CS239838B1 - A method of producing human immunoglobulins for intravenous administration - Google Patents

A method of producing human immunoglobulins for intravenous administration Download PDF

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CS239838B1
CS239838B1 CS844767A CS476784A CS239838B1 CS 239838 B1 CS239838 B1 CS 239838B1 CS 844767 A CS844767 A CS 844767A CS 476784 A CS476784 A CS 476784A CS 239838 B1 CS239838 B1 CS 239838B1
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Czechoslovakia
Prior art keywords
maltose
immunoglobulins
intravenous administration
pepsin
human immunoglobulins
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CS844767A
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Czech (cs)
Slovak (sk)
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CS476784A1 (en
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Imrich Banda
Jozef Bulik
Alfred Stachy
Jozef Andrasina
Anton Lucansky
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Imrich Banda
Jozef Bulik
Alfred Stachy
Jozef Andrasina
Anton Lucansky
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Priority to CS844767A priority Critical patent/CS239838B1/en
Publication of CS476784A1 publication Critical patent/CS476784A1/en
Publication of CS239838B1 publication Critical patent/CS239838B1/en

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Abstract

Sposob přípravy 1'udských .imunoglobulínov pre intravenóznu aplikáeiu, pri ktorom antikomplementárna aktivita a hypotenzívny účinok imunoglobulínov sa znižuje inkubáclou pri teplote -f-37 CC a kyslom pH za přítomnosti pepsínu v prostředí maltózy. Maltóza má antiagregačný a stabilizačný účinok na 1'udskě bielkoviny, čím zabraňuje nežiadúcim štrukturálnym změnám imunoglobulínov. Přítomnost maltózy tiež priaznivo vplýva na rýchlosť rozpúšťania botového výrobku. Podstata spósobu výroby 1'udských imunoglobulínov- pre intravenóznu aplikáeiu spočívá v -tom, že imunoglobulíny získané etanolovou frakcionáciou sa v prostředí 0,1 až 5 % maltózy pri pH 3,8 až 4,2 a teplote -j-37 stupňov C inkubuje za přítomnosti pepsínu po dobu 18 až 25 hodin. Nízkomolekulárne látky sa odstraňujú dialýzou oproti 0,1 až 5 % roztoku maltózy. Dialyzát po- nastavení příslušných p-arametrov sa sterilizuje filtráciou, rožplňuje a lyofilizuje.A method of preparing human immunoglobulins for intravenous administration, in which the anticomplementary activity and hypotensive effect of immunoglobulins is reduced by incubation at a temperature of -f-37 CC and an acidic pH in the presence of pepsin in a maltose environment. Maltose has an antiaggregatory and stabilizing effect on human proteins, thereby preventing undesirable structural changes in immunoglobulins. The presence of maltose also favorably affects the dissolution rate of the finished product. The essence of the method of producing human immunoglobulins for intravenous administration consists in that immunoglobulins obtained by ethanol fractionation are incubated in a medium of 0.1 to 5% maltose at a pH of 3.8 to 4.2 and a temperature of -j-37 degrees C in the presence of pepsin for 18 to 25 hours. Low molecular weight substances are removed by dialysis against a 0.1 to 5% maltose solution. The dialysate, after adjusting the appropriate p-parameters, is sterilized by filtration, diluted and lyophilized.

Description

Vynález sa .lýka, sposobu, přípravy Iudských .iinunoglolj ulili ov pre imtravenóznu aplikáciu, pří ktorom ša dosiahne zníženie antikomplěmentárnej aktivity a hypotenzívneho účinku imunoglobulínov. V súčasnej době imunoglobulíiny používané k liíntravenéznej aplikácii sa u nás pripravujú tým spůsobom, že z imunoglobulínov izolovaných etanolovou frakcionáciou sa odstraňujú látky s antikomplementárnou aktivitou a hypoteinzívnym účinkom, buď dialýzou pomocou dialyzačných čriev (Štěpánek I.: AO 202 180 a AO 208 86Š), alebo pomocou ultrafiltračného zariadenia s definovanými velkosťami pórov.The invention is directed to the preparation of human immunoglobulins for intravenous administration, whereby the reduction of anticomplex activity and the hypotensive effect of immunoglobulins can be achieved. Nowadays, immunoglobulins used in the L-application are prepared by removing from the immunoglobulins isolated by ethanol fractionation substances with anti-complementary activity and hypotensive activity, either by dialysis using dialysis gut (Stepan I .: AO 202 180 and AO 208 86), or by means of an ultrafiltration device with defined pore sizes.

