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WO2009157595A1 - Procédé de préparation d'un hydrogel d'acide poly-gamma glutamique - Google Patents

Procédé de préparation d'un hydrogel d'acide poly-gamma glutamique Download PDF

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Publication number
WO2009157595A1
WO2009157595A1 PCT/KR2008/003601 KR2008003601W WO2009157595A1 WO 2009157595 A1 WO2009157595 A1 WO 2009157595A1 KR 2008003601 W KR2008003601 W KR 2008003601W WO 2009157595 A1 WO2009157595 A1 WO 2009157595A1
Authority
WO
WIPO (PCT)
Prior art keywords
gamma
glutamic acid
poly
hydrogel
molecular weight
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2008/003601
Other languages
English (en)
Inventor
Moon-Hee Sung
Jae-Chul Choi
Ji Young Byun
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BioLeaders Corp
Kookmin University
Original Assignee
BioLeaders Corp
Kookmin University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by BioLeaders Corp, Kookmin University filed Critical BioLeaders Corp
Priority to PCT/KR2008/003601 priority Critical patent/WO2009157595A1/fr
Publication of WO2009157595A1 publication Critical patent/WO2009157595A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/042—Gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/88—Polyamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/28—Treatment by wave energy or particle radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/81—Preparation or application process involves irradiation
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2389/00—Characterised by the use of proteins; Derivatives thereof

