WO2002085399A1 - Preparations contenant un peptide - Google Patents

Preparations contenant un peptide Download PDF

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Publication number
WO2002085399A1
WO2002085399A1 PCT/JP2002/003898 JP0203898W WO02085399A1 WO 2002085399 A1 WO2002085399 A1 WO 2002085399A1 JP 0203898 W JP0203898 W JP 0203898W WO 02085399 A1 WO02085399 A1 WO 02085399A1
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WO
WIPO (PCT)
Prior art keywords
sustained
release preparation
metastin
preparation according
peptide
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PCT/JP2002/003898
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English (en)
Japanese (ja)
Inventor
Shigeyuki Takada
Tetsuya Ohtaki
Yoshihiro Omachi
Takao Yamada
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Takeda Chemical Industries, Ltd.
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Publication of WO2002085399A1 publication Critical patent/WO2002085399A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a preparation containing metastin (a peptide encoded by the KiSS-1 gene: hereinafter sometimes referred to as a KiSS-1 peptide) or a derivative thereof or a salt thereof.
  • metastin a peptide encoded by the KiSS-1 gene: hereinafter sometimes referred to as a KiSS-1 peptide
  • KiSS-1 peptide is a C-terminal partial peptide of the protein encoded by the cancer metastasis suppressor gene KiSS-1 (Genomics ⁇ 54, pp.145-148, 1998). Since the transposition ability of the KiSS-1 gene is reduced when human chromosome 6 is transferred to C8161 melanoma, the subtractive hybridizer method was used from the low-transferred strain obtained by transferring chromosome 6 and the parent strain ( It has been found that transfection of the KiSS-1 gene into C8161 melanoma results in a decrease in the metastatic potential according to the expression level (Subtractive Hybridization Technique) (J. Natl. Cancer Inst. , 88, 1731-1737, 1996). It has also been reported that the translocation of the KiSS-1 gene reduces the metastatic potential of human breast cancer cell MDA-MB-435 (Cancer Research, 57, 2384-2387, 1997).
  • Metastin a peptide cut out from the KiSS-1 gene product, is expected to have cancer metastasis-suppressing activity because its gene is a cancer metastasis-suppressing gene.
  • metastin inhibits chemotaxis and invasion of CH0 cells that express the human receptor for metastin ⁇ 7 ⁇ 5, and in vivo to the lung of B16-BL6 malignant melanoma that expresses hOT7T175 Weakens the metastatic properties (Nature, vol. 411, p. 613, 2001, etc.). Furthermore, that the present gene is expressed in a large amount in the placenta (J. Natl. Cancer Inst., Vol. 88, pp.
  • T7T 175 which is a human receptor of the peptide, Due to its high expression in the placenta and relatively high expression in the knee (eg, Nature 411, 613-617, 2001, etc.), the peptide plays an important role in the placenta. Alternatively, it is expected that this peptide also exerts some physiological functions in the knee.
  • metastin or its derivatives or salts thereof should be administered at high doses for a long period of time to obtain sufficient pharmacological effects. Is required.
  • an aqueous solution of metastin or a derivative thereof or a salt thereof is administered subcutaneously, there is a concern about the occurrence of side effects and the inconvenience and pain of the patient in actual administration for treatment or prevention. Therefore, development of a useful preparation containing metastin or a derivative thereof or a salt thereof capable of solving these problems is desired. Disclosure of the invention
  • the present inventors have conducted intensive studies and as a result, when metastin, its derivative or its salt is administered as a sustained-release preparation, it acts on highly metastatic cancer cells and suppresses metastasis In addition, the sustained release of metastin or its derivatives or its salts over a long period of time does not require high doses to achieve medicinal effects, so that side effects can be reduced and daily administration is not required.
  • the present inventors have found that the preparation of the present invention has excellent properties as a clinical medicine, such as reduced inconvenience and pain, and completed the present invention.
  • sustained-release preparation containing metastin or a derivative or salt thereof
  • a peptide wherein metastin or a derivative thereof contains the amino acid sequence at the 47th to 54th position from the N-terminus of the amino acid sequence represented by SEQ ID NO: 1 and comprises 8 to 54 amino acid residues Or a sustained-release preparation according to the above (1), which is a derivative thereof,
  • sustained-release preparation according to (3) wherein the peptide is a peptide consisting of the amino acid sequence represented by SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4 or SEQ ID NO: 5.
  • the sustained-release preparation according to the above (1) which is a capsule,
  • sustained-release preparation which comprises metastin or a derivative thereof or a salt thereof, and any other pharmaceutically active substance.
  • FIG. 1 is a graph showing the time course of blood metastin (1-54) concentration (pmol / ml) after subcutaneous administration of sustained-release metastin (1-54) -containing microcapsules in rats.
  • the “metastin” used in the present invention includes all 54 consecutive amino acids from the N-terminal to the first to 54th amino acids in the amino acid sequence represented by SEQ ID NO: 1.
  • the term “metastin derivative” used in the present invention refers to a peptide having an amino acid residue and having an amide (one C ⁇ NH 2 ) at the C-terminus.
  • the physiological activity of metastin for example, metastin and its receptor
  • SEQ ID NO: 1 cell stimulating activity of receptor-expressing cells caused by metastin, etc.
  • the C-terminus may be an amide (one-CO NH 2 ), or may be any of a carboxylate group (—CO OH), a carboxylate group (COO—), and an ester (one COOR). It is preferable that the C-terminal carbonyl group is an amidated amide.
  • the metastin derivative has substantially the same activity as the metastin physiological activity, and in the amino acid sequence represented by SEQ ID NO: 1, the amino acid sequence at the 47th to 54th amino acid sequence from the N-terminal ( The length is not particularly limited as long as it has (8 essential amino acid residues), but a peptide consisting of 8 to 54 amino acid residues (preferably, 8 to 15 amino acid residues) Alternatively, a derivative thereof is preferably used.
  • amino acid sequence represented by SEQ ID NO: 1 a peptide or a derivative thereof containing the 47th to 54th amino acid sequence from the N-terminal and consisting of 8 to 54 amino acid residues
  • amino acid sequence represented by SEQ ID NO: 1 a peptide comprising the amino acid sequence at the 47th to 54th position from the N-terminus and consisting of 8 to 15 amino acid residues, or a peptide thereof.
  • Derivatives are preferred.
  • the arrangement of eight essential amino acid residues is as follows: May be located at any site, as long as the derivative has substantially the same activity as the metastin bioactivity, but the eight essential amino acid residues are located at the C-terminus. Is desirable. That is, in the amino acid sequence represented by SEQ ID NO: 1, the 47th to 54th amino acid sequence from the N-terminal is A peptide or derivative thereof having 8 to 54 amino acid residues at the C-terminus is preferable. In particular, in the amino acid sequence represented by SEQ ID NO: 1, the 47th to 54th amino acid sequence from the N-terminal is Peptides having 8 to 15 amino acid residues at the C-terminus or derivatives thereof are preferred.
  • the C-terminal of a peptide represented by a specific amino acid sequence has an amide (-CONH 2 ), a carboxyl group (—COOH), a carboxylate group (COCT) and an ester (1-COH). COOR).
