WO2008023717A1

WO2008023717A1 - Ophthalmic agent comprising pacap peptide

Info

Publication number: WO2008023717A1
Application number: PCT/JP2007/066226
Authority: WO
Inventors: Seiji Shioda; Akemichi Baba
Original assignee: Showa University; Taisho Pharmaceutical Co., Ltd.; Osaka University
Priority date: 2006-08-22
Filing date: 2007-08-22
Publication date: 2008-02-28
Also published as: JP2009269818A

Abstract

Disclosed s a novel agent for promoting the secretion of tear. The agent comprises a peptide capable of acting on a PAC1 receptor or a pharmaceutically acceptable salt thereof.

Description

Specification

Ophthalmic preparation containing PACAP peptide

Technical field

[0001] The present invention relates to a lacrimal secretion promoter comprising a PACAP peptide as an active ingredient. In particular, the present invention relates to a lacrimal secretion promoter that can be used as a therapeutic agent for ophthalmic diseases accompanied by a decrease in lacrimal secretion, comprising a PACAP peptide as an active ingredient.

Background art

[0002] In today's society, the number of scenes where eyes are abused is increasing rapidly. One of the disease factors is dry eye. In general, dry eye is a condition in which the cornea or conjunctiva on the surface of the eyeball has been damaged due to a decrease in the amount of tears secreted or qualitative changes in tears. On the surface of normal eyes, tears blink to form a thin film that protects the eyes from dryness, dust, and bacteria. However, when it becomes dry eye, the surface of the eye cannot be sufficiently protected, and the cornea and conjunctiva are damaged. Since dry eyes can damage the surface of the eye simply by dryness, early measures are necessary before developing into various eye diseases.

[0003] The lacrimal fluid is composed of three layers: an oil layer, an aqueous layer, and a mucin layer. As a general treatment method for dry eye used so far, artificial tears intended to replenish the aqueous layer For the purpose of replenishing the liquid instillation mucin layer, instillations such as sodium chondroitin sulfate and sodium hyaluronate, which have a water retention effect, are being carried out. However, neither of these promotes natural tear secretion.

[0004] PACAP (Pituitary Adenylate Cyclase—Activating Polypeptide) is an index of a bio-assay system that activates adenylate cyclase in the anterior pituitary cells from the hypothalamus of the Hedge. It is a peptide consisting of 38 amino acid residues isolated in this way. There are several reports on the pharmacological effects of PACAP and PACAP derivatives. For example, JP 2004-168697 A discloses a therapeutic agent for retinal diseases containing a PACAP derivative peptide. In addition, International Publication WO2003 / 039577 describes dry eye containing a VIP derivative peptide having a predetermined amino acid sequence as an active ingredient and a therapeutic agent for diseases associated with dry eye. It is.

Patent Document 1: Japanese Patent Application Laid-Open No. 2004-168697

Patent Document 2: International Publication WO2003 / 039577

Disclosure of the invention

Problems to be solved by the invention

[0006] An object of the present invention is to provide a novel tear secretion promoter. The present invention made it a problem to be solved to provide a lacrimal secretion promoter that is particularly useful as a therapeutic agent for ophthalmic diseases accompanied by a decrease in lacrimal secretion such as dry eye.

Means for solving the problem

[0007] As a result of intensive studies to solve the above-mentioned problems, the inventors of the present invention consisted of PACAP38 consisting of the amino acid sequence shown in SEQ ID NO: 2 in the sequence listing or the amino acid sequence shown in SEQ ID NO: 1 in the sequence listing. It was demonstrated that intravenous administration of PACAP27 or ophthalmic administration can promote tear secretion, and it was found to be effective in the treatment of ophthalmic diseases associated with decreased tear secretion such as dry eye. The present invention has been completed based on these findings.

[0008] That is, according to the present invention, a lacrimal secretion promoter containing a peptide that acts on the PAC 1 receptor or a pharmaceutically acceptable salt thereof is provided.

According to the present invention, His- Ser- Asp- Gly- lie- Phe- Thr- Asp- Ser- Tyr- Ser- Arg- Tyr- Arg- Lys- Gin- Met- Ala- Val- Lys- Lys- Tyr— Leu— Ala— Ala — Val— Leu peptide, His— Ser— Asp— Gly— lie— Phe— Thr— Asp— Ser — i yr— Ser— Arg— Tyr— Arg— Lys— Gin— Met—Ala—Val—Lys—Lys—i yr—Leu—Ala—Ala—Val—Leu—Gly—Lys—Arg—Tyr—Lys—Gin—Arg—Val—Lys—Asn—Lys— Alternatively, a tear secretion promoting agent containing a pharmaceutically acceptable salt thereof is provided.

