JP2007016024A - Roflumilast eye drop - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To enhance pharmaceutical effects of roflumilast for an eye drop containing the roflumilast as an active ingredient. <P>SOLUTION: The eye drop having enhanced pharmaceutical effects of the roflumilast can be prepared by formulating an eye drop containing the roflumilast as the active ingredient with at least one kind of thickening agent. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to an ophthalmic solution containing roflumilast as an active ingredient and having enhanced medicinal efficacy of roflumilast.

Roflumilast is represented by the chemical name N- (3,5-dichloropyridin-4-yl) -3-cyclopropylmethoxy-4-difluoromethoxybenzamide and represented by the following chemical structural formula.

  Roflumilast is useful in mediating or inhibiting the enzyme activity of phosphodiesterase IV, and Patent Document 1 is known to be useful as a therapeutic agent for allergic and inflammatory diseases, particularly asthma and bronchitis. It has also been suggested to be effective in the treatment of allergic and inflammatory diseases in the eye. Patent Document 2 describes ophthalmic preparations such as eye ointments and suspension type ophthalmic solutions and oral ophthalmic preparations as ophthalmic preparations containing roflumilast as an active ingredient.

  On the other hand, polymer compounds such as polyvinyl alcohol, carboxyvinyl polymer, and hydroxypropylmethylcellulose are used as thickening agents in the ophthalmic solution field. Patent Documents 2 and 3 describe several cellulose derivatives and vinyl polymer compounds as suspension stabilizers for suspension ophthalmic solutions containing roflumilast as an active ingredient.

However, none of the above references suggests that the efficacy of roflumilast can be enhanced by adding a thickening agent to the ophthalmic solution containing roflumilast as an active ingredient.
Japanese National Patent Publication No. 8-512041 WO03 / 099278 pamphlet International Publication Number 03/099334 Pamphlet

  The phosphodiesterase IV inhibitor is considered to be useful for the treatment of eye diseases such as allergic conjunctivitis, spring catarrh, and blepharitis due to the effects described above. Among the inhibitors, roflumilast has high phosphodiesterase IV inhibitory activity and is expected as a new therapeutic agent for the above eye diseases. Therefore, further enhancing the drug efficacy of roflumilast is an interesting issue.

  In addition, phosphodiesterase IV inhibitors have been reported to cause side effects such as nausea, vomiting, headache, diarrhea when used at high doses, and this has the problem of limited clinical usefulness. . This problem is no exception for roflumilast, which has the same inhibitory action. In addition, ophthalmic preparations such as eye drops and eye ointments are widely used to adapt to eye diseases, but since these are usually administered frequently, it is not possible to neglect the problem of this side effect. Can not. Therefore, if the drug efficacy can be enhanced, the amount of roflumilast can be reduced while maintaining the desired drug efficacy, and side effects can be avoided or suppressed to a minimum. Therefore, enhancing the efficacy of roflumilast is also an interesting issue from the viewpoint of avoiding side effects.

  On the other hand, since roflumilast is sparingly soluble, there are usually restrictions on the form of ophthalmic preparations that can be applied, and forms of eye ointments and suspension eye drops are assumed. However, although ophthalmic ointment and suspension ophthalmic solution are widely used as ophthalmic preparations, ophthalmic ointment is not preferable in terms of usability due to its stickiness, and suspension ophthalmic solution allows the drug to settle out by stationary storage. In use, sufficient shaking is required for uniform dispersion, which is not preferable in terms of convenience. In addition, it cannot be denied that suspension type ophthalmic solutions may cause problems such as drug aggregation and caking. Therefore, it is also a big problem to prepare a dissolved ophthalmic solution.

  Therefore, the present inventors have intensively studied the above ophthalmic solution, and as a result of preparing and examining various roflumilast ophthalmic solutions containing general-purpose additives, surprisingly, vinyl polymer compounds, cellulose derivatives The present inventors have found that the efficacy of roflumilast can be enhanced by adding a thickening agent such as This is known to improve the sustained effect of the drug by blending the thickener, but it is not known at all to enhance the drug effect itself by blending the thickener. Even so, it is a surprising discovery. In addition, according to the present invention, the concentration can be lowered while maintaining the efficacy of roflumilast, so that side effects due to the phosphodiesterase IV inhibitory action can be avoided or minimized.

