JP2014024794A - Aqueous composition containing timolol or pharmaceutically acceptable salt thereof and photostabilization method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a timolol composition having stable pharmacological activity against light in any of pH, osmotic pressure ratio, content, and characteristics.SOLUTION: An aqueous composition contains timolol or pharmaceutically acceptable salt thereof, and edetic acid salt. The aqueous composition preferably contains boric acid buffer agent. The edetic acid salt is preferably sodium edetate. When the concentration of timolol or pharmaceutically acceptable salt thereof is 1 to 10 mg/mL, and the concentration of sodium edetate is 0.1 to 1.5 mg/mL, the concentration of boric acid is preferably 10 to 25 mg/mL.

Description

The present invention relates to timolol or a pharmaceutically acceptable salt thereof (hereinafter referred to as “timolol” or “timolol maleate” also includes a pharmaceutically acceptable salt thereof). And an aqueous composition containing edetates.
More specifically, the present invention relates to providing an aqueous composition that is stable to light by inhibiting the decomposition of timolol contained in the aqueous composition by light by incorporating edetate salts and a boric acid buffer.

Glaucoma is a disease characterized by increased intraocular pressure. In humans, this increase in intraocular pressure unbalanced the secretion rate of aqueous humor secreted from the ciliated epithelium into the posterior chamber and the drainage resistance of aqueous humor drained from the anterior chamber. As a result. In general, it is considered that the main cause of this imbalance is that the drainage path of the aqueous humor is clogged and its outflow resistance increases.
Typical chronic glaucoma is said to be a very scary disease with a slow but progressively narrowed field of vision and ultimately the risk of blindness.
Drugs administered to treat glaucoma are usually administered to patients over a long period of time, but preservatives, antioxidants, chelating agents, etc. that are usually included in the drugs may cause corneal epithelial disorder depending on long-term use. It has been known that this has been a major problem in the use of glaucoma patients.
Timolol is known to be useful for the treatment of glaucoma, but it is also known to be a drug having pharmacological activity unstable to light.
When an aqueous composition containing a drug such as timolol having pharmacological activity that is unstable to light is used, photolysis is likely to occur, and phenomena specific to photolysis such as turbidity and coloring appear.
In order to stably hold a drug having such unstable pharmacological activity, it is necessary to take a light-shielding means using a packaging material that contains the preparation containing the drug, that is, to shield the container that contains the preparation from light. If you do not use light-shielding means such as supplementary light-shielding bags, wind light-shielding films, etc. to shield light, use colored containers, or apply aluminum wrapping, you must avoid photolysis. It is difficult.

In order to solve these difficulties, various attempts have been made to stabilize light-unstable drugs without taking the above-described light shielding means.
As a method for this, in order to stabilize a medicinal component unstable to light, for example, by adding boric acid and / or borax and a polyhydric alcohol to an ophthalmic solution containing the light unstable component. In order to improve the light stability over a long period of time even if it contains ketotifen or its salt, which is different from light-stabilizing method (Japanese Patent Publication No. 7-23302) and timolol, but unstable to light In addition, there is disclosed a method in which the stability to light is improved by blending ketotifen with an imidazoline compound and an amino acid at a certain ratio (Japanese Patent Laid-Open No. 2004-17570).
With regard to timolol, the only composition (eyedrops) containing (S) -timolol base hemihydrate that eliminates the timolol maleate (ie, the burden of unwanted salts) and is more sensitive to light than timolol. Only a method for increasing the stability (Japanese Patent No. 3094233) is disclosed.
Timolol is generally known as a non-selective β-blocker and has an excellent intraocular pressure lowering action. Therefore, it has been widely used as a standard treatment (eye drops) for all glaucoma. As a therapeutic agent for glaucoma and ocular hypertension, “thymoptol ophthalmic solution” is known.

Japanese Patent Publication No. 7-23302 JP 2004-17570 A Japanese Patent No. 3094233

However, as described above, timolol is extremely unstable with respect to light and easily decomposed, and a sufficient effect has not yet been obtained to keep it stable.
Also in the “thymoptol ophthalmic solution”, as a storage and storage condition, it is determined that light is shielded under storage at room temperature.

