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WO2003088999A1 - Procede de production d'une preparation d'immunoglobuline - Google Patents

Procede de production d'une preparation d'immunoglobuline Download PDF

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Publication number
WO2003088999A1
WO2003088999A1 PCT/JP2003/003306 JP0303306W WO03088999A1 WO 2003088999 A1 WO2003088999 A1 WO 2003088999A1 JP 0303306 W JP0303306 W JP 0303306W WO 03088999 A1 WO03088999 A1 WO 03088999A1
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WO
WIPO (PCT)
Prior art keywords
immunoglobulin
treatment
heat treatment
fraction
solution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2003/003306
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English (en)
Japanese (ja)
Inventor
Yoshio Itagaki
Katsuhiro Uriyu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mitsubishi Tanabe Pharma Corp
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Mitsubishi Pharma Corp
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 Mitsubishi Pharma Corp filed Critical Mitsubishi Pharma Corp
Priority to AU2003221431A priority Critical patent/AU2003221431A1/en
Publication of WO2003088999A1 publication Critical patent/WO2003088999A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • the present invention relates to a method for producing an immunoglobulin preparation. Specifically, the present invention relates to a production method including a liquid heating step.
  • immunoglobulin preparations containing IgG as a main component have been widely used for prevention and treatment of various infectious diseases.
  • Various methods for producing immunoglobulin have been studied and many have been reported.
  • methods for preparing non-chemically modified immunoglobulins include ethanol fractionation, polyethylene glycol fractionation (Japanese Patent Application Laid-Open No. 53-47515), polyethylenedaricol and hydroxyxethyl starch. (JP-A-51-91321), acid treatment (JP-A-57-322288), anion exchanger treatment (JP-A-59-228) No. 501546, Japanese Patent Application Laid-Open No.
  • various production methods have been reported in which the immunoglobulin obtained by the above method is further subjected to a heat treatment in order to supply a safer immunoglobulin preparation as a plasma fraction preparation.
  • a liquid heating method a method using a high-concentration sugar or sugar alcohol as a stabilizer (Japanese Patent Application Laid-Open No. 61-191622) and a method using a high-concentration sorbie as a stabilizer are disclosed.
  • a method of using a low ionic strength and acidic pH using toll Japanese Patent Application Laid-Open No. 63-146,332) has been reported.
  • the drying and heating methods include albumin, glycine, and polyethylene glycol as stabilizers.
  • the above-mentioned heat-treated immunoglobulin preparation reduces the aggregates (polymer) of immunoglobulin and obtains a preparation with excellent stability.
  • polyethylene glycol fractionation method and bentonite method are used. And a long time was required for the treatment process. Therefore, development of a method for producing an immunoglobulin preparation that includes a heat treatment step for an immunoglobulin solution and that is simpler and has reduced aggregates is desired.
  • CSL removes the corn fractionation method (supernatant III) or fibrinogen (fraction I) obtained by purification by a method based on the Cohn-Onc1ey method
  • a method is disclosed in which an immunoglobulin solution obtained by the ion exchange chromatography method is heated in a liquid state at a protein concentration of about 3 (w / V)% or less (Table 2). 5 857 publication).
  • the publication is characterized in that post-treatment after liquid heating is unnecessary, and no purification treatment is performed after the heating treatment.
  • the obtained immunoglobulin preparation has an aggregate concentration of 0.21% when the protein concentration is 0.5% and the stabilizer (sucrose) concentration is 40%.
  • An object of the present invention is to provide a method for producing an immunoglobulin preparation which includes a heat treatment step for an immunoglobulin solution, is simpler, and has reduced aggregates.
  • the inventors of the present invention have conducted an in-depth study in consideration of the above circumstances. As a result, under specific conditions, the solution containing immunopurine was subjected to liquid heating and, if necessary, membrane treatment. The present inventors have found that the intended purpose can be achieved by removing the molecular fraction by isoelectric focusing and treatment with anion exchanger or anion exchanger, and have completed the present invention.
  • the immunoglobulin-containing solution is used at a protein concentration of 3 (w / v)% or less and in the presence of a stabilizer of 10 (wZv)% or more; H 5.2 ⁇ 0.5, conductivity Heat treatment at 0.1-1 mS i, followed by isoelectric point fractionation and / or anion exchanger treatment at pH 7-9, conductivity 0.0 l-l mS i.
  • the immunoglobulin-containing aqueous solution is not particularly limited as long as it is an aqueous solution containing immunoglobulin.
  • the I1 + III fraction, the II fraction, and the like obtained by corn ethanol fractionation are preferable.