  Furthermore, it has also been found that the medicinal effect of roflumilast can be enhanced more effectively by making the roflumilast ophthalmic solution into a soluble form by blending a surfactant. According to the present invention, even an ophthalmic solution containing insoluble roflumilast can be used to prepare a stable dissolved ophthalmic solution while maintaining a desired medicinal effect. An excellent ophthalmic solution can be provided.

That is, the present invention
(1) An ophthalmic solution containing roflumilast as an active ingredient, and by adding at least one thickening agent, the medicinal effect of roflumilast is enhanced and the viscosity at 25 ° C. is 1.5 to 500 mPa · s. Eye drops,
(2) The ophthalmic solution according to the above (1), wherein the ophthalmic solution has a viscosity at 25 ° C. of 1.5 to 50 mPa · s,
(3) The ophthalmic solution according to (1), wherein the concentration of roflumilast is 0.00001 to 0.05% (W / V),
(4) The ophthalmic solution according to (1), wherein the concentration of roflumilast is 0.0001 to 0.03% (W / V),
(5) The ophthalmic solution according to the above (1), wherein the thickening agent is hydroxypropyl methylcellulose, polyvinyl alcohol or carboxyvinyl polymer.
(6) The ophthalmic solution according to the above (1), wherein a surfactant is further blended to form a dissolution type
(7) The ophthalmic solution according to (6), wherein the surfactant is at least one selected from polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, and polyoxyl 40 monostearate,
(8) In an ophthalmic solution containing roflumilast as an active ingredient, a method of enhancing the medicinal effect of roflumilast by blending at least one thickening agent and setting the viscosity at 25 ° C. to 1.5 to 500 mPa · s,
About.

  The content of roflumilast, which is an active ingredient of the ophthalmic solution in the present invention, may be a concentration that can exert a therapeutic effect and is a concentration that provides a soluble ophthalmic solution, but is preferably 0.00001 to 0.05% (W / V), more preferably 0.0001 to 0.03% (W / V).

  Examples of the thickening agent used in the present invention include vinyl polymer compounds such as polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, and polyvinyl methyl ether; hydroxypropyl methylcellulose, hydroxypropylethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, Cellulose derivatives such as ethylmethylcellulose, ethylpropylcellulose, carboxymethylcellulose or salts thereof, carboxypropylcellulose or salts thereof; polysaccharides such as hyaluronic acid or salts thereof, dextran, cyclodextrin; sodium polyacrylate, sodium chondroitin sulfate, etc. A high molecular compound is also mentioned. Preferred thickening agents include hydroxypropyl methylcellulose, polyvinyl alcohol or carboxyvinyl polymer.

In the present invention, the blending amount of the thickening agent varies depending on the molecular weight and type of the thickening agent and thus cannot be unconditionally specified. The viscosity of the eye drop of the present invention is an E-type viscometer (25 ° C., shear rate). : It is preferable to select the compounding amount of the thickening agent as appropriate so that it becomes 1.5 to 500 mPa · s at 100 s ⁻¹ ). This is because the ophthalmic solution having a viscosity of 1.5 Pa · s or more can effectively enhance the efficacy of roflumilast, and if the ophthalmic solution is too high, the ophthalmic solution becomes sticky. This is because it is not preferable in terms of usability such that it becomes difficult to perform the filtration process for aseptic treatment of eye drops. The viscosity of the ophthalmic solution is more preferably 1.5 to 50 mPa · s.

The viscosity of the ophthalmic solution of the present invention is measured using an RS100 type rotational viscometer (HAAKE), which is an E type viscometer, and the shear rate is in the range of 0.3 s ⁻¹ to 200 s ⁻¹ at a measurement temperature of 25 ° C. Is the value when the shearing speed when raised at 100 s ^-1 is.

  The “dissolving type” of the dissolution type ophthalmic solution of the present invention refers to a state in which roflumilast is dissolved in the liquid solvent of the ophthalmic solution.

