JP5367992B2 - Aerosol for transdermal administration containing transdermal drug - Google Patents

Description

  The present invention relates to an aerosol drug for transdermal absorption. More specifically, the present invention relates to an aerosol of a transdermal drug with suppressed occurrence of dripping at an application site.

The aerosol technology for injecting the contents contained in a pressure-resistant container into a mist or foam using the pressure of gas is used in many fields such as the paint field and the pharmaceutical field.
Normally, this aerosol device (aerosol can) is attached to the tip of the stem with a valve mechanism that is opened by pushing down the stem supported so as to be movable in the vertical direction while being biased upward by a spring. Button (actuator) that can be used. In use, the valve mechanism is opened by pressing the button downward or the like, and the contents in the container are ejected from the nozzle through the depressed stem.

  Aerosols have many advantages such as simple operation, rapid administration, multiple use, low microbial contamination, drug stability against air and light, etc. In the pharmaceutical field, it is widely used as a dosage form intended for external use or inhalation administration of a drug.

The aerosol agent has a problem that when a large amount of content is sprayed to obtain the expected effect, dripping occurs at the application site and the feeling of use is lowered. For this reason, research and development on the composition of contents for suppressing dripping are being conducted.
For example, it is known that by adding a carboxyvinyl polymer to an aerosol composition for gel formation, the stock solution is thickened (gelled), and dripping at the application site can be prevented (Patent Document 1).
In addition, it is known that dripping is difficult by adding an aliphatic hydrocarbon to the aerosol composition (Patent Document 2).
In addition, an aerosol composition containing a specific amount of polyvinylpyrrolidone, carboxyvinyl polymer, one or more bases, alcohols, water and a pharmacologically active ingredient in the stock solution and adjusting the mass ratio of the stock solution and the propellant is suitable. It is known that it has a good viscosity, does not drip during injection, has little stickiness, and has a good feeling of use (Patent Document 3).
However, none of these was sufficient for suppressing dripping at the application site.

On the other hand, in a device related to aerosol, it is known that an injection pattern is flattened in one direction in order to prevent unnecessary diffusion and the like.
For example, there is known an aerosol nozzle that obtains a spray pattern that approximates a rectangular shape that can be efficiently sprayed and applied to a target portion or can prevent the aerosol contents from being scattered outside the target portion (Patent Document 4).
Further, an injector is known in which the contents of a container can be sprayed in the form of mist, foam, or powder in a layered spray pattern and can solve problems such as diffusion toward the user (Patent Document 5).
Japanese Patent Laid-Open No. 11-35419 JP 2006-321760 A JP 2007-22994 A JP 2001-205145 A JP 2001-300353 A

  However, all of these aerosol devices are for preventing unnecessary diffusion and scattering, and no consideration is given to dripping at the application site after injection. Moreover, it is not in the field of medicine or the like that is intended to absorb the contents from the skin that is the application site.

  Accordingly, an object of the present invention is to provide an aerosol containing a transdermally absorbable drug in which the occurrence of dripping at the application site is suppressed.

First, in view of the prior art, the present inventors have intensively studied the composition of contents such as a transdermal drug.
However, it has been discovered that the increase in viscosity causes clogging of the device and causes jetting troubles, and there is inevitably a limit to preventing dripping only by increasing the viscosity as has been done conventionally.
Therefore, further diligent investigation was conducted, and attention was paid to the structure of the member related to the device. It was found that by using a device that exhibits a spray pattern that flatly spreads in one direction at the time of spraying, the occurrence of dripping can be suppressed. The present inventors have also found that an excellent medicinal effect can be obtained by using an aerosol agent, thereby completing the present invention.

That is, the present invention is provided with a pair of protrusions protruding toward the both sides of the injection hole in the injection direction, one direction is sealed in a container of Lud devices that Teisu the injection pattern spread in a flat during injection, at least one containing percutaneous absorption drug, in which the percutaneous absorption drug to provide for transdermal administration aerosol comprising a raw liquid is an anti-inflammatory agent.

  ADVANTAGE OF THE INVENTION According to this invention, as a result of suppressing the dripping in an application site | part, the usability | use_condition can be provided and the aerosol agent excellent in the medicinal effect can be provided.