  • a paste of a fraction equivalent to these containing immunoglobulin A method in which these fractions are suspended in an aqueous solvent to extract immunoglobulins is described. At this time, an aqueous medium having a volume of at least 2 times, preferably at least 5 times the volume of the fraction is used. (Liquid heating)
  • This step is for inactivating viruses that may be contaminated in the drug product.
  • the protein concentration is 3 (w / v)% or less, preferably 0.
  • a stabilizer is added for the purpose of ensuring the stability of immunoglobulin.
  • saccharides for example, monosaccharides such as glucose, disaccharides such as sucrose, sugar alcohols such as sorbitol
  • examples include amino acids, organic acids, and nonionic surfactants.
  • sucrose or sorbitol is used.
  • the amount of the stabilizer to be added is 100 g or more, preferably 100 to 700 g, more preferably about 300 to 700 g per liter of the immunoglobulin solution.
  • the pH is 5.2 ⁇ 0.5, more preferably about 5.2 ⁇ 0.2, and the conductivity is about 0.01 to: L mSi, more preferably about 0.1 to 0.3mSi. Is exemplified.
  • the liquid heating treatment conditions include 50 to 70 ° C (preferably about 60 ° C) for 10 minutes to 20 hours (preferably about 10 hours).
  • alcohols are considered to be contained in fractions II + III and II in which the starting material is obtained by ethanol fractionation of corn, but the alcohol concentration of the immunoglobulin solution during the heat treatment is considered.
  • the alcohol concentration is 1.0% or less, preferably 0.3% or less, and more preferably 0.1%.
  • Examples of a method for removing the alcohol content from the starting material include dialysis treatment using water for injection as an external solution.
  • This step is the c specifically intended to remove the high concentration of the stabilizing agent after the liquid heating such external solution and the dialysis treatment can be exemplified water for injection.
  • This step is for removing the high molecular weight (IgG) fraction generated by the heat treatment.
  • the high molecular fraction is precipitated, and the supernatant fraction is collected.
  • the protein concentration are about 0.1 to 4 (w / v)%, more preferably about 1 to 3.5 (w / v)%. It is. PH conditions are, for example, about 7 to 9, and more preferably about 7.5 to 8.5.
  • the conductivity is, for example, about 0.1 to 1 mSi, more preferably about 0.1 to 0.3 mSi.
  • This step is also for removing the high molecular weight fraction (IgG) generated by the heat treatment.
  • the non-adsorbed fraction (pass fraction) is recovered by subjecting the aqueous solution containing immunoglobulin from which the stabilizer has been removed by the above-mentioned process to contact treatment with an anion exchanger.
  • An anion exchanger is obtained by bonding a substituent having an anion exchange ability (anion exchange group) to an insoluble carrier. Examples of such a substituent include a getylaminoethyl group (DEAE) and a quaternary aminoethyl group (QAE).
  • insoluble carrier examples include cross-linked dextran (trade name: Cephadettas, manufactured by Pharmacia), cellulose, agarose (trade name: Sepharose, manufactured by Bulmasia), polyvinyl (trade name: Topar, manufactured by Tosoh), polyacrylamide, and the like.
  • anion exchangers can also be used.
  • the processing conditions include, for example, pH of 7 to 9, more preferably about 7 to 8.5.
  • the conductivity is, for example, about 0.1 ⁇ : LmSi, more preferably about 0.1 to 0.3 mSi.
  • the concentration of the protein in the solution is about 0.1 to 4 (w / v)%, and more preferably about 1 to 3.5 (w / v)%.
  • a contact treatment is performed with the anion exchanger equilibrated with the above aqueous solvent.
  • the anion exchanger lm1 is mixed with about 10 to 100 ml of the solution to be treated, stirred at 0 to 4 ° C for about 30 minutes to 2 hours, and then centrifuged (60000 to 80 00 rpm, 10-30 minutes) and collect the supernatant.
  • This step is for removing viruses that may be contaminated in the immunoglobulin preparation.
  • a method of filtering the aqueous solution containing immunoglobulin treated in the above-mentioned step using a porous membrane for example, a hollow fiber shape, a sheet shape, etc.
  • a porous membrane for example, a hollow fiber shape, a sheet shape, etc.
  • the material of the porous membrane used in the present invention is not particularly limited, but preferably includes regenerated cellulose.
  • the shape include a hollow fiber shape and a sheet shape, and the hollow fiber shape is preferable.
  • the porous hollow fiber of the regenerated cellulose is preferably subjected to a microphase separation method from a cellulose cuprammonium solution [American 'Chemical-Society (Am. Chem. Soc.), 9, 197-228]. (19985)].
  • the average pore size of the porous membrane is 1 to 100 nm, preferably 10 to 75 nm, more preferably 10 to 50 nm, particularly preferably 35 ⁇ 2 nm or 20 ⁇ 2 nm, and the film thickness is preferably Is 35 ⁇ 3, and the membrane is preferably of a multilayer structure.
  • the inner diameter is preferably 330 ⁇ 30 ⁇ .
  • the porous membrane is in the form of a hollow fiber, it is preferably used in the form of a module.