Definitions

  • the present invention relates to a method for preparing poly(gamma-glutamic acid) hydrogel, and more particularly, to a method for preparing poly(gamma-glutamic acid) hydrogel which is nontoxic and has high water absorption rate, the method comprising dissolving poly-gamma-glutamic acid in a salt solution and subjecting the resulting solution to cross-linking through irradiation of gamma rays.
  • Hydrogel is a three-dimensional, hydrophilic, polymeric network capable of containing large amounts of water, which is made up of a polymer or a copolymer, and form a stable three-dimensional network structure in which structural anistropy is hardly induced by an external force. Since such a structure is formed by forces including covalent bonding, hydrogen bonding, van der Waals interaction or physical interaction etc., hydrogel is thermodynamically stable and does not change its degree of swelling in an aqueous solution, and thus, has mechanical and physicochemical properties corresponding to those of an intermediary form between liquid and solid.
  • Swelling behavior of hydrogel can be adjusted according to a chemical structure and hydrophilicity of a polymer and crosslinking rate between polymeric chains, so that hydrogels with various properties can be produced in various shapes according to components and preparation methods thereof.
  • Applications of hydrogels in the field of biomaterials have been drawing increasing attention since the first hydrogels based on poly(hydroxyethyl methacrylate)(PHEMA) were developed in 1960s by wichterle et al., and, after calcium alginate hydrogel was developed in 1980s, various hydrogels have been developed as a biomaterial using natural polymers or synthetic polymers as a result of mainly studies on physicochemical properties of hydrogel.
  • hydrogels have been widely used in the cosmetic industry, and currently, are being usefully used from medical applications to industrial applications, including a drug delivery system, embolization, scaffolds, chemical valves, separation, concentration and stabilization of proteins, immune assay, bioreactors, sensors, chromatography, cosmetic filler, etc., by introducing various additional functions thereto.
  • hydrogels When hydrogels are produced from natural polymers, they may not have sufficient mechanical properties, and may contain pathogens or evoke immune/inflammatory responses but they do offer several advantageous properties such as biocompatibility, biodegradability and may contain biologically recognizable residues capable of facilitating smooth cell activities, whereas when hydrogels are produced from synthetic polymers, they don't have original physiological activities, but may provide suitably structured matrices whose degradability and functionality were controlled.
  • combining natural polymers with synthetic polymers has been attempted in such a way that disadvantages of the respective natural polymers and synthetic polymers are complemented and advantages thereof are strengthened.
  • poly- gamma-glutamic acid is a viscose polymer consisting of D-L-glutamic acid polymerized through ⁇ gamma ⁇ -glutamyl bonds, which is a natural amino acid polymer produced from the genus Bacillus strain.
  • the inventive poly(gamma-glutamic acid) hydrogel is produced using poly-gamma-glutamic acid having ultra high molecular weight, and thus it has both advantages of natural polymers, i.e, biocompatibility and biodegradability, and advantageous physical properties of synthetic polymers, compared with the existing poly(gamma-glutamic acid) hydrogels.
  • the present inventors obtained a patent relating to poly-gamma- glutamate with high molecular weight and a method for using the same (Korean Patent Registration No. 10-0399,091), and a patent relating to a method for producing ⁇ -PGA using a halophilic Bacillus subtilis var. chungkookjang that produces ⁇ -PGA with high molecular weight (Korean Patent Registration No. 10-0500,796). Also, the present inventors obtained patents relating to an anticancer composition, an immune adjuvant and an immune enhancing agent, which contain ⁇ -PGA (Korean Patent Registration Nos. 10-0496,606; 10-0517,114; and 10-0475,406).
  • the present inventors have identified the effects of ⁇ -PGA by continuously developing applications for ⁇ -PGA, including studies on the use of ⁇ -PGA in medical applications, such as development of hyaluronidase inhibitor containing poly-gamma-glutamic acid(Korean Patent Registration No. 10-0582,120) and the discovery of anticancer effects of poly- gamma-glutamic acid through enhanced immunity (Poo, H.R. et al., Journal of Immunology, 178:775, 2007).
  • the molecular weight of traditional poly-gamma-glutamic acid is 50,000- 1,000,000Da, so that it is a limiting factor in application thereof, especially in industrial production.
  • Poly(gamma-glutamic acid) hydrogel is known to be an eco-friendly material characterized by absorption, biodegradability and plasticity, which is synthesized by inter- molecular cross-linking of a biopolymer used as a raw material, poly-gamma-glutamic acid produced from Bacillus subtilis var. chungkookjang through microbial fermentation.
  • cross-linking methods mainly include chemical treatments using cross-linking agents such as epoxy resins or gamma rays or e-beam irradiation, but the chemical treatment methods have a safety problem due to toxicity of chemical materials and problems involving a complicated process due to a recovery process, and radiation crosslinking methods have a disadvantage in that they produce low yields of hydrogel due to cross-linking inefficiency.
  • the present inventors have made extensive efforts to overcome the problems occurring in the prior art, and, as a result, confirmed that, when poly(gamma-glutamic acid) hydrogel is produced by dissolving poly-gamma-glutamic acid in a salt solution and then cross-linking the resulting solution by irradiating gamma rays, the produced poly(gamma-glutamic acid) hydrogel is nontoxic, has superior absorption property and moisturizing property, and the yield thereof increases, thereby completing the present invention.
  • the present invention provides a method for preparing poly(gamma-glutamic acid) hydrogel, which comprises dissolving poly- gamma-glutamic acid in a salt solution and then irradiating gamma rays thereto.
  • Fig. 1 is a graph showing the results obtained by measuring water absorption rates of the inventive poly(gamma-glutamic acid) hydrogel and conventional hydrogels.
  • Fig. 2 is a graph showing the results obtained by measuring water absorption rates of the inventive poly(gamma-glutamic acid) hydrogel, according to the molecular weight thereof.
  • Fig. 3 is a graph showing the results obtained by measuring water absorption rates of the inventive poly(gamma-glutamic acid) hydrogel at various salt concentrations.
  • Fig. 4 is a graph showing the results obtained by measuring safety of the inventive poly(gamma-glutamic acid) hydrogel, according to the molecular weight thereof.
  • the present invention relates to a method for preparing poly(gamma-glutamic acid) hydrogel, which comprises dissolving poly-gamma-glutamic acid in a salt solution and then irradiating gamma rays thereto.
  • the present invention is intended to provide a method for preparing poly(gamma-glutamic acid) hydrogel having high water absorption rate in high yield, which solves safety problems such as toxicity of chemical substances, occurring by conventional chemical cross-linkage, and doesn't require a treatment process such as a recovery process, etc. by preparing poly-gamma-glutamic acid using microorganisms, adding salt to the prepared poly-gamma-glutamic acid, and cross-linking the resulting solution through irradiation of gamma rays.