In the present invention, as the `` device that exhibits a spray pattern that spreads flat in one direction at the time of spraying '', a known device can be used, and is not particularly limited as long as it exhibits a spray pattern that spreads flat in one direction. From the standpoint of medicinal effect, a device in which the contents are liquefied at the application part is preferable. It is more preferable to use a device that blocks the injection of the gas and exhibits an injection pattern that spreads flatly in one direction.
Such an “injection pattern that spreads flat in one direction” is a direction in which an injection pattern (the shape of a region to which the contents are applied) formed on the plane when the aerosol agent is injected perpendicularly to the plane is in a certain direction. The injection width is not particularly limited as long as the injection width is longer than the injection width in the other direction, and examples thereof include a substantially elliptical injection pattern and a substantially rectangular injection pattern. Of these, the length in the longitudinal direction: the length in the short direction of the “injection pattern flattened in one direction” is preferably 1.5: 1 to 15: 1, and 2: 1 to 10: 1. Is more preferable, and 2: 1 to 6: 1 is particularly preferable. Here, the longitudinal direction refers to the direction spread by the ejection of the device, and the short direction refers to the direction orthogonal to the longitudinal direction. In addition, the injection angle of the injection that exhibits an injection pattern flattened in one direction is preferably a maximum angle of 25 ° to 55 °, a minimum angle of 5 ° to 25 °, and a maximum angle of 30 ° to 30 °. More preferably, the angle is 50 ° and the minimum angle is 5 ° to 20 °.
Further, “one direction” means an arbitrary direction, and may be, for example, an injection pattern that flattenes in the vertical direction or an injection pattern that flattenes in the horizontal direction.

In the present invention, the injection amount of the contents is preferably 0.001 g / sec to 10 g / sec from the viewpoint of obtaining a sufficient medicinal effect by reaching a sufficient amount of the percutaneously absorbed drug to the application site and suppressing dripping. It is more preferably 0.01 g / sec to 5 g / sec, particularly preferably 0.1 g / sec to 1 g / sec. In addition, the said injection amount means the measured value at the time of making internal pressure constant on 25 degreeC temperature conditions.

  As a preferred specific example of “a device that exhibits an injection pattern that spreads flat in one direction at the time of injection”, (I) a device including a pair of protrusions that protrude in the injection direction from both sides sandwiching the injection hole; A device having a groove extending in one direction provided from the outer surface in a region to be included, (III) a shape having a relatively long hole width in one direction compared to the hole width in another direction, such as a substantially elliptical shape or a substantially rectangular shape. A device provided with a nozzle is mentioned.

If the “device that presents an ejection pattern that flatly spreads in one direction during ejection” is a device that includes (I) a pair of projections that project toward the ejection direction from both sides sandwiching the ejection port, projections located on both sides that sandwich the ejection port Acts as a baffle plate, and the contents ejected from the nozzle hole are obstructed by the projections and exhibit an ejection pattern that spreads flat in a direction in which no projections are provided.
In this case, the position, shape, number, and the like of the protrusions are not particularly limited, and can be appropriately set so that the ejection pattern has a flat shape. Specific examples of such devices are shown in FIGS. In FIG. 1, the nozzle (4) is provided with a nozzle hole (2) and protrusions (3) located on the left and right sides thereof, and the nozzle is fitted into the button (1). When the contents are ejected from the nozzle hole, the left and right protrusions act as baffle plates, and thus present an ejection pattern that spreads flat in the vertical direction. In FIG. 2, the nozzle (4) is provided with a nozzle (2) and a projection (3) positioned above and below the nozzle (4), and the nozzle is inserted into the button (1). When the contents are ejected from the ejection port, the upper and lower protrusions act as baffle plates, and thus present an ejection pattern that spreads flat in the lateral direction.
In (I), a nozzle provided with a pair of protrusions protruding in the injection direction from both sides sandwiching the injection hole is arranged around the injection direction in that a flat direction can be arbitrarily set by rotation of the nozzle. A device having a button that is rotatably inserted is preferable.

If the device that has a spray pattern that flatly spreads in one direction during spraying is a device that has a groove extending in one direction provided from the outer surface in the area containing the nozzle (II), the wall surface of the groove acts as a baffle plate Then, the contents ejected from the nozzle hole are blocked by the wall surface of the groove and present a spray pattern that spreads flat in the direction in which the groove extends. In this case, the depth, width and the like of the groove are not particularly limited, and can be appropriately set so that the spray pattern has a flat shape. A specific example of such a device (only a button is shown) is shown in FIG. In FIG. 3, the nozzle (4) is provided with a groove (7) extending in the lateral direction from the outer surface in a region including the nozzle hole (2), and the nozzle is fitted into the button (1). When the contents are ejected from the nozzle hole, the wall surface of the groove acts as a baffle plate, resulting in a spray pattern that spreads flat in the lateral direction.
In (II), a nozzle with a groove extending in one direction provided from the outer surface in the area around it is rotated around the injection direction in that the flat direction can be arbitrarily set by rotating the nozzle. A device comprising a button that is slidably inserted is preferred.