Accordingly, the present inventors have focused on solutions to these problems, and formulated an aqueous composition by blending edetate salts and borate buffer in predetermined proportions with timolol having pharmacological activity unstable to light. As a result, it was found that the light stability of the aqueous composition was improved, and the present invention was completed.
Furthermore, the present inventors reduce the risk of damage to the eyes of glaucoma patients when using the aqueous composition as eye drops for treating glaucoma, and cause corneal epithelial disorders when used. As it has been found that even when it does not contain such preservatives, antioxidants, surfactants, etc., it is possible to reduce irritation at the time of instillation by filling a sterile eyedrop container that can ensure sterility even after opening. is there.
The present invention includes an edetate salt in timolol, which is a non-selective β-blocker, and a boric acid buffer added at a predetermined ratio to obtain an aqueous composition. It is characterized by improved stability.

Thus, the aqueous composition according to the first invention for achieving the above object is characterized by containing timolol or a pharmaceutically acceptable salt thereof and edetate salts.
In the said invention, it is preferable to contain a boric acid type buffer.
The edetate is preferably sodium edetate.
Further, the boric acid buffer is preferably boric acid or a salt thereof.
When the concentration of timolol or a pharmaceutically acceptable salt thereof is 1 mg / mL to 10 mg / mL, the concentration of sodium edetate is preferably 0.1 mg / mL to 1.5 mg / mL. Further, when the concentration of timolol or a pharmaceutically acceptable salt thereof is 1 mg / mL to 10 mg / mL, and the concentration of sodium edetate is 0.1 mg / mL to 1.5 mg / mL, the concentration of boric acid is 10 mg / mL. It is preferable that it is mL-25mg / mL.
Moreover, it is preferable that pH is adjusted to 5.0-8.0.
The aqueous composition is preferably an eye drop, an eye wash, a nasal drop or an ear drop.
The aqueous composition is an eye drop, and is filled in a sterile eye drop container that can keep the internal solution in a sterile state even after opening, and does not contain preservatives and surfactants, or the content thereof is corneal. The amount is preferably not more than an amount that does not cause epithelial damage.
In addition, the sterile eye drop container comprises a laminated peeling container formed by laminating an inner layer bag that can be peeled from the outer layer bottle on the inner surface of the outer layer bottle, and a stopper attached to the mouth of the laminated peeling container, The outer layer bottle is provided with a vent hole for introducing outside air between the inner layer bag and the outer layer bottle, and is provided with a discharge path for discharging the internal solution contained inside the inner layer bag, A structure in which a filter and a check valve are provided in the discharge passage is preferable.
Next, in the method for photostabilizing an aqueous composition according to the second invention for achieving the above-mentioned object, timolol or a pharmaceutically acceptable salt thereof and edetates are mixed in the aqueous composition. Is preferred.
In the said invention, it is preferable to mix | blend a boric acid type buffer.
The edetate is preferably sodium edetate.
Further, the boric acid buffer is preferably boric acid or a salt thereof.
When the concentration of timolol or a pharmaceutically acceptable salt thereof in the aqueous composition is 1 mg / mL to 10 mg / mL, the concentration of sodium edetate is preferably 0.1 mg / mL to 1.5 mg / mL. When the concentration of timolol or a pharmaceutically acceptable salt thereof in the aqueous composition is 1 mg / mL to 10 mg / mL, and the concentration of sodium edetate is 0.1 mg / mL to 1.5 mg / mL, boric acid The concentration of is preferably 10 mg / mL to 25 mg / mL.
Moreover, it is preferable that pH is adjusted to 5.0-8.0.

According to the present invention, even if an aqueous composition containing timolol is exposed to light, there is no change in any of pH, osmotic pressure ratio, content, and properties, and a stable aqueous composition can be obtained. The composition can be applied as eye drops, eye wash, nasal drops, ear drops and the like.
In particular, when an eye drop for treating glaucoma containing timolol as an active ingredient can be maintained, the medicinal effect of the timolol can be sustained, so that a highly effective action can be obtained for the treatment of glaucomatous eye diseases.

It is a graph which shows the result of a pH test. It is a graph which shows the result of an osmotic pressure ratio test. It is a graph which shows the result of a content test. It is an expanded sectional view which shows the mouth part structure of a sterile eye drop container. It is a perspective view of the bottle of a sterile eye drop container.

