JP2021130636A - Aerosol preparation - Google Patents

Abstract

To provide a diclofenac-containing aerosol preparation having a low abundance ratio of fine particles having a particle diameter of 10 μm or less.SOLUTION: There is provided an aerosol preparation in which an aerosol composition comprising a chemical solution and a propellant is accommodated in a container equipped with an injection valve device, where an actuator of the injection valve device is a jetting button having a mechanical breakup mechanism, the chemical solution contains diclofenac and/or a pharmaceutically acceptable salt thereof, hydroxypropyl cellulose and ethanol, the mass ratio between hydroxypropyl cellulose and ethanol is 1:30 to 1:50 and the mass ratio between the chemical solution and the propellant is 40:60 to 50:50.SELECTED DRAWING: None

Description

The present invention relates to an aerosol preparation.

Aerosol preparations, which are widely used as pharmaceuticals, are characterized in that the drug solution can be sprayed directly from the container to the affected area without soiling the fingers. For example, an aerosol preparation containing an anti-inflammatory analgesic and an antifungal drug (athlete's foot therapeutic agent) as an active ingredient is clinically used, and specifically, an aerosol preparation containing diclofenac is used.

JP-A-2009-178215

In an aerosol preparation containing diclofenac, it is desired to reduce the abundance of fine particles having a particle diameter of 10 μm or less in order to prevent the invasion of fine particles ejected from the aerosol preparation into the lungs. Therefore, the present invention aims to improve the safety of the aerosol preparation containing diclofenac, and provides an aerosol preparation containing diclofenac in which the abundance of fine particles having a particle size of 10 μm or less to be injected is 0.6% or less. The purpose.

As a result of diligent research by the present inventors to achieve the above object, an aerosol composition containing hydroxypropyl cellulose and ethanol in a predetermined ratio and a chemical solution and a propellant in a predetermined ratio is placed in a predetermined container. It was found that the contained aerosol preparation had a low abundance of fine particles having a particle size of 10 μm or less. The present inventors have also found that water-soluble polymers other than hydroxypropyl cellulose have poor solubility in chemical solutions and / or aerosol compositions containing diclofenac. Based on these findings, the present inventors have completed the present invention.
That is, in the aerosol preparation of the present invention, the aerosol composition containing the chemical solution and the propellant is contained in a container provided with the injection valve device, and the actuator of the injection valve device is an injection button having a mechanical break-up mechanism. The chemical solution contains diclofenac and / or a pharmaceutically acceptable salt thereof, hydroxypropyl cellulose and ethanol, and has a mass ratio of hydroxypropyl cellulose to ethanol of 1:30 to 1:50. The mass ratio of the agent is 40:60 to 50:50.

Since the aerosol preparation of the present invention has a low abundance of fine particles having a particle size of 10 μm or less to be ejected, there is little possibility that the fine particles invade the lungs of the user during use.

In the aerosol preparation of the present invention, an aerosol composition containing a chemical solution and an injection agent is contained in a container provided with an injection valve device, and the actuator of the injection valve device is an injection button having a mechanical break-up mechanism. Unlike the straight type injection button, the injection button having a mechanical breakup mechanism has a narrow groove formed on the back side of the injection port. Since the aerosol composition swirls in this groove, it is generally considered that an injection button having a mechanical breakup mechanism injects fine particles having a smaller particle size than a straight type injection button. However, surprisingly, the aerosol composition contained in the aerosol preparation of the present invention has a large particle size when injected with an injection button having a mechanical breakup mechanism, that is, the abundance of fine particles having a particle size of 10 μm or less is low. The present inventors have found that this is the case.

The hole diameter of the injection port is 0.3 mm to 1.0 mm, preferably 0.3 mm to 0.6 mm. The diameter of the stem hole of the valve device is preferably 0.3 mm or less.

As the container for filling the aerosol composition, a general container used as an aerosol preparation can be used, and typically, a metal container made of aluminum, steel, tin, etc. is used, and the metal container is used. The inner surface may be coated with an epoxy resin, a phenol resin, a polyamide-imide resin, or the like.

Next, the aerosol composition to be filled in the aerosol preparation of the present invention will be described. The aerosol composition comprises a chemical solution and a propellant. The mass ratio of the chemical solution to the propellant in the aerosol composition is 40:60 to 50:50, preferably 40:60 to 45:55. When the mass ratio is within the above numerical range, the aerosol preparation has a sufficiently low abundance of fine particles having a particle size of 10 μm or less and is excellent in usability. For example, when the abundance rate of fine particles having a particle size of 10 μm or less is 0.6% or less, the possibility that the fine particles invade the lungs is low. Therefore, when the abundance rate of fine particles having a particle size of 10 μm or less in the aerosol preparation is 0.6% or less, it can be said that the abundance rate of fine particles having a particle size of 10 μm or less is sufficiently low.

