JP2024076376A - Pharmaceutical composition for promoting tear secretion or pharmaceutical composition for preventing or treating corneal and conjunctival disorders - Google Patents

Abstract

[Problem] When selective serotonin reuptake inhibitors (SSRIs), which increase the concentration of serotonin in the brain, were used as eye drops, they did not exhibit the effect of promoting lacrimal secretion. [Solution] The object of the present invention is to provide a pharmaceutical composition for promoting lacrimal secretion, which contains as an active ingredient a compound that increases the concentration of noradrenaline in the brain, and which is for ophthalmic use (with the proviso that venlafaxine or a pharmacologically acceptable salt thereof is excluded from the compounds that increase the concentration of noradrenaline in the brain). [Selected Figure] None

Description

The present invention relates to a pharmaceutical composition for promoting tear secretion or a pharmaceutical composition for preventing or treating corneal and conjunctival disorders.

Dry eye is a corneal and conjunctival epithelial disorder caused by a lack of tears that cover the surface of the eye. Eye drops containing hyaluronic acid and artificial tears are used to treat such corneal and conjunctival epithelial disorders. Eye drops containing a drug that has a tear-secreting effect (Diquas ophthalmic solution 3%) are also used as a treatment.

Patent document 1 discloses that increasing the concentration of serotonin in the brain has a preventive or therapeutic effect on corneal and conjunctival disorders.

Patent Publication 2016-050180

However, when selective serotonin reuptake inhibitors (SSRIs), which increase the concentration of serotonin in the brain, were used as eye drops, they did not have the effect of promoting tear secretion (see the examples below).

As a result of further research, the inventors discovered that the use of a drug that inhibits the reuptake of noradrenaline as an eye drop promotes tear secretion, thus completing the present invention.

The object of the present invention is to
A pharmaceutical composition for promoting tear secretion, comprising as an active ingredient a compound that increases intracerebral noradrenaline concentration,
The pharmaceutical composition for promoting lacrimal secretion is for ophthalmic use.
Pharmaceutical composition for promoting tear secretion (provided that the above-mentioned compounds that increase intracerebral noradrenaline concentration exclude venlafaxine or a pharmacologically acceptable salt thereof)
The purpose of this project is to provide

By using the pharmaceutical composition of the present invention, it is possible to promote tear secretion, thereby preventing or treating corneal and conjunctival epithelial disorders.

Another object of the present invention is to provide
A pharmaceutical composition for preventing or treating a corneal and conjunctival disorder, comprising a compound that increases intracerebral noradrenaline concentration as an active ingredient,
The preventive or therapeutic agent for corneal and conjunctival disorders is for ophthalmic use.
A pharmaceutical composition for preventing or treating corneal and conjunctival disorders (provided that venlafaxine or a pharmacologically acceptable salt thereof is excluded from the above-mentioned compounds that increase intracerebral noradrenaline concentration)
The purpose of this project is to provide

By using the pharmaceutical composition of the present invention, corneal and conjunctival disorders can be prevented or treated.

The compound that increases the brain noradrenaline concentration may be at least one selected from the group consisting of serotonin-noradrenaline reuptake inhibitors, selective noradrenaline reuptake inhibitors, and tetracyclic antidepressants.

The concentration of the serotonin-noradrenaline reuptake inhibitor may be 0.15 wt% or more. The concentration of the selective noradrenaline reuptake inhibitor may be 0.3 wt% or more. The concentration of the tetracyclic antidepressant may be 0.15 wt% or more.

The serotonin-noradrenaline reuptake inhibitor may be duloxetine or a pharmacologically acceptable salt thereof, or milnacipran or a pharmacologically acceptable salt thereof. The selective noradrenaline reuptake inhibitor may be atomoxetine or a pharmacologically acceptable salt thereof. The tetracyclic antidepressant may be maprotiline or a pharmacologically acceptable salt thereof.

Definitions For convenience, certain terms used in this application are collected here. Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The singular forms "a,""an," and "the" include plural references unless the context clearly dictates otherwise.