  The ophthalmic solution according to the present invention may be further dissolved to contain a surfactant. The surfactant improves the water-solubility of roflumilast, thereby making the ophthalmic solution of roflumilast into a dissolution type and effectively enhancing the medicinal effect of roflumilast in the ophthalmic solution. Specific examples of the surfactant include polysorbate 80 [polyoxyethylene sorbitan monooleate], polysorbate 60 [polyoxyethylene sorbitan monostearate], polysorbate 40 [polyoxyethylene sorbitan monopalmitate], polyoxyethylene sorbitan monolaurate. Polyoxyethylene fatty acid esters such as polyoxyethylene sorbitan trioleate and polysorbate 65 [polyoxyethylene sorbitan tristearate]; polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, poly Polyoxyethylene castor oil derivatives such as oxyl 40 castor oil; polyoxyethylene (160) polyoxypropylene (30) glycol [Pluronic F68], polyoxyethylene (42) polyoxypropylene (67) glycol [Pluronic P123], poly Oxyethylene (54) Polyoxypropylene (39) Glycol [Pluronic P85], Polyoxyethylene (196) Polyoxypropylene (67) Glycol [Pluronic F127], Polyoxyethylene (20) Polyoxypropylene (20) Glycol [Pluronic] Polyoxyethylene polyoxypropylene glycol such as L-44]; polyoxyl 40 stearate, sucrose fatty acid ester, and the like. Polyoxyethylene sorbitan monooleate], polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, and the like stearic acid polyoxyl 40. These surfactants can be used alone or in combination of two or more. Particularly preferred surfactants include polysorbate 80 [polyoxyethylene sorbitan monooleate] or polyoxyl 35 castor oil, which is widely used as an additive for eye drops.

  The blending amount of the surfactant can be appropriately increased or decreased according to the amount of roflumilast contained in the ophthalmic solution of the present invention, and is preferably a blending amount capable of dissolving roflumilast in the ophthalmic solution. For example, if the surfactant is polyoxyl 35 castor oil, the blending amount is preferably 1 to 10% (W / V), more preferably 2 to 6% (W / V). Moreover, if it is polysorbate 80, the compounding quantity becomes like this. Preferably it is 1-10% (W / V), More preferably, it is 2-6% (W / V).

  The ophthalmic solution of the present invention can be prepared by a widely used method, and an isotonic agent, a buffer, a pH adjuster, a stabilizer, a preservative, and the like can be blended as necessary.

  Examples of the isotonizing agent include glycerin, propylene glycol, polyethylene glycol, trihalose, sucrose, sorbitol, mannitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.

  Examples of the buffer include phosphoric acid, phosphate, boric acid, borax, citric acid, acetic acid, ε-aminocaproic acid, trometamol, and the like.

  Examples of the pH adjuster include hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, sodium carbonate, sodium hydrogen carbonate and the like.

  Examples of the stabilizer include edetic acid and sodium edetate.

  Examples of the preservative include general-purpose sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, chlorhexidine gluconate, chlorobutanol and the like. These preservatives can also be used in combination.

  The pH of the ophthalmic solution of the present invention is preferably set to 4.0 to 8.5, and the osmotic pressure ratio is preferably set to around 1.0.

  An eye disease in which the eye drop of the present invention is used is a disease involving allergy or inflammation. For example, allergic conjunctivitis, spring catarrh, atopic keratoconjunctivitis, infectious keratoconjunctivitis, blepharitis, pruritus associated with eye surgery such as cataract surgery, dry keratoconjunctivitis, uveitis, age-related macular degeneration, diabetic retinopathy, etc. Can be mentioned.

  The number of instillations of the ophthalmic solution of the present invention can be appropriately selected depending on the symptoms, age, dosage form, etc., but one dose to several drops may be instilled once to several times a day (for example, 1 to 6 times).

  As will be described in detail in the section of the pharmacological test described later, the ophthalmic solution of the present invention containing a thickening agent such as hydroxypropylmethylcellulose, polyvinyl alcohol or carboxyvinyl polymer is compared with the comparative example in which no thickening agent is added. Obviously excellent efficacy is observed. That is, the efficacy of roflumilast can be enhanced by blending at least one thickening agent. Moreover, since the ophthalmic solution of the present invention can reduce the amount of roflumilast while maintaining a desired medicinal effect, the side effects of the phosphodiesterase IV inhibitor can be avoided or minimized. In addition, a soluble roflumilast ophthalmic solution can be prepared by blending a surfactant, and an ophthalmic solution superior to conventional ones in terms of usability and convenience can be provided.

  Pharmacological tests and formulation examples are shown below, but these examples are for better understanding of the present invention and do not limit the scope of the present invention.

[Pharmacological test]
Conjunctival inflammation suppression test using allergic conjunctivitis model Conjunctival inflammation of N- (3,5-dichloro-4-pyridyl) -3-chloropropylmethoxy-4-difluoromethoxybenzamide (roflumilast) using allergic conjunctivitis model Suppression tests for (edema / hyperemia) were examined.

