JP2024014507A - External liquid agent containing loxoprofen - Google Patents

Abstract

To provide an external liquid agent containing loxoprofen sodium that is superior in safety, usability, percutaneous absorptivity, stability, and productivity.SOLUTION: An external liquid agent includes an external application composition that contains loxoprofen sodium hydrate, peppermint oil, isopropanol, purified water and a pH regulator, the external application composition packed in a container. In the external application composition, a content of the peppermint oil is 0.5-4 mass% and a content of the isopropanol is 30-60 mass%. The external application composition has a pH of 5-8.SELECTED DRAWING: Figure 1

Description

The present invention relates to a topical solution containing loxoprofen sodium.

Loxoprofen sodium has excellent anti-inflammatory and analgesic effects and is widely used in clinical settings not only as an oral agent but also as an external agent. Various dosage forms such as poultices, tapes, gels, liquids (lotions), and pump sprays are used as external preparations for transdermally absorbing loxoprofen for local action. Among these, liquid preparations (lotions) are not only easy to apply to various areas using an applicator container, but also have very little stickiness and are less sticky on the skin than pap or tape preparations that seal the skin. Loxoprofen sodium-containing topical liquid preparations have great advantages because they do not cause irritation or stuffiness, and they are easy to use, allowing you to put on clothes immediately after application.

Various liquid preparations for external use containing loxoprofen sodium have been proposed to date. Namely, a topical anti-inflammatory analgesic containing loxoprofen sodium, menthol, ethanol, and water filled in a roll-on container made of polypropylene (Patent Document 1), loxoprofen sodium hydrate containing tocopherol acetate as an antioxidant, 15% by weight % of isopropanol and l-menthol, which does not cause clouding due to precipitation of menthol (Patent Document 2), loxoprofen sodium hydrate, menthol, ethanol, water, and A lotion containing 1,3-butylene glycol (Patent Document 3), a liquid or gel containing loxoprofen, 0.1 to 60% by weight of isopropanol based on the entire formulation, and further l-menthol or tocopherol acetate. (Patent Document 4), an external preparation containing loxoprofen and/or a pharmaceutically acceptable salt thereof, menthol, an alcohol having 1 to 4 carbon atoms, preferably ethanol, and water filled in a bent-neck container. (Patent Document 5, Patent Document 6), loxoprofen or a salt thereof, and a composition containing one or more selected from terpenes, chlorpheniramine or a salt thereof, diphenhydramine or a salt thereof, and a polyhydric alcohol (Patent Document 7) , loxoprofen or a salt thereof, isopropanol, and a saturated higher fatty acid salt (Patent Document 8), etc. have been proposed.

JP2013-63961A JP2015-27971A International Publication No. 2017/111167 JP 2017-200909 Publication JP2019-119686A JP 2019-119743 Publication JP2020-203933A Patent No. 6189668

However, these external liquid preparations have problems in that when applied to the skin, they dry slowly, feel sticky, or irritate, and are not completely satisfactory in terms of safety and usability. In addition, cloudiness may occur, causing problems with stability, and transdermal absorption may be low, resulting in failure to obtain sufficient medicinal efficacy. These problems have usually been solved by adding various formulation additives. However, when the number of formulation additives constituting a liquid formulation is large, the manufacturing process becomes complicated and a great deal of effort is required to maintain quality. Therefore, by reducing the number of additives that make up the external liquid as much as possible, we have created a liquid for external use that dries quickly, has excellent application feel, is safe, has excellent stability and transdermal absorption, and can be easily manufactured. development was desired.

Therefore, an object of the present invention is to provide a loxoprofen sodium-containing liquid preparation for external use that is excellent in safety, usability, percutaneous absorption, stability, and productivity.

Therefore, as a result of intensive research, the present inventors prepared a topical composition by blending loxoprofen sodium hydrate, peppermint oil, isopropanol, purified water, and a pH adjuster, and adjusted the pH within a specific range. The present inventors have discovered that by doing so, it is possible to obtain an external preparation that has excellent usability, safety, transdermal absorption, and stability despite having a small number of formulation additives, and has completed the present invention.