“Devices that exhibit an injection pattern that flatly spreads in one direction during injection” are (III) substantially elliptical, rectangular, etc., where the hole width in one direction is relatively long compared to the hole width in the other direction. In the case of a device having a nozzle hole, the wall surface of the nozzle hole in the direction with a relatively small hole width acts more strongly as a baffle plate than the wall surface of the nozzle hole in a direction with a relatively large hole width. The injection in the short direction is blocked as compared with the injection in the long direction, and exhibits an injection pattern that spreads flat in the direction of the long hole width. In this case, the shape and size of the nozzle hole are not particularly limited, and can be set as appropriate so that the injection pattern has a flat shape. A specific example of such a device (only a button is shown) is shown in FIG. In FIG. 4, the nozzle (4) is provided with a vertically long elliptical nozzle hole (2), and the nozzle is fitted into the button (1). When the contents are ejected from the ejection port, lateral ejection with a relatively short hole width is blocked, and an ejection pattern spreading flat in the longitudinal direction is exhibited.
In (III), a device including a button in which a nozzle having a nozzle hole is rotatably inserted around the injection direction is preferable in that a flat direction can be arbitrarily set by rotation of the nozzle.

Moreover, in this invention, the device provided with the nozzle of patent document 4, the sprayer of patent document 5, etc. can be used.
As a commercial product of a device that exhibits an injection pattern that spreads flat in one direction at the time of injection, F-96 (manufactured by Maruichi Co., Ltd .: provided with a pair of protrusions that protrude in the injection direction from both sides sandwiching the injection hole ) And the like.

  1 to 4 show a case where the button of the device is a set of a plurality of members (a configuration in which the nozzle is fitted into the button), but the button may be a single member as a whole. An example of such a button is shown in FIG.

Although FIGS. 1-5 showed the example at the time of employ | adopting a button as a member which acts on force to open and close a valve, this invention is not limited to this, The well-known used for opening and closing a valve in a device Means may be employed.
Examples of such known means include a trigger type cap. A specific example of the trigger type cap is shown in FIG. In this case, the valve is opened by applying a force to the trigger (9) of the trigger type cap (8), and the contents are injected from the nozzle (2). In this case, since the left and right protrusions (3) act as baffle plates, an ejection pattern spreading flat in the vertical direction is exhibited. In addition, although the specific example provided with a pair of protrusion which protrudes toward the injection direction from both sides which pinch | interpose a nozzle hole was shown in FIG. 6, like the case of a button, it is in one direction provided from the outer surface in the area | region containing a nozzle hole. Other configurations such as a configuration including an extending groove and a configuration including a nozzle hole having a relatively long hole width in a certain direction, such as a substantially elliptical shape or a substantially rectangular shape, may be employed.

  The diameter of the nozzle hole in the device is not particularly limited and can be appropriately selected depending on the viscosity of the contents. For example, in the case of adopting a circular nozzle hole, the dripping suppression effect, the adhesion rate of the contents, and the viewpoint of safety Therefore, it is preferable to be within the range of 0.35 to 0.65 mmΦ.

  A known valve can be used for the device, and a valve having a quantitative function may be used. Further, a valve that can be used upside down, such as a metal valve / check valve system, a system with a weight attached to the tip of a flexible dip tube, or a jumbo pipe system, may be used.

In the present invention, the “container” of the device is not limited as long as it is used as a container for the device.
Examples of the material include tinplate, aluminum, stainless steel, glass, and plastic. Moreover, in order to avoid reaction with the content and the container surface, you may coat resin on the surface in a container. Examples of such a resin include epoxy phenol, epoxy amino, and polyamide imide.

  In the present invention, the “stock solution” may be any solution, suspension, dispersion, gel or other liquid form at normal temperature and normal pressure.

