JPH0723302B2 - Photostabilization method for eye drops and stabilized eye drops - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION TECHNICAL FIELD The present invention provides a method for stabilizing an eye drop solution containing a photolabile drug and the stabilized eye drop solution.

BACKGROUND ART Many pharmaceuticals are unstable to light, and in order to prevent decomposition during use, they are shielded from light or other innovative formulations are used in practical applications.

However, when pharmaceuticals are dissolved in water, they are more susceptible to photodecomposition than solid preparations, resulting in phenomena such as coloration.
In the case of aqueous preparations such as eye drops, it is difficult to solve this problem from the formulation standpoint, and currently light-blocking methods are used. However, complete light blocking is practically difficult, and a method for stabilizing the eye drops themselves through formulation-specific modifications is desired. One major reason that research into light-stabilizing eye drop formulations is not easy is that eye drops are administered to the eye, a highly sensitive organ, and therefore there are limitations on the substances that can be incorporated.

DISCLOSURE OF THE INVENTION The present invention provides a method for stabilizing eye drops against light, characterized by incorporating boric acid and/or borax and a polyhydric alcohol into an eye drop containing a photolabile drug as an ingredient, and the stabilized eye drop.

There are many drugs that are unstable to light, but drugs that have an aromatic ring in their chemical structure that has a hydroxy group, a lower alkoxy group, or a primary or secondary amine as a substituent are generally considered to be unstable to light. Examples of such compounds include bunazosin, prazosin, terazosin, epinephrine, and phenylephrine. The drugs used in the present invention may, of course, be in the form of a pharmaceutically acceptable salt, such as a hydrochloride salt.

The polyhydric alcohol is not particularly limited as long as it is a compound having a plurality of hydroxy groups, and examples thereof include glycerin, polyethylene glycol, propylene glycol, mannitol,
Glucose and the like.

Eye drops containing light-labile drugs are used in practice by shielding them from light, but complete light shielding is practically difficult, and a method for stabilizing the eye drops by modifying the formulation itself is desired. Since eye drops are administered to the eye, a highly sensitive organ, special consideration must be given to the substances to be incorporated. After extensive research into light stabilization methods, the present inventors have found that this problem can be solved by combining boric acid and/or borax, which are recognized as safe additives for eye drops, with a polyhydric alcohol.

Although the detailed mechanism of photostabilization by boric acid and/or borax and polyhydric alcohols has not yet been elucidated, it is presumed that stabilization occurs through the formation of a complex in aqueous solution via boron and polyhydric alcohols. The present invention can be widely applied to drugs capable of forming such complexes, and is not limited to the aforementioned drug groups.

Detailed data will be explained in the stability test section.
For example, bunazosin hydrochloride, which has the effect of lowering intraocular pressure,
The mixture of boric acid and/or borax with polyhydric alcohol did not discolor even when exposed to strong light of 3,000 lux for 200 hours, whereas the mixture of boric acid alone or polyhydric alcohol alone was decomposed by light and discolored.

In this way, it was found that formulations containing only boric acid or only polyhydric alcohols do not have a stabilizing effect against light, but that the use of boric acid and/or borax in combination with polyhydric alcohols increases light stability.

The amount of boric acid or borax used in the present invention is not particularly limited as long as it can exert its effect, and can be determined depending on the type and concentration of the drug, but is preferably 0.5 to 2.5%.The amount of polyhydric alcohol used is also not particularly limited as long as it can exert its effect, and can be determined depending on the type and concentration of the drug, but is preferably 0.1 to 2.0%.

The ophthalmic solution of the present invention may be prepared by a known method, in which boric acid and/or borax and a polyhydric alcohol are added to a solution of a photolabile drug and dissolved therein, and if necessary, an isotonic agent such as sodium chloride or potassium chloride, a stabilizer such as sodium edetate, a preservative such as benzalkonium chloride, a pH adjuster such as sodium hydroxide or dilute hydrochloric acid, etc. may be added.
There are no particular restrictions as long as it is within the range acceptable as a medicine.
A preferable range is 4.5 to 8. Examples are shown below.