The drug solution contains diclofenac and / or a pharmaceutically acceptable salt thereof, hydroxypropyl cellulose and ethanol. By combining hydroxypropyl cellulose and ethanol, it is possible to sufficiently reduce the abundance of fine particles having a particle size of 10 μm or less while increasing the solubility of the chemical solution.

Examples of the pharmaceutically acceptable salt of diclofenac include sodium salt, eporamine salt (1- (2-hydroxyethyl) pyrrolidine salt), and ammonium salt, and among these, the sodium salt is preferable.

The concentration of diclofenac and / or a pharmaceutically acceptable salt thereof in the drug solution is 0.1% by mass to 5% by mass, preferably 1% by mass to 3% by mass. The concentration of hydroxypropyl cellulose in the chemical solution is 0.5% by mass to 2% by mass, preferably 1 to 1.5% by mass. When the concentration is within the above numerical range, the aerosol preparation has an excellent usability. The viscosity of hydroxypropyl cellulose in a 2% by mass aqueous solution may be 100 mPa · S to 5000 mPa · S, or 1000 mPa · S to 4000 mPa · s. Here, the viscosity of the 2% by mass aqueous solution means a value measured at 20 ° C. using a B-type viscometer. From the viewpoint of the solubility of the chemical solution, the chemical solution preferably does not contain a water-soluble polymer other than hydroxypropyl cellulose (hydrophobicized hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, etc.). The concentration of ethanol in the chemical solution is 30 to 70% by mass, preferably 40 to 50% by mass. When the concentration is within the above numerical range, the aerosol preparation has a sufficiently low abundance of fine particles having a particle size of 10 μm or less.

In addition to the above components, the chemical solution may contain water, a pH adjuster, an antioxidant, a wetting agent, a surfactant, a cooling agent, an absorption accelerator and the like.

Water serves as a medium for dissolving or dispersing hydroxypropyl cellulose and other components. The water content may be, for example, 10% by mass to 60% by mass or 30% by mass to 50% by mass based on the total mass of the chemical solution.

Examples of the pH adjuster include lactic acid, acetic acid, formic acid, tartaric acid, oxalic acid, benzoic acid, malic acid, citric acid and amines (diethanolamine and the like), but lactic acid is preferable. The pH of the aerosol composition may be 5.0 to 9.0 or 6.0 to 8.0.

Examples of the antioxidant include tocopherol and its ester derivative, ascorbic acid and its ester derivative, dibutylhydroxytoluene, butylhydroxyanisole, 2-mercaptobenzimidazole and the like. One type of antioxidant may be used alone, or two or more types may be used in combination. As the antioxidant, dibutylhydroxytoluene is preferable from the viewpoint of further suppressing the decomposition of diclofenac. The content of the antioxidant may be, for example, 0% by mass to 1% by mass based on the total mass of the chemical solution.

Wetting agents include glycerin, polyethylene glycol, propylene glycol, D-sorbitol, xylitol, mannitol, erythritol and urea. As the wetting agent, one type may be used alone, or two or more types may be used in combination. As the moisturizer, propylene glycol is preferable from the viewpoint of moisturizing the skin. The content of the wetting agent may be, for example, 1% by mass to 10% by mass or 1% by mass to 5% by mass based on the total mass of the chemical solution.

Examples of the surfactant include nonionic surfactants (polysorbate 20, polysorbate 80, polysorbate 60, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, etc.) and ionic surfactants. Examples include surfactants and amphoteric surfactants. The content of the surfactant may be, for example, 0% by mass to 10% by mass based on the total mass of the chemical solution.

Examples of the refreshing agent include thymol, l-menthol, dl-menthol, l-isopulegol, peppermint oil and the like, and l-menthol is preferable. The content of the refreshing agent may be, for example, 1% by mass to 5% by mass or 1% by mass to 3% by mass based on the total mass of the chemical solution.

Examples of the absorption enhancer include fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid and linolenic acid, methyl laurate, hexyl laurate, isopropyl palmitate and myristin. Fatty acid esters such as isopropyl acid, myristyl myristate, octyldodecyl myristate, cetyl palmitate, diisopropyl adipate, diethyl sebacate, diisopropyl sebacate, dimethyl succinate, dibutyl adipate, diisobutyl adipate, dioctyl adipate, sebacic acid Examples thereof include dicarboxylic acid esters such as dioctyl, diethyl phthalate, and dibutyl phthalate, and aliphatic alcohols such as lauryl alcohol, myristic alcohol, oleyl alcohol, isostearyl alcohol, cetyl alcohol, and octyldodecanol. From the viewpoint of further improving the absorption of diclofenac sodium into the skin, the absorption enhancer is preferably diisopropyl adipate. The content of the absorption accelerator may be, for example, 1% by mass to 10% by mass or 3% by mass to 7% by mass based on the total mass of the chemical solution.

