JP3418751B2 - Fluorometholone suspension ophthalmic solution - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an improved composition of a suspension type eye drop containing fluorometholone, which is an anti-inflammatory synthetic corticosteroid, as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Fluorometholone is a drug that has been used in medicine as an anti-inflammatory steroid, but is widely used especially in the form of eye drops. By the way, since fluorometholone is a drug which is hardly soluble in water, it has been put to practical use in the form of a suspension type eye drop. Since the suspension type eye drops do not dissolve the drug, it is necessary to shake the eye drop container at the time of use to uniformly redisperse the precipitated / aggregated drug before use. Therefore, a method of blending a suspension type eye drop with a nonionic surfactant such as polysorbate 80 to facilitate redispersion has been used.

[0003]

DISCLOSURE OF INVENTION Problems to be Solved by the Invention In the suspension type eye drops of fluorometholone, the above-mentioned measures have been taken in order to improve the redispersibility of the drug. There is a need for an improvement to facilitate the above. In the case of suspension type eye drops, the drug, which is in a uniform dispersion state during preparation of the preparation, forms an agglomerate during storage, and does not completely return to the original homogeneous dispersion state even when shaken (irreversible agglomerate formation ), And improvements to reduce this agglomerate formation are also desired.

[0004]

[Means for Solving the Problems] Therefore, as a result of earnest research on means for solving the above problems, by adding a nonionic surfactant and a cellulosic polymer, excellent redispersibility, Moreover, it was found that a fluorometholone suspension type eye drop having almost no aggregate formation can be obtained.
The nonionic surfactant has a function of improving the redispersibility of the drug, but it has been difficult to sufficiently prevent the formation of an aggregate of the drug only by the nonionic surfactant. Therefore, as a result of research on additives that reduce the formation of drug aggregates, it was found that a cellulosic polymer is suitable. The cellulosic polymer intervenes between the drug particles that have been precipitated and concentrated to reduce the frequency of contact between the particles, and by its action, the cohesiveness of the drug is moderated. On the other hand, in the case of blending only the cellulosic polymer, it becomes difficult to remove the air bubbles adhering to the eye drop container and the redispersibility of the drug is lowered. Therefore, the inventors have found that by using this nonionic surfactant and a cellulosic polymer in combination, the disadvantages of both can be compensated and the advantages can be utilized, and the present invention has been completed.

Further, as a result of research on appropriate blending amounts of the nonionic surfactant and the cellulosic polymer, the blending amount of the nonionic surfactant is 0.0001-
0.5% is preferable, more preferably 0.001 to 0.
1%, and the blending amount of the cellulosic polymer is 0.000
1 to 0.003% is preferable, more preferably 0.00
It was found to be 05 to 0.002%. Incidentally, in the present invention, all% are shown by W / V.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION A fluorometholone suspension type eye drop is used for medical treatment at a concentration of 0.02 to 0.1%.
When carrying out the present invention, it is preferable to adjust the concentration, but the concentration is not particularly limited. The suspension type eye drop of the present invention can be produced according to the method for producing a commercially available fluorometholone suspension type eye drop. Examples of the nonionic surfactant used in the present invention include polysorbate 80, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and polyoxyl stearate 40.
And the like, and examples of the cellulosic polymer include hydroxypropylmethylcellulose, methylcellulose, hydroxypropylethylcellulose and the like. In the suspension type eye drop of the present invention, in addition to the above-mentioned essential components, if necessary, an additive commonly used in eye drops, that is, a preservative such as benzalkonium chloride, an isotonic agent such as sodium chloride, etc. Agent,
Stabilizers such as sodium edetate and buffering agents such as sodium hydrogen phosphate can be added. The pH of the eye drop is not particularly limited as long as it is in a range commonly used for eye drops, but is preferably 4 to 8.

[0007]

EXAMPLE Example 1 (Effect test of the invention) Effect of Addition of Hydroxypropyl Methyl Cellulose and Polysorbate 80 on Redispersibility and Cohesion of Fluorometholone Suspension (Part 1) (Preparation of Test Suspension) A suspension having the formulation shown in Table 1 as a test suspension. The agent was prepared.

In order to simplify the explanation, only the essential ingredients for comparing and judging the effect of the present invention are shown in the prescription,
Other additives were benzalkonium chloride, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium chloride, and sodium edetate.

