JP2015027971A - Loxoprofen-containing external application agent - Google Patents

Abstract

An object of the present invention is to provide a loxoprofen-containing external preparation that maintains a clear appearance even when stored at low or high temperatures. An external coating agent comprising the following components (A) and (B). (A) Loxoprofen or its salt (B) Isopropanol [Selection] None

Description

  The present invention relates to an external coating agent containing loxoprofen or a salt thereof.

As a preparation to be applied to the skin, an external preparation for skin is known, which is roughly classified into an application agent and a patch.
Examples of the coating agent include an external solid agent (tick agent), an external liquid agent (liniment agent, lotion agent), an ointment, a cream agent, and a gel agent. Among these, the external solid agent is stored in an appropriate container. In this case, since the drug can be applied to the skin without staining hands and fingers, it is difficult to cause discomfort during use.
However, when formulating a solid preparation for external use using various drugs, problems often arise in the hardness and shape retention of the preparation. Although various studies have been made so far (Patent Documents 1 to 6), none of them is necessarily satisfactory in terms of hardness, shape retention, appearance transparency, and the like of the preparation.

  By the way, loxoprofen is a kind of phenylpropionic acid type non-steroidal anti-inflammatory analgesic (NSAID). As an external preparation for skin using this, it contains loxoprofen sodium hydrate, and it is a poultice and tape that has osteoarthritis, myalgia, swelling / pain after trauma, and anti-inflammatory / analgesic effects. Although an agent and a gel agent are known (patent documents 7 to 9 and non-patent document 1), an external solid preparation containing loxoprofen has not been known yet.

Japanese Patent Laid-Open No. 55-2645 JP-A-56-79619 JP-A-57-42613 JP-T 6-505245 JP 2003-176209 A JP 2004-161714 A JP 2002-128701 A JP 2004-43512 A International Publication No. 2006/048939

The 16th revision Japanese Pharmacopoeia Manual Sasakawa Shoten Co., Ltd. C-5359-5364

  It is an object of the present invention to provide a loxoprofen-containing external coating agent that maintains a clear appearance even when stored at low or high temperatures.

  As a result of intensive studies, the present inventors have found that a loxoprofen-containing external preparation that maintains a clear appearance even after storage at low or high temperatures can be obtained by using isopropanol together with loxoprofen or a salt thereof. The present invention has been completed.

That is, this invention provides the external application | coating agent containing the following components (A) and (B).
(A) Loxoprofen or a salt thereof (B) Isopropanol

  The external coating agent of the present invention has a high commercial value because it maintains a clear appearance even after storage at low or high temperatures and has high storage stability.

<Component (A)>
The loxoprofen or a salt thereof contained in the external application agent of the present invention includes loxoprofen itself, a pharmaceutically acceptable salt of loxoprofen, and a solvate of these with water or alcohol. In the present invention, loxoprofen sodium hydrate (chemical name: Monosodium 2- [4-[(2-oxocyclopentyl) methyl] phenyl] propanoate dihydrate) is preferable.
Loxoprofen or a salt thereof is a known compound, and can be produced by a known method, or a commercially available product can be used.

  Further, the content of loxoprofen or a salt thereof (in terms of loxoprofen sodium anhydrate) may be appropriately determined according to the desired anti-inflammatory analgesic effect, and is preferably 0.01 to 10 parts by mass in 100 parts by mass of the external application agent. 0.1-5 mass parts is more preferable, and 0.5-3 mass parts is still more preferable.

<Component (B)>
Isopropanol contained in the external coating agent of the present invention is one known compound of dihydric alcohols whose formula is represented as CH ₃ CH (OH) CH ₃ . Depending on the nomenclature, it is also expressed as 2-propanol, propan-2-ol, isopropyl alcohol, and the like.
The content of isopropanol may be appropriately determined according to the clarity control ability or the like in the external application agent that isopropanol has, and is preferably 5 to 70 parts by mass, more preferably 7 to 60 parts by mass in 100 parts by mass of the external application agent. Preferably, 10-50 mass parts is more preferable.
Moreover, as mass ratio [(B) / (A)] of content of (A) loxoprofen or its salt (in terms of loxoprofen sodium anhydrate) and (B) isopropanol, 1-60 are preferable, and 3-50 Is more preferable, and 5 to 40 is more preferable.