Next, embodiments of the present invention will be described with reference to the drawings. However, the technical scope of the present invention is not limited by these embodiments, and various forms can be made without changing the gist of the invention. Can be implemented. Further, the technical scope of the present invention extends to an equivalent range.
The light-stable aqueous composition obtained by the present invention may contain other medicinal ingredients useful for the treatment of eye diseases such as glaucoma. Examples of the other medicinal ingredients include, but are not limited to, latanoprost, travoprost, bimatoprost, brinzolamide, dorzolamide, Rho kinase inhibitor, bunazosin, brimonidine, abnormal cannabidiol compound, EP4 receptor agonist and the like.
The edetic acid used in the present invention is preferably sodium edetate, and the boric acid buffer is preferably boric acid. Moreover, an organic amine can be mix | blended. The organic amine is preferably trometamol or monoethanolamine.

Thus, the aqueous composition according to the present invention is characterized in that timolol, edetic acids, and boric acid buffer are blended in a predetermined ratio.
At this time, the concentration of timolol is preferably 1 mg / mL to 10 mg / mL, and more preferably 2 mg / mL to 7 mg / mL.
At the concentration of timolol, the concentration of edetic acids is preferably 0.1 mg / mL to 1.5 mg / mL, and more preferably 0.5 mg / mL to 1.3 mg / mL.
Further, when the concentration of timolol and the concentration of edetic acids are used, the concentration of the boric acid buffer is preferably 10 mg / mL to 25 mg / mL, and more preferably 10 mg / mL to 20 mg / mL. preferable.
Furthermore, the concentration when the organic amine is blended is preferably 0.05 mg / mL to 10 mg / mL, more preferably 0.05 mg / mL to 7 mg / mL.
The pH of the aqueous composition of the present invention is not particularly limited as long as it is within a generally acceptable range, but is preferably adjusted to pH 5.0 to 8.0.
To the aqueous composition of the present invention, a pH adjuster, a buffer, a solubilizer, a tonicity agent, a stabilizer and the like may be appropriately added as other additives.

As the pH adjuster, boric acid may be further increased within a range that does not affect the amount of boric acid that is the object of the present invention, and the pH adjustment range cannot be compensated for by the amount of boric acid. In this case, other pH adjusters, for example, borax, hydrochloric acid, sodium hydroxide, potassium hydroxide, phosphoric acid, acetic acid and other acids / bases can be added. These other pH adjusters may be used alone or in combination of two or more.
As the above-mentioned buffering agent, other buffering agents such as borax, phosphate buffering agents (sodium phosphate, sodium hydrogenphosphate, Organic phosphates such as potassium dihydrogen phosphate), citric acid buffers (citric acid, sodium citrate, etc.), acetic acid buffers (acetic acid, sodium acetate, potassium acetate, etc.), monoethanolamine, diethanolamine, trometamol, etc. Etc. can be blended. These buffering agents may be used alone or in combination of two or more.
Examples of the solubilizer include propylene glycol and polyethylene glycol. These solubilizers may be used alone or in combination of two or more.

Examples of isotonic agents include glycerin, sorbitol, propylene glycol, polyethylene glycol, D-mannitol and the like. These tonicity agents may be used alone or in combination of two or more.
Examples of the stabilizer include sodium edetate and citric acid.
According to the present invention, not only stably maintaining an aqueous composition containing timolol which is unstable to light, but also benzalkonium chloride, benzethonium chloride, etc., which have been added for the purpose of solubilizing agents and preservatives. do not need.
As described above, benzalkonium chloride, benzethonium chloride, and the like cause corneal epithelial damage and are therefore not preferable to be added. Even if it is a case where it mix | blends, the content shall be below the quantity which does not generate | occur | produce a corneal epithelial disorder.
Furthermore, when the aqueous composition of the present invention is used as an eye drop for glaucoma treatment (in this case, other medicinal ingredients useful for the treatment of eye diseases such as glaucoma may be added), it is in a sterile state even after opening. It is desirable to use it as an eye drop filled in a sterile eye drop container capable of ensuring the above.

