LU86508A1 - PROCESS FOR EXTRACTING MILK PROTEINS, PRODUCTS, APPLICATION OF THE PROCESS, AND PHARMACEUTICAL COMPOSITIONS - Google Patents
PROCESS FOR EXTRACTING MILK PROTEINS, PRODUCTS, APPLICATION OF THE PROCESS, AND PHARMACEUTICAL COMPOSITIONS Download PDFInfo
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- LU86508A1 LU86508A1 LU86508A LU86508A LU86508A1 LU 86508 A1 LU86508 A1 LU 86508A1 LU 86508 A LU86508 A LU 86508A LU 86508 A LU86508 A LU 86508A LU 86508 A1 LU86508 A1 LU 86508A1
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- elution
- carried out
- lactotransferrin
- proteins
- adsorption
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- 238000000034 method Methods 0.000 title claims description 38
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 9
- 102000014171 Milk Proteins Human genes 0.000 title claims description 5
- 108010011756 Milk Proteins Proteins 0.000 title claims description 5
- 235000021239 milk protein Nutrition 0.000 title claims description 5
- 108010063045 Lactoferrin Proteins 0.000 claims description 25
- 102000012174 Lactotransferrin Human genes 0.000 claims description 25
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 18
- 238000010828 elution Methods 0.000 claims description 18
- 239000005862 Whey Substances 0.000 claims description 12
- 102000007544 Whey Proteins Human genes 0.000 claims description 12
- 108010046377 Whey Proteins Proteins 0.000 claims description 12
- 235000018102 proteins Nutrition 0.000 claims description 11
- 102000004169 proteins and genes Human genes 0.000 claims description 11
- 108090000623 proteins and genes Proteins 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 10
- 229910052742 iron Inorganic materials 0.000 claims description 9
- 238000001179 sorption measurement Methods 0.000 claims description 9
- 150000001768 cations Chemical group 0.000 claims description 5
- 150000002500 ions Chemical class 0.000 claims description 5
- 235000013336 milk Nutrition 0.000 claims description 5
- 239000008267 milk Substances 0.000 claims description 5
- 210000004080 milk Anatomy 0.000 claims description 5
- 238000000108 ultra-filtration Methods 0.000 claims description 5
- 239000005018 casein Substances 0.000 claims description 4
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 claims description 4
- 235000021240 caseins Nutrition 0.000 claims description 4
- 239000011347 resin Substances 0.000 claims description 4
- 229920005989 resin Polymers 0.000 claims description 4
- 108060003951 Immunoglobulin Proteins 0.000 claims description 3
- 125000002091 cationic group Chemical group 0.000 claims description 3
- 239000008139 complexing agent Substances 0.000 claims description 3
- 102000018358 immunoglobulin Human genes 0.000 claims description 3
- 229940072221 immunoglobulins Drugs 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 239000000243 solution Substances 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000008363 phosphate buffer Substances 0.000 description 9
- 238000011033 desalting Methods 0.000 description 8
- 239000000872 buffer Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 235000020185 raw untreated milk Nutrition 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 238000002523 gelfiltration Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 229920002684 Sepharose Polymers 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000003385 bacteriostatic effect Effects 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 102000008133 Iron-Binding Proteins Human genes 0.000 description 1
- 108010035210 Iron-Binding Proteins Proteins 0.000 description 1
- 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 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012149 elution buffer Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 229910001447 ferric ion Inorganic materials 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000012510 hollow fiber Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 238000009928 pasteurization Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000012465 retentate Substances 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/06—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from serum
- C07K16/065—Purification, fragmentation
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
- A23C9/00—Milk preparations; Milk powder or milk powder preparations
- A23C9/14—Milk preparations; Milk powder or milk powder preparations in which the chemical composition of the milk is modified by non-chemical treatment
- A23C9/146—Milk preparations; Milk powder or milk powder preparations in which the chemical composition of the milk is modified by non-chemical treatment by ion-exchange
- A23C9/1465—Chromatographic separation of protein or lactose fraction; Adsorption of protein or lactose fraction followed by elution
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23J—PROTEIN COMPOSITIONS FOR FOODSTUFFS; WORKING-UP PROTEINS FOR FOODSTUFFS; PHOSPHATIDE COMPOSITIONS FOR FOODSTUFFS
- A23J1/00—Obtaining protein compositions for foodstuffs; Bulk opening of eggs and separation of yolks from whites
- A23J1/20—Obtaining protein compositions for foodstuffs; Bulk opening of eggs and separation of yolks from whites from milk, e.g. casein; from whey
- A23J1/205—Obtaining protein compositions for foodstuffs; Bulk opening of eggs and separation of yolks from whites from milk, e.g. casein; from whey from whey, e.g. lactalbumine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/79—Transferrins, e.g. lactoferrins, ovotransferrins
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Food Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Polymers & Plastics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Analytical Chemistry (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
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BREVET D'INVENTION Société Anonyme dite : ROUSSEL-UCLAFPATENT OF INVENTION Société Anonyme known as: ROUSSEL-UCLAF
Procédé d'extraction de protéines du lait, produits, application du procédé, et compositions pharmaceutiques.Method for extracting milk proteins, products, application of the method, and pharmaceutical compositions.
