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NOVEL CELL MEMBRANE-PERMEATING PEPTIDE meetings

Foreign code F170008944
File No. (S2015-1544-N0)
Posted date Feb 1, 2017
Country WIPO
International application number 2016JP064767
International publication number WO 2016186140
Date of international filing May 18, 2016
Date of international publication Nov 24, 2016
Priority data
  • P2015-101497 (May 19, 2015) JP
Title NOVEL CELL MEMBRANE-PERMEATING PEPTIDE meetings
Abstract The present invention addresses the problem of providing a novel membrane permeability-improving agent which can be applied to polymeric drugs. More specifically, the present invention addresses the problem of providing: a drug carrier which can improve the absorption efficiency of a polymeric drug in the small intestine; and a membrane permeation-improving agent containing the carrier. According to the present invention, a cell membrane-permeating peptide can be provided, which comprises an amino acid sequence selected from the group consisting of the following amino acid sequences: an amino acid sequence DNPGN (SEQ ID NO: 1); an amino acid sequence SRPAF (SEQ ID NO: 2); an amino acid sequence NDPRN (SEQ ID NO: 3); and an amino acid sequence MSVAN (SEQ ID NO: 4). According to the present invention, a cell membrane-permeating composition can also be provided, which comprises the peptide and a physiologically active substance.
Outline of related art and contending technology BACKGROUND ART
Oral administration can be by a simple naturally in everyday life can be taken from the relatively safe non-invasive drug delivery method can be taken. In addition, that the gut structure and suitable for drug absorption, absorption from the surface area thereof is large, the development of pharmaceutical dosage forms as oral preparations has been desired. However, in order to enable the oral administration of drugs that must be overcome is the problem of some non-.
One, before shifting to the systemic circulation of the drug in the alimentary canal and may be decomposed by an enzyme at the same time. As a solution for this purpose, in the stomach by the enteric formulation technology or the like to prevent deactivation of the drug, drug is delivered to the intestinal tract is possible. Another problem is that the, drug intestinal mucosa, can be employed with sufficient transmission of the epithelium. Absorption in the gastrointestinal tract and pharmacokinetic of pharmaceuticals in oral administration of pharmacological activity is one of the critical determinant of. However, expected as a next generation pharmaceutical nucleic acid-soluble polymers such as pharmaceutical agents for extremely poor gastrointestinal absorption, in clinical, but oral administration by intravenous injection is limited to the method of administration.
So far, for an improved gastrointestinal absorption of a medicament in order to achieve, temporarily increase the permeability of biological membrane material and additives such as absorption promoters have been used for studies. Is an absorption enhancer, surfactant, fatty acid, alcohol or the like can be cited. However, absorption promoters and additives is, by opening and closing of tight junctions nonspecifically increase gastrointestinal absorption, diluted with water or the like in the living body to receive an adequate effect may not be exhibited, then, the safety of the local mucosa failure or the like in question. Therefore, the practical use are limited by the seat. In addition, these methods, the efficiency of absorption of a medicament for the improvement of the low molecular weight can be applied, absorption of a medicament to improve the efficiency of the polymer is insufficient.
In addition, the human immunodeficiency virus (HIV) peptide -1 Tat, peptide HIV-1 Lev, penetratin, transportan, arginine oligomers such as a membrane-bound peptides can be used to increase the gastrointestinal absorption of studies have been made. However, in basic research and promote absorption of insulin from the gastrointestinal tract and are available, and its efficiency is still about 20%, but is made with the clinical application, the sequence may be even more efficient has been sought. Further, a stem cell membrane-penetrating peptide-based co-polymer bonded to the transepithelial and improve absorption of a drug absorption enhancer also has been proposed (patent document 1).
In addition, liposomes modified with chitosan has been developed (non-patent document 1). The transport mechanism is used mainly for the transmission of spaces, acting on the actin F -, to attenuate the tight junctions. However, with respect to transcellular transport, through the interaction of mucin adsorption endocytosis is said to be in the barrier layer. This also has not reached the clinical application.