Nedostatkom takto připraveného výrobku je dlhá doba rozpustnosti a možnosť reagregácie molekúl imunoglobulínov v priebehu technologického postupu, resp. počas skladovania. V zahraničí ,k přípravě imunoglobulínov pre intravenóznu aplikáciu sa používajú technologické postupy štiepenia imunoglobulínov pepsínom (Koch F.: Dtsch. med. Wschr. 88 : 282,, 1963, Schultz Η. E., Schwick. G.: Dtsch. med. Wschr. 87 :1643, 19o2j, popřípadě opíacovaním imuhoglohulínoy, inkubáciou pri kyslom pH za přítomnosti pepslnu (Barandun S., Kistler P., Jeunet F., Istiker H.: Vox Sang. 7, 1962, str. 157 ,až 174).The drawback of the thus prepared product is the long solubility time and the possibility of re-aggregation of immunoglobulin molecules during the technological process, respectively. during storage. Abroad, for the preparation of immunoglobulins for intravenous administration, pepsin (Koch F .: Dtsch. Med. Wschr. 88: 282, 1963, Schultz. E., Schwick. G .: Dtsch. Med. Wschr. 87: 1643, 19o2j, optionally by washing with immunoglobulin, by incubation at acidic pH in the presence of pepsin (Barandun S., Kistler P., Jeunet F., Istiker H .: Vox Sang. 7, 1962, pages 157-174).

Nedostatkom takto vyrobených prípravkov sú změněné biologické vlastnosti, ako schopnost opsonizácie a iné biologické aktivity.The drawbacks of the formulations thus produced are altered biological properties, such as the ability of opsonization and other biological activities.

Podstata nového- sposobu přípravy ludských imunoglobulínov pre intravenóznu , aplikáciu spočívá v tom, že 5 až 8 % roztok ’ iihunoglobulínov o-bsahujúci 0,1 -až 5 o/o mal•tózy pri pH 3,8 až 4,2 a teplote 36 až 38 °C sa inkubuje za přítomnosti pepsínu po dobu 18 až 26 hodin. Po ukončení inkubácie pH rožtofcu sa upravuje na hodnotu 6,8 až 7,0 a potom sa roztok dialyzuje oproti 0,1 ažThe nature of the novel process for the preparation of human immunoglobulins for intravenous administration is that a 5-8% solution of immunoglobulins containing 0.1 to 5% o / o maltose at a pH of 3.8 to 4.2 and a temperature of 36 ° C. to 38 ° C is incubated in the presence of pepsin for 18-26 hours. After the pH incubation is completed, the pH is adjusted to 6.8-7.0 and then the solution is dialysed against 0.1 to 0.1%.

Hodhoténie kvality výrobku Stanovené parametre vzhlad rozpustnost antikom. aktivita hypotenzívny účinok (pokles tlaku) Výrobok připravený stavajúcou techn-ol. mierna opalesce-ncia 30‘ 0,71 j/mg bielk. —5,0 % 0,0-0,1 5 % roztoku maltózy, Dlalyzát po nastavení, příslušných parametrov sa,,filtru je ,cez; bakteriologické filtre, rozplňujé, namrazuje ,a lyofilizuje.Product Quality Implications Specified parameters for solubility by antique. activity hypotensive effect (pressure drop) Product prepared by technol. slight opalescence 30 ‘0.71 j / mg white. -5.0% 0.0-0.1 5% maltose solution; bacteriological filters, fill, freeze, and lyophilize.