  Moreover, isopropanol can be manufactured by a well-known method, and a commercially available thing can be used. For example, “isopropanol” described in the 16th revised Japanese Pharmacopoeia manual may be used.

The external coating agent of the present invention is prepared by adding components (A) and (B) to components (C) and (described later) as necessary, based on the known methods described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations. D) It can be manufactured by mixing with other commonly used formulation additives, dissolving or dispersing, and solidifying as desired.
Examples of the dosage form of the external coating agent of the present invention include an external solid agent (tick agent), an external liquid agent (liniment agent, lotion agent), an ointment, a cream agent, a gel agent, and the like. An external liquid agent is preferable, and an external solid agent is more preferable in consideration of stickiness and spreadability that lead to discomfort during application / rubbing of the external application agent. Moreover, as a base of an external solid agent, a soap gel base is preferable.

<Ingredient (C)>
The external coating agent of the present invention preferably contains an alcohol (hereinafter sometimes referred to as component (C)) as a base, and the alcohol of component (C) is composed of isopropanol as component (B) and a component (described later). E) An alcohol other than those having an alcoholic hydroxyl group among terpenes.
Alcohols are broadly classified into monohydric alcohols and polyhydric alcohols, and one kind may be used alone, or two or more kinds may be used in combination.
Examples of the monohydric alcohol include methanol, ethanol, methanol-modified alcohol, propanol, butanol, isobutanol, octaacetyl sucrose-modified alcohol, phenylethyl alcohol, phenylethyl alcohol-modified alcohol, and the like. Among these, ethanol, methanol-modified alcohol, octaacetyl sucrose-modified alcohol, phenylethyl alcohol, phenylethyl alcohol-modified alcohol and the like are preferable.

  The polyhydric alcohol has a plurality of alcoholic hydroxyl groups, specifically, dihydric alcohols such as ethylene glycol, propylene glycol, 1,3-butylene glycol, polyethylene glycol, polypropylene glycol, and polyoxyethylene polyoxypropylene glycol. A trihydric alcohol such as glycerin; a sugar alcohol such as erythritol, sorbitol, and mannitol; Among these, propylene glycol, 1,3-butylene glycol, polyethylene glycol, and glycerin are preferable.

As content of alcohol, it is 10-90 mass parts normally in 100 mass parts of external coating agents, 15-85 mass parts is preferable, 20-80 mass parts is more preferable, and 30-70 mass parts is still more preferable.
In addition, as a mass ratio [(C) / (A)] of the content of (A) loxoprofen or a salt thereof (in terms of loxoprofen sodium anhydride) and (C) alcohol, the dosage form of the external coating is a solid for external use. In the case of an agent, 10 to 90 are preferable, 15 to 85 are more preferable, 20 to 80 are more preferable, and 30 to 70 are particularly preferable from the viewpoint of imparting appropriate hardness thereto.

Moreover, as total content of the isopropanol of a component (B) and the said monohydric alcohol, 5-70 mass parts is preferable in 100 mass parts of external application agents, 7-60 mass parts is more preferable, 10-50 masses Part is more preferable.
Moreover, as content of the said polyhydric alcohol, 5-80 mass parts is preferable in 100 mass parts of external application | coating agents, 10-70 mass parts is more preferable, and 20-60 mass parts is further more preferable.
The polyhydric alcohol is preferably a combination of one or more selected from the group consisting of propylene glycol, 1,3-butylene glycol and polyethylene glycol and glycerin. In this case, as content of glycerol, 1-100 mass parts is preferable in 100 mass parts of external application agents, 3-50 mass parts is more preferable, 5-40 mass parts is further more preferable.