By adopting such a configuration, a prescription (preparation) of a corneal epithelial disorder-preserving agent that is usually blended becomes possible. Corneal epithelial disorder preservatives are formulated to prevent bacteria and fungi from contaminating the liquid medicine in the eye drop container when the eye drop container nozzle comes into contact with the eyeball or tears during patient use. Say. For example, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, benzyl alcohol, phenylethyl alcohol, paraoxybenzoic acid esters and the like.
As the sterile eye drop container, one having a structure as described in the following patent document previously proposed by the present applicants is desirable. As such, for example, a PF container (a delamination container; a container developed by the applicant and used in the ophthalmic field) can be used. Japanese Unexamined Patent Application Publication No. 2009-291326 (Title of Invention: Discharge Container with Filter) discloses the structure of a PF container.
The aseptic ophthalmic container is formed by laminating and forming an outer layer bottle having a mouth portion provided at the upper end of a squeezed low and low barrel body through a shoulder, and detachable from the outer layer bottle on the inner surface of the outer layer bottle. An inner layer bag, wherein the outer layer bottle is provided with an introduction hole for introducing outside air between the outer layer bottle and the inner layer bag, wherein the mouth portion is attached to the mouth portion. The stopper includes a discharge passage for discharging the internal solution contained in the bottle body, a filter disposed in the discharge passage, and a check valve. The filter is a discharge container with a filter disposed on the discharge downstream side of the check valve.
The discharge container with a filter is further provided between the check valve and the filter with a reservoir for storing the internal solution that has permeated the closed check valve, and between the check valve and the filter. The spacer further includes a spacer, and the spacer holds the check valve and the filter at a predetermined interval, and the storage portion is provided in the spacer.

Here, it is preferable to use a filter having pores (for example, 0.2 μm or less) through which bacteria (bacterial width: 0.2 to 10 μm) cannot pass.
Further, as a feature of the sterile eye drop container, when the inner solution is discharged at the time of instillation, the volume of the inner solution remaining in the container is reduced by the discharge area, and the peelable inner layer bag of the laminated peel bottle becomes the outer layer bottle. Since it peels more and shrinks according to the volume change, there is no inhalation of air coming into contact with the internal solution from the discharge path, so that bacteria and fungi mixed in the outside air can be prevented from entering the container.
As a result, the formulation of benzalkonium chloride or benzethonium chloride, which has been added for the purpose of solubilizing agents and preservatives, is not required at all, and the light-shielding bag is shielded to shield the eye drop container. It is not necessary to provide a light shielding means such as using a light-shielding film or the like to wind light, or using a colored container or aluminum packaging.
<Test example>

In order to confirm the effect of the present invention, the test conducted with the comparative example and the results thereof will be described.
Timolol 0.25% ophthalmic solution and timolol 0.5% ophthalmic solution of the following formulation were respectively prescribed. In Example 1, in timolol 0.25% ophthalmic solution, 3.42 mg of timolol maleic acid was mixed with 18.5 mg of boric acid and 1.0 mg of monoethanolamine, and sodium edetate was not added.
In Example 2, timolol 0.25% ophthalmic solution was mixed with 3.42 mg of timolol maleic acid, 18.5 mg of boric acid, 1.0 mg of sodium edetate, and 1.1 mg of monoethanolamine.
In Example 3, in timolol 0.5% ophthalmic solution, 6.84 mg of timolol maleic acid was mixed with 17.0 mg of boric acid and 1.3 mg of monoethanolamine, and sodium edetate was not added.
In Example 4, timolol 0.5% ophthalmic solution was mixed with 6.84 mg of timolol maleic acid, 16.0 mg of boric acid, 1.0 mg of sodium edetate, and 1.3 mg of monoethanolamine.
In each of Examples 1 to 4, each formulation was aseptically dust-free (0.22 μm) and filled in 5 ml each in a PF container. As control drugs, 0.25% tymoptol ophthalmic solution was selected as Comparative Example 1 of the original product, and 0.5% ophthalmic solution Tymoptol (manufactured by MSD Corporation) was selected as Comparative Example 2. In Comparative Examples 1 and 2 of the control drug, benzalkonium chloride, sodium dihydrogen phosphate, sodium hydrogen phosphate hydrate, and sodium hydroxide are blended as additives.
In addition, the display of the timolol maleate of the comparative example 1 and the comparative example 2 is a thing in 1 mL (refer Table 1).