[0009]

[Table 1]

As the hydroxypropylmethyl cellulose, one manufactured by Shin-Etsu Chemical Co., Ltd. was used.

The above test suspension was prepared according to the following method.

First, in the above formulation, a concentrated suspension (1%) containing an excess of fluorometholone was prepared by stirring with a stirrer for about 1 hour, and further with a high-speed rotary stirrer to about 3
Stir for 0 minutes. This concentrated suspension was diluted with a base material (the above formulation minus fluorometholone) so that the concentration of fluorometholone was a predetermined concentration (0.1%).
This liquid was sieved with a metal sieve having an opening of 75 μm to prepare a test suspension.

(Effect Judgment Method) The suspension prepared as described above was filled in a 5 ml eyedrop container, and the container was kept at 5 ° C. (10 bottles) at 40 ° C. (10 bottles) or 60 ° C. (20 bottles) for 2 weeks. After standing and storing, it was left to stand at room temperature for 1 day, and the redispersibility and the formation of aggregates in each formulation were visually inspected.

Also, the storage temperature was changed to 5 ° C. and 40 ° C. every day, and after standing upright for 8 days (displayed as “5 ° C. or 40 ° C. alternate storage”), it was left at room temperature for 1 day (20 pieces) ) Was similarly examined.

The inspection was carried out according to the following method.

The eye drop container was gently rotated, and the number of rotations required until the sedimented layer of the drug under the eye drop container was completely redispersed was counted (index of redispersibility).

The gentle rotation was further continued, and the number of drug aggregates in the dispersed phase at a total of 200 rotations was counted. The drug aggregate refers to a drug aggregate that can be visually observed as a mass.

(Results) The results are shown in Tables 2-5. All the results are represented by the average value of the number of cases shown in the above (effect determination method).

[0019]

[Table 2]

[0020]

[Table 3]

[0021]

[Table 4]

[0022]

[Table 5]

As is clear from the results shown in the above table,
Formulations 1 and 2 of the present invention require significantly less number of revolutions for redispersion and improved agglomerate numbers compared to Control Formulation 1. Further, as compared with Control Formulation 2 in which polysorbate 80, which is a nonionic surfactant, is not added, there is no difference in the number of agglomerates, but the number of revolutions required for redispersion is significantly small, and the nonionic surfactant The compounding effect of polysorbate 80, which is an agent, and hydroxypropylmethylcellulose, which is a cellulosic polymer, is remarkable.

2. Effect of Addition of Hydroxypropyl Methyl Cellulose and Polysorbate 80 on Redispersibility and Cohesion of Fluorometholone Suspension (Part 2) In order to investigate a more appropriate blending range of ingredients to be blended,
An experiment was conducted in the same manner as in the above-mentioned test (No. 1) using the suspending agents having the formulations shown in Tables 6 and 7.

[0025]

[Table 6]

[0026]

[Table 7]

(Results) The results are shown in Tables 8 and 9. All the results are represented by the average value of the number of cases shown in the above (effect determination method).

[0028]

[Table 8]

[0029]

[Table 9]

As is clear from the results shown in Tables 8 and 9, polysorbate 8 which is a nonionic surfactant.
In a formulation in which 0.005% of 0 is blended, hydroxypropylmethylcellulose, which is a cellulosic polymer, is blended within the range of 0.0001% to 0.003%,
The number of rotations required for redispersion is remarkably small, and the number of aggregates is improved. In particular, when hydroxypropylmethyl cellulose is blended within the range of 0.0005% to 0.002%, the number of aggregates is remarkably improved.

3. Effect of Addition of Methyl Cellulose and Polysorbate 80 on Redispersibility and Cohesion of Fluorometholone Suspension (Preparation of Test Suspension Agent) As a test suspension agent, a suspension agent having the formulation shown in Table 10 was prepared. In the formulation, for the sake of simplicity, only the essential components for comparing and determining the effect of the present invention are shown, but other additives include benzalkonium chloride, sodium hydrogen phosphate, and dihydrogen phosphate. Sodium, sodium chloride, and sodium edetate were mixed.

[0032]

[Table 10]

Methyl cellulose used was manufactured by Shin-Etsu Chemical Co., Ltd. The test suspension was prepared and the effect was determined in the same manner as in the test of the above item 1 except for storage conditions. The storage conditions in this test are that the storage temperature is changed to 5 ° C and 50 ° C every day, and it is stored upright for 1 week (displayed as "5 ° C or 50 ° C alternating storage"), then left at room temperature for 1 day (number of cases). 10). (Results) The results are shown in Table 11. All the results are represented by the average value of the number of cases shown above.