<Component (D)>
The external coating agent of the present invention preferably contains a saturated higher fatty acid salt (hereinafter sometimes referred to as component (D)) as a base when the dosage form of such a coating agent is used as a solid agent.
The saturated higher fatty acid salt is preferably one having 12 to 22 carbon atoms. Examples include laurate, myristate, pentadecanoate, palmitate, margarate, stearate, isostearate, arachidate, behenate, etc., and these may be used alone Two or more kinds may be used in combination. Among these, those having 14 to 22 carbon atoms are more preferable, specifically, palmitate, myristate, stearate and isostearate are preferable, and stearate and isostearate are more preferable. It is done.
Moreover, as such a salt, inorganic salts, such as aluminum salt, potassium salt, sodium salt, magnesium salt, are preferable, and sodium salt is especially preferable.
Specific examples of the saturated higher fatty acid salt include sodium myristate, potassium myristate, sodium palmitate, aluminum stearate, potassium stearate, sodium stearate, magnesium stearate, sodium isostearate and the like. More preferred is sodium stearate.

  When a saturated higher fatty acid salt is used as a solid preparation for external use, a saturated higher fatty acid, preferably a compound having 12 to 22 carbon atoms, and a compound that dissociates a cation that forms a salt with this (such as potassium hydroxide and sodium hydroxide) ) May be added to form a saturated higher fatty acid salt. A soap base or a medicinal soap containing a saturated higher fatty acid salt (such as a sodium salt of a saturated higher fatty acid) may also be used.

The content of the saturated higher fatty acid salt in the external solid preparation is preferably 0.1 to 30 parts by mass, more preferably 0.5 to 20 parts by mass, and further preferably 1 to 15 parts by mass in 100 parts by mass of the external solid preparation. 5 to 10 parts by mass is preferable.
In addition, the mass ratio [(D) / (A)] of the content of (A) loxoprofen or a salt thereof (in terms of loxoprofen sodium anhydrate) and (D) a saturated higher fatty acid salt is appropriate for a solid preparation for external use. From the viewpoint of imparting hardness, 1 to 25 is preferable, 3 to 15 is more preferable, and 5 to 10 is more preferable.

  Examples of other preparation additives described above include oils such as diisopropyl adipate, crotamiton, squalane, squalene, diethyl sebacate, castor oil, isopropyl palmitate, isopropyl myristate, cetyl myristate, myristyl myristate; sucrose fatty acid Surfactant such as ester, sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyglycerin fatty acid ester, sodium lauryl sulfate, lauromacrogol, polyoxyethylene cetyl ether; oleyl alcohol, lauryl alcohol, etc. Higher alcohols; hydrochloric acid, sodium acetate hydrate, tartaric acid, sodium tartrate, sodium hydroxide, sodium carbonate hydrate, sodium lactate, sodium malate pH adjusting agents such as Um; antioxidants, and the like. These may be used alone or in combination of two or more.

Examples of the antioxidant include sodium nitrite, ascorbic acid, L-ascorbic acid stearate, sodium hydrogen sulfite, alpha thioglycerin, sodium edetate, erythorbic acid, cysteine hydrochloride, dry sodium sulfite, and citric acid hydrate. , Potassium dichloroisocyanurate, dibutylhydroxytoluene, sodium thioglycolate, sodium thiomalate, natural vitamin E, tocopherol, d-δ-tocopherol, tocopherol acetate, concentrated mixed tocopherol, ascorbic acid palmitate, sodium pyrosulfite, Butylhydroxyanisole, 1,3-butylene glycol, benzotriazole, pentaerythrityl-tetrakis [3- (3,5-di-t-butyl-4-hydroxypheny ) Propionate], propyl gallate, 2-mercaptobenzimidazole, and malic acid. Among them, sodium nitrite, sodium hydrogen sulfite, dibutylhydroxytoluene, natural vitamin E, tocopherol, d-δ-tocopherol, tocopherol acetate, sodium pyrosulfite, butylhydroxyanisole, 1,3-butylene glycol, sodium pyrosulfite, etc. preferable.
When the antioxidant is contained in the external application agent of the present invention, the content thereof may be appropriately determined according to the type of the antioxidant, etc., but 0.01 to 50 mass in 100 parts by mass of the external application agent. Part is preferable, 0.02 to 10 parts by mass is more preferable, and 0.03 to 2 parts by mass is further preferable.