Inventeurs : Pierre, Frédéric, Emmanuel MONSAN; Philippe, André THIBAULT; Claudine BROSSARD et Christine, Solange, Jeanne BRUVIERInventors: Pierre, Frédéric, Emmanuel MONSAN; Philippe, André THIBAULT; Claudine BROSSARD and Christine, Solange, Jeanne BRUVIER
Convention Internationale : Priorité d’une demande de brevet déposée en France le 11 juillet 1985 sous le N° 85-10649.International Convention: Priority of a patent application filed in France on July 11, 1985 under N ° 85-10649.
La présente demande a pour objet un procédé d'extraction de protéines du lait, notamment celles capables de fixer le fer, son application à la préparation notamment de lactotransferrines, les produits obtenus par le procédé et les compositions pharmaceutiques les renfermant.The present application relates to a process for extracting milk proteins, in particular those capable of fixing iron, its application to the preparation in particular of lactotransferrins, the products obtained by the process and the pharmaceutical compositions containing them.
5 Des procédés de préparation de protéines, notamment de5 Processes for preparing proteins, in particular for
Lactotransferrines et/ou d'immunoglobulines ont déjà été décrits. On peut citer notamment le brevet français nH 2 505 615 et l'article de Chéron (C.R. Acad. Sc. Paris t 284 (14 février 1977)).Lactotransferrins and / or immunoglobulins have already been described. Mention may in particular be made of the French patent nH 2 505 615 and the article by Chéron (C.R. Acad. Sc. Paris t 284 (February 14, 1977)).
Ces procédés ne permettent pas de préparer la lactotransferrine 10 avec une qualité, un rendement et un matériel compatible avec une préparation industrielle .These methods do not make it possible to prepare lactotransferrin 10 with a quality, a yield and a material compatible with an industrial preparation.
Le procédé de la présente demande permet de préparer des lactoprotéines, notamment la lactotransferrine en une seule étape d'adsorption-élution sur échangeur d'ions, à pH constant, dans des 15 conditions non dénaturantes et particulièrement douces, avec un matériel léger et industriel, et en un temps réduit.The process of the present application makes it possible to prepare lactoproteins, in particular lactotransferrin in a single adsorption-elution step on an ion exchanger, at constant pH, under non-denaturing and particularly mild conditions, with light and industrial equipment. , and in a reduced time.
C'est ainsi que la présente demande a pour objet un procédé d'extraction des protéines du lait, notamment de celles capables de fixer le fer, à partir d'un lait substantiellement débarrassé de la caséine et des matières grasses, 20 par adsorption sur échangeur d'ions puis élution des protéines adsorbées, caractérisé en ce que l'adsorption et l'élution sont réalisées à pH constant.This is how the present application relates to a process for extracting milk proteins, in particular those capable of fixing iron, from a milk substantially free of casein and fat, by adsorption on ion exchanger then elution of the adsorbed proteins, characterized in that the adsorption and the elution are carried out at constant pH.
L'échangeur d'ions utilisé peut être un échangeur d'anions, mais de préférence un échangeur de cations. Afin d'obtenir une élution plus rapide et plus facile pour éviter la dénaturation des protéines, on utilise de 25 préférence une résine cationique faible, par exemple une résine * 4t > 2 * » carboxyméthylique comme celles commercialisées sous les noms CM Trisacryl (IBF) ou CM Sépharose (Pharmacia).The ion exchanger used can be an anion exchanger, but preferably a cation exchanger. In order to obtain a faster and easier elution in order to avoid denaturation of the proteins, a weak cationic resin is preferably used, for example a * 4t> 2 * carboxymethyl resin such as those sold under the names CM Trisacryl (IBF). or CM Sepharosis (Pharmacia).
Lorsque l’on utilise une résine cationique, l'adsorption et l'élution sont réalisées à un pH inférieur au point isoélectrique de la 5 lactotransferrine, de préférence entre pH 5 et pH 8,5, notamment entre pHWhen a cationic resin is used, adsorption and elution are carried out at a pH below the isoelectric point of lactotransferrin, preferably between pH 5 and pH 8.5, especially between pH
6,5 et 8,3, et tout particulièrement entre pH 7 et pH 8.6.5 and 8.3, and especially between pH 7 and pH 8.