1. Test 1
1. The concentration of roflumilast was kept constant, and the effect on the allergic conjunctivitis inhibitory effect of the thickener formulation was examined. 1-1. Preparation of test solution

  Polyoxyl 35 castor oil (5 g, surfactant) and roflumilast (0.01 g) are placed in a 100 mL flask and purified water, hydroxypropylmethylcellulose 2906 (manufactured by Shin-Etsu Chemical Co., Ltd., trade name: Metrolose 65SH4000) (0.5 g), phosphoric acid Sodium hydrogen (appropriate amount) and sodium chloride (appropriate amount) were added and dissolved by stirring. Thereafter, the pH was adjusted to 7 using sodium hydroxide or dilute hydrochloric acid, and purified water was added to make a total volume of 100 mL to obtain a transparent eye drop (viscosity: 11.7 mPa · s). Hereinafter, this is designated as test solution 1.

  A 5% polyvinyl alcohol aqueous solution (20 g) was used in place of hydroxypropylmethylcellulose (0.5 g), and other operations were carried out in the same manner as in Example 1 to obtain a transparent eye drop (viscosity: 1.7 mPa · s). It was. Hereinafter, this is designated as Test Solution 2. In addition, 5% polyvinyl alcohol aqueous solution was prepared by dissolving polyvinyl alcohol (made by Kuraray Co., Ltd., trade name: Kuraray Poval PVA-205) (5 g) in a 100 mL flask, adding 80 mL of purified water, and heating to dissolve polyvinyl alcohol at about 60 ° C. The mixture was cooled with stirring with a magnetic ruler, and purified water was added to make a total volume of 100 mL.

Comparative Example 1

  Hydroxypropylmethylcellulose (0.5 g) was not added, and other operations were performed in the same manner as in Example 1 to obtain a transparent eye drop (viscosity: 1.2 mPa · s). Hereinafter, this is referred to as Comparative Solution 1.

Table 1 shows the test solution and the comparative solution prepared by the above operation. In order to simplify the table, only the roflumilast and the thickening agent, which are components necessary for comparatively determining the effects of the present invention, are described in the formulation of Table 1.

1-2. Test Method Aluminum hydroxide gel-adsorbed ovalbumin was suspended in physiological saline (20 μg / mL), and 100 μL each was injected under the binocular conjunctiva of a 5-week-old male Hartley guinea pig to perform active sensitization. . Ovalbumin 0.05% (W / V) physiological saline solution 15 days after sensitization, and Ovalbumin 0.5% (W / V) physiological saline solution 10 μL / eye 22 days after sensitization Each eye was instilled into both eyes to induce allergic conjunctivitis.

  30 minutes before ophthalmic ophthalmic administration on the 22nd day after sensitization, the test solution or comparative solution was instilled into both eyes of the guinea pig at 10 μL / eye. As a control, a physiological saline solution containing 0.001% (W / V) hydroxypropylmethylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., trade name: TC5R) was administered dropwise to both eyes of the guinea pig at 10 μL / eye.

1-3. Evaluation Method 30 minutes after administration of ovalbumin on the 22nd day after sensitization, guinea pig conjunctival inflammation was evaluated by scoring according to the following evaluation criteria (Table 2).

Inhibition rate = 100 − ([average value of conjunctival inflammation score of test solution or comparison solution] ÷ [average value of control conjunctival inflammation score] × 100)

Table 3 shows the inhibition rates of Test Solution 1, Test Solution 2, and Comparative Solution 1 (16 or 18 eyes).

1-4. Test results and discussion As is apparent from Table 3, the test solution containing the thickening agent (the ophthalmic solution of the present invention) contains the same amount of roflumilast compared to the comparative solution containing no thickening agent. Despite this, a remarkable difference was observed in its efficacy. Therefore, it was confirmed that the effect of suppressing the allergic conjunctival inflammation state of roflumilast was enhanced by adding a thickening agent to the ophthalmic solution containing roflumilast as an active ingredient.

2. Test 2
The effect of suppressing the allergic conjunctivitis by the thickener formulation when the concentration of roflumilast was changed was investigated.