  Further, when malic acid and / or citric acid hydrate is used as an antioxidant, it is preferably used in combination with higher fatty acids such as myristic acid, palmitic acid, stearic acid, and isostearic acid. The content of malic acid and / or citric acid hydrate in the case of containing an antioxidant is preferably 0.1 to 3 parts by mass in 100 parts by mass of the external solid preparation, while the content of higher fatty acids is as follows. 0.1 to 5 parts by mass is preferable.

  Further, the external application agent of the present invention includes drugs other than loxoprofen or a salt thereof, for example, local irritation component, analgesic component, anti-inflammatory component, bactericidal / disinfecting component, astringent / protective component, blood circulation promoting component, antihistamine component, Herbal medicines etc. are mentioned, and these may contain 1 type, or 2 or more types.

Examples of the local stimulation component include capsaicin, terpenes, nonanoic acid vanillylamide, and the like.
Examples of the analgesic component include salicylic acid, glycol salicylate, and methyl salicylate.
Examples of the anti-inflammatory component include glycyrrhizic acid, glycyrrhetinic acid, dipotassium glycyrrhizinate and the like.
Examples of the sterilizing / disinfecting component include thymol. Examples of the astringent / protective component include zinc oxide.
Examples of the blood circulation promoting component include benzyl nicotinate, heparin-like substances, sodium polyethylene sulfonate, and the like.

Antihistamine components include, for example, azelastine hydrochloride, alimemazine tartrate, istipendil hydrochloride, iproheptin hydrochloride, epinastine hydrochloride, emedastine fumarate, carbinoxamine diphenyl disulfonate, carbinoxamine maleate, Clemastine fumarate, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, ketotifen fumarate, difeterol hydrochloride, difeterol phosphate, diphenylpyraline hydrochloride, diphenylpyraline theocrate , Diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, triprolysine hydrochloride, tripelenamine hydrochloride, tondilamine hydrochloride, phenetazine hydrochloride, promethazine hydrochloride, mequitazi , Methdilazine hydrochloride, main blanking hydro Linna Paji sills salts include emetine Das Chin fumarate salt.
Examples of herbal medicines include arnica, gold, yellow cocoon, yellow ream, dry cinnamon cinnamon, safflower, mountain lion, horse chestnut, salmon, wood tempura, salmon plum, and extracts thereof (extract, tincture, etc.). It is done.

<Ingredient (E)>
As described above, the external application agent of the present invention can contain various drugs. Among them, terpenes (hereinafter referred to as components (E) from the viewpoint of local stimulating action and shape retention based on analgesic and analgesic action. )).) Is preferably included. Terpenes are not particularly limited, and examples include monoterpenes and sesquiterpenes.
Examples of such terpenes include, for example, isoborneol, iron, osimene, carbeol, carbotanaseton, carbomenton, carvone, caren, caron, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellic acid, Citronellol, Cineol, Cymen, Silvestrene, Isotjojol, Tujon, Terpineol, Terpinene, Terpinolene, Tricyclene, Nerol, Pinene, Pinoccampheol, Pinol, Piperithenone, Ferrandral, Ferrandrene, Fentchen, Fentyl alcohol, Perillyl alcohol , Perylaldehyde, borneol, myrcene, menthol, menthone, yonor, yonon, linalool, limonene, etc. It may be used in combination thereof alone or. Among these, camphor, geraniol, citronellal, terpineol, borneol, menthol, limonene and the like are preferable, camphor and menthol are more preferable, and dl-camphor, l-menthol and dl-menthol are particularly preferable.

