WO2000043015A1

WO2000043015A1 - Eye drops

Info

Publication number: WO2000043015A1
Application number: PCT/JP2000/000286
Authority: WO
Inventors: Yasuto Koyama; Nobuto Kanagawa
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1999-01-25
Filing date: 2000-01-21
Publication date: 2000-07-27
Also published as: AU2129500A

Abstract

Eye drops characterized by containing a quinazoline derivative represented by formula (I) (wherein A and B each represents lower alkylene and X, Y, and Z each represents halogeno) or a pharmacologically acceptable salt thereof in an amount of 0.001 to 10.0 W/V%.

Description

Description Ophthalmic solution Technical field

The present invention relates to an ophthalmic solution of a quinazoline derivative represented by the following chemical structural formula (I) or a pharmaceutically acceptable salt thereof, and is used in the medical field.

(In the formula, A and B each represent a lower alkylene group, and X, Y, and Ζ each represent a halogen atom.)

Background art

The quinazoline derivative (I) or a pharmaceutically acceptable salt thereof used in the present invention is a known compound, for example, the method described in Japanese Patent Application Laid-Open No. 62-96476. It can be manufactured by a method according to this, such as diabetic neuropathy [eg, diabetic peripheral neuropathy (eg, neuralgia, etc.), diabetic autonomic neuropathy (eg, impotence, etc.)], diabetic kidney Is useful for the treatment and prevention of diabetic complications such as diabetic retinopathy, diabetic retinopathy, diabetic corneal disorder and diabetic cataract.Compound (II) described below is currently in clinical trials for use in diabetic neuropathy, etc. Is being promoted. Problems to be solved by the invention

When the quinazoline derivative (I) of the present invention or a pharmaceutically acceptable salt thereof is used in the ophthalmic field, systemic side effects may occur when administered orally, intramuscularly or intravenously. You. Therefore, in the ophthalmic field, an eye drop for topical administration is preferred as a preparation that can reduce the occurrence of such side effects and achieve the intended purpose with a small dose. Means for solving the problem

As a result of intensive studies, the inventors of the present invention have found that an ophthalmic solution of a quinazoline derivative (I) or a pharmaceutically acceptable salt thereof can be introduced into a body sufficient for attaining drug efficacy even at a very low drug concentration. The present inventors have found that the present invention exhibits migration, particularly intraocular migration, and completed the present invention.

In the present specification, the definition of each symbol in the general formula (I) is as follows.

A and B each represent a lower alkylene group. Here, the lower alkylene group is a linear or branched alkylene group having 1 to 6 carbon atoms, and preferably has 1 to 4 carbon atoms. Specific examples include a methylene group, an ethylene group, a trimethylene group, a propylene group and the like, and a methylene group and an ethylene group are particularly preferred.

X, Υ, and それぞれ each represent a halogen (chlorine, bromine, fluorine, iodine) atom, and particularly preferably, X is a chlorine atom, Υ is a bromine atom, and Ζ is a fluorine atom.

In the present invention, in the general formula (I), Α and Β are a methylene group, X is a chlorine atom, Y is a bromine atom, and Z is a fluorine atom. (Ie:

A compound represented by the following formula: [3- (4-bromo-1-2-fluorobenzyl) -1 7-chloro-1,2,4-dioxo-1,2,3,4—tetrahydroquinazolin-1-yl Acetic acid is particularly preferred [hereinafter referred to as compound (II)].

Pharmaceutically acceptable salts of the compound include, for example, inorganic bases (eg, sodium, potassium, calcium, magnesium, aluminum, ammonium, etc.), organic bases (eg, ethanol Primary amines such as amino, acetylamine, diethanolamine, dicyclohexylamine, N, N'-secondary amines such as dibenzylethylenediamin, trimethylamine, Salts with basic substances such as triethylamine, pyridine, picolin, and tertiary amines such as triethanolamine.

Diluents such as distilled water and physiological saline are used as diluents for non-aqueous solutions or suspensions for use in preparing eye drops. Examples include vegetable oil, liquid paraffin, mineral oil, propylene glycol, and p-octyldodecanol. In addition, eye drops include buffering agents, tonicity agents, preservatives, preservatives, thickeners, stabilizers, antioxidants, pH regulators, chelating agents that are ordinarily incorporated into eye drops. And various additives can be appropriately compounded.

The buffer is added for the purpose of keeping the pH constant at, for example, about 5.0 to 8.0, and includes a borate buffer, a citrate buffer, a tartrate flame buffer, and a phosphate buffer. Salt buffer, acetate buffer, etc. are used . The amount of these buffers to be added is such that the buffer is added for the purpose of addition, that is, within a range that can keep pH constant within the above range, for example. The tonicity agent is added for the purpose of making it isotonic with tears, and sugars such as budose sugar, mannitol, sorbitol, glycerin, concentrated glycerin, polyethylene glycol, and propylene glycol Polyhydric alcohols such as coal, and salts such as sodium chloride and sodium citrate are used. These isotonic agents are added in such an amount that the osmotic pressure of the eye drops becomes the same as that of tears.

As the preservative, parabens such as benzalkonium chloride, methyl paraoxybenzoate, propyl parahydroxybenzoate, and chlorobutanol are used. Parabens can also be used as a mixture. The above preservatives can also be used as preservatives.

Glycerin, carboxymethylcellulose, and hydroxypropyl polymer are used as thickeners, sodium sulfite, propylene glycol, etc. are used as stabilizers, and acetic acid is used as antioxidants. Corbic acid, sodium ascorbate, tocopherol, sodium thiosulfate, etc. are used as pH regulators, such as hydrochloric acid, citric acid, phosphoric acid, acetic acid, tartaric acid, and sodium hydroxide. , Sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, etc., and examples of the chelating agent include sodium edetate, sodium citrate, etc. . The above chelating agents can be used as preservatives or stabilizers.