Le produit de départ est de préférence un lait cru dont on a préalablement retiré la majeure partie de la caséine et des matières grasses. On utilise par exemple un lactosérum doux ou acide. Le lait ne 10 doit pas avoir été soumis à des opérations détruisant les protéines ou les dégradant, telles que pasteurisation dans des conditions violentes, comme quelques minutes à 90nc par exemple, ou écrémage. Le lait cru peut être, par exemple, décaséiné par précipitation à l'aide d'acide chlorhydrique.The starting product is preferably raw milk from which most of the casein and fat have been previously removed. For example, a mild or acid whey is used. The milk must not have been subjected to operations destroying the proteins or degrading them, such as pasteurization under violent conditions, such as a few minutes at 90 nm for example, or skimming. Raw milk can, for example, be decasinated by precipitation using hydrochloric acid.
La séparation du caillé et du lactosérum est réalisée selon les 15 techniques habituellement utilisées pour les séparations liquide-solide, telles que décantation, centrifugation ou, de préférence, filtration.The separation of the curd and the whey is carried out according to the techniques usually used for liquid-solid separations, such as decantation, centrifugation or, preferably, filtration.
Dans le cas de la filtration, la membrane choisie ne doit pas de préférence, fixer, par adsorption par exemple, les protéines ; on utilise par exemple une membrane de nature cellulosique.In the case of filtration, the membrane chosen should preferably not fix the proteins, for example by adsorption; for example, a cellulosic membrane is used.
20 Dans des conditions préférentielles de mise en oeuvre, on part d'un lactosérum concentré. Le lactosérum peut être concentré selon les méthodes classiques comme par évaporation par exemple, dans une proportion variant de 2 à 20 fois par exemple et de préférence d'environ 5 fois.Under preferential processing conditions, one starts with a concentrated whey. The whey can be concentrated according to conventional methods such as by evaporation for example, in a proportion varying from 2 to 20 times for example and preferably about 5 times.
Le lactosérum concentré est de préférence dessalé, de manière à 25 diminuer sa force ionique.The concentrated whey is preferably desalted, so as to decrease its ionic strength.
Ces dernières conditions de concentration et force ionique sont avantageusement remplies en une seule étape si l'on effectue une ultrafiltration. La nature de l'ultrafilire doit être choisie de manière à ne pas adsorber les lactoprotéines de manière trop importante, et à les 30 retenir. Le seuil de sélectivité sera par exemple choisi entre 10 000 et 70 000, et de préférence entre 25 000 et 50 000, l'ultrafiItre peut se présenter sous forme plane, tubulaire, sous la forme de fibres creuses ou de spirales. Comme ultrafiltres ne fixant pas ou fixant peu les lactoprotéines, notamment la lactotransferrine, on peut citer 35 particulièrement ceux de nature polysulfonique commercialisés sous le nom Millipore, notamment ceux de référence PSED 0HV 10.These latter concentration and ionic strength conditions are advantageously fulfilled in a single step if an ultrafiltration is carried out. The nature of the ultrafilter must be chosen so as not to adsorb the lactoproteins too much, and to retain them. The selectivity threshold will for example be chosen between 10,000 and 70,000, and preferably between 25,000 and 50,000, the ultrafiltrator can be in planar, tubular form, in the form of hollow fibers or spirals. As ultrafilters which do not fix or little fixing the lactoproteins, in particular lactotransferrin, mention may be made particularly of those of polysulfonic nature marketed under the name Millipore, in particular those of reference PSED 0HV 10.
Le dessalage et la concentration sont ainsi réalisés par le même dispositif, avec le même appareillage ; le dessalage est dans ce cas de préférence effectué par diafiItration (ultrafiltration sous légère 40 surpression) avec 1/2 à 2 volumes d'eau distillée par exemple.Desalting and concentration are thus carried out by the same device, with the same apparatus; desalting is in this case preferably carried out by diafiItration (ultrafiltration under slight overpressure) with 1/2 to 2 volumes of distilled water for example.
· 3 * , L'adsorption des lactoprotéines et leur élution sont réalisées en utilisant une même concentration du produit tampon pour conserver le pH choisi, et en modifiant seulement la force ionique à l'aide de chlorure de sodium. Les différentes forces ioniques sont choisies de manière à éluer 5 d'abord les protéines indésirables, puis seulement la protéine désirée.· 3 *, The adsorption of lactoproteins and their elution are carried out by using the same concentration of the buffer product to maintain the chosen pH, and by only modifying the ionic strength using sodium chloride. The different ionic strengths are chosen so as to elute the undesirable proteins first, then only the desired protein.
