WO2022050176A1 - ペプチドを含む組成物及びその用途 - Google Patents

ペプチドを含む組成物及びその用途 Download PDF

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Publication number
WO2022050176A1
WO2022050176A1 PCT/JP2021/031436 JP2021031436W WO2022050176A1 WO 2022050176 A1 WO2022050176 A1 WO 2022050176A1 JP 2021031436 W JP2021031436 W JP 2021031436W WO 2022050176 A1 WO2022050176 A1 WO 2022050176A1
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Prior art keywords
gly
hyp
cys
pro
composition according
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PCT/JP2021/031436
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English (en)
French (fr)
Japanese (ja)
Inventor
健太郎 小嶋
寛 田中
陽一郎 新開
隆規 小出
慎一郎 市瀬
博 能勢
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Kola-Gen Pharma Inc
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Kola-Gen Pharma Inc
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Priority to JP2022546284A priority Critical patent/JP7774276B2/ja
Priority to EP21864234.6A priority patent/EP4209505A4/en
Priority to US17/924,554 priority patent/US20230295269A1/en
Priority to CN202180036243.9A priority patent/CN115698054A/zh
Publication of WO2022050176A1 publication Critical patent/WO2022050176A1/ja
Anticipated expiration legal-status Critical
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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
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/16—Materials or treatment for tissue regeneration for reconstruction of eye parts, e.g. intraocular lens, cornea

Definitions

  • the present invention relates to a composition containing a novel peptide and its use.
  • the macula is the part of the retina that is most closely related to visual acuity.
  • a disease in which a hole is opened in the macula is called a macular hole, and when this disease occurs, it becomes difficult to see things.
  • This macular hole is attributed to aging of the eye, especially age-related changes in the vitreous. Due to the strong adhesion between the retina and the vitreous cortex, age-related atrophy of the vitreous collagen fibers exerts tension on the retina, resulting in anterior traction that creates cracks in the retina and the macula. It is thought to be a circular hole. This disease is predominant in the elderly, and the number of patients is steadily increasing with the rapid increase in the elderly population in recent years.
  • the only treatment for macular hole is vitreous surgery, which closes the macular hole by removing the vitreous body that is the cause. If the symptoms of the macular hole are mild and the circular hole is small, the closure rate is high, but if the symptoms progress and the circular hole is large, the closure rate of the circular hole is poor and visual acuity cannot be expected to recover.
  • the visual acuity recovery rate of vitreous surgery is 70%, and the hospitalization period is 3 to 7 days.
  • the treatment of macular hole can obtain closure of the macular hole, but because it removes the endoscopic boundary membrane, which is the basement membrane, there is no foothold for reconstructing macular cells after surgery, and it can be cured. There is a problem that quality is not guaranteed. As described above, the development of an effective therapeutic agent for macular hole is desired.
  • an object of the present invention is to provide a novel therapeutic agent for macular hole, aiming at recovery of visual function QOV and improvement of postoperative QOL after vitreous surgery for macular hole.
  • the present inventors have diligently studied an artificial collagen-like polypeptide membrane. As a result, using a composition containing a special peptide, it is possible to provide a scaffold necessary for retinal cell regeneration, close the circular hole by simply pasting it, and recover / improve visual function and reduce the burden on the patient. Was found, and further research was continued to complete the present invention.
  • Equation (I) -(P 1 , P 2 , P 3 )-(I) (In formula (I), P 1 , P 2 and P 3 may be the same or different, and are peptide chains independently represented by the following formula (II). P 1 , P 2 and P 3 form a trimer with a triple helix structure and are polymerized by oxidative cross-linking with disulfide bonds by cysteine (Cys) residues contained in each peptide chain.
  • R 1 and R 2 are peptide groups consisting of any 2-10 amino acid residues that have amino and carboxy terminus, respectively, and are independent of each other and contain at least 2 Cysteine residues.
