Film-forming topical preparations

Abstract

To provide a film-forming topical formulation with excellent adhesion to the skin and resistance to cracking of the film.SOLUTION: The film-forming topical formulation comprises a drug, an organic solvent, nitrocellulose, and an absorption promoter.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a film-forming external preparation. [Background technology]

[0002] Film-forming topical preparations have been developed that incorporate a film-forming agent into the topical preparation to form a thin film on the skin after application of the topical preparation to the skin. Film-forming topical preparations do not require a support such as a patch, and are therefore expected to improve the feel of use.

[0003] Patent Document 1 describes an aerosol composition that contains nitrocellulose as a film-forming agent and has excellent drying and peeling properties. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] JP 2005-281167 A Summary of the Invention [Problem to be solved by the invention]

[0005] The present inventors have investigated a film-forming external preparation containing nitrocellulose and found that it does not have sufficient adhesion to the skin and cracks in the film occur. The object of the present invention is to provide a film-forming external preparation that has excellent adhesion to the skin and is less likely to cause cracks in the film. [Means for solving the problem]

[0006] The present inventors have conducted extensive research to solve the above problems, and have found that a film-forming external preparation containing an absorption enhancer, particularly a surfactant, has excellent adhesion to the skin and is less likely to crack. Furthermore, they have also found that such a film-forming external preparation improves the skin permeability of the drug and maintains skin permeation for about one week. Based on these findings, the present inventors have completed the present invention.

[0007] That is, the film-forming external preparation of the present invention contains a drug, an organic solvent, nitrocellulose and an absorption enhancer. Effect of the Invention

[0008] The film-forming topical preparation of the present invention, when made into an aerosol preparation, has excellent adhesion to the skin and is less likely to cause cracking of the film. In addition, the film-forming topical preparation of the present invention has excellent skin permeability of the drug. [Brief description of the drawings]

[0009] [Figure 1] FIG. 2 is a perspective view of the sprayer with the lid closed. [Diagram 2] FIG. 2 is a perspective view of the sprayer with the lid open. [Diagram 3] FIG. 2 is a perspective view showing the positional relationship between the can and a lid serving as a cover. [Figure 4] FIG. 1 is a perspective view showing a spray can with a lid attached as a cover to the can. [Diagram 5] FIG. 1 is a perspective view showing a spray can with a lid attached as a cover to the can. [Figure 6] FIG. 2 is a front view and a plan view of the sprayer with the lid closed. [Figure 7] 7 is a cross-sectional view taken along line AA in FIG. 6. [Figure 8] FIG. 8 is an enlarged view of line BB in FIG. [Figure 9] FIG. 2 is a left side view and a top view of the can. [Figure 10] FIG. 2 is a front view and a plan view of the can. [Figure 11]FIG. 2 is a left side view and a top view of the sprayer with a lid attached to the can as a cover. [Figure 12] FIG. 4 is an enlarged cross-sectional view showing the change in state of the upper part of the spray. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The film-forming external preparation of the present invention contains a drug, an organic solvent, nitrocellulose and an absorption enhancer.