Par exemple, l'élution des protéines capables de fixer le fer, notamment la lactotransferrinne, est avantageusement précédée de 1 à 5 élutions de force ionique moindre, et de préférence de 1 à 3 élutions. Le tampon d'élution est de préférence anionique tel un tampon phosphate.For example, the elution of proteins capable of fixing iron, in particular lactotransferrinne, is advantageously preceded by 1 to 5 elutions of lower ionic strength, and preferably from 1 to 3 elutions. The elution buffer is preferably anionic such as a phosphate buffer.
10 L'êluat intéressant est ensuite avantageusement dessalé pour éliminer les petites molécules de poids moléculaire inférieur à 1 000. Le dessalage est réalisé classiquement, par exemple par tamisage à l'aide d'ultrafiItres Millipore ou par chromatographie par perméation de gels, 625 par exemple.10 The eluate of interest is then advantageously desalted to remove small molecules with a molecular weight of less than 1,000. Desalting is carried out conventionally, for example by sieving using Millipore ultrafiltrators or by gel permeation chromatography, 625 by example.
15 Le procédé selon la présente invention est particulièrement performant, car un cycle complet de préparation de lactotransferrine pure à partir de lactosérum par ultrafiltration et séparation sur échangeur de cations est réalisé en 9 heures, alors qu'un procédé tel que celui de Chéron ci-dessus cité nécessite 24 heures, soit trois fois plus de temps 20 environ.The process according to the present invention is particularly efficient, since a complete cycle for preparing pure lactotransferrin from whey by ultrafiltration and separation on a cation exchanger is carried out in 9 hours, while a process such as that of Chéron above. above mentioned requires 24 hours, that is to say approximately three times more time 20.
Les lactoprotéines substantiellement pures en solution peuvent alors avantageusement être séchées, notamment par lyophilisation.The substantially pure lactoproteins in solution can then advantageously be dried, in particular by lyophilization.
Les protéines fixant le fer peuvent avantageusement être soumises à l'action d'un complexant, de préférence un chélatant, plus affine qu'elles 25 pour le fer, afin d'augmenter leur capacité en fixation de fer. On utilise par exemple un tampon phosphate EDTA.The iron-binding proteins can advantageously be subjected to the action of a complexing agent, preferably a chelating agent, which is more refined than they are for iron, in order to increase their iron fixing capacity. For example, an EDTA phosphate buffer is used.
Le complexant peut être éliminé par dessalage selon les techniques déjà indiquées.The complexing agent can be removed by desalting according to the techniques already indicated.
La présente demande a aussi pour objet les produits obtenus par les 30 procédés cidessus décrits, notamment La lactotransferrine et les immunoglobulines. Le procédé ci-dessus décrit est avantageusement utilisé pour leur préparation et l'invention a ainsi également pour objet l'application du procédé décrit ci-dessus à leur préparation.The present application also relates to the products obtained by the processes described above, in particular lactotransferrin and immunoglobulins. The process described above is advantageously used for their preparation and the invention thus also relates to the application of the process described above to their preparation.
L'intérêt en thérapeutique des lactoprotéines est bien connu, en 35 particulier l'activité bactériostatique de la lactotransferrine. C'est pourquoi la présente demande a enfin pour objet les compositions pharmaceutiques renfermant les produits obtenus par le procédé ci-dessus décrit. En effet, la lactotransferrine obtenue par le procédé de la présente invention a conservé ses propriétés bactériostatiques.The interest in therapeutics of lactoproteins is well known, in particular the bacteriostatic activity of lactotransferrin. This is why the present application finally relates to pharmaceutical compositions containing the products obtained by the process described above. Indeed, the lactotransferrin obtained by the process of the present invention has retained its bacteriostatic properties.
40 A titre de médicaments, les produits obtenus par le procédé ci-dessus < 4 ♦ peuvent être incorporés dans des compositions pharmaceutiques destinées à la voie digestive ou parentérale.As medicaments, the products obtained by the above process <4 ♦ can be incorporated into pharmaceutical compositions intended for the digestive or parenteral route.