  • a peptide derivative means that the C-terminus has a carboxy group (one COOH) or a carboxylate group (COO_ ) And an ester (a COOR), each of which includes a lipoxyl form, a carboxylate form, and an ester form, and the C-terminal of the peptide represented by the specific amino acid sequence has a lipoxyl group
  • (COOH) a peptide derivative is an amide in which the C-terminus has been converted to any of an amide (-CONH 2 ), a carboxylate group (COO-) and an ester (-COOR) , Carboxylates and esters.
  • an amide having an amide (one CONH 2 ) at the C-terminus is preferably used.
  • the metastin or a derivative thereof may be, for example, any of a fermentation product, a synthetic compound, a synthetic peptide, and the like, or may be of natural origin, and may be a recombinant peptide produced by a genetic engineering technique. May be.
  • metastin or a derivative thereof examples include, for example, metastin or a derivative thereof derived from all mammals such as humans, monkeys, baboons, chimpanzees, bushus, sea lions, higgins, horses, mice, rats, and the like. Among them, those derived from humans are preferred. When the preparation of the present invention is applied to humans, it is particularly preferable to use metastin derived from human or a derivative thereof.
  • the metastin or a derivative thereof used in the present invention preferably, for example, in the amino acid sequence represented by SEQ ID NO: 1, the amino acid sequence at the 47th to 54th position from the N-terminus is located at the C-terminus, and 8 to 15 amino acids Petit consisting of amino acid sequence And so on.
  • a peptide comprising the amino acid sequence represented by SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4 or SEQ ID NO: 5 (especially an amide thereof), and the like can be mentioned.
  • a mouse or rat-derived peptide (Kiss-1 gene product) containing the amino acid sequence represented by SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3 described in WO 01/751 04 is used. Is also good.
  • the C-terminus of metastin or a derivative thereof is usually an amide (one CONH 2 ), but may be an ester (one COOR), a hydroxyl group (one COOH), or a hydroxyl group (COO—).
  • an amide in which the C-terminal carbonyl group is amidated is particularly preferable.
  • R in the ester e.g., methyl, Echiru, n- propyl, C E, such as isopropyl or n- butyl - 6 alkyl group, for example, C 3 of cyclopentyl Le, cyclohexane, etc.
  • cyclohexyl - 8 cycloalkyl group for example, C 7 such as phenyl, alpha-naphthyl C 6 ⁇ 2 Ariru group such as for example, benzyl, phenylene route C DOO 2 alkyl or a- naphthylmethyl etc.
  • a- Nafuchiru 2 alkyl Le group such phenethyl —
  • pivaloyloxymethyl groups commonly used as oral esters are used.
  • the metastin or its derivatives used in the present invention N-terminal of the Amino group protecting groups such as Mechionin residues (e.g., C 2, such as a formyl group, Asechiru - 6 Ashiru group - C E such as 6 Arukanoiru group ),
  • the N-terminal side is cleaved in vivo, the dalminyl mill group is oxidized with glutamine, and the substituent on the side chain of the amino acid in the molecule (for example, mono-OH, one SH, -COOH, amino group, Imida zone Ichiru group, indole group, Guanijino group, etc.) a suitable protecting group (e.g., formyl group, C 2 such Asechiru - such as 6 Arukanoiru group (: Bok 6 Ashiru group ) Or complex peptides such as so-called glycopeptides to which sugar chains are bound.
  • Mechionin residues e.g.,
  • the sugar chains include, for example, D-mannose And neutral sugars such as D-galactose and L-fructose; amino sugars such as D-darcosamine and D-galactosamine; and sialic acid.
  • Metastin or a derivative thereof may form a salt, and as a salt of metastin or a derivative thereof, a pharmacologically acceptable salt is particularly preferable.
  • salts include salts with inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, etc.), and organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, conodic acid) , Tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, etc.), salts with inorganic bases (eg, alkali metal salts such as sodium salt, potassium salt, etc.); calcium salts And alkaline earth metal salts such as magnesium salts; aluminum salts and ammonium salts; salts with organic bases (eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, trietano, etc.). .
  • inorganic acids eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, etc
  • Metastin or a derivative thereof used in the present invention can be obtained by a known method (for example, a method described in WO 00/24890, J. Chem. Soc., Perkin Trans. 1, 1748, 2001) and the like. Alternatively, it can be produced according to a method analogous thereto, for example, according to a known peptide synthesis method, or can be produced by cleaving a known peptide or precursor with an appropriate peptide.
  • the method for synthesizing the peptide may be, for example, either a solid phase synthesis method or a liquid phase synthesis method.
  • the target peptide can be produced by condensing a partial peptide or amino acid capable of constituting the peptide or the precursor with the remaining portion, and removing the protecting group when the product has a protecting group. Can be done. Examples of known condensation methods and elimination of protecting groups include the methods described in the following [1] to [5].
  • the sustained-release preparation containing metastin or a derivative thereof or a salt thereof of the present invention preferably contains one carrier (carrier or base).
  • the carrier include proteins, polysaccharides, polymers (biodegradable polymers and non-biodegradable polymers), ribosomes, and inorganic substances.
  • Proteins include, for example, collagen, gelatin, fibrin, serum albumin and the like.
  • polysaccharide examples include starch, hyaluronic acid, chitosan, chitin, alginate, agarose, dextran, and cellulose derivatives.
  • biodegradable polymer examples include aliphatic polyesters, polyphosphazenes, polyorthoesters, and the like.
  • non-degradable polymer in vivo examples include polyglycerin fatty acid ester, silicon, ethyl vinyl acetate copolymer, polyhydroxyethyl methyl methacrylate, polyvinyl alcohol, and polyvinylpyrrolidone.
  • ribosomes include, in addition to ordinary ribosomes, for example, polyethylene glycol (PEG) -modified ribosomes, sugar-modified ribosomes, and the like.
  • PEG polyethylene glycol
  • Examples of the inorganic substance include hydroxyapatite, tricalcium phosphate, calcium phosphate, calcium sulfate, and the like.
  • a polymer for example, a biodegradable polymer, a non-biodegradable polymer, etc.
  • a biodegradable polymer is, for example, an aliphatic polymer.
  • the non-degradable polymer in vivo such as polyester, for example, polyglycerin fatty acid ester and the like are preferable.
  • a lactic acid / daricholic acid polymer or the like is used as the aliphatic polyester.
  • the composition ratio of lactic acid / daricholic acid polymer (lactic acid / daricholic acid; LZG ratio) (mol%) is preferably about 100Z0 to about 40Z60, more preferably about 100Z0 to about 50/50, and particularly preferably about 75/50.
  • the weight average molecular weight of the lactic acid / daricholic acid polymer having a weight average molecular weight of about 3,000 to about 80,000, preferably about 5,000 to about 25,000, and more preferably about 5,000 to about 25,000, Preferably, it is about 7,000 to about 20,000.
  • the dispersity (weight average molecular weight / number average molecular weight) of the lactic acid / daricholic acid polymer is preferably about 1.2 to about 4.0, more preferably about 1.5 to about 3.5.