[0011] The drug is not particularly limited as long as it can be administered transdermally. Specific examples of the drug include steroid anti-inflammatory drugs such as prednisolone, dexamethasone, hydrocortisone, fluocinolone acetonide, betamethasone valerate, betamethasone dipropionate, clobetasone butyrate, and prednisolone succinate; methyl salicylate, glycol salicylate, indomethacin, ketoprofen, diclofenac, ibuprofen, ibuprofen piconol, flurbiprofen, felbinac, ketorolac, loxoprofen, suprofen, pranoprofen, tiaprofen, flufenamic acid, and tenidap. non-steroidal anti-inflammatory drugs and their ester derivatives, such as aspirin, actarit, mizoribine, oxaprozin, mofezolac, etodolac, auranofin, indomethacin funercil, etc.; anti-allergic drugs, such as tranilast, azelastine, ketotifen, ibudilast, oxatomide, emedastine, epinastine, etc.; antihistamines, such as diphenhydramine, chlorpheniramine, promethazine, tripelennamine, etc.; central nervous system drugs, such as chlorpromazine, nitrazepam, diazepam, phenobarbital, reserpine, etc.; Hormones such as insulin, testosterone, norethisterone, methyltestosterone, progesterone, clobetasol propionate, deprodone propionate, estradiol, etc.; antihypertensives such as clonidine, reserpine, guanethidine, efonidipine, alprenolol, nifedipine, bisoprolol, etc.; cardiac stimulants such as digitoxin, digoxin, etc.; antiarrhythmics such as propranolol, procainamide, ajmaline, pindolol, tulobuterol, mexiletine, etc.; nitroglycerin, isosorbide dinitrate, papaverine, etc. coronary vasodilators such as lidocaine, procaine, benzocaine, tetracaine, and other local anesthetics; analgesics such as morphine, aspirin, codeine, acetanilide, aminopyrine, acetaminophen, and other analgesics; muscle relaxants such as tizanidine, eperisone, tolperisone, inaperisone, dantrolene, and other antifungal agents; acetophenylamine, nitrofurazone, pentamycin, naphthiomate, miconazole, omoconazole, clotrimazole, neticonazole, efinaconazole, butenafine, and other antifungal agents;Anticancer drugs such as 5-fluorouracil, busulfan, actinomycin, bleomycin, and mitomycin; urinary incontinence drugs such as terolidine and oxybutynin; antiepileptic drugs such as nitrazepam and meprobamate; anti-Parkinson's drugs such as chlorzoxazone, levodopa, amantadine, selegiline, ranolazine, and ropinirole; granisetron, azasetron, ondansetron, ramosetron, palonosetron, etc. antiemetics; drugs for treating frequent urination such as oxybutynin and imidafenacin; calcium antagonists such as nifedipine, nicardipine, and nilvadipine; narcotic analgesics such as fentanyl and morphine; antidizziness drugs such as diphenidol and betahistine; cardiovascular drugs such as benzothiazepines; antitussives and expectorants such as ketotifen, tulobuterol, and tranilast; vinpocetine, nicergoline, nicorandil, clenchiaceme maleate, and fas Examples of such agents include cerebral circulation improvers such as cerebrovascular dementia drugs such as docosahexaenoic acid, vinconate, and nebracetam; Alzheimer's treatment agents such as donepezil, amylidine, memantine, rivastigmine, and galantamine; polypeptide hormone agents such as rootinizing hormone-releasing hormone and thyrotropin releasing hormone; immunomodulators such as polysaccharides, auranofin, and lobenzarit; cholagogues such as ursodesoxycholic acid; diuretics such as hydroflumethiazide; diabetes drugs such as tolbutamide; gout treatment agents such as colchicine; smoking cessation aids such as nicotine; central nervous system stimulants such as methylphenidate; antipsychotic drugs such as olanzapine, risperidone, and asenapine; hair growth agents such as minoxidil; vitamins; prostaglandins; hypnotics and sedatives; autonomic nervous system agents; and peripheral vasodilators. The above-mentioned drug may be in the form of a free substance or a pharma- ceutically acceptable salt. From the viewpoint of skin permeability, it is preferable that the drug is an acidic drug such as ketoprofen, diclofenac, felbinac, or loxoprofen, and it is particularly preferable that the drug is diclofenac or a pharma-ceutically acceptable salt thereof. The drug concentration may be 1% by mass to 30% by mass (based on the total mass of the film-forming external preparation (however, in the case of an aerosol preparation, based on the total mass of the drug solution excluding the propellant); the same applies below).

[0012] The organic solvent is a medium for dissolving or dispersing the drug and other components. Specific examples include methanol, ethanol, isopropanol, ethyl acetate, n-butyl acetate, acetone, ether, trichloroethane, benzyl alcohol, methyl isobutyl ketone, and methyl ethyl ketone. From the viewpoint of solubility, the organic solvent is preferably at least one selected from ethanol and ethyl acetate. The concentration of the organic solvent can be 60% by mass to 90% by mass.