  • the module is composed of a porous hollow fiber membrane having a membrane area of preferably 0.001 to 1. Om 2 and a container for filling the same, and an adhesive for integrating them. .
  • the processing conditions for filtration using a porous membrane are ⁇ ⁇ 6-7, low ionic strength (Specifically, from 0.1 to L m S i, preferably about 0.1 to 0.3 mS i).
  • the aqueous solvent may contain solutes similar to those described in the above steps.
  • the protein concentration in the solution is about 0.1 to 4 (w / v)%, preferably about 1 to 3.5 (w / v)%.
  • the immunoglobulin preparation can be used as an intravenous immunoglobulin or intramuscular immunoglobulin preparation, preferably as an intramuscular immunoglobulin preparation.
  • the immunoglobulin preparation may be further purified within a range not inconsistent with the object of the present invention to prepare, for example, a preparation conforming to the standard for intravenous preparations.
  • the range that does not contradict the object of the present invention refers to a range in which polyethylene glycol treatment or bentonite treatment is not performed. It may contain pharmacologically acceptable additives (eg, carriers, excipients, diluents, etc.), stabilizers or pharmaceutically necessary components used for pharmaceuticals.
  • the stabilizer examples include monosaccharides such as glucose, disaccharides such as saccharose and maltose, sugar alcohols such as mannitol and sorbitol, neutral salts such as sodium chloride, amino acids such as glycine, polyethylene glycol, Nonionic surfactants such as polyoxyethylene-polyoxypropylene copolymer (pull nick) and polyoxyethylene sorbitan fatty acid ester (Tween) are exemplified.
  • the addition amount of sugars and amino acids is 1 to 10 (w / v). /. It is preferable that about 0.1 to 1 (wZv)% of salt and about 0.1 to 0.1 (w / V)% of surfactant are added.
  • the aqueous solution containing immunoglobulin is filtered using a porous membrane.
  • the filtration pressure is preferably 0.1 to 1 kgf Zcm 2 , more preferably 0.1 to 0.5 kgf Z cm 2 , and particularly preferably 0.1 to 0.3 kgf / cm 2 .
  • the processing temperature is preferably 4 to 50 ° C., and the processing time is 10 minutes to 10 hours, preferably 1 to 5 hours.
  • a cross filter that filters while applying a strain rate to the fluid is used.
  • the aqueous solution containing immunoglobulin is concentrated after the filtration treatment using a porous membrane. Specifically, it is performed to adjust the protein concentration to about 10 to 20 (w / v)%, preferably about 13 to 17 (w / v)%. It is performed by performing diafiltration using water for injection.
  • the obtained fraction can be made into a liquid preparation by dispensing aliquots. Further, a dry preparation can be obtained by subjecting the liquid preparation to a treatment such as freeze-drying.
  • This formulation has a protein concentration of 10 to 20 (w / v)%, preferably 13 to 17 (w / v)%, pH 6 to 8, preferably 6.4 to 7.6, and an osmotic pressure of 1 To 3, preferably about 1 to 2. It also contains pharmacologically acceptable additives (eg, carriers, excipients, diluents, etc.), stabilizers, or pharmaceutically necessary components that are commonly used in pharmaceuticals within the scope not contrary to the object of the present invention. It may be. The kind of the stabilizer and the amount to be added are as described above. It is not necessary to add preservatives (such as thimerosal) that are usually added to immunoglobulin preparations for intramuscular injection.
  • preservatives such as thimerosal
  • the IgG aggregate content in this preparation is not more than 2.5 (w / w)%, preferably not more than 1 (w / w)% based on the total amount of immunoglobulin, and the titer (measles antibody titer) is It is preferably at least about 5U / 15 Omg protein.
  • the present preparation may be a liquid preparation or a dry preparation. Liquid preparations can be dissolved as they are, while dry preparations can be dissolved in water for injection and injected into the patient's muscle.
  • HB s antigen, anti-HCV antibody, anti-HIV-1 antibody, anti-HIV-2 antibody Negative and screened by ALT (GPT) value, and nucleic acid amplification test for HIV, HBV and HCV
  • the second fraction prepared by the cold ethanol method of corn was suspended in water for injection, and the protein concentration was 1 (w). / v) was adjusted to be%.
  • Sorbitol was added to each immunoglobulin solution at 500 g per liter of solution, and the pH was adjusted to 5.2. The mixture was heated in a liquid state (solution state) at 60 ° C for 10 hours.
  • Sorbitol was removed by dialysis using water for injection as an external solution, adjusted to pH 7.8, subjected to isoelectric focusing, and the supernatant fraction was collected. Further, anion exchanger treatment was performed using DEAE-cellulose (Whatman) under the conditions of H7.8, and the non-adsorbed fraction (pass fraction) was collected. The minute was removed. Further, glycine was added to a concentration of 2.25 (wZv)% and sodium chloride to a concentration of 0.5 (wZv)%, and the pH was adjusted to 6. Adjusted to 6. The membrane was filtered using a porous membrane having an average pore diameter of 35 nm (BMM: Planova 35, manufactured by Asahi Kasei Corporation).