That is, the present invention provides the following inventions [1] to [6].
[1] A liquid preparation for external use in which a container is filled with an external composition containing loxoprofen sodium hydrate, peppermint oil, isopropanol, purified water, and a pH adjuster, wherein the content of peppermint oil in the external composition is 0. 5 to 4% by mass, isopropanol content is 30 to 60% by mass, and the pH of the external composition is 5 to 8.
[2] The external liquid preparation according to [1], wherein the content of loxoprofen sodium hydrate in the external composition is 0.5 to 3% by mass.
[3] The liquid preparation for external use according to [1] or [2], wherein the viscosity at 20° C. of the composition for external use is 80.0 mPa·s or less.
[4] The external liquid preparation according to any one of [1] to [3], wherein the container is equipped with an applicator stopper having a polyurethane applicator sponge at the opening.
[5] The external liquid preparation according to [4], wherein the container consists of a bottle, a cap, and an applicator stopper having an applicator sponge, and the average pore diameter of the applicator sponge is 40 to 100 μm.
[6] The external liquid preparation according to [5], wherein the thickness of the application sponge is 1 to 3 mm and the area is 10 to 1000 mm ² .

According to the present invention, to provide an easy-to-use external liquid preparation that has improved safety, transdermal absorbability, usability, productivity, stability, etc., and can safely and maximally exhibit the pharmacological effects of loxoprofen sodium hydrate. became possible.

3 is a graph showing the amount of loxoprofen sodium permeated through the skin in Test Example 3. FIG. 1 is a schematic diagram showing a preferred embodiment of a container used for the external liquid preparation of the present invention.

The external liquid preparation of the present invention is composed of an external composition containing loxoprofen sodium hydrate as an active ingredient and a container filled with the composition. Loxoprofen sodium hydrate (common name) has a chemical name: Monosodium 2-{4-[(2-oxocyclopentyl)methyl]phenyl}propanoate dihydrate, a molecular formula: C ₁₅ H ₁₇ NaO _{3.2H 2} O, and a molecular weight of 304. 31 It is a non-steroidal anti-inflammatory and analgesic drug (NSAIDs). As a medical drug, its efficacy or effect is to treat diseases and symptoms such as osteoarthritis, muscle pain, and swelling and pain after trauma. The indications are: pain in the joints, joint pain, muscle pain, tendonitis (hand/wrist pain), elbow pain (tennis elbow, etc.), bruises, sprains.
The external liquid preparation of the present invention preferably contains 0.5 to 3% by mass of this loxoprofen sodium hydrate in the external composition, more preferably 1 to 2% by mass, particularly preferably 1.13% by mass (anhydrous 1% by mass).

The external composition used in the present invention contains peppermint oil, isopropanol, purified water, and a pH adjuster in addition to the loxoprofen sodium hydrate. One embodiment of a suitable container for use in the external liquid preparation of the present invention is one in which a sponge-like application part is provided at the opening. Generally, in external liquid preparations, dripping during application is suppressed by increasing the viscosity with a polymer or the like. However, when a polymer is used, components may precipitate on the sponge application area or on the skin surface when applied. Loxoprofen sodium may also form analogs under acidic conditions. Therefore, formulation additives other than those mentioned above, such as polyhydric alcohols, cellulose derivatives, and synthetic polymer thickeners, may impair the feeling of use and stability, so the external composition used in the present invention should not be used. It is preferable not to do so.

The peppermint oil used in the present invention is an essential oil obtained by steam distilling the above-ground parts of peppermint plants, cooling the oil, and removing the solid content. The peppermint oil preferably contains 30.0% by mass or more of menthol, more preferably 35.0% by mass or more, and particularly preferably 39.0% by mass or more. Furthermore, the peppermint oil used in the present invention preferably has an optical rotation of -17.0 to -36.0°, more preferably -18.0 to -30.0°, particularly -19.0°. The angle is preferably in the range of -25.0°. Furthermore, the acid value of the peppermint oil used in the present invention is preferably 1.0 or less, particularly preferably 0.5 or less.
The content of peppermint oil in the external composition is preferably 0.5 to 4% by mass, more preferably 1 to 3% by mass, and particularly preferably 1.5 to 2.5% by mass. preferable.

The external composition used in the present invention further contains isopropanol and purified water. The amount of isopropanol in the external composition is preferably 30 to 60% by weight, more preferably 35 to 50% by weight, and particularly preferably 40 to 45% by weight. Further, the amount of purified water in the external composition is preferably 40 to 70% by weight, more preferably 50 to 65% by weight, and particularly preferably 55 to 60% by weight.

