JPH06298649A - Azelastine eye drop composition - Google Patents

Abstract

PURPOSE:To obtain an azelastine-containing preparation for eye drop, having slight irritation, being stable as a preparation, having relatively alleviated bitterness. CONSTITUTION:An eye drop-composition contains (A) azelastine hydrochloride having excellent antiallergic action and (B) boric acid, glutamic acid or its salt contributing to alleviation of irritation and improvement in stability. The amounts of the components blended are 0.0005-2% (W/V) of the component A, 0.01-5.0(W/V)%, preferably 0.05-2.0% (W/V) of boric acid (salt) and 0.01-0.3% (W/V), preferably 0.05-0.25% (W/V) of glutamic acid (salt). The composition has preferably pH about 4.0-8.0, more preferably pH 5.0-7.0.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an eye drop composition containing azelastine as a medicinal component.

[0002]

2. Description of the Related Art At present, as antiallergic eye drops, there are eye drops containing sodium cromoglycate, ketotifen fumarate, anlenoxanox, etc. as active ingredients, and allergic eye diseases, namely allergic conjunctivitis, spring catarrhal, etc. Is used for the disease. Of these, azelastine has a chemical name of 4- (4-chlorobenzyl) -2- (hexahydro-1-methyl-1Hazepin-4-yl) -1-
(2H) -phthalazinone, which has an excellent antiallergic action. The usefulness of azelastine as the main active ingredient in eye drops can be recognized from its pharmacological action, but it has problems of strong irritation and bitterness, and therefore the development of this preparation requires further resolution of these problems. Has been.

Japanese Patent Application Laid-Open No. HEI-1 is an application related to the patent for this formulation.
No. 153,639, which describes a drug to be used on the nose or eyes and a method of using the drug. However, the present application mainly focuses on nose drops, and the description of eye drops is small.
In the above, only one example of using polyvinyl alcohol is disclosed, and it does not mention at all the problem of the formulation of the eye drop, such as the presentation or solution of the above-mentioned problems such as irritation and bitterness. Further, when polyvinyl alcohol is used, the strong irritation of the azelastine-containing preparation cannot be alleviated. Further, when polyvinyl alcohol and boric acid used in the present invention are combined, there is a problem such as gel formation.

[0004]

DISCLOSURE OF THE INVENTION The present invention provides an azelastine-containing preparation for eye drops, which is less irritating, stable as a preparation, and relatively less bitter.

[0005]

The azelastine eye drop composition of the present invention is characterized by containing the following components (A) and (B). (A) Azelastine hydrochloride. (B) Boric acid, glutamic acid or salts thereof.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, azelastine as the component (A) is used as a main active ingredient for allergic eye diseases, and the amount of azelastine in the eye drop composition is 0.00
The standard is to add 05-2% (w / v). In addition, hereinafter,% is expressed as weight (w) / volume (v)% unless otherwise specified.

In the present invention, boric acid, glutamic acid or a salt thereof, which is added as the component (B), is added to an azelastine-containing eye drop preparation and contributes to alleviation of irritation and improvement of stability. The eye drops may be blended alone or in combination of two or more.

Boric acid or a salt thereof is preferably contained in the ophthalmic composition in an amount of 0.01 to 5.0%, preferably 0.02 to 2.0%. Further, glutamic acid or a salt thereof is preferably blended in the eye drop composition in an amount of 0.01 to 0.3%, preferably 0.05 to 0.25.
%.

The salt is not particularly limited as long as it is pharmacologically acceptable, but a sodium salt is typical. Boric acid or its salt is used as a buffer in eye drops, but when used in combination with azelastine, it specifically improves the irritation and bitter taste of azelastine eye drops, and improves stability. Let

The azelastine ophthalmic composition of the present invention may contain various optional components in addition to the above essential components (A) and (B). For example, polysorbate 80, polyoxyl stearate, polyoxyethylene hardened castor. Nonionic surfactants such as oil derivatives can be used. In addition, polyhydric alcohols such as ethanol, propylene glycol, glycerin, and polyethylene glycol can be used as the solvent.

