JP2017119637A - Lacrimation promoting composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To discover an agent that controls secretion of lacrimal fluid.SOLUTION: A lacrimation control composition comprises an agonist or antagonist for the serotonin 5-HTreceptor as an active ingredient.SELECTED DRAWING: None

Description

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

  Dry eye symptoms are chronic diseases of tears and keratoconjunctival epithelium due to various factors, and one of the factors that has been attracting attention in recent years is work performed while looking at the display screen (VDT) of a personal computer (PC) (VDT work) ) There is a load on the eyes.

  With the improvement of IT technology and Internet infrastructure, opportunities to use PCs in daily life are increasing dramatically. Intel estimates that there are about 1 billion PCs connected to the Internet in the world, and most office workers now work while looking at VDT (Visual Display Terminals). As the frequency of PC use increases, the number of people complaining of dry eye symptoms that are thought to be caused by VDT work is increasing, 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 people with dry eye in Japan, and the market size of the keratoconjunctival disease treatment agent associated with dry eye has been increasing further in recent years. VDT work reduces the number of blinks to about one-fourth the normal amount and increases tear evaporation, which is thought to contribute to the development of dry eye symptoms.

  As a method of relieving this dry eye symptom, there are a method of replenishing deficient tears from the outside by instilling artificial tears, and a method of closing a punctum by inserting a plug called a punctum plug into the punctum Many have been used. However, both methods are only temporary symptomatic treatments. Therefore, there is a need for a composition that fundamentally improves symptoms such as eye strain, dryness of the eyes, foreign body sensation, or discomfort by increasing the amount of tear secretion rather than such symptomatic treatment. Yes.

In December 2010, Santen Pharmaceutical launched Diquas (registered trademark), a P2Y ₂ receptor agonist, as a composition that increases the secretion of tears. This preparation acts on the P2Y ₂ receptor on the conjunctival epithelium and goblet cell membrane, and exerts an effect on dry eye by promoting secretion of water and mucin by increasing intracellular calcium concentration. Unlike conventional symptomatic treatments such as instillation of artificial tears and insertion of punctum plugs, this formulation is a revolutionary pharmaceutical product in that it exhibits a therapeutic effect on dry eye by promoting tear secretion. However, since it is an eye drop, it takes time and effort to instill several times a day.

Further, as other compositions for promoting lacrimal secretion, an agent for promoting lacrimal secretion and treating keratoconjunctive disorder (Patent Document 1) containing an angiotensin converting enzyme (ACE) inhibitor as an active ingredient, angiotensin converting enzyme (ACE) Tear secretion promoting composition containing an inhibitory peptide as an active ingredient (Patent Document 2), tear 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 peptides that activate ceptor-2 / protease-activated receptor 2) have a lacrimal secretion promoting action (Patent Documents 5 and 6), and future development of a new lacrimal secretion promoting preparation is expected. Is done.

Japanese Patent Laid-Open No. 10-218792 JP 2012-136440 A JP 2012-121827 A JP 2001-58958 A JP 2001-181208 A JP 2005-187482 A

However, the above-mentioned patent documents do not disclose any relationship between brain serotonin activity and lacrimation. The relationship between serotonin 5-HT ₃ receptor agonists or antagonists and lacrimation has not been known.

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

As a result of intensive studies, the present inventors can exert a high lacrimal secretion promoting effect or suppressing effect, particularly by orally administering a serotonin 5-HT ₃ receptor agonist or antagonist. As a result, the present invention has been completed.

  That is, the present invention includes the following aspects.

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

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

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

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

Item 5. The composition according to Item 4, wherein the antagonist of serotonin 5-HT ₃ receptor is ondacetron 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 preparation.

Item 7. A preventive or therapeutic agent for keratoconjunctival disorder, comprising a serotonin 5-HT ₃ receptor agonist as an active ingredient.

  Item 8. The preventive or therapeutic agent according to Item 6, wherein the keratoconjunctival disorder is dry eye.

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

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

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

  As used herein, “prevention” refers to preventing, suppressing, or delaying the decrease or increase in tear secretion, maintaining tear secretion, increasing or decreasing tear secretion. And / or preventing, suppressing, or delaying the onset of cornea and / or conjunctival disorder (hereinafter referred to as keratoconjunctival disorder) or lacrimation.