  • polyglycerin fatty acid esters include tetraglycerol monopalmitate (TGMP), tetraglycerol monopalmitate (TGDP), tetraglyceryl tripalmitate (TGTP), tetraglycerol hexapalmitate (TGHP), and tetraglycerol monopalmitate.
  • TGMS Tetradari Serol Distearate
  • TGTS Tetraglycerol Tristearate
  • TGHS Tetraglycerol Hexstearate
  • HGPS Hexaglycerose-Lpentastearate
  • TGHP Tetra Laglycerol hexapalmitate
  • the sustained-release preparation of the present invention is produced according to a known method.
  • the sustained-release preparation of the present invention is prepared by mixing metastin or a derivative thereof or a salt thereof with a carrier (for example, the above-mentioned carrier) usually used in the production of a sustained-release preparation, and molding as necessary.
  • a carrier for example, the above-mentioned carrier
  • the amount of metastin or a derivative or salt thereof used is about 0.01 to about 50% (wZw), preferably about 0.1 to about 30% (w / w) based on the carrier. Used as
  • sustained-release preparation of the present invention examples include, for example, (A) a sustained-release preparation containing metastin or a derivative thereof or a salt thereof using polyglycerol fatty acid ester, which is a non-degradable polymer in vivo, as a carrier. [Hereinafter, KiSS-1 peptide containing sustained release And (B) a method for producing a KiSS-1 peptide-containing sustained-release preparation using a biodegradable lactic acid / glycolic acid polymer as a carrier.
  • KiSS-1 peptide-containing sustained-release preparation using polyglycerin fatty acid ester as carrier
  • the amount of metastin or a derivative thereof or a salt thereof to be used varies depending on the type of metastin or a derivative thereof or a salt thereof, a desired pharmacological effect and duration of the effect, and the like. To about 50% (w / w), preferably about 0.1 to about 30% (w / w).
  • the lactate noglycolic acid polymer is dissolved in an organic solvent (preferably dichloromethane) and emulsified after adding an aqueous solution of metastin or a derivative or salt thereof. This is vacuum-dried to obtain lactic acid / glycolic acid polymer powder in which metastin or a derivative thereof or a salt thereof is uniformly dispersed. This is heated and cooled to form a disk, film, rod, etc. In this way, it is possible to obtain a sustained-release preparation of lactic acid z-daricholic acid polymer containing a predetermined amount of metastin or a derivative thereof or a salt thereof.
  • the heating temperature is about 50 to about 100 ° C
  • the cooling temperature is about 0 to about 40 ° C.
  • the amount of metastin or a derivative thereof or a salt thereof varies depending on the type of metastatin or a derivative thereof or a salt thereof, a desired pharmacological effect and a duration of the effect. 0 1 to about 5 0% (w / w), preferably about 0.1 to about 30% (w / w), particularly preferably about 1 to about 20% (w / w).
  • the lactic acid / glycolic acid polymer is dissolved in an organic solvent (preferably, dichloromethane, etc.), and the powder of metastin or a derivative thereof or a salt thereof is added and then uniformly dispersed.
  • the resulting dispersion is dried under vacuum to obtain lactic acid / daricholic acid polymer powder in which metastin or a derivative thereof or a salt thereof is uniformly dispersed.
  • This is heated and cooled to form a disc, film, rod, etc.
  • a sustained-release preparation of a polymer of lactic acid-Z-glycolic acid containing a predetermined amount of metastin or a derivative thereof or a salt thereof can be obtained.
  • the heating temperature, the cooling temperature, and the amount of metastin or a derivative or salt thereof used are the same as described above.
  • W / OZW emulsions and O / W emulsions respectively consist of (i) an aqueous solution, dispersion or suspension of metastin or a derivative or salt thereof as an internal aqueous phase, and an organic solvent solution of lactic acid / daricholic acid polymer as an oil phase. Or (ii) dissolving or suspending metastin or a derivative or salt thereof in an organic solvent solution of lactic acid-Z-glycolic acid polymer to obtain an oil phase, and converting the U) or ( ⁇ ) into water (Outer aqueous phase), and dispersed and emulsified.
  • metastin or a derivative thereof or a salt thereof is dissolved, dispersed or suspended in water to produce an internal aqueous phase.
  • concentration of metastin or a derivative or salt thereof in an aqueous solution, dispersion or suspension is, for example, 0.01 to 90% (w / w), preferably 0.01 to 80% (w / w). / w).
  • the amount of the above-mentioned metastin or its derivative or its salt used depends on the type of metastin or its derivative or its salt, the desired pharmacological effect and the duration of the effect. However, based on the lactic acid / glycolic acid polymer, about 0.01 to about 50% (w / w), preferably about 0.1 to about 30% (w / w), particularly preferably about 0.1 to about 30% (w / w) 1 to about 20% (w / w).
  • gelatin agar, sodium alginate, polyvinyl alcohol or basic amino acids (eg, arginine, histidine, lysine, etc.) should be added to the internal aqueous phase to increase the incorporation of metastin or its derivatives or its salts into microcapsules. May be added (eg, excipients, auxiliaries, etc.).
  • the amount of the drug-retaining substance to be added is generally about 0.01 to about 10 times the weight of metastin or a derivative or salt thereof.
  • the inner aqueous phase may be used after being freeze-dried to a powder state and then dissolved by adding water to an appropriate concentration.
  • a lactic acid Z-glycolic acid polymer is dissolved in an organic solvent to produce an oil phase.
  • organic solvent examples include halogenated hydrocarbons (eg, dichloromethane, chloroform, chloroethane, trichloroethane, carbon tetrachloride, etc.), fatty acid esters (eg, ethyl acetate, butyl acetate, etc.), aromatic hydrocarbons (eg, benzene, Toluene, xylene, etc.), of which dichloromethane is preferred.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, chloroethane, trichloroethane, carbon tetrachloride, etc.
  • fatty acid esters eg, ethyl acetate, butyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, Toluene, xylene, etc.
  • the concentration of the lactic acid Z-daricholic acid polymer in the organic solvent varies depending on the type and molecular weight of the lactic acid Z-daricholic acid polymer and the type of the organic solvent, but the weight of citric acid / daricholic acid polymer / (weight of organic solvent + (Weight of lactic acid / daricholic acid polymer)] (X100%) is usually about 0.01 to about 90% (w / w), preferably about 0.01 to about 70% (w / w). / w). It is better to dissolve so that there is no undissolved matter.
  • aqueous solution, dispersion or suspension (inner aqueous phase) of the above-mentioned metastin or a derivative thereof or a salt thereof is added to an organic solvent solution (oil phase) of the lactic acid noglycolic acid polymer thus obtained, and the mixture is homogenized. Disperse and emulsify with a mixer etc. to produce W / ⁇ emulsion.
  • the above (ii) that is, an oil phase obtained by dissolving or suspending metastin or a derivative thereof or a salt thereof in an organic solvent solution of a lactic acid / glycolic acid polymer is produced as follows. First, an organic solvent solution of a lactic acid / daricholic acid polymer is produced. As the organic solvent, those similar to the organic solvent used in producing the above wzo emulsion are used.
