JPH11180993A - Production of sialic acid - Google Patents
Production of sialic acidInfo
- Publication number
- JPH11180993A JPH11180993A JP9350622A JP35062297A JPH11180993A JP H11180993 A JPH11180993 A JP H11180993A JP 9350622 A JP9350622 A JP 9350622A JP 35062297 A JP35062297 A JP 35062297A JP H11180993 A JPH11180993 A JP H11180993A
- Authority
- JP
- Japan
- Prior art keywords
- sialic acid
- exchange resin
- whey
- acid compound
- anion exchange
- 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.)
- Pending
Links
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 title claims description 72
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 title description 31
- 239000005862 Whey Substances 0.000 claims abstract description 41
- 102000007544 Whey Proteins Human genes 0.000 claims abstract description 41
- 108010046377 Whey Proteins Proteins 0.000 claims abstract description 41
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 22
- 239000008101 lactose Substances 0.000 claims abstract description 22
- 239000013078 crystal Substances 0.000 claims abstract description 19
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000012452 mother liquor Substances 0.000 claims abstract description 16
- -1 sialic acid compound Chemical class 0.000 claims description 51
- 239000003957 anion exchange resin Substances 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 17
- 238000000909 electrodialysis Methods 0.000 claims description 9
- 239000003729 cation exchange resin Substances 0.000 claims description 7
- 239000002994 raw material Substances 0.000 abstract description 13
- 239000003456 ion exchange resin Substances 0.000 abstract description 9
- 229920003303 ion-exchange polymer Polymers 0.000 abstract description 9
- 238000010612 desalination reaction Methods 0.000 abstract description 5
- 239000002537 cosmetic Substances 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 235000013305 food Nutrition 0.000 abstract description 4
- 125000005629 sialic acid group Chemical group 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 125000000129 anionic group Chemical group 0.000 abstract 2
- 238000011033 desalting Methods 0.000 description 27
- 239000000243 solution Substances 0.000 description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 10
- 235000013336 milk Nutrition 0.000 description 7
- 239000008267 milk Substances 0.000 description 7
- 210000004080 milk Anatomy 0.000 description 7
- 239000011347 resin Substances 0.000 description 7
- 229920005989 resin Polymers 0.000 description 7
- OIZGSVFYNBZVIK-FHHHURIISA-N 3'-sialyllactose Chemical compound O1[C@@H]([C@H](O)[C@H](O)CO)[C@H](NC(=O)C)[C@@H](O)C[C@@]1(C(O)=O)O[C@@H]1[C@@H](O)[C@H](O[C@H]([C@H](O)CO)[C@H](O)[C@@H](O)C=O)O[C@H](CO)[C@@H]1O OIZGSVFYNBZVIK-FHHHURIISA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- 108010067454 caseinomacropeptide Proteins 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 5
- 239000004310 lactic acid Substances 0.000 description 5
- 235000014655 lactic acid Nutrition 0.000 description 5
- 125000000962 organic group Chemical group 0.000 description 5
- 238000001179 sorption measurement Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 229920002125 Sokalan® Polymers 0.000 description 4
- 235000013351 cheese Nutrition 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000001766 physiological effect Effects 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- 102000003886 Glycoproteins Human genes 0.000 description 3
- 108090000288 Glycoproteins Proteins 0.000 description 3
- 150000001450 anions Chemical class 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 238000001728 nano-filtration Methods 0.000 description 3
- 229920001542 oligosaccharide Polymers 0.000 description 3
- 150000002482 oligosaccharides Chemical class 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 235000013350 formula milk Nutrition 0.000 description 2
- 150000002270 gangliosides Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 230000001172 regenerating effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010058780 Meningitis neonatal Diseases 0.000 description 1
- 208000006816 Neonatal Sepsis Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、ホエーまたは乳糖
結晶母液からシアル酸化合物を分離する方法に関する。
さらに詳細には、本発明は、各種ホエーの脱塩工程にお
いて、脱塩効率を高めるのと同時に、シアル酸化合物を
簡便かつ効率的に分離・回収する方法に関する。The present invention relates to a method for separating sialic acid compounds from whey or lactose crystal mother liquors.
More specifically, the present invention relates to a method for easily and efficiently separating and recovering a sialic acid compound while increasing the desalting efficiency in a step of desalting various whey.
