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WO1995026984A1 - Procede de production d'une composition renfermant le facteur de croissance 1 insulinoide bovin - Google Patents

Procede de production d'une composition renfermant le facteur de croissance 1 insulinoide bovin Download PDF

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Publication number
WO1995026984A1
WO1995026984A1 PCT/JP1995/000620 JP9500620W WO9526984A1 WO 1995026984 A1 WO1995026984 A1 WO 1995026984A1 JP 9500620 W JP9500620 W JP 9500620W WO 9526984 A1 WO9526984 A1 WO 9526984A1
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WO
WIPO (PCT)
Prior art keywords
igf
milk
composition containing
growth factor
composition
Prior art date
Application number
PCT/JP1995/000620
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English (en)
Japanese (ja)
Inventor
Ken Kato
Hiroaki Matsuyama
Yukihiro Takada
Yoshihiro Kawasaki
Toshiaki Uchida
Masatoshi Yahiro
Original Assignee
Snow Brand Milk Products Co., Ltd.
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 Snow Brand Milk Products Co., Ltd. filed Critical Snow Brand Milk Products Co., Ltd.
Priority to NL9520002A priority Critical patent/NL194730C/nl
Publication of WO1995026984A1 publication Critical patent/WO1995026984A1/fr

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Classifications

    • 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
    • C07K14/575—Hormones
    • C07K14/65—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a method for producing a composition containing insulin-like growth factor-11.
  • This insulin-like growth factor-11-containing composition has a bone strengthening effect and is useful for the prevention and treatment of osteoporosis.
  • calcium salts such as calcium carbonate, calcium lactate, and calcium phosphate
  • natural calcium agents such as bovine bone meal, eggshell, and fish bone powder
  • some of these calcium forms insoluble salts in the digestive tract and are not well absorbed by the body.
  • Vita Mi emissions D 3 and calcium Bok Nin formulation is used, the use of these medicines, tinnitus, headache, such as anorexia May have side effects. Therefore, due to the nature of the disease osteoporosis, long-term oral There is a demand for the development of foods that can be used and can be expected to have a preventive or therapeutic effect.
  • IGF-1 insulin-like growth factor-11
  • IGF-1 insulin-like growth factor-11
  • somatomedin a polypeptide having a molecular weight of about 7,800 belonging to the class of somatomedin, and activates osteoblasts. It is known to be a factor that plays an important role in bone metabolism, such as increasing bone mass and strengthening bone.
  • IGF-1 receptor is present in the gastrointestinal tract, suggesting that orally ingested IGF-1 acts via a gastrointestinal receptor [hormones and Clinical, Vol. 39, pp. 31-37, 1991].
  • This IGF-1 has been confirmed to be present in human milk [J. Clin. Endocrinol. Metab., Vol. 58, pp. 955-959, 1 1984), but it was also confirmed to be present in all organs including serum and liver [Pr0N atl. Acad. Sci. USA, Vol. 81, 9] Pp. 35-93, 1984).
  • IGF-1 is also present in milk, and it has been reported that the chemical structure of IGF-1 is exactly the same as that of human IGF-1 [Biochem. J , Vol. 251, pp. 95-103, 198 8 years]. This indicates that espresso IGF-1 has the same effect as human insulin-like growth factor-11, and if espresso IGF-1 is present in milk, it is added to food. It is safe to say that there is no problem at all.
  • the present inventors have previously proposed a method for preparing a composition containing IGF-1 by heat-treating milk or a raw material derived from milk [Japanese Patent Application No. 5-97272]. .
  • the IGF-1 content of the IGF-1 containing composition is about 10 to 25 // gg, and development of a method for preparing a composition having a higher IGF-1 content is desired.
  • this method also has a problem that milk protein precipitated by heating cannot be used effectively.
  • the present inventors have conducted intensive studies on a method of isolating IGF-1 from milk or a milk-derived material.
  • the present inventors have found that a composition having a high content of 1 can be obtained, and have completed the present invention. Therefore, Akira has a chemical structure identical to that of human IGF-1 and is useful for bone strengthening and prevention and treatment of osteoporosis.
  • the task is to provide Disclosure of the invention
  • the milk or raw material derived from milk used in the present invention includes, for example, skim milk, cheese whey, acid whey, colostrum, and the like, whey protein concentrate (WPC), whey protein isolate (WPI), Whole milk powder, skim milk powder, whey powder, etc. may be reduced. Further, it is preferable to heat these raw materials before they are brought into contact with the cation exchanger. In other words, the amount of impurities adsorbed on the cation exchanger is reduced by heating the raw materials and denaturing major milk proteins such as casein, ⁇ -lactalbumin, and ⁇ -lautoglopurin present in milk. Can be done. As a result, the content of IGF-1 in the composition is improved.
