Patent Application
20080085858
Six-week-old BALB/c mice (male, Charles River Japan, Inc.) which are purchased are used for the experiment. After at least one week of quarantine and taming, seven-week-old mice which normally increased in weight and does not apparently show any abnormality are subjected to the experiment. The mice are placed in plastic cages (6 mice per cage) in a breeding room which is kept at a room temperature (19 to 25° C.) and a humidity of 30 to 70% and is illuminated for 12 hours a day (from 7:00 a.m. to 7:00 p.m.). The mice are allowed to freely intake commercially available pellets and water.
As an antigen solution, Oxazolone (Sigma-Aldrich) is dissolved in acetone (Kanto Kagaku) to prepare 0.5 w/v % of oxazolone-acetone solution. BALB/c mice are each applied with 100 μL of the antigen solution to the shaved abdomen for sensitization. Mice are shaved on abdomen on the previous day of the sensitization. The reaction is induced by an epicutaneous application of the antigen solution (10 μL) on the inner side of the ear 5 days after the sensitization. The test compound (the PDE-IV inhibitor or a pharmaceutically acceptable salt thereof and/or the immunosuppressant) is prepared by dissolving in acetone to make the concentration to the desired concentration (test compound solution). The test compound solution (10 μL each, total of 20 μL) is applied to inner side and outer side of the ear 3 hours before and 2 hours after inducing the reaction. This group is referred to as a test compound administration group. The group in which sensitization and inducing reaction are carried out and applied with the acetone 3 hours before and 2 hours after inducing the reaction is referred to as a positive control group, and the group which is unsensitized but the reaction is induced and applied with the acetone 3 hours before and 2 hours after inducing the reaction is referred to as a negative control group. Ear thickness is measured with a dial thickness gauge (Ozaki Seisakusho) just before and 24 hours after the application for inducing the reaction, and the difference in the thickness is used as an indication of ear swelling. The inhibition ratio (%) against ear swelling is calculated using the following:
Inhibition ratio (%)=[{(value in positive control group)−(value in test compound administration group)}/{(value in positive control group)−(value in negative control group)}]×100
The above results show that the simultaneous administration of the PDE-IV inhibitor or a pharmaceutically acceptable salt thereof and the immunosuppressant has a therapeutic effect on chronic skin diseases.
Six-week-old BALB/c mice (male, Charles River Japan, Inc.) were purchased. After one week of quarantine and taming, mice which steadily increased in weight and did not apparently show any abnormality were subjected to the experiment. The mice were placed in plastic cages (6 mice per cage) in a breeding room which was kept at a room temperature (19 to 25° C.) and a humidity of 30 to 70% and was illuminated for 12 hours a day (from 7:00 a.m. to 7:00 p.m.). The mice were allowed to freely intake commercially available pellets and water.
As an antigen solution, Oxazolone (Sigma-Aldrich) was dissolved in acetone (Kanto Kagaku) to prepare 0.5 w/v % of oxazolone-acetone solution. BALB/c mice were each applied with 100 μL of the antigen solution to the shaved abdomen for sensitization. Mice were shaved on abdomen on the previous day of the sensitization. The reaction was induced by an epicutaneous application of the antigen solution (10 μL) on the inner side of the ear 5 days after the sensitization. Compound (I) and Tacrolimus were prepared by dissolving in acetone to make the concentration to 10 mg/mL and 0.01 mg/mL, respectively (Compound (I) solution, Tacrolimus solution). Compound (I) solution (10 μL each, total of 20 μL) was applied to inner side and outer side of the ear 3 hours before and 2 hours after inducing the reaction (Compound (I) administration group). Similarly, Tacrolimus solution (10 μL each, total of 20 μL) was applied to inner side and outer side of the ear 3 hours before and 2 hours after inducing the reaction (Tacrolimus administration group). Further, 20 μL of solution in which Compound (I) and prednisolone were dissolved in acetone to make the concentration to 10 mg/mL and 0.01 mg/mL, respectively, was similarly applied to inner side and outer side of the ear (combined administration group). The group in which sensitization and inducing reaction were carried out and applied with the acetone 3 hours before and 2 hours after inducing the reaction was referred to as a positive control group, and the group which was unsensitized but the reaction was induced and applied with the acetone 3 hours before and 2 hours after inducing the reaction was referred to as a negative control group. Ear thickness was measured with a dial thickness gauge (Ozaki Seisakusho) just before and 24 hours after inducing the reaction, and the difference in the thickness was used as an indication of ear swelling. The inhibition ratio (%) against ear swelling was calculated using the following:
Inhibition ratio (%)=[{(value in positive control group)−(value in test compound administration group)}/{(value in positive control group)−(value in negative control group)}]×100
Test compound administration group: Compound (I) administration group, Tacrolimus administration group or combined administration group
The results are shown in Table 1.