The numerical ranges and parameters set forth in the present invention are approximate, but the numerical values set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Also, as used herein, the term "about" generally means within 10%, 5%, 1% or 0.5% of a given value or range. Alternatively, the term "about" means within an acceptable standard error as considered by one of ordinary skill in the art.

The term "effective amount" as referred to herein refers to an amount of a component sufficient to produce a desired response. For therapeutic purposes, an effective amount is also an amount in which the therapeutically beneficial effects of the component outweigh the toxic or deleterious effects. An effective amount of a drug need not cure a disease or condition, but may delay, hinder or prevent the onset of the disease or condition, or alleviate the disease or condition, and treat the disease or condition. An effective amount may be administered once, twice or more times within a given period of time, divided into one, two or more doses in an appropriate dosage form. The specific effective or sufficient amount will vary depending on factors such as the particular condition being treated, the physical condition of the patient (e.g., the patient's weight, age, or sex), the type of mammal or animal being treated, the duration of treatment, the nature of any concurrent therapy (if any), the particular formulation employed, the structure of the compound or its derivatives, and the like. An effective amount may be expressed, for example, in cell counts, grams, milligrams or micrograms, or as milligrams per kilogram of body weight (mg/Kg). Alternatively, the effective amount can be expressed as a concentration (e.g., cell concentration, molar concentration, mass concentration, volume concentration, mass molar concentration, molar fraction, mass fraction, and mixture ratio) of the active ingredient (e.g., a compound of the present disclosure). One of skill in the art can calculate the human equivalent dose (HED) of a pharmaceutical agent (such as a compound of the present invention) based on the dose determined from an animal model. For example, the maximum safe dose for use in human subjects can be estimated according to industry guidance issued by the U.S. Food and Drug Administration (FDA) entitled "Estimation of the Maximum Safe Starting Dose for Early Clinical Trials of Therapeutic Agents in Healthy Adult Volunteers."

The following describes an embodiment of the present invention. The following embodiment is merely an example, and the scope of the present invention is not limited to the embodiment described below. Note that explanations of similar content will be omitted as appropriate to avoid repetition.

Pharmaceutical Composition In the present embodiment, a pharmaceutical composition for promoting tear secretion or a pharmaceutical composition for preventing or treating a corneal and conjunctival disorder is provided. The pharmaceutical composition for promoting tear secretion or a pharmaceutical composition for preventing or treating a corneal and conjunctival disorder according to the present embodiment contains a compound that increases intracerebral noradrenaline concentration as an active ingredient.

Compounds that increase brain noradrenaline concentrations include serotonin-noradrenaline reuptake inhibitors (SNRIs), selective noradrenaline reuptake inhibitors, and tetracyclic antidepressants. In one embodiment, the compound that increases brain noradrenaline concentrations is at least one selected from the group consisting of serotonin-noradrenaline reuptake inhibitors, selective noradrenaline reuptake inhibitors, and tetracyclic antidepressants. In another embodiment, the compound that increases brain noradrenaline concentrations is a serotonin-noradrenaline reuptake inhibitor and/or a selective noradrenaline reuptake inhibitor.

Serotonin-noradrenaline reuptake inhibitors include venlafaxine, O-desmethylvenlafaxine, duloxetine, clomipramine, desmethylclomipramine, milnacipran, and imipramine, and pharmacologically acceptable salts thereof. In some embodiments, serotonin-noradrenaline reuptake inhibitors do not include venlafaxine and its pharmacologically acceptable salts.

Selective noradrenaline reuptake inhibitors include reboxetine, atomoxetine, and pharmacologically acceptable salts thereof.

Tetracyclic antidepressants include maprotiline, mianserin, and setiptiline, as well as pharmacologically acceptable salts thereof.

Pharmacologically acceptable salts include acid addition salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid) and organic acids (e.g., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, paratoluenesulfonic acid, and glutamic acid).