[0009] Preferably, the lacrimal secretion promoter of the present invention is a therapeutic agent for ophthalmic diseases accompanied by a decrease in lacrimal secretion.

Preferably, the ophthalmic disease associated with decreased tear secretion is dry eye.

Preferably, the lacrimal secretion promoter of the present invention is a drug that is locally administered to the eye. Preferably, the lacrimal secretion promoter of the present invention is an eye drop.

[0010] According to yet another aspect of the present invention, peptides acting on the PAC 1 receptor (eg, His- Ser- Asp Lrly lie- Phe- ir- Asp- ¾er- Tyr- Ser Arg- fyr- Arg — Lys — Gin— Met— Ala— Val— Lys— Lys— Tyr— Leu— Ala— Ala— Val— Leu peptide, His— Ser— Asp— Gly— lie— Phe— Thr— Asp — Ser— Tyr— Ser— Arg— Tyr— Arg— Lys— Gin— Met— Ala— Val— Lys— Lys— Tyr— Leu— Ala— Ala— Val— Leu— Gly— Lys— Arg— Tyr— Ly s — Gin— Arg— Val— Lys— Asn— Lys)), or a pharmaceutically acceptable salt thereof, which comprises administering to a mammal, including a human, a tear fluid. A method is provided for promoting secretion.

[001 1] According to yet another aspect of the present invention, a peptide acting on the PAC 1 receptor (eg, His— Ser— Asp— Gly— lie— Phe— Thr) for the production of a lacrimation promoter. — Asp— Ser— i yr— Ser— Arg— Tyr— Arg— Lys— Gin— Met— Ala— Val— Lys— Lys— i, yr— Leu — Ala— Ala— Val— Leu, a peptide represented by His — Ser— Asp— Gly— lie— Phe— Thr —Asp— Ser— Tyr— Ser— Arg— Tyr— Arg— Lys— Gin— Met— Ala— Val— Lys— Lys — Tyr— Leu— Ala— Ala— Val Use of a pharmaceutically acceptable salt thereof, or a peptide represented by: Leu—Gly—Lys—Arg—Tyr—Lys—Gin—Arg—Val-Lys-Asn-Lys).

The invention's effect

[0012] The lacrimal secretion promoter of the present invention is useful as a therapeutic agent for ophthalmic diseases accompanied by a decrease in lacrimal secretion such as dry eye.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, embodiments of the present invention will be described in detail.

The lacrimation promoter composition of the present invention is characterized by containing PACAP or a pharmaceutically acceptable salt thereof as an active ingredient.

[0014] PACAP used as an active ingredient in the present invention is not particularly limited as long as it is a peptide that acts on the PAC 1 receptor. Specific examples include His-Ser-Asp-Gly-lie-Phe-Thr- Asp- ser- Tyr- ser- Arg- i "yr- Arg- Lys- ln- Met- Ala- Val- Lys- Lys Tyr Leu- Ala- Ala- Val- Leu (SEQ ID NO: 1 in the sequence listing), or His — Ser— Asp — Gly— He— Phe— Thr— Asp— Ser— Tyr— Ser— Arg— Tyr— Arg— Lys— Gin— Met — Ala— Val— Lys— Lys— Tyr—Leu— Ala— Ala— Val— Leu— Gly Examples include peptides having 27 or 38 amino acid residues consisting of Lys—Arg—Tyr—Lys—Gin—Arg—Val—Lys—Asn—Lys (SEQ ID NO: 2 in the sequence listing). Also called PACAP). The present invention relates to a peptide having a lacrimal secretion promoting action. That is, the present invention relates to PACAP for improving lacrimal gland secretion disorder in dry eye patients and patients with siedalene syndrome.