The preparation of the eye drops is performed by a conventional method, or by a sterilizing operation at an appropriate stage or by a sterilization treatment at an appropriate stage.

Further, the preparation of the present invention may appropriately contain a component having another kind of medicinal effect, as long as the object of the present invention is not violated.

The dose and frequency of administration of the active ingredient of the present invention depend on the symptom of the disease to be treated, age, weight, dosage form, treatment period, desired therapeutic effect, and the like. More usually, the quinazoline derivative (I) or a pharmaceutically acceptable salt thereof is preferably 0.001 to 10: owZv%, preferably 0.01 to: L. 0 WZV. %, Most preferably 0.1 to 0.5 W / V%, several times per eye per day, preferably 1 to 6 times, 1 drop, preferably 1 to 4 drops be able to.

The formulation of eye drops containing the quinazoline derivative (I), which is the active ingredient of the present invention, or a pharmaceutically acceptable salt thereof can be used to determine the solubility of the active ingredient, the stability of the preparation, and the ability of the drug to migrate into the lens. It is carried out with the optimal formulation in terms of the antiseptic and antiseptic effects.

As a result of various studies on this optimal formulation, preferred additives used in the formulation of the present invention include sodium edetate, concentrated glycerin, and phenol. Ravens (for example, methyl paraoxybenzoate, propyl parabenzoate and the like or a mixture thereof).

Of the above additives, sodium edetate is used in the range of 0.001 to 0.5 V%, preferably 0.005 to 0.1 WZV%, and concentrated glycerin. 1.0 to 5.0 WZV%, preferably 2.0 to 5.0 W / V%, methyl paraoxybenzoate: 0.0! It is preferable to use a preparation containing 0.1 to 0.1 W / V% and propyl paraoxybenzoate in a range of 0.01 to 0.1% iwzv%.

The ophthalmic solution of the present invention can be used, for example, for the treatment and prevention of diabetic complications such as cataract, retinopathy, corneal disorder and dry eye.

Example

Hereinafter, the present invention will be described with reference to examples.

Example 1

Concentrated glycerin (2.47 W / V%) and an appropriate amount of distilled water for injection Sodium edetate (0.01 W, V%) was dissolved in the mixture, but methyl paraoxybenzoate (0.04 W_ / V%) and propyl parabenzoate (0.0%) were dissolved. 2 W / V%) dissolved in an appropriate amount of distilled water for injection, mixed with Compound (II) (0.3 W / V%), dispersed, and added an appropriate amount of 0.1 N sodium hydroxide. Lithium was added and dissolved, the pH was adjusted to 7.5 with an appropriate amount of 0.1 N hydrochloric acid, and the whole amount was adjusted by adding an appropriate amount of distilled water for injection to prepare eye drops.

Example 2

In the same manner as in Example 1 (pH 7.0), eye drops having the following compounding amounts were prepared.

Compound (II) 0.3 W / V%

Sodium edetate 0.0 1 W / V%

Concentrated glycerin 2.83 W / V%

Methyl paraoxybenzoate 0.02 6 W / V% Propyl paraoxybenzoate 0.014 W / V%

0.1 N sodium hydroxide

0.1 N hydrochloric acid

Appropriate amount of distilled water for injection

Example 3

In the same manner as in Example 1 (pH 75), eye drops having the following amounts were prepared.

Compound (II) 0.3 W / V%

Sodium edetate 0.0 1 W / V%

Concentrated glycerin 2.83 W / V%

Methyl paraoxybenzoate 0.026 W / V% Propyl paraoxybenzoate 0.014 W / V%

0.1 N sodium hydroxide 0.1 N hydrochloric acid qs

Appropriate amount of distilled water for injection

Example 4

In the same manner as in Example 1 (pH 7.5), eye drops having the following amounts were prepared.

Compound (II) 0.30 W / V% Sodium edetate 0.01 W / V% Concentrated glycerin 2.83 W / V% Methyl paraoxybenzoate 0.04 W / V% Paraxy Propyl benzoate 0.02 W / V%

0.1 N sodium hydroxide

0.1 N hydrochloric acid qs

Distilled water for injection

Claims

Claims General

Expression

I

\ / 1

An ophthalmic solution comprising 0.0001 to 10.0 w, v% of a quinazoline derivative represented by the formula or a pharmaceutically acceptable salt thereof.

2. The ophthalmic solution according to claim 1, wherein, in the general formula (I), A and B represent a methylene group, X represents a chlorine atom, Y represents a bromine atom, and Z represents a fluorine atom.

3. The ophthalmic solution according to claim 1 or 2, comprising a chelating agent as an additive.

4. The ophthalmic solution according to claim 3, wherein the chelating agent is sodium edetate.

5. The ophthalmic solution according to claim 4, wherein the additive contains sodium edetate, concentrated glycerin, and parabens.

6.As additives, sodium edetate is 0.001 to 0.5W ZV%, concentrated glycerin is 1.0 to 5.0W / V%, methyl paraoxybenzoate 6. The ophthalmic solution according to claim 5, comprising 0.01 to 0.1 WZV% and 0.01 to 0.1 wzv% of propyl paraoxybenzoate.

7. — The quinazoline derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof is 0.01 to 1. ow / v%, and sodium edetate is 0.005 to 0.1 V%, concentrated glycerin 2.0 to 5.0 W / V%, methyl paraoxybenzoate 0.01 to 0.1 WZV ⁰ / ^ propyl paraoxybenzoate 0.01 to 0 7. The ophthalmic solution according to claim 6, which contains 1 W / V%.