  In the present specification, “treatment” prevents, suppresses, or delays the decrease or increase in tear secretion, maintains the tear secretion, increases or decreases the tear secretion. And / or cure, alleviate, ameliorate, or suppress symptoms of keratoconjunctival disorder or lacrimation, and “treatment” includes “prevention”.

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

According to another aspect of the present invention, there is provided a tear secretion inhibiting composition comprising a serotonin 5-HT ₃ receptor antagonist as an active ingredient.

According to still another aspect of the present invention, there is provided a prophylactic or therapeutic agent for keratoconjunctival disorder, which contains 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 preventive or therapeutic agent for keratoconjunctival disorder or a composition for promoting lacrimal secretion.

According to still another aspect of the present invention, there is provided a prophylactic or therapeutic agent for lacrimation, comprising 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 manufacture of a preventive or therapeutic agent for lacrimation or a composition for promoting lacrimal secretion.

Examples of keratoconjunctival disorders include dry eye, Sjogren's syndrome, Stevens-Johnson syndrome, keratoconjunctivitis, and the like, preferably dry eye.

Examples of keratoconjunctival disorders include dry eye, Sjogren's syndrome, Stevens-Johnson syndrome, keratoconjunctivitis, and the like, preferably dry eye.

  Lacrimation (also referred to as “Namida eyes”) is a symptom of bloating eyes or overflowing tears.

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

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

A “serotonin 5-HT ₃ receptor antagonist” (also referred to as “antagonist”) refers to a compound that binds to the 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 anything. Preferably, it is an agonist or antagonist selective for the serotonin 5-HT ₃ receptor.

Serotonin 5-HT ₃ receptor agonists include serotonin, m-chlorophenylbiguanide, 2-methyl-5-hydroxytryptamine (2-methyl-5-HT) (2-Methyl-5-hydroxytryptamine) ), 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.

A preferred serotonin 5-HT ₃ receptor agonist includes SR 57227 or its hydrochloride salt.

Examples of serotonin 5-HT ₃ receptor antagonists include metoclopramide (especially high dose administration), 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, such as 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 Acid addition salts with organic acids such as sulfonic acid and glutamic acid may also be used. The agonist or antagonist may be commercially available, or can be produced by a known method.

A preferred serotonin 5-HT ₃ receptor agonist includes SR 57227 or its hydrochloride salt.

A preferred serotonin 5-HT ₃ receptor antagonist includes ondansetro.

  The preventive or therapeutic agent or pharmaceutical composition of the present invention can be blended with a pharmaceutical carrier as necessary, and various administration forms can be adopted depending on the purpose of prevention or treatment. Oral administration, intravenous administration, transmucosal Various administration methods such as administration, subcutaneous administration, intramuscular administration, and topical ocular administration can be selected as appropriate, and these administration forms can be produced by conventional formulation methods known to those skilled in the art. The preventive or therapeutic agent or pharmaceutical composition of the present invention is preferably administered in a dosage form other than eye drops, and particularly preferably administered orally. In the case of oral preparations, tablets, granules, powders, capsules, liquids (including syrups, liquids, suspensions, emulsions, pills, elixirs, etc. can be selected as appropriate. Modifications such as stabilization, easy absorption, sustained release, easy disintegration, and difficulty disintegration are also possible.

  For pharmaceutical carriers, various organic or inorganic carrier materials commonly used as pharmaceutical materials are used. Excipients, binders, disintegrants, lubricants, colorants in solid preparations; solvents, dissolution aids, suspensions in liquid preparations It is blended as a turbidity agent, tonicity agent, buffering agent, soothing agent and the like. If necessary, additives such as excipients, binders, lubricants, stabilizers, preservatives, solvents, bases, coating agents, corrigents, or coloring agents may be used in the preparation. May be.