[0015] PACAP used in the present invention can be synthesized according to known peptide synthesis methods described in, for example, JP-A-8-333276 and JP-A-9-100237. For example, azide method, acid chloride method, acid anhydride method, mixed acid anhydride method, DCC method, active ester method (P-nitrophenyl ester method, N-hydroxysuccinimide ester method, cyanomethyl ester method, etc.) It can be synthesized by a method using Woodward reagent K, a carboimidazole method, a redox method, a DCC-additive (HONB, HOBt, HOSu) method, or the like. The synthesis method may be either a solid phase synthesis method or a liquid phase synthesis method. That is, the amino acid that can constitute the peptide of the present invention and the remaining part are condensed, and when the product has a protecting group, the protecting peptide is eliminated to synthesize the target peptide. Any known method may be used as the condensation method or the removal of the protecting group. After the reaction, the peptide used in the present invention can be purified by combining ordinary purification methods such as solvent extraction, distillation, column chromatography, liquid chromatography, recrystallization and the like.

[0016] In the present invention, a pharmaceutically acceptable salt of PACAP can be used as an active ingredient. Pharmaceutically acceptable salts of PACAP include: salts with alkali metals such as sodium or potassium; salts with alkaline earth metals such as calcium or magnesium; and salts with inorganic bases such as aluminum salts or ammonium salts. Salts: Salts with organic bases such as trimethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N, N-dibenzylethylenediamine; hydrochloric acid, hydrobromic acid , Salts with inorganic acids such as nitric acid, sulfuric acid or phosphoric acid; formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, succinic acid, succinic acid, malic acid, methanesulfonic acid, benzene A salt with an organic acid such as sulfonic acid or p-toluenesulfonic acid; and a salt with a polymer acid such as tannic acid, carboxymethyl cellulose, polylactic acid, polyglycolic acid, etc. It is not a thing.

[0017] PACAP or a pharmaceutically acceptable salt thereof used in the present invention may be administered parenterally or orally as a lacrimation promoter. For parenteral administration, for example, it may be administered as an injection such as intravenous injection, subcutaneous injection or intramuscular injection, may be administered as a suppository, or may be administered percutaneously to the skin. Or it may be administered topically to the eye.

[0018] PACAP or a pharmaceutically acceptable salt thereof used in the present invention may be administered as it is, but it is preferable to administer it in the form of a preparation suitable for the dosage form employed. Formulations include injections, suppositories, powders, granules, tablets, capsules, syrups, solutions, aerosols, ointments, creams, lotions, nasal drops and topical ophthalmic preparations (for example, point Ophthalmic preparations, ophthalmic ointments or sustained-release preparations), but are not limited thereto.

[0019] Injections include, for example, solvents (such as distilled water for injection), stabilizers (such as sodium edetate), isotonic agents (such as sugar alcohols such as sodium chloride, glycerin and mannitol), pH adjusters (such as Hydrochloric acid, citrate, sodium hydroxide, etc.), suspending agents (methylcellulose, etc.) can be used, and suppositories are formulated using, for example, suppository bases (cocoa butter, macrogonores, etc.) can do. In addition, any pharmaceutical carrier suitable for formulating a solid preparation, for example, excipients (starch, glucose, fructose, sucrose, etc.), lubricants (magnesium stearate, etc.), disintegrating agents (starch, crystalline cellulose, etc.) ), Binders (starch, gum arabic, etc.) can be used to formulate powders, granules, tablets, etc. In addition, syrups and solutions can be formulated using stabilizers (such as sodium edetate), suspending agents (such as gum arabic and carmellose), flavoring agents (such as simple mouthwater and glucose), and fragrances. it can.

[0020] To formulate ointments, creams, lotions, nasal drops and topical ophthalmic agents, for example, ointment bases (such as petrolatum and lanolin), solvents (such as physiological saline and purified water), Stabilizers (sodium edetate, citrate, etc.), wetting agents (such as glycerin), emulsifiers (such as polybutylpyrrolidone), suspending agents (hydroxypropylmethylcellulose, hydroxymethylcellulose) , Methylcellulose), surfactant (polysorbate 80, polyoxyethylene hydrogenated castor oil, etc.), preservative (benzalkonium chloride, parabens, chlorobutanol, etc.), buffer (boric acid, borax, sodium acetate, kenic acid) Buffer agents, phosphate buffer agents, etc.), isotonic agents (sodium chloride, glycerin, mannitol, etc.), pH adjusters (hydrochloric acid, sodium hydroxide, etc.), etc., can be appropriately selected and used. In addition, sustained-release preparations for topical use include gel molded products such as collagen, intraocular implants and scleral plugs formed from biodegradable polymers such as polylactic acid, or non-biodegradable intraocular devices. Implantable preparations can be used.