【０００２】[0002]
【従来の技術】シアル酸は細胞表面糖鎖の末端や糖蛋白
質糖鎖の末端に存在し、様々な生理機能を持つことが知
られている。シアル酸は乳中ではオリゴ糖、ガングリオ
シド、糖タンパク質等として存在している。これらのシ
アル酸化合物は、感染防御活性、乳酸菌増殖活性等の生
理活性を有していることが知られている。例えば、シア
ル酸と乳糖が結合したシアリルラクトースについては、
胃炎の原因菌といわれているカンピロバクター・ピロリ
（Campylobacter pylori）の付着を阻害すること(Infec
t Immun., vol.56, pp.2896-2906, 1988) 、および新生
児の脳膜炎や敗血症の原因菌であるＳ型大腸菌の付着を
阻害すること(Acta Paediatr., vol.82, pp.903-912, 1
993)が報告されている。また、育児用粉乳等に配合した
シアリルラクトースとグリコマクロペプチド（ＧＭＰ）
は、乳酸菌増殖活性を有すること(Biosci. Biotech. Bi
ochem., vol.58, pp.1720-1722, 1994) が報告されてい
る。これらの生理効果があるため、シアル酸化合物は育
児用粉乳等に配合され利用されている。2. Description of the Related Art It is known that sialic acid is present at the terminal of a cell surface sugar chain or the terminal of a glycoprotein sugar chain and has various physiological functions. Sialic acids are present in milk as oligosaccharides, gangliosides, glycoproteins and the like. It is known that these sialic acid compounds have physiological activities such as infection-protection activity and lactic acid bacteria growth activity. For example, for sialyllactose in which sialic acid and lactose are bound,
Inhibiting the attachment of Campylobacter pylori, which is said to be the causative agent of gastritis (Infec
t Immun., vol. 56, pp. 2896-2906, 1988), and inhibiting the adhesion of S-type Escherichia coli, the causative bacterium of neonatal meningitis and sepsis (Acta Paediatr., vol. 82, pp. 903- 912, 1
993) has been reported. In addition, sialyl lactose and glycomacropeptide (GMP) blended in infant milk powder, etc.
Has lactic acid bacteria growth activity (Biosci. Biotech. Bi
ochem., vol.58, pp.1720-1722, 1994). Because of these physiological effects, sialic acid compounds have been used in infant formulas and the like.
【０００３】シアル酸化合物は、通常、牛乳等の乳また
はホエーから分離されることが多い。しかし、乳中には
多量の乳糖や有機酸が存在しており、これらとシアル酸
化合物とを分離することが困難であり、解決法が求めら
れていた。従来、乳またはホエーから工業的にシアル酸
化合物を分離する方法としては、擬似移動床式クロマト
分離装置（ＳＭＢ）を用いて牛乳等の乳からシアリルラ
クトースを工業的規模で分離・回収する方法 (特開平7-
79800号公報) 、親水性の樹脂母体に弱塩基性交換基を
導入した陰イオン交換体を用いてホエーからＧＭＰを分
離する方法 (特開平7-132049号公報) が知られている。
しかし、前者の方法では、前処理として蛋白除去が必要
であり、かつ、分離係数の異なるシアル酸化合物を同時
に精製するには運転条件が煩雑になる等の問題点があ
る。また、後者の方法では、前処理として原料ホエーの
pHを４〜６に調節する必要がある点や、使用する樹脂の
耐薬品性や物理耐久性が低い点から、工業規模での大量
処理には適していない。さらに、これら従来の方法は、
それぞれが、シアル酸含有オリゴ糖、シアル酸含有ペプ
タイドのそれぞれを単独で分離する方法であり、シアル
酸化合物をまとめてホエーから分離する方法については
知られていない。[0003] Sialic acid compounds are usually often separated from milk such as milk or whey. However, a large amount of lactose and organic acids are present in milk, and it is difficult to separate these from sialic acid compounds, and a solution has been demanded. Conventionally, as a method for industrially separating a sialic acid compound from milk or whey, a method for separating and recovering sialyllactose from milk such as milk using an artificial moving bed type chromatographic separation apparatus (SMB) on an industrial scale ( JP-A-7-
No. 79800), and a method of separating GMP from whey using an anion exchanger in which a weakly basic exchange group is introduced into a hydrophilic resin matrix (Japanese Patent Application Laid-Open No. 7-132049) is known.
However, in the former method, there is a problem that protein removal is required as a pretreatment, and operating conditions are complicated to simultaneously purify sialic acid compounds having different separation coefficients. In the latter method, the raw material whey is used as a pretreatment.
It is not suitable for large-scale treatment on an industrial scale because it requires adjusting the pH to 4 to 6 and the resin used has low chemical resistance and physical durability. Furthermore, these conventional methods are:
These are methods for separating sialic acid-containing oligosaccharides and sialic acid-containing peptides, respectively, and there is no known method for separating sialic acid compounds from whey.