  • Pro is a proline residue
  • Hyp is a hydroxyproline residue
  • Gly is a glycine residue
  • m and n are independently integers of 4 or more
  • X is a peptide group represented by repeating 1 or more and 4 or less of -Xaa-Yaa-Gly-
  • Xaa and Yaa independently indicate amino acid residues.
  • (3) X is -Phe-Hyp-Gly-Glu-Arg-Gly-, -Pro-Arg-Gly-Gln-Hyp-Gly-Val-Met-Gly-Phe-Hyp-Gly- and -Pro-Lys
  • composition according to (1) wherein X is a peptide group consisting of amino acid residues selected from -Pro-Arg-Gly- or -Phe-Hyp-Gly-Glu-Arg-Gly-.
  • R 1 and R 2 are peptide groups consisting of amino acid residues of two or more Cys (cysteine) residues independently of each other.
  • the peptide chain represented by the above formula (II) is R 1- (Pro-Hyp-Gly) m-Pro-Arg-Gly- (Pro-Hyp-Gly) n-R 2 (i) as well as R 1- (Pro-Hyp-Gly) m-Phe-Hyp-Gly-Glu-Arg-Gly-(Pro-Hyp-Gly) nR 2 (ii)
  • the composition according to (1) which is more selected.
  • the peptide chain represented by the formula (II) is represented by the following SEQ ID NO:.
  • composition according to any one of (1) to (7), which further contains a water-soluble filler (9) The composition according to (8), wherein the water-soluble filler is a sugar. .. (10) The composition according to (9), wherein the sugar is one or more of glucose, lactose, sucrose, mannitol, trehalose, and sorbitol. (11) The composition according to (10), wherein the sugar is glucose. (12) The composition according to any one of (8) to (11), wherein the water-soluble filler is present in an amount of 10 to 50% based on the total weight of the composition.
  • a pharmaceutical product comprising the composition according to any one of (1) to (15).
  • a device comprising the composition according to any one of (1) to (15).
  • a therapeutic agent for an eye disease containing the composition according to any one of (1) to (15).
  • the therapeutic agent for an eye disease according to (18), wherein the eye disease is a macular hole or retinal detachment.
  • a method for treating an eye disease which comprises a step of administering a therapeutically effective amount of the composition according to any one of (1) to (15) to a subject.
  • the peptide membrane made of the composition of the present invention has high transparency and is ideal for the treatment of macular hole.
  • the present invention it is possible to control cell adhesion, proliferation, differentiation, etc. by changing the hardness of the scaffold.
  • the application test to the MIO-M1 cell defect part of the peptide membrane of this invention is shown. It is shown that MIO-M1 cells adhere to and proliferate on the peptide membrane of the present invention.
  • the efficacy and safety verification (in vivo) in the cynomolgus monkey model are shown.
  • composition of the present invention contains two or more kinds of polymerized peptides.
  • Polymerized peptide (first component)
  • the polymerized peptide of the present invention is Equation (I) -(P 1 , P 2 , P 3 )-(I)
  • P 1, P 2 and P 3 may be the same or different, and are peptide chains independently represented by the following formula (II).
  • P 1 , P 2 and P 3 form a trimer with a triple helix structure and are polymerized by oxidative cross-linking with disulfide bonds by cysteine (Cys) residues contained in each peptide chain.
  • R 1 and R 2 are peptide groups consisting of any 2-10 amino acid residues that have amino and carboxy terminus, respectively, and are independent of each other and contain at least 2 Cys residues.
  • m and n are independently integers of 4 or more
  • X is a peptide group represented by repeating 1 or more and 4 or less of -Xaa-Yaa-Gly-.
  • the polymerized peptide of the present invention is a polymerized peptide having a structural unit of a trimer peptide formed from three peptide chains represented by the following formula (I) and being oxidatively crosslinked.
  • P 1 , P 2 and P 3 may be the same or different, and are independent peptide chains represented by the following formula (II), P 1 , P 2 and P. 3 forms a trimer having a triple spiral structure, and may be cross-linked with a disulfide bond by a cysteine (Cys) residue contained in each peptide chain, and the trimer may be a disulfide bond of the Cys.