  • the solution was subjected to diafiltration using water for injection, and concentrated to a final protein concentration of 15 (w / v) ° / o.
  • the solution was sterilized and filtered using a filter having a pore size of 0.22 Aim (manufactured by Millipore) to obtain a final preparation.
  • Immunoglobulin was heated in liquid form according to Example 1.
  • the sorbitol was removed by dialyzing water for injection as an external solution, isoelectric focusing was performed under the conditions of a protein concentration of 3 (w / v)% and pH 7.8, and the supernatant fraction was collected. Recovered, and a protein concentration of 3 (w / v).
  • Anion exchanger treatment was performed using DE AE-cellulose under the condition of H7.8 to collect the non-adsorbed fraction (pass fraction) and remove the polymer fraction generated by liquid heating. .
  • membrane filtration was performed using a porous membrane having an average pore diameter of 20 nm (BMM: Branova 21, Asahi Kasei Corporation).
  • the solution was diafiltered using water for injection, and concentrated to a final protein concentration of 15 (w / v)%. To this 15% solution, add glycine to 2.25 (w / v)% and sodium chloride to 0.5 (w / v)%, and adjust the pH to 6.5. The solution was sterilized and filtered using a filter having a pore size of 0.22 ⁇ m to obtain a final preparation.
  • Example 2 The operation was performed in the same manner as in Example 2 except that ion-exchanged cellulose filter paper (DE81, manufactured by Wattman Japan) having a wet weight of 0.5% was used as the anion exchanger.
  • ion-exchanged cellulose filter paper DE81, manufactured by Wattman Japan
  • the properties of the immunoglobulin preparation for intramuscular injection prepared according to the examples were as follows.
  • the optimal pH of the immunoglobulin solution during the heat treatment was examined.
  • An immunoglobulin aqueous solution was prepared by adding an immunoglobulin solution to a protein concentration of 5% and a sorbitol concentration of 50% as a stabilizer.
  • the ⁇ H of each immunoglobulin solution was adjusted to 4.7, 5.0, 5.2, 5.5, and 5.7, and then heat-treated at 60 ° C. for 10 hours.
  • the composition (polymer (aggregate), dimer, monomer, etc.) of each immunoglobulin after the heat treatment was measured, and the results are shown in Table 1.
  • the protein amount was obtained by measuring the absorbance at a wavelength of A280 nm using a spectrophotometer.
  • the composition of immunoglobulin is 11 ⁇ .
  • the c- immunoglobulin solution examined for the optimal concentration of the immunoglobulin solution during the heat treatment was adjusted so that the protein concentration was 1.0, 2.5, 5.0, 7.5 (w / v)%. Sorbitol was blended as a stabilizer at 50 (wZv)%. Furthermore, after adjusting the pH to 5.2 ⁇ 0.5, it was subjected to a heat treatment at 60 ° C. for 10 hours. The composition of each immunoglobulin after the heat treatment was measured in the same manner as in 1) above, and the results are shown in Table 2.
  • the optimal concentration of the stabilizer contained during the heat treatment of the immunoglobulin solution was examined.
  • the immunoglobulin solution was adjusted so that the protein amount was 5 ⁇ 1 (w / v)%, and was blended so that the sorbitol was 50, 55, 60 and 65 (w / v)%, respectively.
  • Each immunoglobulin solution was heated at 60 ° C for 10 hours.
  • the composition of each immunoglobulin after the heat treatment was measured in the same manner as in 1) above, and the results are shown in Table 3.
  • the immunoglobulin solution adjusted to a protein concentration of 3 (w / v)% was heated at 60 ° C for 10 hours at pH 5.2 and sorbitol at 50 (w / v)%. After that, sorbitol was removed with an ultrafiltration membrane (UF membrane: MW 50,000). Then, the effect of removing the polymer fraction when the anion exchanger was treated under various pH conditions was examined.
  • the composition of each immunoglobulin after the treatment was measured in the same manner as in 1) above, and the results are shown in Table 7.
  • the IgG fraction heat-treated at a protein concentration of 3 (w / v)% was adjusted to pH 8.0, and a commercially available ion exchanger filter paper (DE81, manufactured by Whatman Japan or P81) was used. And Whatman Japan Co., Ltd.) were added so that the wet weight was 3%, and the effect of removing the polymer fraction was examined. Compared to DEAE-cellulose (5% wet weight) treatment. The results are shown in Table 8. 03306
  • the IgG fraction heated at a protein concentration of 3 (w / v)% is adjusted to a protein concentration of 1 to 5 (w / v)% and a pH of 6.5 to 8.2 and allowed to stand.
  • isoelectric focusing was performed, and the effect of removing the polymer fraction was examined. Table 9 shows the results.
  • the IgG fraction heat-treated at a protein concentration of 3 (w / v)% was added to pH 5.5.
  • viruses that may be contaminated are inactivated and safety is further improved.
  • the other original properties can be maintained without being impaired, and a quality equal to or higher than the conventional level can be secured. Therefore, it is possible to provide immunoglobulin preparations that are safer than before and have the same usefulness to the clinical setting.