【０００４】一方、工業的なホエーまたは乳糖結晶母液
の脱塩方法として、電気透析脱塩法、イオン交換樹脂脱
塩法、両者を組み合わせた方法、ナノフィルトレーショ
ンとイオン交換樹脂脱塩を組み合わせた方法等が利用さ
れている。特に、最近では環境問題から、イオン交換樹
脂脱塩法で排出される再生廃液を減少させる必要が生じ
ており、電気透析法とイオン交換樹脂を組み合わせた方
法や、ナノフィルトレーションとイオン交換樹脂を組み
合わせた方法に移行してきている。イオン交換樹脂脱塩
法では、まず、Ｈ形の強酸性カチオン交換樹脂にホエー
を通液することで、ナトリウム、カリウム、カルシウム
等のカチオンを水素イオンに交換し、次いで、ＯＨ形の
アニオン交換樹脂に通液することで、リン酸、塩素、ク
エン酸、乳酸等のアニオンを水酸化物イオンに交換して
脱塩を行っている。そして、シアル酸化合物は、乳酸や
クエン酸に比べて、アニオン交換樹脂に対する親和力の
弱いアニオンとして存在するため、そのうちの一部だけ
が脱塩時にアニオン交換樹脂に吸着して、アニオン交換
樹脂の再生時に樹脂から脱離し、再生廃液に混入して廃
棄されている現状にある。On the other hand, industrial methods for desalting whey or lactose crystal mother liquors include electrodialysis desalting, ion exchange resin desalting, a method combining the two, and a combination of nanofiltration and ion exchange resin desalting. And other methods are used. In particular, recently, due to environmental issues, it has become necessary to reduce the amount of regenerated effluent discharged by the ion exchange resin desalination method. Is shifting to a method that combines In the ion exchange resin desalting method, first, whey is passed through a strongly acidic cation exchange resin in the H form to exchange cations such as sodium, potassium and calcium into hydrogen ions, and then the OH form anion exchange resin To exchange salts of anions such as phosphoric acid, chlorine, citric acid, and lactic acid with hydroxide ions to perform desalting. The sialic acid compound is present as an anion having a lower affinity for the anion exchange resin than lactic acid or citric acid, and only a part of the sialic acid compound is adsorbed to the anion exchange resin at the time of desalting, thereby regenerating the anion exchange resin. At present, the resin is sometimes detached from the resin, mixed with the reclaimed waste liquid, and discarded.
【０００５】[0005]
【発明が解決しようとする問題点】本発明は、シアル酸
化合物を含むホエーまたは乳糖結晶母液の脱塩工程を有
効に活用し、脱塩を行うのと同時に、食品、医薬、化粧
品あるいは飼料等の素材として利用可能なシアル酸化合
物を大量に、簡便かつ効率的に分離・回収する方法を提
供することを課題とする。なお、本発明では、オリゴ
糖、ガングリオシド、糖タンパク質等のシアル酸含有物
質類の総称としてシアル酸化合物と記述する。DISCLOSURE OF THE INVENTION The present invention effectively utilizes the desalting step of a whey or lactose crystal mother liquor containing a sialic acid compound to perform desalting and, at the same time, food, medicine, cosmetics or feed. It is an object of the present invention to provide a method for easily and efficiently separating and recovering a large amount of a sialic acid compound which can be used as a raw material of a sialic acid. In the present invention, sialic acid compounds are generally referred to as sialic acid-containing substances such as oligosaccharides, gangliosides, and glycoproteins.
【０００６】[0006]
【課題を解決するための手段】本発明者らは、上述の問
題点を解決するために、シアル酸化合物を含むホエーま
たは乳糖結晶母液からシアル酸化合物を大量に、簡便か
つ効率的に分離する方法について鋭意検討を行った。そ
の結果、脱塩工程において、まずホエーまたは乳糖結晶
母液の塩強度を調整してから、弱塩基性アニオン交換樹
脂を用いたイオン交換樹脂脱塩を行うことで、アニオン
交換樹脂へのシアル酸化合物の吸着量が増大すること、
及び、イオン濃度を調整した溶離液を用いることで、不
純物の少ないシアル酸化合物を回収できることを見出
し、本発明を完成するに至った。Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have separated a large amount of a sialic acid compound from a whey or lactose crystal mother liquor containing the sialic acid compound easily and efficiently. The method was studied diligently. As a result, in the desalting step, first, the salt strength of the whey or lactose crystal mother liquor is adjusted, and then the desalting of the ion exchange resin using a weakly basic anion exchange resin is performed. Increase in the adsorption amount of
Further, they have found that a sialic acid compound having a small amount of impurities can be recovered by using an eluent having an adjusted ion concentration, thereby completing the present invention.
【０００７】本発明は、従来のホエー脱塩設備を用い
て、従来のホエーまたは乳糖結晶母液脱塩工程をほとん
ど変更することなく、従来の工程中で廃棄されていたシ
アル酸化合物を、簡便かつ効率的に分離・回収すること
を可能とする。即ち、本発明によれば、脱塩ホエーまた
は脱塩乳糖結晶母液を生産する時の副産物としてシアル
酸化合物を得ることができるため、工業的に大量かつ安
価にシアル酸化合物を供給することが可能となる。本発
明により得られたシアル酸化合物は、優れた生理活性を
有しており、食品、医薬、化粧品あるいは飼料等の素材
として利用できる。According to the present invention, a sialic acid compound which has been discarded in a conventional whey or lactose crystal mother liquor can be easily and simply removed by using a conventional whey desalination facility with little modification. It enables efficient separation and recovery. That is, according to the present invention, since a sialic acid compound can be obtained as a by-product when producing a desalted whey or a desalted lactose crystal mother liquor, it is possible to industrially supply the sialic acid compound in large quantities and at low cost. Becomes The sialic acid compound obtained by the present invention has excellent physiological activity and can be used as a material for foods, medicines, cosmetics, feeds, and the like.
