JPH06234643A - Steroid external preparation - Google Patents

Abstract

PURPOSE:To provide an antiinflammatory external preparation excellent in antiinflammatory effect and with extremely low in side effects, containing a prodrug-type antiinflammatory steroid. CONSTITUTION:This antiinflammatory external preparation contains such a steroid compound as to have an ester linkage derived from 12-22C aliphatic carboxylic acid at the 21st site, an ester linkage derived from 2-5C aliphatic carboxylic acid (in the case of dexamethasone, additionally 5C alicyclic carboxylic acid) at the 17th site in an antiinflammatory steroid bearing hydroxyl groups at the 17th and 21st sites (pref. hydrocortisone, predonisolone, methyl predonisolone, dexamethasone, betamethazone). Percutaneous administration of this external preparation to inflammated lesions results in percutaneous absorption of the steroid ester, which is then specifically concentrated to the inflammated sites, breaking the ester linkage depending on the degree of inflammation, thus, manifesting the medicinal virtues of the steroid. The rest of extra portion of the preparation administered is passed through the skin as the inactive intact form, migrating into the blood and being detoxified and metabolized in the liver and then excreted.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an anti-inflammatory external preparation containing a prodrug type anti-inflammatory steroid, which has an excellent anti-inflammatory effect and extremely few side effects.

[0002]

BACKGROUND OF THE INVENTION Steroids have many effects such as anti-inflammatory, anti-allergic and immunosuppressive and are widely used as pharmaceuticals. Depending on the purpose of use, site of action, etc., injections, oral preparations, suppositories, external preparations are used. Preparations of various dosage forms are known. The widespread use of such steroid preparations is due to the strong activity of steroids, but side effects also strongly appear in proportion to this activity. Therefore, clinically, the current situation is that steroids are always used in consideration of their effects and side effects. Especially for transdermal administration in the dermatological field, development of more active steroids has been actively carried out.Therefore, systemic side effects such as adrenal insufficiency, skin atrophy, etc. are observed in long-term use and in the elderly and children. The problem of local side effects such as rosacea-like dermatitis has been highlighted. In particular, not only steroids in the active form but also preparations using prodrug-type steroid derivatives are converted to steroid active forms immediately after percutaneous absorption, exerting their effects more than necessary, and causing side effects at the same time. ing. Therefore, there is a demand for the development of an external preparation for steroids, which exerts a medicinal effect efficiently because it is excellent in concentration on tissues intended for anti-inflammatory and does not exert more than necessary effect, and therefore has extremely few side effects. .

[0003]

SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide a steroid external preparation having excellent anti-inflammatory effect and extremely few side effects. In particular, the object of the present invention is to exert an effective drug efficiency because of its excellent concentration on the tissue targeted for anti-inflammatory, and not only to exert the effect in proportion to the drug dose, but to administer the drug. The surplus is to provide an anti-inflammatory external preparation with few side effects that can be metabolically excreted as an inactive form.

[0004]

[Means for Solving the Problems] In order to achieve such an object, the inventors of the present invention have conducted various studies and found that an aliphatic carboxylic acid having 12 to 22 carbon atoms was derived from the 21st position of an antiinflammatory steroid. The ester bond of is a carbon number of 2 to 5 at the 17-position.
For external use containing a steroid compound having an ester bond derived from an aliphatic carboxylic acid (however, when the anti-inflammatory steroid is dexamethasone, it is a fatty acid having 2 to 5 carbon atoms or an alicyclic carboxylic acid having 5 carbon atoms) The present inventors have completed the present invention by finding that the above-mentioned problems can be solved by using an agent.

That is, the external preparation of the present invention comprises an ester bond derived from a fatty acid having 12 to 22 carbon atoms at the 21-position of an anti-inflammatory steroid and an aliphatic carboxylic acid having 2 to 5 carbon atoms at the 17-position (provided that the anti-inflammatory property is When the steroid is dexamethasone, it contains a steroid compound having an ester bond derived from a fatty acid having 2 to 5 carbon atoms or an alicyclic carboxylic acid having 5 carbon atoms.

In the present invention having the above-mentioned constitution, as the anti-inflammatory steroid, any steroid having an anti-inflammatory activity having hydroxyl groups at the 17- and 21-positions can be used. For example, hydrocortisone, prednisolone, methylprednisolone. , Dexamethasone, betamethasone, beclomethasone, fludroxycortide and the like, and particularly, hydrocortisone, prednisolone,
Preference is given to using methylprednisolone, dexamethasone or betamethasone.