###P < 0.05 (Student's t-test, compared to the Compound (I) administration group)
+++P < 0.001 (Student's t-test, compared to the Tacrolimus administration group)
In the Compound (I) administration group and the Tacrolimus administration group, a significant inhibition effect on ear swelling was observed, and the inhibition ratios were 34% (P<0.001) and 36% (P<0.001), respectively. Further, in the combined administration group of Compound (I) and Tacrolimus, the inhibition ratio was 68%, and significant inhibition was exhibited compared with the Compound (I) administration group and the Tacrolimus administration group.
Therefore, it was confirmed that by the combined administration of Compound (I) and Tacrolimus, namely, by the combined administration of the PDE-IV inhibitor and the immunosuppressant, a superior therapeutic effect on chronic skin diseases can be observed compared with the cases where the each agents is administered alone.
On the other hand, the immunosuppressant exhibits a strong antiinflammatory effect and is a good medicine as a therapeutic agent for chronic skin diseases. However, it has been reported that the immunosuppressant has a side effect such as carcinogenicity (Cancer, Vol. 80, p. 1141 (1997)).
The results of the above test show that the dose of the immunosuppressant conventionally used for treating chronic skin diseases can be decreased by using Compound (I) or a pharmaceutically acceptable salt thereof and the immunosuppressant in combination. In other words, the dose of the immunosuppressant conventionally used for treating chronic skin diseases can be decreased by the pharmaceutical composition, the therapeutic and/or preventive agent for chronic skin diseases, the kit, the kit for treating and/or preventing chronic skin diseases or the method for treating and/or preventing chronic skin diseases of the present invention, and it is expected that the effect of the immunosuppressant used as a single preparation can be improved, and the above side effect can be also decreased.
As described above, the therapeutic and/or preventive agent for chronic skin diseases of the present invention can be used, administered or produced as a single preparation or a combination of preparations as long as they are prepared so as to contain the respective active ingredients of the PDE-IV inhibitor or a pharmaceutically acceptable salt thereof and the immunosuppressant. These pharmaceutical compositions or the therapeutic and/or preventive agents for chronic skin diseases are preferably in a unit dose form suitable for oral administration such as a tablet, or parenteral administration such as an injection or an external preparation. When a combination of preparations is used or administered, the preparations can be administered simultaneously or separately with an interval.
These preparations can be prepared by an ordinary method properly using the respective active ingredients and a pharmaceutically acceptable diluent, excipient, disintegrant, lubricant, binder, surfactant, water, physiological saline, vegetal oil solubilizer, isotonizing agent, preservative, antioxidant or the like.
In order to prepare a tablet, for example, an excipient such as lactose, a disintegrant such as starch, a lubricant such as magnesium stearate, a binder such as hydroxypropyl cellulose, a surfactant such as a fatty acid ester, a plasticizer such as glycerin, an antiseptic such as benzoic acid or the like may be used according to an ordinary method.