  In the present invention, the “transdermally absorbable drug” can be used without particular limitation as long as it has transdermal absorbability regardless of whether it is a systemic drug or a topical drug. Specifically, for example, hydrocortisone, Prednisolone, dexamethasone, triamcinolone, betamethasone, actarit, acemetacin, ampiroxicam, ibuprofen, indomethacin, etodolac, ketoprofen, zaltoprofen, diclofenac, sulindac, celecoxib, thiaprofenic acid, tenoxicam, naproxenfenprofenfirfluam , Mefenamic acid, medicoxib, meloxicam, mofezolac, lefecoxib, loxoprofen, lobenzalite, lornoxicam, bufexamac, antipyrine, -Anti-inflammatory agents such as menthol, glycyrrhetinic acid, glycyrrhizic acid, methyl salicylate, glycol salicylate, ethylene glycol salicylate, arnica tincture, horse chestnut seed extract, dried licorice extract; skeletal muscle relaxants such as eperisone, tolperisone, tizanidine, pridinol; Vasodilators such as nitroglycerin, isosorbide nitrate, carpronium, minoxidil; vasoconstrictors such as nafazoline, phenylephrine, benzyl nicotinate; clotrimazole, miconazole, econazole, croconazole, isoconazole, pyrrolnitrin, butenafine, terbinafine, omoconazole , Lanoconazole, riranaphthate, itraconazole, fluconazole, tolnaftate, sulconazole, bifonazo Antifungal agents such as: lidocaine, dibucaine, oxyprocaine, etc .; local anesthetics such as crotamiton, ictamol; antihistamines such as diphenhydramine, clemastine, isothipentyl; d-camphor, dl-camphor, d-borneol, fennel oil, Refreshing agents such as cinnamon oil, peppermint oil, bergamot oil, eucalyptus oil, peppermint water, geraniol, and agate; anti-herpes agents such as acyclovir and salts thereof (metal salts such as sodium salt and potassium salt; hydrochloride salt, sulfuric acid Mineral salts such as salts and nitrates; organic acid salts such as citrate, fumarate, tannate, salicylate, etc.), and one or more of these can be used at the same time . The aerosol of the present invention is, for example, an anti-inflammatory agent as a transdermal drug, specifically, for example, indomethacin, ferbinac, methyl salicylate, glycol salicylate, ethylene glycol salicylate, diclofenac, ketoprofen, l-menthol, ibuprofen, flurbipro. It can be suitably used as an aerosol agent for external analgesic and anti-inflammatory, containing at least one selected from the group consisting of phen, loxoprofen, dried sashish extract and salts thereof.

  In the present invention, the blending amount of the transdermally absorbable drug is not particularly limited and can be appropriately determined according to the drug to be used. For example, 0.001 to 5% by mass is preferable with respect to the total mass of the stock solution. -2 mass% is more preferable, and 0.1-1.5 mass% is especially preferable.

  In the present invention, it is preferable that a film-forming polymer is blended in the stock solution from the viewpoint of dripping suppression effect and medicinal effect. By blending the film-forming polymer with the stock solution, a uniform film is formed at the application site, and dripping is further suppressed. Moreover, percutaneous absorption is accelerated | stimulated by the obstruction | occlusion effect by film formation, and a medicinal effect becomes more remarkable. In the present invention, examples of the “film-forming polymer” include methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, and hydroxybutylcellulose. , Celluloses such as nitrocellulose, carboxymethylcellulose, potassium carboxymethylcellulose, carboxymethylcellulose calcium, sodium carboxymethylcellulose, carboxymethylethylcellulose; vinyl polymers such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl acetate; carboxyvinyl polymer Acrylic polymers such as guar gum, xanthan gum, locust bean gum, tragacanth, gum arabic, gellan gum, sodium chondroitin sulfate, sodium hyaluronate, sodium alginate, calcium alginate, etc., carrageenan, quince seed, galactan, mannan, starch Natural water-soluble polymers such as pectin, dextrin, curdlan, casein, collagen and the like, and one or more of these can be used simultaneously. In the present invention, celluloses are preferable from the viewpoint of dripping suppression effect and medicinal effect, and more preferably at least one selected from the group consisting of methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. , Hydroxypropylcellulose, and hydroxypropylmethylcellulose are more preferably selected from the group consisting of hydroxypropylcellulose and hydroxypropylmethylcellulose, and a combination of hydroxypropylcellulose and hydroxypropylmethylcellulose is particularly preferable.

  In the present invention, the blending amount of the film-forming polymer that is arbitrarily blended is not particularly limited and can be appropriately determined according to the polymer to be used, etc. 0.03 to 2 mass% is preferable with respect to the total mass of the stock solution, and 0.05 to 1 mass% is more preferable.