Moreover, when the said terpenes are contained in the external application | coating agent, you may use the essential oil containing the above terpenes.
Such essential oils include, for example, anise oil, ylang ylang oil, iris oil, fennel oil, orange oil, cananga oil, chamomile oil, kayap oil, caraway oil, kubeb oil, grapefruit oil, cinnamon oil, coriander oil, saffron oil Oil, salamander, perilla oil, citriodora oil, citronella oil, ginger oil, gingergrass oil, gingergrass oil, spearmint oil, mint oil, geranium oil, geranium oil, clove oil, turpentine oil, spruce oil , Neroli oil, basil oil, peppermint oil, palmarosa oil, pimento oil, petitgren oil, bay oil, peniroyal oil, henoposi oil, bergamot oil, bored rose oil, pepper oil, marjolan oil, mandarin oil, melissa oil, eucalyptus oil, lime Oil, lavender oil, linaloe oil, lemon , Lemongrass oil, rose oil, rosemary oil, Roman chamomile oil, and the like, may be used in combination thereof alone or.
Among these, ylang ylang oil, fennel oil, orange oil, chamomile oil, cinnamon oil, perilla oil, citronella oil, ginger oil, camphor oil, mint oil, geranium oil, clove oil, turpentine oil, spruce oil, neroli oil Mint oil, palmarosa oil, bergamot oil, eucalyptus oil, lavender oil, linaloe oil, lemon oil, rose oil, rosemary oil, roman chamomile oil, etc., camphor oil, mint oil, mint oil are more preferable, mint Oil is particularly preferred.

Further, the content of terpenes may be appropriately determined according to the local stimulating action based on the desired analgesic and analgesic action in the external application agent, and preferably 0.01 to 15 parts by mass in 100 parts by mass of the external application agent. 0.1-10 mass parts is more preferable, and 0.5-7 mass parts is still more preferable.
Moreover, as a mass ratio [(E) / (A)] of content of (A) loxoprofen or a salt thereof (in terms of loxoprofen sodium anhydrate) and (E) terpenes, 0.01 to 15 is preferable, 0.1-10 are more preferable and 0.5-7 are still more preferable.

  When terpenes have a hydroxyl group, from the viewpoint of suppressing ester formation between the hydroxyl group and the carboxy group of loxoprofen, metal carbonates such as urea, calcium carbonate and magnesium carbonate, sodium hydrogen sulfite, 2-mercaptobenzimidazole Etc. may be further contained. The content of these components in the case of containing them may be appropriately examined, but it is preferable to contain 0.5 to 3 parts by mass of urea in 100 parts by mass of the external coating agent. In this case, in particular, 0.01 to 3 parts by mass of metal carbonate is preferably contained, 0.01 to 2 parts by mass of sodium bisulfite is preferably contained, and 0.01 to 2 parts by mass of 2-mercaptobenzimidazole. It is preferable to contain a part.

  The external coating agent of the present invention is stored in a container, and it is preferable to use a sealed container as the container. Examples of the sealed container include a bottle, a jar bottle, a tube container, an extrusion type and a dial type lifting and lowering type container. The external solid agent is preferably an extrusion-type or dial-type lift-down type container from the viewpoint of use and storage.

As described in Examples below, the external coating agent of the present invention has a clear appearance even after being stored at a low temperature or a high temperature, and thus has a high commercial value.
Moreover, since loxoprofen or a salt thereof exhibits an anti-inflammatory analgesic effect as a phenylpropionic acid-based nonsteroidal anti-inflammatory analgesic, the external application agent of the present invention can be used as a medical drug or an OTC drug, and transdermally absorbed. It is extremely useful as a type of analgesic / anti-inflammatory agent. Applicable symptoms and diseases include osteoarthritis, shoulder periarthritis, tendon / tendonitis, peritonitis, humerus condyleitis, muscle pain, swelling / pain after trauma, shoulder stiffness, shoulder stiffness Pain, low back pain, joint pain, tendonitis, elbow pain, bruise, sprain, fracture pain, muscle fatigue and the like.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these Examples.