In order to prepare an injection, for example, water, physiological saline, a vegetal oil such as soybean oil, any of various solvents, a solubilizer, an isotonizing agent, a preservative, an antioxidant or the like may be used according to an ordinary method.
Suitable dosage forms for the external preparations, but not limited to, include preparations that are formed into cream, paste, jelly, gel, emulsion, liquid, or the like by dissolving or mixing and dispersing the active ingredient in base (e.g. ointments, liniments, lotions or the like); preparations that are formed by dissolving or mixing and dispersing the active ingredient and percutaneous absorption promoters in base, and then spreading them on supporting materials such as polyethylene, polyester, polyethylene terephthalate and the like (e.g. cataplasms, tapes or the like); and the like. Examples of above base include any pharmaceutically acceptable base, and known bases such as ointments, liniments, lotions and the like can be used. Examples of such base include sodium alginate; polymers such as gelatin, corn starch, tragacanth gum, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, xanthan gum, dextrin, carboxymethyl starch, polyvinyl alcohol, sodium polyacrylate, methoxyethylene-maleic anhydride copolymer, polyvinyl ether, polyvinyl pyrrolidone and the like; fats and oils such as yellow beeswax, olive oil, cacao oil, sesame oil, soybean oil, camellia oil, peanut oil, beef tallow, lard, lanolin and the like; vaseline such as white vaseline, yellow vaseline and the like; paraffin; hydrocarbon gel ointments [for example, Plastibase [trade name (manufactured by Taisho Pharmaceutical Co., Ltd.)]; higher fatty acids such as stearic acid and the like; higher alcohols such as cetyl alcohol, stearyl alcohol and the like; polyethylene glycol; water and the like. Examples of above percutaneous absorption promoter include any pharmaceutically acceptable percutaneous absorption promoter, for example, alcohols such as methanol, ethanol, diethylene glycol, propylene glycol and the like; polar solvents such as dimethyl sulfoxide, dodecyl pyrrolidone and the like; urea; esters such as ethyl laurate, isopropyl myristate, cetyl octanoate and the like; azone; olive oil and the like. Additionally, inorganic fillers such as kaolin, bentonite, zinc oxide, titanium oxide and the like; viscosity-controlling agents; anti-aging agents; pH-controlling agents; humectants such as glycerin, propylene glycol and the like; and the like may be added to the base, if necessary.
Furthermore, the above external preparations may also contain diluents, flavors, and one or more additives selected from excipients, disintegrants, lubricants, binders, surfactants, plasticizers, antiseptics and the like, which are exemplified in the oral administration.
When using or administering the PDE-IV inhibitor or a pharmaceutically acceptable salt thereof and the immunosuppressant as a combination of various preparations, the dosages and the dosage frequencies may vary with the effects of each active ingredients, the dosage forms, age, weight and symptom of patients, and the like. Generally, the PDE-IV inhibitor or a pharmaceutically acceptable salt thereof and the immunosuppressant are preferably administered in a dose described below.
In the oral administration, such as tablets, the PDE-IV inhibitor or a pharmaceutically acceptable salt thereof and the immunosuppressant in a dose of 0.01 mg to 1000 mg and 0.01 to 1000 mg, respectively, preferably, 0.05 to 300 mg, and 0.1 to 300 mg, respectively, more preferably 0.5 to 200 mg, and 0.5 to 200 mg, respectively are administered to an adult patient once or several times a day simultaneously or separately with an interval.
In the parenteral administration, such as injection, the PDE-IV inhibitor or a pharmaceutically acceptable salt thereof and the immunosuppressant in a dose of 1 μg to 100 mg and 0.01 to 1000 mg, respectively, preferably, 5 μg to 30 mg and 0.05 to 100 mg, respectively, more preferably 10 μg to 20 mg, and 0.1 to 10 mg, respectively are administered to an adult patient once or several times a day simultaneously or separately with an interval.
