TW202224686A - Ophthalmic solution of tafluprost - Google Patents

Abstract

There is provided with a novel ophthalmic solution of tafluprost. The ophthalmic solution contains tafluprost and a biguanide or alcohol antiseptic agent.

Description

Tafluprost eye drops

The present invention relates to a kind of tafluprost eye drops.

Tafluprostaglandin (16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-quaternary (tetranor) prostaglandin F2α) is a derivative of prostaglandin F2α, with eye drops Morphology is used to treat glaucoma. Patent Document 1 proposes to add ethylenediaminetetraacetic acid or dibutylhydroxytoluene to eye drops in order to suppress decomposition of tafluprost during storage. Patent Document 1 further proposes adding polysorbate 80 or polyoxyethylene hardened castor oil 60 to eye drops in order to suppress adsorption of tafluprost to a resin container. In addition, Non-Patent Document 1 discloses a Tapros (registered trademark) eye drop containing polysorbate 80, EDTA and benzalkonium chloride in addition to tafluprost, and a Tapros (registered trademark) trademark) Mini Eye Drops, which are disposable formulations that do not contain benzalkonium chloride. [Prior Art Literature] [Patent Literature]

[Patent Document 1] Japanese Patent Laid-Open No. 2002-161037 [Non-patent literature]

[Non-patent document 1] Tapros (registered trademark) eye drops 0.0015% and Tapros (registered trademark) mini eye drops 0.0015% are imitations [Non-patent document 2] European Union Risk Assessment Report, tetrasodium ethylenediaminetetraacetate (Na ₄ EDTA), 1st Priority List, Volume 51

[The problem to be solved by the invention]

As mentioned above, tafluprost eye drops have a problem that they are easily decomposed during storage, and Patent Document 1 and Non-Patent Document 1 improve the stability by adding EDTA. However, EDTA is irritating. For example, Non-Patent Document 2 reports a case in which eye drops containing EDTA showed sensitization to the eyes. Therefore, it is desirable to reduce the content of EDTA in tafluprost eye drops. [Means of Solving Problems]

As a result of intensive research, the inventors of the present invention unexpectedly found that by selecting appropriate preservatives or surfactants, the practical preservation of tafluprost can be obtained even if the content of EDTA is reduced, and the present invention was completed.

The eye drops according to one embodiment of the present invention contain tafluprost and a biguanide-based or alcohol-based preservative. [Effect of invention]

This is to provide a new type of eye drops of tafluprost that can obtain practical preservation although the content of EDTA is reduced.

[Form of implementing the invention]

Embodiments will be described in detail below. In addition, the following embodiments are not inventions that limit the scope of the claims, and all combinations of the features described in the embodiments are not essential to the invention. Two or more of the features described in the embodiments can be combined arbitrarily.

The eye drops according to one embodiment of the present invention contain tafluprost and a biguanide-based or alcohol-based preservative.

The content of tafluprost in the eye drops can be appropriately selected according to the use of the eye drops. For example, the content of tafluprost in eye drops may be more than 0.01 mg/mL, and may also be less than 0.1 mg/mL, less than 0.05 mg/mL, or less than 0.02 mg/mL.

Biguanide-based or alcohol-based preservatives can inhibit the growth of microorganisms in eye drops. In addition, by using biguanide-based or alcohol-based preservatives instead of benzalkonium chloride, which is commonly used as a preservative, the reduction in the content of tafluprost in eye drops can be suppressed. That is, when benzalkonium chloride is used as a preservative without adding EDTA, the content of tafluprost in the eye drops is greatly reduced. On the other hand, even when ethylenediaminetetraacetic acid is not added, by using a biguanide-based or alcohol-based preservative instead, it is possible to significantly suppress a decrease in the content rate. Therefore, biguanide-based or alcohol-based preservatives are suitable as preservatives for tafluprost-containing eye drops.

In one embodiment, the biguanide-based or alcohol-based preservative can be added to eye drops to suppress the decrease in the tafluprost content with time. The effect of suppressing the decrease in the content of tafluprost caused by biguanide-based or alcohol-based preservatives can also be confirmed when EDTA is added, but the amount of EDTA added is reduced or EDTA is not added. It is more pronounced with tetraacetic acid.

Biguanide preservatives refer to preservatives with biguanide skeleton (N-C(=N)-N-C(=N)-N). Examples of biguanide-based preservatives include polyhexamethylene (polyhexamethylene biguanide) and chlorhexidine.

Alcohol-based preservatives refer to preservatives with hydroxyl groups. Examples of alcohol-based antiseptics include chlorobutanol, methylparaben, propylparaben, and the like.