2-1. Preparation of test solution

  Polyoxyl 35 castor oil (5 g, surfactant) and roflumilast (0.01 g) were placed in a 100 mL flask, purified water and carboxyvinyl polymer (0.3 g) were added and dissolved by stirring. Thereafter, the pH was adjusted to 7 using sodium hydroxide or dilute hydrochloric acid, and purified water was added to make a total volume of 100 mL to obtain a transparent eye drop (viscosity: 453.8 mPa · s). Hereinafter, this is designated as test solution 3.

  Take polyoxyl 35 castor oil (5 g, surfactant) and roflumilast (0.01 g) in a 100 mL flask, add purified water, 5% aqueous polyvinyl alcohol (36 g), concentrated glycerin (appropriate amount), and borax (appropriate amount) and dissolve with stirring. did. Thereafter, the pH was adjusted to 8 using sodium hydroxide or dilute hydrochloric acid, and purified water was added to make a total volume of 100 mL to obtain a transparent eye drop (viscosity: 2.4 mPa · s). Hereinafter, this is designated as test solution 4.

Comparative Example 2

  Polysorbate 80 (0.005 g, surfactant) and roflumilast (0.1 g) were placed in a 100 mL flask, purified water and hydroxypropylmethylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., trade name: TC5R) (0.005 g) were added and dissolved by stirring. . Thereafter, the pH was adjusted to 7 using sodium hydroxide or dilute hydrochloric acid, and purified water was added to make a total volume of 100 mL to obtain a suspension type ophthalmic solution (viscosity: <1.0 mPa · s). Hereinafter, this is referred to as Comparative Solution 2.

Table 4 shows the test solution and the comparative solution prepared by the above operation. In order to simplify the table, only the roflumilast and the thickening agent, which are components necessary for comparatively determining the effects of the present invention, are described in the formulation of Table 4.

2-2. Test method and evaluation method The test was performed in the same manner as the method 1-2. As a control for each test solution, a solution obtained by removing only roflumilast from each test solution was used. Evaluation was performed by the same method as 1-3. Table 5 shows the inhibition rate (%) of the test solution and the comparison solution (number of cases: 16 or 18 eyes).

2-3. Test results and discussion As is apparent from Table 5, the dissolved ophthalmic solution in which a thickening agent is mixed with an ophthalmic solution containing 0.01% roflumilast as an active ingredient contains 0.1% roflumilast as an active ingredient. Compared with the suspension type ophthalmic solution, although the amount of roflumilast was 1/10, the inhibition rate was about the same. Therefore, the effect of making the dissolution type ophthalmic solution is remarkably shown.

3. Test 3
The effect of suppressing allergic conjunctivitis when the blending amount of polyvinyl alcohol and the pH of the ophthalmic solution were changed was examined.

3-1. Preparation of test solution

  The amount of 5% aqueous polyvinyl alcohol solution added was 60 g, and sodium hydrogen phosphate (appropriate amount) was used instead of borax (appropriate amount), and other operations were performed in the same manner as in Example 4 to produce a transparent ophthalmic solution (viscosity: 4.4 mPa · s) was obtained. Hereinafter, this is designated as test solution 5.

  The amount of 5% polyvinyl alcohol aqueous solution added was 28 g, sodium hydrogen phosphate (appropriate amount) was used instead of borax (appropriate amount), and other operations were carried out in the same manner as in Example 4 to produce a transparent ophthalmic solution (viscosity: 2.4 mPa · s) was obtained. Hereinafter, this is designated as test solution 6.

  The pH was adjusted to 5 and other operations were performed in the same manner as in Example 4 to obtain a transparent eye drop (viscosity: 2.4 mPa · s). Hereinafter, this is designated as test solution 7.

Table 6 shows test solutions prepared by the above operations. In order to simplify the table, only the roflumilast and the thickening agent, which are components necessary for comparative determination of the effects of the present invention, are described in the formulation of Table 6.

3-2. Test method and evaluation method The test was performed in the same manner as the method 1-2. Saline was used as a control. The evaluation method was the same as 1-3. Table 7 shows the inhibition rate (%) of the test solution (number of cases: 16 or 18 eyes).

3-3. Test results and discussion As is apparent from Table 7, the dissolution type ophthalmic solution in which polyvinyl alcohol is blended with ophthalmic solution containing 0.01% of roflumilast as an active ingredient changes the blending amount of polyvinyl alcohol or the pH of the ophthalmic solution. All of these were found to enhance the allergic conjunctival inflammation-suppressing effect of roflumilast.

[Formulation example]
The following preparations were obtained according to the preparation methods of the examples. In addition, in the following formulation example, the compounding quantity of each component is a content in 100 mL.

