JPH0778019B2 - Foamed anti-inflammatory analgesic preparation - Google Patents

Description

TECHNICAL FIELD The present invention relates to a foam aerosol anti-inflammatory analgesic preparation. More specifically, it relates to a foam aerosol anti-inflammatory analgesic preparation having a strong anti-inflammatory and analgesic effect, less side effects on the skin, and excellent stability of the active ingredient.

[Conventional technology]

As a prior art of an aerosol formulation containing an anti-inflammatory analgesic, Japanese Patent Publication No. 52-21051, JP 54-46818,
There are those described in JP-A-56-135414 and JP-A-61-83117, and further as an active ingredient, an anti-inflammatory analgesic such as methyl salicylate and glycol salicylate-
Aerosol products containing topical stimulants such as menthol, dl-camphor, benzyl nicotinate and capsaicin are already on the market.

However, these products have not sufficient anti-inflammatory and analgesic effects and have side effects on the skin such as redness, rash and degreasing of the skin, and thus they have not always had satisfactory physical properties.

The problems of these existing products are considered to be caused by the following causes, and it was difficult to solve them by the conventional techniques.

(B) During spraying, the active ingredient cannot be applied to the affected area due to scattering outside the skin.

(B) Prescriptions are limited in order to pass the explosiveness test and flammability test prescribed in Ministry of International Trade and Industry Notification No. 557.

(C) In order to dissolve the active ingredient contained in the formulation in an amount of 5 to 15% by weight, lower alcohols such as ethyl alcohol and isopropyl alcohol must be incorporated in a large amount of 30 to 50% by weight.

In addition, as a prior art of foam aerosol formulation, Japanese Patent Publication No.
Although the application of foam aerosol to the cosmetics field is described in Japanese Patent No. 053, there is no example of incorporating an antiphlogistic analgesic as an active ingredient, and the foam antiphlogistic analgesic aerosol preparation of the present invention is a completely novel invention. is there.

Furthermore, when a foam aerosol formulation containing an anti-inflammatory drug is produced, the anti-inflammatory drug is originally a highly lipophilic drug, so liquid separation or foam formation may not occur. The active ingredient targeted by the invention is 0.3 to 15
It is not possible to obtain a foam anti-inflammatory analgesic aerosol formulation which is blended in a large amount such as wt%.

[Problems to be solved by the invention]

The present inventors have tried to solve the following problems of the prior art and commercial products.

(A) The anti-inflammatory and analgesic effect is weak, and the duration of drug effect is short.

(B) Since it contains a large amount of lower alcohol, side effects such as redness, rash, and degreasing on the skin are observed.

(C) The stability of the active ingredient over time is not sufficient.

(D) Since it is necessary to pass the explosiveness test and the flammability test, it is prescriptively limited.

(E) There is dripping or stickiness, and the feeling of use is not good.

(F) When spraying, inhale gas to hurt throat.

The present inventors believe that reducing the amount of lower alcohol to be blended is a method for solving the problems of the prior art, and as a result of various studies, the active ingredient was aerosolized in an emulsified state, resulting in the above problems. It came to the goal of resolving the points.

[Means for solving problems]

The present invention comprises an anti-inflammatory analgesic 0.3 to 15% by weight, an ether surfactant 0.1 to 5% by weight, water 3 to 20% by weight, a powder 0.1 to 5% by weight, a lower alcohol 2.5% by weight or less and a propellant 60 to 60%. 9
The present invention relates to a foam aerosol anti-inflammatory analgesic preparation containing 0% by weight.

The foamed aerosol anti-inflammatory analgesic preparation of the present invention comprises an anti-inflammatory analgesic which is an active ingredient in an amount of 0.3 to 15% by weight, and an ether surfactant of 0.1.
~ 5 wt%, water 3-20 wt%, powder 0.1-5 wt%, lower alcohol 2.5 wt% or less and propellant 60-90 wt%
It contains.

More specifically, as the active ingredient of the present invention,
Non-steroidal anti-inflammatory drugs such as methyl salicylate, glycol salicylate, ketoprofen, indomethacin, flurbiprofen, suprofen, biphenylacetic acid, diclofenac (trade name: voltaren), loxoprofen, ibuprofen, thiaprofen, piroxicam, fentiazac, pranoproc Fen, kridanak, bendazac, bufexamac, ibuprofen piconol and the like, and topical stimulants such as menthol, peppermint oil, dl-camphor, thymol, ginger extract, vanillyl nonylate, benzyl nicotinate, capsaicin, capsicum extract. , Arnica extract and the like. The above active ingredients may be used alone or in combination of two or more kinds. Further, the compounding amount of the active ingredient is slightly different depending on the kind, but it is 0.3 to 15% by weight, preferably 0.5 to 10% by weight, in which the anti-inflammatory and analgesic effect is sufficiently exhibited.
The ratio of the active ingredient in the anti-inflammatory analgesic preparation is 0.3
When it is less than wt%, sufficient antiphlogistic and analgesic effects are not exerted, and when it exceeds 15 wt%, liquid separation or bubbles are not formed.