The content of the preservative in the eye drops can be appropriately selected according to the required preservative properties of the eye drops. For example, when polyhexamide is used as a preservative, the content of polyhexamide may be 0.001 mg/mL or more or 0.0025 mg/mL or more, and may be 0.05 mg/mL or less or 0.02 mg/mL or less. When chlorhexidine is used as a preservative, the content of chlorhexidine may be 0.002 mg/mL or more or 0.005 mg/mL or more, and may also be 0.5 mg/mL or less or 0.2 mg/mL or less. In addition, when chlorobutanol is used as a preservative, the content of chlorobutanol may be 1.0 mg/mL or more or 2.5 mg/mL or more, and may be 25 mg/mL or less or 10 mg/mL or less.

In addition, eye drops can also contain two or more kinds of preservatives. On the other hand, the eye drops of one embodiment contain substantially no or no benzalkonium chloride in order to suppress a decrease in the content rate of tafluprost.

The solvent of the eye drops is not particularly limited, and water is generally used. The pH of the eye drops is not particularly limited as long as it can be instilled into the eyes, and may be, for example, 4 or more or 6 or more, or 8 or less or 7.5 or less.

The eye drops of one embodiment of the present invention may further contain a surfactant. Surfactants increase the solubility of tafluprost in eye drops. The type of the surfactant is not particularly limited, and as the surfactant, for example, a nonionic surfactant can be used. Examples of the nonionic surfactant include polyoxyethylene hardened castor oil, polyoxyethylene monostearate, polysorbate, polyoxyethylene polyoxypropylene glycol, and sucrose fatty acid ester.

In one embodiment, by adding polyoxyethylene hardened castor oil or polyoxyethylene monostearate as a surfactant to the eye drops, the decrease in the content of tafluprost can be suppressed over time. . Therefore, polyoxyethylene hardened castor oil or polyoxyethylene glycol monostearate are suitable as surfactants for eye drops containing tafluprost. In particular, by using biguanide-based or alcohol-based preservatives, and further using polyoxyethylene hardened castor oil or monostearic acid polyoxyethylene glycol as surfactants, even if EDTA is not added, it can still be significantly inhibited. The content rate of tafluprost decreased.

Polyoxyethylene hardened castor oil can use polyoxyethylene hardened castor oil 10, polyoxyethylene hardened castor oil 20, polyoxyethylene hardened castor oil 40, polyoxyethylene hardened castor oil 60, polyoxyethylene hardened castor oil 80 or polyoxyethylene hardened castor oil Vinyl Hardened Castor Oil 100 etc. Monostearic acid polyoxyethylene glycol can use monostearic acid polyoxyethylene glycol (25), monostearic acid polyoxyethylene glycol (40) or monostearic acid polyoxyethylene glycol (100), etc. .

The content of the surfactant in the eye drops can be appropriately selected according to the concentration of tafluprost. In addition, when polyoxyethylene hardened castor oil or polyoxyethylene monostearate is used as the surfactant, its content can be appropriately selected according to the stability of the required eye drops. For example, the content of polyoxyethylene hardened castor oil or polyoxyethylene monostearate may be 0.1 mg/mL or more or 0.25 mg/mL or more, and may be 25 mg/mL or less or 10 mg/mL or less. In one embodiment, by increasing the addition amount of polyoxyethylene hardened castor oil or polyoxyethylene glycol monostearate, the decrease in the content of tafluprost can be suppressed more strongly. From this viewpoint, the content of polyoxyethylene hardened castor oil or polyoxyethylene glycol monostearate may be 1.0 mg/mL or more, 2.5 mg/mL or more, or 5.0 mg/mL or more. Eye drops may contain two or more surfactants.

In addition, the eye drops may also contain two or more surfactants. On the other hand, the eye drops of one embodiment contain substantially no or no polysorbate in order to suppress a decrease in the content rate of tafluprost.

The eye drops may further contain additives. Examples of additives include stabilizers, isotonic agents, buffers, pH adjusters, thickeners, and the like.

Examples of the stabilizer include ascorbic acid, tocopherol, dibutylhydroxytoluene, polyvinylpyrrolidone, and the like. On the other hand, in one embodiment, the content of EDTA in the eye drops is reduced. For example, in one embodiment, from the viewpoint of reducing the irritation of the eye drops, the concentration of EDTA in the eye drops may be less than 0.5 mg/mL, less than 0.3 mg/mL or less than 0.15 mg/mL. The potion may be substantially free or completely free of EDTA.

Examples of the isotonic agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glycerin, propylene glycol, polyethylene glycol, glucose, sorbitol, mannitol, trehalose, maltose, and sucrose.

