THE NATIONALUS009782331B2 HUMAN MINI (12 ) United States Patent (10 ) Patent No. : US 9 ,782 , 331 B2 Imoto ( 45) Date of Patent: Oct . 10 , 2017 ( 54 ) DISPERSION AND METHOD FOR FORMING ( 2013. 01 ) ; A61K 8 /64 (2013 . 01 ) ; A61K 8 /731 HYDROGEL (2013 .01 ) ; A61K 8 / 733 ( 2013 .01 ) ; A61K 9 / 06 (2013 .01 ) ; A61K 47/ 10 ( 2013 .01 ) ; A61K 47 / 14 ( 71 ) Applicant: NISSAN CHEMICAL INDUSTRIES , ( 2013 . 01 ) ; A61K 47 / 186 ( 2013 . 01 ) ; A61K LTD . , Tokyo ( JP ) 47 /24 ( 2013 .01 ) ; A61K 47136 (2013 .01 ) ; A61K 47/ 38 ( 2013 .01 ) ; A61K 47 /42 (2013 .01 ) ; A61Q 19 / 00 ( 2013 .01 ) ; B01J 13 / 00 ( 2013 .01 ) ; BOIJ ( 72 ) Inventor: Takayuki Imoto , Funabashi ( JP ) 13 /0052 (2013 .01 ) ; C07K 5 /06026 ( 2013 . 01 ) ; CO7K 5 /0806 ( 2013 .01 ) ; CO7K 5 / 1008 ( 73 ) Assignee : NISSAN CHEMICAL INDUSTRIES , ( 2013 .01 ) ; C09K 3 / 00 ( 2013 .01 ) ; A61K LTD ., Tokyo (JP ) 2800 /10 ( 2013 .01 ) ; A61K 2800 /48 ( 2013 .01 ) ; A61K 2800 /52 (2013 .01 ) ; A61K 2800 /5922 ( * ) Notice : Subject to any disclaimer, the term of this (2013 . 01 ) ; A61K 2800 /805 (2013 . 01 ) patent is extended or adjusted under 35 8 ) Field of Classification Search U . S . C . 154 ( b ) by 0 days . None See application file for complete search history. ( 21) Appl. No .: 14 /904 , 284 ( 56 ) References Cited (22 ) PCT Filed : Jul. 3 , 2014 U . S . PATENT DOCUMENTS 5 ,385 , 688 A * 1/ 1995 Miller .. CO9K 5 / 20 ( 86 ) PCT No. : PCT/ JP2014 / 067802 252 / 70 § 371 (c )( 1 ), 2010 /0279955 AL 11 /2010 Miyachi et al . ( 2 ) Date : Jan . 11, 2016 (Continued ) FOREIGN PATENT DOCUMENTS ( 87 ) PCT Pub. No .: WO2015 / 005219 2172475 AL 4 / 2010 PCT Pub. Date : Jan . 15 , 2015 E 2319894 A1 5 /2011 ( Continued ) (65 ) Prior Publication Data US 2016 /0129119 A1 May 12, 2016 OTHER PUBLICATIONS Suzuki et al, “ Supramolecular Hydrogels Formed by L - Lysine Foreign Application Priority Data Derivatives, " Chemistry Letters , vol. 33 , No . 11 , 2004 , pp . 1496 ( 30 ) 1497 . Jul. 9 , 2013 ( JP ) .. .. .. .. 2013 - 143791 (Continued ) (51 ) Int. Cl. A61K 8 / 04 ( 2006 .01 ) Primary Examiner — Yate K Cutliff C09K 3 / 00 ( 2006 .01 ) (74 ) Attorney , Agent, or Firm — Oliff PLC BOIJ 13 / 00 ( 2006 .01 ) A61K 8 /64 ( 2006 .01 ) (57 ) ABSTRACT A610 19 / 00 ( 2006 . 01 ) An object is to provide dispersion containing lipid peptide A61K 9 /06 ( 2006 .01 ) type compound useful as low molecular weight gelator, such A61K 47 /42 ( 2017 .01 ) CO7K 5 / 062 ( 2006 .01 ) as lipid dipeptide and lipid tripeptide , and dissolution accel CO7K 5 / 083 ( 2006 .01 ) erator capable of dissolving the lipid peptide type compound COZK 5 / 103 ( 2006 .01 ) at lower temperature and more easily . It is also an object to A61K 8 / 44 ( 2006 .01 ) provide dispersion that can form hydrogel by simpler A61K 8 / 34 ( 2006 .01 ) method and under milder condition ( low temperature ) and A61K 8 / 37 ( 2006 .01 ) from which gel can be obtained as gel having high thermal A61K 8 /41 ( 2006 .01 ) stability , and providemethod for forming the gel. Dispersion A61K 8 /55 ( 2006 .01 ) including: a lipid peptide type compound in which peptide A61K 8 / 73 ( 2006 .01 ) portion formed by repetition of at least two or more identical A61K 47 / 10 ( 2017 .01 ) or different amino acids is bonded to lipid portion including A61K 47 / 14 (2017 . 