WO1992005789A1

WO1992005789A1 - Eye drops for cataract

Info

Publication number: WO1992005789A1
Application number: PCT/JP1991/001265
Authority: WO
Inventors: Itaru Yamamoto; Mitsushi Hikida; Shiro Mita
Original assignee: Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo; Santen Pharmaceutical Co., Ltd.
Priority date: 1990-09-28
Filing date: 1991-09-24
Publication date: 1992-04-16

Abstract

Eye drops for cataract containing as the active ingredient 2-O-α-D-glucopyranosyl-L-ascorbic acid which is excellent in stability and tissue migration and can liberate ascorbic acid readily by the action of α-glucosidase.

Description

Specification

Title of invention

Anti-cataract eye drops Technical field

The present invention relates to an anti-cataract ophthalmic solution containing 2-0-α-D-glucoviranosyl-L-ascorbic acid as an active ingredient. Background art

Cataract is an intractable disease that causes s' opacity and loss of vision. Cataract is a disease that is caused by various factors, and its onset mechanism and its therapeutic agents have been studied in various ways.

Ascorbic acid, called vitamin C, is an indispensable substance in living organisms and is known to exhibit various pharmacological effects. Ascorbic acid is involved in the redox system in the lens together with glutathione, and plays a role in preventing acid dying by its strong reducing power, and has the effect of preventing clouding of the lens (Ophthalmic Research, 14, 167 (1982), Experimental Eye Research, 40, 445 (1985), etc.). Also, it is said that the amount of ascorbic acid is decreased in the clouded lens (Proceedings of National Academy Seiences, 82, 7193 (1985) and others). Therefore, administration of Asukorubin acid showed an effect on progression prevention of cataracts, that thought to help treat cataracts (Proceedings of National Academy Seiences, 82 , 7193 (1985) , etc.) ₀ However, Asukorubin acid acid I arsenate There is a problem in terms of stability. In particular, the stability of aqueous solutions is even lower, and it has not been easy to apply them to clinical practice as aqueous preparations such as eye drops. In order to solve this stability problem, studies have been conducted on deriving ascorbic acid into a stable derivative and on a method for improving the formulation.

Various compounds ⁵ 'have been synthesized as stable derivatives of ascorbic acid, such as those in which the hydroxyl group of ascorbic acid has been converted into an ester ester sulfate. Glucopyranosyl-scorbic acid was also synthesized for the same purpose. As an example of darcoviranosi ruascorbic acid, the glucopyranosyl group is located at the 6th position of ascorbic acid. Combined (Japanese Patent Publication Showa 48-38 158) and those combined at the third position (Japanese Published Patent Publication Showa 59-59 196) have been reported.

In order to be used as a medicinal product, it is necessary to have not only excellent stability, but also good tissue transferability, and the ability to easily release ascorbic acid when administered to a living body. You. Japanese Unexamined Patent Publication (Kokai) No. Sho 59-59 9619 discloses the application of 3-0-glucoviranosyl-L-ascorbic acid to eye drops. is there. Glucovilanosyl-ascorbic acid is degraded by glucosidase to release ascorbic acid.Although α-glucosidase is widely distributed in living organisms, only a small amount of 3-glucosidase is present. No (Biochimica et Biophyisica Acta, 1035, 44 (1990)) Considering the release of ascorbic acid, α-type is preferred. Also, the 6-glucoviranosyl derivative disclosed in JP-B-48-38158 is insufficient in stability (Biochimica et Biophyisica Acta, 1035, 44 (1990)).

Recently, Yamamoto et al. Reported on the synthesis and biochemical studies of 2-0-α-D-glucoviranosyl-L-ascorbic acid in which the hydroxyl group at the 2-position of ascorbic acid was replaced with an α-type by a glucose molecule. (Biochimica et Biophyisica Acta, 1035, 44 (1990), Journal of Biochemistry, 107, 222 (1990), Agricaltural and Bio logical Chemistry, 54. 1697 (1990), 1989 Pharmaceutical Affairs Daily, No. 765-8, pages 11 to 13 (issued on February 22, 1990).

This 2-0-α-D-glucoviranosyl-L-ascorbic acid is an excellent compound which is very stable even in an aqueous solution and is rapidly decomposed to ascorbic acid by α-glucosidase. The power reported is not yet applied to the field of ophthalmology.It is completely unknown whether this compound has the ability to migrate into the eye and actually exert an effect on cataracts. However, new research was needed.