Ces compositions pharmaceutiques peuvent être/ par exemple/ solides ou liquides et se présenter sous les formes pharmaceutiques couramment 5 utilisées en médecine humaine/ comme par exemple/ les comprimés/ simples ou dragéifiés/ les gélules, les granulés, les suppositoires, les collyres, les solutions nasales . Elles sont préparées selon les méthodes usuelles. Le ou les principes actifs peuvent y être incorporés à des excipients habituellement employés dans ces compositions pharmaceutiques, tels que le 10 talc, la gomme arabique, le lactose , l'amidon, le stéarate de magnésium, le beurre de cacao, les véhicules aqueux ou non, les corps gras d'origine animale ou végétale, les dérivés paraffiniques, les glycols, les divers agents mouillants, dispersants ou émulsifiants, les conservateurs.These pharmaceutical compositions can be / for example / solid or liquid and can be presented in the pharmaceutical forms commonly used in human medicine / such as for example / tablets / simple or sugar-coated / capsules, granules, suppositories, eye drops, nasal solutions. They are prepared according to the usual methods. The active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or no, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
Les applications des lactotransferrines obtenues par le procédé de 15 l'invention s'étendent, bien entendu, à d'autres secteurs tels que vétérinaires, nutritionnels ou agro-alimentaire.The applications of the lactotransferrins obtained by the process of the invention extend, of course, to other sectors such as veterinary, nutritional or agrifood.
Les exemples qui suivent illustrent la présente invention, sans toutefois la limiter.The examples which follow illustrate the present invention, without however limiting it.
Exemple 1 : Extraction de lactotransferrine 20 On ajoute sous agitation 15,8 ml d'acide chlorhydrique à 37-39% à 3,5 l de lait cru, laisse précipiter à 40**C pendant 1 heure, filtre sur membrane cellulosique, soumet les 2100 ml de lactosérum ainsi obtenus à une ultrafiltration sur membrane Millipore de nature polysulfonique à seuil de coupure 25000 (Référence PSED 0HV 10), par diafiItration avec un 25 même volume d'eau distillée, puis concentre à 420 ml.EXAMPLE 1 Extraction of Lactotransferrin 20 15.8 ml of 37-39% hydrochloric acid are added with stirring to 3.5 l of raw milk, left to precipitate at 40 ** C for 1 hour, filter on cellulose membrane, subject the 2100 ml of whey thus obtained at an ultrafiltration on a Millipore membrane of polysulfonic nature with cutoff threshold 25000 (Reference PSED 0HV 10), by diafiItration with the same volume of distilled water, then concentrated to 420 ml.
On ajuste à 7,0 le pH de la solution concentrée à l'aide de soude et ajuste la force ionique à 0,15 H à l'aide de chlorure de sodium (en mesurant au conductimètre). 400 ml de solution sont passés, au débit de 3 ml/mn, sur une colonne de 25 mm de diamètre interne remplie de 100 ml de 30 CM Sépharose CL 6B (Pharmacia) préalablement équilibré dans un tampon phosphate 0,15 M pH 7,0, en effectuant les élutions au débit de 3 ml/mn avec un tampon phosphate 0,1 M pH 7,0 dont la force ionique est ajustée à w l'aide de chlorure sodium, selon le gradient suivant :The pH of the concentrated solution is adjusted to 7.0 using sodium hydroxide and the ionic strength is adjusted to 0.15 H using sodium chloride (by measuring with a conductivity meter). 400 ml of solution are passed, at a flow rate of 3 ml / min, over a column 25 mm in internal diameter filled with 100 ml of 30 CM Sepharose CL 6B (Pharmacia) previously equilibrated in a 0.15 M phosphate buffer pH 7, 0, by carrying out the elutions at the flow rate of 3 ml / min with a 0.1 M phosphate buffer, pH 7.0, the ionic strength of which is adjusted using w using sodium chloride, according to the following gradient:
270 ml à 0,15 M270 ml at 0.15 M
35 145 ml à 0,25 M35 145 ml at 0.25 M
145 ml à 0,30 M.145 ml at 0.30 M.
La lactotransferrine est éluée avec 430 ml à 0,4 M. On opère un dessalage sur gel G 25 Pharmacia, lyophilise la solution obtenue et obtient 84 mg de lactotransferrine.The lactotransferrin is eluted with 430 ml at 0.4 M. Desalting is carried out on a G 25 Pharmacia gel, lyophilizes the solution obtained and obtains 84 mg of lactotransferrin.
40 Exemple 2 : Extraction de lactotransferrine ; ' 5 * · .Example 2: Extraction of lactotransferrin; '5 * ·.
»"
On opère comme indiqué à L'exemple 1 à partir de 1,5 l de lait cru.The procedure is as indicated in Example 1 from 1.5 l of raw milk.
150 ml de solution sont passés sur colonne au débit de 1 ml/mn. On effectue une élution avec 150 ml de tampon phosphate 0,15 M.pH 7,0 de 5 force ionique 0,25 H, puis élue la lactotransferrine avec 80 ml de tampon pH. 7,0 de force ionique 0,43 M.150 ml of solution are passed through a column at a flow rate of 1 ml / min. Elution is carried out with 150 ml of 0.15 M.pH 7.0 phosphate buffer, 0.25 H ionic strength, then the lactotransferrin is eluted with 80 ml of pH buffer. 7.0 ionic strength 0.43 M.
