Topical composition for treating dermatitis

Abstract

To provide a topical therapeutic agent for skin, comprising an antedrug steroidal anti-inflammatory agent, developed to ensure both effectiveness and safety, wherein the topical application agent for skin sustains a steroid effect even after termination of drug use, suppressing recurrence of dermatitis.SOLUTION: This invention demonstrates that inclusion of an antedrug steroidal anti-inflammatory agent such as prednisolone valerate acetate, and ceramides such as N-stearoyl dihydrosphingosine (and hydrogenated soybean phospholipid) makes it possible to sustain a steroid effect even after termination of drug use, suppressing recurrence of dermatitis symptoms.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an external application preparation containing a steroidal anti-inflammatory drug such as an anti-drug steroid, which is used as a treatment for dermatitis, and in particular to an external application preparation for skin that suppresses the recurrence of inflammation even after treatment (after administration of the steroidal anti-inflammatory drug has ended). [Background technology]

[0002] Steroidal anti-inflammatory drugs such as prednisolone valerate acetate are widely used to treat skin diseases such as eczema, dermatitis, and pruritus.

[0003] Prednisolone valerate acetate is called an anti-drug steroid, and although it exerts excellent medicinal effects locally on the skin when applied, it is known that after it is absorbed into the body through the skin, it is metabolized in the body and its pharmacological activity decreases, which reduces systemic side effects. Therefore, it is considered to be a steroidal anti-inflammatory drug that can be expected to achieve both efficacy and safety.

[0004] However, although a high therapeutic effect is observed during the administration period due to the action of the steroidal anti-inflammatory drug, once administration of the drug is discontinued, there is a problem that the efficacy of the drug decreases in a relatively short period of time and dermatitis recurs.

[0005] When prescribed by a doctor as a prescription drug, the patient can be instructed to continue applying the drug for a while even after symptoms have improved. However, when the patient purchases the drug as an over-the-counter drug and self-medicates, the patient is responsible for managing its application, which can lead to the problem of the patient not applying the drug after symptoms have eased and the symptoms recurring.

[0006] Human ceramide, which is used as a component to provide functions such as a barrier function to protect the skin from external stimuli and a moisture-retaining function, is one of the components that make up the intercellular lipids found in the stratum corneum of human skin. Its chemical structure consists of a sphingoid base skeleton and its amino group (-NH 2Ceramide is a compound in which a saturated fatty acid or a monounsaturated fatty acid is bonded to a sphingoid base via an amide bond. It is known that there are 12 types of ceramides, mainly due to the combination of a sphingoid base and a fatty acid (Non-Patent Document 1).

[0007] Ceramides in the human stratum corneum are thought to play a physicochemical role in determining the barrier to cell permeability and water retention in the skin, as well as a physicochemical role as a matrix for membrane protein binding, as well as a physiological role in signal transduction and cell regulation related to apoptosis, cell growth arrest, differentiation, senescence, and immune response. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Masukawa, Y., et al., J. Lipid Res. 2008. 49: 1466-1476 [Non-Patent Document 2] Robson, KJ, et al., J. Lipid Res. 1994. 35: 2060-2068 Summary of the Invention [Problem to be solved by the invention]

[0009] The present invention aims to provide an external skin treatment agent using an anti-drug steroidal anti-inflammatory drug, which has been developed to be both effective and safe, in which the effect of the steroid is sustained and dermatitis is unlikely to recur even after use of the drug has ceased. [Means for solving the problem]

[0010] According to the present invention, by containing an anti-drug steroidal anti-inflammatory drug such as prednisolone valerate acetate and a ceramide such as N-stearoyldihydrosphingosine (and hydrogenated soybean phospholipid), it has been shown that the effect of the steroid is sustained even after administration of the drug has ceased, and the recurrence of dermatitis symptoms can be suppressed.