[0021] In addition, an adsorption preventing component can be used for the purpose of preventing the peptide from adsorbing to the glass or the resin container. Specific examples of the adsorption preventing component used here include polyoxyethylene alcohol ether, polyoxyethylene fatty acid ester, polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, gelatin, albumin Or polygenin. The solvent for dissolving the adsorption preventing component and the peptide is not particularly limited as long as it is physiologically acceptable, and examples thereof include physiological saline.

[0022] The tear secretion promoter of the present invention can be administered to a mammal (eg, rat, rabbit, cat, Inu, pig, monkey, human, etc.), thereby promoting tear secretion. be able to. Preferably, the tear secretion promoter of the present invention is administered to a human. When administering the lacrimal secretion promoter of the present invention to an adult patient, the dose of PACAP per administration is usually 0.000001 to;! OOmg for injections, and preferably <0.0001 to 0.00. lmg, usually 0.;!-500mg, preferably;!-50mg. Also, when applied topically to the eyes of adult patients (normally, PACAP is contained in 0.001— 3. Ow / v%, preferably (0.001—0.5 w / v%). Eye drops are preferably instilled at a dose of 20-50 1 per dose;! -8 times per day.

[0023] The lacrimal secretion promoter of the present invention may contain other dry eye treatment components in combination with the PACAP peptide as needed and necessary. Further, the lacrimal secretion promoter of the present invention can be used in combination with other medicinal ingredients unless it is contrary to the object of the present invention. [0024] The lacrimal secretion promoter of the present invention can be used, for example, as a therapeutic agent for ophthalmic diseases accompanied by a decrease in lacrimal secretion. As an ophthalmic disease accompanied by a decrease in tear secretion in the present specification, it is possible to mention dry eye. That is, the lacrimal secretion promoter of the present invention includes, for example, tear reduction, dry eye, Siedallen syndrome, dry keratoconjunctivitis, Stevens-Johnson syndrome, dry eye related to VDT (Visual Display Terminal) work, etc. Can be used to treat dry eye.

[0025] The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example

[0026] (i) Reagent:

His— Ser— Asp— Giy— lie— Phe— Thr— Asp— ¾er— Tyr— ¾er— Arg— i, yr— Arg— Lys— Gin— Met— Ala— Val— Lys— Lys— Tyr— Leu— Ala— Is it composed of an amino acid sequence represented by Ala-Val-Leu-Gly-Lys-Arg-Tyr-Lys-Gln-Arg-Val-Lys-Asn-Lys (SEQ ID NO: 2 in the sequence listing)? Hachihachi? 38 (^ ¾10 ^ ₁ ) Choby 3-56-83-〇-116-? 116

— Thr— Asp— Ser— Tyr— Ser— Arg— Tyr— Arg— Lys— Gin— Met— Ala— Val— Lys

— Lys— Tyr— Leu— Ala— Ala— Val— Leu (SEQ ID NO: 1 in the sequence listing) PACAP27 consisting of the amino acid sequence was purchased as a freeze-dried product from Peptide Institute, Inc. (Osaka City). . PACAP has the same amino acid sequence between mammals and is identical.

[0027] (ii) Animals:

PACAP knockout mice (C57BL / 6 strain) were provided by Prof. Akimichi Baba of Osaka University and were bred and maintained in the SPF animal breeding room of Showa University. All genetically modified animals are bred and maintained in accordance with Showa University genetic modification experiment safety management regulations, and all laboratory animals are tested in accordance with the Showa University Animal Experiment Guidelines with the approval of the Showa University Animal Experiment Committee. It was. In addition, all the tests from FIG. 2 to FIG. 8 were conducted using C57BL / 6N mice purchased from Nippon Thiers River.

[0028] (iii) Results:

(1) Abnormal lacrimal glands and decreased tear volume in PACAP knockout mice (Fig. 1) Histological findings of the lacrimal gland were performed by the following method.

The animals were anesthetized by administration of Nembutal 50 mg / kg and fixed by perfusion with 4% paraformaldehyde. The eyeball was taken out with the lacrimal gland attached, and further immersed and fixed overnight with 4% paraformaldehyde. Tissues were prepared by preparing 6-micrometer sections after embedding in paraffin, and staining and staining with hematoxylin and eosin.