Next, each ophthalmic solution was fixed in a flat plate shape, and illumination was installed on the top. The PF container was placed on its side and fixed so that the long diameter portion (thin portion) was in the horizontal direction and the short diameter portion (thick portion) was in the vertical direction. The control drug was removed from the shrink label, placed on its side and fixed.
Note that a D65 fluorescent lamp was used for illumination, the illuminance was measured with an illuminometer, and sampling was performed at the measurement timing shown below.
The number of sampled samples was n = 3, and the following measurement items were performed.

<Test items and test methods>
The measurement items were property, pH, osmotic pressure ratio, and content, and each was tested. The test method was performed in accordance with JP, General Rules and General Formulations for properties, pH and osmotic pressure ratio, and the content was measured by HPLC.
Measurement time: 300,000, 600,000, 1.2 million Lux · hr at the start of storage
With respect to the original control drug (Comparative Example 1 and Comparative Example 2), measurement was performed only at 1.2 million Lux · hr at the start of storage.
<Property test>
The test was conducted according to JP, General Rules, and General Rules for Preparations.
The test results are shown in Table 2.

From the results of the above property tests, no changes in properties were observed in Example 1, Example 2, Example 3, and Example 4 with 300,000 Lux · hr irradiation and 600,000 Lux · hr irradiation. When hr, as shown in Table 2, some changes were observed in Example 4 (slightly yellow clear), Comparative Example 1 (very slightly yellow clear) and Comparative Example 2 (light yellow clear).
<PH test>
The test was conducted according to JP, General Rules, and General Rules for Preparations.
The test results are shown in Table 3 and FIG.
From the results of the pH test, the pH in Example 2 and Example 4 slightly increases, but is within a range that does not affect eye irritation. In Example 1 and Example 3, there was no change in pH.

<Osmotic pressure ratio test>
The test was conducted according to JP, General Rules, and General Rules for Preparations.
The test results are shown in Table 4 and FIG.
From the results of the osmotic pressure ratio measurement test, no changes were observed in Example 1, Example 2, Example 3, Example 4, Comparative Example 1, and Comparative Example 2.

<Content test>
The test was performed by HPLC.
The test results are shown in Table 5 and FIG.
As can be seen from the results of the content test, about 20% decrease in content was observed in Example 1 and Example 3 where sodium edetate was not blended, but about 5% in Example 2 blended with sodium edetate, In Example 4, the content was reduced by about 10%, which was a better result than the group not containing sodium edetate.
In Comparative Examples 1 and 2, a content reduction of 50% or more was observed.
From the above results, in each of the formulations of Example 1, Example 2, Example 3, and Example 4, a result that was more stable to light than Comparative Example 1 and Comparative Example 2 was obtained. Also, in Example 1 and Example 2, Example 2 containing sodium edetate gave a more stable result, and in Example 3 and Example 4, Example 4 containing sodium edetate was better. Stable results were obtained. Although not shown in the results, trometamol was blended in place of monoethanolamine, but similar results were obtained.
From the above results, sodium edetate improved the light stability of timolol under light irradiation by D65 fluorescent lamp.

Thus, according to the present embodiment, even when the aqueous composition containing timolol is exposed to light, there is no change in any of pH, osmotic pressure ratio, content and property, and a stable aqueous composition can be obtained. did it. The aqueous composition could be applied as eye drops, eye washes, nasal drops, ear drops and the like.
In particular, when an eye drop for treating glaucoma containing timolol as an active ingredient is used, the medicinal effect of the timolol can be maintained, so that a highly effective action can be obtained for the treatment of glaucomatous eye diseases.