Examples of the buffer include phosphates, citrates, acetates, carbonates, tartrates, borates, tris, and the like.

Examples of pH adjusters include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.

Examples of thickeners include carboxyvinyl polymers, polyvinyl alcohol, hydroxyethyl cellulose, hypromellose, methyl cellulose, and glycerin.

The eye drops of one embodiment can be accommodated in a container. The type of container is not particularly limited, and may be a glass container or a resin-made container. The material of the resin-made container may be, for example, polyethylene, polypropylene, polyethylene terephthalate, or cyclic polyolefin.

The manufacturing method of the eye drops is not particularly limited. For example, eye drops can be produced by dissolving tafluprost, biguanide-based or alcohol-based preservatives and other additives as required in purified water.

The eye drops of another embodiment of the present invention contain tafluprost and polyoxyethylene hardened castor oil or polyoxyethylene monostearate. That is, by using polyoxyethylene hardened castor oil or polyoxyethylene glycol monostearate in place of polysorbate, which is commonly used as a surfactant, the reduction in the content of tafluoroprostaglandin in eye drops can be suppressed. For example, when polysorbate is used as a surfactant without adding ethylenediaminetetraacetic acid, the content of tafluprost in eye drops is greatly reduced. On the other hand, even when ethylenediaminetetraacetic acid is not added, by using polyoxyethylene hardened castor oil or monostearic acid polyoxyethylene glycol as a surfactant instead, it is possible to significantly suppress a decrease in the content rate. Therefore, polyoxyethylene hardened castor oil or polyoxyethylene glycol monostearate are suitable as surfactants for eye drops containing tafluprost.

In one embodiment, by adding polyoxyethylene hardened castor oil or polyoxyethylene glycol monostearate to the eye drops, the decrease in the content of tafluprost can be suppressed over time. The effect of suppressing the decrease in the content of tafluprost caused by polyoxyethylene hardened castor oil or polyoxyethylene monostearate can also be confirmed when EDTA is added, but the effect of EDTA It is more pronounced when the addition amount is reduced or no EDTA is added.

At this time, the addition amount of polyoxyethylene hardened castor oil and polyoxyethylene glycol monostearate can be set to be the same as the above-mentioned embodiment. The eye drops may further contain the above-mentioned biguanide-based or alcohol-based preservatives or other preservatives such as benzalkonium chloride. In addition, the eye drops are as described above, and may contain other additives, and the content of EDTA may also be reduced. That is, from the viewpoint of reducing the irritation of eye drops, the concentration of EDTA in eye drops may be less than 0.5 mg/mL, less than 0.3 mg/mL, or less than 0.15 mg/mL, and eye drops may be substantially less than 0.15 mg/mL. Contains no or no EDTA at all.

The eye drops of another embodiment of the present invention contain tafluprost, polyhexanamide and polyoxyethylene hardened castor oil. Polyhexanamide and polyoxyethylene hardened castor oil each have the effect of suppressing the decrease in the content of tafluprost, and the combined use of these can significantly suppress the decrease in the content of tafluprost. The eye drops are as described above, and can further contain other additives, and the content of EDTA can also be reduced.

The eye drop of one embodiment is an agent for reducing the content rate of tafluprost and anti-tafluprost. Here, as the agent for reducing the content rate of tafluprost, a biguanide-based or alcohol-based antiseptic, polyoxyethylene hardened castor oil, or polyoxyethylene monostearate can be used. In addition, as the agent for reducing the content rate of tafluprost, polycaprolactam, chlorhexidine, or chlorobutanol can be used. By adding such an agent for reducing the content rate of tafluprost, it is possible to suppress the decrease in the content rate of tafluprost in eye drops containing tafluprost over time compared with the case where it is not added. The eye drops are as described above, and can further contain other additives, and the content of EDTA can also be reduced.

In one embodiment, the agent for reducing the content rate of tafluprost can reduce the content rate of tafluprost after the eye drops containing tafluprost is stored at 40° C. for 1 month, and the content rate without tafluprost Compared with the preventive agent, the increase is more than 10%, more than 20%, more than 30% or more than 50%.

In addition, the content rate of tafluprost after storing the eye drops of the above-mentioned embodiments at 40°C for 1 month may be 80% or more, 90% or more, 95% or more, 97% or more, 98% or more, or 99%. above. Furthermore, the content of tafluprost after storing the eye drops of the above-mentioned embodiments at 40°C for 3 months may be 80% or more, 90% or more, 95% or more, 97% or more, 98% or more, or 99% or more. %above. Furthermore, the content of tafluprost after storing the eye drops of the above embodiments at 60° C. for 4 weeks may be 80% or more, 90% or more, 95% or more, 98% or more, or 99% or more.