The external composition used in the present invention further contains a pH adjuster to adjust the pH to a predetermined range. The pH of the external composition used in the present invention is preferably 5 to 8, more preferably 5 to 7, still more preferably 5.5 to 6.5, from the viewpoint of skin irritation and stability. It is preferable to adjust it within the range of . Here, pH refers to a value measured with a glass electrode type hydrogen ion concentration indicator.

The pH adjuster is not particularly limited as long as it can adjust the pH of the external composition to the above range, but includes inorganic pH adjusters such as sodium hydroxide, potassium hydroxide, and hydrochloric acid, acetic acid, and lactic acid. , citric acid, malic acid, tartaric acid, maleic acid, fumaric acid, adipic acid, salicylic acid, and their salts, and these may be used alone or in combination of two or more. Furthermore, an acidic pH adjusting agent and a basic pH adjusting agent may be used in combination to have a buffering effect.
Preferred specific examples of the pH adjuster used in the present invention include lactic acid, tartaric acid, citric acid, and malic acid. A particularly preferred specific example is lactic acid from the viewpoint of usability, productivity, etc. I can do it.
In the present invention, the content of the pH adjuster in the external composition is preferably 0.05 to 2% by mass, more preferably 0.1 to 1.5% by mass, particularly 0.15 to 2% by mass. Preferably, it is 1% by mass. When lactic acid is used as a pH adjuster, it is preferably 0.05 to 0.5% by mass, more preferably 0.1 to 0.3% by mass, particularly 0.05% by mass, more preferably 0.1% to 0.3% by mass, in the external composition. It is preferably 2% by mass.

In addition to the above-mentioned pharmaceutical additives, the external liquid preparation of the present invention contains pharmaceutical additives that can be commonly used in pharmaceuticals, such as colorants, fragrances, preservatives, solubilizers, stabilizers, surfactants, preservatives, etc. It is also possible to add one or more selected from the following. In order not to increase the number of constituent components, it is preferable not to add it as much as possible. Specific examples of these excipients can be found in the Pharmaceutical Excipients Dictionary 2021 (edited by the Japan Pharmaceutical Excipients Association, published by Yakuji Nippo), the Pharmaceutical Affairs Agency No. 1204 No. 1 (Pharmaceutical Affairs Administrative Law), and the website of the Japan Pharmaceutical Excipients Association. (http://www.jpec.gr.jp/).

The external liquid preparation of the present invention is provided by filling a container with the above-mentioned external composition. A preferred embodiment of the container is a container equipped with an applicator stopper having an applicator sponge at the opening. For example, as shown in FIG. It is a container consisting of a cap 1 for covering and an applicator stopper 4 having an applicator sponge 3, and the external composition filled in the container is applied to the skin by passing through the applicator sponge and being discharged from the container. The material of the container is related to stability and feeling of use, and in particular, the material of the application part sponge of the applicator stopper that comes into direct contact with the skin affects the feeling of use. It is preferable to use polyurethane as the material for the application section sponge. The average pore diameter of the application sponge is preferably 10 to 150 μm, particularly preferably 40 to 100 μm. In this specification, the average pore diameter means a value measured by an electron microscope. The thickness of the sponge is usually in the range of 1 to 3 mm, preferably 1.5 to 2.5 mm, and particularly preferably 2 mm. The area of the application sponge is not particularly limited, but in consideration of ease of application, feeling of use, etc., it is usually in the range of 10 to 1000 mm ² , preferably 100 to 600 mm ² , and particularly It is preferably 300 to 400 mm ² .
Furthermore, the material of the bottle, cap, and applicator stopper (excluding the applicator part) is preferably vinyl chloride, acrylonitrile/styrene, polyethylene, polyethylene terephthalate, polypropylene, polymethylpentene, etc., and particularly polyethylene, polyethylene terephthalate, or polypropylene. is preferred.

The method for producing the external composition used in the present invention is not particularly limited, but in general, liquid components such as purified water, peppermint oil, and isopropanol are mixed, loxoprofen sodium hydrate is dissolved therein, and a pH adjuster is added. Although it is preferable to manufacture by adding and adjusting the pH and filling the container into a container, other methods can also be used depending on the characteristics of the formulation equipment.