Test example 1
Loxoprofen sodium hydrate, l-menthol, Japanese pharmacopoeia concentrated glycerin, propylene glycol, ethanol, isopropanol, and water were mixed and dissolved so as to have the concentrations shown in Table 1 to obtain a liquid for external use. The obtained external preparation 100 g was filled in a transparent glass bottle and sealed.
The external appearance of the resulting external liquid preparation (clearness / presence / absence of foreign matter and precipitates) was confirmed with the naked eye, and then stored at 60 ° C. and −20 ° C. to examine the external appearance of the external liquid preparation one month later. . The results are shown in Table 1.

  It was determined that the liquids for external coating agents of Reference Example 1 and Example 1 were clear and had no particular problem.

Test example 2
Loxoprofen sodium hydrate, l-menthol, sodium stearate, Japanese pharmacopoeia concentrated glycerin, propylene glycol, ethanol, isopropanol and water are mixed and dissolved so that the concentrations shown in Table 2 are obtained. Got. 100 g of the obtained liquid for external solid preparation was filled in a transparent glass bottle and solidified at room temperature to obtain an external solid preparation filled in the glass bottle.
The external appearance of the obtained solid preparation for external use (clearness, presence or absence of foreign matter and precipitates) was confirmed with the naked eye, and then stored at 60 ° C. and −20 ° C., and the appearance of the external solid preparation after 1 month was observed. Inspected. The results are shown in Table 2.

  When the external solid preparation of Comparative Example 1 was stored at a high temperature and a low temperature, insoluble matters and crystals were precipitated, and a clear appearance could not be maintained. On the other hand, it was clear that the solid preparation for external use of Example 2 was clear even when stored under severe high and low temperatures, and there was no particular problem.

Test example 3
The solid preparation for external use of Example 2 obtained in Test Example 2 was stored at 40 ° C. and 75% relative humidity, and the decrease rate before and after storage in the solid preparation for external use after 1 week was measured. The reduction rate was determined by measuring the volume of the external solid preparation before and after storage. As a result, the reduction rate was 6%, and almost no volume reduction of the external solid preparation was observed compared to the time when the storage was started.

Test example 4
Each component shown in Tables 3 and 4 was heated and dissolved as desired, filled into a container, and cooled to room temperature to produce external preparations of Formulations 1-13.

Claims (9)

External coating agent containing the following components (A) and (B).
(A) Loxoprofen or a salt thereof (B) Isopropanol   The external application agent according to claim 1, wherein component (A) is loxoprofen sodium hydrate.   Furthermore, the external application | coating agent of Claim 1 or 2 containing component (E) terpenes.   Ingredient (E) is isoborneol, iron, osimene, carveol, carbotanaceton, carbomenton, carvone, caren, caron, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellal acid, citronellol, cineol, Cymene, Silvestrene, Isotjojol, Tujon, Terpineol, Terpinene, Terpinolene, Tricyclene, Nellore, Pinene, Pinoccampheol, Pinol, Piperithenone, Ferrandral, Ferrandrene, Fentchen, Fentyl Alcohol, Perillyl Alcohol, Perillyl Aldehyde , Borneol, Myrcene, Menthol, Mentone, Yonor, Yonon, Linalool and Limonene Topical application agent according to claim 3, wherein at species or more.   Content of a component (A) is 0.01-10 mass parts in 100 mass parts of external application agents in conversion of loxoprofen sodium anhydride, The external application agent of any one of Claims 1-4.   Content of a component (E) is 0.01-15 mass parts in 100 mass parts of external application agents, The external application agent of any one of Claims 3-5.   Furthermore, the external application | coating agent of any one of Claims 1-6 containing a component (D) saturated higher fatty acid salt.   The external coating agent according to claim 7, wherein the component (D) is a saturated higher fatty acid salt having 12 to 22 carbon atoms.   The external application agent according to any one of claims 1 to 8, wherein the dosage form is an external liquid agent or an external solid agent.