【０００８】本発明においては、ホエーまたは乳糖結晶
母液を原料溶液として用いる。原料溶液の塩強度調整方
法としては、工業的に利用されている電気透析脱塩法、
イオン交換樹脂脱塩法、ナノフィルトレーション脱塩法
やそれらを組み合わせた方法が挙げられるが、シアル酸
化合物の回収率及びコストとの点から電気透析脱塩法を
用いることが好ましい。調整後の塩強度には特に制限は
ないが、塩強度が低い程、後の工程中のイオン交換樹脂
脱塩において、単位樹脂量当たりで処理できる原料溶液
量が多くなり、かつ、アニオン交換樹脂へのシアル酸化
合物の吸着量も増大するため、脱塩効率や経済効率も考
慮すると電気伝導度を3.0mS/cm以下に調整することが好
ましい。例えば、ゴーダチーズホエーの場合、電気伝導
度が通常 6.0〜6.5mS/cmであるが、塩強度を調整して電
気伝導度を2.5mS/cm、1.2mS/cmまで減少させる調整を行
うことにより、シアル酸化合物の吸着量は、それぞれ未
調整の場合の14倍、17倍に増大する。[0008] In the present invention, whey or lactose crystal mother liquor is used as a raw material solution. As a method for adjusting the salt strength of the raw material solution, an electrodialysis desalting method used industrially,
Examples thereof include an ion exchange resin desalting method, a nanofiltration desalting method, and a combination thereof, and it is preferable to use an electrodialysis desalting method from the viewpoint of the recovery rate and cost of the sialic acid compound. The salt strength after the adjustment is not particularly limited, but the lower the salt strength, the larger the amount of the raw material solution that can be processed per unit resin amount in the ion exchange resin desalination in the subsequent process, and the more the anion exchange resin is. Since the amount of the sialic acid compound adsorbed on the surface also increases, it is preferable to adjust the electric conductivity to 3.0 mS / cm or less in consideration of desalting efficiency and economic efficiency. For example, in the case of Gouda cheese whey, the electrical conductivity is usually 6.0 to 6.5 mS / cm, but by adjusting the salt strength to reduce the electrical conductivity to 2.5 mS / cm, 1.2 mS / cm , The adsorption amount of the sialic acid compound increases by 14 times and 17 times, respectively, when no adjustment is made.
【０００９】本発明で用いるアニオン交換樹脂は、弱塩
基性アニオン交換樹脂であれば特に制限はないが、好ま
しくは、物理的強度、シアル酸化合物の吸着量及び溶
出、脱塩効率の点から、アクリル母体のものを用いる。
このような弱塩基性アニオン交換樹脂としては、ダイア
イオンＷＡ１０（三菱化学社製）、デュオライトＡ−３
７５、デュオライトＡ−３６８（住友化学工業社製）及
びアンバーライトＩＲＡ−９３（オルガノ社製）等が市
販されている。ちなみに、強塩基性アニオン交換樹脂を
用いた場合のシアル酸化合物の吸着量は、弱塩基性アニ
オン交換樹脂を用いた場合の吸着量の10％程度である。The anion exchange resin used in the present invention is not particularly limited as long as it is a weakly basic anion exchange resin, but is preferably used in view of physical strength, adsorption amount and elution of sialic acid compound, and desalting efficiency. Use an acrylic matrix.
Examples of such weakly basic anion exchange resins include DIAION WA10 (manufactured by Mitsubishi Chemical Corporation) and Duolite A-3.
75, Duolite A-368 (manufactured by Sumitomo Chemical Co., Ltd.) and Amberlite IRA-93 (manufactured by Organo) are commercially available. Incidentally, the adsorption amount of the sialic acid compound when the strong basic anion exchange resin is used is about 10% of the adsorption amount when the weak basic anion exchange resin is used.
【００１０】弱塩基性アニオン交換樹脂からシアル酸化
合物を溶出させるための溶離液は、イオン濃度が 0.005
〜1.5Mの範囲のものであれば特に制限はないが、イオン
濃度が低い程溶出が遅くなり、また、イオン濃度を高く
すると溶離液のコスト及びその後の脱塩コストが増大す
る点から、好ましくはイオン濃度が0.01〜1.0Mの塩溶液
を用いる。特に、溶離液として水酸化ナトリウムを用い
る場合は、シアル酸化合物の溶出と同時にアニオン交換
樹脂の再生を行うことができる。また、アニオン交換樹
脂との親和力が水酸化物イオンより低い、酢酸や塩酸を
溶離液として用いてシアル酸化合物を溶出させることに
より、クエン酸や乳酸の混入が少ない高純度のシアル酸
化合物を得ることもできる。溶離液によって溶出したシ
アル酸化合物を含む溶液については、常法に従って濃縮
あるいは乾燥して用いることができる。また、必要に応
じて、さらに電気透析やナノフィルトレーションを行っ
て溶液中の塩類を除去することで、簡便にシアル酸化合
物の純度を高めることもできる。なお、このようにして
ホエーから得られたシアル酸化合物の構成比は、シアル
酸量で比較すると、シアリルラクトース：ＧＭＰ：その
他が、約４：３：３の割合である。The eluent for eluting the sialic acid compound from the weakly basic anion exchange resin has an ion concentration of 0.005.