In the present invention, components such as a solubilizer, a neutralizing agent, a preservative, a stabilizer, a wetting agent, and an oil can be used in the stock solution according to the purpose of blending, if necessary.
Examples of the solubilizer include lower alcohols such as ethyl alcohol and isopropanol; monohydric alcohols such as benzyl alcohol, stearyl alcohol and oleyl alcohol; concentrated glycerin, 1,3-butylene glycol, 2-ethyl-1,3- Examples thereof include polyhydric alcohols such as hexanediol and polypropylene glycol.
Examples of the neutralizing agent include organic acids such as citric acid, tartaric acid, and lactic acid; inorganic acids such as phosphoric acid and hydrochloric acid; alkali hydroxides such as sodium hydroxide; amines such as triethanolamine, diethanolamine, and diisopropanolamine. Etc.
Examples of the preservative include p-hydroxybenzoates, benzalkonium chloride, and the like.
Examples of the stabilizer include sodium sulfite, sodium hydrogen sulfite, dibutylhydroxytoluene, butylhydroxyanisole, edetic acid and the like.
Examples of the wetting agent include polyhydric alcohols such as glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, isopropylene glycol, sorbitol, and polyethylene glycol.
Examples of the oil component include hydrocarbons such as squalane and liquid paraffin; esters such as isopropyl myristate, diisopropyl adipate and octyldodecyl myristate.

  In the present invention, the viscosity of the undiluted solution at 25 ° C. is not particularly limited, but from the viewpoint of dripping suppression effect, medicinal effect, and prevention of device clogging, a rotational speed of 60 rpm using a B-type viscometer (No. 2 rotor). Is preferably 5 to 3000 mPa · s, more preferably 10 to 500 mPa · s, and particularly preferably 20 to 80 mPa · s. Examples of the B-type viscometer include those manufactured by Toki Sangyo Co., Ltd. In addition, the viscosity of the undiluted solution may be measured as it is, or the content of the aerosol agent of the present invention is jetted, and the remaining propellant in some cases is ultrasonicated from the jetted content. The viscosity of the resulting stock solution may be measured by volatilization by, for example.

  In the present invention, a propellant is used for jetting the contents. The type of the propellant is not particularly limited. Specifically, for example, fluorinated hydrocarbons such as CFC11, CFC12, CFC114, HCFC22, HCFC123, HCFC141b, HFA134a, and HFA227; hydrocarbons such as propane and n-butane; dimethyl ether and the like Ethers; compressed gas such as nitrogen gas, nitrous oxide gas, carbon dioxide gas, and the like, and one or more of these can be used simultaneously. In the present invention, dimethyl ether is particularly preferred from the viewpoint of usability and compatibility with water and organic solvents. The propellant may be filled in the same container as the stock solution or in a separate container. In the case of filling in another container, for example, a double-structure aerosol container as disclosed in Japanese Patent No. 293248 is used, and the stock solution is placed in the inner cylinder (inner bag), and the inner cylinder (inner bag). And filling the gap between the outer cylinders with a propellant.

  In the present invention, the mass ratio of the stock solution and the propellant is not particularly limited, but from the viewpoint of suppressing the spray amount and dripping, the stock solution: propellant is preferably 35:65 to 95: 5, and 50:50 to 80:20. Is particularly preferred.

  In the present invention, the spray particle diameter is not particularly limited, but is preferably 50 to 200 μm and more preferably 100 to 150 μm from the viewpoint of suppressing suction by respiration and ensuring safety. The spray particle size can be measured by a laser diffraction particle size distribution measuring device (SPRAYTEC: manufactured by MALVERN).

  The aerosol agent of the present invention can be produced by enclosing a stock solution and a propellant in a container of a device according to a conventional method.

As shown in Examples below, aerosols of the present invention is preferably 0.01 to 500 / cm ² to the application site, more preferably 0.1 to 250 mg / cm ^2, particularly preferably 1 to 50 mg / cm ² When applied, sufficient medicinal effects are obtained, and dripping is suppressed. Therefore, when the coating amount in the aerosol agent of the present invention is within the above range, it is possible to provide an aerosol agent having particularly good usability and excellent medicinal effect.

  The aerosol agent of the present invention is used by opening a valve by an operation such as depressing a button, thereby causing the contents to be ejected in a spray pattern that spreads flat in one direction from the nozzle. This will be described with reference to FIG. 1. When the button (1) is pushed down, a force acts on the valve (not shown) via the stem (5), and the valve is opened, whereby the container (6 ) Is injected as a mist, a paste, or the like from the nozzle (2). In this case, the projections (3) provided on both sides of the nozzle hole act as a baffle plate, and the contents are jetted with a jet pattern spreading flat in the vertical direction. The aerosol preparation of the present invention can be widely used for drug administration means by transdermal absorption such as external administration and inhalation administration, depending on the type of transdermal drug used, etc., prevention / treatment of various diseases, alleviation of various symptoms, etc. Can be used for For example, in the case of using an anti-inflammatory agent such as indomethacin, ferbinac, methyl salicylate, glycol salicylate, ethylene glycol salicylate, diclofenac, ketoprofen, ibuprofen, flurbiprofen, and loxoprofen and their salts as a transdermal drug, Can be used to relieve symptoms such as muscle pain, bruises, sprains, back pain, joint pain, tendonitis (hand and wrist pain), elbow pain (tennis elbow, etc.) and shoulder pain associated with stiff shoulders. In addition to spraying the aerosol of the present invention directly on the application site, it can be further spread as necessary to prevent / treat various diseases and alleviate various symptoms.