[0013] Nitrocellulose functions as a film-forming agent. For example, industrial nitrocellulose (nitrocellulose) conforming to the JIS K6703-1995 standard, moistened with a moistening agent such as isopropanol at 25% to 35% by mass (based on the total mass of the product), can be used as nitrocellulose. Specific examples include RS 1 / 32, RS 1 / 16, RS 1 / 8, RS 1 / 4, RS 1 / 2, RS 1, RS 2, RS 5, RS 7, RS 20, RS 60, RS 120, RS 500, SS 1 / 8, SS 1 / 4, SS 1 / 2, and SS20 (manufactured by KOREA CNC LTD.). The concentration of nitrocellulose can be 3% to 18% by mass.

[0014] The absorption enhancer enhances the adhesion of the film-forming external preparation to the skin and inhibits the occurrence of cracks in the film. The absorption enhancer may be any compound that has been known to have an absorption enhancing effect in the skin. Examples of the absorption enhancer include surfactants and fatty acid esters (isopropyl palmitate, isopropyl myristate, ethyl oleate, etc.). Examples of the nonionic surfactant include polyoxyethylene alkyl ethers such as polyoxyethylene oleyl ether, polyoxyethylene lauryl ether, and polyoxyethylene stearyl ether; polyethylene glycol fatty acid esters such as polyethylene glycol monooleate; polyoxyethylene glycerin fatty acid esters such as polyoxyethylene glyceryl monostearate; polyoxyethylene sorbitol fatty acid esters such as polyoxyethylene sorbitol tetraoleate; and polyoxyethylene polyoxypropylene alkyl ethers such as polyoxyethylene polyoxypropylene cetyl ether. From the viewpoint of enhancing the adhesion of the external preparation to the skin and inhibiting the occurrence of cracks in the film, the absorption enhancer is preferably a surfactant, and particularly preferably a nonionic surfactant or an anionic surfactant. The concentration of the absorption enhancer can be from 1% by mass to 15% by mass.

[0015] The film-forming external preparation preferably contains a pH adjuster. By containing a pH adjuster, the skin permeability of the drug is improved. Examples of the pH adjuster include hydrochloric acid, citric acid, gluconic acid, succinic acid, acetic acid, tartaric acid, lactic acid, boric acid, maleic acid, phosphoric acid, sulfuric acid, adipic acid, malic acid, glucono-δ-lactone, monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine, diisopropanolamine, triisopropanolamine, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, sodium bicarbonate, sodium citrate, sodium acetate, sodium lactate, calcium lactate, and meglumine. From the viewpoint of improving the skin permeability of the drug, the pH adjuster is preferably lactic acid. The concentration of the pH adjuster can be 0.1% by mass to 10% by mass.

[0016] The film-forming external preparation may contain, in addition to the above-mentioned components, a plasticizer, a moisturizer, a stabilizer, a preservative, a refreshing agent, a fragrance, and the like.

[0017] Plasticizers include higher alcohols such as oleyl alcohol, octyldodecanol, myristyl alcohol, isostearyl alcohol, and lauryl alcohol.

[0018] The humectants include polyhydric alcohols such as sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, liquid paraffin, 1,3-propanediol, and 1,4-butanediol.

[0019] Stabilizers include, for example, oxybenzone, dibutylhydroxytoluene (BHT), sodium edetate, and UV absorbers (eg, dibenzoylmethane derivatives).

[0020] Preservatives include paraoxybenzoic acid esters (for example, methylparaben, ethylparaben, and propylparaben).

[0021] Examples of the cooling agent include thymol, l-menthol, dl-menthol, l-isopulegol, and peppermint oil.

[0022] The film-forming external preparation may be in the form of a lotion, liniment, gel, or the like, or may be in the form of an aerosol preparation.

[0023] When the film-forming external preparation is in the form of an aerosol preparation, the aerosol composition can be produced by filling an aerosol container with a drug solution containing the above-mentioned components, attaching a valve to the container, and filling the container with a propellant. Furthermore, an aerosol preparation can be produced by attaching an ejection button to the container.