Navrhnutý sposob přípravy ludských imunoglobulínov pre intravenóznu aplikáciu odstraňuje nežiaduce vlastnosti imunoglobulínov, pričom pri technolo-gickom postupe sa dbá o. to, -aby v čo najmenšej miere .bola narušená štruktúra imunoglobulínov. Příklad 1 K 100 ml 5 až 8 % roztoku imunoglobulínov obsahujúcich 1,5 % maltózy, ktorých pH sa upraví na hodnotu 3,8 až 4,2, přidá sa 50 miligr-amov pepsínu -o účinnosti 1 : 110 000 a potom sa inkubuje pri teplote. -)-37 °C po dobu 25 hodíp. Po skončení inkubácie pH roztoku sa upraví na hodnotu 6,8 a diallyzuje oproti 0,1 až 5 % roztoku maltózy pri teplotě -)-4 °C po dobu 12 až 48 hodin. Po úpravě obsahu bielkovín na hodnotu 4,5 až 5,5 % sa roztok imunoglobulínov filtruje cez bakteriologické filtre, rozplňujé, namr-azuje a lyofilizuje. P r i k 1 a d 2 K 100 ml 5 až 8 % roztoku imunoglobulínov obsahujúcich 1,0 % maltózy, ktorých pil sa upraví na hodnotu 3,8 až 4,2, přidá sa 50 mg pepsínu o účinnosti 1 : 10 000 a potom sa inkubuje pri teplote -j-37 °C po dobu 18 hcidín. Po -skončení inkubácie sa pH roztoku upraví na hodnotu 6,8 a di-alyzuje oproti 0,1 až 5 % roztoku maltózy pri teplote +4 °C po dobu 12 až 48 hodin. Po úpravě % bielkovín na hodnotu 4,5 až 5,5 sa rozltok imunoglobulínov filtruje cez bakteriologické filtre, rozplňujé, namrazuje a lyofilizuje.The proposed method for the preparation of human immunoglobulins for intravenous administration removes the undesirable properties of immunoglobulins while ensuring that the structure of immunoglobulins is impaired in the process. Example 1 To 100 ml of a 5-8% solution of immunoglobulins containing 1.5% maltose, the pH of which is adjusted to 3.8 to 4.2, 50 milligrams of pepsin-1: 110,000 efficacy is added and then incubated at temperature. -) - 37 ° C for 25 hours. After incubation, the pH of the solution is adjusted to 6.8 and diallysed against 0.1-5% maltose solution at -40 ° C for 12-48 hours. After adjusting the protein content to 4.5-5.5%, the immunoglobulin solution is filtered through bacteriological filters, filled, squashed and lyophilized. Example 1 To 100 ml of a 5 to 8% solution of immunoglobulins containing 1.0% maltose to which the pH is adjusted to 3.8 to 4.2, 50 mg of pepsin having an efficacy of 1: 10,000 are added and then incubated. at -j-37 ° C for 18 hours. Upon completion of the incubation, the pH of the solution is adjusted to 6.8 and dialyzed against 0.1 to 5% maltose solution at + 4 ° C for 12 to 48 hours. After adjusting the protein% to 4.5-5.5, the immunoglobulin spillage is filtered through bacteriological filters, filled, frozen and lyophilized.

Výrobok připravený podlá PV čirý .· 2‘ 0,08 j/mg bielk. . 0,0 0,0 0,0Product prepared by PV clear. · 2 ‘0.08 / / mg white. . 0.0 0.0 0.0

Claims (2)

PREDMETSUBJECT 1. Sposob výroby ludských imunoglobulínov pre intravenóznu aplikáciu vyznáčujúci sa tým, že 5 až 8 % rozltok imunoglobulínov získaný etanolovou frakcionáciou sa v prostředí 0,1 až 5 % maltózy za přítomnostiA process for the production of human immunoglobulins for intravenous administration, characterized in that a 5 to 8% immunoglobulin solution obtained by ethanol fractionation is in the presence of 0.1 to 5% maltose in the presence of VYNALEZU pepsínu pri kyslom pH inkubuje pri teplote 36 až 38 )°C po dobu 18 až 25 Hodin.OF THE INVENTION pepsin at acid pH incubates at 36-38 ° C for 18-25 hours. 2. Sposob podlá bodu í,’ 'vyznáčujúci sa tým, že roztok imunoglobulínov p-o ínkubacii sa dialyzuje oproti 0,1 až 5 % roztoku maltózy po dobu 12 až 48 hodin.2. The method according to claim 1, characterized in that the immunoglobulin solution by β-incubation is dialyzed against a 0.1 to 5% maltose solution for 12 to 48 hours.
CS844767A 1984-06-22 1984-06-22 A method of producing human immunoglobulins for intravenous administration CS239838B1 (en)

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