01) C10 - 24 aliphatic group ; dissolution accelerator having, in (Continued ) molecules thereof, hydrophilic portion and hydrophobic ( 52 ) U . S . CI. portion , the hydrophilic portion having betaine structure ; ??? .. .. .. A61K 8 / 04 (2013 .01 ) ; A61K 8 / 042 ( 2013 .01 ) ; A61K 8 /342 ( 2013 .01 ) ; A61K 8 /345 and water; and method for producing hydrogel by use of the ( 2013 . 01 ) ; A61K 8 /375 (2013 . 01 ) ; A61K 8 /416 dispersion . (2013 .01 ) ; A61K 8 /442 (2013 .01 ) ; A61K 8 /55 16 Claims, No Drawings US 9 ,782 , 331 B2 Page 2 (51 ) Int . CI. WO 2012 / 133787 A1 10 / 2012 ( 2017 .01 ) WO 2012 / 144609 Al 10 / 2012 A61K 47 / 18 WO 2014003015 AL 1 /2014 A61K 47 /24 ( 2006 .01 ) WO 2014054699 Al 4 / 2014 A6IK 4736 ( 2006 .01 ) A61K 4738 ( 2006 .01 ) OTHER PUBLICATIONS ( 56 ) References Cited Jung et al , Self Assembly of a Sugar -Based Gelator in Water : Its Remarkable Diversity in Gelation Ability and Aggregate Structure , U . S . PATENT DOCUMENTS Langmuir , vol . 17, 2001, pp . 7229 - 7232 . Hamachi et al, Solid -phase lipid synthesis (SPLS ) - 2 : incidental 2011/ 0183913 A1 * 7 / 2011 Miyamoto . .. .. A61K 9 / 0014 discovery of organogelators based on artificial glycolipids , Tetra 514 / 18 . 8 hedron Letters , vol . 42 , 2001 , pp . 6141 -6145 . 2012 /0258059 Al 10 / 2012 Iwama et al . Suzuki et al, Supramolecular hydrogel formed by 2014 /0113976 A1 4 /2014 Matsumoto et al. glucoheptonamide of L - lysine : simple preparatin and excellent hydrogelation ability , Tetranderon , vol. 63, 2007 , pp . 7302 -7308 . FOREIGN PATENT DOCUMENTS Matsuzawa et al , Assembly and Photoinduced Organization of Mono - and Oligopeptide Molecules Containing an Azobenzene 2700691 A1 2 / 2014 Moiety , Advanced Functional Matter, vol . 17 , 2007 , pp . 1507 - 1514 . 2002 - 047172 A 2 / 2002 2007 - 209874 A 8 / 2007 Oct . 7 , 2014 International Search Report issued in International 2011 -036760 A 2 / 2011 Patent Application No . PCT/ JP2014 /067802 . JP 2012 -030221 A 2 / 2012 Nov. 9 , 2016 Extended Search Report issued in European Patent wo 2009 / 005151 AL 1 / 2009 Application No. 14822909 . 9 . WO 2009005152 A1 1 / 2009 wo 2011 /052613 Al 5 / 2011 * cited by examiner US 9 , 782 ,331 B2 DISPERSION AND METHOD FOR FORMING condition of about 100° C . to dissolve and disperse the HYDROGEL gelator in water , and leaving the resultant solution to stand still at room temperature . TECHNICAL FIELD PRIOR ART DOCUMENTS The present invention relates to a dispersion containing a low molecular weight lipid peptide type compound useful as Patent Documents a thickener or a gelator, and a method for forming a hydrogel using the dispersion . Patent Document 1 : International Publication No . WO 2009/ 10 005151 pamphlet BACKGROUND ART Patent Document 2 : International Publication No . WO 2009/ 005152 pamphlet A hydrogel contains water as a solvent and thus is useful as a gel having high biocompatibility . Such a hydrogel is Non -Patent Documents used in various fields such as applications for commodities 15 such as paper diapers , cosmetics and aromatics . Non -patent Document 1 : Suzuki, Masahiro . Yumoto , Examples of a conventional hydrogel include polymer Mariko . Mutsumi, Shirai . Hirofusa , Hanabusa , Kenji . gels formed through such steps that polymer chains are Chemistry Letters , 33 ( 11 ) , 1496 - 1497 cross - linked to form a three - dimensional network structure , Non - patent Document 2 : Jong Hwa Jung , Georeg