[0024] The propellant may be a known substance used in aerosol preparations, such as dimethyl ether, liquefied petroleum gas (LPG), nitrogen gas, carbon dioxide gas, alternative fluorocarbon gas, etc. The ratio (mass ratio) of the drug solution to the propellant may be 1:9 to 9:1.

[0025] The container for housing the aerosol composition can be a typical container used for aerosol formulations. Typically, a metal container made of aluminum, steel, tinplate, or the like is used, and the inner surface of the metal container may be coated with an epoxy resin, a phenolic resin, a polyamideimide resin, or the like.

[0026] The structure of a spray 1, which is an example of a container for accommodating an aerosol composition, will be described with reference to Figures 1 to 12. The spray 1 is a device that sprays a given substance (e.g., a film-forming external preparation) in the form of mist, foam, or the like, using a high-pressure propellant.

[0027] 1 and 2 are both perspective views of the sprayer 1. The sprayer 1 includes a can 10 that contains an aerosol composition and a lid 20 that is removably attached to one end of the can 10. FIG. 1 shows a state in which the lid 20 is closed, and FIG. 2 shows a state in which the lid 20 is open. In the present disclosure, the side on which the lid 20 is closed is defined as the upper side of the sprayer 1, and the opposite side, i.e., the bottom side of the can 10, is defined as the lower side of the sprayer 1. An injection button 11 is provided at the upper end of the can 10. An injection hole 12 is provided on the side of the injection button 11. When a user presses the injection button 11 toward the bottom of the can 10, the aerosol composition is released from the injection hole 12 to the outside. A side wall 13 is provided so as to surround at least a part of the side of the injection button 11. A receiving frame 14 formed in a concave shape (for example, U-shaped) facing downward is provided on the part of the side wall 13 facing the injection hole 12. A cylindrical protrusion extending upward is formed in the center of the end face (top face) of the lid 20. A through hole 21 is formed inside the protrusion along the up-down direction (also called the axial direction of the lid 20). A groove 22 is formed around the entire circumference of the outer surface of the protrusion. In other words, the groove 22 is formed along the through hole 21.

[0028] FIG. 3 is a perspective view showing the positional relationship between the can 10 and the lid 20 when the lid 20 is attached to the can 10 as a cover. FIG. 4 and FIG. 5 are perspective views showing the spray 1 with the lid 20 attached to the can 10 as a cover. FIG. 4 is a view of the spray 1 from the injection hole 12 side, and FIG. 5 is a view of the spray 1 from the opposite side. As shown in these figures, the receiving frame 14 of the can 10 and the groove 22 of the lid 20 are formed so that the groove 22 fits detachably into the receiving frame 14. A user can attach the lid 20 to the can 10 by placing the lid 20 sideways relative to the can 10 and pushing the lid 20 into the can 10 so that the groove 22 fits into the receiving frame 14. As a result, the can 10 and the lid 20 are integrated so that the injection hole 12 and the internal space 23 of the lid 20 are in communication with each other. "The injection hole and the internal space of the lid are in communication with each other" means that the injection hole and the internal space are connected so that the aerosol composition discharged from the injection hole can pass through the internal space of the lid. The spray range of the aerosol composition is limited by the internal space 23. That is, the lid 20 attached in front of the injection hole 12 (i.e., in the spray direction of the aerosol composition) functions as a cylindrical cover for limiting the spray range. The mark 11a formed on the end face (upper face) of the injection button 11 indicates the direction in which the injection hole 12 is located, and also indicates the side to which the lid 20 is attached as a cover.

[0029] 6 is a front view and a plan view of the sprayer 1 with the lid 20 closed. In this disclosure, the side directly facing the injection hole 12 is defined as the front of the sprayer 1. The left side view, right side view, and rear view of the sprayer 1 are the same as the front view. The bottom view of the sprayer 1 is represented by a single circle. As shown in the plan view, the injection button 11 is visible through the through hole 21 of the lid 20 even when the lid 20 is closed.

[0030] Fig. 7 is a cross-sectional view taken along line AA in Fig. 6. Fig. 8 is an enlarged view taken along line BB in Fig. 7. An internal space 15 of can 10 containing the aerosol composition and jet hole 12 are connected by a thin tubular passage 16 extending vertically. In response to pressing of jet button 11, the aerosol composition passes from internal space 15 through passage 16 to jet hole 12 and is sprayed from jet hole 12 to the outside.