  • the poly-gamma-glutamic acid is produced by a microorganism.
  • the microorganism is Bacillus subtilis var. chungkookjang (KCTC 0697BP), and a process for the isolation and identification thereof, and its physiological properties and the like thereof are described in detail in Korean Patent Registration 10-2001-1481 and WO 02/055671.
  • the morphological and physiological properties of the strain are as follows. When cultured in an LB agar plate, the strain forms milky white colonies, and the strain is characterized in that the growth thereof since it is gram positive bacteria growing actively at a culture temperature higher than 37 0 C under aerobic conditions, is reduced at a culture temperature higher than 55 0 C.
  • the inventive strain is halotolerant bacteria capable of growing at a salt(NaCl) concentration of 9.0%, which can also be grown at sodium chloride (NaCl), which is higher than the salt concentration at which a general Bacillus subtilis strain can grow, and it is a typical Bacillus strain forming endospores upon liquid culture or solid culture in an LB liquid medium for more than 70hrs.
  • the sequence of the inventive strain shows high homology (99.0%) with that of Bacillus subtilis.
  • the average molecular weight of poly-gamma-glutamic acid which is produced by Bacillus subtilis chungkookjang (KCTC 0697BP), is 13,00OkDa, and more than 95% of the ⁇ -PGA has molecular weight ranging from 3,000 to 15,00OkDa.
  • the prepared poly- gamma-glutamic acid may be cut with a suitable method to have a given molecular weight for use weight to use, or may be separated with a suitable method to recover according to molecular weight for use.
  • the molecular weight of the poly-gamma-glutamic acid which is used to prepare the inventive poly(gamma-glutamic acid) hydrogel having ultra high molecular weight, is preferably 2,00OkDa- 15,00OkDa, and more preferably 5,00OkDa- 15,00OkDa, and when the molecular weight thereof is less than 2,00OkDa, there is a problem in that hydrogel properties deteriorate to cause low yield, and when the molecular weight thereof is more than 15,00OkDa, there is a problem in that it is hard to produce hydrogel in a general process.
  • the salt is used to produce poly(gamma-glutamic acid) hydrogel in high yield by promoting cross-linking of poly-gamma-glutamic acid with gamma rays, and may be selected from the group consisting of H 2 PO 4 , K 2 HPO 4 , NaH 2 PO 4 , Na 2 HPO 4 , (NH 4 ) 2 SO 4 , (NH 4 ) 2 S 2 O 8 , MgSO 4 , NaCl, CaCl 2 and a mixture thereof and preferably K 2 HPO 4 .
  • the amount of salt added is 0.001-2 parts by weight based on 100 parts by weight of the poly-gamma-glutamic acid and preferably 0.01-lpart by weight.
  • the inventive cross-linking method using irradiation of gamma-ray has advantages in that it involves no safety problems such as toxicity and the like as well as does not require treatment process including recovery process to simplify production process, compared with the prior chemical cross-linking method.
  • poly-gamma-glutamic acid may be irradiated with gamma rays at a dose range of 1 to 10OkGy, and preferably, 5 to 5OkGy. If poly- gamma-glutamic acid is cross-linked by irradiation with a dose lower than IkGy, there may be a problem in that hydrogel properties deteriorate to cause low yield, and if poly-gamma-glutamic acid is cross-linked by irradiation with a dose higher than 10OkGy, there may be a problem of discoloration and shape change.
  • the inventive poly(gamma-glutamic acid) hydrogel has a high water absorption rate due to the use of poly-gamma-glutamic acid with high molecular weight as well as a very high level of safety against toxicity and the like by a cross-linkage using gamma- ray irradiation of poly-gamma-glutamic acid added with salt, not by chemical cross linkage.
  • the inventive poly(gamma-glutamic acid) hydrogel may be added to a cosmetic composition.
  • the poly(gamma-glutamic acid) hydrogel may be added thereto at a concentration of 0.001-5 parts by weight per 100 parts by weight of the cosmetic composition based on dry weight, and preferably 0.01-3 parts by weight based on the dry weight thereof.
  • the cosmetic composition according to the present invention can be formulated into toner, nutrient lotion, nutrient cream, massage cream, essence, pack and the like, and according to the type of formulation, the purpose of use, etc, the composition may additionally contain additives such as colorants, preservatives, surfactants, oil, water, moisturizing agents, thickeners, chelating agents, fragrances, and the like.
  • the cosmetic composition according to the present invention may be used according to the conventional method, and frequency of use thereof may be varied according to user's skin condition or preference.
  • 3L of a basal medium for poly-gamma-glutamic acid production (a medium containing 5% L-glutamic acid: 5% glucose, 1% (NH 4 ) 2 SO 4 , 0.27% KH 2 PO 4 , 0.42% Na 2 HPO 4 12H 2 O, 0.9% NaCl, 0.3% MgSO 4 7H 2 O, 5m/L Vitamin solution, pH 6.8) in a 5L fermentor was inoculated with 2% culture broth of Bacillus subtilis var chungkookjang (KCTC 0697BP) and then cultured at a stirring speed of 150 rpm, an air injection rate of 1.2 vvm and a temperature of 37 0 C for 60 hours. After completion of the culture, bacterial cells were removed using a filter press to obtain a ⁇ - PGA-containing sample solution.
  • KCTC 0697BP Bacillus subtilis var chungkookjang
  • poly-gamma-glutamic acid Molecular weight of the obtained poly- gamma-glutamic acid was measured using GPC (gel permeation column), and as a result, it was confirmed that poly-gamma-glutamic acids having molecular weights of 1-15,00OkDa was produced, and it were separated according to molecular weight through a heating process poly-gamma-glutamic acids having average molecular weights of 5OkDa, 50OkDa, 2,00OkDa, 5,00OkDa and 7,00OkDa, respectively, thus producing poly-gamma-glutamic acid.
  • GPC gel permeation column
  • O.lg of the poly (gamma- glutamic acid) hydrogel having an average molecular weight of 7,00OkDa prepared in Example 2 was added to 200ml of distilled water to gelatinize and then allowed to stand at room temperature for 48 hrs, followed by filtering the resulting solution with a sieve to remove unabsorbed water. The weight of gelatinized material was measured to calculate water absorption rate of the added hydrogel. Moreover, in order to compare its water absorption rate to that of conventional products, water absorption rate of poly(gamma-glutamic acid) hydrogel from Vedan Co. was measured by the same method as described above.
  • the poly(gamma- glutamic acid) hydrogel of the present invention absorbed water 3500 times its own weight while poly- gamma-glutamic acid from Vedan Co. absorbed water 300 times its own weight, thus confirming that the inventive poly(gamma-glutamic acid) hydrogel is an excellent material having high water absorption rate compared with other company's product.
  • poly (gamma- glutamic acid) hydrogel according to the present invention is safe and shows high hygroscopic property, and thus it can be used as highly moisturizing cosmetics and water absorptive gels, as well as applied to high value-added new materials having various uses for moisturizing.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Dispersion Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Birds (AREA)
  • Organic Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Polyamides (AREA)