  • the heating temperature may be set according to the following equation.
  • the salt concentration of the raw material there is no particular limitation on the salt concentration of the raw material to be brought into contact with the cation exchanger.
  • the salt concentration of the raw material is high, adsorption to the cation exchanger becomes poor, and The IGF-1 recovery rate decreases. Therefore, it is preferable to adjust the salt concentration to the same level as or less than that of ordinary milk.
  • the milk or the milk-derived material is brought into contact with the cation exchanger, it is preferable to carry out a treatment with a clarifier or the like in advance to remove fine precipitates and the like contained in the material.
  • the method of contacting milk or a raw material derived from milk with a cation exchanger there is no particular limitation on the method of contacting milk or a raw material derived from milk with a cation exchanger, and a method using a conventional packed bed type column, a method using a rotary column, or Cation exchange can be performed according to a method such as a batch method.
  • the contact time between the milk or the milk-derived material and the cation exchanger there is no particular limitation on the contact time between the milk or the milk-derived material and the cation exchanger, and it is better to keep the contact for a long time, but if the contact is carried out for an excessively long time, the raw material deteriorates. It is desirable to set the time from minutes to 24 hours.
  • the temperature of the raw material to be brought into contact with the cation exchanger is not particularly limited, but is preferably 4 to 40 ° C. When the temperature exceeds 40 ° C, the raw material deteriorates significantly.
  • the value of the cation exchanger Z raw material is larger than 1 Z10 (w / w)
  • the cost of the cation exchanger becomes relatively high.
  • the value of the cation exchanger raw material is smaller than 13,000, the recovery rate of PG IGF-1 becomes extremely poor.
  • Examples of the cation exchanger that can be used in the present invention include CM—cellulofine, CM—cellulose, microprep CM strong cation exchange support, and CM—Sepharose having a carboxymethyl group as an exchange group.
  • CM-Sephadex, C-Sulferosyl, etc. Sulfonated chitopearl having sulfonate group as an exchange group, SP-Toyo-Pearl, S-Sepharose, SP-Sephadex, Indion S3, S-Suefrosil, Microbrep Examples include S Strong Cation Extraction Sabot.
  • a solution having a salt concentration of less than 0.1 M wash the ion exchanger with deionized water.
  • a part of the contaminating milk protein can be removed from the cation exchanger, and as a result, the content of PG-IGF-1 in the composition can be improved. It is preferable to do it.
  • This elution method may be performed according to a commonly used elution method, but the salt concentration of the eluate used for elution must be in the range of 0.1 M to 0.3 M.
  • the concentration of IGF- 1 Cannot be eluted sufficiently.
  • the salt concentration of the eluate exceeds 0.3 M, proteins other than IGF-1 adsorbed on the cation exchanger will be eluted together, and as a result, Reduces IGF-1 content.
  • the pH of this eluate is preferably 5 or more and less than 8, and therefore, eluents such as Tris-HCl buffer, phosphate buffer, carbonate buffer, etc.
  • a neutral salt such as sodium chloride, potassium chloride, or ammonium acetate
  • a neutral salt solution having a salt concentration of 0.1 M or more and 0.3 M or less and having no buffer capacity can be used as the eluate, which is preferable in terms of improving operability and reducing costs.
  • the eluate containing the thus-obtained IGF-1 fraction is subjected to a conventional method, for example, ion exchange resin, reverse osmosis membrane, ultrafiltration membrane, dialysis membrane.
  • Desalting and concentration can be performed by a method using an electrodialysis membrane, a gel filtration carrier, or the like, or by a method combining these methods.
  • a combination of filtration and diamond filtration is preferred, since concentration and desalting can be performed simultaneously.
  • the ultrafiltration membrane that can be used at this time may be any ultrafiltration membrane as long as the molecular weight cut off is 10 kDa or less.
  • the concentrate of the composition containing the IGF-1 can be used as it is, but if necessary, a dry powder of the composition containing the IGF-1 can be obtained by a method such as spray drying or freeze drying.