The pharmaceutical composition of this embodiment is administered in an amount effective to promote tear secretion, whether administered alone or in combination with other therapeutic agents.

The concentration of the serotonin-noradrenaline reuptake inhibitor in the pharmaceutical composition of this embodiment may be 0.15 wt% or more. In one embodiment, the concentration of the serotonin-noradrenaline reuptake inhibitor is 0.15 to 10 wt%, and may be within a range between any two values selected from the group consisting of 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 wt% (e.g., 0.2 to 5 wt%).

In one embodiment, the concentration of milnacipran or a pharmacologically acceptable salt thereof in the pharmaceutical composition is 0.15 to 10 wt%, and may be within a range between any two values selected from the group consisting of 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 wt% (e.g., 0.2 to 5 wt%).

In one embodiment, the concentration of duloxetine or a pharmacologically acceptable salt thereof in the pharmaceutical composition is 0.15 to 10 wt%, and may be within a range between any two values selected from the group consisting of 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 wt% (e.g., 0.2 to 5 wt%).

The concentration of the selective noradrenaline reuptake inhibitor in the pharmaceutical composition of this embodiment may be 0.3 wt% or more. In one embodiment, the concentration of the selective noradrenaline reuptake inhibitor is 0.3 to 10 wt%, and may be within a range between any two values selected from the group consisting of 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 wt% (e.g., 0.5 to 5 wt%).

In one embodiment, the concentration of atomoxetine or a pharmacologically acceptable salt thereof in the pharmaceutical composition is 0.3 to 10 wt%, and may be within a range between any two values selected from the group consisting of 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 wt% (e.g., 0.3 to 5 wt%).

The concentration of the tetracyclic antidepressant in the pharmaceutical composition of this embodiment may be 0.15 wt% or more. In some embodiments, the concentration of the tetracyclic antidepressant is 0.15 to 10 wt%, and may be within a range between any two values selected from the group consisting of 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 wt% (e.g., 0.15 to 0.5 wt%).

In one embodiment, the concentration of maprotiline or a pharmacologically acceptable salt thereof in the pharmaceutical composition is 0.15 to 10 wt%, and may be within a range between any two values selected from the group consisting of 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 wt% (e.g., 0.15 to 0.5 wt%).

The total dosage of the serotonin-noradrenaline reuptake inhibitor, selective noradrenaline reuptake inhibitor, or tetracyclic antidepressant, and any combination thereof, may be determined by the attending physician within the scope of sound medical judgment. The effective amount for a subject may depend on the severity of the subject; the subject's age, weight, general health, sex, and diet; the time of administration; the route of administration; the rate of excretion or degradation of the serotonin-noradrenaline reuptake inhibitor, selective noradrenaline reuptake inhibitor, or tetracyclic antidepressant; the duration of treatment; and any other drugs used in combination or concomitantly with the composition. The dosage of the composition need not be a constant amount per administration. For example, a lower dosage may be administered than is necessary to achieve the desired effect, and the dosage may be gradually increased until the desired effect is achieved.

"Corneal and conjunctival disorders" refers to disorders of the cornea and/or conjunctiva, including dry eye, Sjögren's syndrome, Stevens-Johnson syndrome, keratoconjunctivitis, etc., and is preferably dry eye.

"Prevention" means preventing, inhibiting, or delaying a decrease in tear secretion, maintaining tear secretion, increasing tear secretion, and/or preventing, inhibiting, or delaying the onset of corneal and conjunctival disorders.

"Treatment" means preventing, inhibiting, or delaying the decrease in tear production, maintaining tear production, increasing tear production, and/or curing, alleviating, ameliorating, or suppressing the symptoms of keratoconjunctival disorders, and "treatment" includes "prevention."

The pharmaceutical composition according to this embodiment is for ophthalmic use, and is preferably for eye drops. The pharmaceutical composition according to this embodiment can be used as an ophthalmic agent such as a medicine or a quasi-drug. Here, ophthalmic agents include eye drops, artificial tears, eyewashes, eye ointments, contact lens wetting solutions, contact lens care agents (including contact lens disinfectants, contact lens preservatives, contact lens cleaners, contact lens cleaning and preservatives, etc.), etc.