Après dessalage et lyophilisation, on obtient 40 mg de lactotransferrine.After desalting and lyophilization, 40 mg of lactotransferrin are obtained.
Exemple 5 : Extraction de lactotransferrine.Example 5: Extraction of lactotransferrin.
10 Le lactosérum est préparé et déposé sur l'échangeur cationique faible comme indiqué à l'exemple 1.The whey is prepared and deposited on the weak cation exchanger as indicated in Example 1.
On pratique alors un lavage de la colonne et de l'échangeur avec 200 ml de tampon Phosphate 0,1 H pH 7,0 dont la force ionique est ajustée à 0,15 H à l'aide de chlorure de sodium. La lactotransferrine est ensuite 15 éluée avec 100 ml de même tampon dont la force ionique est ajustée à 1 M à l'aide de chlorure de sodium. Le dessalage est effectué de la même façon que précédemment (filtration sur gel 625 Pharmacia). Après lyophilisation, le rendement de l'opération est d'environ 90 mg de lactotransferrine pour 3,5 l de lait.The column and the exchanger are then washed with 200 ml of 0.1 H phosphate buffer pH 7.0, the ionic strength of which is adjusted to 0.15 H using sodium chloride. The lactotransferrin is then eluted with 100 ml of the same buffer, the ionic strength of which is adjusted to 1 M using sodium chloride. Desalting is carried out in the same way as above (filtration on 625 Pharmacia gel). After lyophilization, the yield of the operation is approximately 90 mg of lactotransferrin per 3.5 l of milk.
20 Exemple 4 :20 Example 4:
Le lactosérum est préparé comme dans les exemples précédents. On ajuste son pH à 7,0 à l'aide de soude. On ajoute ensuite la solution d'AZARI et BAUGH à raison de 1 ml par litre de lactosérum.The whey is prepared as in the previous examples. Its pH is adjusted to 7.0 using sodium hydroxide. Then add the AZARI and BAUGH solution at a rate of 1 ml per liter of whey.
On laisse la saturation de la lactotransferrine en ions ferriques se 25 réaliser à température ambiante pendant 2 heures. La solution est ensuite centrifugée puis ultra-fiItrée comme dans les exemples précédents.The lactotransferrin saturation with ferric ions is allowed to take place at room temperature for 2 hours. The solution is then centrifuged and then ultra-filtered as in the previous examples.
On passe 400 ml du rétentat obtenu sur 100 ml d'échangeur cationique faible puis, après un lavage avec 200 ml de tampon phosphate 0,15 M pH400 ml of the retentate obtained are passed over 100 ml of weak cation exchanger and then, after washing with 200 ml of 0.15 M pH phosphate buffer
7,0, la lactotransferrine saturée est éluée avec 100 ml du même tampon 30 dont la force ionique est ajustée à 1 M à l'aide de chlorure de sodium.7.0, the saturated lactotransferrin is eluted with 100 ml of the same buffer 30, the ionic strength of which is adjusted to 1 M using sodium chloride.
La préparation est dessalée par filtration sur gel (625) puis lyophilisée.The preparation is desalted by gel filtration (625) and then lyophilized.
v On dissout la lactotransferrine saturée, dessalée dans un tamponv The saturated, desalted lactotransferrin is dissolved in a buffer
Phosphate/Citrate 0,05 M pH 4,5, à raison de 1 mg par ml de tampon.0.05 M Phosphate / Citrate pH 4.5, at a rate of 1 mg per ml of buffer.
35 La désaturation s'effectue pendant 12 heures à +4«C. La solution de lactotransferrine désaturée est ensuite dessalée par filtration sur gel (G25) puis lyophilisée.35 The desaturation is carried out for 12 hours at + 4 ° C. The desaturated lactotransferrin solution is then desalted by gel filtration (G25) and then lyophilized.
Composition de la solution d'AZARI et BAUGH.Composition of the AZARI and BAUGH solution.
Préparer une solution 0,1 M en citrate de sodium et 0,1 M en 40 bicarbonate de sodium.Prepare a 0.1 M solution in sodium citrate and 0.1 M in sodium bicarbonate.
' ‘ . , 6 * A 100 ml de cette préparation, ajouter 232 mg de chlorure ferrique-ôHjO.'‘. , 6 * To 100 ml of this preparation, add 232 mg of ferric chloride-HHjO.
Exemple 5 :Example 5:
Du lactosérum est préparé et concentré comme dans les exemples 5 précédents. On ajuste à 7,0 le pH de la solution concentrée à l'aide de soude.Whey is prepared and concentrated as in the previous examples. The pH of the concentrated solution is adjusted to 7.0 with sodium hydroxide.