In the present invention, the 21st carbon number is 12 to 2
The ester bond derived from the aliphatic carboxylic acid of 2 means that the group in which the —OH group has been removed from the carboxyl group of the fatty acid forms an ester bond with the hydroxyl group at position 21 of the anti-inflammatory steroid. Therefore, the ester bond referred to in the present invention is formed by reacting the aliphatic carboxylic acid as a reactive derivative (eg, acid anhydride, active ester, acid halide, etc.) and then ester-bonding it to the 21-position of the anti-inflammatory steroid. May be The aliphatic carboxylic acid having 12 to 22 carbon atoms is preferably a fatty acid, and may be linear or branched, saturated or unsaturated. In particular, linear myristic acid, palmitic acid, stearic acid, palmitoleic acid, oleic acid, linoleic acid, linoleic acid, eicosapentaenoic acid and the like can be mentioned as preferable ones.

In the present invention, the ester bond derived from an aliphatic carboxylic acid having 2 to 5 carbon atoms at the 17-position means that the group obtained by removing the --OH group from the carboxyl group of the acid is the 17-position hydroxyl group of the anti-inflammatory steroid. And an ester bond is formed. Therefore, the ester bond in the present invention means that the acid is converted into a reactive derivative (for example, an active ester, an acid halide, an acid anhydride, etc.) and then converted into an anti-inflammatory steroid.
It may be formed by forming an ester bond at the 7-position. The fatty carboxylic acid having 2 to 5 carbon atoms may be either a fatty acid or an alicyclic carboxylic acid, and is linear.
It may be branched, saturated or unsaturated. Particularly preferred are linear acetic acid, propionic acid, butyric acid, valeric acid and the like.

In the present invention, one type of steroid ester may be used, or two or more types may be used in combination.
The steroid ester body can be manufactured as follows. The anti-inflammatory steroid is reacted with an ortho fatty acid ester to form an intramolecular ortho ester (first step), the ortho ester body is hydrolyzed to obtain a 17-ester body (second step), and the 17-ester body is obtained. It reacts with fatty acid halide to esterify the 21st position (3rd
Process) is manufactured.

The first step is preferably carried out in the presence of a catalyst such as camphorsulfonic acid, p-toluenesulfonic acid and methanesulfonic acid. It is preferable to use tetrahydrofuran, dioxane or the like as the solvent. The reaction temperature is generally 0 to 50 ° C., preferably about room temperature, and the reaction time is generally 1 to 8 hours, preferably 2 to 5 hours.

The second step is a step of hydrolyzing the product of the first step in the presence of a Lewis acid such as aluminum chloride, titanium tetrachloride or tin tetrachloride, or an acid such as hydrochloric acid, acetic acid or oxalic acid. The treatment time is usually 10 to 100 hours, preferably 18 to 66 hours, and is usually performed in the presence of a solvent such as methanol or ethanol.

The third step is a step of reacting the 17-ester form obtained in the second step with a reactive derivative of a fatty acid such as a fatty acid halide or a fatty acid anhydride to esterify the 21st position. The reaction may be carried out in the presence of a deoxidizing agent such as triethylamine, dimethylaminopyridine or pyridine. As the solvent, methylene chloride, chloroform and the like are used. The treatment time is usually 30 minutes to 30 hours, preferably 1 to 18 hours, and the reaction temperature is generally -10 ° C to 50 ° C.
C, preferably 0 C to room temperature.

The dosage form of the external preparation of the present invention may be a dosage form that can be used as a medicine and can be administered by transdermal absorption, such as an ointment, a cream, a patch, a tape, and a spray. Dosage forms such as agents are mentioned. These formulations can be prepared by conventional means for formulation, using conventional carriers such as excipients, emulsifiers, stabilizers, etc., if necessary. As the carrier to be used, such as an excipient, an emulsifier, a stabilizer, etc., any physiologically usable carrier can be used.

The content of the steroid ester in the external preparation of the present invention can be appropriately changed depending on the administration method of the external preparation, the indication disease, the dosage form, etc., but is not particularly limited, but is based on the same steroid drug. It is preferred to use the amount as standard. The usage is not particularly limited as it can be appropriately determined depending on the disease to be applied, the degree of disease, the age of the patient, etc., but it is usually applied to the affected area several times a day.