The external preparation (e.g. ointment, cream or the like) generally contains 1 to 1000 mg, preferably, 3 to 300 mg, of the PDE-IV inhibitor or a pharmaceutically acceptable salt thereof and 1 to 1000 mg, preferably, 3 to 300 mg, of the immunosuppressant in 1 g of paste and is generally administered by applying it once or several times a day.
When using or administering the PDE-IV inhibitor or a pharmaceutically acceptable salt thereof and the immunosuppressant as a single preparation, the dosages and the dosage frequencies may vary with the effects of active ingredients, the dosage forms, age, weight and symptom of patients, and the like. They are preferably used or administered as a single preparation prepared in a dose when used or administered as a combination of the above several preparations, respectively.
However, these dosages and frequencies vary based on the above-mentioned various conditions.
The embodiments of the present invention will now be described with following Examples but the scope of the present invention is not limited to these Examples.
A tablet including the following composition is prepared by a conventional process. Compound (I) (40 g), lactose (286.8 g) and potato starch (60 g) are mixed, followed by adding 10% hydroxypropylcellulose aqueous solution (120 g) thereto. After the resulting mixture is kneaded, granulated, and dried according to a conventional process, the size of the granules is prepared for tablet pressing. The granules are mixed with magnesium stearate (1.2 g) and then pressed to make tablets (each tablet containing 20 mg of the active ingredient) by a tablet making machine having a striker of 8 mm diameter (Kikusui Co., Type RT-15).
A tablet including the following composition is prepared by a conventional process. Compound (III) (40 g), lactose (286.8 g) and potato starch (60 g) are mixed, followed by adding 10% hydroxypropylcellulose aqueous solution (120 g) thereto. After the resulting mixture is kneaded, granulated, and dried according to a conventional process, the size of the granules is prepared for tablet pressing. The granules are mixed with magnesium stearate (1.2 g) and then pressed to make tablets (each tablet
(50) Use according to any one of (47) to (49), wherein the immunosuppressant is an immunosuppressant selected from a group consisting of Tacrolimus, Pimecrolimus, Ascomycin, Rapamycin, FTY 720, Azathioprine, Cyclophosphamide, Methotrexate, Mizoribine and Cyclosporin A.
(51) Use according to any one of (47) to (50), wherein the chronic skin disease is a disease selected from a group consisting of contact dermatitis, atopic dermatitis, seborrheic dermatitis, nummular eczema, lichen simplex chronicus Vidal, autosensitization dermatitis, stasis dermatitis, asteatotic eczema, and psoriasis.
(53) Use of (a) a PDE-IV inhibitor or a pharmaceutically acceptable salt thereof and (b) an immunosuppressant for the manufacture of a therapeutic and/or preventive agent for chronic skin diseases to be administered simultaneously or separately with an interval, which comprises (a) and (b), as containing 20 mg of the active ingredient) by a tablet making machine having a striker of 8 mm diameter (Kikusui Co., Type RT-15).
A tablet including the following composition is prepared by a conventional process. Compound (V) (40 g), lactose (286.8 g) and potato starch (60 g) are mixed, followed by adding 10% hydroxypropylcellulose aqueous solution (120 g) thereto. After the resulting mixture is kneaded, granulated, and dried according to a conventional process, the size of the granules is prepared for tablet pressing. The granules are mixed with magnesium stearate (1.2 g) and then pressed to make tablets (each tablet containing 20 mg of the active ingredient) by a tablet making machine having a striker of 8 mm diameter (Kikusui Co., Type RT-15).
A tablet including the following composition is prepared by a conventional process. Tacrolimus (40 g), lactose (286.8 g) and potato starch (60 g) are mixed, followed by adding 10% hydroxypropylcellulose aqueous solution (120 g) thereto. After the resulting mixture is kneaded, granulated, and dried according to a conventional process, the size of the granules is prepared for tablet pressing. The granules are mixed with magnesium stearate (1.2 g) and then pressed to make tablets (each tablet containing 20 mg of the active ingredient) by a tablet making machine having a striker of 8 mm diameter (Kikusui Co., Type RT-15).