[0034]

[Table 11]

As is clear from the results shown in the above table,
Formulations 11 and 12 of the present invention show no difference in the number of revolutions required for redispersion as compared with Control Formulation 1, but the number of aggregates is significantly smaller. In addition, a control formulation 5 containing no polysorbate 80 which is a nonionic surfactant
Compared with, the number of rotations required for re-dispersion is significantly less,
The compounding effect of polysorbate 80, which is a nonionic surfactant, and methylcellulose, which is a cellulosic polymer, is clear.

Example 2 (Formulation Example) According to the preparation method described in Example 1, the following formulation was obtained.
In the following formulation examples, the blending amount of each component is indicated by the content in 1 ml.

[0037] Formulation example 1             Ingredient content     Fluorometholone 1 mg     Hydroxypropyl methylcellulose 0.01mg     Polysorbate 80 0.01mg     Benzalkonium chloride 0.05mg     Sodium edetate 0.1 mg     Sodium hydrogen phosphate 6mg     Sodium dihydrogen phosphate 0.6 mg     Sodium chloride suitable amount     Sterile purified water

In the above formulation, the amount of hydroxypropylmethyl cellulose blended is 0.001, 0.005,
Change to 0.02, 0.05 or 0.1 mg, and change the blending amount of polysorbate 80 to 0.005, 0.02,
The same preparation as in Preparation Example 1 can be obtained by changing the amount to 0.05, 0.1, 0.3 or 0.5 mg.

[0039] Formulation example 2             Ingredient content     Fluorometholone 1 mg     Methylcellulose 0.02mg     Polysorbate 80 0.1 mg     Benzalkonium chloride 0.05mg     Sodium edetate 0.1 mg     Sodium hydrogen phosphate 6mg     Sodium dihydrogen phosphate 0.6 mg     Sodium chloride suitable amount     Sterile purified water

In the above formulation, the compounding amount of methylcellulose was changed to 0.001, 0.005, 0.01, 0.05 or 0.1 mg, and the compounding amount of polysorbate 80 was 0.005, 0.01, The same preparation as in Preparation Example 2 can be obtained by changing the amount to 0.05, 0.3 or 0.5 mg.

[0041]

INDUSTRIAL APPLICABILITY The present invention relates to an improved composition of a suspension type eye drop containing fluorometholone, which is widely used as an anti-inflammatory steroid, as an active ingredient. By blending with a molecule, an improved composition having particularly excellent redispersibility is provided.

─────────────────────────────────────────────────── ─── Continuation of the front page (56) Reference JP-A-11-29463 (JP, A) JP-A-50-83268 (JP, A) JP-A-1-213228 (JP, A) JP-B-31- 9998 (JP, B1) Special Table 9-509166 (JP, A) (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 31/57 A61K 9/00-9/72 A61K 47/00- 47/48 A61P 29/00

Claims (6)

(57) [Claims] 1. A fluorometholone suspension type eye drop comprising 0.0001 to 0.003% of a cellulosic polymer and 0.0001 to 0.5% of a nonionic surfactant as an active ingredient. A suspension-type eye drop characterized in that it enhances the redispersibility of fluorometholone, which is the above, and suppresses the formation of aggregates. 2. The eye drop according to claim 1, wherein the cellulosic polymer is hydroxypropylmethyl cellulose. 3. The eye drop according to claim 1, wherein the cellulosic polymer is methyl cellulose. 4. The eye drop according to claim 1, wherein the nonionic surfactant is polysorbate 80. 5. A fluorometholone suspension-type eye drop comprising 0.0001 to 0.003% of hydroxypropylmethylcellulose and 0.0001 to 0.5% of polysorbate 80, which is used as an active ingredient of fluorometholone. A suspension type eye drop characterized by enhancing redispersibility and suppressing the formation of aggregates. 6. A fluorometholone suspension type eye drop comprising 0.0001 to 0.003% of a cellulosic polymer and 0.0001 to 0.5% of a nonionic surfactant. A method of increasing the redispersibility of fluorometholone as an active ingredient and suppressing the formation of aggregates.