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Abstract

L'invention concerne un procédé de production d'une préparation d'immunoglobuline impliquant le chauffage d'une solution d'immunoglobuline, et a pour but de fournir un procédé simplifié, avec intervention d'agrégats en nombre réduit. En particulier, le procédé consiste, dans une première étape, à chauffer une solution aqueuse contenant de l'immunoglobuline, la concentration en protéine étant égale ou inférieure à 3 % (m/v), en présence d'une quantité égale ou supérieure à 10 % (m/v) d'un stabilisant à un pH de 5,2 ? 0,5 et à une conductivité de 0,01 à 1 mSi et, dans une seconde étape, à un pH de 7 à 9 et à une conductivité de 0,01 à 1 mSi, à effectuer une électrofocalisation et/ou un traitement échangeur anionique, le cas échéant, conjointement avec une étape de filtration, en utilisant une membrane poreuse de 1 à 100 nm de diamètre de pores moyen, et en ajustant le pH à 6 7.
PCT/JP2003/003306 2002-04-22 2003-03-19 Procede de production d'une preparation d'immunoglobuline Ceased WO2003088999A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003221431A AU2003221431A1 (en) 2002-04-22 2003-03-19 Process for producing immunogloblin preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2002-119654 2002-04-22
JP2002119654A JP2005320248A (ja) 2002-04-22 2002-04-22 免疫グロブリン製剤の製造方法

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WO2003088999A1 true WO2003088999A1 (fr) 2003-10-30

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AU (1) AU2003221431A1 (fr)
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1984000891A1 (fr) * 1982-08-30 1984-03-15 Baxter Travenol Lab Procede de fabrication de compositions contenant de la gamma globuline
JPS6042336A (ja) * 1983-08-18 1985-03-06 Nippon Seiyaku Kk 免疫グロブリンの製造方法
EP0253313A2 (fr) * 1986-07-09 1988-01-20 Green Cross Corporation Procédé pour le traitement par la chaleur de gamma-globuline chimiquement non modifiée
EP0278422A2 (fr) * 1987-02-06 1988-08-17 Green Cross Corporation Solutions de gamma-globulines injectables
WO1998003550A1 (fr) * 1996-07-18 1998-01-29 Csl Limited Pasteurisation de solutions d'immunoglobulines

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1984000891A1 (fr) * 1982-08-30 1984-03-15 Baxter Travenol Lab Procede de fabrication de compositions contenant de la gamma globuline
JPS6042336A (ja) * 1983-08-18 1985-03-06 Nippon Seiyaku Kk 免疫グロブリンの製造方法
EP0253313A2 (fr) * 1986-07-09 1988-01-20 Green Cross Corporation Procédé pour le traitement par la chaleur de gamma-globuline chimiquement non modifiée
EP0278422A2 (fr) * 1987-02-06 1988-08-17 Green Cross Corporation Solutions de gamma-globulines injectables
WO1998003550A1 (fr) * 1996-07-18 1998-01-29 Csl Limited Pasteurisation de solutions d'immunoglobulines

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TW200305436A (en) 2003-11-01
AU2003221431A1 (en) 2003-11-03

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