JP6698345B2 - Tear secretion promoting composition - Google Patents

Description

  The present invention relates to ophthalmic compositions. In particular, it relates to a composition for promoting lacrimal secretion and a composition for suppressing lacrimal secretion.

  Dry eye symptom is a chronic disease of tear fluid and corneal conjunctival epithelium caused by various factors, and one of the factors that has been attracting attention in recent years is work performed while observing the display screen (VDT) of a personal computer (PC) (VDT work ) Has a load on the eyes.

  With the improvement of IT technology and the enhancement of Internet infrastructure, the chances of using a PC in daily life have increased dramatically. According to an estimate by Intel Corp. in the United States, there are about 1 billion PCs connected to the Internet in the world, and most office workers are now working while looking at VDT (Visual Display Terminals). With the increasing frequency of use of PCs, an increasing number of people are complaining of dry eye symptoms that may be caused by VDT work, and dry eye symptoms are beginning to be taken up as a serious health problem in industrialized countries. It is said that there are more than 8 million dry eye patients in Japan, and the market size of a therapeutic agent for keratoconjunctival diseases associated with dry eye has expanded further in recent years. It is considered that VDT work reduces the number of blinks to about one-fourth that of normal blinks and increases the evaporation of tears, which is one of the causes of the onset of dry eye symptoms.

  As a method of alleviating this dry eye symptom, there is a method of externally replenishing the insufficient tear fluid by instilling artificial tear fluid, or a method of inserting a plug called a punctal plug into the punctum to close the punctum. It has been used a lot. However, both methods are only temporary symptomatic treatments. Therefore, instead of such symptomatic treatment, there is a demand for a composition that fundamentally improves symptoms such as eye strain, eye dryness, foreign body sensation or discomfort by increasing the amount of tear secretion. There is.

In December 2010, Santen Pharmaceutical Co., Ltd. launched Diquas (registered trademark), which is a P2Y ₂ receptor agonist, as a composition for increasing the amount of tears. This preparation acts on the P2Y ₂ receptor on the conjunctival epithelium and goblet cell membrane, and promotes secretion of water and mucin by increasing intracellular calcium concentration, thereby exerting an effect on dry eye. Unlike conventional symptomatic treatments such as artificial tear instillation and insertion of punctal plugs, this formulation is a breakthrough drug in that it promotes the production of dry eye by promoting tear secretion. However, since it is an eye drop, it takes time and effort to apply it several times a day.

In addition, as another composition that promotes tear secretion, an agent for promoting tear secretion and a keratoconjunctival disorder containing an angiotensin converting enzyme (ACE) inhibitor as an active ingredient (Patent Document 1), angiotensin converting enzyme (ACE). Lacrimal secretion promoting composition containing an inhibitory peptide as an active ingredient (Patent Document 2), Lacrimal secretion promoting composition containing an angiotensin II receptor antagonist (ARB) as an active ingredient (Patent Document 3), and chymase inhibition A tear secretion promoter (Patent Document 4) containing a drug as an active ingredient is disclosed. In addition, PAR-2 (Protease-activated re
It has been disclosed that a peptide that activates ceptor-2/protease-activated receptor 2) has a lacrimal secretion promoting action (Patent Documents 5 and 6), and development of new lacrimal secretion promoting preparation is expected To be done.

JP, 10-218792, A JP2012-136440A JP2012-121827A JP, 2001-58958, A JP 2001-181208 A JP, 2005-187482, A

However, the above-mentioned patent documents do not disclose any relation between the serotonin activity in the brain and the lacrimal secretion. The relationship between serotonin 5-HT ₃ receptor agonists or antagonists and lacrimal secretion was unknown.

  An object of the present invention is to provide a composition capable of regulating lacrimal gland secretion, which can be used for treatment of diseases and the like based on lacrimal gland secretion.