John , and that a noncovalent bond is formed between the three - 20 Mitsutosish Mausda , Kaname Yoshida . Seiji Shinnkai. dimensional network structure and the solvent such as water, and Toshimi Shimizu Langumir 2001 , 17 , 7229 - 7232 so that the three - dimensional network structure swells to Non - patent Document 3 : I . Hamachi. S . Kivonaka . S . form a polymer gel. Many studies for the physical properties S hinkai, Tetrahedron Lett. , 2001, 42 , 6141. I. Hamachi, S . of the polymer gel and many developments of the applica Kiyonaka , S . Shinaki, Chem . Commun . , 2000 , 1281 tions of the polymer gel have been performed with respect 25 Non - patent Document 4 : Masahiro Suzuki, Sanae Owa, to natural polymer gels formed from polysaccharide such as Hirofusa Shirai and Kenji Hanabusa . Tetrahedron 2007 63 agarose and protein , and synthetic polymer gels in which 7302 - 7308 polymer chains are cross - linked to each other through a Non - patent Document 5 : Yoko Matsuzawa, Katsuyuki Ueki, chemical covalent bond , such as an acrylamide gel. Masaru Yoshida , Nobuyuki Tamaoki, Tohru Nakamura , Recently , besides the above gels containing polymer 30 Hideki Sakai, and Masahiko Abe , Adv . Funct. Mater. compounds, hydrogels formed by the self - assembly of an 2007 , 17 . 1507 - 1514 organic compound having a relatively low molecular weight have been found and various hydrogels have been studied . SUMMARY OF THE INVENTION The formation of the gel by the self - assembly of a low molecular weight compound has been elucidated to occur 35 Problem to be Solved by the Invention through the following steps: in a substances ( low molecular weight compounds ) group in a random state at first, mol It is an object of the present invention to provide a ecules of the substances associate spontaneously while they dispersion containing a lipid peptide type compound useful are having directionality by, for example , an intermolecular as a low molecular weight gelator , such as a lipid dipeptide non - covalent interaction between the molecules of the sub - 40 and a lipid tripeptide, and a dissolution accelerator capable stances under an appropriate external condition in a of dissolving the lipid peptide type compound at a lower medium ) to form a macro molecule -assembly : and plural temperature and more easily . macro molecule - assemblies form a network and the network It is also an object of the present invention to provide a swells with a surrounding solvent to form a gel . Examples dispersion that can form a hydrogel by a simpler method and of a driving force for this molecule association ( self -assem - 45 under a milder condition ( low temperature ) and from which bly ) include a force by an action of a hydrogen bond having a gel can be obtained as a gel having high thermal stability , a relatively weak bonding strength , and a force by a van der and provide a method for forming the gel . Waals interaction ( non -hydrogen bond ) having a bonding strength even weaker than that of the hydrogen bond . Means for Solving the Problems Many of the low molecular weight gelators that have been 50 disclosed are an amphipathic compound having a combina As a result of assiduous research intended to overcome tion of a hydrophobic portion of a long -chain alkyl group these disadvantages, the inventors of the present invention and a hydrophilic portion .