In addition, sugars such as glucose and sugar alcohols such as xylit, mannitol and sorbit can be used. Further, benzalkonium chloride, chlorobutanol, methylparaben, propylparaben or the like can be used as a preservative, and sodium edetate or the like can be added as a chelating agent.

The eye drop composition of the present invention has a pH of 4.0 to 4.0.
It is preferably about 8.0, more preferably pH 5.0 to 7.
It is preferably 0, and can be prepared with an appropriate pH adjusting agent. The eye drop composition of the present invention may be added so that the osmotic pressure ratio is usually 1, and can be adjusted with a polyhydric alcohol such as sodium chloride, potassium chloride or glycerin.

[0013]

EFFECTS OF THE INVENTION According to the eye drop composition of the present invention, azelastine is uniformly dissolved, and the resulting eye drop has significantly reduced irritation and relatively little bitterness. Further, the azelastine eye drop composition of the present invention exhibits an excellent pharmacological effect as shown in the antiallergic test using ovalbumin shown in Experimental Example 2 described later, and maintains good stability. Furthermore, the eye drop composition of the present invention does not cause precipitation,
At the same time, it can withstand a high temperature heating test and can be expected to have sufficient stability.

[0014]

Example 1 50 mg of azelastine hydrochloride is precisely weighed, added to an appropriate amount of purified water, 2 g of boric acid and 100 mg of borax, and well stirred. After adding 1 g of concentrated glycerin to this liquid, 200 mg of glucose is added. Separately, 100 ml of 0.5% benzalkonium chloride solution and 100 ml of 0.5% disodium ethylenediaminetetraacetic acid aqueous solution are prepared, and 1 ml of each of these solutions is taken and added to the above solution. Further, 0.15 ml of ethanol was added, and then purified water was added to adjust the pH so that the total amount was 100 ml, to give the eye drop composition of the present invention.

Example 2 25 mg of azelastine hydrochloride was precisely weighed, added to an appropriate amount of purified water, 1.5 g of boric acid and 0.2 g of sodium glutamate, and stirred well. After adding 0.1 g of mannitol to this liquid, 0.1 g of chlorobutanol is added, and 0.001 N hydrochloric acid is further added so as to have a volume of 50%. Add 0.1% benzalkonium chloride solution to this solution.
After adding ml, add purified water and adjust the pH to bring the total volume to 1
The volume is adjusted to 00 ml to obtain the eye drop composition of the present invention.

Example 3 75 mg of azelastine hydrochloride was precisely weighed and 0.0004
In addition to N-sulfuric acid, 1 g of boric acid was further added, and further 15 mg of glutamic acid and 0.21 of sodium glutamate.
Add g and stir well. Chlorobutanol (0.1 g) is added to this solution to make the total amount 100 ml to give the eye drop composition of the present invention.

Example 4 An eye drop composition of the present invention was prepared according to the following formulation.

Comparative Example 1 An eye drop composition of Comparative Example was prepared according to the following formulation.

Experimental Example 1 [Rabbit eye mucous membrane irritation test (Dr
aize method)] 48 hours before the test, 2% fluorescein sodium was added.
1 ml is instilled on the rabbit ocular mucosa, immediately washed with about 20 ml of warm water, and it is confirmed that the cornea is not damaged by using an ultraviolet test lamp. At 10:00 am and 2:00 pm on the test day, 0.1 ml each of the test drugs prepared in Examples 1 to 4 and Comparative Example 1 was instilled into the right eye of the rabbit, and the eyelids were carefully adjusted for about 1 second. The ocular mucosa after 24 hours and 48 hours was treated with Dr
Aize criterion (Draize method, 1959, FD
It was scored according to A) and the results are shown in Table 1.