[0011] More specifically, in order to solve the above-mentioned problems, the present application provides the following aspects: [1]:An anti-drug steroidal anti-inflammatory drug and ceramide-containing topical skin application; [2]: The topical skin application preparation according to [1], wherein the ceramide is N-stearoyldihydrosphingosine; [3]: The topical skin application preparation according to [1] or [2], wherein the prodrug steroidal anti-inflammatory drug is prednisolone valerate acetate; [4]: The skin topical application preparation according to [2], which contains 0.1 to 1 wt% N-stearoyldihydrosphingosine; [5]: The skin topical application preparation according to [3], containing 0.1 to 0.3 wt % of prednisolone valerate acetate; [6]: A topical skin application preparation according to [1] or [2], which improves the duration of action of an anti-drug steroidal anti-inflammatory drug. [7]: The topical skin application preparation according to [6], which suppresses recurrence of inflammation even after administration of an anti-drug steroidal anti-inflammatory drug has ceased; [8]: A topical skin application agent containing an anti-drug steroidal anti-inflammatory drug, ceramide and hydrogenated soybean phospholipid; [9]: The skin topical application preparation according to [8], wherein the ceramide is N-stearoyldihydrosphingosine;

[10] : The topical skin application preparation according to [8] or [9], wherein the prodrug steroidal anti-inflammatory drug is prednisolone valerate acetate;

[11] : The skin topical application preparation according to [9], which contains 0.1 to 1% by weight of N-stearoyldihydrosphingosine and 0.1 to 1% by weight of hydrogenated soybean phospholipid;

[12] : The skin topical application preparation according to

[10] , which contains 0.1 to 0.3% by weight of prednisolone valerate acetate and 0.1 to 1% by weight of hydrogenated soybean phospholipid;

[13] : A topical skin application preparation according to [8] or [9], which has an improved duration of action of an anti-drug steroidal anti-inflammatory drug;

[14] : A topical skin application preparation according to

[13] , which suppresses recurrence of inflammation even after administration of an anti-drug steroidal anti-inflammatory drug has ceased;

[15] : A method for improving the duration of action of an anti-drug by incorporating ceramide into an external skin application agent containing an anti-drug steroidal anti-inflammatory drug;

[16] : The method according to

[15] , wherein the ceramide is N-stearoyldihydrosphingosine;

[17] : The method according to

[15] or

[16] , wherein the prodrug steroidal anti-inflammatory drug is prednisolone valerate acetate;

[18] : The method according to

[16] , which contains 0.1 to 1% by weight of N-stearoyldihydrosphingosine;

[19] : The method according to

[17] , containing 0.1 to 0.3% by weight of prednisolone valerate acetate;

[20] : An agent for improving the duration of action of topical skin application preparations containing ceramide and containing prodrug steroidal anti-inflammatory drugs;

[21] : The sustained release improver according to

[21] , wherein the ceramide is N-stearoyldihydrosphingosine;

[22] : The sustained release enhancer according to

[20] or

[21] , wherein the prodrug steroidal anti-inflammatory drug is prednisolone valerate acetate;

[23] : The sustained release improver according to

[21] , containing 0.1 to 1% by weight of N-stearoyldihydrosphingosine;

[24] : The sustained release improver according to

[22] , containing 0.1 to 0.3% by weight of prednisolone valerate acetate. Effect of the Invention

[0012] According to the present invention, by providing a topical skin lining agent containing an anti-drug steroidal anti-inflammatory drug such as prednisolone valerate acetate and a ceramide such as N-stearoyldihydrosphingosine (and hydrogenated soybean phospholipid), the effect of the steroid component can be sustained even after the administration of the topical skin lining agent is terminated, and the recurrence of dermatitis symptoms can be suppressed.As a result, even if the application of the topical skin lining agent is terminated at the stage when symptoms are alleviated, the effect of the drug contained in the topical skin lining agent can be sustained, and a topical skin lining agent can be provided that allows patients to determine the administration and termination at their own discretion. [Brief description of the drawings]

[0013] [Figure 1] FIG. 1 shows the rate of change in erythema (skin redness) at the end of application of a test preparation for 3 days compared to before application began. [Diagram 2] FIG. 2 shows the rate of change in erythema (skin redness) two days after the end of application of a test preparation for three days, compared to before application began. [Diagram 3] FIG. 3 shows the rate of change in erythema (skin redness) at the end of application of a test preparation for 3 days compared to before application began. [Figure 4] FIG. 4 shows the rate of change in erythema (skin redness) two days after the end of application of a test preparation for three days, compared to before application began. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The inventors of the present invention have conducted extensive research to solve the above-mentioned problems, and as a result have demonstrated that, as described above, by providing a topical skin preparation that combines a pro-drug steroidal anti-inflammatory drug with ceramide, it is possible to provide a topical skin preparation that maintains the effect of the steroid ingredient even after administration of the topical skin preparation has ceased, thereby suppressing the recurrence of dermatitis symptoms.