The mass ratio of hydroxypropyl cellulose to ethanol is 1:30 to 1:50, preferably 1:30 to 1:45. When the mass ratio is within the above numerical range, the aerosol preparation has a sufficiently low abundance of fine particles having a particle size of 10 μm or less and is excellent in usability.

As the propellant, a known substance used in an aerosol preparation can be used, and examples thereof include dimethyl ether, liquefied petroleum gas (LPG), nitrogen gas, carbon dioxide gas, and alternative freon gas, which are compatible with the chemical solution. From the viewpoint, the propellant is preferably dimethyl ether.

The aerosol composition of the present invention can be produced by a conventional method. For example, each component of a chemical solution is mixed until uniform, the chemical solution is filled in an aerosol container, a valve of the container is attached, and injection is performed. It can be produced by filling with an agent. Further, by attaching an injection button to the container, an aerosol preparation can be produced.

By spraying the aerosol preparation on the affected area, pain and inflammation in the affected area can be relieved.

Test Example 1
The components shown in Table 1 were weighed and mixed until uniform to obtain a chemical solution. Next, the obtained chemical solution is filled in an aerosol container, a valve is attached to the aerosol container, and then the solution is filled so that the mass ratio of the undiluted solution and the propellant (dimethyl ether) is 45:55 to obtain an aerosol composition. rice field. Then, by attaching an injection button to the aerosol container, aerosol preparations 1 to 6 were prepared.

The obtained chemical solution and aerosol composition were visually confirmed, and the solubility was evaluated according to the following criteria. In addition, the abundance of fine particles having a particle size of 10 μm or less and the gas pressure were measured under the following conditions. The evaluation results are shown in Table 2.
Criteria for solubility A: White turbidity and no insoluble matter B: White turbidity or insoluble matter Measurement conditions for the abundance of fine particles with a particle size of 10 μm or less Measuring device: Spraytech STP5311 (Malvern Panalytical Ltd)
Measurement method: Laser diffraction method Particle size distribution measurement Measurement temperature: 25 ° C
Measuring range: 0.1 to 200 μm
Lens used: 100mm-300mm
Focal length: 30 cm (distance from the detector lens to the measurement point)
Injection distance: 15 cm (distance from the injection port to the measurement point)
Injection time: 3 seconds Analysis model formula: Rosin Ramler formula Gas pressure measurement conditions Measuring device: Pressure gauge PG-208 (Nippon Densan Copal Electronics Co., Ltd.)
Measurement method: Measure by pressing a pressure gauge against the stem of the aerosol formulation container.

As can be seen from the results shown in Table 2, it was confirmed that when hydroxypropyl cellulose is contained in the chemical solution, it is possible to provide an aerosol preparation having excellent solubility and a low abundance of fine particles having a particle size of 10 μm or less. rice field. It was confirmed that the aerosol preparation containing no water-soluble polymer in the chemical solution has a high abundance of fine particles having a particle size of 10 μm or less. In addition, it was confirmed that other water-soluble polymers have poor solubility and are not suitable for producing aerosol compositions.

Test Example 2
The components shown in Table 3 were weighed and mixed until uniform to obtain a chemical solution. Next, the obtained chemical solution is filled in an aerosol container, a valve is attached to the aerosol container, and then the solution is filled so that the mass ratio of the undiluted solution and the propellant (dimethyl ether) is 45:55 to obtain an aerosol composition. rice field. Then, by attaching an injection button to the aerosol container, aerosol preparations 7 to 13 were prepared.

Similar to Test Example 1, the obtained chemical solution and aerosol composition were visually confirmed to evaluate the solubility, and the abundance and gas pressure of fine particles having a particle size of 10 μm or less of the aerosol preparation were measured. In addition, quick-drying and stickiness were evaluated under the following conditions. The evaluation results are shown in Table 4.
Evaluation of quick-drying The aerosol preparation was sprayed on the forearm for 1 second and evaluated according to the following criteria.
1: Slow 2: Slightly fast 3: Fast Evaluation of stickiness The aerosol preparation was sprayed on the forearm for 1 second, and after drying, it was evaluated by the following criteria whether or not it was sticky to the touch with fingers.
1: Sticky 2: Almost non-sticky 3: Non-sticky

As can be seen from the results shown in Table 4, when the concentration of hydroxypropyl cellulose in the chemical solution is 1.0 to 1.5% by mass, the abundance rate of fine particles having a particle size of 10 μm or less is low, and the feeling of use (fastness) is low. It was confirmed that an aerosol preparation having excellent dryness and stickiness can be provided. When the concentration of hydroxypropyl cellulose in the chemical solution was 1.8% by mass or more, it was confirmed that the quick-drying property was insufficient.