In the present invention, as an active ingredient other than the above-mentioned active ingredient, an anti-rash agent such as diphenhydramine, chlorpheniramine maleate, glycyrrhetinic acid, and diphenhydramine salicylate may be added in addition to the active ingredient.

The surfactant is added to emulsify the active ingredient solution in water, and the type and amount of the surfactant are particularly important in order to add a large amount of the active ingredient.

As the surfactant, an ether-based surfactant, which is a nonionic surfactant, is used from the viewpoint of the reaction stability with the active ingredient, the solvent and the propellant, and the corrosiveness with the metal container for aerosol. .

Examples of ether surfactants include polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene alkylphenyl ether, single chain length polyoxyethylene alkyl ether, polyoxyethylene secondary alcohol ether, and polyoxy. Examples thereof include ethylene sterol ether, polyoxyethylene lanolin derivative, polyoxyethylene polyoxypropylene alkyl ether and the like. The ether-based surfactant is blended in one kind or a combination of two or more kinds according to the emulsification conditions, and the blending amount thereof is
It is 0.1 to 5% by weight, preferably 0.5 to 3% by weight. When the proportion of the surfactant in the anti-inflammatory analgesic preparation is less than 0.1% by weight, strong shaking is required to uniformly disperse the active ingredient, additives, surfactant, water, lower alcohol and propellant. Alternatively, shaking for a long time is required, and when it exceeds 5% by weight, the amount of the active ingredient used is decreased and the active ingredient remains on the skin forever, and the feeling of use is deteriorated.

In addition, a part of the ether-based surfactant may be replaced with another surfactant.

Other surfactants include nonionic surfactants such as sorbitan fatty acid ester, glycerin fatty acid ester, decaglycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, propylene glycol fatty acid ester, polyoxyethylene castor. Lecithin and saponin which are preferable from the viewpoint of safety because they are ester type surfactants such as oil derivatives and hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene sorbitol fatty acid ester, etc. or have less skin irritation. A surfactant derived from a natural product such as is used.

The amount of water is 3 to 20% by weight, preferably 5 to 15% by weight. The ratio of water in the anti-inflammatory analgesic preparation is 3
When it is less than 10% by weight, it is not foamed, and when it exceeds 20% by weight, the water-insoluble oily active ingredient is difficult to disperse uniformly with the aqueous ingredient, and the drying becomes slow.

Addition of powder improves the emulsion stability of the anti-inflammatory analgesic in a metal container for aerosol, and also serves as an anti-slip when rubbing the anti-inflammatory analgesic on the skin, enhancing the massage effect. You can As the powder,
Water-insoluble powders such as talc, zinc white, nylon powder, silicone powder, magnesium oxide, titanium oxide, soft (precipitated) calcium carbonate, heavy magnesium carbonate, soft magnesium carbonate, heavy calcium carbonate,
Yellow iron oxide, red iron oxide, black iron oxide, sunflower, chromium oxide, anhydrous silicic acid, magnesium silicate, kaolin, bentonite, mica, titanium mica, bismuth oxychloride,
Zirconium oxide, chromium hydroxide, calamine, polyethylene powder, polystyrene powder, acrylic resin powder, cellulose powder, inorganic pigments such as titanium oxide and organic polymer powder such as nylon 12 are used, and the blending amount of these is 0.2- It is 5% by weight, preferably 0.5-2% by weight. When the ratio of the powder in the anti-inflammatory analgesic preparation is less than 0.2% by weight, the effect of obtaining an emulsion by shaking the water component and the oil component is small, and when it exceeds 5% by weight, it is in an aerosol container. It causes caking and causes the valve to clog. The powder has a particle size of 100 μm or less, preferably 20 to 5
Those having a thickness of 0 μm can be used. If the particle size exceeds 100 μm, fill the aerosol container with the obtained anti-inflammatory analgesic preparation,
When spraying the anti-inflammatory analgesic preparation, the spray port may be clogged.