  EXAMPLES Hereinafter, although this invention is demonstrated concretely using an Example, this invention is not limited to these Examples.

Production Example 1 A stock solution was produced by the following method.
(1) 0.5 g of hydroxypropyl methylcellulose 2906 (Metroze 65SH-1500: Shin-Etsu Chemical Co., Ltd.) and 0.1 g of hydroxypropyl cellulose (HPC-SSL: Nippon Soda) were added to and dispersed in 30 g of 80 ° C. water, and then cooled. The aqueous phase was obtained by swelling.
(2) 6 g of propylene glycol, 7 g of polyethylene glycol, 1.8 g of benzyl alcohol, 4 g of diisopropyl adipate and 36 g of isopropanol were mixed to obtain a uniform solution. Next, 1 g of l-menthol and 1 g of indomethacin were dissolved in the obtained uniform solution to obtain a main drug phase.
(3) An aqueous solution in which 0.01 g of sodium edetate is dissolved in 5 g of water is added to the liquid obtained by mixing and stirring the aqueous phase obtained in (1) and the active ingredient phase obtained in (2). Further, an appropriate amount of 1.2 mass% diisopropanolamine aqueous solution was added and well mixed with stirring to produce 100 g of a stock solution having a pH of 5.8. The viscosity of the undiluted solution was measured at 60 rpm using a B-type viscometer (No. 2 rotor, Toki Sangyo Co., Ltd.) and found to be 50 mPa · s at 25 ° C.

Example 1 A device (nozzle in the device: F-96 (manufactured by Maruichi Co., Ltd.)) that exhibits a jet pattern that spreads flatly in one direction, with 65 parts by mass of the stock solution obtained in Production Example 1 and 35 parts by mass of dimethyl ether. Airtight filling of Example 1 was obtained. In addition, it was 110 micrometers when the spray particle diameter of the aerosol agent of Example 1 was measured with the laser explanatory particle size distribution measuring apparatus (SPRAYTEC: product made by MALVERN).

Comparative Example 1 65 parts by mass of the undiluted solution obtained in Production Example 1 and 35 parts by mass of dimethyl ether were hermetically filled into a device (nozzle in the device: F-158 (manufactured by Maruichi Co., Ltd.)) having a spray pattern that spreads in a substantially circular shape. And the aerosol agent of the comparative example 1 was obtained. In addition, it was 110 micrometers when the spray particle diameter of the aerosol agent of the comparative example 1 was measured with the laser diffraction particle size distribution measuring apparatus (SPRAYTEC: product made by MALVERN).

Test Example 1 The following evaluation items were evaluated for the aerosol agents of Example 1 and Comparative Example 1. The results are shown in Table 1.

Measurement of injection amount As for the injection amount, each aerosol agent is immersed in a 25 ° C water bath for 30 minutes or more, and after constant internal pressure, it is sprayed for 10 seconds, and the weight of the aerosol agent before and after injection. The injection amount was obtained by comparing

Measurement of injection range (area) Regarding the injection range (area), each aerosol agent was injected for 1 second perpendicularly to the paper surface from a position 15 cm away from the alcohol thermal paper affixed to the vertical surface. Area).

Evaluation of dripping With regard to dripping, alcohol sprayed onto the vertical surface of the alcohol thermal paper was sprayed for 1 second perpendicular to the paper surface from a distance of 15 cm and completely dripped. (The length of the portion deviated from the sprayed area due to dripping) was measured. In addition, in the aerosol agent of Example 1, it sprayed in both the case where the direction where a spray pattern spreads flatly was made into the horizontal direction with respect to the ground, and the vertical direction, and the liquid dripping was measured, respectively. In Table 1, (horizontal direction) is when the direction in which the spray pattern spreads flat is the horizontal direction with respect to the ground, and (vertical direction) is when the direction in which the spray pattern spreads flat is the vertical direction with respect to the ground The data is shown.
Separately, each aerosol agent is sprayed for 1 second from a distance of 10 to 15 cm so that the applied amount is 20 mg / cm ^{2 on} the skin of 5 healthy individuals, and sensory evaluation is performed using the following three evaluation items. Was done.
A: No sagging occurs and the feeling in use is good.
○: A slight amount of dripping occurs, but it can withstand some use.
X: Sagging occurs and it cannot be used.