[0015]

The action and effect of the present invention: When the external preparation of the present invention is transdermally administered to an affected area of inflammation, the steroid ester body is concentrated percutaneously after percutaneous absorption, and the ester bond is broken according to the degree of inflammation. The medicinal effects of steroids develop.
However, the surplus of the administered drug passes through the skin as an inactive steroid ester body, is transferred to the blood, and is excreted and metabolized and excreted in the liver. In addition, the external preparation of the present invention, which is transdermally administered to a non-inflamed part, remains as an inactive steroid ester body and is excreted through the same route as the above-mentioned surplus.

Therefore, when the external preparation of the present invention is administered transdermally, the steroid ester is concentrated in the inflammatory disease site, the required amount of the drug works effectively, and sufficient drug effect is exerted, while the surplus drug and other than the diseased site are exerted. Since the drug administered to (i) is metabolized and excreted in the inactive form as it is without causing side effects, the side effects caused by steroids can be significantly reduced.

[0017]

EXAMPLES The present invention will be described in more detail based on the following reference examples, examples and clinical examples, but the present invention is not limited thereto.

Reference Example 1 (1-1) Prednisolone (2.00 g, 5.55 mmol), triethyl orthopropionate (2.2 ml, 1
1 mmol) and tetrahydrofuran (20 ml) were mixed at room temperature, and then camphorsulfonic acid (206 mg,
0.887 mmol) was added. This mixture at room temperature for 3
After stirring for an hour, triethylamine (0.5 ml) was added. The mixture was stirred at room temperature for 15 minutes, poured into saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, the extract was washed with saturated brine, and the solvent was evaporated under reduced pressure. The crude product was dissolved in methanol (30 ml) and a 0.3% aqueous solution of aluminum chloride (10 ml) was added. After stirring this mixed solution at room temperature for 18 hours, methanol was distilled off under reduced pressure. Concentrate
It was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. When the precipitated product was recrystallized from chloroform / hexane,
Prednisolone-17-propionate (2.05 g)
was gotten.

(1-2) Prednisolone-17-propionate (1.00 g, 2.40 mmol), 4-dimethylaminopyridine (58 mg), triethylamine (0.50 ml, 3.6 mmol), and methylene chloride (15 ml). ) Was mixed at 0 ° C. A methylene chloride solution (5 ml) of palmitic acid chloride (875 mg, 3.18 mmol) was added dropwise thereto. After stirring at 0 ° C to room temperature for 3 hours, the mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography. Recrystallization of the precipitated product from ether / hexane gave prednisolone-17-propionate-2.
White crystals of 1-palmitate (1.32 g) were obtained. Melting point: 103-104 ° C

¹ HNMR (DMSO-d ₆ ): δ0.85 (t, J = 6.
8Hz, 3H), 0.91 (s, 3H), 0.99 (t, J = 7.4Hz, 3H), 0.96
-1.10 (m, 2H), 1.18-1.33 (m, 24H), 1.34-1.42
(m, 1H), 1.39 (s, 3H), 1.52-1.61 (m, 3H), 1.66-
1.76 (m, 3H), 1.93 (d, J = 12.5Hz, 1H), 1.98-2.12
(m, 2H), 2.27-2.35 (m, 3H), 2.37 (t, J = 7.2Hz, 2
H), 2.50-2.57 (m, 1H), 2.73 (t, J = 11.6Hz), 4.32
(s, 1H), 4.77 (s, 2H), 4.82 (s, 1H), 5.92 (s, 1H),
6.17 (d, J = 10.1Hz, 1H), 7.32 (d, J = 10.1Hz, 1H)

In the same manner as in Reference Example 1, the following Reference Examples 2 to 2
Thirteen compounds were synthesized. Reference Example 2 Prednisolone-17-butyrate-21-palmitate (white crystal, melting point: 76 to 78 ° C.) ¹ HNMR (DMSO-d ₆ ): δ0.85 (t, J = 7.4Hz, 6H), 0.
92 (s, 3H), 0.96-1.08 (m, 2H), 1.19-1.33 (m, 24
H), 1.34-1.43 (m, 1H), 1.40 (s, 3H), 1.51 (sext, J
= 7.4Hz, 2H), 1.50-1.60 (m, 3H), 1.65-1.76 (m, 3
H), 1.92 (dd, J = 3.1, 13.6Hz, 1H), 2.01-2.12 (m, 2
H), 2.28 (t, J = 7.4Hz, 2H), 2.26-2.33 (m, 1H), 2.3
7 (t, J = 7.3Hz, 2H), 2.50-2.57 (m, 1H), 2.69-2.7
6 (m, 1H), 4.32 (s, 1H), 4.78 (s, 2H), 4.82 (d, J =
3.7Hz, 1H), 5.92 (s, 1H), 6.17 (d, J = 10.1Hz, 1H),
7.32 (d, J = 10.1Hz, 1H)