A tablet including the following composition is prepared by a conventional process. Compound (I) (40 g), Tacrolimus (40 g), lactose (246.8 g) and potato starch (40 g) are mixed, followed by adding 10% hydroxypropylcellulose aqueous solution (120 g) thereto. After the resulting mixture is kneaded, granulated, and dried according to a conventional process, the size of the granules is prepared for tablet pressing. The granules are mixed with magnesium stearate (1.2 g) and then pressed to make tablets (each tablet containing 20 mg of Compound (I) and 20 mg of Tacrolimus) by a tablet making machine having a striker of 8 mm diameter (Kikusui Co., Type RT-15).
A tablet including the following composition is prepared by a conventional process. Compound (III) (40 g), Cyclosporin A (40 g), lactose (246.8 g) and potato starch (40 g) are mixed, followed by adding 10% hydroxypropylcellulose aqueous solution (120 g) thereto. After the resulting mixture is kneaded, granulated, and dried according to a conventional process, the size of the granules is prepared for tablet pressing. The granules are mixed with magnesium stearate (1.2 g) and then pressed to make tablets (each tablet containing 20 mg of Compound (III) and 20 mg of Cyclosporin A) by a tablet making machine having a striker of 8 mm diameter (Kikusui Co., Type RT-15).
An injection including the following composition is prepared by a conventional process. Compound (IV) (1 g) is dissolved in purified soybean oil, and purified egg-yolk lecithin (12 g) and glycerin (25 g) for injection are added thereto. Injectable distilled water is added to the resulting mixture to make the total volume to 1000 mL, and the resulting mixture is kneaded and emulsified according to a conventional process. The resulting dispersion is filtered with a 0.2 μm disposable membrane filter under sterile condition and is dispensed into glass vials at a volume of 2 mL per vial (each vial contains 2 mg of the active ingredient) under the sterile condition to obtain the injections.
An injection including the following composition is prepared by a conventional process. Cyclosporin A (1 g) is dissolved in purified soybean oil, and purified egg-yolk lecithin (12 g) and glycerin (25 g) for injection are added thereto. Injectable distilled water is added to the resulting mixture to make the total volume to 1000 mL, and the resulting mixture is kneaded and emulsified according to a conventional process. The resulting dispersion is filtered with a 0.2 μm disposable membrane filter under sterile condition and is dispensed into glass vials at a volume of 2 mL per vial (each vial contains 2 mg of the active ingredient) under the sterile condition to obtain the injections.
An injection including the following composition is prepared by a conventional process. Compound (VI) (1 g) and Pimecrolimus (1 g) is dissolved in purified soybean oil, and purified egg-yolk lecithin (12 g) and glycerin (25 g) for injection are added thereto. Injectable distilled water is added to the resulting mixture to make the total volume to 1000 mL, and the resulting mixture is kneaded and emulsified according to a conventional process. The resulting dispersion is filtered with a 0.2 μm disposable membrane filter under sterile condition and is dispensed into glass vials at a volume of 2 mL per vial (each vial contains 2 mg of the Compound (VI) and 2 mg of Pimecrolimus) under the sterile condition to obtain the injections.
An external preparation including the following composition is prepared according to a conventional process. White Vaseline (65 g) is heated with stirring, and propylene glycol (25 g) is added thereto. To the resulting mixture, a mixture of Compound (I) (5 g) and cetyl octanoate (5 g) is added and dispersed with continuous stirring and heating. Then, the dispersion is gradually cooled to about 25° C. and put into an appropriate vessel to obtain the external ointment.