Evaluation of medicinal effects Regarding the evaluation of medicinal effects, each aerosol formulation was sprayed for 1 second from a distance of 10-15 cm so that the applied amount was 20 mg / cm ^{2 on} the skin of 5 people with muscle pain. Was applied to the site of myalgia and sensory evaluation was performed in the following three stages.
A: The contents stayed in the application part and felt very effective.
○: The contents slightly fell from the application part, but felt that it was effective to some extent.
X: The contents spilled from the coated part and did not feel so effective.

  The aerosol agent of Example 1 having a device that exhibits a spray pattern that flatly spreads in one direction is compared to the aerosol agent of Comparative Example 1 that has a device that exhibits a spray pattern that extends in a substantially circular shape. Although there was no difference in the injection amount and area of the product, the dripping suppression effect and medicinal effect were excellent. The present invention is not limited to the following inferences, but such excellent medicinal effect is that the amount of content adhered per unit area of the coated part is increased due to the suppression of dripping, forming a film. In the case of containing a functional polymer, it was presumed that the percutaneous absorbability of the percutaneously absorbable drug was enhanced in combination with the blocking effect.

Production Example 2
(1) After 0.5 g of methyl cellulose (Metroses SM-4000: Shin-Etsu Chemical Co., Ltd.) and 0.1 g of hydroxypropyl cellulose (HPC-SSL: Nippon Soda) were added to 30 g of water at 80 ° C. and dispersed, cooled and swollen. An aqueous phase was obtained.
(2) 6 g of propylene glycol, 7 g of polyethylene glycol, 1.8 g of benzyl alcohol, 4 g of diisopropyl adipate and 36 g of isopropanol were mixed to obtain a uniform solution. Next, 5 g of 1-menthol, 2 g of methyl salicylate, 1 g of glycol salicylate, 2 g of dl-camphor, 0.5 g of eucalyptus oil and 0.1 g of glycyrrhizic acid were dissolved in the obtained homogeneous solution to obtain a main drug phase.
(3) An aqueous solution in which 0.01 g of sodium edetate is dissolved in 5 g of water is added to the liquid obtained by mixing and stirring the aqueous phase obtained in (1) and the active ingredient phase obtained in (2). Further, an appropriate amount of 1.2 mass% diisopropanolamine aqueous solution was added and well mixed with stirring to produce 100 g of a stock solution having a pH of 5.8. Furthermore, 65 parts by mass of the obtained undiluted solution and 35 parts by mass of dimethyl ether were hermetically filled into a device (nozzle in the device: F-96 (manufactured by Maruichi Co., Ltd.)) exhibiting a spray pattern that flattened in one direction.

  When the aerosol agent of Production Example 2 produced by the above method was used, dripping was suppressed and the medicinal effect was excellent.

Production Example 3
(1) 0.5 g of hydroxypropyl methylcellulose 2208 (Metroise 90SH-4000: Shin-Etsu Chemical Co., Ltd.) and 0.1 g of hydroxypropyl cellulose (HPC-SSL: Nippon Soda) were added to 30 g of 80 ° C. water and dispersed, and then cooled. The aqueous phase was obtained by swelling.
(2) 6 g of propylene glycol, 7 g of polyethylene glycol, 1.8 g of benzyl alcohol, 4 g of diisopropyl adipate and 36 g of isopropanol were mixed to obtain a uniform solution. Next, 1 g of menthol and 3 g of felbinac were dissolved in the obtained uniform solution to obtain a main drug phase.
(4) An aqueous solution in which 0.01 g of sodium edetate is dissolved in 5 g of water in a liquid obtained by adding and mixing the aqueous phase obtained in (1) and the main drug phase obtained in (3) and stirring. Further, an appropriate amount of 1.2% by mass diisopropanolamine aqueous solution was added and well mixed with stirring to produce 100 g of a pH 5.8 stock solution. Furthermore, 65 parts by mass of the obtained undiluted solution and 35 parts by mass of dimethyl ether were hermetically filled into a device (nozzle in the device: F-96 (manufactured by Maruichi Co., Ltd.)) exhibiting a spray pattern that flattened in one direction.

  When the aerosol agent of Production Example 3 produced by the above method was used, dripping was suppressed and the medicinal effect was excellent.