The pharmaceutical composition of this embodiment may be adjusted to various pH levels depending on the purpose. The pH is preferably 3 to 12, more preferably 4 to 11, even more preferably 5 to 10, even more preferably 5 to 9, and even more preferably 5 to 8.

The dosage and frequency of administration of the pharmaceutical composition of this embodiment can be appropriately selected depending on the symptoms of the subject. For example, about 1 to 3 drops may be administered to an adult about 1 to 6 times per day.

The pharmaceutical composition according to this embodiment is suitably formulated with a pharmaceutical carrier as needed. Examples of pharmaceutical carriers include solvents, solubilizers, emulsifiers, isotonicity agents, buffers, pH adjusters, and the like. Furthermore, any known additives or pharmacologically acceptable additives commonly used in the pharmaceutical field, such as stabilizers, preservatives, and antioxidants, can also be used as needed.

Solvents include, but are not limited to, purified water, ethanol, propylene glycol, polyethylene glycol, macrogol, edible oils (sesame oil, corn oil, olive oil, etc.), etc. Solubilizers include, but are not limited to, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, etc.

The emulsifier is not particularly limited, but examples thereof include carmellose, hydroxypropyl cellulose, propylene glycol, polyvinylpyrrolidone, methylcellulose, glycerin monostearate, polyvinyl alcohol, lecithin (egg yolk lecithin, soybean lecithin), deoxycholic acids, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan monooleate (polysorbate 80), polyoxyethylene sorbitan monolaurate, etc., with lecithin being preferred and egg yolk lecithin being more preferred. The content of the emulsifier may be 0.1 to 3.0 w/v% of the total pharmaceutical composition.

Isotonicity agents are not particularly limited, but examples include glucose, D-sorbitol, sodium chloride, D-mannitol, glycerin, etc., with glycerin being preferred. The amount of glycerin contained is calculated to make the pharmaceutical composition isotonic as a whole.

Buffering agents include, but are not limited to, citrates (trisodium citrate dihydrate, sodium citrate, disodium citrate, etc.), phosphates (sodium dihydrogen phosphate, sodium phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, etc.), borates (sodium borate, potassium borate), acetates (sodium acetate trihydrate, sodium acetate, potassium acetate, etc.), carbonates (sodium carbonate, sodium bicarbonate, etc.), etc.

Examples of pH adjusters include, but are not limited to, hydrochloric acid and sodium hydroxide.

The stabilizer is not particularly limited, but examples thereof include EDTA, sodium oleate, casein, and sodium caseinate. EDTA includes EDTA-2Na and EDTA-4Na. The content of EDTA may be 0.001 to 0.1 w/v% of the total pharmaceutical composition.

Preservatives include, but are not limited to, quaternary ammonium salts (benzalkonium chloride, benzethonium chloride, etc.), paraoxybenzoic acid esters (ethyl paraoxybenzoate, methyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate), chlorhexidine gluconate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, etc.

Examples of antioxidants include polyphenols, ascorbic acid, t-butylhydroquinone, butylhydroxyanisole, butylhydroxytoluene, L-cysteine hydrochloride, sodium sulfite, sodium hydrogen sulfite, α-tocopherol, and derivatives thereof.

Method for promoting tear secretion or method for preventing or treating a corneal and conjunctival disorder In another embodiment, a method for promoting tear secretion or a method for preventing or treating a corneal and conjunctival disorder is provided.

The method for promoting tear secretion includes a step of administering the pharmaceutical composition for promoting tear secretion to the eye of a subject. The method for preventing or treating a corneal and conjunctival disorder includes a step of administering the pharmaceutical composition for preventing or treating a corneal and conjunctival disorder to the eye of a subject.