[0031] 9 is a left side view and a top view of can 10. The right side view of can 10 is symmetrical to the left side view. FIG. 10 is a front view and a top view of can 10.

[0032] FIG. 11 is a left side view and a plan view of the sprayer 1 with the lid 20 attached to the can 10 as a cover. The right side view of the sprayer 1 is symmetrical to the left side view. FIG. 12 is an enlarged cross-sectional view showing the state change of the upper part of the sprayer 1. The diagram showing state S1 is a cross-sectional view taken along line DD in FIG. 11, enlarged based on line CC. State S1 is an initial state in which the spray button 11 is not pressed. When the user presses the spray button 11, the upper part of the sprayer 1 transitions to state S2. In state S2, the spray hole 12 and the central axis 100 of the lid 20 (and the internal space 23) coincide or nearly coincide. When the user stops pressing the spray button 11, the upper part of the sprayer 1 returns to state S1.

[0033] As described above, the spray according to one aspect of the present disclosure includes a can having a spray button with a spray hole and a side wall surrounding at least a portion of the side of the spray button, and a lid removably attached to the can. A through hole corresponding to the spray hole and a groove along the through hole are formed in an end of the lid. A concave receiving frame is formed in a portion of the side wall facing the spray hole. The groove is removably fitted into the receiving frame, thereby communicating the spray hole with the internal space of the lid. EXAMPLES

[0034] Test Example 1: Evaluation of Water Resistance The components shown in Tables 1 and 2 were weighed out (unit: parts by weight) and mixed until uniform to obtain topical preparations. The solubility of the topical preparations obtained, the presence or absence of film formation, and the water resistance of the film were evaluated under the following conditions.

[0035] Solubility evaluation The solubility of the topical preparation was evaluated by visual observation. Evaluation criteria A: Dissolves uniformly B: Two-layer separation occurs C: Undissolved matter or precipitates are generated

[0036] Evaluation of the presence or absence of film formation 0.1 g of the topical preparation was dropped onto a liner (plastic film) and then spread over an area with a diameter of 5 cm. The presence or absence of film formation was evaluated visually. Evaluation criteria A: Forms a film C: A film is formed but not uniformly or no film is formed

[0037] Water resistance evaluation of the film 0.1 g of the topical preparation was dropped onto a liner (plastic film), and then spread over an area of ​​5 cm in diameter to form a film. After the film was formed, purified water was dropped onto the film, and the state of the film was visually evaluated 5 minutes later. Evaluation criteria A: The film is not dissolved and is attached. B: Part of the coating has dissolved or peeled off C: The film is dissolved

[0038] [Table 1]

[0039] [Table 2]

[0040] As shown in Tables 1 and 2, it was confirmed that the topical preparations containing aminoalkyl methacrylate copolymer and nitrocellulose have excellent solubility, film-forming ability, and film water resistance. Taking water resistance into consideration, it was confirmed that the most excellent film-forming agent is nitrocellulose.

[0041] Test Example 2: Evaluation of skin permeation duration and improvement of cracks The components shown in Tables 3 and 4 below were weighed out (unit: parts by mass) and mixed until uniform to obtain a film-forming topical preparation. The skin permeability of the obtained topical preparation was evaluated under the following conditions.

[0042] Hairless mouse skin permeability test The amount of diclofenac permeated through the skin of the prepared film-forming topical preparations was measured using hairless mice. First, the dermis side of the excised hairless mouse skin was placed in a flow-through diffusion cell as the receptor liquid side. Then, 40 mg of each of the prepared film-forming topical preparations was dropped onto the hairless mouse skin (stratum corneum side) and the cells were separated by 5 cm. 2 The cell was then filled with phosphate buffered saline, and warm water was circulated around the cell so that the skin surface temperature was 32±1°C. Sampling was performed every 6 hours, and the flow rate of the receptor solution obtained at each point was accurately measured, and the drug concentration was measured by high performance liquid chromatography. The amount of skin permeation was measured from the measured values ​​of flow rate and drug concentration.