  • Cys cysteine
  • R 1 and R 2 are amino-terminal and carboxy-terminal, respectively, and consist of any 2-10 amino acid residues, including at least 2 Cys residues that are independent of each other. It is a peptide group.
  • X is a peptide group represented by repetition of 1 or more and 4 or less with-(Xaa-Yaa-Gly)- as a basic unit.
  • M and n are independently integers of 4 or more. )]]]
  • the Xaa and Yaa independently indicate amino acid residues, for example, proline (Pro or P) residue, hydroxyproline (Hyp or O) residue, arginine (Arg or R) residue, and lysine (Lys).
  • K residue, valine (Val or V) residue, leucine (Leu or L) residue, isoleucine (Ile or I) residue, serine (Ser or S) residue, treonine (Thr or T) residue , Alanin (Ala or A) residue, glycine (Gly or G) residue, phenylalanine (Phe or F) residue, methionine (Met or M) residue, glutamate (Glu or E) residue, aspartic acid (Asp) Or D) residue, asparagine (Asn or N) residue, glutamine (Gln or Q) residue, histidine (His or H) residue, tryptophan (Trp or W) residue or tyrosine (Tyr or Y) residue
  • the number of Cys residues contained within 10 residues from the N-terminal and C-terminal of the peptide chain may be independently the same or different, and may be 2 or more or 3 residues. As mentioned above, it may be 4 or more residues and 5 or more residues.
  • the peptide groups from each of the amino terminal and the carboxy terminal containing at least 2 residues of cysteine (Cys) residue are within 9 residues and within 8 residues, in addition to 10 residues or less. , 7 residues or less, 6 residues or less, 5 residues or less, 4 residues or less or 3 residues or less.
  • polymerized peptide refers to a peptide polymerized via a disulfide bond formed by oxidative cross-linking between cysteine residues contained in the peptide.
  • the degree of polymerization of the polymerized peptide of the present invention is 2 or more, and the degree of polymerization is not particularly limited as long as it can form a gel containing the polymerized peptide of the present invention, preferably a hydrogel, but the average degree of polymerization is less than 100, 100. It may be ⁇ 500, 500 ⁇ 1000, 1000 ⁇ 5000, 5000 ⁇ 10000 or 10000 or more.
  • the structure of the peptide is described in the three-letter or one-letter notation of amino acids well known to those skilled in the art.
  • the amino acid is L-form.
  • the amino acids herein are 20 L-amino acids known to be used in the translation of proteins common in molecular biology, as well as modified amino acid residues well known in the art, such as 4-.
  • hydroxy-L-proline, 4-fluoro-L-proline and N-isobutyl group glycine As used herein, hydroxylproline is 3-hydroxyproline or 4-hydroxy-L-proline, which is represented by "Hyp" in three-letter notation and "O" in one-letter notation.
  • the polymerized peptide according to the present invention can be produced by using a commercially available amino acid and by a known method for chemically synthesizing a peptide (Patent No. 645862).
  • a nucleic acid sequence encoding a desired amino acid sequence is produced, incorporated into an expression vector, a recombinant expression vector is prepared by a known method, and the transformant is introduced into an appropriate host such as a microorganism such as Escherichia coli. To make.
  • an appropriate host such as a microorganism such as Escherichia coli.
  • a recombinant peptide chain is produced. Therefore, by recovering the recombinant peptide chain produced from the culture, the recombinant peptide chain used in the present invention is produced.
  • Such a peptide chain can be obtained by separating and purifying it by using a separation means such as high performance liquid chromatography, and can be used for producing a triple-stranded peptide.
  • a polymerized peptide in which a plurality of cysteine residues are incorporated in the peptide chain is produced, and the peptide is disulfided by oxidative cross-linking with an oxidizing agent such as dimethyl sulfoxide (DMSO) or air oxidation, which is not limited thereto.
  • DMSO dimethyl sulfoxide
  • Derivatized peptides cross-linked by bonds are provided.