There is no particular limitation as long as the concentration is in the range of ~ 1.5M, but the lower the ion concentration, the slower the elution, and the higher the ion concentration, the higher the cost of the eluent and the subsequent desalting cost. Uses a salt solution having an ion concentration of 0.01 to 1.0M. In particular, when sodium hydroxide is used as the eluent, the anion exchange resin can be regenerated simultaneously with the elution of the sialic acid compound. In addition, by eluting the sialic acid compound using acetic acid or hydrochloric acid as an eluent, the affinity of the sialic acid compound with the anion exchange resin is lower than that of the hydroxide ion, thereby obtaining a high-purity sialic acid compound with less contamination of citric acid and lactic acid. You can also. The solution containing the sialic acid compound eluted by the eluent can be used after being concentrated or dried according to a conventional method. Further, if necessary, the purity of the sialic acid compound can be easily increased by further performing electrodialysis or nanofiltration to remove salts in the solution. The sialic acid compound thus obtained from whey has a composition ratio of sialyllactose: GMP: others of about 4: 3: 3 when compared by the amount of sialic acid.
【００１１】シアル酸化合物を除去したホエーまたは乳
糖結晶母液は、通常の脱塩処理を行ったものとなんら変
わらないため、脱塩ホエーまたは脱塩乳糖結晶母液とし
て利用可能である。即ち、本発明によれば、ホエーまた
は乳糖結晶母液の脱塩処理工程に従って、脱塩ホエーま
たは脱塩乳糖結晶母液を製造するのと同時に、簡便かつ
効率的にシアル酸化合物を分離できる。[0011] The whey or lactose crystal mother liquor from which the sialic acid compound has been removed is not different from that subjected to ordinary desalting treatment, and thus can be used as a desalted whey or desalted lactose crystal mother liquor. That is, according to the present invention, the sialic acid compound can be simply and efficiently separated at the same time that the desalted whey or the desalted lactose crystal mother liquor is produced according to the step of desalting the whey or the lactose crystal mother liquor.
【００１２】次に、本発明を比較例および実施例を挙げ
て具体的に説明する。なお、シアル酸化合物量は、結合
しているシアル酸量に比例するとみなし、シアル酸量を
測定することでシアル酸化合物量を評価した。また、シ
アル酸量の測定はＨＰＬＣ法で行った。即ち、試料溶液
4.5mlに対して1N硫酸水溶液0.5ml を加えて撹拌し、密
栓付き試験管に移し80℃で30分間加熱した。この条件下
でシアル酸化合物中のシアル酸は全て遊離する。次い
で、この試料を、0.45μm のフィルターで濾過し、次の
条件下でＨＰＬＣ測定に供した。装置はLC modul1 （Wa
ters社製）、カラムはshodex DE-613 + shodex KG-811
+ shodex KG-811 （昭和電工社製）、カラム温度は55
℃、溶媒は 0.3％リン酸水溶液、流速は 1.0ml/minで行
った。Next, the present invention will be specifically described with reference to comparative examples and examples. The amount of the sialic acid compound was considered to be proportional to the amount of the bound sialic acid, and the amount of the sialic acid compound was evaluated by measuring the amount of the sialic acid. The amount of sialic acid was measured by the HPLC method. That is, the sample solution
0.5 ml of a 1N aqueous sulfuric acid solution was added to 4.5 ml, and the mixture was stirred, transferred to a test tube with a stopper, and heated at 80 ° C. for 30 minutes. Under these conditions, all of the sialic acid in the sialic acid compound is released. Next, this sample was filtered through a 0.45 μm filter and subjected to HPLC measurement under the following conditions. The equipment is LC modul1 (Wa
ters), column is shodex DE-613 + shodex KG-811
+ shodex KG-811 (Showa Denko), column temperature 55
C., the solvent was a 0.3% phosphoric acid aqueous solution, and the flow rate was 1.0 ml / min.
【００１３】[0013]
【比較例１】固形６％のチーズホエー 20 l を電気透析
脱塩装置（ＴＳ２、トクヤマ社製）で、電気伝導度2.5m
S/cmに塩強度を調整した後、強酸性カチオン交換樹脂
（ＩＲ１２０Ｂ、Ｈ形、オルガノ社製）0.42 l、弱塩基
性アニオン交換樹脂（デュオライトＡ−３７５、ＯＨ
形、住友化学工業社製）1.1 l の順に通液して脱塩し
た。次いで、弱塩基性アニオン交換樹脂を脱イオン水で
洗浄した後、1.0M水酸化ナトリウム溶液 2 lで樹脂の再
生を行いながらシアル酸化合物を溶出させた。また、同
様な処理を、弱塩基性アニオン交換樹脂の代わりに強塩
基性アニオン交換樹脂（ダイヤイオンＳＡ２０ＡＰ、Ｏ
Ｈ形、三菱化学社製）1.1 l を用いて行った。表１に示
すとおり、弱塩基性アニオン交換樹脂は、強酸性カチオ
ン交換樹脂に比較してシアル酸の製造に優れていること
がわかる。ちなみにアニオン交換樹脂処理したホエー溶
液の灰分含量は、固形あたり 0.6％であった。[Comparative Example 1] 20 l of cheese whey having a solid content of 6% was subjected to an electrodialysis desalter (TS2, manufactured by Tokuyama Corporation) to have an electric conductivity of 2.5 m.
