JPS63270625A - Antiallergic eye drop - Google Patents

Abstract

PURPOSE:To obtain an antiallergic eye drop, having antihistaminic action and useful for treating allergic ophthalmopathy, such as allergic conjunctivitis, by solubilizing and containing cyproheptadine in a specific concentration. CONSTITUTION:Saccharides, such as D-mannitol, or an isotonizing agent, such as glycerol or boric acid, is added to cyproheptadine or salts thereof and, as necessary, a preservative, buffer agent, stabilizer, etc., are added and dissolved. The cyproheptadine is preferably in a concentration so as to exhibit remedial effects, i.e. >=0.01%. After dissolution, a pH adjustor, such as sodium hydroxide, is used to adjust pH to 4.5-8 to afford the aimed substance. The eye drop in an amount of one several drops a time is normally applied to eyes several times a day.

Description

DETAILED DESCRIPTION OF THE INVENTION "Industrial Field of Application" The present invention provides eye drops useful for the treatment of allergic eye diseases such as allergic conjunctivitis.

"Prior Art" Cyproheptadine or its salts have antihistamine effects and are used as oral medicines such as powders and tablets to treat allergic diseases.

``Problems that the invention attempts to solve'' When using eye drops, the drug is usually dissolved in a liquid that has been fortified with sodium chloride.

However, cyproheptadine or its salts have low solubility in such a solution, and we considered solubilizing cyproheptadine or its salts and applying them to eye drops.

"Means for Solving the Problem" The present invention is an eye drop characterized by containing cyproheptadine or its salts at a concentration that can exert its medicinal efficacy, and for this purpose, a method for solubilizing cyproheptadine or its salts to form an eye drop. As a result of intensive research, we found that sugars such as D-mannitol and glycerin.

It has been found that by using polyethylene glycol or boric acid as an isotonic agent, cyproheptadine or its salt q can be dissolved in water at a concentration sufficient to be effective as an eye drop.

"Disclosure of the Invention" Cyproheptadine or its salts have an antihistamine effect and are useful drugs as antiallergic agents.

However, its use as a medicine has been limited due to poor solubility. The present inventors have overcome the poor solubility and made it possible to apply it as an eye drop.

Just in case. Hereinafter, cyprohebutadine salt dispersion will be explained as a representative example of cyproheptadine or its salts. In order for cyproheptadine hydrochloride to exhibit antiallergic effects in the eyes, a concentration of 0.01% or more is required as described below, and in order to maintain the concentration of cyproheptadine hydrochloride, which has poor solubility, at 0.01% or more. Therefore, it was necessary to consider solubilization.

When considering the solubilization of drugs with poor solubility in applied research to eye drops, a surfactant is usually used. Add polysorbate 80, a typical surfactant, to physiological saline.
．． Solubilization of 1% cyproheptadine hydrochloride was investigated, but almost no change in solubility was observed. As described above, the problem of solubilization could not be solved simply by adding a surfactant, and special measures were required.

Therefore, when sugar odors such as D-mannitol, glycerin, propylene glycol, polyethylene glycol, or boric acid are used as isotonic agents, the solubility of cyproheptadine hydrochloride is significantly improved, making it possible to apply it as eye drops and L7. I discovered that.

The tonicity agent can be used alone or in combination of two or more.

The concentration of cyproheptadine hydrochloride may be a concentration that can exhibit a therapeutic effect, that is, 0.01% or more.

There is no particular need to set an upper limit on the concentration, and it is sufficient to mix it at a concentration that can sufficiently exhibit its effects.

It is better if the pH is within the range acceptable for ophthalmic preparations.
．． A range of 5 to 8 is preferred.

This preparation contains additives commonly used in eye drops such as paraoxybenzoic acid ester and chloride pair f/L/
Preservatives such as conium, buffering agents such as sodium phosphate, stabilizers such as sodium edetate.

A pH adjuster such as sodium hydroxide can be used as necessary.

In addition, all other ophthalmic drugs (epinephrine, naphazoline hydrochloride, berberine chloride, sodium azulene sulfonate, lysozyme chloride, etc.) may be added as necessary.

A general method for producing the eye drops of the present invention includes the following method.

Add a naturalizing agent such as cyproheptadine hydrochloride to sterile purified water, and if necessary, add preservatives, buffering agents, stabilizers, etc. and dissolve. After dissolution, adjust the pI using a pH adjuster such as sodium aqueous dispersion.