The term "subject" refers to an animal, including humans, treatable by the pharmaceutical compositions and/or methods of the present embodiments. The term "subject" is intended to refer to both male and female genders, unless one gender is specified. Thus, the term "subject" includes any mammal that can benefit from the methods of the present disclosure. Examples of "subjects" include, but are not limited to, humans, rats, mice, guinea pigs, monkeys, pigs, goats, cows, horses, dogs, cats, birds, and chickens. In an exemplary embodiment, the subject is a human.

Use of a compound that increases intracerebral noradrenaline concentration In another embodiment, there is provided the use of a compound that increases intracerebral noradrenaline concentration for the manufacture of a pharmaceutical composition for promoting tear secretion or a pharmaceutical composition for the prevention or treatment of corneal and conjunctival disorders.

The samples shown in Table 1 were instilled into the eyes of rabbits to test whether each sample had a tear secretion effect.

Milnacipran hydrochloride was purchased from Tokyo Chemical Industry Co., Ltd., venlafaxine hydrochloride from BLD Pharmatech, duloxetine hydrochloride from Tokyo Chemical Industry Co., Ltd., sertraline hydrochloride from Combi-Blocks, and atomoxetine hydrochloride from Tokyo Chemical Industry Co., Ltd. Maprotiline hydrochloride was purchased from Tokyo Chemical Industry Co., Ltd. Purified water (ultrapure water) was produced using an ultrapure water production system (ADVANTEC, model: RFU666HA).

A 3% venlafaxine hydrochloride solution (sample No. 6) was prepared by adding 0.3 mL of PBS(+) and 0.67 mL of ultrapure water to 30 mg of venlafaxine hydrochloride.

Each sample was administered to rabbits (male, Japanese white) by eye drop. For samples 1 to 6 and 10, physiological saline (Otsuka saline injection, serial number: 0C71S, Otsuka Pharmaceutical Factory, Inc.) was used as a control. For samples 7 to 9, 5% glucose was used as a control. For samples 11 to 13, PBS(-) was used as a control. For samples 14 to 16, 10 mM glutamic acid-Na glutamic acid buffer (pH 4.25) (L-glutamic acid (Fujifilm Wako Pure Chemical Industries, Ltd.), L-sodium glutamate "For manufacturing only" (Fujifilm Wako Pure Chemical Industries, Ltd.)) was used as a control. The dose of each sample and control was 50 μL/eye. 12 minutes after administration of each sample, the rabbit was restrained with an Oshida-type fixator and ocular surface anesthesia was performed with oxyprocaine eye drop. 15 minutes after administration of the sample (3 minutes after ocular surface anesthesia), a Schirmer test strip (Ayumi Pharmaceutical) folded at the fold line at the tip was inserted into the conjunctival sac of the rabbit's lower eyelid. One minute after insertion, the Schirmer test strip was removed from the rabbit, and the wetted length of the Schirmer test strip (Schirmer value (mm/min)) was read from the memory printed on the strip.

Samples No. 1 to 5
Significant differences were detected in the groups administered 0.2%, 1% and 5% milnacipran hydrochloride, a serotonin-noradrenaline reuptake inhibitor, compared to the group administered physiological saline (Tables 2 and 3).

Sample No. 6
No significant difference was detected between the saline eye drop treatment group and the 3% venlafaxine hydrochloride eye drop treatment group, a serotonin-noradrenaline reuptake inhibitor (Table 4, paired t-test).

Samples No. 7 to 9
A significant difference was detected between the group administered 0.2% eye drops of duloxetine hydrochloride, a serotonin-noradrenaline reuptake inhibitor, and the group administered 5% glucose solution (Table 5).

Sample No. 10
No significant difference was detected between the saline eye drop treatment group and the selective serotonin reuptake inhibitor sertraline hydrochloride 0.1% eye drop treatment group (Table 6, paired t-test).

Samples No. 11 to 13
A significant difference was detected in the group administered 0.5% atomoxetine hydrochloride, a selective noradrenaline reuptake inhibitor, compared to the group administered PBS(-) (Table 7).