  • the oxidizing agent for producing the polymerized peptide of the present invention includes oxygen, iodine, hydrogen peroxide, sodium bromate (sodium bromate), potassium bromate, sodium perborate or perboronic acid. Examples include, but are not limited to, potassium and the like.
  • the formation of a crosslink by the disulfide bond of the present invention can be confirmed, for example, by quantifying the residual thiol group after the oxidative crosslink reaction with an Ellman reagent.
  • the polymerized peptide thin film having higher strength described below is provided.
  • the composition of the present invention contains two or more different polymerized peptides. Different polymerized peptides can be selected depending on the bioactive strength and the physical strength of the polymerized peptide thin film. The proportion of different polymerized peptides in the composition can be adjusted. For example, three types of the following peptides can be used to form a membrane with a combination of 5: 5: 1, 5: 4: 1, and 5: 3: 1.
  • C2s CCPO (GPO) 4 GPR (GPO) 4 GCC H-Cys-Cys-(Pro-Hyp-Gly) 5-Pro-Arg-Gly-(Pro-Hyp-Gly) 4-Cys-Cys-OH SEQ ID NO: 2
  • C3s CCCPO (GPO) 4 GPR (GPO) 4 GCCC H-Cys-Cys-Cys-(Pro-Hyp-Gly) 5-Pro-Arg-Gly-(Pro-Hyp-Gly) 4-Cys-Cys-Cys-OH SEQ ID NO: 1
  • C3s-GFOGER CCCPO (GPO) 3 GFOGER (GPO) 4 GCCC H-Cys-Cys-Cys-(Pro-Hyp-Gly) 4-Phe-Hyp-Gly-Glu-Arg-Gly-(Pro-Hyp-Gly) 4-Cys-Cys-Cys-OH S
  • GFOGER is an integrin-binding sequence, and the presence of this sequence allows cells to adhere. Therefore, the bioactivity intensity will be increased by appropriately blending C3s-GFOGER.
  • the content (%) of the "polymerized peptide" in the entire composition (composition containing the polymerized peptide and the water-soluble filler) according to the present invention is preferably 50 to 90%. (In this specification, “%” indicates weight percent unless otherwise specified.).
  • Water-soluble filler (second component)
  • the composition of the present invention may contain a water-soluble filler in addition to the polymerized peptide. ..
  • Water-soluble fillers include potassium carbonate, sodium carbonate, ammonium carbonate, calcium lactate, mannitol, urea, inositol, magnesium succinate, sorbitol, and carbohydrates (eg, glucose, lactose, sucrose, mannitol, trehalose, and sorbitol).
  • carbohydrates eg, glucose, lactose, sucrose, mannitol, trehalose, and sorbitol.
  • glucose is preferred.
  • the content (%) of the "water-soluble filler" in the entire composition (composition containing the polymerized peptide and the water-soluble filler) according to the present invention is preferably 10 to 50%.
  • composition of the present invention can contain an excipient in addition to the polymerized peptide and the water-soluble filler.
  • Excipients include mannitol, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyethylene glycol, polyvinylpyrrolidone, crystalline cellulose, lactose, sucrose, starch, cornstarch, titan oxide (TiO2), light anhydrous silicic acid, etc. It can be exemplified. These excipients may be used alone or in combination of two or more.
  • polymerized peptides can be dissolved in a solvent and then gelled to produce a hydrogel of a peptide membrane. Further, different polymerized peptides can be dissolved in a solvent and then added to a water-soluble filler and gelled to produce a hydrogel of a peptide membrane.
  • the hydrogel can be dried to produce a polymerized peptide thin film which is a sheet-like film.
  • This polymerized peptide thin film can be used, for example, as a therapeutic material for macular holes.
  • the polymerized peptide thin film of the present invention can be stored for a long period of time at room temperature by being dried as compared with a hydrogel made of a polymerized peptide before drying, and the interaction between peptide molecules is changed, so that the water is re-watered. Even when combined, it imparts stronger strength compared to the original hydrogel. Therefore, the polymerized peptide thin film of the present invention has further improved strength and can be used as a heat-resistant medical material that can be heat-sterilized.