Reference Example 3 Prednisolone-17-valerate-21-palmitate (white crystal, melting point: 73 to 76 ° C.) ¹ HNMR (DMSO-d ₆ ): δ0.84 (t, J = 7.4Hz, 3H), 0 .
85 (t, J = 6.9Hz, 1H), 0.92 (s, 3H), 0.96-1.08 (m,
2H), 1.20-1.34 (m, 26H), 1.35-1.43 (m, 1H), 1.40
(s, 3H), 1.47 (quint, J = 7.4Hz, 2H), 1.55 (quint, J
= 7.4Hz, 2H), 1.52-1.60 (m, 1H), 1.64-1.76 (m, 3
H), 1.92 (dd, J = 3.3, 13.6Hz, 1H), 2.01-2.12 (m, 2
H), 2.30 (t, J = 7.4Hz, 2H), 2.27-2.33 (m, 1H), 2.3
7 (t, J = 7.4Hz, 2H), 2.50-2.57 (m, 1H), 2.68-2.7
6 (m, 1H), 4.32 (s, 1H), 4.77 (s, 2H), 4.82 (d, J =
4.0Hz, 1H), 5.92 (s, 1H), 6.17 (dd, J = 2.0, 10.0Hz,
1H), 7.32 (d, J = 10.0Hz, 1H)

Reference Example 4 Dexamethasone-17-propionate-21-palmitate (white crystal, melting point: 88 to 89 ° C.) ¹ HNMR (DMSO-d ₆ ): δ0.84 (t, J = 7.0Hz, 3H), 0 .
85 (t, J = 6.7Hz, 3H), 1.00 (s, 3H), 1.01 (t, J = 7.5H
z, 3H), 1.15-1.19 (m, 1H), 1.20-1.33 (m, 24H),
1.38 (dq, J = 5.0, 12.4Hz, 1H), 1.49 (s, 3H), 1.56 (q
uint, J = 7.1Hz, 2H), 1.64 (d, J = 13.6Hz, 1H), 1.76-
1.84 (m, 2H), 2.03 (dt, J = 8.0, 11.7Hz, 1H), 2.13
(d, J = 13.8Hz, 1H), 2.31-2.46 (m, 6H), 2.63 (dt, J
= 5.5, 12.8Hz, 1H), 3.17-3.25 (m, 1H), 4.15-4.20
(m, 1H), 4.74 (d, J = 16.5Hz, 1H), 4.85 (d, J = 16.5H
z, 1H), 5.42-5.44 (m, 1H), 6.01 (s, 1H), 6.22 (d
d, J = 2.0, 10.0Hz, 1H), 7.27 (d, J = 10.0Hz, 1H)

Reference Example 5 Dexamethasone-17-butyrate-21-palmitate (oil) ¹ HNMR (DMSO-d ₆ ): δ0.82-0.89 (m, 9H), 1.00
(s, 3H), 1.15-1.34 (m, 25H), 1.38 (dq, J = 5.0, 1
2.2Hz, 1H), 1.49 (s, 3H), 1.51 (sext, J = 7.4Hz, 2H),
1.56 (quint, J = 7.3Hz, 2H), 1.63 (d, J = 13.7Hz, 1H),
1.76-1.85 (m, 2H), 2.03 (dt, J = 8.1, 12.0Hz, 1H),
2.11 (d, J = 13.5Hz, 1H), 2.34 (t, J = 7.4Hz, 2H), 2.38
(t, J = 7.3Hz, 2H), 2.27-2.46 (m, 2H), 2.63 (dt, J
= 5.5, 13.2Hz, 1H), 3.17-3.26 (m, 1H), 4.18 (brs,
1H), 4.74 (d, J = 16.4Hz, 1H), 4.86 (d, J = 16.4Hz, 1
H), 5.43 (d, J = 3.1Hz, 1H), 6.01 (s, 1H), 6.22 (d, J
= 10.1Hz, 1H), 7.28 (d, J = 10.1Hz, 1H)