"Example" Formulation 1 (in 100ml) Bunazosin hydrochloride 0.1g Boric acid 1.24g Concentrated glycerin 0.3g Benzalkonium chloride 0.005g Sodium hydroxide (as needed) Sterile purified water (as needed) Manufacturing method Add bunazosin hydrochloride, concentrated glycerin, and benzalkonium chloride to 80ml of sterile purified water and dissolve, then adjust the pH to 6.0 with sodium hydroxide. Add sterile purified water to make up to 100ml. Using the same method, the following solutions were prepared:

Formula 2 (in 100ml) pH 6.0 Bunazosin hydrochloride 0.1g Boric acid 1.0g Concentrated glycerin 0.5g Benzalkonium chloride 0.005g Sodium chloride 0.23g Sodium hydroxide Appropriate amount Sterile purified water Appropriate amount Formula 3 (in 100ml) pH 6.0 Bunazosin hydrochloride 0.01g Boric acid 1.24g Mannitol 0.6g Benzalkonium chloride 0.005g Sodium hydroxide Appropriate amount Sterile purified water Appropriate amount Formula 4 (in 100ml) pH 6.0 Bunazosin hydrochloride 0.1g Boric acid 1.4g Mannitol 0.5g Benzalkonium chloride 0.005g Sodium hydroxide Appropriate amount Sterile purified water Appropriate amount Formula 5 (in 100ml) pH 7.5 Epinephrine bitartrate 2.0g Borax 2.5g, polyethylene glycol 0.9g, benzalkonium chloride 0.005g, sodium edetate 0.01g, dilute hydrochloric acid, appropriate amount, sterile purified water, appropriate amount. Formula 6 (in 100ml) pH 6.0 Prazosin hydrochloride 0.05g, boric acid 1.0g, concentrated glycerin 0.5g, benzalkonium chloride 0.005g, sodium hydroxide, appropriate amount, sterile purified water, appropriate amount. Formula 7 (in 100ml) pH 6.0 Bunazosin hydrochloride 0.01g, boric acid 2.0g, propylene glycol 0.1g, benzalkonium chloride 0.005g, sodium edetate 0.01g, sodium hydroxide, appropriate amount, sterile purified water, appropriate amount. Formula 8 (in 100ml) pH 5.5 Bunazosin hydrochloride 0.5g, boric acid 0.5g, concentrated glycerin 2.0g Sodium hydroxide, appropriate amount Sterile purified water, appropriate amount Formulation 9 (in 100ml) pH 6.0 Bunazosin hydrochloride 0.1g Boric acid 1.24g Borax 0.1g Concentrated glycerin 0.3g Benzalkonium chloride 0.005g Sodium hydroxide, appropriate amount Dilute hydrochloric acid, appropriate amount Sterile purified water, appropriate amount "Stability test" Bunazosin hydrochloride was used as a representative example of a drug to examine its stability against light.

(Experimental method) The solution of Formulation 1 was placed in a polypropylene eye dropper container, and then irradiated with light of 3000 lux for 200 hours, and its appearance was examined. The following two types of solutions were prepared as controls for comparison.

Control 1 (per 100ml) Bunazosin Hydrochloride 0.1g Boric Acid 1.24g Benzalkonium Chloride 0.005g Sodium Hydroxide (as needed) Sterile Purified Water (as needed) Control 2 (per 100ml) Bunazosin Hydrochloride 0.1g Concentrated Glycerin 0.3g Benzalkonium Chloride 0.005g Sodium Hydroxide (as needed) Sterile Purified Water (as needed) (Experimental Results) Table 1 shows the appearance of each solution before and after exposure.

As shown in Table 1, only boric acid was added (Control 1).
In the case of the formulation containing only boric acid or concentrated glycerin (Control 2), the color of the solution changed from colorless to pale red due to decomposition by light. However, in the formulation 1 of the present invention containing boric acid and concentrated glycerin, no coloring was observed and decomposition by light was prevented.

When bunazosin hydrochloride was omitted from Formulation 1, no effect of light was observed.

As shown by these results, boric acid or polyhydric alcohol alone is ineffective, but it has been found that the photostability of the compound is increased by using boric acid and/or borax in combination with a polyhydric alcohol.

INDUSTRIAL APPLICABILITY The present invention makes it easy to apply a photolabile drug to an eye drop by combining boric acid and/or borax with a polyhydric alcohol.

──────────────────────────────────────────────────── Continued from the front page (72) Inventor: Yoichi Kawashima 3-8-54, Nishisakaidani-cho, Oharano, Nishikyo-ku, Kyoto City, Kyoto Prefecture (56) References: Patent Publication No. 1986-501566 (JP, A)

Claims (5)

[Claims] [Claim 1] A method for photostabilizing an eye drop, characterized by compounding boric acid and/or borax and a polyhydric alcohol to an eye drop containing a drug that is unstable to light as an ingredient. 2. The method for photostabilization according to claim 1, wherein the drug is a compound having an aromatic ring having a hydroxy group, a lower alkoxy group, or a primary or secondary amino group as a substituent, or a salt thereof. 3. The method for photostabilization according to claim 1, wherein the drug is bunazosin hydrochloride. 4. The method for photostabilization according to claim 1, wherein the drug is bunazosin hydrochloride and the polyhydric alcohol is glycerin. 5. Bunazosin hydrochloride eye drops, which are light-stabilized eye drops containing boric acid and/or borax and glycerin.