[0015] Therefore, in the first aspect of the present invention, it is possible to provide a skin topical application agent that contains antedrug steroidal anti-inflammatory drug and ceramide.The skin topical application agent having this composition can improve the duration of the action of antedrug steroidal anti-inflammatory drug, and more specifically, has the effect of suppressing recurrence of inflammation even after the administration of antedrug steroidal anti-inflammatory drug is completed.

[0016] Ceramide, which is used as one of the components of the present invention, is one of the components constituting the intercellular lipids found in the stratum corneum of human skin, and has a chemical structure consisting of a sphingoid base skeleton and its amino group (-NH 2 ) to which a saturated fatty acid or a monounsaturated fatty acid is bonded via an amide bond. It is known that such ceramides include 12 types of components, which are mainly formed by combinations of sphingoid bases and fatty acids as shown below (Non-Patent Document 1). Representative ceramides are shown in Table 1 below. In this table, the notation "ceramide + number" at the bottom of each column is the old name, which has been revised to the revised name "ceramide + alphabet" at the top of each column in accordance with academic fields such as dermatology.

[0017] [Table 1]

[0018] Here, the fatty acid is N: Non-hydroxy (Non hydroxy FA) A: Alpha hydroxy FA EO: Ester-linked Omega hydroxy FA are shown respectively.

[0019] In addition, as a sphingoid base, DS: Dihydrosphingosine S: Sphingosine P: Phytosphingosine H: 6-Hydroxysphingosine are shown respectively.

[0020] Ceramide in the human stratum corneum plays a physicochemical role in determining the barrier against cell permeability and water retention function in the skin, and is also considered to play a physiological role in signal transduction and cell regulation related to apoptosis, cell proliferation arrest, differentiation, aging, and immune response, as well as a physicochemical role as a matrix for membrane protein binding. In the topical skin application of the present invention, it can also be added as an essential component to utilize functions such as the barrier function and water retention function that protect the skin from such external stimuli in order to improve the pathological condition of the skin of patients suffering from dermatitis.

[0021] These ceramides are known to exist in the body (within the stratum corneum) in a free state in the ratios shown in Table 2 below (Non-Patent Document 2).

[0022] [Table 2]

[0023] The ceramide used in the present invention may be any of the ceramides described above, and may be selected based on criteria such as a ceramide that is frequently present in the body, or a ceramide that is decreased in the skin of patients suffering from dermatitis.

[0024] In the present invention, for example, N-stearoyldihydrosphingosine, which is a component classified as ceramide NDS (ceramide 10) (formerly known as ceramide NG and ceramide 2), may be used. N-stearoyldihydrosphingosine is a substance that has been shown to improve the barrier and enhance water retention by reinforcing ceramide when applied to a rough skin model caused by surfactant treatment on the inside of the forearm.

[0025] When N-stearoyldihydrosphingosine is used as an example of a ceramide in the topical skin application preparation of the present invention, the topical skin application preparation may contain 0.1 to 50.0 mg (0.01 to 5 mass%), preferably 1.0 to 10.0 mg (0.1 to 1 mass%), and more preferably 2.0 to 5.0 mg (0.2 to 0.5 mass%) of N-stearoyldihydrosphingosine per 1 g of the topical skin application preparation.

[0026] In the present invention, an anti-drug steroid anti-inflammatory drug is used as one of the components. In general, an anti-drug is a drug designed to exert excellent medicinal effects at the applied site, and then be absorbed from the applied site and metabolized in the systemic system, and the medicinal effects are quickly lost. Among them, an anti-drug steroid is developed as a drug that is expected to be effective and safe by introducing a site that is easily metabolized into the steroid structure and modifying the site, thereby increasing the retention and medicinal effects at the applied site, while reducing systemic side effects (such as adrenal secretory dysfunction and immunosuppressive effects) after absorption.

[0027] The anti-drug steroid anti-inflammatory drug that can be used in the present invention can include, but is not limited to, difluprednate (DFBA), hydrocortisone butyrate propionate (HBP), prednisolone valerate acetate (PVA), hydrocortisone butyrate (HCB), etc., among the above-mentioned anti-drug steroids.In the present invention, it is preferable to use prednisolone valerate acetate (PVA), which is classified as a medium steroid and is widely used as a commercially available drug, from the viewpoint of safe use by patients themselves.