Reference Example 6 Dexamethasone-17-valerate-21-palmitate (oil) ¹ HNMR (DMSO-d ₆ ): δ 0.80 -0.88 (m, 9H), 1.00
(s, 3H), 1.15-1.33 (m, 27H), 1.37 (dq, J = 4.9, 1
2.7Hz, 1H), 1.47 (quint, J = 7.2Hz, 2H), 1.49 (s, 3
H), 1.56 (quint, J = 7.4Hz, 2H), 1.63 (d, J = 13.1Hz, 1
H), 1.76-1.85 (m, 2H) .2.02 (dt, J = 7.9, 12.1Hz, 1
H), 2.11 (d, J = 13.7Hz, 1H), 2.29-2.46 (m, 6H), 2.6
3 (dt, J = 5.4, 12.6Hz, 1H), 3.17-3.26 (m, 1H), 4.1
7 (brs, 1H), 4.73 (d, J = 16.4Hz, 1H), 4.86 (d, J = 16.
4Hz, 1H), 5.43 (brs, 1H), 6.02 (s, 1H), 6.22 (dd, J
= 1.9, 10.1Hz, 1H), 7.28 (d, J = 10.1Hz, 1H)

Reference Example 7 Betamethasone-17-propionate-21-palmitate (amorphous) ¹ HNMR (DMSO-d ₆ ): δ0.85 (t, J = 7.0Hz, 3H), 0.
87 (s, 3H), 1.03 (t, J = 7.5Hz, 3H), 1.11 (q, J = 9.8H
z, 1H), 1.20-1.34 (m, 27H), 1.39 (dq, J = 4.8, 12.8H
z, 1H), 1.50 (s, 3H), 1.55 (quint, J = 7.3Hz, 2H), 1.
72 (d, J = 13.3Hz, 1H), 1.83-1.92 (m, 3H), 2.07 (q,
J = 7.7Hz, 1H), 2.24 (d, J = 13.3Hz, 1H), 2.32-2.50
(m, 6H), 2.63 (dt, J = 4.8, 13.0Hz, 1H), 4.22 (brs, 1
H), 4.44 (d, J = 16.8Hz, 1H), 4.69 (d, J = 16.8Hz, 1H),
5.51 (d, J = 5.1Hz, 1H), 6.02 (s, 1H), 6.23 (dd, J = 1.
7, 10.1Hz, 1H), 7.27 (d, J = 10.1Hz, 1H)

Reference Example 8 Betamethasone-17-butyrate-21-palmitate (oil) Reference Example 9 Betamethasone-17-valerate-21-palmitate (oil) Reference Example 10 Hydrocortisone-17-butyrate-2
1-palmitate (white crystal, melting point: 84 to 85 ° C.) Reference Example 11 Hydrocortisone-17-valerate-2
1-palmitate (white crystal, melting point: 92-94 ° C) Reference Example 12 Hydrocortisone-17-propionate-21-palmitate (white crystal, melting point: 70-73)
C.) Reference Example 13 Methylprednisolone-17-valerate-21-palmitate (oil)

Examples 1 to 5 Preparation of Ointment 1 g of any of the steroid ester compounds shown in Reference Examples 1 to 5 was dissolved in 2 g of absolute ethanol, and this was dissolved at about 60 ° C.
Added to 99g of gelled hydrocarbon (external regulation) heated to
Stir to dissolve. After homogenization, ethanol was distilled off under reduced pressure and cooled to room temperature to produce an ointment. In addition, what used the steroid ester body of the reference example 1 is Example 1, and it is Examples 2-5 in order corresponding to the steroid ester body of the reference examples 2-5 used similarly below.

Examples 6 to 9 1 g of any of the steroid ester compounds shown in Reference Examples 6 to 9, 1 g of cetanol, 9.5 g of paraffin, 11.4 g of white petrolatum, 3.8 g of liquid paraffin, 2 g of exposed beeswax, whale wax 2 g, squalane 5.7 g, octyldodecanol 9.5 g, parapenes 0.04 g, crotamiton 1 g, and an emulsifier (a mixture of glyceryl monostearate: polyoxyethylene cetyl ether: sorbitan monostearate = 3: 3: 1). The same shall apply hereinafter), 13.3 g is weighed and heated to 70 to 75 ° C. to obtain a uniform liquid (this is called liquid A). On the other hand, 8 g of propylene glycol, 0.3 g of citric acid and 32 g of purified water are weighed and dissolved by heating at 75 to 80 degrees (this is referred to as solution B). Next, the liquid B was divided into 3 to 4 parts, which were dividedly put into the liquid A to be emulsified and then allowed to cool to produce a cream preparation. In addition,
Example 6 uses the steroid ester form of Reference Example 6, and Examples 7 to 9 correspond to the steroid ester forms of Reference Examples 7 to 9 used in the same manner.