The additive is not particularly limited as long as it is generally used for oral administration. Specific examples of additives that can be used are shown below.
(1) Excipients: starches, lactose, sucrose, glucose, mannitol, calcium sulfate, calcium carbonate, talc, trehalose, xylitol.
(2) Binder: starch, cellulose, gelatin, sodium alginate, polyvinyl alcohol, polyvinyl pyrrolidone, gum arabic, dextrin.
(3) Lubricant: sucrose fatty acid ester, polyethylene glycol, talc, waxes, stearic acid and salts thereof.
(4) Stabilizer: Ascorbic acid, chelating agent, reducing substance, tocopherol, sodium bisulfite.
(5) Preservative: benzoic acid and its salts, paraoxybenzoic acid esters, chlorobutanol.
(6) Solvent: purified water, physiological saline, ethanol, glycerin, vegetable oils.
(7) Base: Vaseline, vegetable oil, talc, macrogol.
(8) Coating agent: sucrose, gelatin, hydroxypropylmethylcellulose.
(9) Flavoring agents: sucrose, glucose, saccharin, xylitol, ascorbic acid, citric acid, menthol.
(10) Colorant: Water-soluble food coloring.

  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 Preparation General Rules).

When the composition of the present invention is a food composition, an agonist or antagonist of serotonin 5-HT ₃ receptor is contained as a component in food that regulates tear secretion. The food may be a general health food including a health food such as a food for specified health use, a functional labeling food, and a functional nutrition food, or a health food, and a food supplement.

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

  In particular, taking once a day is advantageous in that it requires less administration frequency than instillation and provides good compliance while producing effects.

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

EXAMPLES Hereinafter, although an Example and a test example are given and this invention is demonstrated further in detail, the scope of the present invention is not limited to these.

[Example 1] Tryptophan-deficient diet <Method>

Animals 8-week-old female C57BL / 6 mice (purchased from CLEA Japan) were used as model animals. The experiment was conducted with the approval of the Animal Experimentation Ethics Committee of Keio University School of Medicine.
Animals were quarantined and acclimatized one week prior to the experiment with free access to food and water under conditions of a temperature of 23 ± 2 ° C, humidity of 60 ± 10%, and a 12 hour light / dark cycle (8am to 8pm). Ingested.

As a standard tryptophan-deficient diet , a feed based on the composition of AIN93G (oriental yeast) was used. As the tryptophan-deficient diet, AIN93G from which tryptophan (Trp) was removed was used.
During the acclimation period, a standard diet was given and then switched to a tryptophan-deficient diet. Control continued to feed the standard diet without switching to a tryptophan-deficient diet.

Tear secretion ability measurement The tear secretion ability was measured over 7 days after a tryptophan-deficient diet.
A cotton thread (ZONE-QUICK (registered trademark), Showa Yakuhin Kako Co., Ltd.) was inserted into the left and right external eye corners of the mouse for 15 seconds, and the length of the cotton thread that was browned by tear penetration was measured with an accuracy of 0.5 mm. . The average of left and right eyes was taken as the amount of lacrimal secretion of the individual.

Measurement of blood 5-HT concentration The blood 5-HT concentration determined from the abdominal aorta was measured by HPLC.

<Result>
The results are shown in FIG. The 5-HT concentration in the blood gradually decreased one day after switching to a tryptophan-deficient diet, and decreased by about 70% on the seventh day compared to before switching (FIG. 1A). During this time, the tear volume gradually decreased and reached a plateau from the third day to the seventh day with a decrease of about 20% from before switching (FIG. 1B).

[Example 2]
Mice fed the tryptophan deficient diet of Example 1 were injected intraperitoneally with 5-HT. Two days after switching to a tryptophan-deficient diet, 5-HT was injected intraperitoneally. Thereafter, lacrimal secretion was measured at 5-minute intervals.

<Result>
The results are shown in FIG. Tear secretion was enhanced depending on the amount of 5-HT administered. The accelerating effect was observed between 5 and 10 minutes after administration, and a significant effect was observed when administered at 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, the serotonin 5-HT _1a receptor antagonist Way-100635, the serotonin 5-HT _2a receptor antagonist and the serotonin 5-HT ₇ receptor antagonist SB269970 were used.

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

Ondansterone was used as a serotonin 5-HT ₃ receptor antagonist. Serotonin 5-HT ₃ receptor antagonists include 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.

  Agonists and antagonists were administered continuously using an osmotic pump (Alzet) implanted subcutaneously in the ventral side of the mouse so that the amount was 0.24 μL per hour.

  Saline was used as the vehicle.

<Result>
The results are shown in FIG.