[0028] When prednisolone valerate acetate is used as the prodrug steroidal anti-inflammatory drug, it can be contained in an amount of 0.1 to 15 mg (0.01 to 1.5% by mass) per 1 g of the topical skin application preparation, more preferably 0.5 to 3 mg (0.05 to 0.3% by mass), even more preferably 1.0 to 2.0 mg (0.10 to 0.20% by mass), and most preferably 1.5 mg (0.15% by mass).

[0029] The present invention also found that by further containing hydrogenated soybean phospholipid in the skin topical application in addition to the anti-drug steroidal anti-inflammatory drug and ceramide contained in the skin topical application, the affected area can be protected from drying and an excellent barrier function repair effect can be exhibited, and the skin topical composition having this composition can also improve the duration of the action of the anti-drug steroidal anti-inflammatory drug, and more specifically, it has the effect of suppressing the recurrence of inflammation even after the administration of the anti-drug steroidal anti-inflammatory drug is completed. That is, the present invention provides a skin topical application containing an anti-drug steroidal anti-inflammatory drug, ceramide and hydrogenated soybean phospholipid as a specific second aspect.

[0030] In this embodiment as well, the prodrug steroidal anti-inflammatory drug and ceramide that can be used as the components of the present invention can have the properties as described above.

[0031] The hydrogenated soybean phospholipid that can be used as one of the components of the present invention is a substance that is also called hydrogenated soybean lecithin because it is a hydrogenated soybean phospholipid. The hydrogenated soybean lecithin is characterized by a significantly increased proportion of phosphatidylcholine in the phospholipid composition and a high emulsifying power compared to soybean lecithin. Therefore, hydrogenated lecithin is a substance that is expected to have a synergistic effect with heparinoids because it has high skin affinity and moisturizing effect. In addition, as for the fatty acid composition, the proportion of unsaturated fatty acids such as linoleic acid and oleic acid is significantly reduced compared to soybean lecithin, while the proportion of stearic acid, a saturated fatty acid, is significantly increased, so it is characterized by a very high stability against heat and oxidation compared to soybean lecithin.

[0032] The oil-in-water emulsion composition of the present invention may contain 0.01 to 5 mass %, preferably 0.1 to 1 mass %, and more preferably 0.2 to 0.5 mass %, of hydrogenated soybean phospholipid based on the total weight of the oil-in-water emulsion composition.

[0033] The present invention is also based on the discovery that, as described above, by combining an anti-drug steroidal anti-inflammatory drug with ceramide, it is possible to improve the duration of action of a topical skin composition, and more specifically, it is possible to suppress the recurrence of inflammation even after administration of an anti-drug steroidal anti-inflammatory drug has been discontinued. In a third aspect, the present invention can also provide a method for improving the duration of action of an anti-drug by incorporating ceramide in an external skin application containing an anti-drug steroidal anti-inflammatory drug.

[0034] In this embodiment as well, the prodrug steroidal anti-inflammatory drug and ceramide that can be used as the components of the present invention can have the properties as described above.

[0035] The present invention is also based on the discovery that, as described above, by combining a pro-drug steroidal anti-inflammatory drug with a ceramide, it is possible to improve the duration of action of a topical skin composition, and more specifically, to suppress the recurrence of inflammation even after administration of the pro-drug steroidal anti-inflammatory drug has been discontinued. Based on this discovery, in a fourth aspect, the present invention can also provide an agent for improving the duration of action of a topical skin application containing a ceramide, which contains a pro-drug steroidal anti-inflammatory drug, as a use of ceramide.

[0036] In this embodiment as well, the prodrug steroidal anti-inflammatory drug and ceramide that can be used as the components of the present invention can have the properties as described above.

[0037] The present invention will be described in more detail below with reference to examples, but the following examples are not intended to limit the present invention in any way. EXAMPLES

[0038] Example 1: Preparation of test formulations In this example, a test formulation was prepared for use in the present invention.

[0039] For each of the preparation examples and comparative examples shown in Table 3, the components were weighed, and the oil phase and the water phase containing the compositions shown were heated to 70 to 80° C. and stirred to dissolve. It was confirmed by visual inspection that the components were dissolved clearly.