As a result of intensive studies, the present inventors have shown that a serotonin 5-HT ₃ receptor agonist or antagonist, particularly orally administered, can exert a high lacrimal secretion promoting effect or suppressive effect. The present invention has been completed and the present invention has been completed.

  That is, the present invention includes the following aspects.

Item 1. A lacrimal secretion regulating composition containing, as an active ingredient, a serotonin 5-HT ₃ receptor agonist or antagonist.

Item 2. The composition according to Item 1, which is a composition for promoting lacrimal secretion containing the agonist of serotonin 5-HT ₃ receptor as an active ingredient.

Item 3. The composition according to Item 2, wherein the serotonin 5-HT ₃ receptor agonist is SR 57227A.

Item 4. The composition according to Item 1, which is a composition for suppressing tear secretion containing an antagonist of serotonin 5-HT ₃ receptor as an active ingredient.

Item 5. The composition according to Item 4, wherein the serotonin 5-HT ₃ receptor antagonist is ondasetron or a pharmaceutically acceptable salt thereof.

  Item 6. The lacrimal secretion promoting composition according to any one of Items 1 to 5, which is an oral agent.

Item 7. A prophylactic or therapeutic agent for keratoconjunctival disorders, which comprises the serotonin 5-HT ₃ receptor agonist as an active ingredient.

  Item 8. The preventive or therapeutic agent according to Item 8, wherein the keratoconjunctival disorder is dry eye.

Item 9. A prophylactic or therapeutic drug for lacrimation comprising the serotonin 5-HT ₃ receptor antagonist as an active ingredient.

The lacrimal secretion regulating composition containing the agonist or antagonist of the serotonin 5-HT ₃ receptor of the present invention can regulate lacrimal secretion. For example, when a serotonin 5-HT ₃ receptor agonist having a lacrimal secretion promoting effect is used, lacrimal secretion can be promoted and a decrease in lacrimal secretion due to maintenance stress can be prevented.

Effect of tryptophan deficient diet on tear production. (A) Changes in blood 5-HT concentration and body weight. N=6, mean ± standard deviation, ***p <0.001 vs day 0. (B) Change in tear volume. N=6, mean ± standard deviation, ***p <0.001 vs Control. Effect of 5-HT administration to tryptophan-deficient mice. N=6, mean±standard deviation, ***p<0.001 vs Vehicle. Effect of administration of serotonin 5-HT ₃ receptor agonists and antagonists. (A) Effect of antagonist administration on lacrimal gland weight and lacrimal secretion. N=5, mean ± standard deviation, ***p <0.001 vs Saline. (B) Effect of administration of an agonist on the lacrimal secretion under the condition of lowering blood 5-HT concentration. Administration of the agonist was started one day before the switch to a tryptophan-deficient diet. N=5, mean±standard deviation, ***p<0.001 vs Vehicle. (C) Effect of agonist administration on lacrimal gland weight. N=5, mean±standard deviation, ***p<0.001 vs Vehicle. (D) Histological changes in the lacrimal gland. (E) Western blot analysis of the orphany marker LC3-II. Intracellular calcium ion concentrations of serotonin 5-HT ₃ receptor agonist in the lacrimal gland ([Ca2 +] i) Effect of the (A) 5-HT. (B) SR57227A. (C) Effect of Ca 2+ free and serotonin 5-HT ₃ receptor antagonists. (D) Expression analysis of serotonin 5-HT ₃ receptor subtypes at the receptor. SR57227A enhances lacrimal secretion in normal mice. N=5, mean ± standard deviation, * p <0.05 vs pre-dose (0). Inhibition of SR57227A on decreased lacrimal secretion in mouse stress-induced dry eye model. N=5, mean±standard deviation, *p<0.05 vs solvent control.

  As used herein, the term "prevention" refers to preventing, suppressing, or delaying the decrease or increase in the amount of lacrimal fluid secretion, maintaining the amount of lacrimal fluid secretion, and increasing or decreasing the amount of lacrimal fluid secretion. And/or preventing, suppressing, or delaying the onset of corneal and/or conjunctival disorders (hereinafter referred to as keratoconjunctival disorders) or lacrimal disease.