  As shown in FIG. 3A, the amount of lacrimal secretion was significantly reduced by the administration of ondansterone. Such a decrease was not seen with the administration of Way-100635, Keanserin and SB269970. A decrease in lacrimal gland weight was also observed with a decrease in tear secretion.

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

  FIG. 3D shows the histological changes of the lacrimal gland. It was observed that administration of ondansterone induces acinar cell shrinkage in the lacrimal gland. Similar changes were observed with tryptophan-deficient diets. Acinar cell shrinkage was almost completely restored by administration of the agonist.

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

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

<Method and results>
Intracellular calcium ion concentration measurement [Ca ²⁺ ] i was measured using a lacrimal gland collected from Sprague-Dawley rats, and published in the literature: Imada T, Nakamura S & Kitamura N et al. PLoS One 9, e106338 (2014). It carried out according to the method of description.

Results As shown in FIG. 4A, the addition of 5-HT ₃ (0.1 to 10 μM) increases the intracellular calcium ion concentration ([Ca ²⁺ ] i) in the acinar cells of the lacrimal gland. The inventor of the present application has found that [Ca ²⁺ ] i increases even when SR57227A is added as shown in FIG. 4B.
As shown in FIG. 4C, the increase in [Ca ²⁺ ] i was not observed by the addition of Ca ²⁺ free and ondansterone, and tear secretion occurred via the 5-HT ₃ receptor and Ca ^2+. It is thought that there is.
In addition, Ca ²⁺ free can be replaced with a saline 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 without ₂ was used.

[Example 5]
The effect of serotonin 5-HT ₃ receptor agonists in normal individuals was verified.

<Method>
In the same manner as in Example 2, SR57227A was administered once at a dose of 0.1 mg / kg to mice taking the standard diet. The administration route was intraperitoneal.
Tear measurement was performed before administration and at intervals of 5 minutes after administration until 30 minutes later.

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

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

<Method>
Reduction treatment (stress treatment)
Literature: Nakamura, S., Tanaka, J., Imada, T. et al. Journal of Functional Foods 10, 346-354 (2014), restrained stress was applied to female 8-week-old C57BL / 6 mice. . Mice are restrained in polypropylene centrifuge tubes (capacity approx. 60 ml) with breathable / excretable treatment for 4 hours per day. During restraint, air was blown over the mouse face (wind speed 0.5-1.0 m / s). Food and drink were freely consumed in the cage except for restraint treatment time.

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

Tear measurement was performed in the same manner as in Example 1 before the stress treatment and during the administration period.

<Results and discussion>
The results are shown in FIG. In the solvent control by stress treatment, tear secretion decreased to about 1/4, whereas SR57227A administration significantly reduced the decrease compared to the solvent control. This result shows that the administration of a serotonin 5-HT ₃ receptor agonist can be expected to have a dry eye prevention effect (suppressing a decrease in tear secretion).

The above results suggest that serotonin 5-HT ₃ receptor agonists or antagonists have the effect of regulating tear secretion at doses that can be taken by humans. In particular, it has been confirmed that serotonin 5-HT ₃ receptor agonists can effectively suppress dry eye symptoms in test animals orally administered with the agent of the present invention.

Claims (9)

A composition for regulating tear secretion, comprising an agonist or antagonist of serotonin 5-HT ₃ receptor as an active ingredient. The composition according to claim 1, which is a composition for promoting lacrimal secretion, comprising a serotonin 5-HT ₃ receptor agonist as an active ingredient. _3. The composition of claim 2, wherein the serotonin 5-HT3 receptor agonist is SR 57227A. The composition according to claim 1, which is a tear secretion inhibiting composition comprising a serotonin 5-HT ₃ receptor antagonist as an active ingredient. 5. The composition of claim 4, wherein the serotonin 5-HT ₃ receptor antagonist is ondacetron or a pharmaceutically acceptable salt thereof.   The composition for promoting lacrimal secretion according to any one of claims 1 to 5, which is an oral preparation. A prophylactic or therapeutic agent for keratoconjunctival disorder, comprising a serotonin 5-HT ₃ receptor agonist as an active ingredient.   The preventive or therapeutic agent according to claim 6, wherein the keratoconjunctival disorder is dry eye. A prophylactic or therapeutic agent for lacrimation, comprising an antagonist of serotonin 5-HT ₃ receptor as an active ingredient.