  • a heat sterilization step since PIG IGF-1 has a relatively heat-stable property, it is possible to add a heat sterilization step as is usually performed.
  • the IGF-1 content of the IGF-1 containing composition obtained by the method of the present invention was measured by an immunoassay using an anti-IGF-1 antibody.
  • the recovery of IGF-1 from the raw material was about 40% on average.
  • the recovery rate of PIG IGF-1 recovered from colostrum by a combination of acid extraction and positive ion exchange chromatography was described in literature [Biochem. J., Vol. 233, pp. 207-213, 1 986], 25%, and the method of the present invention exceeded it.
  • the composition containing casein and whey protein is contained in the composition containing the casein IGF-1.
  • proteins such as lactoferrin, lactopaboxidase, and secretory components are included. Although these proteins have physiological activity, these proteins do not affect the physiological action of the IGF-1 at all, so there is no substantial problem with the inclusion of these proteins. If inconvenient, these proteins can be inactivated by treatment such as heating.
  • lactopoxidase can be separated by a method such as rechromatography or inactivated by making it acidic.
  • the pharmaceutical composition containing IGF-1 obtained by the method of the present invention has a bone-strengthening effect, and thus can be added to foods and drinks, pharmaceuticals, feeds, and the like to impart effects such as prevention and treatment of osteoporosis.
  • calcium, calcium carbonate, calcium lactate, eggshell, or calcium with good absorbability, such as milk-derived calcium is added to foods, drinks, medicines, feeds, etc., containing this composition containing IGF-1.
  • these effects can be further enhanced.
  • no acute toxicity was observed for the composition containing IGF-1.
  • FIG. 1 shows the osteoblast proliferation-promoting effect of the composition containing PIG IGF-1 obtained in Examples 1 to 9 below.
  • FIG. 2 shows the bone-strengthening action of the composition containing PIG IGF-1 obtained in Example 5 below.
  • the eluate was desalted and concentrated using an ultrafiltration membrane having a molecular weight cutoff of 10 kDa, and then lyophilized to obtain 450 mg of a powdery IGF-1 containing composition.
  • a radioimmunoassay RIA
  • 1,000 sterile non-sterilized skim milk (pH 6.5) is passed through a column packed with 1 kg of SP Toyo Pearl (manufactured by Tosoh I), thoroughly washed with deionized water, at a flow rate of 30 ml / min. Liquid. After passing the solution through, thoroughly wash the SP Toyo Par with deionized water, and then add 0.15M sodium chloride and 0.05M carbonate The adsorbed IGF-1 was eluted with a buffer (pH 7.5).
  • the eluate is subjected to ultrafiltration and diafiltration using a membrane having a molecular weight cut-off of 8 kDa, desalted and concentrated, and then freeze-dried to obtain a powdery composition containing IGF-1 50. g was obtained.
  • a radioimmunoassay RIA
  • Whey protein concentrate to be a 10% strength by weight was prepared Hoe one protein solution (P H 6. 8) 40 1 fully dissolved in distilled water.
  • This whey protein solution was passed through a column packed with 400 g of CM-cellulofine (manufactured by Seikagaku Corporation) sufficiently washed with deionized water at a flow rate of 2 Om 1 Z min. After passing the solution through, thoroughly wash the CM-cell fin with 0.03 M phosphate buffer (pH 7.4) containing 0.02 M sodium chloride, and then add 0.20 M sodium chloride.
  • the adsorbed IGF-1 was eluted with a 0.10 M citrate buffer (pH 6.2).
  • the eluate was desalted and concentrated by an electrodialysis (ED) method, and then freeze-dried to obtain 1.3 g of a powdery IGF-11-containing composition.
  • the content of the IGF-1 contained in the composition containing the IGF-1 was measured by a radioimmunoassay (RIA) and found to be 35 gZg.
  • RIA radioimmunoassay
  • the whey protein isolate (WPI) was sufficiently dissolved in distilled water to a concentration of 10% by weight to prepare a whey protein solution (pH 6.5) 801.
  • This whey protein solution was passed through a column packed with 800 g of SP-Sepharose (manufactured by Pharmacia) thoroughly washed with deionized water at a flow rate of 24 m 1 Z minute. After passing through, 0.01 M containing sodium chloride 0.05 M carbonate After the SP-Sepharose was thoroughly washed with buffer (pH 7.6), it was adsorbed with 0.20 M citrate buffer (pH 5.7) containing 0.1 M sodium chloride. IGF-1 was eluted.
  • the eluate was desalted by ion exchange chromatography, and then spray-dried to obtain 29.6 g of a powdery IGF-1 containing composition.
  • the content of the IGF-1 contained in the composition containing the IGF-1 was measured by radioimmunoassay (RIA) and found to be 51.2 gZg.
  • the eluate was desalted with a reverse osmosis (RO) membrane, concentrated, and then spray-dried to obtain 176 g of a powdery IGF-1 containing composition in powder form.