  • the concentration of the lactic acid / daricholic acid polymer in the organic solvent solution varies depending on the molecular weight of the lactic acid / daricholic acid polymer and the type of the organic solvent; however, [weight of lactic acid z glycolic acid polymer Z (weight of organic solvent + weight of lactic acid (X100%) is usually about 0.01 to about 70% (w / w), preferably about 1 to about 60% (w / w). is there.
  • metastin or a derivative thereof or a salt thereof is dissolved or suspended in an organic solvent solution of lactic acid-Z-glycolic acid polymer to produce an oil phase.
  • the amount of metastin or a derivative thereof or a salt thereof used is such that the ratio of the metastin or a derivative thereof or a salt thereof to the lactic acid-z-glycolic acid polymer is the same as that in the case of producing the above w / o emulsion (i). Just choose.
  • the amount of the outer aqueous phase used is usually about 1 to about 100,000 times as much as the above (i) or (ii), preferably about 10 to about 5,000 times, particularly preferably about 10 to about 5,000 times. It is 50 to about 1, 000 times the volume.
  • An emulsifier is usually added to the external aqueous phase.
  • the emulsifier generally stable
  • any substance that can form an O / W emulsion or a zero-w emulsion can be used.
  • Examples include anionic surfactants, nonionic surfactants, polyoxyethylene castor oil derivatives, polyvinylpyrrolidone, polyvinyl alcohol, and carboxymethyl. Cellulose, lecithin, gelatin, hyaluronic acid and the like can be mentioned, among which polyvinyl alcohol is preferable.
  • the concentration of the emulsifier in the external aqueous phase is usually about 0.001 to about 20% (w / w), preferably about 0.01 to about 10% (wZw), and particularly preferably about 0. 0 5 to about 5% (w / w).
  • the WZO ZW emulsion or O / W emulsion thus obtained (hereinafter These are sometimes simply abbreviated as emulsions) by subjecting them to an underwater drying method, whereby microcapsules can be produced by removing the organic solvent contained in these emulsions.
  • microcapsules obtained in this manner are collected by centrifugation or a sieve or the like, and, if desired, a sugar or sugar alcohol, an inorganic salt or the like, preferably a coagulation inhibitor such as mannitol or sorbitol in order to prevent aggregation of the microcapsules. After adding lyophilized.
  • the mixing ratio (weight ratio) of the microcapsules and the anti-agglomeration agent is about 50: 1 to about 1: 1, preferably about 20: 1 to about 1: 1, and more preferably about 10: 1 to about 5: 1. : 1.
  • the method of adding the anti-agglomeration agent is not particularly limited as long as the microcapsules and the anti-agglomeration agent are uniformly mixed, and examples thereof include a method of dispersing the microcapsules in an aqueous solution of the anti-agglomeration agent.
  • micro-force capsule thus obtained is heated and dried under reduced pressure, if necessary, to more completely remove the water and the solvent in the microcapsules.
  • a powder of metastin or a derivative thereof or a salt thereof may be used in an organic solvent solution in which a lactic acid / z-dalicholate polymer is dissolved (phase 0). It can also be produced by a method (for example, the s / ozw method or the like) by removing the solvent from the szo-type dispersion liquid dispersed in water.
  • a polymer of lactic acid “glycolic acid” is dissolved in an organic solvent, and powder (S phase) of metastin or a derivative or salt thereof is added and dispersed in the organic solvent.
  • the mixing ratio (weight ratio) of metastin or a derivative thereof or a salt thereof and a lactic acid / daricholic acid polymer is, for example, about 1: 10,000 to about 1: 1, preferably about 1: 1. 1,000 to about 2: 5, more preferably about 1: 100 to about 1: 3
  • external physical energy for example, ultrasonic irradiation, a one-bottle type stirrer, a homogenizer and the like are used.
  • the organic solvent dispersion (SZO type dispersion) thus prepared is further added to an aqueous solvent (W phase), and the same external physical energy as described above, for example, ultrasonic irradiation, turbine An szozw emulsion is formed using a stirrer or a homogenizer. Thereafter, the oil phase solvent is evaporated to produce microcapsules.
  • the volume of the aqueous phase is generally selected from about 1 to about 100,000 times the volume of the oil phase. More preferably, it is selected from about 10-fold to about 5,000-fold, particularly preferably from about 50-fold to about 1,000-fold.
  • An emulsifier may be added to the outer aqueous phase.
  • the emulsifier may be any as long as it can form a generally stable s / ozw emulsion.
  • examples of the emulsifier include anionic surfactants, nonionic surfactants, polyoxyethylene castor oil derivatives, polyvinylpyrrolidone, polyvinyl alcohol, carboxymethylcellulose, lecithin, gelatin, hyaluronic acid and the like. These may be used in appropriate combinations.
  • the concentration of the emulsifier in the external aqueous phase is preferably from about 0.001% to about 20% (w / w). More preferably, it is about 0.01% to about 10% (w / w), particularly preferably about 0.05% to about 5% (w / w).
  • microcapsules obtained in this manner are separated by centrifugation or filtration, and then the emulsifier and the like adhering to the surface of the microcapsules are removed by washing with distilled water, and dispersed again in distilled water or the like. Lyophilize. Thereafter, if necessary, the mixture is heated to further remove water and organic solvents in the micro force cell. It may be heated under reduced pressure.
  • the heating conditions are heating and drying at a temperature not lower than the glass transition temperature of the lactic acid / daricholic acid polymer used, and at such a level that the particles of the microcapsules do not adhere to each other.
  • the lactic acid / daricholic acid polymer is heated and dried in a temperature range from the glass transition temperature to about 30 ° C higher than the glass transition temperature.
  • the glass transition temperature refers to an intermediate point obtained when the temperature is raised at a heating rate of 10 to 20 ° C. per minute using a differential scanning calorimeter.
  • the microcapsules thus obtained may be added with an anticoagulant in order to prevent coagulation of the particles.
  • the anticoagulant examples include water-soluble polysaccharides such as mannitol, lactose, glucose, starches (eg, corn starch), hyaluronic acid and alkali metal salts thereof, proteins such as glycine, fibrin, collagen, sodium chloride, and phosphoric acid Inorganic salts such as sodium hydrogen and the like are appropriately used.
  • the microcapsules can be formed into a disc shape, a film shape, a rod shape (rod shape) or the like by heating and then cooling as in the case of the above (B_l-a).
  • a polyvalent metal compound such as zinc oxide may be added to the organic solvent.
  • the amount of zinc oxide to be used is, for example, about 0.01 to about 100 parts by weight, preferably about 0.1 to about 20 parts by weight, based on 100 parts by weight of the lactic acid / daricholic acid polymer.
  • the particle size of zinc oxide is usually about 0.001 to about 10 ⁇ m, preferably about 0.05 to about 1 m.
  • a sustained-release preparation obtained using a polyvalent metal compound such as zinc oxide has excellent properties such as “high drug uptake rate” and “sustained drug release over a long period of time”. Have.
  • metastin or a derivative thereof or a salt thereof may be dissolved in an aqueous solution of a volatile salt such as ammonium acetate and freeze-dried before use.
  • the freeze-dried product of metastin or a derivative thereof or a salt thereof obtained by treating with ammonium acetate as described above has a small particle size and has excellent operability, and thus is advantageous in producing a sustained-release preparation. .