[0043] Coating adhesion and crack evaluation Some of the topical preparations shown in Table 5 were filled into an aerosol container, and a valve was attached to the aerosol container, followed by filling the container with the topical preparation and propellant (dimethyl ether) in a mass ratio of 1:1 to obtain a film-forming aerosol composition. A spray button was then attached to the aerosol container to produce a film-forming aerosol preparation. The obtained film-forming aerosol preparation was sprayed onto the skin for 1 second, and the film properties after 4 hours were visually observed, and the adhesion and cracks were evaluated according to the following criteria. A: More than 90% adhesion, no cracks observed B: More than 90% of the surface is attached, but some cracks are visible. C: Less than 90% adhesion or many cracks

[0044] [Table 3]

[0045] [Table 4]

[0046] [Table 5]

[0047] It was confirmed that topical preparations 12 and 13 have low skin permeability. In addition, topical preparation 14 has superior permeability compared to topical preparations 12 and 13, but when made into an aerosol preparation, it was confirmed that adhesion to the membrane was reduced and cracks occurred (aerosol preparation 3).

[0048] On the other hand, it was confirmed that topical preparations 15 and 16, which contain a surfactant as an absorption enhancer, have good skin permeability, and furthermore, when made into an aerosol preparation, they have excellent adhesion of the film and can suppress the occurrence of cracks (aerosol preparations 4 and 5). In addition, the results of topical preparations 17 to 19 confirmed that the permeability was further improved by adding lactic acid as a pH adjuster.

[0049] Test Example 3: Confirmation of skin permeation persistence in human skin The components shown in Table 6 below were weighed out (unit: parts by weight) and mixed until uniform to obtain a film-forming external preparation. The human skin permeability of the obtained film-forming external preparation was evaluated under the following conditions.

[0050] Human skin permeability test The amount of diclofenac permeated through the skin was measured using human skin cut (dermatome) to a thickness of about 500 μm from the stratum corneum side for testing. First, the excised human skin was placed in a flow-through diffusion cell with the dermis side as the receptor liquid side. Then, 80 mg of the prepared film-forming topical preparation was dropped onto the human skin (stratum corneum side), and the cell was allowed to stand for 5 cm. 2 The cell was then filled with phosphate buffered saline, and warm water was circulated around the cell so that the skin surface temperature was 32±1°C. Sampling was performed every 6 hours, and the flow rate of the receptor solution obtained at each point was accurately measured, and the drug concentration was measured by high performance liquid chromatography. The amount of skin permeation was measured from the measured values ​​of flow rate and drug concentration.

[0051] [Table 6]

[0052] [Table 7]

[0053] As is clear from the results shown in Table 7, it was confirmed that the obtained film-forming external preparation maintained the skin permeability of the drug for one week. [Explanation of symbols]

[0054] 1...spray, 10...can, 11...spray button, 11a...mark, 12...spray hole, 13...side wall, 14...receiving frame, 15...internal space, 16...passage, 20...lid, 21...through hole, 22...groove, 23...internal space.

Claims

1. containing a drug, an organic solvent, nitrocellulose, an absorption enhancer, and a pH adjuster, The absorption enhancer is at least one selected from polyoxyethylene alkyl ethers and polyethylene glycol fatty acid esters. Film-forming topical preparation.

2. 2. The film-forming external preparation according to claim 1, wherein the absorption enhancer is at least one selected from polyoxyethylene oleyl ether and polyethylene glycol monooleate.

3. A film-forming topical preparation according to claim 1 or 2, further comprising at least one plasticizer selected from oleyl alcohol, octyldodecanol, myristyl alcohol, isostearyl alcohol and lauryl alcohol.

4. 4. The film-forming external preparation according to claim 1, wherein the organic solvent is at least one selected from the group consisting of ethanol and ethyl acetate.

5. The film-forming external preparation according to any one of claims 1 to 4, wherein the drug is an acidic drug.

6. The film-forming external preparation according to any one of claims 1 to 5, which is an aerosol preparation.

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