  • RO reverse osmosis
  • RIA radioimmunoassay
  • a whey protein concentrate (WP C) is sufficiently dissolved in distilled water to a concentration of 10% by weight to prepare a whey protein solution (PH 6.8), and this solution is heated at 90 ° C for 10 minutes.
  • the supernatant obtained by centrifugation at 17,000 XG was applied to a column packed with 500 g of Indeion S 3 (manufactured by Organo) thoroughly washed with deionized water at a flow rate of 18 m 1 / In minutes. After the infusion, wash Indion S 3 thoroughly with 0.07 M Tris-HCl buffer. After that, the adsorbed IGF-1 was eluted with a 0.3 M sodium chloride solution (pH 7.3).
  • the eluate was desalted by gel filtration chromatography, and then lyophilized to obtain 1.4 g of a powdery IGF-1 containing composition.
  • RIA radioimmunoassay
  • the eluate is subjected to ultrafiltration and membrane filtration with a membrane having a molecular weight cut-off of 10 kDa, desalted and concentrated, and then lyophilized to form a powdered IGF-1 containing composition 1 .5 g were obtained.
  • a radioimmunoassay RIA
  • the discharged liquid was desalted and concentrated by a reverse osmosis (R0) membrane, and then spray-dried to obtain 1.3 g of a powdery IGF-1 containing composition.
  • the content of the IGF-1 contained in the composition containing the IGF-1 was measured by radioimmunoassay (RIA) and found to be 114 / g / g.
  • Unsterilized cheese whey (pH 6.5) 201 was passed through a column packed with 300 g of C-sfluorosyl (manufactured by IBF) thoroughly washed with deionized water at a flow rate of 25 ml. After passing through, wash C-sulferosyl thoroughly with deionized water, and further thoroughly with 0.07 M phosphate buffer (pH 7.2), then contain 0.25 M sodium chloride The adsorbed IGF-1 was eluted with a 0.05 M citrate buffer (pH 6.5). The eluate was desalted and concentrated using a nanofiltration membrane, and then lyophilized to obtain 890 mg of a powdery IGF-1 containing composition. When the content of the Pacific IGF-1 contained in the composition containing the Pacific IGF-11 was measured by radioimmunoassay (RIA), it was found to be 43 gZg. Test example 1
  • a cultured osteoblast-like cell line (MC 3T3— ⁇ ⁇ ) was inoculated into a 96-well flat bottom cell culture plate, and ⁇ -MEM medium containing 0.3% by weight of serum (F10 w Laboratories) was added. For 18 hours. At the time of this culturing, a solution 21 containing a composition containing the IGF-1 at a concentration of 0.5% by weight was added to 100 zl of the medium. After culture, thymidine labeled with tritium was added, and 2 hours later, the radioactivity of thymidine incorporated into the cells was measured to determine the osteoblast proliferation activity.
  • Figure 1 shows the results. In FIG.
  • the radioactivity of the group to which the medium containing no IGF-1 was added was 100%, and the cell proliferation of the group to which the medium containing the IGF-1 was added was determined from the radioactivity. Showed activity. According to this, the group to which the IGF-1 containing composition obtained in Examples 1 to 9 was added was 1.8 to 1.8 times less than the group to which no IGF-1 containing composition was added. 2. It showed a 7-fold osteoblast proliferation activity.
  • the experimental animals were 4-week-old SD female rats, and each test group consisted of 7 animals.
  • the osteoporosis model rat was preliminarily reared for one week, subjected to ovariectomy, and further reared on a calcium-deficient diet for five weeks before the experiment.
  • shamrats that had undergone only sham surgery and had no ovaries removed were also used in the experiment.
  • the osteoporosis model rat was divided into three groups: a control group (group A), a group administered with the IGF-1 containing composition (B), and a group containing the IGF-1 plus calcium (C). Each of the test feeds shown in 1 was bred for 3 weeks.
  • FIG. 2 shows the results. According to this, the femoral fracture stress showed a statistically significantly higher value in the group administered with the IGF-1 containing composition (B) than in the control group (A). Further, the group administered with the composition containing calcium IGF-1 and calcium (C) showed a statistically significantly higher value than the group administered with the composition containing calcium IGF-1 (B).
  • the IGF-1 composition which contains highly IGF-1 from milk or a raw material derived from milk. Since the composition containing bone IGF-1 has a bone strengthening effect, it is useful for preventing or treating various osteoarticular diseases, particularly osteoporosis. Also, By ingesting this IGF-1 composition during the human growth period, the maximum bone mass can be increased. Therefore, this composition containing IGF-1 is useful as a material for foods and drinks, medicines, feeds and the like.

