WO2008023717A1 - Agent ophtalmique comprenant un peptide pacap - Google Patents

Agent ophtalmique comprenant un peptide pacap Download PDF

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Publication number
WO2008023717A1
WO2008023717A1 PCT/JP2007/066226 JP2007066226W WO2008023717A1 WO 2008023717 A1 WO2008023717 A1 WO 2008023717A1 JP 2007066226 W JP2007066226 W JP 2007066226W WO 2008023717 A1 WO2008023717 A1 WO 2008023717A1
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WO
WIPO (PCT)
Prior art keywords
lys
arg
ala
tyr
ser
Prior art date
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PCT/JP2007/066226
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English (en)
Japanese (ja)
Inventor
Seiji Shioda
Akemichi Baba
Original Assignee
Showa University
Taisho Pharmaceutical Co., Ltd.
Osaka University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Showa University, Taisho Pharmaceutical Co., Ltd., Osaka University filed Critical Showa University
Publication of WO2008023717A1 publication Critical patent/WO2008023717A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a lacrimal secretion promoter comprising a PACAP peptide as an active ingredient.
  • 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.
  • 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.
  • tears blink to form a thin film that protects the eyes from dryness, dust, and bacteria.
  • 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.
  • the lacrimal fluid is composed of three layers: an oil layer, an aqueous layer, and a mucin layer.
  • an oil layer As a general treatment method for dry eye used so far, artificial tears intended to replenish the aqueous layer
  • instillations such as sodium chondroitin sulfate and sodium hyaluronate, which have a water retention effect, are being carried out.
  • PACAP Pulitary Adenylate Cyclase—Activating Polypeptide
  • 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.
  • JP 2004-168697 A discloses a therapeutic agent for retinal diseases containing a PACAP derivative peptide.
  • 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
  • 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.
  • 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.
  • a lacrimal secretion promoter containing a peptide that acts on the PAC 1 receptor or a pharmaceutically acceptable salt thereof is provided.
  • 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—
  • a tear secretion promoting agent containing a pharmaceutically acceptable salt thereof is provided.
  • the lacrimal secretion promoter of the present invention is a therapeutic agent for ophthalmic diseases accompanied by a decrease in lacrimal secretion.
  • the ophthalmic disease associated with decreased tear secretion is dry eye.
  • the lacrimal secretion promoter of the present invention is a drug that is locally administered to the eye.
  • the lacrimal secretion promoter of the present invention is an eye drop.
  • peptides acting on the PAC 1 receptor eg, His- Ser- Asp Lrly lie- Phe- ir- Asp- 3 ⁇ 4er- 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.
  • a peptide acting on the PAC 1 receptor (eg, His— Ser— Asp— Gly— lie— Phe— Thr) for the production of a lacrimation promoter.
  • 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.
  • the lacrimation promoter composition of the present invention is characterized by containing PACAP or a pharmaceutically acceptable salt thereof as an active ingredient.
  • 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
  • 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.
  • 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.
  • 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.
  • 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
  • a salt with a polymer acid such as tannic acid, carboxymethyl cellulose, polylactic acid, polyglycolic acid, etc. It is not a thing.
  • PACAP or a pharmaceutically acceptable salt thereof used in the present invention may be administered parenterally or orally as a lacrimation promoter.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 buffer
  • borax sodium acetate, kenic acid
  • Buffer agents phosphate buffer agents, etc.
  • isotonic agents sodium chloride, glycerin, mannitol, etc.
  • pH adjusters hydrochloric acid
  • 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.
  • 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.
  • 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.
  • the tear secretion promoter of the present invention is administered to a human.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • PACAP knockout mice C57BL / 6 strain
  • mice 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.
  • 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.
  • RT-PCR reverse transcription polymerase chain reaction
  • 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.
  • PACAP 528 bp
  • the immunostaining method of PAC 1R was visualized by preparing a frozen section of 8 ⁇ m lacrimal gland and using a PAC 1R-specific antibody and a secondary antibody labeled with a fluorescent dye (Alexa).
  • FIG. 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 ( ⁇ 6, 1 ( ⁇ 8, 10 _10, 10 _12 ⁇ ) 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.
  • 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.
  • 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.
  • 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 shows the results of measuring changes in tear secretion by intravenous administration of PACAP38.
  • 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.

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  • Health & Medical Sciences (AREA)
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Abstract

L'invention concerne un nouvel agent permettant de favoriser la sécrétion de larmes. L'agent comprend un peptide capable d'agir sur un récepteur PAC1 ou un sel pharmaceutiquement acceptable de ce composé.
PCT/JP2007/066226 2006-08-22 2007-08-22 Agent ophtalmique comprenant un peptide pacap WO2008023717A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2006225219A JP2009269818A (ja) 2006-08-22 2006-08-22 Ｐａｃａｐペプチドを含む眼科用剤
JP2006-225219 2006-08-22

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WO2008023717A1 true WO2008023717A1 (fr) 2008-02-28

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012136369A1 (fr) 2011-04-08 2012-10-11 Hmfra Hungary Limited Liability Company Préparations ophtalmiques à base de pacap (polypeptide activant l'adénylate cyclase pituitaire), restaurant la fonction visuelle normale dans le cas d'un glaucome précoce
CN111344300A (zh) * 2017-11-14 2020-06-26 千寿制药株式会社 Pacap的稳定化肽

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6698358B2 (ja) * 2015-03-12 2020-05-27 Ｓｈｉｏｄａライフサイエンス株式会社 汗分泌促進剤及び該汗分泌促進剤を含有するドライスキンの予防薬又は治療薬
JP7328696B2 (ja) 2018-01-30 2023-08-17 Ｓｈｉｏｄａライフサイエンス株式会社 角膜上皮細胞走化促進剤
CN114173874A (zh) 2019-05-14 2022-03-11 千寿制药株式会社 含pacap肽或pacap的稳定化肽的神经营养性角膜炎的预防或治疗用组合物
EP3974027A4 (fr) 2019-05-14 2023-08-16 Senju Pharmaceutical Co., Ltd. Peptide pacap stabilisé

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005102375A1 (fr) * 2004-04-23 2005-11-03 Senju Pharmaceutical Co., Ltd. Promoteur de la neuritogénèse de la cornée contenant du pacap et son dérivé

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005102375A1 (fr) * 2004-04-23 2005-11-03 Senju Pharmaceutical Co., Ltd. Promoteur de la neuritogénèse de la cornée contenant du pacap et son dérivé

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012136369A1 (fr) 2011-04-08 2012-10-11 Hmfra Hungary Limited Liability Company Préparations ophtalmiques à base de pacap (polypeptide activant l'adénylate cyclase pituitaire), restaurant la fonction visuelle normale dans le cas d'un glaucome précoce
CN111344300A (zh) * 2017-11-14 2020-06-26 千寿制药株式会社 Pacap的稳定化肽

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