* 10 litres de préparation sont passés au débit de 6 litres àl'heure sur une colonne de 10 cm de diamètre remplie de 600 ml de CM Sepharose Fast-Flow (Pharmacia) préalablement équilibré dans un tampon phosphate 10 0,15 M pH 7,0.* 10 liters of preparation are passed at a flow rate of 6 liters per hour on a column 10 cm in diameter filled with 600 ml of CM Sepharose Fast-Flow (Pharmacia) previously equilibrated in 0.15 M phosphate buffer pH 7, 0.
Après le dépôt, on lave la colonne avec un litre de tampon phosphate 0,15 M pH 7,0 puis avec un litre du même tampon dont la force ionique est ajustée à 0,3 M à l'aide de chlorure de sodium.After the deposition, the column is washed with one liter of 0.15 M phosphate buffer, pH 7.0, then with one liter of the same buffer, the ionic strength of which is adjusted to 0.3 M using sodium chloride.
La lactotransferrine est ensuite éluée avec 600 ml du même tampon 15 dont la force ionique est ajustée cette fois à 1 M.The lactotransferrin is then eluted with 600 ml of the same buffer 15, the ionic strength of which is adjusted this time to 1 M.
On opère un dessalage par filtration sur gel (625) puis on lyophilise la préparation. On obtient environ 30 mg de lactotransferrine par litre de substrat.Desalting is carried out by gel filtration (625) and then the preparation is lyophilized. About 30 mg of lactotransferrin are obtained per liter of substrate.
Exemple 6 : Composition pharmaceutique.Example 6: Pharmaceutical composition.
20 On a préparé des gouttes nasales ayant la composition suivante : - lactotransferrine ........................................... 5 mg - stabilisant ............................................... 250 mg - eau distillée q.s.p. .........................................5 Ml.20 Nasal drops having the following composition were prepared: - lactotransferrin .................................... ....... 5 mg - stabilizer ....................................... ........ 250 mg - distilled water qs ......................................... 5 Ml.
Claims (13)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8510649A FR2584727B1 (en) | 1985-07-11 | 1985-07-11 | PROCESS FOR EXTRACTING MILK PROTEINS, PRODUCTS, APPLICATION OF THE PROCESS, AND PHARMACEUTICAL COMPOSITIONS |
| FR8510649 | 1985-07-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| LU86508A1 true LU86508A1 (en) | 1987-02-04 |
Family
ID=9321210
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LU86508A LU86508A1 (en) | 1985-07-11 | 1986-07-10 | PROCESS FOR EXTRACTING MILK PROTEINS, PRODUCTS, APPLICATION OF THE PROCESS, AND PHARMACEUTICAL COMPOSITIONS |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS6219523A (en) |
| BE (1) | BE905087A (en) |
| CH (1) | CH668428A5 (en) |
| DE (1) | DE3623474C2 (en) |
| DK (1) | DK327386A (en) |
| FR (1) | FR2584727B1 (en) |
| GB (1) | GB2179947B (en) |
| IT (1) | IT1195855B (en) |
| LU (1) | LU86508A1 (en) |
| NL (1) | NL8601814A (en) |
| SE (1) | SE8602877L (en) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0621077B2 (en) * | 1986-07-15 | 1994-03-23 | 雪印乳業株式会社 | Hematopoietic agent |
| IE61701B1 (en) * | 1986-07-17 | 1994-11-30 | Morinaga Milk Industry Co Ltd | Process for producing bovine lactoferrin in high purity |
| FR2613725A1 (en) * | 1987-04-07 | 1988-10-14 | Agronomique Inst Nat Rech | Process for the production of active lactoperoxydase and lactoferrin from whey and the substances produced by this process |
| JPH0725800B2 (en) * | 1987-04-10 | 1995-03-22 | 雪印乳業株式会社 | Method for separating and purifying lactoferrin from milk using sulfate esterification product |
| SE458818B (en) * | 1987-11-27 | 1989-05-16 | Svenska Mejeriernas Riksforeni | PROCEDURE FOR EXTRACTION OF PURE FRACTIONS OF LACTOPEROXIDAS AND LACTOFERRIN FROM MILK SERUM |
| FR2626472B1 (en) * | 1988-02-02 | 1991-06-14 | Roussel Uclaf | USE OF MILK PROTEINS FOR THE MANUFACTURE OF AN ANTI-VIRAL DRUG |