[0029] The results are shown in FIG. Compared to the wild type, PACAP knockout mice showed a narrowed lacrimal gland cavity.

[0030] Next, the amount of tears was measured by the cotton thread method. For measurement of tear volume, we used cotton thread (Zone Quick: Menicon), which is actually used for diagnosis of tear volume such as dry eye in humans. The zone quick was inserted into the lower eyelids of both eyes of the mouse for 30 seconds, and the total length of the cotton thread infiltrated with the tear was regarded as the tear volume. Figure 1 shows the measurement results. PACAP knockout mice (8.86 ± 2.11.) Showed a significant decrease in tear volume compared to wild type (17.18 ± 5.00) and heterozygous type (15.66 ± 3.48) (ANOVA, Dunnet's post hoc test).

[0031] (2) Expression of PACAP and PACAP receptor (PAC1R) in lacrimal gland (Fig. 2)

To examine the expression of PACAP and PAC1R in the lacrimal gland, reverse transcription polymerase chain reaction (RT-PCR) and immunostaining were performed. In RT-PCR, specific cDNAs for PACAP, PAC1R and the internal standard GAPDH mRNA were amplified using the following primers, and the products were detected by agarose gel electrophoresis.

[0032] PACAP; 528 bp

Fw: 5'-CTTGTGCAGAAGCTGCAGTCCCCAGACATG-3 '(IJ No. 3) No. 4)

[0033] PAC1R; 384, 387 bp (hip hop type), 303 bp (short type)

Fw: 5'-ATGACCATGTGTAGCGGAGCAAGGCTGG-3 '(SEQ ID NO: 5)

Re: 5'- CTACAAGTATGCTATTCGGCGTCC-3 '(SEQ ID NO: 6)

[0034] GAPDH; 498 bp

Fw: 5'-GCCAAGGTCATCCATGACAAC-3 '(SEQ ID NO: 7) Re: 5'-GTCCACCACCCTGTTGCTGTA-3 '(SEQ ID NO: 8)

[0035] The immunostaining method of PAC 1R was visualized by preparing a frozen section of 8 μm lacrimal gland and using a PAC 1R-specific antibody and a secondary antibody labeled with a fluorescent dye (Alexa).

[0036] The results are shown in FIG. By the RT-PCR method and immunohistochemical technique, PACAP and PAC 1R were expressed in the lacrimal gland, and PAC 1R positive reaction (green fluorescence) was strongly expressed especially in the acinar cell base of the lacrimal gland. Blue fluorescence is due to nuclear staining with DAPI.

[0037] (3) Effects of promoting tear secretion by intravenous administration of PACAP38 (Figures 3 and 4)

The intravenous continuous administration experiment of PACAP38 followed Ohtaki et al 2006 PNAS (103 (19): 7488_93) (Fig. 3). That is, from the jugular vein, solvent (0.1% BSA in PBS), PACAP38 (5 nmol / kg) or PACAP38 + PACAP6_38 (PAC 1R antagonist, 50 nmol / kg) (PACAP6-38 Osmotic pump (Alzet, model 1007D 0.5 μ / hour) with force neutralization in the femoral vein . The osmotic pump was filled with the above solvent, PACAP38 (32 pmol / μ1) or PACAP38 + PACAP6-38 (320 pmol / μ1). Four days after the start of administration, the tear volume was measured by the cotton thread method described above.

[0038] The measurement results are shown in FIG. PACAP administration group (24.0 ± 1.) compared to vehicle administration group (16.5 ± 0.7)

6) significantly increased tear secretion (ρ <0.01, ANOVA, Dunnet's post hoc test vs. solvent administration group). This effect was significantly suppressed in the PACAP and PACAP6-38 group. (17.5 ± 1 0, p <0.05, ANOVA, Dunnet's post hoc test vs. PACAP administration group)

[0039] (4) Effect of promoting lacrimal secretion by administration of PACAP 38 drops (Figures 5 and 6)

Changes in tears after administration of PACAP 38 drops were examined over time. Figure 5 shows the experimental schedule. Wild type mice are anesthetized with pentobarbital, and after stabilizing, tear volume is measured (pre). Saline in both eyes or ^{PACAP38 (1 (Τ 6, 1} (Τ 8, 10 _10, 10 _12 Μ) solution 1 1 instilled and the solution remaining after the 7.5 minute was wiped off by a cotton swab. After administration 15, After 30, 45, 60 and 120 minutes, the tear volume was measured by the cotton thread method.