Examples 10 to 13 Production of creams 1 g of steroid long-chain fatty acid ester derivative shown in Reference Examples 10 to 13, 1 g of cetanol, 9.5 g of paraffin, 11.4 g of white petrolatum, 3.8 g of liquid paraffin. , 2 g of exposed beeswax, 2 g of spermaceti, squalane 5.
7 g, octyldodecanol 9.5 g, parapenes 0.
04 g, 1 g of crotamiton and 13.3 g of an emulsifier are weighed and heated to 70 to 75 ° C. to obtain a uniform liquid (this is called liquid A). On the other hand, Macrogol 400 8 g, citric acid 0.3 g and purified water 32 g are weighed and dissolved by heating at 75 to 80 degrees (this is referred to as solution B). Next, the liquid B is added to 3 to 4
The mixture was divided, and the mixture was dividedly added to the liquid A to emulsify and then allowed to cool to produce a cream. In addition, what used the steroid ester body of Reference Example 10 is Example 10, and it is Examples 11-13 in order corresponding to the steroid ester body of Reference Examples 11-13 used similarly below.

Clinical Example 1 Ointment of Example 1 (concentration 1%) and ointment diluted with the same base as used in Example 1 (concentration 0) were applied to 3 healthy persons (male, 20 to 35 years old). 0.1%), the same base and commercially available betamethasone valerate ointment (0.12%) were used to perform a vasoconstriction test. For the test, a fin chamber (inner diameter 10 mm, aluminum dish) containing 100 mg of each drug was used, and the back surface was coated and fixed for 6 hours. After removing the fin chamber, 3,
The vasoconstriction ability was observed after 6 and 24 hours. As a result, with betamethasone valerate ointment, a pallor phenomenon due to vasoconstriction was clearly seen after 3 and 6 hours, and disappeared after 24 hours. In particular, a strong bleaching phenomenon was observed after 6 hours. On the other hand, the same phenomenon was not observed for all the other three agents at all observations. Therefore, it was found that the other three agents remained inactive in normal skin.

Clinical Example 2 For the psoriasis (male 44 years old, back), the ointment of Example 1 was tested in the same manner as in Clinical Example 1. The observation time was only 3 or 6 hours after the fin chamber was removed. As a result, a pallor phenomenon was observed in all cases, confirming that this drug was a prodrug.

Clinical Example 3 The ointment of Example 6 (concentration 1%) was applied to psoriasis (male 52 years old, olecranon) 2-3 times a day for 2 weeks. The symptom of the affected area was relieved from the 8th day after the application, and thereafter healed rapidly during the application.
During this time, no side effects specific to steroids were observed.

Clinical Example 4 The ointment of Example 6 (concentration 1%) was applied to the lichenified lesion of atopic dermatitis (female 33 years old, knee pelvis) several times a day for one week. From the 3rd day after application, the application site was relieved, and after 1 week, it healed cleanly. No side effects were observed.
It was confirmed by Clinical Examples 3 and 4 that this drug exerts effective efficacy as an active substance in the affected area.

Front page continuation (72) Inventor Masanori Sugiura 2-25-1 Otani Otani, Hirakata City, Osaka Prefecture Midori Cross Central Research Institute Co., Ltd. (72) Riki Fukaya 2-25-1 Otani Otani, Hirakata, Osaka Prefecture Midori Central Research Institute, Inc.

Claims (1)

[Claims] 1. A carbon number 12 at position 21 of an anti-inflammatory steroid.
The ester bond derived from the aliphatic carboxylic acid of
An ester bond derived from an aliphatic carboxylic acid having 2 to 5 carbon atoms (however, when the anti-inflammatory steroid is dexamethasone, it is a fatty acid having 2 to 5 carbon atoms or an alicyclic carboxylic acid having 5 carbon atoms). An anti-inflammatory external preparation containing a steroid compound.