  As used herein, the term "treatment" prevents, suppresses, or delays the decrease or increase in tear production, maintains the tear production, and increases or decreases the tear production. And/or to cure, alleviate, ameliorate, or suppress the symptoms of keratoconjunctival disorder or lacrimation, and “treatment” includes “prevention”.

According to one aspect of the present invention, there is provided a lacrimal secretion promoting composition containing a serotonin 5-HT ₃ receptor agonist as an active ingredient.

According to another aspect of the present invention, there is provided a composition for suppressing lachrymal secretion, which comprises a serotonin 5-HT ₃ receptor antagonist as an active ingredient.

According to still another aspect of the present invention, there is provided a preventive or therapeutic agent for keratoconjunctival disorders, which comprises a serotonin 5-HT ₃ receptor agonist as an active ingredient.

According to still another aspect of the present invention, there is provided use of a serotonin 5-HT ₃ receptor agonist for the manufacture of a prophylactic or therapeutic agent for keratoconjunctival disorders or a composition for promoting tear secretion.

According to still another aspect of the present invention, there is provided a prophylactic or therapeutic agent for lacrimation, which comprises a serotonin 5-HT ₃ receptor antagonist as an active ingredient.

According to still another aspect of the present invention, there is provided use of a serotonin 5-HT ₃ receptor antagonist for the production of a prophylactic or therapeutic agent for lacrimation or a composition for promoting tear secretion.

The keratoconjunctival disorder includes dry eye, Sjogren's syndrome, Stevens-Johnson syndrome, keratoconjunctivitis and the like, and preferably dry eye.

The keratoconjunctival disorder includes dry eye, Sjogren's syndrome, Stevens-Johnson syndrome, keratoconjunctivitis and the like, and preferably dry eye.

  Lacrimal disease (also known as "blunt eyes") is a symptom of irritating eyes or overflowing tears.

The serotonin 5-HT ₃ receptor is one subtype of the serotonin receptor whose expression can be confirmed in the central nervous system and the peripheral nervous system. The serotonin 5-HT ₃ receptor is known to be an ion channel type receptor.

“Serotonin 5-HT ₃ receptor agonist” (also referred to as “agonist”) refers to a compound that binds to serotonin 5-HT ₃ receptor and activates the receptor.

The “antagonist of serotonin 5-HT ₃ receptor” (also referred to as “antagonist”) refers to a compound that binds to serotonin 5-HT ₃ receptor and inhibits activation of the receptor.

Serotonin 5-HT ₃ receptor agonists or antagonists are those having an effect on the serotonin 5-HT ₃ non receptor receptor selectively do not act on serotonin receptors other than serotonin 5-HT ₃ receptor Including any of the Preferred are agonists or antagonists selective for serotonin 5-HT ₃ receptors.

Serotonin 5-HT ₃ receptor agonists include serotonin, m-chlorophenylbiguanide, 2-methyl-5-hydroxytryptamine (2-methyl-5-HT) (2-Methyl-5-hydroxytryptamine). ), N-Methylquipazine (N-Methylquipazine), 1-Phenylbiguanide, Quipazine, RS 56812 ((R)-N-(1-Azabicyclo[2.2.2]oct-3-yl) -2-(1-methyl-1H-indol-3-yl)-2-(1-methyl-1H-indol-3-yl)-2-oxoacetamide), SR 57227 (1-(6-Chloro-2- pyridinyl)-4-piperidinamine hydrochloride) and the like. You may use these individually or in mixture of 2 or more types.

Preferred serotonin 5-HT ₃ receptor agonists include SR 57227 or its hydrochloride.

Examples of serotonin 5-HT ₃ receptor antagonists include metoclopramide (particularly, administration at high dose), renzapride, ondansetron, alosetron, memantine and the like. You may use these individually or in mixture of 2 or more types.