Abstract

Le procédé ci-décrit permet de préparer un hydrogel d'acide poly(gamma glutamique), et plus particulièrement, de préparer un hydrogel d'acide poly(gamma glutamique) qui est non toxique et possède un taux d'absorption d'eau élevé, ledit procédé comprenant la dissolution de l'acide poly(gamma glutamique) dans une solution saline, et la soumission de la solution obtenue à réticulation par irradiation de rayons gamma. L'hydrogel d'acide poly(gamma glutamique) selon l'invention est sûr et doué d'une propriété hygroscopique élevée. Il peut par conséquent être utilisé à titre de produit cosmétique très hydratant et de gel absorbeur d'eau, et être également appliqué à de nouvelles substances à valeur ajoutée ayant diverses utilisations dans le domaine de l'hydratation.
PCT/KR2008/003601 2008-06-24 2008-06-24 Procédé de préparation d'un hydrogel d'acide poly-gamma glutamique Ceased WO2009157595A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021242936A1 (fr) * 2020-05-26 2021-12-02 Zymochem, Inc. Polymères absorbants à haute performance biodégradables et leurs procédés

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100399091B1 (en) * 2002-07-10 2003-09-22 Bioleaders Corp Macromolecular weight poly(gamma-glutamic acid) and its use
WO2007002705A2 (fr) * 2005-06-24 2007-01-04 Inframat Corporation Composite antimicrobien, procede de fabrication et utilisation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100399091B1 (en) * 2002-07-10 2003-09-22 Bioleaders Corp Macromolecular weight poly(gamma-glutamic acid) and its use
WO2007002705A2 (fr) * 2005-06-24 2007-01-04 Inframat Corporation Composite antimicrobien, procede de fabrication et utilisation

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
HYUK JOON CHOI ET AL.: "Synthesis and Characterization of pH-sensitive and biodegradable hydrogels prepared by r-irradiation using microbial poly(r-glutamic acid) and poly( epsilon -lysine)", JOURNAL OF APPLIED POLYMER SCIENCE, vol. 58, no. 4, 1995, pages 807 - 814 *
KANG, HAHK SOO ET AL.: "Polyelectrolyte Complex Hydrogel Composed of Chitosan and Poly(r-Glutamic Acid) for Biological Application: Preparation, Physical Properties, and Cytocompatibility", JOURNAL OF APPLIED POLYMER SCIENCE, vol. 103, 2007, pages 386 - 394 *
MASAO KUNIOKA ET AL.: "Preparation Conditions and Swelling Equilibria of Biodegradable Hydrogel Prepared from Microbial Poly(r-glutamic acid) and Poly( e -lysine)", JOURNAL OF ENVIRONMENTAL POLYMER DEGRADATION, vol. 4, no. 2, 1996 *
MASAO KUNIOKA: "Biodegradable Water Absorbent Synthesized from Bacterial Poly(amino acid)s", MACROMOLECULAR BIOSCIENCE, vol. 4, 2004, pages 324 - 329 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021242936A1 (fr) * 2020-05-26 2021-12-02 Zymochem, Inc. Polymères absorbants à haute performance biodégradables et leurs procédés
JP2023528308A (ja) * 2020-05-26 2023-07-04 ザイモケム， インコーポレイテッド 生分解性高性能吸収性ポリマーおよびその方法
US11717805B2 (en) 2020-05-26 2023-08-08 Zymochem, Inc. Biodegradable high-performance absorbent polymers and methods thereof
US12053758B2 (en) 2020-05-26 2024-08-06 Zymochem, Inc. Biodegradable high-performance absorbent polymers and methods thereof

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