Production Example 4
(1) Carboxyvinyl polymer (Carbopol: Nikko Chemicals) 0.6 g Hydroxypropylmethylcellulose 2906 (Metroze 65SH-1500: Shin-Etsu Chemical) 0.5 g and Hydroxypropylcellulose (HPC-SSL: Nippon Soda) 0.1 g 80 After adding to 30 g of water at 0 ° C. and dispersing, the mixture was cooled and swollen to obtain an aqueous phase.
(2) 6 g of propylene glycol, 7 g of polyethylene glycol, 1.8 g of benzyl alcohol, 4 g of diisopropyl adipate and 36 g of isopropanol were mixed to obtain a uniform solution. Next, 1 g of arnica tincture, 0.1 g of horse chestnut seed extract, 1 g of glycol salicylate and 0.3 g of l-menthol were dissolved in the obtained uniform solution to obtain a main drug phase.
(3) An aqueous solution in which 0.01 g of sodium edetate is dissolved in 5 g of water is added to the liquid obtained by mixing and stirring the aqueous phase obtained in (1) and the active ingredient phase obtained in (2). Further, an appropriate amount of 1.2 mass% diisopropanolamine aqueous solution was added and well mixed with stirring to produce 100 g of a stock solution having a pH of 5.8. Furthermore, 65 parts by mass of the obtained undiluted solution and 35 parts by mass of dimethyl ether were hermetically filled into a device (nozzle in the device: F-96 (manufactured by Maruichi Co., Ltd.)) exhibiting a spray pattern that flattened in one direction.

  When the aerosol agent of Production Example 4 produced by the above method was used, dripping was suppressed and the medicinal effect was excellent.

Production Example 5
(1) 0.5 g of hydroxypropyl methylcellulose 2906 (Metroze 65SH-1500: Shin-Etsu Chemical Co., Ltd.) and 0.1 g of hydroxypropyl cellulose (HPC-SSL: Nippon Soda) were added to and dispersed in 30 g of 80 ° C. water, and then cooled. The aqueous phase was obtained by swelling.
(2) 6 g of propylene glycol, 7 g of polyethylene glycol, 1.8 g of benzyl alcohol, 4 g of diisopropyl adipate and 36 g of isopropanol were mixed to obtain a uniform solution. Next, 0.595 g of dried dried shrimp was dissolved in the obtained uniform solution to obtain a main drug phase.
(3) An aqueous solution in which 0.01 g of sodium edetate is dissolved in 5 g of water is added to the liquid obtained by mixing and stirring the aqueous phase obtained in (1) and the active ingredient phase obtained in (2). Further, an appropriate amount of 1.2 mass% diisopropanolamine aqueous solution was added and well mixed with stirring to produce 100 g of a stock solution having a pH of 5.8. Furthermore, 65 parts by mass of the obtained composition for aerosol agent and 35 parts by mass of dimethyl ether were hermetically filled in a device (nozzle: F-96: manufactured by Maruichi Co., Ltd.) having a spray pattern spreading flat in one direction.

  When the aerosol agent of Production Example 5 produced by the above method was used, dripping was suppressed and the medicinal effect was excellent.

It is a figure which shows the specific example of the device used for this invention. It is a figure which shows the specific example of the button of the device used for this invention. It is a figure which shows the specific example of the button of the device used for this invention. It is a figure which shows the specific example of the button of the device used for this invention. It is a figure which shows the specific example of the button of the device used for this invention. It is a figure which shows the specific example of the trigger type cap of the device used for this invention.

Explanation of symbols

1 Button 2 Port 3 Protrusion 4 Nozzle 5 Stem 6 Container 7 Groove 8 Trigger Cap 9 Trigger

Claims (3)

A pair of protrusions protruding toward the both sides of the injection hole in the injection direction, one direction is sealed in a container of Lud devices that Teisu the injection pattern spread in a flat during injection, comprising at least one percutaneous absorption drug and transdermal administration aerosol comprising a raw liquid such percutaneous absorption drug is an anti-inflammatory agent.   The anti-inflammatory agent is at least one selected from the group consisting of indomethacin, ferbinac, methyl salicylate, glycol salicylate, ethylene glycol salicylate, diclofenac, ketoprofen, ibuprofen, flurbiprofen, loxoprofen, and dried scorpion extract and salts thereof. The aerosol agent according to claim 1, wherein The device comprises a nozzle and button, said pair of projections are provided on the nozzle, the nozzle is one that is fitted to said button so as to be rotatable Ri jetting direction peripheral, wherein Item 3. The aerosol agent according to item 1 or 2.