  • the sustained-release preparation of the present invention can be produced in various forms as it is or using pharmaceutically acceptable additives (eg, stabilizers, preservatives, soothing agents, etc.) as desired.
  • pharmaceutically acceptable additives eg, stabilizers, preservatives, soothing agents, etc.
  • preparations include parenteral preparations (eg, injections, implants, suppositories, etc.), oral preparations (eg, solid preparations such as capsules, tablets, granules, powders, etc., syrups, emulsions, suspensions) And the like).
  • Made Stabilizers as pharmaceutically acceptable additives include, for example, human serum albumin and polyethylene glycol; preservatives such as benzyl alcohol and phenol; and soothing agents such as benzalkonium chloride. And pro-hydrochloric acid.
  • the content of metastin or a derivative thereof or a salt thereof in the preparation of the present invention can be appropriately selected usually from the range of about 0.01
  • the sustained-release preparation of the present invention may be prepared by adding metastin or a derivative thereof or a salt thereof to an aqueous solvent (eg, distilled water, physiological saline, Ringer's solution, etc.) or an oily solvent (eg, olive oil, sesame oil, cottonseed oil, corn oil) Or vegetable oils such as propylene glycol, etc.), and then dissolved in a suspension or emulsified, and then sold in a container for a sustained-release preparation [eg, Duros (trade name, manufactured by Alza).
  • an aqueous solvent eg, distilled water, physiological saline, Ringer's solution, etc.
  • an oily solvent eg, olive oil, sesame oil, cottonseed oil, corn oil
  • vegetable oils such as propylene glycol, etc.
  • the sustained-release preparation of the present invention may be a parenteral preparation (eg, intramuscular, intraperitoneal, subcutaneous, organ, etc.) as a microcapsule or a preparation prepared by using microcapsules as a raw material in various dosage forms.
  • Solids such as injections or implants for intranasal preparations, transmucosal preparations for the nasal cavity, rectum, uterus, etc., oral preparations (eg, capsules (eg, hard capsules, soft capsules, etc.), granules, powders, etc.)
  • the preparations of the present invention are particularly preferably for injection.
  • the sustained-release preparation is a microcapsule
  • the microcapsule may be used as a dispersant (eg, a surfactant such as Tween80, HC0-60, or a polysaccharide such as carboxymethylcellulose, sodium alginate, or hyaluronic acid).
  • a dispersant eg, a surfactant such as Tween80, HC0-60, or a polysaccharide such as carboxymethylcellulose, sodium alginate, or hyaluronic acid.
  • a practical sustained-release injection can be obtained by using an aqueous suspension with a preservative (eg, methyl paraben, propyl paraben, etc.), an isotonic agent (eg, sodium chloride, mannitol, sorbitol, glucose, etc.).
  • a preservative eg, methyl paraben, propyl paraben, etc.
  • an isotonic agent eg, sodium chloride, manni
  • vegetable oils such as sesame oil and corn oil, or mixtures of these with phospholipids such as lecithin, or dispersed with medium-chain fatty acid triglycerides (eg, Migliol 812), are used as oily suspending agents. It should be a sustained-release injection.
  • the particle size of the microphone mouth capsule is within a range that satisfies the degree of dispersion and needle penetration for use as a suspension injection.
  • the average particle diameter may be, for example, in the range of about 0.1 to about 300 / ⁇ .
  • the average particle size is preferably in the range from about 1 to about 150 m, particularly preferably in the range from about 2 to about 100 m.
  • Aseptic treatment of the above microcapsules includes, but is not particularly limited to, a method of sterilizing the entire production process, a method of sterilizing with a gamma ray, and a method of adding a preservative.
  • the preparation of the present invention is safe and has low toxicity, it can be used, for example, for human mammals (for example, monkeys, baboons, chimpanzees, pigs, sea lions, sheep, sheep, dogs, dogs, cats, mice, rats, etc.). Can be administered.
  • human mammals for example, monkeys, baboons, chimpanzees, pigs, sea lions, sheep, sheep, dogs, dogs, cats, mice, rats, etc.
  • the preparation of the present invention can be used for treating or preventing all diseases in which the physiological activity of metastin is involved.
  • the preparation of the present invention since the preparation of the present invention has a cancer metastasis inhibitory activity, it can be used for any cancer (eg, lung cancer, stomach cancer, liver cancer, knee cancer, colon cancer, rectal cancer, colon cancer, prostate cancer, ovarian cancer, cervical cancer). , Breast cancer, kidney cancer, bladder cancer, brain tumor, etc.).
  • the preparation of the present invention has a function of regulating knee function, it can be effectively used for treatment or prevention of various knee diseases (for example, acute or chronic knee inflammation, knee cancer, etc.).
  • the preparation of the present invention since the preparation of the present invention has a placental function regulating action, it is useful for treating or preventing choriocarcinoma, hydatidiform mole, invasive mole, miscarriage, fetal growth deficiency, abnormal glucose metabolism, abnormal lipid metabolism or parturition. It can be used effectively.
  • the dosage of the preparation of the present invention depends on the type and content of the active ingredient metastin or a derivative thereof or a salt thereof, dosage form, duration of release, administration subject, administration route, administration purpose, target disease, symptoms, etc.
  • the amount of the active ingredient may be appropriately maintained in the body at a pharmaceutically effective concentration for a desired duration.
  • one dose of metastin or a derivative or salt thereof may be, for example, about 0.1 to 0.1 mg / day.
  • An amount in the range of about 10 O mg Z kg body weight, preferably in the range of about 1 to 5 O mg / kg body weight is used.
  • the administration frequency is once a week, once every two weeks, once every 1 month, once every 2 months, once every 6 months, etc., the type and content of the KiSS-1 peptide, dosage form, release Can be appropriately selected depending on the duration of the disease, the target disease, the target animal, and the like.
  • Preferred is a one-week to two-month sustained-release preparation, more preferably a one-week to one-month sustained-release preparation.
  • the preparation of the present invention may be used as a medicament for various diseases in which metastin or a derivative thereof or a salt thereof is pharmaceutically effective, particularly a chemotherapeutic agent for cancer treatment, a hormonal therapeutic agent, and an immunotherapeutic agent.
  • concomitant drug a chemotherapeutic agent for cancer treatment
  • a hormonal therapeutic agent e.g., a hormone that is administered to cancer treatment
  • an immunotherapeutic agent e.g., an immunotherapeutic agent for cancer treatment
  • concomitant drug e.g., chemotherapeutic agent for cancer treatment, a hormonal therapeutic agent, and an immunotherapeutic agent.
  • the timing of administration of the preparation of the present invention and the concomitant drug is not limited, and these may be administered to the subject simultaneously or with a time lag.
  • the dose can be appropriately selected based on the clinically used dose.