After adjusting the salt strength to S / cm, 0.42 l of a strongly acidic cation exchange resin (IR120B, H type, manufactured by Organo) and a weakly basic anion exchange resin (Duolite A-375, OH
(Manufactured by Sumitomo Chemical Co., Ltd.) in the order of 1.1 l for desalting. Next, the weakly basic anion exchange resin was washed with deionized water, and then the sialic acid compound was eluted while regenerating the resin with 2 L of 1.0 M sodium hydroxide solution. In addition, a similar treatment is carried out by replacing a weakly basic anion exchange resin with a strongly basic anion exchange resin (Diaion SA20AP, O
(Type H, manufactured by Mitsubishi Chemical Corporation) 1.1 l. As shown in Table 1, it can be seen that the weakly basic anion exchange resin is more excellent in producing sialic acid than the strongly acidic cation exchange resin. Incidentally, the ash content of the whey solution treated with the anion exchange resin was 0.6% per solid.
【００１４】[0014]
【表１】 ─────────────────────────────────── 溶出液 原料液 ────────────── ────── シアル酸濃度 シアル酸回収量 シアル酸含量 ─────────────────────────────────── 強塩基性アニオン交換樹脂 0.32 (g/l) 0.64 (g) 5.18 (g) 弱塩基性アニオン交換樹脂 2.40 4.80 ───────────────────────────────────[Table 1] ─────────────────────────────────── Eluate raw material liquid ─────── ─────── ────── Sialic acid concentration Sialic acid recovery amount Sialic acid content ─────────────────────────── ──────── Strongly basic anion exchange resin 0.32 (g / l) 0.64 (g) 5.18 (g) Weakly basic anion exchange resin 2.40 4.80 ────────────── ─────────────────────
【００１５】[0015]
【比較例２】原料溶液の塩強度が弱塩基性アニオン交換
樹脂へのシアル酸吸着量に及ぼす影響を調べるために、
次の試験を行った。固形６％のチーズホエーについて、
電気透析脱塩装置（ＴＳ２、トクヤマ社製）で電気伝導
度2.5mS/cmに塩強度を調整したホエーと、未調整のホエ
ーとを原料溶液に用い、それぞれを、強酸性カチオン交
換樹脂（ＩＲ１２０Ｂ、Ｈ形、オルガノ社製）1.0 l 、
弱塩基性アニオン交換樹脂（デュオライトＡ−３７５、
ＯＨ形、住友化学工業社製）1.0 l の順に通液して脱塩
した。貫流点に達した時点で、脱イオン水を通液して水
押しを行った。ホエー通液開始から水押し終了までの全
量を回収し、原料溶液と回収された溶液のそれぞれにつ
いて、シアル酸濃度及び液量を測定することによって、
樹脂に吸着したシアル酸化合物量を算出した。その結
果、吸着したシアル酸化合物のシアル酸量は、未調整ホ
エーでは 0.38gであるのに対して、塩強度を調整したホ
エーでは5.2gであった。Comparative Example 2 In order to investigate the effect of the salt strength of the raw material solution on the amount of sialic acid adsorbed on the weakly basic anion exchange resin,
The following tests were performed. About 6% solid cheese whey
A whey prepared by adjusting the salt strength to an electric conductivity of 2.5 mS / cm by an electrodialysis desalter (TS2, manufactured by Tokuyama Corporation) and an unadjusted whey are used as raw material solutions, and each is made of a strongly acidic cation exchange resin (IR120B). , H type, manufactured by Organo Corporation) 1.0 l,
Weakly basic anion exchange resin (Duolite A-375,
(OH form, manufactured by Sumitomo Chemical Co., Ltd.) was passed in the order of 1.0 l to desalinate. When the flow-through point was reached, deionized water was passed through to push water. By collecting the whole amount from the start of whey passage to the end of water pushing, by measuring the sialic acid concentration and the amount of each of the raw material solution and the recovered solution,
The amount of the sialic acid compound adsorbed on the resin was calculated. As a result, the amount of sialic acid of the adsorbed sialic acid compound was 0.38 g in the unadjusted whey, while it was 5.2 g in the salt adjusted whey.