<Aseptic eye drop container>
Next, the structure of a sterile eye drop container filled with an aqueous composition containing timolol will be briefly described with reference to FIGS. 4 and 5. A detailed configuration is disclosed in Japanese Patent Application Laid-Open No. 2009-291326.
The sterile eye drop container 10 is peelable from the outer layer bottle 1 on the inner surface of the outer layer bottle 1 having the mouth portion 11a provided on the upper end of the squeezed low and low barrel portion 11b through the shoulder. In the delamination bottle 11 in which the outer layer bottle 1 is provided with an introduction hole 17 for introducing outside air between the outer layer bottle 1 and the inner layer bag 2. The mouth portion 11a includes a stopper body 12 attached to the mouth portion 11a, and the stopper body 12 has a discharge passage for discharging the internal solution contained in the bottle body portion and the discharge body. A filter 25 and a check valve 23 disposed in the middle of the path are provided, and the filter 25 is a discharge container with a filter disposed on the discharge downstream side of the check valve 23.
The discharge container with a filter is further provided between the check valve 23 and the filter 25 with a reservoir 14 for storing the internal solution that has permeated the closed check valve 23, The spacer 24 is further provided between the filter 25, the spacer 24 holds the check valve 23 and the filter 25 at a predetermined interval, and the storage portion 14 is provided in the spacer 24.
By using such a sterile eye drop container 10, the aqueous composition containing timolol of the present invention can be used satisfactorily.

Claims (17)

  An aqueous composition comprising timolol or a pharmaceutically acceptable salt thereof and edetate salts.   The aqueous composition according to claim 1, comprising a boric acid buffer.   The aqueous composition according to claim 1 or 2, wherein the edetate is sodium edetate.   The aqueous composition according to any one of claims 1 to 3, wherein the boric acid buffer is boric acid or a salt thereof.   The concentration of sodium edetate is 0.1 mg / mL to 1.5 mg / mL when the concentration of timolol or a pharmaceutically acceptable salt thereof is 1 mg / mL to 10 mg / mL. An aqueous composition as described in 1.   When the concentration of timolol or a pharmaceutically acceptable salt thereof is 1 mg / mL to 10 mg / mL, and the concentration of sodium edetate is 0.1 mg / mL to 1.5 mg / mL, the concentration of boric acid is 10 mg / mL to The aqueous composition according to any one of claims 1 to 5, which is 25 mg / mL.   pH is adjusted to 5.0-8.0, The aqueous composition as described in any one of Claims 1-6 characterized by the above-mentioned.   The aqueous composition according to any one of claims 1 to 7, which is an eye drop, an eye wash, a nasal drop or an ear drop.   A method for photostabilizing an aqueous composition comprising mixing timolol or a pharmaceutically acceptable salt thereof and edetate in an aqueous composition.   The light stabilization method according to claim 9, further comprising a boric acid buffer.   The light stabilization method according to claim 9 or 10, wherein the edetate is sodium edetate.   The light stabilization method according to claim 9, wherein the boric acid buffer is boric acid or a salt thereof.   The concentration of sodium edetate is 0.1 mg / mL to 1.5 mg / mL when the concentration of timolol or a pharmaceutically acceptable salt thereof in the aqueous composition is 1 mg / mL to 10 mg / mL. 13. The method for light stabilization of the aqueous composition according to any one of 12 above.   The concentration of boric acid when the concentration of timolol or a pharmaceutically acceptable salt thereof in the aqueous composition is 1 mg / mL to 10 mg / mL and the concentration of sodium edetate is 0.1 mg / mL to 1.5 mg / mL The method of photostabilizing the aqueous composition according to any one of claims 9 to 13, wherein is 10 mg / mL to 25 mg / mL.   pH is adjusted to 5.0-8.0, The light stabilization method as described in any one of Claims 9-14 characterized by the above-mentioned.   The aqueous composition is an eye drop, and is filled in a sterile eye drop container that can keep the internal solution in a sterile state even after opening, and does not contain preservatives and surfactants, or the content thereof is corneal. The eye drop according to claim 8, wherein the amount is not more than an amount that does not cause epithelial damage.   The aseptic eye drop container comprises a delamination container formed by laminating an inner layer bag that can be delaminated from the outer layer bottle on the inner surface of the outer layer bottle, and a stopper attached to the mouth of the delamination container. The bottle is provided with a vent hole for introducing outside air between the inner layer bag and the outer layer bottle, and is provided with a discharge path for discharging the inner solution agent contained in the inner layer bag. The ophthalmic solution according to claim 16, wherein a filter and a check valve are provided on the road.