  • gel stiffness refers to the robustness of a gel to degradation by phagocytic cells such as macrophages in vivo.
  • the hardness of this gel is affected by the degree of cross-linking polymerization of the gel, the difference in the branched structure of the cross-linked peptide chain, and the like. For example, if the gel contains a large amount of crosslinks due to disulfide bonds, a hard gel is formed.
  • composition of the present invention may be used as it is as a therapeutic agent for macular hole or retinal detachment, or may be made into various dosage forms by a method known to those skilled in the art using a pharmaceutically acceptable carrier or excipient. You may prescribe it.
  • the carrier or excipient to be used is known to those skilled in the art and can be appropriately selected.
  • the drug of the present invention can be produced by means and methods known to those skilled in the art. For example, in the case of producing an injection or an infusion solution, a pharmaceutically acceptable carrier such as physiological saline or phosphate buffered saline can be used.
  • compositions comprising thickeners, absorption promoters, pH regulators, preservatives, dispersants, wetting agents, stabilizers, preservatives, suspending agents, surfactants, etc. in the preparation of the agents of the present invention. Agents may be used.
  • the dosage form of the drug of the present invention is not particularly limited, and can be appropriately selected according to the site, size, type, patient condition, etc. of the macular hole or retinal detachment to be treated.
  • the agent of the present invention may be liquid, semi-solid, or solid. Examples of dosage forms of the agents of the present invention include, but are not limited to, thin films.
  • the agent of the present invention may be in the form of a lyophilized product suspended on a pharmaceutically acceptable carrier such as physiological saline or phosphate buffered saline at the time of administration.
  • the administration route of the drug of the present invention is not particularly limited, and can be appropriately selected according to the site, size, type, patient condition, etc. of the macular hole or retinal detachment to be treated.
  • Examples of the route of administration of the drug of the present invention include, but are not limited to, indwelling by infusion or incision.
  • the dose of the drug of the present invention can be appropriately determined by a doctor according to the type, site, size, type, patient condition, etc. of the macular hole or retinal detachment for treatment.
  • the agent of the present invention can be administered once or multiple times.
  • the above number of times can be determined by the doctor in consideration of the site and species of the macular hole, the condition of the patient, and the like.
  • the present invention provides, in yet another embodiment, the use of the above composition for producing a therapeutic agent for macular hole or retinal detachment.
  • the present invention provides, in yet another embodiment, the use of the above composition for the treatment of macular hole or retinal detachment.
  • the present invention provides, in yet another embodiment, a method for treating macular hole, which comprises administering the above composition to a patient with macular hole or retinal detachment.
  • Resin CTC 2-chlorotrityl chloride
  • reagent BCA Bicinchoninic acid
  • BSA Bovine serum albumin
  • DCM dichloromethane DIC: N, N'-diisopropylcarbodiimide
  • DIEA N, N-diisopropylethylamine
  • DMAP N, N-dimethylaminopyridine
  • DMF N, N-dimethylformamide
  • DMSO Dimethyl sulfoxide
  • DTNB 5,5'-dithiobis-2-nitrobenzoic acid
  • DTT Dithiothreitol
  • EDT Ethanedithiol
  • EDTA ethylenediaminetetraacetic acid
  • FBS Fetal bovine serum
  • HOBt 1-Hydroxybenzotriazole
  • MeCN acetonitrile
  • MeOH Methanol
  • MOPS 3-Morpholine Propane Sulfonic Acid
  • NEM N-Ethylmaleimide
  • PBS Phosphate buffer PMSF
  • CD Circular dichroism
  • DDR Discoidin domain receptor
  • ECM extracellular matrix
  • FAK focal adhesion kinase
  • HDF Human skin fibroblasts
  • HRP Horseradish Peroxidase
  • HSPG Heparan Sulfate Proteoglycan
  • PEDF Factor derived from pigment epithelium
  • SDS-PAGE Sodium Dodecyl Sulfate-Polyacrylamide Gel
  • Electrophoresis vWF von Willebrand factor
  • Method for Producing Peptide Membrane Weigh each peptide powder C2s, C3s, C3s-GFOGER and dissolve in degassed 0.05% TFA solution to 12.5 mg / mL. After heating at 85 ° C for 5 minutes, leave it at room temperature for a while and let it stand at 4 ° C for 1 day. Mix C2s solution, C3s solution, and C3s-GFOGER solution at a ratio of 5: 4: 1, and add and mix DMSO to a final concentration of 10%. The mixture is poured onto an acrylic plate as a mold, and the mixture is allowed to stand at room temperature for 3 days in a closed container under wet conditions.