【００１６】[0016]
【実施例１】固形６％のチーズホエー 30 l を電気透析
脱塩装置（ＴＳ２、トクヤマ社製）で電気伝導度 1.25m
S/cmに塩強度を調整した後、強酸性カチオン交換樹脂
（ＩＲ１２０Ｂ、Ｈ形、オルガノ社製）0.5 l 、弱塩基
性アニオン交換樹脂（ダイアイオンＷＡ１０、ＯＨ形、
三菱化学社製）1.0 l の順に通液して脱塩した。次い
で、弱塩基性アニオン交換樹脂を脱イオン水で洗浄した
後、0.1M酢酸ナトリウム溶液 4 lでシアル酸化合物を溶
出した。こうして得た溶出液のシアル酸濃度は1.3g/lで
あり、そのうち、シアリルラクトースのシアル酸が0.5g
/l、ＧＭＰのシアル酸が0.4g/lであった。また、クエン
酸は含まれていなかった。Example 1 30 l of cheese whey having a solid content of 6% was subjected to an electroconductivity of 1.25 m using an electrodialysis desalter (TS2, manufactured by Tokuyama Corporation).
After adjusting the salt strength to S / cm, 0.5 l of a strongly acidic cation exchange resin (IR120B, H type, manufactured by Organo) and a weakly basic anion exchange resin (Diaion WA10, OH type,
The solution was passed in the order of 1.0 l for desalting. Next, the weakly basic anion exchange resin was washed with deionized water, and then the sialic acid compound was eluted with 4 l of a 0.1 M sodium acetate solution. The sialic acid concentration of the eluate thus obtained was 1.3 g / l, of which sialic acid of sialyl lactose was 0.5 g.
/ l, sialic acid of GMP was 0.4 g / l. Also, no citric acid was contained.
【００１７】[0017]
【実施例２】ホエーＵＦ透過液をエバポレーターで固形
30％まで濃縮し、シーディングによって生成した乳糖結
晶を除去した乳糖結晶母液を原料溶液とした。この原料
溶液2 lを電気透析脱塩装置（ＴＳ２、トクヤマ社製）
で電気伝導度1.0mS/cmに塩強度を調整した後、強酸性カ
チオン交換樹脂（ＩＲ１２０Ｂ、Ｈ形、オルガノ社製）
0.5 l 、弱塩基性アニオン交換樹脂（ダイアイオンＷＡ
１０、ＯＨ形、三菱化学社製）1.0 l の順に通液して脱
塩した。次いで、弱塩基性アニオン交換樹脂を脱イオン
水で洗浄した後、0.5M塩酸溶液 1.0 lでシアル酸化合物
を溶出した。このようにして得たシアル酸化合物の溶出
液を、再度、電気透析で電気伝導度0.1mS/cmまで脱塩し
た後、凍結乾燥を行い、シアル酸化合物を含む粉末6gを
得た。この粉末のシアル酸含量は26％であった。[Example 2] Whey UF permeate was solidified with an evaporator
The lactose crystal mother liquor was concentrated to 30% to remove lactose crystals generated by seeding and used as a raw material solution. 2 L of this raw material solution is electrodialyzed and desalted (TS2, manufactured by Tokuyama Corporation)
After adjusting the salt strength to an electric conductivity of 1.0 mS / cm with, a strongly acidic cation exchange resin (IR120B, H type, manufactured by Organo)
0.5 l, weakly basic anion exchange resin (Diaion WA
(10, OH form, manufactured by Mitsubishi Chemical Corporation) in order of 1.0 l to desalinate. Next, after washing the weakly basic anion exchange resin with deionized water, the sialic acid compound was eluted with 1.0 L of 0.5 M hydrochloric acid solution. The eluate of the sialic acid compound thus obtained was again desalted by electrodialysis to an electric conductivity of 0.1 mS / cm, and then lyophilized to obtain 6 g of a powder containing the sialic acid compound. The sialic acid content of this powder was 26%.
【００１８】[0018]
【発明の効果】本発明は、従来のホエー脱塩設備を用い
て、従来のホエー脱塩工程をほとんど変更することな
く、従来の工程中で廃棄されていたシアル酸化合物を、
簡便かつ効率的に分離・回収することを可能とする。即
ち、本発明によれば、脱塩ホエーを生産する時の副産物
としてシアル酸化合物を得ることができるため、工業的
に大量かつ安価にシアル酸化合物を供給することが可能
となる。本発明により得られたシアル酸化合物は、優れ
た生理活性を有しており、食品、医薬、化粧品あるいは
飼料等の素材として利用できる。また、このシアル酸化
合物は、乳糖や有機酸が除去されているので、シアリル
ラクトースやＧＭＰを分離精製するための原料として有
用である。According to the present invention, a sialic acid compound which has been discarded in a conventional whey desalting process can be obtained by using a conventional whey desalting facility without substantially changing the conventional whey desalting process.
It enables simple and efficient separation and recovery. That is, according to the present invention, since a sialic acid compound can be obtained as a by-product when producing desalted whey, it is possible to industrially supply the sialic acid compound in large quantities and at low cost. The sialic acid compound obtained by the present invention has excellent physiological activity and can be used as a material for foods, medicines, cosmetics, feeds, and the like. In addition, since the sialic acid compound is free of lactose and organic acids, it is useful as a raw material for separating and purifying sialyl lactose and GMP.