Then, the present inventors diligently studied the application of 2-0-α-D-glucoviranosyl-L-ascorbic acid to the field of ophthalmology, and as a result, found that it was useful as an anti-cataract eye drop. Disclosure of the invention

The present invention relates to an anti-cataract ophthalmic solution containing 2-0-α-D-darcoviranosyl-L-ascorbic acid as an active ingredient. In the present invention, the term anti-cataract is used in a broad sense including amelioration, prevention of progression and prevention of cataract. The 2-0-α-D-glucoviranosyl-L-ascorbic acid (the chemical structural formula is shown below) used in the present invention is prepared by the method described in Japanese Patent Application No. 1-2744518. What was synthesized by the above may be used.

CH ₂ OH

2-0-α-D-glucopyranosyl-L-ascorbic acid The present inventors have noted that although ascorbic acid has a problem in stability, it is useful for the treatment of cataract, and Derivatives were applied to cataracts. As a result, they found that 2-0-α-D-glucoviranosyl-L-ascorbic acid, which has excellent stability and easily releases ascorbic acid by α-glucosidase, is particularly excellent as a therapeutic agent for cataract.

There are various methods to determine the effects of drugs on cataracts. In the present invention, as an experimental cataract model, a cataract model of chicken embryo induced by adrenocortical hormone (Nishigori et al., Experimental Eye Research, 36, 617-622) (1983)). Although detailed data is described in the section on pharmacological tests, when experiments were performed using hydrocortisone sodium succinate as an adrenocortical hormone, the 2-0-α-D-glucopyranosyl-L-ascorbic acid administration group showed clouding of the lens. Significantly reduced. In addition, experiments were performed using ascorbic acid and its stable derivative, ascorbic acid monophosphate ester, as compounds for comparison. 2— 0— α— D—Glucobilanosyl The administration of 1L-ascorbic acid performed better than the administration of the ascorbic acid-ascorbic acid-2-phosphate compound. In other words, 2-0-α-D-glucoviranosyl-L-ascorbic acid not only has excellent stability in aqueous solution, but also has particularly excellent effects including transferability to tissues. I understood that.

This $ kika proves that 2-0-α-D-glucoviranosyl-L-ascorbic acid is useful as a therapeutic agent for cataract.

Of course, 2-0-α-D-glucoviranosyl-L-ascorbic acid exerts its effect by releasing ascorbic acid by α-glucosidase, and 2-0-α- 1-D-glucoviranosyl-L-ascorbic acid. This includes the possibility that the acid compound itself exerts its effect.

Examples of the dosage form of eye drops include eye drops and eye ointments.

The dose of 2-0-α-D-glucoviranosyl-L-ascorbic acid can be appropriately selected according to the strength S that varies depending on the dosage form, symptoms, age, and the like. For example, in the case of eye drops, it is preferable to administer a solution having a concentration of 0.05 to 15%, more preferably 0.1 to 5% one to several times a day.

For the preparation of 2-0-α-D-glucoviranosyl-L-ascorbic acid, no special method is required, and a method commonly used for ordinary eye drops may be used.

For example, in the case of eye drops, isotonic agents such as sodium chloride, potassium chloride, and glycerin; buffering agents such as sodium hydrogen phosphate, disodium hydrogen phosphate, boric acid, ibsilone and aminocabronic acid; sodium edetate; Stabilizers, preservatives such as methylparaben, ethylparaben, chlorobenzalkonium, chlorobutanol, etc., and preservatives such as dilute hydrochloric acid, sodium hydroxide, etc., are added as needed to formulate pharmaceuticals in the usual manner. be able to. In the case of an eye ointment, a base can be prepared by adding an ointment base such as white petrolatum or liquid paraffin by an ordinary method. BEST MODE FOR CARRYING OUT THE INVENTION

2-0-α-D-darcoviranosyl-L-ascorbic acid Is shown. In addition, as for the production method of each preparation, a method generally used in each dosage form may be used.

1. Eye drops

Formulation Example 1 in 100 ml

2-0- α-D-Cul] viranosyl-L-ascorbic acid 0.05 g

Boric acid 1.8 g

Benzalkonium chloride 0.005 g

Dilute hydrochloric acid

Sodium hydroxide

Sterile purified water Formulation example 2 In 100 ml

2-0-a-D-Curucovilan-L-as: I-rubic acid 0.1 g

0.8 g of sodium chloride

Epsilon aminocaproic acid 0.2 g

Chlorobutenool 0.15 g

Methyl paraben 0.026 g

Propylparaben 0.014 g

Dilute hydrochloric acid

Sodium hydroxide

Sterile purified water Formulation example 3 in 10 Oml

2-0- α-D-glu: I Viranosyl-L-ascorbic acid 0.5 g

0.85 g sodium chloride

Sodium edetrate 0.01

Benzalkonium chloride 0.005 g

Sodium hydroxide

Sterile purified water Formulation Example 4 in 100 ml

2-0-a-D-talcoviranl-L-ascorbi: / acid 1.0 g sodium chloride 0.4 g boric acid 0.8 g sodium edetate 0.011 benzalkonium chloride 0.005 g sodium hydroxide