The serotonin 5-HT ₃ receptor agonist or antagonist may be a pharmaceutically acceptable salt, and such salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphorus. Inorganic acids such as acids, 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, paratoluene It may be an acid addition salt with an organic acid such as sulfonic acid or glutamic acid. The agonist or antagonist may be a commercially available product, or can be produced by a known method.

Preferred serotonin 5-HT ₃ receptor agonists include SR 57227 or its hydrochloride.

The antagonists of the preferred serotonin 5-HT ₃ receptor include Ondansetoro down.

  The preventive or therapeutic agent or pharmaceutical composition of the present invention can be mixed with a pharmaceutical carrier as necessary, and various administration forms can be adopted according to the purpose of prevention or treatment, and oral administration, intravenous administration, transmucosal administration can be performed. Various administration methods such as administration, subcutaneous administration, intramuscular administration, and ocular topical administration can be appropriately selected, and these administration forms can be manufactured by conventional formulation methods known to those skilled in the art. The prophylactic or therapeutic agent or pharmaceutical composition of the present invention is preferably administered in a dosage form other than eye drops, and is preferably orally administered. In the case of oral preparations, tablets, granules, powders, capsules, liquids (including syrups, water, suspensions, emulsions, pills, elixirs and the like can be appropriately selected from these dosage forms. Modifications such as stabilization, easy absorption, sustained release, easy disintegration, and difficult disintegration can be applied.

  As the pharmaceutical carrier, various organic or inorganic carrier substances that are commonly used as a formulation material are used. Excipients, binders, disintegrating agents, lubricants, coloring agents in solid formulations; solvents, solubilizing agents, suspending agents in liquid formulations It is blended as a turbidity agent, a tonicity agent, a buffering agent, a soothing agent and the like. If necessary, the formulation may further contain additives such as an excipient, a binder, a lubricant, a stabilizer, a preservative, a solvent, a base, a coating agent, a flavoring agent or a coloring agent. May be.

The additive is not particularly limited as long as it is generally used for oral administration. Specific examples of the additives that can be used are shown below.
(1) Excipients: starches, lactose, sucrose, glucose, mannitol, calcium sulfate, calcium carbonate, talc, trehalose, xylitol.
(2) Binders: starch, cellulose, gelatin, sodium alginate, polyvinyl alcohol, polyvinylpyrrolidone, gum arabic, dextrin.
(3) Lubricants: sucrose fatty acid ester, polyethylene glycol, talc, waxes, stearic acid and salts thereof.
(4) Stabilizers: ascorbic acid, chelating agents, reducing substances, tocopherols, sodium bisulfite.
(5) Preservatives: benzoic acid and its salts, paraoxybenzoic acid esters, chlorobutanol.
(6) Solvent: Purified water, physiological saline, ethanol, glycerin, vegetable oils.
(7) Base: Vaseline, vegetable oils, talc, macrogol.
(8) Coating agent: sucrose, gelatin, hydroxypropyl methylcellulose.
(9) Flavoring agents: white sugar, glucose, saccharin, xylitol, ascorbic acid, citric acid, menthol.
(10) Colorant: Water-soluble food dye.

  The preparation of the present invention can be produced according to a conventional method (for example, the method described in the 16th revised Japanese Pharmacopoeia general rules).

When the composition of the present invention is a food composition, a serotonin 5-HT ₃ receptor agonist or antagonist is contained as an ingredient in the food that regulates the secretion of tears. The food may be a food for specified health use, a food with health claims such as a food with functional claims and a food with nutritional claims, or a general food including health foods and food supplements.

The amount of the agonist or antagonist of the serotonin 5-HT ₃ receptor in the prophylactic or therapeutic agent or composition of the present invention varies depending on the symptoms, age, dosage form, etc. of the subject, but when administered orally, the weight of the subject The daily dose is 0.01 mg/kg to 20 mg/kg, preferably 0.05 mg/kg to 10 mg/kg per day, divided into 1 to several times, preferably 1 to 3 times per day. When administered once or twice a day, it is general that the single dose is about 0.5 mg to 500 mg.