[0040] Fig. 6 shows the measurement results. Ophthalmic administration 15 minutes after the saline treated group (11.2 ± 0.50) to Te ratio base PACAP10- 10- ⁸ M treated group (17.3 ± 1.95, 16.8 ± 1.79 ) increased significantly tear amount in was observed (p <0.05, ANOVA, Dunnet's post hoc test vs. saline administration group). This Action of lasted until after 45 minutes administration (saline: 11.7 ± 0.81, PACAP 10- "V: 20.6 ± 1.95 p <0.01, PACPA 10- 8 M: 18.2 ± 2.35 p <0.05). The post-instillation 120 minutes In all groups, tear volume returned to the basic level.

[0041] (5) Effect of promoting lacrimal secretion by administration of PACAP27 eye drops (Figures 7 and 8)

It performed diluted to a final concentration of 10- ⁸ M of PACAP27 at physiological saline to prepare a test solution. 8 ~; Change in tear volume was examined according to Fig. 7 for 10-week-old C57BL / 6 mice (male). In other words, it was PACAP27 in mice subjected to anesthetized with pentobarbital (10- ⁸ M) 1 ^ 1 instilled. After 7.5 minutes, the test reagent was wiped off, and the amount of tears was measured by the cotton thread method at 15, 30, 45, 60, and 120 minutes after the start of instillation. For the cotton thread method, the zone quick (Menicon, Nagoya Japan), which is used for clinical diagnosis of dry eye, was used to measure the length of color change (infiltrated with tears) after 30 seconds of eyelid insertion. .

[0042] Fig. 8 shows the measurement results. Compared to the physiological saline group, PACAP27 significantly promoted lacrimal secretion from 15 to 30 minutes after instillation. This effect almost disappeared 120 minutes after administration.

Brief Description of Drawings

[0043] FIG. 1 shows the histological findings of lacrimal glands and the measurement of tear volume in wild-type and PACAP knockout mice.

FIG. 2 shows the results of examining the expression of PACAP and PACAP receptor (PAC1R) in the lacrimal gland.

FIG. 3 shows a schematic diagram of a continuous intravenous administration experiment of PACAP38.

[FIG. 4] FIG. 4 shows the results of measuring changes in tear secretion by intravenous administration of PACAP38.

Yes

FIG. 5 shows an experimental schedule for examining changes in tears over time after administration of PACAP 38 drops.

FIG. 6 shows the results of examining changes in tears over time after administration of PACAP 38 drops.

FIG. 7 shows an experimental schedule for examining changes in tears over time after administration of PACAP27 instillation.

FIG. 8 shows the results of examining changes in tears over time after administration of PACAP27 instillation.

Claims

The scope of the claims

[1] A lacrimation promoter comprising a peptide that acts on the PAC1 receptor, or a pharmaceutically acceptable salt thereof.

[2] His— ser— Asp— Lrly— lie— Phe— hr— Asp— Ser— i yr— Ser— Arg— Tyr— Arg— Lys— Gin— Met— Ala— Val— Lys— Lys— Tyr— Leu— Ala— Ala— Val— Leu peptide, His— Ser— Asp— Gly— lie— Phe— Thr— Asp— Ser— Tyr— Ser— Arg— Tyr— Arg— Lys— Gin— Met— Ala -Val- Lys- Lys- Tyr- Leu- Ala- Ala- Val- Leu-Gly- Lys- Arg- Tyr- Lys- Gin- Arg- Val- Lys- Asn- Lys A lacrimal secretion promoter containing a pharmaceutically acceptable salt thereof.

[3] The agent for promoting lacrimal secretion according to claim 1 or 2, which is a therapeutic agent for ophthalmic diseases accompanied by a decrease in lacrimal secretion.

[4] The agent for promoting lacrimal secretion according to claim 3, wherein the ophthalmic disease accompanied by a decrease in lacrimal secretion is dry eye.

[5] The lacrimal secretion promoter according to any one of claims 1 to 4, which is a drug locally administered to the eye.

[6] The lacrimal secretion promoter according to any one of claims 1 to 5, which is an eye drop.