[0040] After confirming dissolution, the aqueous phase was gradually added to the oil phase while stirring to pre-emulsify, and then the mixture was emulsified by stirring at about 6000 rpm using a homogenizer (Omni Homogenizer GLH, Yamato Scientific Co., Ltd.) to obtain each formulation. The resulting formulation was cooled while stirring to obtain an oil-in-water emulsion composition.

[0041] [Table 3]

[0042] Example 2: Measurement of the durability of the erythema suppression effect In this example, the durability of the erythema suppressing effect was confirmed when the test preparation containing a steroidal anti-inflammatory drug prepared in Example 1 was applied.

[0043] The subject in this example was a male in his 30s who had redness (erythema) due to inflammation on the skin on the back of his hand due to rough hands, and the emulsion composition of the test formulation was applied to the skin on the outside of the third joints of his index finger, middle finger, ring finger, and little finger (back of the hand), and redness was measured. The emulsion composition was applied by applying the test formulation to each measurement site three times a day (morning, afternoon, and evening), and the same procedure was used for three consecutive days.

[0044] Erythema measurements were performed by connecting an erythema measurement probe (Mexameter MX18) to a measuring device (MDD4, Courage+Khazaka) to measure erythema (redness of the skin). Measurements were taken before the start of application of the test formulation, at the end of application (after 3 days of application), and 2 days after the end of application. Erythema redness was measured as a percentage change according to the following formula: Rate of change = Measurement value at the end of application / Measurement value before application x 100

[0045] The results at the end of application are shown in Figure 1, and the results two days after application are shown in Figure 2. When the test preparations were applied for three days, it was shown that erythema (redness of the skin) was suppressed to 60-70% of the initial level for all test preparations. However, two days after application of the test preparations was completed, in Comparative Example 1, the erythema had returned to about 90% of the initial level.

[0046] From these results, the following was considered: - The efficacy of prednisolone acetate valerate or betamethasone valerate suppressed dermatitis and reduced erythema during the application period; In Comparative Example 1, dermatitis recurred and erythema reoccurred after application, whereas in Preparation Example 1, erythema suppression was maintained even after application was terminated; In both Comparative Examples 2 and 3, the suppression of erythema was maintained even after application had ceased, and no recurrence of dermatitis was observed.

[0047] Of these test preparations, prednisolone valerate acetate is an anti-drug steroid that is metabolized in the body and its pharmacological activity decreases, which is said to reduce side effects. However, it has been found that its efficacy does not last long (especially after application has ceased).

[0048] Furthermore, as in Preparation Example 1, by combining prednisolone valerate acetate with N-stearoyldihydrosphingosine and hydrogenated soybean phospholipid, the recurrence of dermatitis was suppressed.

[0049] Betamethasone valerate, which is not an antedrug, did not cause recurrence of dermatitis. This is presumably due to its skin retention and sustained pharmacological activity.

[0050] Example 3: Measurement of the durability of the erythema suppression effect In this example, the duration of the erythema suppression effect when the test preparation containing a steroidal anti-inflammatory drug produced in Example 1 was applied to a subject other than those in Example 2 was confirmed.

[0051] The subject in this example was a male in his 20s who had redness (erythema) due to inflammation of the skin of his fingers caused by rough hands, and the emulsion composition of the test formulation was applied to the skin on the inside (palm) between the second and third joints of the index finger, middle finger, ring finger, and little finger, and the redness was measured. The emulsion composition was applied by applying the test formulation to each measurement site three times a day (morning, afternoon, and evening), and the same procedure was used for three consecutive days.

[0052] Erythema measurements were performed by connecting an erythema measurement probe (Mexameter MX18) to a measuring device (MDD4, Courage+Khazaka) to measure erythema (redness of the skin). Measurements were taken before the start of application of the test formulation, at the end of application (after 3 days of application), and 2 days after the end of application. Erythema redness was measured as a percentage change according to the following formula: Rate of change = Measurement value at the end of application / Measurement value before application x 100

[0053] The results at the end of application are shown in Figure 3, and the results two days after application are shown in Figure 4. When the test preparations were applied for three days, it was shown that erythema (redness of the skin) was suppressed to 60-80% of the initial level regardless of the test preparation applied. However, in Comparative Example 1, erythema had returned to about 100% of the initial level two days after application of the test preparation was completed.