  In particular, if taken once a day, it is advantageous in that the administration frequency is lower than in the case of instillation, and the compliance is good while producing the effect.

  The administration period is not particularly limited, but for a certain period or more, for example, 4 days or more, 7 days or more, 10 days or more, 14 days or more, 20 days or more, or 1 month or more long-term administration, keratoconjunctival disorder or tearing It is more useful for prevention or treatment of.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the scope of the present invention is not limited thereto.

[Example 1] Tryptophan-deficient diet <Method>

Animal As a model animal, 8-week-old female C57BL/6 mouse (purchased from CLEA Japan) was used. The experiment was performed under the approval of the Animal Experiment Ethics Committee of Keio University School of Medicine.
Animals should be isolated and acclimated for 1 week prior to experimentation under conditions of temperature 23 ± 2°C, humidity 60 ± 10%, 12-hour light-dark cycle (8 am to 8 pm) and free access to food and water. Ingested.

As a standard diet for tryptophan-deficient diet , a feed based on the composition of AIN93G (Oriental yeast) was used. As a tryptophan-deficient diet, AIN93G from which tryptophan (Trp) was removed was used.
During the acclimatization period, they were given a standard diet and then switched to a tryptophan-deficient diet. Controls continued to receive the standard diet without switching to the tryptophan deficient diet.

Measurement of lacrimal secretion capacity The lacrimal secretion capacity was measured over 7 days of feeding a tryptophan-deficient diet.
A cotton thread (ZONE-QUICK (registered trademark), Showa Yakuhin Kako Co., Ltd.) was inserted into the left and right external canthus of the mouse for 15 seconds, and the length of the cotton thread that turned brown due to the permeation of tear fluid was measured with an accuracy of 0.5 mm. . The average of the left and right eyes was defined as the tear production amount of the individual.

Blood 5-HT Concentration Measurement Blood 5-HT concentration determined from the abdominal aorta was measured by the HPLC method.

<Results>
The results are shown in Figure 1. Blood 5-HT concentration gradually decreased one day after switching to a tryptophan-deficient diet, and decreased by about 70% on day 7 compared to before switching (Fig. 1A). During this period, the tear volume also gradually decreased, reaching a plateau from day 3 to day 7 with a decrease of approximately 20% from before switching (FIG. 1B).

[Example 2]
5-HT was intraperitoneally injected to the mice fed the tryptophan-deficient diet of Example 1. 5-HT was intraperitoneally injected 2 days after switching to a tryptophan-deficient diet. Then, the amount of tear secretion was measured at 5-minute intervals.

<Results>
The results are shown in Figure 2. Tear secretion was promoted depending on the amount of 5-HT administered. The promoting effect was observed between 5 and 10 minutes after the administration, and a remarkable effect was observed at the doses of 0.1 and 1 mg/kg.

[Example 3]
The effects of administration of serotonin 5-HT ₃ receptor agonists and antagonists to mice were evaluated.
As controls, Way-100635, an antagonist of serotonin 5-HT _1a receptor, Antagonist of serotonin 5-HT _2a receptor, and SB269970 of serotonin 5-HT ₇ receptor antagonist were used.

<Method>
With SR57227A as agonists of serotonin 5-HT ₃ receptor. The dose of agonist was 72 μg/kg/day.

Using warm Setoron as antagonists of serotonin 5-HT ₃ receptor. Serotonin 5-HT ₃ Receptor Antagonist Controls Serotonin 5-HT _1a Receptor Antagonist Way-100635, Serotonin 5-HT _2a Receptor Antagonist and Serotonin 5-HT ₇ Receptor Antagonist SB269970 Was used. The dose of the antagonist was 120 μg/kg/day.