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Abstract

Procédé de production d'une composition renfermant le facteur 1 de croissance insulinoïde bovin, consistant à mettre du lait ou un produit dérivé du lait au contact d'un échangeur de cations et à procéder à l'élution du facteur de croissance 1 insulinoïde bovin adsorbé. Etant donné que ce facteur de croissance 1 peut renforcer les os, la composition renfermant abondamment ce facteur est utile pour l'élaboration d'aliments, de boissons, de médicaments ou d'éléments nutritionnels efficaces pour la prévention ou le traitement de diverses maladies ostéo-articulaires, notamment l'ostoporose.
PCT/JP1995/000620 1994-03-31 1995-03-31 Procede de production d'une composition renfermant le facteur de croissance 1 insulinoide bovin WO1995026984A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
NL9520002A NL194730C (nl) 1994-03-31 1995-03-31 Werkwijze voor het bereiden van een samenstelling welke runder-insuline-achtige groeifactor-1 bevat.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP6/85333 1994-03-31
JP08533394A JP3501495B2 (ja) 1994-03-31 1994-03-31 ウシインスリン様増殖因子−１含有組成物の製造法

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WO1995026984A1 true WO1995026984A1 (fr) 1995-10-12

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000062785A1 (fr) * 1999-04-15 2000-10-26 Takara Shuzo Co., Ltd. Remedes
CN106699869A (zh) * 2008-05-14 2017-05-24 维多利亚农业服务控股公司 血管生成素富集的乳级分

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090324733A1 (en) * 2005-09-09 2009-12-31 Murray Goulburn Co-Opeartive Co Limited Composition of Whey Growth Factor Extract for Reducing Muscle Inflammation
CN101282763B (zh) * 2005-09-09 2012-09-26 墨累古尔本合作有限公司 来源于乳的组合物及其用于增强肌肉量或肌肉力量的用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63501567A (ja) * 1985-08-22 1988-06-16 グロペップ　プロプライエタリー　リミテッド 生長因子

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63501567A (ja) * 1985-08-22 1988-06-16 グロペップ　プロプライエタリー　リミテッド 生長因子

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000062785A1 (fr) * 1999-04-15 2000-10-26 Takara Shuzo Co., Ltd. Remedes
CN106699869A (zh) * 2008-05-14 2017-05-24 维多利亚农业服务控股公司 血管生成素富集的乳级分

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JP3501495B2 (ja) 2004-03-02
NL194730C (nl) 2003-01-07
NL194730B (nl) 2002-09-02
NZ282898A (en) 1997-04-24
JPH07267995A (ja) 1995-10-17
NL9520002A (nl) 1996-06-03

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