An external preparation including the following composition is prepared according to a conventional process. White Vaseline (65 g) is heated with stirring, and propylene glycol (25 g) is added thereto. To the resulting mixture, a mixture of Compound (II) (5 g) and cetyl octanoate (5 g) is added and dispersed with continuous stirring and heating. Then, the dispersion is gradually cooled to about 25° C. and put into an appropriate vessel to obtain the external ointment.
An external preparation including the following composition is prepared according to a conventional process. White Vaseline (65 g) is heated with stirring, and propylene glycol (25 g) is added thereto. To the resulting mixture, a mixture of Compound (III) (5 g) and cetyl octanoate (5 g) is added and dispersed with continuous stirring and heating. Then, the dispersion is gradually cooled to about 25° C. and put into an appropriate vessel to obtain the external ointment.
An external preparation including the following composition is prepared according to a conventional process. White Vaseline (65 g) is heated with stirring, and propylene glycol (25 g) is added thereto. To the resulting mixture, a mixture of Compound (IV) (5 g) and cetyl octanoate (5 g) is added and dispersed with continuous stirring and heating. Then, the dispersion is gradually cooled to about 25° C. and put into an appropriate vessel to obtain the external ointment.
An external preparation including the following composition is prepared according to a conventional process. White Vaseline (65 g) is heated with stirring, and propylene glycol (25 g) is added thereto. To the resulting mixture, a mixture of Compound (VIII) (5 g) and cetyl octanoate (5 g) is added and dispersed with continuous stirring and heating. Then, the dispersion is gradually cooled to about 25° C. and put into an appropriate vessel to obtain the external ointment.
An external preparation including the following composition is prepared according to a conventional process. White Vaseline (69.5 g) is heated with stirring, and propylene glycol (25 g) is added thereto. To the resulting mixture, a mixture of Cyclosporin A (0.5 g) and cetyl octanoate (5 g) is added and dispersed with continuous stirring and heating. Then, the dispersion is gradually cooled to about 25° C. and put into an appropriate vessel to obtain the external ointment.
An external preparation including the following composition is prepared according to a conventional process. White Vaseline (69.5 g) is heated with stirring, and propylene glycol (25 g) is added thereto. To the resulting mixture, a mixture of FTY 720 (0.5 g) and cetyl octanoate (5 g) is added and dispersed with continuous stirring and heating. Then, the dispersion is gradually cooled to about 25° C. and put into an appropriate vessel to obtain the external ointment.
An external preparation including the following composition is prepared according to a conventional process. White Vaseline (69.5 g) is heated with stirring, and propylene glycol (25 g) is added thereto. To the resulting mixture, a mixture of Tacrolimus (0.5 g) and cetyl octanoate (5 g) is added and dispersed with continuous stirring and heating. Then, the dispersion is gradually cooled to about 25° C. and put into an appropriate vessel to obtain the external ointment.
An external preparation including the following composition is prepared according to a conventional process. White Vaseline (64.5 g) is heated with stirring, and propylene glycol (25 g) is added thereto. To the resulting mixture, a mixture of Compound (I) (5 g), Cyclosporin A (0.5 g) and cetyl octanoate (5 g) is added and dispersed with continuous stirring and heating. Then, the dispersion is gradually cooled to about 25° C. and put into an appropriate vessel to obtain the external ointment.
An external preparation including the following composition is prepared according to a conventional process. White Vaseline (64.5 g) is heated with stirring, and propylene glycol (25 g) is added thereto. To the resulting mixture, a mixture of Compound (III) (5 g), Cyclosporin A (0.5 g) and cetyl octanoate (5 g) is added and dispersed with continuous stirring and heating. Then, the dispersion is gradually cooled to about 25° C. and put into an appropriate vessel to obtain the external ointment.
An external preparation including the following composition is prepared according to a conventional process. White Vaseline (64.5 g) is heated with stirring, and propylene glycol (25 g) is added thereto. To the resulting mixture, a mixture of Compound (I) (5 g), Tacrolimus (0.5 g) and cetyl octanoate (5 g) is added and dispersed with continuous stirring and heating. Then, the dispersion is gradually cooled to about 25° C. and put into an appropriate vessel to obtain the external ointment.