The viscosity of the external composition of the present invention is determined to be 80 mP·s or less at 20°C from the viewpoint of feeling of use and prevention of clogging when using a container equipped with an application stopper having the above-mentioned application part sponge. It is preferably at most 40 mP·s, more preferably at most 20 mP·s, and even more preferably at most 10 mP·s. As used herein, the viscosity of the composition for external use means a value measured using a B-type viscometer when the composition is rotated for 2 minutes at an appropriate spindle and rotation speed selected according to the viscosity.

A particularly preferred embodiment of the external liquid preparation of the present invention includes 1.13% by mass of loxoprofen sodium hydrate, 2% by mass of peppermint oil, 40% by mass of isopropanol, 56.67% by mass of purified water, and 0.2% by mass of lactic acid. The composition for external use has a pH of 5.5 to 6.5 and a viscosity of 20 mP·s or less, the material of the application stopper is polyethylene, polypropylene, or polyethylene terephthalate, and the sponge-like application part has an average pore diameter of 40 to 100 μm. , made of polyurethane and having a thickness of 2 mm and an area of 300 to 400 mm ² .

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

Manufacturing example 1
Preparation of external composition (1):
External compositions having the compositions shown in Tables 1 to 3 were prepared. After stirring a mixture of a portion of purified water and isopropyl alcohol, peppermint oil (menthol content: 41.5%, optical rotation: -20.9°, acid value: 0.2) and loxoprofen sodium hydrate were added. After dissolving and stirring uniformly, the pH was adjusted to about 6 with a pH adjuster, and the remaining purified water was added to the total amount of 100 g to obtain a composition for external use.

Manufacturing example 2
Preparation of external composition (2)
External compositions having the compositions shown in Tables 4 and 5 were prepared. After stirring a mixture of a portion of purified water and isopropyl alcohol, loxoprofen sodium hydrate and other components except for the pH adjuster are dissolved and stirred uniformly, the pH is adjusted with the pH adjuster, and the remaining purified The total amount was adjusted to 100 g with water to obtain a composition for external use.

Test Example 1: Usage Feeling of External Composition For the external compositions prepared in Production Examples 1 and 2, 10 panelists applied 1 g of each sample, 2 samples on the left and right arms, and conducted a relative sensory evaluation. Based on the average, (i) stickiness, (ii) drying speed of the liquid, (iii) liquid remaining after drying, (iv) ease of application, (v) feeling of effectiveness immediately after application, and (vi) time of application. We evaluated the usability of each item regarding skin irritation. (i) to (iv) were scored on a six-point scale from 1 to 6, and when the average value was 1 or more but less than 3, it was marked ×, when it was 3 or more and less than 5, it was given △, and when it was 5 or more, it was given 0. (v) to (vi) are scored on an 8-point scale from 1 to 8. If the average value is 1 or more but less than 3, it is ×, if it is 3 or more and less than 5, it is -, and if it is 5 or more and less than 7, it is △. Cases of 7 or more were marked as ○. The results are shown in Table 6. In addition, the evaluation of each usability item according to the classification of the average rating value is shown below.
- Stickiness: “I don’t feel it (〇), I feel it a little (△), I feel it (×)”
・Drying speed of liquid: “Fast (〇), Normal (△), Slow (×)”
・Remaining agent after drying: “No (〇), Slightly (△), Yes (×)”
・Ease of application: “Easy to apply (〇), Slightly difficult to apply (△), Difficult to apply (×)”
・Efficacy immediately after application: “I feel it strongly (〇), I feel it (△), I feel it weakly (-), I don’t feel it (×)”
・Skin irritation during application: “I don’t feel it (〇), I feel it weakly (△), I feel it (-), I feel it strongly (×)”

It was shown that all of the external compositions of Examples had excellent feel when used, and the external compositions of Examples 1-13, 1-14, and 1-15 had particularly excellent feeling when applied. In addition, all of the external compositions of Examples were excellent in safety, with no skin irritation associated with application.