Furthermore, one embodiment of the present invention relates to a method for suppressing a decrease in the content rate of tafluprost in eye drops containing tafluprost. The method may include adding a biguanide-based or alcohol-based preservative, polyoxyethylene hardened castor oil, or polyoxyethylene glycol monostearate to the tafluprost-containing eye drops. Also, the method can also include adding polycaprolactam, chlorhexidine, or chlorobutanol to the tafluprost-containing eye drops. As mentioned above, the eye drops may further contain other additives, and the content of EDTA in the eye drops may also be reduced. In one embodiment, by adding these additives to the eye drops containing tafluprost, compared with the case without adding, the content of tafluprost after being stored at 40°C for 1 month can be improved. The rate increased by more than 10%, more than 20%, more than 30% or more than 50%. [Example]

(Example 1) Tafluprost (3mg), polysorbate 80 (100mg), sodium dihydrogen phosphate hydrate (400mg), and 20% polyhexamethylene hydrochloride solution (2mg) were dissolved in purified water, and hydrochloric acid (or hydrochloric acid) was added. Sodium) to adjust the pH to 6.0, and prepare 200 mL of eye drops.

Next, the stability test of the obtained eye drops was performed. Specifically, 9 mL of the obtained eye drops were filled in a 9 mL glass container (3 mL of eye drops were filled in a 5 mL polyethylene container in Table 5), and stored at 40°C (accelerated test) for 1 month (and some implementations). e.g. 3 months). Then, tafluprost was quantified by high performance liquid chromatography, and the residual rate of tafluprost was measured.

(Examples 2 to 16) Eye drops of the compositions shown in Tables 1 to 5 were prepared in the same manner as in Example 1. Moreover, the stability test of the obtained eye drops was carried out in the same manner as in Example 1.

(Comparative Examples 1 to 4) Eye drops having compositions shown in Tables 1, 2, and 5 were prepared in the same manner as in Example 1. Moreover, the stability test of the obtained eye drops was carried out in the same manner as in Example 1.

Table 1 shows the composition and stability test results of the eye drops obtained in Comparative Examples 1-3 and Examples 1-6.

From Comparative Examples 1 to 3, as in Non-Patent Document 1, when benzalkonium chloride (preservative) and polysorbate 80 (surfactant) are used in combination, ethylenediamine needs to be added in order to prevent the decomposition of tafluprost. Tetraacetic acid; the stability of tafluprost is significantly reduced if EDTA is not added.

On the other hand, from the comparison between Comparative Example 3 and Example 1, it can be seen that the stability of tafluprost remains stable even if EDTA is not added by using polyhexamethylene amide instead of benzalkonium chloride as a preservative. Greatly improved.

On the other hand, from the comparison between Comparative Example 3 and Example 2, it can be seen that the polyoxyethylene hardened castor oil is used as a surfactant to replace the sorbitol ester, and the stability of tafluprost is stable even when EDTA is not added. Sex can still be greatly improved.

As mentioned above, it is confirmed that the stability of tafluprost can be improved in Example 3 using polyhexamethylene amide and polyoxyethylene hardened castor oil, and higher stability can be obtained than Examples 1 and 2 using each of them alone. . In addition, in Comparative Examples 1 and 2, even if the addition amount of polysorbate was increased, the stability could not be improved; and in Examples 3 and 4, it was confirmed that by increasing the addition amount of polyoxyethylene hardened castor oil, further improvement could be achieved. Stability of tafluprost. As in Examples 3 and 4, the stability of using polyhexamethylene amide and polyoxyethylene hardened castor oil in combination is improved compared to the stability of using ethylenediaminetetraacetic acid in Comparative Examples 1 and 2.

In addition, the stability when polyhexanamide and polyoxyethylene hardened castor oil are used in combination as in Examples 3 and 4 are the same as or higher than the stability when ethylenediaminetetraacetic acid is further added, as in Examples 5 and 6. That is, the stability obtained when combining polyhexanamide and polyoxyethylene hardened castor oil was increased to such an extent that no clear improvement was seen with further addition of ethylenediaminetetraacetic acid.

These results show that polyhexanamide and polyoxyethylene hardened castor oil, respectively, have a high effect of enhancing the stability of tafluprost. In addition, these results show that when these additives are used, even if the addition amount of EDTA is reduced, tafluprost eye drops with practical stability can be obtained.

Table 2 shows the accelerated test at 40°C for 3 months for the eye drops obtained in Comparative Example 1 and Examples 3 to 6, which was conducted to investigate the stabilization effects of polyhexamide and polyoxyethylene hardened castor oil in more detail. the result of.