An external preparation including the following composition is prepared according to a conventional process. White Vaseline (64.5 g) is heated with stirring, and propylene glycol (25 g) is added thereto. To the resulting mixture, a mixture of Compound (III) (5 g), Tacrolimus (0.5 g) and cetyl octanoate (5 g) is added and dispersed with continuous stirring and heating. Then, the dispersion is gradually cooled to about 25° C. and put into an appropriate vessel to obtain the external ointment.
An external preparation including the following composition is prepared according to a conventional process. White Vaseline (64.5 g) is heated with stirring, and propylene glycol (25 g) is added thereto. To the resulting mixture, a mixture of Compound (V) (5 g), Tacrolimus (0.5 g) and cetyl octanoate (5 g) is added and dispersed with continuous stirring and heating. Then, the dispersion is gradually cooled to about 25° C. and put into an appropriate vessel to obtain the external ointment.
An external preparation including the following composition is prepared according to a conventional process. White Vaseline (64.5 g) is heated with stirring, and propylene glycol (25 g) is added thereto. To the resulting mixture, a mixture of Compound (VII) (5 g), Tacrolimus (0.5 g) and cetyl octanoate (5 g) is added and dispersed with continuous stirring and heating. Then, the dispersion is gradually cooled to about 25° C. and put into an appropriate vessel to obtain the external ointment.
An external preparation including the following composition is prepared according to a conventional process. White Vaseline (64.5 g) is heated with stirring, and propylene glycol (25 g) is added thereto. To the resulting mixture, a mixture of Compound (I) (5 g), FTY 720 (0.5 g) and cetyl octanoate (5 g) is added and dispersed with continuous stirring and heating. Then, the dispersion is gradually cooled to about 25° C. and put into an appropriate vessel to obtain the external ointment.
An external preparation including the following composition is prepared according to a conventional process. White Vaseline (64.5 g) is heated with stirring, and propylene glycol (25 g) is added thereto. To the resulting mixture, a mixture of Compound (VIII) (5 g), FTY 720 (0.5 g) and cetyl octanoate (5 g) is added and dispersed with continuous stirring and heating. Then, the dispersion is gradually cooled to about 25° C. and put into an appropriate vessel to obtain the external ointment.
An external preparation including the following composition is prepared according to a conventional process. White Vaseline (64.5 g) is heated with stirring, and propylene glycol (25 g) is added thereto. To the resulting mixture, a mixture of Compound (I) (5 g), Pimecrolimus (0.5 g) and cetyl octanoate (5 g) is added and dispersed with continuous stirring and heating. Then, the dispersion is gradually cooled to about 25° C. and put into an appropriate vessel to obtain the external ointment.
An external preparation including the following composition is prepared according to a conventional process. White Vaseline (64.5 g) is heated with stirring, and propylene glycol (25 g) is added thereto. To the resulting mixture, a mixture of Compound (II) (5 g), Pimecrolimus (0.5 g) and cetyl octanoate (5 g) is added and dispersed with continuous stirring and heating. Then, the dispersion is gradually cooled to about 25° C. and put into an appropriate vessel to obtain the external ointment.
The present invention provides a pharmaceutical composition comprising (a) PDE-IV inhibitor or a pharmaceutically acceptable salt thereof and (b) immunosuppressant, a therapeutic and/or preventive agent for chronic skin diseases comprising (a) PDE-IV inhibitor or a pharmaceutically acceptable salt thereof and (b) immunosuppressant, and the like.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2004-299104 | Oct 2004 | JP | national |
| 2005-113265 | Apr 2005 | JP | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/JP05/18854 | 10/13/2005 | WO | 00 | 4/10/2007 |