  The agonists and antagonists were continuously administered using an osmotic pump (Alzet) implanted subcutaneously on the ventral side of mice so that the dose was 0.24 μL per hour.

  Saline was used as the vehicle.

<Results>
Results are shown in FIG.

Uni I are shown in Figure 3A, the administration of warm Setoron, tear secretion was markedly decreased. No such reduction was seen with the administration of Way-100635, Keanserin and SB269970. A decrease in the lacrimal gland weight was also observed with the decrease in tear production.

  As shown in FIGS. 3B and 3C, when the agonist was administered to the mice fed the tryptophan-deficient diet according to the method of Example 1, recovery of the decrease in tear production was observed.

Figure 3D shows the histological changes in the lacrimal gland. It was observed that administration of ondansetron induces shrinkage of acinar cells in the lacrimal gland. Similar changes were observed when the tryptophan-deficient diet was administered. Acinar cell shrinkage was almost completely restored by administration of agonist.

  FIG. 3E shows the result of Western blotting of the autophagy marker LC3-II. Administration of ondansterone increased autophagy markers, and administration of SR57227A kept autophagy markers at normal levels.

[Example 4]
The effect of serotonin 5-HT ₃ receptor agonists on intracellular calcium ion concentration ([Ca ²⁺ ]i) in the lacrimal gland was evaluated.

<Method and result>
Measurement of intracellular calcium ion concentration [Ca ²⁺ ]i was measured by using lacrimal glands collected from Sprague-Dawley rats in a document: Imada T, Nakamura S & Kitamura N et al. PLoS One 9, e106338 (2014). It carried out according to the described method.

Results As shown in FIG. 4A, addition of 5-HT ₃ (0.1 to 10 μM) increases intracellular calcium ion concentration ([Ca ²⁺ ]i) in acinar cells of the lacrimal gland. The inventor of the present application found that [Ca ²⁺ ]i was also increased by adding SR57227A as shown in FIG. 4B.
As shown in FIG. 4C, addition of Ca ²⁺ free and ondansetron caused no increase in [Ca ²⁺ ]i, resulting in tear secretion via 5-HT ₃ receptor and Ca ²⁺ . it is conceivable that.
In addition, Ca ²⁺ free is CaCl ₂ in place of normal solution (140 mM NaCl, 5 mM KCl, 10 mM CaCl ₂ , 1 mM MgCl ₂ , 10 mM HEPES, 10 mM dextrose [pH 7.4]). _A solution containing no ₂ was used.

[Example 5]
And verify the effects of the serotonin 5-HT ₃ receptor agonist in a normal individual.

<Method>
In the same manner as in Example 2, SR57227A was single-administered at a dose of 0.1 mg/kg to a mouse ingesting a standard diet. The route of administration was intraperitoneal.
Tear fluid was measured before administration and at 5 minute intervals after administration until 30 minutes later.

<Results>
Results are shown in FIG. Ten minutes after the administration of the serotonin 5-HT ₃ receptor agonist, the lacrimal secretion amount significantly increased as compared with that before the administration (0). After that, it decreased and changed to the value before administration 30 minutes after administration.

[Example 6]
Using a mouse stress dry eye model, the preventive effect of dry eye of a serotonin 5-HT ₃ receptor agonist was evaluated.

<Method>
Reduction treatment (stress treatment)
Reference: Restraint stress was given to female 8-week-old C57BL/6 mice as described in Nakamura, S., Tanaka, J., Imada, T. et al. Journal of Functional Foods 10, 346-354 (2014). .. Mice are restrained in a polypropylene centrifuge tube (capacity approximately 60 ml) which has been subjected to respirable/excretable treatment for 4 hours a day. During restraint, air was blown to the face of the mouse (wind speed 0.5 to 1.0 m/s). Food and beverages were freely ingested in the cage except during the restraint time.