Test Example 3
The components shown in Table 5 were weighed and mixed until uniform to obtain a chemical solution. Next, the obtained chemical solution is filled in an aerosol container, a valve is attached to the aerosol container, and then the solution is filled so that the mass ratio of the undiluted solution and the propellant (dimethyl ether) is 45:55 to obtain an aerosol composition. rice field. Then, by attaching an injection button to the aerosol container, aerosol preparations 14 to 19 were prepared.

Similar to Test Example 2, the obtained chemical solution and aerosol composition were visually confirmed to evaluate the solubility, and the abundance and gas pressure of fine particles having a particle size of 10 μm or less of the aerosol preparation were measured to quickly dry and sticky. Was evaluated. The evaluation results are shown in Table 6.

As can be seen from the results shown in Table 6, when the ethanol concentration in the chemical solution is 40 to 50% by mass, the abundance rate of fine particles having a particle size of 10 μm or less is low, and the usability (quick-drying and stickiness) is excellent. It was confirmed that the aerosol preparation can be provided. It was confirmed that when the ethanol concentration in the chemical solution was 70% by mass, the abundance of fine particles having a particle size of 10 μm or less was not sufficiently low. It was also confirmed that when isopropanol was used instead of ethanol, the quick-drying property was insufficient.

Test Example 4
The components shown in Table 7 were weighed and mixed until uniform to obtain a chemical solution. Next, the obtained chemical solution is filled in an aerosol container, a valve is attached to the aerosol container, and then the solution is filled so that the mass ratio of the undiluted solution and the propellant (dimethyl ether) becomes the numerical value shown in Table 7, and the aerosol composition is prepared. Got Then, by attaching an injection button to the aerosol container, aerosol preparations 20 to 24 were prepared.

Similar to Test Example 2, the obtained chemical solution and aerosol composition were visually confirmed to evaluate the solubility, and the abundance and gas pressure of fine particles having a particle size of 10 μm or less of the aerosol preparation were measured to quickly dry and sticky. Was evaluated. The evaluation results are shown in Table 8.

As can be seen from the results shown in Table 8, when the mass ratio of the chemical solution to the propellant is 40:60 to 50:50, the abundance rate of fine particles having a particle size of 10 μm or less is low, and the feeling of use (quick drying and quick-drying) It was confirmed that it is possible to provide an aerosol preparation having excellent stickiness). It was confirmed that when the mass ratio of the chemical solution to the propellant was 35:65, the abundance rate of fine particles having a particle size of 10 μm or less was not sufficiently low. When the mass ratio of the chemical solution to the propellant was 55:45, it was confirmed that the quick-drying property was insufficient.

Test Example 5
The components shown in Table 9 were weighed and mixed until uniform to obtain a chemical solution. Next, the obtained chemical solution is filled in an aerosol container, a valve is attached to the aerosol container, and then the solution is filled so that the mass ratio of the undiluted solution and the propellant (dimethyl ether) is 45:55 to obtain an aerosol composition. rice field. Then, by attaching an injection button to the aerosol container, aerosol preparations 25 to 29 were prepared.

Similar to Test Example 2, the obtained chemical solution and aerosol composition were visually confirmed to evaluate the solubility, and the abundance and gas pressure of fine particles having a particle size of 10 μm or less of the aerosol preparation were measured to quickly dry and sticky. Was evaluated. The evaluation results are shown in Table 10.

As can be seen from the results shown in Table 10, when the button mechanism is a mechanical breakup and the stem hole diameter of the valve is φ0.3 mm or less, the abundance rate of fine particles having a particle size of 10 μm or less is low and the feeling of use is low. It was confirmed that an aerosol preparation having excellent (quick-drying and stickiness) can be provided.

Claims (5)

An aerosol composition containing a chemical solution and a propellant is an aerosol preparation contained in a container equipped with a jet valve device.
The actuator of the injection valve device is an injection button having a mechanical breakup mechanism.
The drug solution contains diclofenac and / or a pharmaceutically acceptable salt thereof, hydroxypropyl cellulose and ethanol.
The mass ratio of hydroxypropyl cellulose to ethanol is 1:30 to 1:50.
The mass ratio of the chemical solution to the propellant is 40:60 to 50:50.
Aerosol preparation. The aerosol preparation according to claim 1, wherein the diameter of the stem hole of the valve device is 0.3 mm or less. The aerosol preparation according to claim 1 or 2, wherein the concentration of hydroxypropyl cellulose in the chemical solution is 1 to 1.5% by mass. The aerosol preparation according to any one of claims 1 to 3, wherein the propellant is dimethyl ether. The aerosol preparation according to any one of claims 1 to 4, wherein the concentration of ethanol in the drug solution is 40 to 50% by mass.