Lower alcohols such as ethyl alcohol and isopropyl alcohol are blended in order to assist the dissolution of the active ingredient or to give a refreshing feeling when applied. These are not blended in order to prevent side effects such as redness and rashes, or change with time of the active ingredient, or are blended at 2.5% by weight or less, which is a much smaller amount than usual. Of the lower alcohols, ethyl alcohol is preferred.

Propellants include dichlorotetrafluoroethane (CFC-114) and dichlorodifluoromethane (CFC-12)
Freon gas, dimethyl ether, liquefied petroleum gas, etc.
Carbon dioxide, nitrogen gas and the like are available, but chlorofluorocarbon is most preferred from the viewpoints of explosiveness, flammability and chemical stability. The amount of propellant is 60 to 90% by weight, preferably 70 to 85% by weight. If the content in the anti-inflammatory analgesic preparation is less than 60% by weight, the content liquid increases and stickiness occurs, and if it exceeds 90% by weight, the amount of the active ingredient added decreases, which is not preferable.

In addition to the above essential components, the following components can be added. That is, to aid emulsification, cetanol, stearyl alcohol, behenyl alcohol, emulsification aids such as lanolin alcohol, to dissolve the active ingredient, and to promote percutaneous absorption, crotamiton, benzyl alcohol, diisopropyl adipate, diethyl sebacate. ,
Natural animal and vegetable oils such as diisopropyl sebacate, propylene glycol fatty acid ester, glycerin fatty acid ester, peppermint oil, eucalyptus oil, jojoba oil, olive oil, avocado oil, isopropyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, myristic acid Fatty acid esters such as myristyl and octyldodecyl myristate, solubilizing agents such as 2-hexyldecanol and 2-octyldodecanol, and polyhydric compounds such as 1,3-butylene glycol, propylene glycol, and glycerin to enhance the feeling of use and solubility. Hydrocarbons such as alcohol, liquid paraffin and squalane,
Silicone oils such as methylpolysiloxane, methylphenylpolysiloxane, cyclomethicone, etc., and if necessary, preservatives such as methylparaben, ethylparaben, propylparaben, butylparaben, and antioxidants such as dl-α-tocopherol, BHT. can do. In addition, a water-soluble polymer having a film-forming action such as carboxyvinyl polymer, hydroxypropyl cellulose, sodium hyaluronate, etc. can be blended in order to provide sustained drug effect.

The foamed aerosol anti-inflammatory and analgesic preparation of the present invention having the above composition is used by being filled in an aerosol container. As the aerosol container, a pressure-resistant container made of steel or aluminum used in general aerosol products can be used, but in the present invention, the product pressure is 1 to 3 kg / cm ² (gauge pressure) at 25 ° C. Since it can be kept low, it is possible to use a resin container that is difficult to use for ordinary aerosol products. As the material of the aerosol container, ester resins such as polyethylene terephthalate and polybutylene terephthalate, acrylonitrile-styrene copolymer, polycarbonate, polyacetal or polyamide can be used, and further, the polymer and ethylene-vinyl acetate copolymer can be used. A laminate with a polymer or a resin having low gas permeability such as polyvinylidene chloride can also be used. When the aerosol anti-inflammatory analgesic is filled in the aerosol container, the active ingredient, the additive, the surfactant and the powder are filled in the aerosol container in advance, and then the propellant is injected through the valve of the aerosol container. Should be filled. The filling amount of such an anti-inflammatory analgesic preparation varies depending on the internal volume of the aerosol container used, but it is usually in the range of 70 to 110 g per 100 ml of the full volume.

Next, an example of the manufacturing method of the present invention will be described.

To produce the aerosol preparation of the present invention, first, an additive is added to the active ingredient and dissolved, and then a surfactant, water and talc are added and emulsified. After this is filled in an aerosol container, a propellant is press-fitted into this to give an aerosol preparation.

Hereinafter, the present invention will be described more specifically by showing Examples, Reference Examples and Test Examples.

〔Example〕

Example 1 (Component) (wt%)-menthol 3.7 dl-camphor 0.3 methyl salicylate 1.6 glycol salicylate 0.7 eucalyptus oil 0.4 squalane 0.3 1,3-butylene glycol 0.5 polyoxyethylene (20) polyoxypropylene (8) cetyl ether 1 Ethylene alcohol 2 Water 8.5 Talc 1 Freon-114 80-Menthol, dl-camphor, methyl salicylate, glycol salicylate, eucalyptus oil, squalane, 1,3-
Butylene glycol was mixed and heated to 50 ° C. to dissolve. Next, add polyoxyethylene (20) polyoxypropylene (8) cetyl ether, ethyl alcohol,
Water and talc were added and emulsified.