Small intestine absorption of a medicament as a method of improving polymer, proteolytic enzyme inhibitors is a combined method of the drag carrier has been proposed (non-patent document 2). Wherein, the peptide by an inhibitor of proteolytic enzymes, insulin protein formulation can suppress the decomposition of 100%. Then, smart hydrogel drag carrier is filled with insulin, the bioavailability of rats on oral administration and has been improved up to 10% have been reported (non-patent document 3). However, reaching the small intestine is drug absorption includes is still not sufficient. Therefore, oral administration is possible, for the purpose of improving the absorption in the small intestine and a more excellent drug carrier has been desired.
Scope of claims (In Japanese)[請求項1]
下記のアミノ酸配列:アミノ酸配列DNPGN(配列番号1)、SRPAF(配列番号2)、NDPRN(配列番号3)、およびMSVAN(配列番号4)からなる群より選ばれるアミノ酸配列を含む細胞膜透過性ペプチド。
[請求項2]
少なくとも一つの非天然型アミノ酸を含む請求項1に記載の細胞膜透過性ペプチド。
[請求項3]
前記ペプチドが、アミノ酸配列DNPGNET(配列番号5)、TVSRPAF(配列番号6)、HSNDPRN(配列番号7)、およびPFMSVAN(配列番号8)からなる群より選ばれるアミノ酸配列を含む請求項1または2に記載の細胞膜透過性ペプチド。
[請求項4]
前記ペプチドが、アミノ酸配列DNPGN(配列番号1)またはDNPGNE(配列番号9)を含む請求項1または2に記載の細胞膜透過性ペプチド。
[請求項5]
前記ペプチドが環状ペプチドである請求項1~4のいずれか一つに記載の細胞膜透過性ペプチド。
[請求項6]
前記環状ペプチドがCys-Cysジスルフィド結合を含む環状ペプチドである、請求項5に記載の細胞膜透過性ペプチド。
[請求項7]
前記ペプチドが、哺乳動物細胞の小腸上皮細胞を透過するペプチドである請求項1~6のいずれか一つに記載の細胞膜透過性ペプチド。
[請求項8]
下記のアミノ酸配列:DNPGN(配列番号1)、SRPAF(配列番号2)、NDPRN(配列番号3)、およびMSVAN(配列番号4)からなる群より選ばれるアミノ酸配列を含むペプチド、および生理活性物質を含む組成物であって、該ペプチドは、該生理活性物質または該生理活性物質を含む活性物質担体と結合または複合体を形成している細胞膜透過性である組成物。
[請求項9]
前記ペプチドが、少なくとも一つの非天然型アミノ酸を含む請求項8に記載の組成物。
[請求項10]
前記ペプチドが、アミノ酸配列DNPGNET(配列番号5)、TVSRPAF(配列番号6)、HSNDPRN(配列番号7)、およびPFMSVAN(配列番号8)からなる群より選ばれるアミノ酸配列を含む請求項8または9に記載の組成物。
[請求項11]
前記ペプチドが、アミノ酸配列DNPGN(配列番号1)またはDNPGNE(配列番号9)を含む請求項8または9に記載の組成物。
[請求項12]
前記ペプチドが環状ペプチドである請求項8~11のいずれか一つに記載の組成物。
[請求項13]
前記環状ペプチドがCys-Cysジスルフィド結合を含む環状ペプチドである、請求項12に記載の組成物。
[請求項14]
前記生理活性物質が高分子を含む請求項8~13のいずれか一つに記載の組成物。
[請求項15]
前記高分子が、生理活性ペプチドまたはタンパク質を含む請求項14に記載の組成物。
[請求項16]
前記生理活性ペプチドがインスリンである請求項15に記載の組成物。
[請求項17]
前記高分子が核酸を含む請求項14に記載の組成物。
[請求項18]
前記核酸が、アンチセンスDNA、siRNAまたはshRNAである請求項17に記載の組成物。
[請求項19]
前記生理活性物質を含む活性物質担体が、リポソームである請求項8~18のいずれか一つに記載の組成物。
[請求項20]
前記生理活性物質を含む活性物質担体が、シクロデキストリンである請求項8~18のいずれか一つに記載の組成物。
  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • NATIONAL UNIVERSITY CORPORATION KUMAMOTO UNIVERSITY
  • Inventor
  • ITO, Shingo
  • OHTSUKI, Sumio
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JP KE KG KN KP KR KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN ST TD TG
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