Sterile purified water Formulation example 5 in 10 Oml

2-0- a _D-talcoviranosyl-L-ascorbic acid 2.0 g glycerin 1.5 s ibsilone aminocaproic acid 0.2 g chlorobutanol 0.15 g methylparaben 0.026 g propylparaben 0.014 g water Sodium acid

Sterile purified water Formulation example 6 in 10 Oml

2-0- α-D-Cul] viranosyl-L-ascoric acid 5. O g chlorobutanol 0.15 g methyl paraben 0.026 g propyl pyrabene 0.014 g sodium hydroxide

Sterile purified water Formulation example 7 in 10 Oml

2-0- α-D-Culcovranulascoric acid 15.O g Cloth butanol 0.15 g

Methyl paraben 0.026 g

Propylparaben 0.014 g

Sodium hydroxide

Sterile purified water

2. Eye ointment

Formulation Example 8 in 100 g

2-0- α-D-cle :! Vilanl-L-ascorbic acid 2.O g

90 g of white petrolatum

Liquid paraffin 8 g

`` Pharmacological test ''

As a method of examining the effect of a drug on cataract, a method using a cataract model induced using adrenocortical hormone is well known (Nishigori et al., Experimental Eye Research, 36, 617-622 (1983)). Therefore, the effect of 2-0-α-D-glucoviranosyl-L-ascorbic acid on cataract was examined using this model.

(experimental method)

According to the above-mentioned paper, 15-day-old embryonated chick embryos (fertilized hen eggs) were treated with hydrocortisone sodium succinate (hereinafter abbreviated as HC; dosage 0.25 umo 1 / egg) to induce cataract. An aqueous solution of 2-0-α-D-glucopyranosyl-L-ascorbic acid (AA2G) was administered three times at 3, 10, and 20 hours after the induction, and the degree of opacity of the lens 72 hours after the administration of HC was examined. The degree of turbidity was determined according to the method described in the above-mentioned Experimental Eye Research (the opacity of the lens was divided into five stages of I to V; see Table 1). Water was administered to the control group. In addition, for comparison with 2-0-α-D-glucopyranosyl-L-ascorbic acid, an experiment was also conducted simultaneously with the administration of ascorbic acid (ΑΑ) and ascorbic acid-12-phosphate (ΑΑ2Ρ). Table 1 Lens opacity classification table Stage I Transparent lens

Stage もの Somewhat opaque around lens nucleus

Stage m Opaque around lens nucleus

Stage IV The nucleus of the lens is opaque, and the cloudiness is widespread toward the center

Stage V Opaque nucleus around and around lens nucleus

(Result)

Table 2 shows the results. Table 2 Lens opacity 72 hours after induction Stage

I Π m IV V control group 0 0 12.5 50.0 37.5

AA2 G 64.3 28.6 7.10 0 0

10 / imol administration group

AA 28.6 0 28.6 28.6.14.2

1 Oumol administration group

AA2 P 0 37.5 6.3 31.2 25.0

1 Omol administration group As shown in the table, in the control group in which cataract was induced by HC and no drug was administered, all opacity S of stage III or higher was observed, and in particular, the opacity of stage IV or higher was remarkably 80%. % Exceeded.

The effects of the ascorbic acid and ascorbic acid 12-phosphate ester administration groups were observed as compared with the control group, but more than 60% of the patients were stage III or higher.

On the other hand, in the group administered with 2-0-α-D-glucoviranosyl-L-ascorbic acid according to the present invention, 64.3% of stage I was able to completely prevent opacity of the lens, and only 7.1% for stage III and above. It was only%.

The above results demonstrate that 2-0-α-D-glucopyranosyl-L-ascorbic acid is an excellent therapeutic and prophylactic agent for cataract compared to ascorbic acid-ascorbic acid phosphate.

Claims

0 Scope of request

2-0-α-D-glucopyranosyl-L-ascorbic acid as an active ingredient in anti-cataract eye drops.

2-0-α-D-darcoviranosyl-L-ascorbic acid eye drops for use in the treatment or prevention of cataracts.

Use of 2-0-α-D-glucopyranosyl-l-ascorbic acid as an eye drop for the treatment or prevention of cataract.