After this was filled in an aerosol container, Freon-114 was press-fitted to obtain a foam aerosol anti-inflammatory analgesic preparation.

Example 2 (Component) (wt%)-Menthol 1.5 Methyl salicylate 0.5 Nonyl acid vanillyl amide 0.01 Tocopherol acetate 0.5 Eucalyptus oil 0.5 Mint oil 0.2 Squalane 0.5 Methyl polysiloxane 0.2 Propylene glycol 0.6 2-Hexyldecanol 0.5 Polyoxyethylene (20) polyoxy Propylene (8) cetyl ether 1 talc 1 Ethyl alcohol 2.5 Water 10.49 Freon-114 80 By the method according to Example 1, a foam aerosol anti-inflammatory analgesic preparation was obtained.

Example 3 (Component) (wt%)-menthol 2 dl-camphor 0.3 thymol 0.05 methyl salicylate 0.7 glycol salicylate 1 1,3-butylene glycol 0.5 2-octyldodecanol 0.35 crotamiton 0.1 polyoxyethylene (9) cetyl ether 1 Talc 1 Ethyl alcohol 2.1 Water 10.9 Freon-114 80 A foamed aerosol anti-inflammatory analgesic preparation was obtained by the method according to Example 1.

Example 4 (Component) (wt%)-menthol 5 dl-camphor 0.3 methyl salicylate 1.5 tocopherol acetate 1 squalane 1.5 1,3-butylene glycol 2 diisopropyl adipate 0.2 polyoxyethylene (20) polyoxypropylene (8) cetyl ether 1 Talc 1 water 6.5 Freon-114 80 By the method according to Example 1, a foam aerosol anti-inflammatory analgesic preparation was obtained.

Example 5 (Component) (wt%)-menthol 1 dl-camphor 0.7 methyl salicylate 1 ketoprofen 0.2 peppermint oil 0.5 1,3-butylene glycol 0.7 2-hexyldecanol 0.5 diisopropyl sebacate 0.1 polyoxyethylene (10) nonylphenyl ether 1
Lecithin (Recinol S-10, Nikko Chemicals Co., Ltd.)
0.3 Talc 1 Ethyl alcohol 2.4 Water 10.6 Freon-114 76 Propane 4 By the method according to Example 1, a foam aerosol anti-inflammatory analgesic preparation was obtained.

Example 6 (Component) (wt%)-menthol 1.5 dl-camphor 0.5 methyl salicylate 0.7 glycol salicylate 0.6 indomethacin 0.15 eucalyptus oil 0.2 squalane 0.3 dimethylpolysiloxane 0.25 1,3-butylene glycol 12 2-octyldodecanol 0.3 crotamiton 0.2 Polyoxyethylene (23) cetyl ether 1.5 glycerin monostearate 0.1 Zinc white 1.5 Ethyl alcohol 2.5 Water 11.1 Freon-114 77.6 A foam aerosol anti-inflammatory analgesic preparation was obtained by the method according to Example 1.

Example 7 (Component) (wt%)-menthol 2.5 glycol salicylate 0.5 flurbiprofen 0.2 peppermint oil 0.5 1,3-butylene glycol 0.5 crotamiton 0.2 polyoxyethylene (30) polyoxypropylene (6) decyl tetradecyl ether 0.8 Silicone powder 0.7 Ethyl alcohol 2.0 Water 10.0 Freon-114 75 Freon-12 7 By the method according to Example 1, a foam aerosol anti-inflammatory analgesic preparation was obtained.

Example 8 (Component) (wt%)-menthol 2 dl-camphor 0.5 glycol salicylate 1 squalane 0.5 polyoxyethylene (20) polyoxypropylene (8) cetyl ether 1 ethanol 2 water 10 talc 1 freon-114 82 Example 1 A foamed aerosol anti-inflammatory analgesic preparation was obtained by the method according to.

Reference Example 1 (Component) (wt%)-menthol 4.0 dl-camphor 4.5 methyl salicylate 4.0 glycol salicylate 2.0 ethyl alcohol 30.0 water 26.5 talc 4 dimethyl ether 13.0 liquefied petroleum gas 12.0-menthol, dl-camphor, methyl salicylate and glycol salicylate. Dissolved in ethyl alcohol,
Add water to make a stock solution. This stock solution and talc were filled in an aerosol container, and then a mixture of dimethyl ether and liquefied natural gas as a propellant was injected under pressure to obtain an atomized aerosol anti-inflammatory analgesic preparation.

