseases.

8. A transdermal drug efficacy enhancer containing carbonate apatite as an active ingredient.

9. A transdermal agent that enhances the skin penetration of medicinal ingredients, containing carbonate apatite as the active ingredient.

10. A transdermal anti-inflammatory drug containing carbonate apatite as the active ingredient.

11. An anti-inflammatory agent according to claim 10, used for the treatment of atopic dermatitis.

12. A treatment method for inflammatory skin diseases, comprising transdermal administration of a therapeutically effective amount of carbonate apatite to patients with inflammatory skin diseases.

13. Carbonate apatite, which is administered transdermally and used to treat inflammatory skin diseases.

14. Use of carbonate apatite for the manufacture of transdermal anti-inflammatory drugs.

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