  • the mixing ratio of the preparation of the present invention and the concomitant drug can be appropriately selected according to the administration subject, administration route, target disease,
  • Chemotherapeutic agents include, for example, alkylating agents (eg, cyclophosphamide, diphosphamide, dimustine, laemustine, carpocon, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil, tegafur, carmofur, UFT, doxyfluridine, Cytarabine, enocitabine, mercaptopurine, mercaptoprin liposide, thioguanine, etc., anticancer antibiotics (for example, mitomycin, adriamycin, daunorubicin, epirubicin, pyrarubicin, idarubicin, bleomycin, pebromycin, clitincin-derived anticancer agents, etc.) , Vinblastine, vindesine, etoposide, camptothecin, irinotecan, etc.), cisplatin, carpoplatin, neda Platinum, paclitaxel
  • hormonal therapies include corticosteroids (eg, prednisolone, prednisone, dexamethasone, cortisone acetate, etc.), estrogen drugs (eg, estradiol, ethinylestradiol, phosphfestrol, chlorotriacene, etc.), Anti-estrogen drugs (such as epithios-nol, mepithiostan, evening moxifen, clomiphene, etc.), luteinizing hormones (such as hydroxyprogesterone haplonate, dydrogesterone, medroxyprogesterone, norethisterone, norletindrone, etc.), LHRH derivatives (such as leuprorelin acetate) Etc.) I can do it.
  • corticosteroids eg, prednisolone, prednisone, dexamethasone, cortisone acetate, etc.
  • estrogen drugs eg, estradi
  • immunotherapeutic agent examples include microorganisms or bacterial components (eg, muramyl dipeptide derivative, picibanil, etc.), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), and genetic engineering techniques.
  • Cytokinin eg, interferon, interleukin 2 (IL-2), interleukin 12 (IL-12), tumor necrosis factor (TNF), etc.
  • colony stimulating factor eg, granulocyte colony stimulating factor, erythropoietin Etc.
  • drugs that have been shown to improve cachexia in animal models and clinically, such as cyclooxygenase inhibitors (e.g., indomethacin) (Cancer Reseach, Vol. 49, pp. 5935-5939, 1989], progesterone derivatives (eg, megestrol acetate) [Journal of Clinical Oncology, Journal of Clinical Oncology, Vol.
  • sugar Steroids eg, dexamethasone
  • metoclobramides e.g., metoclobramides
  • tetrahydrocannabinols all of which are the same as described above
  • fat metabolism improvers eg, eicosapentaenoic acid, etc.
  • growth hormone IGF-1
  • cachexia Is a factor which induces TNF- a, L I F, IL one 6, antibody against Oncostatin M can also be used in combination with the present invention formulation.
  • general drugs used for treatment or prevention of diseases of the placenta and the knee are also used as concomitant drugs.
  • agents include anti-inflammatory agents, antipyretic analgesics, antibacterial agents, antiviral agents, hormonal agents, etc., which are commonly used in clinical practice.
  • SEQ ID NO: 7 shows the nucleotide sequence of DNA encoding the amino acid sequence represented by SEQ ID NO: 1.
  • SEQ ID NO: 8 shows the nucleotide sequence of DNA encoding the amino acid sequence represented by SEQ ID NO: 2.
  • SEQ ID NO: 3 shows the nucleotide sequence of DNA encoding the amino acid sequence represented by SEQ ID NO: 3. (SEQ ID NO: 9)
  • SEQ ID NO: 10 shows the nucleotide sequence of DNA encoding the amino acid sequence represented by SEQ ID NO: 4. (SEQ ID NO: 10)
  • Example Example 1 shows the nucleotide sequence of DNA encoding the amino acid sequence represented by SEQ ID NO: 5.
  • This SZO dispersion is added to 800 ml of a 0.1% aqueous solution of polyvinyl alcohol, and the mixture is stirred and emulsified using a homomixer. Stir at room temperature for 3 hours to evaporate dichloromethane, and centrifuge (about 2,000 rpm) to collect microcapsules. After washing twice with 400 ml of distilled water, add 0.2 g of D-mannitol and freeze-dry. Further, in order to remove the residual solvent, vacuum drying is performed at 46 ° C for 3 days to obtain microcapsules containing sustained-release metastin (1-54).
  • This S / II dispersion was added to 80% of a 0.1% aqueous solution of polyvinyl alcohol, and the mixture was stirred and emulsified using a homomixer. After stirring at room temperature for 3 hours to evaporate dichloromethane, microcapsules were collected by centrifugation (about 2,000 rpm). Then, after washing twice with 40 Oinl of distilled water, 0.2 g of D-mannitol was added and freeze-dried. Furthermore, in order to remove the residual solvent, vacuum drying was performed at 46 ° C for 3 days to obtain microcapsules containing sustained-release metastin (1-54).
  • HexaGlycerol PentaStearate one of the polyglycerol fatty acid esters, is heated and melted at 70 ° C after heating and melting at 156 Omg.
  • Add 4 Omg of the freeze-dried powder of (1-54)) mix with stirring, aspirate into a 2.0-millimeter implanted needle, and cool and solidify at room temperature.
  • the obtained cylindrical pellets are cut into 10 orchids to obtain a sustained-release metastin (1-154) containing 2.0 mm in length and 10 m in length and containing HGPS.
  • 1 Omg of zinc oxide are dissolved in 2.7 ml of dichloromethane.
  • 30 Omg of a freeze-dried powder of human-derived KiSS-1 peptide (metastin (45-54)) represented by SEQ ID NO: 3 was added and atomized using Polytron (Kinemachi Rikisha). I do.
  • This SZO dispersion is added to a 0.1% aqueous solution of polyvinyl alcohol (80 Offl 1), and the mixture is stirred and emulsified using a homomixer.
  • 30 Omg of a freeze-dried powder of human-derived KiSS-1 peptide (metastin (40-54)) represented by SEQ ID NO: 2 was added and atomized using a Polytron (Kinemachi Rikisha). I do.
  • This S / 0 dispersion is added to a 0.1% aqueous solution of polyvinyl alcohol 80 On 1 and stirred and emulsified using a homomixer.
  • 1 Omg of zinc oxide were dissolved in 2.7 ml of dichloromethane.
  • organic solvent solution was added 1.2 ml of an aqueous solution of human-derived KiSS-1 peptide (metastin (40-54)) represented by SEQ ID NO: 2 at a concentration of 25 Omg / ml, and Polytron (Kinematica) was added.
  • zinc oxide 10 mg
  • 2 Omg of a freeze-dried powder of human KiSS-1 peptide (metastin (1-54)) represented by SEQ ID NO: 1 was added to this organic solvent solution, and the mixture was atomized using Polytron (Kinemachi Rikisha).
  • This SZO dispersion was added to 800 ml of a 0.1% aqueous solution of polyvinyl alcohol, and the mixture was stirred and emulsified using a homomixer. After stirring at room temperature for 3 hours to evaporate dichloromethane, microcapsules were collected by centrifugation (about 2,000 rpm). Then, after washing twice with 400 ml of distilled water, 0.2 g of D-mannitol was added and freeze-dried. Furthermore, in order to remove the residual solvent, vacuum drying was performed at 46 ° C for 3 days to obtain microcapsules containing sustained-release metastin (1-54).
  • 240 fflg of a freeze-dried powder of human-derived KiSS-1 peptide (metastin (1-54)) represented by SEQ ID NO: 1 was added, and the mixture was pulverized using Polytron (Kinemachi Rikisha).