| FR2631785A1 (en) * | 1988-05-27 | 1989-12-01 | Agronomique Inst Nat Rech | METHOD FOR FRACTIONING HUMAN MILK PROTEINS, DRIVING PRODUCTION, IN PARTICULAR LACTOFERRIN AND (ALPHA) -LACTALBUMIN, AND PRODUCTS OBTAINED |
| FR2648321B1 (en) * | 1989-05-12 | 1992-01-17 | Bio Serae Lab | PROCESS OF TREATING A NON-LIQUID FOOD PRODUCT TO ENSURE MICROBIAL DECONTAMINATION, APPLICATIONS IN PARTICULAR TO CHEESE AND MOTHER PREPARATION FOR IMPLEMENTING SAID TREATMENT |
| ATE287415T1 (en) * | 1990-07-13 | 2005-02-15 | Gropep Ltd | GROWTH-PROMOTING ACTIVE INGREDIENT |
| JP3035833B2 (en) * | 1991-01-21 | 2000-04-24 | 雪印乳業株式会社 | Method for producing sialic acids-containing composition |
| JP2961625B2 (en) * | 1991-01-21 | 1999-10-12 | 雪印乳業株式会社 | Method for producing a composition having a high content of α-lactalbumin |
| WO1993002098A1 (en) * | 1991-07-25 | 1993-02-04 | Commonwealth Scientific And Industrial Research Organisation | Isolation of charged particles from fluids |
| KR960702474A (en) * | 1993-05-11 | 1996-04-27 | 쥐. 알. 벨 | SEPARATION OF ANTI-METAL CHELATE ANTIBODIES |
| DK0876106T3 (en) | 1996-01-26 | 2004-08-16 | Univ Massey | Process for separating and recovering proteins from a protein solution |
| US6268487B1 (en) | 1996-05-13 | 2001-07-31 | Genzyme Transgenics Corporation | Purification of biologically active peptides from milk |
| CA2291487A1 (en) | 1997-05-29 | 1998-12-03 | New Zealand Pastoral Agriculture Research Institute Limited | Processes for production of immunoglobulin a in milk |
| AU1313401A (en) * | 1999-10-26 | 2001-05-08 | Fonterra Co-Operative Group Limited | Method of obtaining immunoglobulins from colostrum and dairy sources |
| JP2001231510A (en) * | 2000-02-22 | 2001-08-28 | Snow Brand Milk Prod Co Ltd | Seafood-paste |
| CA2583061C (en) | 2004-10-06 | 2015-02-17 | Kwang Guan Tay | Antibody production method |
| AU2013204850B2 (en) * | 2012-10-08 | 2015-06-25 | Murray Goulburn Co-Operative Co. Limited | Improved process for purifying milk proteins and products thereof |
| AU2013204858B2 (en) * | 2012-10-08 | 2015-06-25 | Saputo Dairy Australia Pty Limited | Improved process for purifying milk proteins and products thereof |
| CN104109204B (en) * | 2013-04-16 | 2017-11-07 | 武汉禾元生物科技股份有限公司 | A kind of method that restructuring lactoferrin is isolated and purified from rice paddy seed |
-
1985
- 1985-07-11 FR FR8510649A patent/FR2584727B1/en not_active Expired
-
1986
- 1986-06-27 SE SE8602877A patent/SE8602877L/en not_active Application Discontinuation
- 1986-07-10 DK DK327386A patent/DK327386A/en not_active Application Discontinuation
- 1986-07-10 BE BE0/216905A patent/BE905087A/en not_active IP Right Cessation
- 1986-07-10 GB GB8616819A patent/GB2179947B/en not_active Expired
- 1986-07-10 CH CH2771/86A patent/CH668428A5/en not_active IP Right Cessation
- 1986-07-10 IT IT48254/86A patent/IT1195855B/en active
- 1986-07-10 NL NL8601814A patent/NL8601814A/en not_active Application Discontinuation
- 1986-07-10 LU LU86508A patent/LU86508A1/en unknown
- 1986-07-11 JP JP61162200A patent/JPS6219523A/en active Pending
- 1986-07-11 DE DE3623474A patent/DE3623474C2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| IT1195855B (en) | 1988-10-27 |
| FR2584727A1 (en) | 1987-01-16 |
| SE8602877L (en) | 1987-01-12 |
| CH668428A5 (en) | 1988-12-30 |
| GB2179947A (en) | 1987-03-18 |
| DK327386A (en) | 1987-01-12 |
| DE3623474C2 (en) | 1995-09-21 |
| SE8602877D0 (en) | 1986-06-27 |
| NL8601814A (en) | 1987-02-02 |
| DK327386D0 (en) | 1986-07-10 |
| JPS6219523A (en) | 1987-01-28 |
| FR2584727B1 (en) | 1988-06-17 |
| IT8648254A0 (en) | 1986-07-10 |
| DE3623474A1 (en) | 1987-01-15 |
| GB2179947B (en) | 1989-07-12 |
| BE905087A (en) | 1987-01-12 |
| GB8616819D0 (en) | 1986-08-20 |
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