(1) Draize Method (Ocular Mucosal Irritation Test Method) Ocular disorders of the cornea, iris, and conjunctiva are evaluated to obtain a total score thereof, and irritation is evaluated according to the following criteria. Overall score 0 to 5: non-irritant overall score 5 to 15: light irritant overall score 15 to 30: stimulant overall score 30 to 60: moderate stimulant overall score 60 to 80: medium to strong irritant overall score 80 ~ 110: Intense stimulant Overall score = Corneal disorder score + Iris disorder score + Conjunctival disorder score

Corneal disorder score (A × B × 5) maximum 80 points A: Opacity (scored in the strongest part) 0 point: no opacity 1 point: sporadic or chronic (details of iris can be clearly distinguished) ) 2 points: The transparent part can be easily discriminated, but the details of the iris are unclear. 3 points: White turbidity makes it difficult to identify the details of the iris, but the size of the pupil is barely discernable 4 points: Strong white turbidity, and the iris is also Can't see through B: Area of obstacle 1 point: 0 to 1/4 2 points: 1/4 to 1/2 3 points: 1/2 to 3/4 4 points: 3/4 or more

Iris disorder score (A × 5), maximum 10 points A: 0 point: No normal change 1 point: Increased wrinkles, hyperemia, swelling, corneal hyperaemia, light reaction positive 2 points: light reaction disappearance, Bleeding, collapse

Conjunctival disorder score [(A + B + C) × 2] Maximum 20 points A: Redness (including eyelid and bulbar conjunctiva) 0 point: normal blood vessel 1 point: hyperemicia higher than normal 2 points: diffuse and deep reddish tone, blood vessel Difficult to distinguish 3 points: Chronic, strong reddish color, beef-like B: Swelling 0 points: No swelling 1 point: Edema-like, stronger than normal (including nictitating membrane) 2 points: Clear edema, partial reversal of eyelids 3 points: Marked edema, mid-lid closure 4 points: Marked edema, eyelid 1/2 to most closed C: Secretion 0 point: No eye oil 1 point: More than normal 2 points: Eyelid and its part due to secretion The tip is moist. 3 points: Eyelid, hair around the eye, and wide moisturizing around the eye area.

[0024]

[Table 1]

[0025]

[Table 2] All of Examples 1 to 4 are determined to be non-stimulative according to the criteria of the Draize method.

Experimental Example 2 Ovalbumin physiological saline (10 mg / ml) was added to 0.4 in ovine albumin in both thigh muscles of 7-week-old Wistar male rats.
Administered pertussis killed liquid (about 2 x 10
4 cells ( ¹⁰ cells / ml) were intraperitoneally administered. After 15 days, blood is collected from the abdominal aorta under ether anesthesia to obtain anti-ovalbumin rat serum. Next, 7-week-old Wistar rats were pretreated with the antiserum stock solution at 25 μl / site under the upper eyelids of the rats.
Administer and passively sensitize. 48 hours after the sensitization, the ovalbumin antigen was dissolved in physiological saline at a concentration of 10 mg / ml, and this solution 0.4 ml / 200 g B.I. W. Was administered from the femoral vein of the rat. After 30 minutes from the antigen challenge, the blue-stained area around the eye was cut off and finely chopped, then added to 10 ml of a mixture of 0.5% Na ₂ SO ₄ and acetone (3: 7), homogenized and extracted for 24 hours, then 3000 r ． p. m. In 10
Centrifuge for minutes, take the supernatant, measure the absorbance at the maximum absorption wavelength near 620 nm, and determine the average dye leakage amount. Here, the above-mentioned operation was carried out for two groups of the drug-administered group to which the eye drop composition of the present invention obtained in Example 2 was administered and the control group to which 6 were not administered, and the allergic inhibition rate was obtained. It should be noted that the drug is instilled 10 times (25 μl each) once a minute 1 hour before administration, and the same instillation is performed after the antigen administration. Do the same operation twice a day in the morning and the next day. In addition, the eye drops are similarly instilled 1 hour before and immediately after the antigen induction. The inhibition rate was calculated by the following formula, and the results are shown in Table 3. Inhibition rate (%) = (1−A / B) × 100 A: Mean dye leakage amount of drug administration group B: Mean dye leakage amount of control group

[0027]

[Table 3]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI Technical display location A61K 47/18 J 7433-4C Z 7433-4C // C07D 403/04 223 7602-4C (C07D 403) / 04 223: 00 237: 00)

Claims (1)

[Claims] 1. (A) Azelastine hydrochloride and (B)
An azelastine eye drop composition comprising boric acid, glutamic acid or a salt thereof.