  • This SZO dispersion was added to a 0.1% aqueous polyvinyl alcohol solution (80 Oml) and stirred and emulsified using a homomixer. After stirring at room temperature for 3 hours to evaporate dichloromethane, microcapsules were collected by centrifugation (about 2,000 rpm). Then, after washing twice with 400 ml of distilled water, 0.24 g of D-mannitol was added and freeze-dried. Further, in order to remove the residual solvent, the microcapsules containing sustained-release metastin (1-54) were obtained by vacuum drying at 46 ° C for 3 days.
  • the S / O dispersion was added to 800 ml of a 0.1% aqueous solution of polyvinyl alcohol, and the mixture was stirred and emulsified using a homomixer. After stirring at room temperature for 3 hours to evaporate dichloromethane, microcapsules were collected by centrifugation (about 2,000 rpm). Then, after washing twice with 40 Oml of distilled water, 0.24 g of D-mannitol was added and freeze-dried. Furthermore, in order to remove the residual solvent, vacuum drying was performed at 46 ° C for 3 days to obtain a microcapsule containing sustained-release metastin (1-54).
  • Experimental example 1
  • the microcapsules containing sustained release metastin (1-54) prepared in Example 10 were The metastin (1-54) was administered subcutaneously at a dose of 6 mg equivalent, and the time-dependent change in blood metastin (1-54) concentration was measured over 2 weeks. The results are shown in Figure 1. As shown in FIG. 1, blood metastin (1-154) concentration was detected over a two-week period. It is apparent from this that the sustained-release preparation of the present invention has excellent sustained-release properties.
  • hOT7T175 cDNA (SEQ ID NO: 6 described in WO 00/24890) was ligated to a pAKKO-neo mammalian cell expression plasmid having neo f as a dominant selectable marker using a standard method, and the ⁇ 0T7T175 expression construct was ligated. Obtained.
  • the 1 ⁇ 0 ⁇ 7 ⁇ 75 expression construct was introduced into B16 cells using Eiiectene (QIAGEN) transfection reagent.
  • the B16 cells were selectively cultured in RPMI 1640 selection medium containing G418 at a final concentration of 1.2 mg / ml, and the formed colonies were isolated using a cloning ring to obtain 17 clones of G418-resistant ⁇ 16 / hl75 cells. The strain was isolated.
  • the 17 transgenic ⁇ 16 ⁇ -175 cell lines were cultured in T25 flasks using RPMI 1640 selection medium containing G418 at a final concentration of 1.2 mg / ml, and total RNA was extracted using RNeasy (QIAGEN).
  • CDNA synthesis was performed using Superscript II (Gibco BRL) using 1 g of RNA extracted from each clone as type III.
  • TadMan PCR was performed using TadMan primer set and TaqMan probe set for T7T175, and several receptor expression strains including cl. 4 were selected.
  • the responsiveness to metastin and metastin (45-54) of the selected 5 clones (cl.4, cl.17, cl.19, cl.2, cl.20) was determined by intracellular Ca using FLIPR. It was examined by detecting changes in 2+ concentration. As a result, for three clones (cl. 4, cl. 17, cl. 19) with high expression levels detected by TaQMan PCR (ca. 1000-7000 copies / ng total thigh), the final concentration was 1 (each). It was confirmed to respond to ⁇ of 6 Micromax metastin or 10- 8 Micromax of metastin (4 5 5 4).
  • Metastin or a derivative thereof or a salt thereof exhibits a more effective pharmacological effect by forming a sustained-release preparation.
  • the sustained-release preparation of the present invention containing metastin or a derivative thereof or a salt thereof is useful for treating or preventing all diseases caused by impaired metastin bioactivity.
  • the preparation of the present invention since the preparation of the present invention has a cancer metastasis inhibitory activity, it is useful for treating or preventing any cancer.
  • the preparation of the present invention since the preparation of the present invention has a placental function regulating action, it is useful for treating or preventing choriocarcinoma, hydatidiform mole, invasive mole, miscarriage, fetal growth deficiency, glucose metabolism disorder, lipid metabolism disorder or delivery abnormality. Useful. Further, since the preparation of the present invention has a knee function-regulating action, it is also useful for treating or preventing knee disease.

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Abstract

L'invention concerne des préparations contenant de la métastatine, possédant une activité permettant d'inhiber la formation de métastase cancéreuse, utiles dans le traitement ou la prévention de cancers, possédant un effet de régulation de fonctions placentaires, utiles dans le traitement ou la prévention de cancer villeux, de môle hydatique, de môle invasive, d'avortement, d'hypoplasie foetale, d'erreur métabolique des sucres, d'erreur métabolique des lipides, ou d'anormalités dans l'accouchement, l'effet du médicament pouvant s'exercer seulement à faible dose, sans effet secondaire, avec une administration non obligatoirement journalière, et permettant de supprimer la douleur et les nuisances chez les patients. L'invention concerne aussi des préparations à libération prolongée utiles dans le traitement ou la prévention d'une quelconque maladie associée à des troubles d'activité physiologique de la métastatine. En raison de leur activité inhibitrice de métastases cancéreuse, ces préparations sont particulièrement utiles dans le traitement ou la prévention de tous cancers. En raison de leur effet de régulation de fonctions placentaires, ces préparations sont utiles dans le traitement ou la prévention de cancer villeux, de môle hydatique, de môle invasive, d'avortement, d'hypoplasie foetale, d'erreur métabolique des sucres, d'erreur métabolique des lipides, ou d'anormalités dans l'accouchement. En raison de leur effet de régulation des fonctions pancréatiques, ces préparations sont aussi utiles dans le traitement ou la prévention de maladies pancréatiques.