Test Example 2: Usability of External Preparation The external compositions of Examples 1-13 were filled into containers with a capacity of 25 g equipped with applicator plugs having applicator sponges with different average pore diameters to obtain liquid preparations for external use. The container is a bottle (polypropylene), a cap (polypropylene), and an applicator stopper (polyethylene), and the applicator sponge (polyurethane) has a thickness of 2 mm and an area of about 3.6 mm ² (see FIG. 2). Using the obtained external liquid, apply the sponge-like application part by touching it to the upper arm, and a panel of 10 people applied 1 g of each sample, 2 samples on the left and right arms, to check the feeling of use in the following items. A relative sensory evaluation was performed and a score was given on a six-point scale from 1 to 6. If the average value was 1 or more and less than 3, it was rated ×, when it was 3 or more and less than 5, it was △, and when it was 5 or more, it was 0. The results are shown in Table 7. In addition, the evaluation of each usability item according to the classification of the average rating value is shown below.
・Dripping: “No (〇), Slightly (△), Yes (×)”
・Clogging: “No (〇), Slightly present (△), Yes (×)”
・Skin feel: “Good (〇), Average (△), Bad (×)”

It was found that when a polyurethane sponge with an average pore diameter of 80 μm was used, dripping was clearly suppressed compared to when a polyurethane sponge with an average pore diameter of 250 μm was used. Furthermore, when polyurethane sponges with an average pore diameter of 80 μm and an average pore diameter of 250 μm were compared in terms of feel, the result was that the polyurethane sponge with an average pore diameter of 80 μm was clearly superior.
In general, polymers are often added to external liquids to prevent dripping, etc., but they reduce manufacturing costs, simplify the manufacturing process, generate impurities, and can clog sponges due to the viscosity of the liquid. Considering properties, etc., it is better to have fewer additive components in a liquid formulation, and by using a polyurethane sponge with an average pore diameter of 80 μm, we decided to invent a formulation with a small number of ingredients and excellent usability. Successful.

Test example 3
Stability Test The external compositions of Example 1-13, Example 1-16, Comparative Example 1-11, and Comparative Example 1-12 were stored at 40° C. for 6 months, filtered, and then evaluated for stability over time. The content of loxoprofen sodium was measured by high performance liquid chromatography, and the remaining amount (%) immediately after production (initial stage) and after 6 months storage was determined, assuming the theoretical value of the content as 100%. The score was evaluated as "○", 90% to 98% as "△", and less than 90% as "x". The properties were observed with the naked eye and evaluated as "○" if it was colorless and clear, and "x" if precipitation of solid components or cloudiness was observed. The results are shown in Table 8.

Examples 1-13 and 1-16 showed excellent stability over time, with no change in properties such as a decrease in content, discoloration, separation of components, or precipitation of precipitates even after storage at 40°C for 6 months. Ta. On the other hand, in Comparative Examples 1-11 and 1-12, which have a low pH range, a decrease in content, precipitation of components, or cloudy liquid was observed.

Test example 4
Transdermal absorption test A skin permeation test was conducted using the external compositions of Example 1-13 and Comparative Example 1-2 under the following conditions, and loxoprofen was measured by HPLC method 6, 12, and 24 hours after application. The amount of skin permeation was measured. The results are shown in Figure 1.
Cell: Vertical diffusion cell Effective curtain area: 1.0cm ²
Receiver solution: physiological saline volume: 8.0 mL
Sample volume: 0.2 mL
Temperature: 32℃
Skin: Hairless rat (HWY/Slc) skin

It was observed that the external compositions of Examples 1-13 exhibited high skin permeability and excellent percutaneous absorption of loxoprofen.

1: Cap 2: Bottle 3: Application sponge 4: Application stopper

Claims (6)

A liquid preparation for external use in which a container is filled with a composition for external use containing loxoprofen sodium hydrate, peppermint oil, isopropanol, purified water, and a pH adjuster, wherein the content of peppermint oil in the external composition is 0.5 to 4. % by mass, the content of isopropanol is 30 to 60% by mass, and the pH of the composition for external use is 5 to 8. The external liquid preparation according to claim 1, wherein the content of loxoprofen sodium hydrate in the external composition is 0.5 to 3% by mass. The liquid preparation for external use according to claim 1, wherein the viscosity of the composition for external use at 20°C is 80.0 mPa·s or less. The external liquid preparation according to any one of claims 1 to 3, wherein the container is equipped with an applicator stopper having a polyurethane applicator sponge at the opening. 5. The external liquid preparation according to claim 4, wherein the container comprises a bottle, a cap, and an applicator stopper having a polyurethane applicator sponge, and the average pore diameter of the applicator sponge is 40 to 100 μm. 6. The external liquid preparation according to claim 5, wherein the application portion sponge has a thickness of 1 to 3 mm and an area of 10 to 1000 mm ² .