Reference Example 2 (Component) (wt%)-menthol 3.5 dl-camphor 2.9 methyl salicylate 2.6 glycol salicylate 1.3 benzyl nicotinate 0.02 ethyl alcohol 35 water 31.68 dimethyl ether 14 liquefied petroleum gas 9-menthol, dl-camphor, methyl salicylate, salicylate Glycol and benzyl nicotinate are dissolved in ethyl alcohol, and water is added to this to make a stock solution. This stock solution was filled in an aerosol container, and then a mixture of dimethyl ether and liquefied petroleum gas as a propellant was injected under pressure to obtain a nebulized aerosol anti-inflammatory analgesic preparation.

Test Example 1 (Sensory Test) The foamy aerosol preparation of Example 1 and Reference Examples 1 and 2
Table 1 shows the duration of irritation and Table 2 shows the side effects of the nebulized aerosol formulation No.

(1) Comparison of duration of stimulation of preparations The preparation of Example 1 and the preparations of Reference Examples 1 and 2 were sprayed on the forearm of 40 healthy males, and the duration of stimulation was measured.

(2) Comparison of Side Effects The preparation of Example 1 and the preparations of Reference Examples 1 and 2 were sprayed onto the forearm of 40 healthy males, and the skin condition after 2 hours was observed.

As can be seen from Tables 1 and 2, the foam aerosol formulation of the present invention was superior in duration of drug effect to the atomized aerosol formulations of Reference Examples 1 and 2 and had less side effects on the skin.

Test Example 2 (Aging Change Test) Table 3 shows the residual amounts of the active ingredients when the foam aerosol preparation of Example 1 and the atomized aerosol preparation of Reference Example 1 were stored at 40 ° C. for 3 months.

As can be seen from Table 3, the foam aerosol formulation of Example 1 was superior to the atomized aerosol formulation of Reference Example 1 in the stability of methyl salicylate and glycol salicylate.

〔The invention's effect〕

Foam aerosol anti-inflammatory analgesic formulation of the present invention, because it is sprayed in the form of a foam, the active ingredient is completely applied to the affected area without scattering around, compared to conventional atomized aerosol formulations,
The anti-inflammatory and analgesic effect is excellent, although the amount of active ingredients contained is small. In addition, when applied to the skin, the anti-inflammatory and analgesic effect is enhanced because the foam imparts a mild irritation to the destroyed skin. Also, since the amount of lower alcohol is very small, skin redness, rash, and
It has very few side effects such as degreasing and is very useful from the viewpoint of safety. In addition to the lower alcohol, the base component other than the propellant is small in compounding amount, so that the active ingredient has good stability over time. In addition, since it does not have the dripping or stickiness as seen in conventional atomized aerosol preparations and has a refreshing feeling, it is also excellent in terms of usability.

From the above points, the foam aerosol anti-inflammatory analgesic preparation of the present invention is a pharmaceutically useful preparation as a therapeutic drug for inflammatory diseases such as joint pain, low back pain, bruise, sprain, myalgia, and tendonitis.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Kunio Oguri, 4-6-12, Kasubehigashi, Kasukabe, Kasukabe, Saitama Prefecture (72) Satoshi Mekata 1-7-24, Mizuo, Ibaraki, Osaka (72) Invention Person Keiichiro Teramoto 1-25-14, Zensho, Otsu City, Shiga Prefecture (56) References JP-A-56-135414 (JP, A) JP-A-62-54784 (JP, A)

Claims (4)

[Claims] 1. An anti-inflammatory analgesic 0.3 to 15% by weight, an ether-based surfactant 0.1 to 5% by weight, water 3 to 20% by weight, powder 0.1 to 5
% By weight, lower alcohols up to 2.5% by weight and propellant 60
A foam aerosol anti-inflammatory and analgesic preparation containing about 90% by weight. 2. An anti-inflammatory analgesic selected from methyl salicylate, glycol salicylate, ketoprofen, indomethacin, flurbiprofen, -menthol, peppermint oil, dl-camphor, thymol, vanillyl nonylate, benzyl nicotinate and capsaicin. The foamed aerosol anti-inflammatory analgesic preparation according to claim 1, which is one kind or two or more kinds. 3. The foam aerosol anti-inflammatory analgesic preparation according to claim 1, wherein the ether-based surfactant is polyoxyethylene polyoxypropylene alkyl ether. 4. The foam aerosol anti-inflammatory analgesic preparation according to claim 1, wherein the lower alcohol is ethanol.