The eye drops produced in this way are usually administered in one to several drops at a time.
It is used to treat allergic eye diseases by instilling eye drops several times a day.

"Example" Examples of the eye drops of the present invention are shown below.
1.8g! Benzalkonium chloride 0.0057 Sodium hydroxide
Appropriate amount of sterile purified water Appropriate amount of sterile purified water Add cyprohebutadine hydrochloride (LO
5y, boric acid], 89't- was added and stirred well to dissolve. Separate 1% benzalkonium chloride, sd, and adjust the pH to 7 using sodium hydroxide.
Ta.

Using the same method as in Example 1, eye drops having the formulations of Examples 2 to 5 were obtained.

Example 2 Crystal 100WII! Cyprohebutadine hydrochloride 0.17 Propylene glycol 2.0 y Benzal chloride 3 nicium
0.0059' Sodium hydroxide Appropriate amount Sterile purified water Appropriate amount Example 3 Crystal] Cyproheptadine hydrochloride in 00d o, 22D-mannitol 2.02 Glycerin 1
．． 3y Benzalkonium chloride 0.005y Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount Example 4 Sibrohebutadine hydrochloride in Quartz 100ze 0-059 Polyethylene glycol 2. Of;'p-znnitol
2.02 Glycerin o, s
y Methyl paraoxybenzoate 0.024 y Propyl paraoxybenzoate 0.0129 Sodium hydroxide Appropriate amount Sterilized 'M water Appropriate amount Example 5 Crystal 100 mF! Medium cibrohebutadine hydrochloride 0.1yD-mannitol 2.02 Glycerin 1
．． 3y Porin Lepe) 80 n, 03/; 1 Disodium phosphate (1,]y Pengolfnium chloride o, nosy sterile purified water
Appropriate dose pharmacological test as an indicator of usefulness for allergic diseases.

The inhibitory effect on anaphylactic reactions is usually investigated.

In this study, passively sensitized rats and actively sensitized guinea pigs were used to investigate the effect of suppressing anaphylactic reactions in the conjunctiva.

(]) Mota's method of suppressing anaphylactic reaction in the conjunctiva of passively sensitized rats (Life Sct, 12,917)
The antiserum against ovalbumin (pCA titer, 1:32) prepared by Iao et al. (Ophthalmia Re+s-, 1963) was used.
(] 980)) The inhibitory effect of cyproheptadine on allergic reactions on the conjunctiva was investigated in accordance with Ic. Cyproheptadine was prescribed as in Example 5, and 0 μl was instilled into the eyes 10 minutes before the antigen challenge.

(Results) Amount of leaked pigment (absorbance) Suppression rate control Q, ]69 Eye drops formulated in Example 5 0.026 g
4.6% absorbance is the average value of 6 samples each.

(2) Suppressive effect on anaphylactic reaction in the conjunctiva using actively sensitized guinea pigs] Guinea pigs sensitized by intraperitoneal administration of 0.5 d of aluminum hydroxide gel (]O”5F/m/) containing 0 μy of ovalbumin using the method of Ln, Garceau et al. (Eur, J. Pharmacol, 134
, 285 (] 987)), the allergic reaction suppressing effect of sibrohebutadine on the conjunctiva was investigated. Cyproheptadine was formulated as in Example 5, and 10 μl was instilled into the eyes 5 and 15 minutes before antigen challenge.

(Results) Amount of leaked pigment (absorbance) Suppression rate control 0.703 Eye drops formulated in Example 5 0.266 fi
The 2.2% absorbance was the average value of 8 samples each.

As described above, the eye drops of the present invention exhibited an excellent anaphylactic reaction suppressing effect.

Also, 0. Using n1% cyproheptadine hydrochloride eye drops,
All tests similar to those described above were conducted, but no significant difference from the control was observed, confirming that a concentration of 0.01% or more is required to exert a therapeutic effect.

"Effects of the Invention" Since the present invention is an eye drop containing cyproheptadine or its salts, it has the effect of being effective in treating allergic eye diseases such as allergic conjunctivitis.

Claims (1)

[Claims] An eye drop containing cyproheptadine or its salts at a concentration that allows it to exhibit its medicinal efficacy.