[0054] These results indicate that although the subjects and inflamed areas on the fingers were different from those in Experiment 1, nearly similar results were obtained.

[0055] As shown in Preparation Example 1, the recurrence of dermatitis was suppressed by combining prednisolone valerate acetate with N-stearoyldihydrosphingosine and hydrogenated soybean phospholipid. [Industrial Applicability]

[0056] According to the present invention, by providing a topical skin lining agent containing an anti-drug steroidal anti-inflammatory drug such as prednisolone valerate acetate and a ceramide such as N-stearoyldihydrosphingosine (and hydrogenated soybean phospholipid), the effect of the steroid component can be sustained even after the administration of the topical skin lining agent is terminated, and the recurrence of dermatitis symptoms can be suppressed.As a result, even if the application of the topical skin lining agent is terminated at the stage when symptoms are alleviated, the effect of the drug contained in the topical skin lining agent can be sustained, and a topical skin lining agent can be provided that allows patients to determine the administration and termination at their own discretion.

Claims

1. A topical skin application agent containing an anti-drug steroidal anti-inflammatory drug and ceramide.

2. 2. The method according to claim 1, wherein the ceramide is N-stearoyldihydrosphingosine.

3. 3. The method according to claim 1, wherein the prodrug steroidal anti-inflammatory drug is prednisolone valerate acetate.

4. The external skin application preparation according to claim 2, containing 0.1 to 1% by weight of N-stearoyldihydrosphingosine.

5. The skin external application preparation according to claim 3, containing 0.1 to 0.3% by weight of prednisolone valerate acetate.

6. 3. The skin topical application preparation according to claim 1 or 2, which has improved durability of the action of the prodrug steroidal anti-inflammatory drug.

7. 7. The external skin application preparation according to claim 6, which suppresses recurrence of inflammation even after administration of an anti-drug steroidal anti-inflammatory drug has ceased.

8. A topical skin application agent containing an anti-drug steroidal anti-inflammatory drug, ceramide and hydrogenated soybean phospholipid.

9. 9. The external skin application preparation according to claim 8, wherein the ceramide is N-stearoyldihydrosphingosine.

10. 10. The method according to claim 8, wherein the prodrug steroidal anti-inflammatory drug is prednisolone valerate acetate.

11. 10. The skin topical application preparation according to claim 9, comprising 0.1 to 1% by weight of N-stearoyldihydrosphingosine and 0.1 to 1% by weight of hydrogenated soybean phospholipid.

12. The skin external application preparation according to claim 10, comprising 0.1 to 0.3% by weight of prednisolone valerate acetate and 0.1 to 1% by weight of hydrogenated soybean phospholipid.

13. 10. The skin topical application preparation according to claim 8 or 9, which has improved durability of the action of the prodrug steroidal anti-inflammatory drug.

14. 14. The external skin application preparation according to claim 13, which suppresses recurrence of inflammation even after administration of an anti-drug steroidal anti-inflammatory drug has ceased.

15. A method for improving the duration of action of an anti-drug by incorporating ceramide into an external skin application agent containing an anti-drug steroidal anti-inflammatory drug.

16. 16. The method of claim 15, wherein the ceramide is N-stearoyldihydrosphingosine.

17. 17. The method of claim 15 or 16, wherein the prodrug steroidal anti-inflammatory drug is prednisolone valerate acetate.

18. The method according to claim 16, comprising 0.1 to 1% by weight of N-stearoyldihydrosphingosine.

19. 18. The method according to claim 17, comprising 0.1 to 0.3% by weight of prednisolone valerate acetate.

20. An agent for improving the duration of action of an external skin application agent containing a prodrug steroidal anti-inflammatory drug, which contains ceramide.

21. 22. The sustained release enhancer of claim 21, wherein the ceramide is N-stearoyldihydrosphingosine.

22. 22. The sustained release enhancer of claim 20 or 21, wherein the prodrug steroidal anti-inflammatory drug is prednisolone valerate acetate.

23. The sustained release enhancer according to claim 21, containing 0.1 to 1% by weight of N-stearoyldihydrosphingosine.

24. The sustained release enhancer according to claim 22, containing 0.1 to 0.3% by weight of prednisolone valerate acetate.

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