Formulation Example 1
Roflumilast 0.01g
Hydroxypropyl methylcellulose 0.5g
Polyoxyl 35 castor oil 5g
Benzalkonium chloride 0.005g
0.01g sodium edetate
Sodium chloride Appropriate amount Sodium hydrogen phosphate Appropriate amount 1N Sodium hydroxide Appropriate amount Hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount In the above formulation, the amount of hydroxypropylmethylcellulose is changed to 0.1 g, 0.3 g, 1 g to prepare a preparation similar to Preparation Example 1. Obtainable. Further, the same preparation as in Preparation Example 1 can be obtained by changing the amount of roflumilast to 0.0003 g, 0.001 g, 0.005 g, and 0.03 g.

Formulation Example 2
Roflumilast 0.01g
Polyvinyl alcohol 1g
Polyoxyl 35 castor oil 5g
Benzalkonium chloride 0.005g
0.01g sodium edetate
Concentrated glycerin appropriate amount Sodium hydrogen phosphate appropriate amount 1N sodium hydroxide appropriate amount hydrochloric acid appropriate amount sterilized purified water appropriate amount In the above formulation, the blending amount of polyvinyl alcohol is 0.1 g, 0.3 g, 0.8 g, 1.4 g, 1.8 g, 2 A formulation similar to Formulation Example 2 can be obtained by changing to 5 g and 5 g. Further, the same preparation as in Preparation Example 2 can be obtained by changing the amount of roflumilast to 0.0003 g, 0.001 g, 0.005 g, and 0.03 g.

Formulation Example 3
Roflumilast 0.01g
Polyvinyl alcohol 1g
Polyoxyl 35 castor oil 3g
Benzalkonium chloride 0.01g
0.01g sodium edetate
Concentrated glycerin appropriate amount Sodium hydrogen phosphate appropriate amount Borax appropriate amount 1N sodium hydroxide appropriate amount hydrochloric acid appropriate amount sterilized purified water appropriate amount In the above formulation, the blending amount of polyvinyl alcohol is 0.1 g, 0.3 g, 0.8 g, 1.4 g, 1. A preparation similar to Preparation Example 3 can be obtained by changing to 8 g, 2.5 g and 5 g. Further, the same preparation as in Preparation Example 3 can be obtained by changing the amount of roflumilast to 0.0003 g, 0.001 g, 0.005 g, and 0.03 g.

Formulation Example 4
Roflumilast 0.01g
Polyvinyl alcohol 1g
Polyoxyl 35 castor oil 3g
Benzalkonium chloride 0.005g
0.01g sodium edetate
Concentrated glycerin appropriate amount Trometamol appropriate amount 1N sodium hydroxide appropriate amount hydrochloric acid appropriate amount sterilized purified water appropriate amount In the above formulation, the compounding amount of polyvinyl alcohol is 0.1 g, 0.3 g, 0.8 g, 1.4 g, 1.8 g, 2.5 g, A preparation similar to Preparation Example 4 can be obtained by changing to 5 g. In addition, a preparation similar to Preparation Example 4 can be obtained by changing the amount of roflumilast to 0.0003 g, 0.001 g, 0.005 g, and 0.03 g.

Claims (8)

An ophthalmic solution containing roflumilast as an active ingredient, wherein the medicinal effect of roflumilast is enhanced by blending at least one thickening agent and the viscosity at 25 ° C. is 1.5 to 500 mPa · s. . The ophthalmic solution according to claim 1, which has a viscosity at 25 ° C. of 1.5 to 50 mPa · s. The ophthalmic solution according to claim 1, wherein the concentration of roflumilast is 0.00001 to 0.05% (W / V). The ophthalmic solution according to claim 1, wherein the concentration of roflumilast is 0.0001 to 0.03% (W / V). The ophthalmic solution according to claim 1, wherein the thickening agent is hydroxypropylmethylcellulose, polyvinyl alcohol or carboxyvinyl polymer. The ophthalmic solution according to claim 1, wherein a surfactant is further blended to form a dissolution type. The ophthalmic solution according to claim 6, wherein the surfactant is at least one selected from polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, and polyoxyl 40 monostearate. In the ophthalmic solution containing roflumilast as an active ingredient, a method of enhancing the medicinal effect of roflumilast by blending at least one thickening agent and setting the viscosity at 25 ° C. to 1.5 to 500 mPa · s.