Table 2 more clearly shows that the combination of polyhexamethylene amide and polyoxyethylene hardened castor oil as in Examples 3 and 4, compared with the use of ethylenediaminetetraacetic acid as in Comparative Example 1, the stability is more obviously improved. In addition, Table 2 more clearly shows that the stability of the combination of polyhexamethylene amide and polyoxyethylene hardened castor oil as in Examples 3 and 4 is higher than that when EDTA is further added as in Examples 5 and 6. . In particular, it was confirmed that a high residual rate of tafluprostaglandin of more than 99% can be achieved by combining polyhexamethylene and polyoxyethylene hardened castor oil.

Table 3 shows the composition and stability test results of the eye drops obtained by using various surfactants in Examples 1, 3, 4, 7 to 10.

As shown in Table 3, when various polyoxyethylene monostearate and polyoxyethylene hardened castor oil were used, it was confirmed that the residual rate of tafluprost was higher than when polysorbate was used.

Table 4 shows the composition and stability test results of the eye drops obtained by using various preservatives in Examples 2 to 3 and 11 to 14.

As shown in Table 4, when polycaprolactam, chlorhexidine, and chlorobutanol were used, it was confirmed that the residual rate of tafluprost was higher than when benzalkonium chloride was used.

Table 5 shows the composition of the eye drops obtained in Comparative Example 4 and Examples 4, 6, 15, and 16 and the results of the stability test when a polyethylene container was used for the container.

As shown in Table 5, when a polyethylene container was used for the container, the same tendency was observed as when a glass container was used. That is, from the comparison between Comparative Example 4 and Example 15, it can be seen that the stability of tafluprost can be greatly improved even if EDTA is not added by using polyhexamethylene chloride as a preservative instead of benzalkonium chloride. improve. In addition, from the comparison between Comparative Example 4 and Example 16, it can be seen that the stability of tafluprost remains unchanged even when EDTA is not added by using polyoxyethylene hardened castor oil instead of polysorbate through the surfactant. can be greatly improved.

Furthermore, in Example 4 in which polyhexanamide and polyoxyethylene hardened castor oil were used in combination, the stability was further improved than in Examples 15 and 16 in which each was used alone. In addition, the stability when combining polyhexanamide and polyoxyethylene hardened castor oil as in Example 4 was the same as in Example 6, and was equal to or higher than that when ethylenediaminetetraacetic acid was further added.

These results show that, regardless of the container, polyhexanamide and polyoxyethylene hardened castor oil, respectively, have a high effect of enhancing the stability of tafluprost. In addition, these results show that, regardless of the container, when these additives are used, even if the addition amount of EDTA is reduced, tafluprost eye drops with practical stability can be obtained.

The present invention is not limited to the above-described embodiments, and various modifications and changes can be implemented within the scope of the gist of the invention.

Claims (10)

An eye drop contains tafluprost and biguanide preservatives or chlorobutanol. As claimed in claim 1, the eye drops contain polycaprolactam or chlorhexidine as the aforementioned preservative. The eye drops according to claim 1, wherein the preservative is polyhexamethylene, and the concentration of the preservative is 0.001 mg/mL or more and 0.05 mg/mL or less. The eye drops according to any one of claims 1 to 3, further comprising polyoxyethylene hardened castor oil or polyoxyethylene monostearate. The eye drops according to any one of claims 1 to 3, which further contain polyoxyethylene hardened castor oil of not less than 0.1 mg/mL and not more than 25 mg/mL. The eye drops according to any one of claims 1 to 3, wherein the concentration of tafluprost is 0.01 mg/mL or more and 0.1 mg/mL or less. An eye drop, wherein, It contains tafluprost, polyoxyethylene hardened castor oil or polyoxyethylene monostearate and preservatives, It does not contain EDTA, or further contains EDTA in a concentration of less than 0.5 mg/mL. An eye drop, which contains tafluprost, polyhexanamide and polyoxyethylene hardened castor oil. A kind of eye drops, it is the eye drops containing the content rate reducing agent of tafluprost and anti-tafluprost, and it is characterized in that: the aforementioned agent for reducing the content rate of tafluprost is polycaprolactam, chlorine Hexidine, chlorobutanol, polyoxyethylene hardened castor oil or polyoxyethylene monostearate. A method for suppressing the decrease in the content rate of tafluprost in eye drops containing tafluprost, comprising adding a biguanide-based preservative or chlorobutanol, polyoxyethylene hardened castor oil or monostearate Acid polyoxyethylene glycol was added to the aforementioned eye drops.