Claims (5)
ニオン交換樹脂に通液し、次いで、弱塩基性アニオン交
換樹脂に吸着したシアル酸化合物を溶出させることを特
徴とする、シアル酸化合物の製造方法。1. A method for producing a sialic acid compound, comprising passing a whey or lactose crystal mother liquor through a weakly basic anion exchange resin and then eluting the sialic acid compound adsorbed on the weakly basic anion exchange resin. Method.
整した後に、弱塩基性アニオン交換樹脂に通液し、次い
で、弱塩基性アニオン交換樹脂に吸着したシアル酸化合
物を溶出させることを特徴とする、シアル酸化合物の製
造方法。2. After adjusting the salt strength of the whey or lactose crystal mother liquor, the solution is passed through a weakly basic anion exchange resin, and then the sialic acid compound adsorbed on the weakly basic anion exchange resin is eluted. A method for producing a sialic acid compound.
整した後に、カチオン交換樹脂、弱塩基性アニオン交換
樹脂の順に通液し、次いで、弱塩基性アニオン交換樹脂
に吸着したシアル酸化合物を溶出させることを特徴とす
る、シアル酸化合物の製造方法。3. After adjusting the salt strength of the whey or lactose crystal mother liquor, the solution is passed through a cation exchange resin and a weakly basic anion exchange resin in this order, and then the sialic acid compound adsorbed on the weakly basic anion exchange resin is eluted. A method for producing a sialic acid compound.
請求項２または請求項３記載の製造方法。4. Adjusting the salt strength by electrodialysis.
The manufacturing method according to claim 2 or 3.
する、請求項２ないし請求項４のいずれかに記載の製造
方法。5. The production method according to claim 2, wherein the salt strength is adjusted to an electric conductivity of 3.0 mS / cm or less.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9350622A JPH11180993A (en) | 1997-12-19 | 1997-12-19 | Production of sialic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9350622A JPH11180993A (en) | 1997-12-19 | 1997-12-19 | Production of sialic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH11180993A true JPH11180993A (en) | 1999-07-06 |
Family
ID=18411728
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP9350622A Pending JPH11180993A (en) | 1997-12-19 | 1997-12-19 | Production of sialic acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH11180993A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009008362A1 (en) * | 2007-07-12 | 2009-01-15 | Yotsuba Milk Products Co., Ltd. | Method for producing composition containing sialic acid compound |
| WO2011040361A1 (en) | 2009-09-29 | 2011-04-07 | 雪印乳業株式会社 | Method for separating sialyllactose material |
| WO2011040360A1 (en) | 2009-09-29 | 2011-04-07 | 雪印乳業株式会社 | Method for separating sialyllactose material |
| JP2011513482A (en) * | 2008-03-14 | 2011-04-28 | フリーズランド ブランズ ビー．ブイ． | Method for isolating sialic acid-containing oligosaccharides and compositions comprising sialic acids comprising oligosaccharides thus obtainable |
| JP2012520666A (en) * | 2009-03-17 | 2012-09-10 | セパレーション テクノロジーズ インベスティメンツ リミテッド | Isolation and purification of whey components |
| JP2019523278A (en) * | 2016-07-28 | 2019-08-22 | フォンテラ コ−オペレイティブ グループ リミティド | Dairy products and processes |
| US12016869B2 (en) | 2016-07-28 | 2024-06-25 | Fonterra Co-Operative Group Limited | Dairy product and process |
-
1997
- 1997-12-19 JP JP9350622A patent/JPH11180993A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009008362A1 (en) * | 2007-07-12 | 2009-01-15 | Yotsuba Milk Products Co., Ltd. | Method for producing composition containing sialic acid compound |
| US20100143535A1 (en) * | 2007-07-12 | 2010-06-10 | Hidemasa Motoshima | Method for producing composition containing sialic acid compound |
| JP2011513482A (en) * | 2008-03-14 | 2011-04-28 | フリーズランド ブランズ ビー．ブイ． | Method for isolating sialic acid-containing oligosaccharides and compositions comprising sialic acids comprising oligosaccharides thus obtainable |
| JP2012520666A (en) * | 2009-03-17 | 2012-09-10 | セパレーション テクノロジーズ インベスティメンツ リミテッド | Isolation and purification of whey components |
| JP2014138592A (en) * | 2009-03-17 | 2014-07-31 | Separation Technologies Investments Ltd | Isolation and purification of whey components |
| JP2016182141A (en) * | 2009-03-17 | 2016-10-20 | セパレーション テクノロジーズ インベスティメンツ リミテッド | Isolation and refinement of whey component |
| WO2011040361A1 (en) | 2009-09-29 | 2011-04-07 | 雪印乳業株式会社 | Method for separating sialyllactose material |
| WO2011040360A1 (en) | 2009-09-29 | 2011-04-07 | 雪印乳業株式会社 | Method for separating sialyllactose material |
| JP2019523278A (en) * | 2016-07-28 | 2019-08-22 | フォンテラ コ−オペレイティブ グループ リミティド | Dairy products and processes |
| US12016869B2 (en) | 2016-07-28 | 2024-06-25 | Fonterra Co-Operative Group Limited | Dairy product and process |
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