Samples No. 14 to 16
A significant difference in tear secretion was detected between the saline eye drop administration group and the 0.25% and 0.5% eye drop administration groups of 0.5% maprotiline hydrochloride solution, a tetracyclic antidepressant (nonselective monoamine reuptake inhibitor) (Table 8).

In conclusion, sertraline hydrochloride, a selective serotonin reuptake inhibitor, did not exhibit a tear secretion promoting effect when used as an eye drop. Milnacipran hydrochloride and duloxetine hydrochloride, which are serotonin and noradrenaline reuptake inhibitors, atomoxetine hydrochloride, a selective noradrenaline reuptake inhibitor, and maprotiline hydrochloride solution, a tetracyclic antidepressant, exhibited a tear secretion promoting effect, while venlafaxine hydrochloride did not.

Claims (8)

A pharmaceutical composition for promoting tear secretion, comprising as an active ingredient a compound that increases intracerebral noradrenaline concentration,
The pharmaceutical composition for promoting lacrimal secretion is for ophthalmic use.
A pharmaceutical composition for promoting tear secretion (provided that the compound that increases intracerebral noradrenaline concentration excludes venlafaxine or a pharmacologically acceptable salt thereof). The pharmaceutical composition for promoting tear secretion according to claim 1, wherein the compound that increases the brain noradrenaline concentration is at least one selected from the group consisting of serotonin-noradrenaline reuptake inhibitors, selective noradrenaline reuptake inhibitors, and tetracyclic antidepressants. The concentration of the serotonin-noradrenaline reuptake inhibitor is 0.15 wt % or more;
The selective noradrenaline reuptake inhibitor has a concentration of 0.3 wt % or more;
The concentration of the tetracyclic antidepressant is 0.15 wt % or more;
The pharmaceutical composition for promoting tear secretion according to claim 2. The serotonin-noradrenaline reuptake inhibitor is duloxetine or a pharmacologically acceptable salt thereof, or milnacipran or a pharmacologically acceptable salt thereof;
the selective noradrenaline reuptake inhibitor is atomoxetine or a pharmacologically acceptable salt thereof;
The tetracyclic antidepressant is maprotiline or a pharmacologically acceptable salt thereof.
The pharmaceutical composition for promoting tear secretion according to claim 2 or 3. A pharmaceutical composition for preventing or treating a corneal and conjunctival disorder, comprising a compound that increases intracerebral noradrenaline concentration as an active ingredient,
The preventive or therapeutic agent for corneal and conjunctival disorders is for ophthalmic use.
A pharmaceutical composition for preventing or treating corneal and conjunctival disorders (provided that the compounds that increase intracerebral noradrenaline concentration exclude venlafaxine or a pharmacologically acceptable salt thereof). The pharmaceutical composition for preventing or treating corneal and conjunctival disorders according to claim 5, wherein the compound that increases the brain noradrenaline concentration is at least one selected from the group consisting of serotonin-noradrenaline reuptake inhibitors, selective noradrenaline reuptake inhibitors, and tetracyclic antidepressants. The concentration of the serotonin-noradrenaline reuptake inhibitor is 0.15 wt % or more;
The selective noradrenaline reuptake inhibitor has a concentration of 0.3 wt % or more;
The concentration of the tetracyclic antidepressant is 0.15 wt % or more;
The pharmaceutical composition for preventing or treating a corneal and conjunctival disorder according to claim 6. The serotonin-noradrenaline reuptake inhibitor is duloxetine or a pharmacologically acceptable salt thereof, or milnacipran or a pharmacologically acceptable salt thereof;
the selective noradrenaline reuptake inhibitor is atomoxetine or a pharmacologically acceptable salt thereof;
The tetracyclic antidepressant is maprotiline or a pharmacologically acceptable salt thereof.
The pharmaceutical composition for preventing or treating a corneal and conjunctival disorder according to claim 6 or 7.