PCT/JP2002/003898 2001-04-20 2002-04-19 Preparations contenant un peptide WO2002085399A1 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004060264A2 (fr) * 2003-01-06 2004-07-22 Takeda Pharmaceutical Company Limited Derives de metastine et utilisation associee
WO2004063221A1 (fr) 2002-12-26 2004-07-29 Takeda Pharmaceutical Company Limited Derive de la metastine et son utilisation
WO2004080479A1 (fr) * 2003-03-12 2004-09-23 Takeda Pharmaceutical Company Limited Agents ameliorant la fonction gonadique
WO2008017372A1 (fr) 2006-08-09 2008-02-14 Maria Vincenza Carriero Peptides ayant une activité pharmacologique pour le traitement de troubles associés à la migration de cellules altérées, tels que le cancer
WO2009131191A1 (fr) 2008-04-24 2009-10-29 武田薬品工業株式会社 Dérivé de métastine et son utilisation
EP2113513A2 (fr) 2004-06-25 2009-11-04 Takeda Pharmaceutical Company Limited Dérivés de métastine et utilisation associée
WO2010013762A1 (fr) 2008-07-30 2010-02-04 武田薬品工業株式会社 Dérivé de métastine et son utilisation
US7786083B2 (en) 2006-10-25 2010-08-31 Takeda Pharmaceutical Company Limited Metastin derivatives and use thereof
US7960348B2 (en) 2005-12-22 2011-06-14 Takeda Pharmaceutical Company Limited Metastin derivatives and use thereof
WO2011078394A2 (fr) 2009-12-22 2011-06-30 Takeda Pharmaceutical Company Limited Formulation à libération prolongée
WO2011162413A1 (fr) * 2010-06-25 2011-12-29 Takeda Pharmaceutical Company Limited Formule à libération prolongée
US8404643B2 (en) 2005-12-22 2013-03-26 Takeda Pharmaceutical Company Limited Metastin derivatives and use thereof
US9682153B2 (en) 2008-09-19 2017-06-20 Nektar Therapeutics Polymer conjugates of therapeutic peptides
WO2019007383A1 (fr) 2017-07-05 2019-01-10 凯惠科技发展(上海)有限公司 Composé peptidique et son application, et composition contenant un composé peptidique

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998043664A1 (fr) * 1997-04-01 1998-10-08 Lg Chemical Limited Composition a liberation continue sous forme de medicaments encapsules dans des microparticules d'acide hyaluronique
WO1999048519A1 (fr) * 1998-03-20 1999-09-30 Takeda Chemical Industries, Ltd. Preparation de polypeptide physiologiquement actif, a liberation prolongee, et production correspondante
WO2000078340A1 (fr) * 1999-06-17 2000-12-28 Riken Preparations a liberation prolongee a base de peptides physiologiquement actifs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998043664A1 (fr) * 1997-04-01 1998-10-08 Lg Chemical Limited Composition a liberation continue sous forme de medicaments encapsules dans des microparticules d'acide hyaluronique
WO1999048519A1 (fr) * 1998-03-20 1999-09-30 Takeda Chemical Industries, Ltd. Preparation de polypeptide physiologiquement actif, a liberation prolongee, et production correspondante
WO2000078340A1 (fr) * 1999-06-17 2000-12-28 Riken Preparations a liberation prolongee a base de peptides physiologiquement actifs

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LEE J.H. ET AL.: "KiSS-1, a novel human malignant melanoma metastasis-suppressor gene", JOURNAL OF THE NATIONAL CANCER INSTITUTE, vol. 88, no. 23, 1996, pages 1731 - 1737, XP002954456 *
PHTAKI T. ET AL.: "Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor", NATURE, vol. 411, no. 6837, 2001, pages 613 - 617, XP002942231 *

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* Cited by examiner, † Cited by third party
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US8361968B2 (en) 2002-12-26 2013-01-29 Takeda Pharmaceutical Company Limited Metastin derivatives and use thereof
US6800611B2 (en) 2003-01-06 2004-10-05 Takeda Chemical Industries, Ltd. Metastin derivatives and their use
WO2004060264A3 (fr) * 2003-01-06 2004-12-02 Takeda Pharmaceutical Derives de metastine et utilisation associee
WO2004060264A2 (fr) * 2003-01-06 2004-07-22 Takeda Pharmaceutical Company Limited Derives de metastine et utilisation associee
WO2004080479A1 (fr) * 2003-03-12 2004-09-23 Takeda Pharmaceutical Company Limited Agents ameliorant la fonction gonadique
US7754220B2 (en) 2003-03-12 2010-07-13 Takeda Pharmaceutical Company Limited Methods of inhibiting secretion of follicle-stimulating hormone and testosterone
EP2113513A2 (fr) 2004-06-25 2009-11-04 Takeda Pharmaceutical Company Limited Dérivés de métastine et utilisation associée
US7625869B2 (en) 2004-06-25 2009-12-01 Takeda Pharmaceutical Company Limited Metastin derivatives and use thereof
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US7960348B2 (en) 2005-12-22 2011-06-14 Takeda Pharmaceutical Company Limited Metastin derivatives and use thereof
US8404643B2 (en) 2005-12-22 2013-03-26 Takeda Pharmaceutical Company Limited Metastin derivatives and use thereof
WO2008017372A1 (fr) 2006-08-09 2008-02-14 Maria Vincenza Carriero Peptides ayant une activité pharmacologique pour le traitement de troubles associés à la migration de cellules altérées, tels que le cancer
EP2230245A1 (fr) 2006-08-09 2010-09-22 Maria Vincenza Carriero Peptides ayant une activité pharmacologique pour traiter des désordres associés à la migration altérée des cellules, tels que le cancer
EP2213680A1 (fr) 2006-08-09 2010-08-04 Maria Vincenza Carriero Peptides ayant une activité pharmacologique pour traiter des désordres associés à la migration altérée des cellules, tels que le cancer
US7786083B2 (en) 2006-10-25 2010-08-31 Takeda Pharmaceutical Company Limited Metastin derivatives and use thereof
US8765909B2 (en) 2006-10-25 2014-07-01 Takeda Pharmaceutical Company Limited Metastin derivatives and use thereof
WO2009131191A1 (fr) 2008-04-24 2009-10-29 武田薬品工業株式会社 Dérivé de métastine et son utilisation
EP3210998A1 (fr) 2008-07-30 2017-08-30 Takeda Pharmaceutical Company Limited Dérivé de métastine et ses utilisations
WO2010013762A1 (fr) 2008-07-30 2010-02-04 武田薬品工業株式会社 Dérivé de métastine et son utilisation
US9682153B2 (en) 2008-09-19 2017-06-20 Nektar Therapeutics Polymer conjugates of therapeutic peptides
US20120302508A1 (en) * 2009-12-22 2012-11-29 Takeda Pharmaceutical Company Limited Sustained-release formulation
CN107412725A (zh) * 2009-12-22 2017-12-01 武田药品工业株式会社 缓释制剂
JP2017160201A (ja) * 2009-12-22 2017-09-14 武田薬品工業株式会社 徐放性製剤
JP2013514968A (ja) * 2009-12-22 2013-05-02 武田薬品工業株式会社 徐放性製剤
CN102665690A (zh) * 2009-12-22 2012-09-12 武田药品工业株式会社 缓释制剂
WO2011078394A2 (fr) 2009-12-22 2011-06-30 Takeda Pharmaceutical Company Limited Formulation à libération prolongée
JP2016029045A (ja) * 2009-12-22 2016-03-03 武田薬品工業株式会社 徐放性製剤
WO2011162413A1 (fr) * 2010-06-25 2011-12-29 Takeda Pharmaceutical Company Limited Formule à libération prolongée
EA021663B1 (ru) * 2010-06-25 2015-08-31 Такеда Фармасьютикал Компани Лимитед Композиция с замедленным высвобождением, способ ее получения и способ лечения рака
US20130210742A1 (en) * 2010-06-25 2013-08-15 Takeda Pharmaceutical Company Limited Sustained-release formulation
JP2013530926A (ja) * 2010-06-25 2013-08-01 武田薬品工業株式会社 徐放性製剤
WO2019007383A1 (fr) 2017-07-05 2019-01-10 凯惠科技发展(上海)有限公司 Composé peptidique et son application, et composition contenant un composé peptidique
US11427615B2 (en) 2017-07-05 2022-08-30 Xdcexplorer (Shanghai) Co., Ltd. Peptide compound and application thereof, and composition containing peptide compound
US11807660B2 (en) 2017-07-05 2023-11-07 Xdcexplorer (Shanghai) Co., Ltd. Peptide compound and application thereof, and composition containing peptide compound
US11981753B2 (en) 2017-07-05 2024-05-14 Shangpharma Innovation Inc. Peptide compound and application thereof, and composition containing peptide compound

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