Drug administration Serotonin 5-HT ₃ receptor agonist (SR57227A) was administered at a dose of 10 mg/kg on the day before the stress treatment and immediately before the stress treatment. The route of administration was intraperitoneal.

Tear fluid measurement In the same manner as in Example 1, before the stress treatment, it was carried out at a proper time during the administration period.

<Results and discussion>
The results are shown in Fig. 6. The stress control reduced the tear production volume to about 1/4 in the solvent control, while SR57227A administration significantly suppressed the decrease in the tear production compared to the solvent control. This result indicates that administration of a serotonin 5-HT ₃ receptor agonist can be expected to have a dry eye preventive effect (suppress a decrease in tear secretion).

The above results suggest that a serotonin 5-HT ₃ receptor agonist or antagonist has an action of regulating the lacrimal secretion ability at a dose that can be taken by humans. In particular, it was confirmed that the agonist of serotonin 5-HT ₃ receptor can effectively suppress the dry eye symptoms of the test animals orally administered with the agent of the present invention.

Claims (9)

A lacrimal secretion regulating composition comprising, as an active ingredient, an agonist or antagonist of serotonin 5-HT ₃ receptor ,
The serotonin 5-HT ₃ receptor agonist is m-chlorophenyl biguanide, 2-methyl-5-hydroxytryptamine, N-methyl quipazine, 1-phenyl biguanide, quipazine, RS 56812(R)-N-(1-Azabicyclo). [2.2.2]oct-3-yl)-2-(1-methyl-1H-indol-3-yl)-2-(1-methyl-1H-indol-3-yl)-2-oxoacetamide), and SR 57227 (1-(6-Chloro-2-pyridinyl)-4-piperidinamine hydrochloride) alone or in combination of two or more, or a pharmaceutically acceptable salt thereof, wherein the serotonin 5-HT ₃ receptor A lacrimal secretion regulating composition, wherein the antagonist is renzapride, ondansetron, and alosetron, alone or in combination of two or more, or a pharmaceutically acceptable salt thereof . The composition according to claim 1, which is a composition for promoting tear secretion containing an agonist of serotonin 5-HT ₃ receptor as an active ingredient. The composition of claim 1 , wherein the serotonin 5-HT ₃ receptor agonist is SR 57227A. The composition according to claim 1, which is a composition for suppressing tear secretion containing an antagonist of serotonin 5-HT ₃ receptor as an active ingredient. Antagonists of serotonin 5-HT ₃ receptor is Onda emissions Setoron or a pharmaceutically acceptable salt thereof A composition according to claim 4.   The lacrimal secretion promoting composition according to any one of claims 1 to 5, which is an oral preparation. A preventive or therapeutic agent for keratoconjunctival disorders , which comprises a serotonin 5-HT ₃ receptor agonist as an active ingredient ,
The serotonin 5-HT ₃ receptor agonist is m-chlorophenyl biguanide, 2-methyl-5-hydroxytryptamine, N-methyl quipazine, 1-phenyl biguanide, quipazine, RS 56812(R)-N-(1-Azabicyclo). [2.2.2]oct-3-yl)-2-(1-methyl-1H-indol-3-yl)-2-(1-methyl-1H-indol-3-yl)-2-oxoacetamide), and A preventive or therapeutic agent for keratoconjunctival disorders, which is a single or two or more of SR 57227 (1-(6-Chloro-2-pyridinyl)-4-piperidinamine hydrochloride), or a pharmaceutically acceptable salt thereof . The preventive or therapeutic agent according to claim 7 , wherein the keratoconjunctival disorder is dry eye. A preventive or therapeutic agent for lacrimation comprising the serotonin 5-HT ₃ receptor antagonist as an active ingredient ,
A prophylactic or therapeutic agent for lacrimation, wherein the serotonin 5-HT ₃ receptor antagonist is renzapride, ondansetron, and alosetron, alone or in combination of two or more, or a pharmaceutically acceptable salt thereof. .