  • Test test method Human Muller cell MIO-M1 strains are seeded on 6-well Transwell plates and cultured in a CO 2 incubator. When the cells become confluent, remove the insert from the plate and transfer to a 60 mm petri dish. Remove the culture medium in the insert by suction, and punch out the center of the bottom surface with a disposable trepan for biopsy with a diameter of 1 mm to confirm that it is perforated. Transfer the insert to a 6-well Transwell plate containing medium and allow the amount of medium to barely soak the bottom of the insert to which the cells are attached. The peptide membrane is placed so as to cover the central perforation of the insert.
  • Verification of efficacy and safety in white rabbit model (in vivo) Test method Anesthetize the rabbit (ketamine + xylazine) and perform an implantation test. Apply a surface anesthetic (Benokiseal ophthalmic solution 0.4%, Santen Pharmaceutical Co., Ltd.) to the right eye. Hold in the supine position, open the right eye with an eyelid opener, and disinfect and wash the eyeball with Isodine solution diluted 40-fold with saline or PA / iodine eye drops / eyewash diluted 4-fold with saline. Then rinse with saline. Cover the surgical site with a protective sheet.
  • a surface anesthetic Bookiseal ophthalmic solution 0.4%, Santen Pharmaceutical Co., Ltd.
  • a circular hole of about 500 ⁇ m is created. After that, a peptide membrane and a peptide membrane to which a water-soluble filler is added are inserted into the eye from the scleral wound and placed in the circular hole.
  • the test substance is fixed by the combined use of viscoelastic substance, nitrogen gas replacement and perfluorocarbon.
  • Optical coherence tomography (OCT) will be performed 2 days and 1 week after the completion of implantation to evaluate the adhesion. result: In the example of combined use with a viscoelastic substance, adhesion was observed after 1 week, and no inflammatory site or the like was observed (Fig. 3: Peptide membrane to which no water-soluble filler was added; Fig. 4: Peptide membrane to which water-soluble filler was added).

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PCT/JP2021/031436 2020-09-02 2021-08-27 ペプチドを含む組成物及びその用途 Ceased WO2022050176A1 (ja)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2022546284A JP7774276B2 (ja) 2020-09-02 2021-08-27 ペプチドを含む組成物及びその用途
EP21864234.6A EP4209505A4 (en) 2020-09-02 2021-08-27 COMPOSITION COMPRISING A PEPTIDE, AND ITS USE
US17/924,554 US20230295269A1 (en) 2020-09-02 2021-08-27 Composition comprising peptide, and use thereof
CN202180036243.9A CN115698054A (zh) 2020-09-02 2021-08-27 包含肽的组合物及其用途

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JP2017014126A (ja) * 2015-06-29 2017-01-19 学校法人早稲田大学 抗微生物活性を有するコラーゲン様ペプチド及びその組成物
JP6455862B2 (ja) 2015-06-25 2019-01-23 学校法人早稲田大学 コラーゲン様構造を有する重合ペプチド及びゲル

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JP6455862B2 (ja) 2015-06-25 2019-01-23 学校法人早稲田大学 コラーゲン様構造を有する重合ペプチド及びゲル
JP2017014126A (ja) * 2015-06-29 2017-01-19 学校法人早稲田大学 抗微生物活性を有するコラーゲン様ペプチド及びその組成物

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