JPH07103045B2 - Method for heat treatment of non-chemically modified γ-globulin - Google Patents
Method for heat treatment of non-chemically modified γ-globulinInfo
- Publication number
- JPH07103045B2 JPH07103045B2 JP61204760A JP20476086A JPH07103045B2 JP H07103045 B2 JPH07103045 B2 JP H07103045B2 JP 61204760 A JP61204760 A JP 61204760A JP 20476086 A JP20476086 A JP 20476086A JP H07103045 B2 JPH07103045 B2 JP H07103045B2
- Authority
- JP
- Japan
- Prior art keywords
- globulin
- chemically modified
- heat treatment
- aqueous solution
- virus
- 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.)
- Expired - Lifetime
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Disinfection or sterilisation of materials or objects, in general; Accessories therefor
- A61L2/02—Disinfection or sterilisation of materials or objects, in general; Accessories therefor using physical processes
- A61L2/04—Heat
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2103/00—Materials or objects being the target of disinfection or sterilisation
- A61L2103/05—Living organisms or biological materials
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/827—Proteins from mammals or birds
- Y10S530/829—Blood
- Y10S530/83—Plasma; serum
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- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は、非化学修飾γ−グロブリン含有水溶液の加熱
処理方法に関する。TECHNICAL FIELD The present invention relates to a heat treatment method for a non-chemically modified γ-globulin-containing aqueous solution.
さらに詳しくは、非化学修飾γ−グロブリンに、特定の
安定化剤を添加し、加熱処理することによる重合体の増
加、抗補体価の上昇を認めず、かつ非化学修飾γ−グロ
ブリンの活性がそこなわれることのない非化学修飾γ−
グロブリン加熱処理方法に関する。More specifically, non-chemically modified γ-globulin is added with a specific stabilizer, and no increase in polymer and increase in anti-complement value are observed by heat treatment, and the activity of non-chemically modified γ-globulin is not observed. Is not chemically modified γ-
The present invention relates to a globulin heat treatment method.
血漿蛋白成分である非化学修飾免疫グロブリンのうち、
特にIgGを主成分とする非化学修飾γ−グロブリン製剤
は、これまで広く各種感染症の予防並びに治療に役立て
られてきたが、熱安定性に欠けること、多種ウイルス、
細菌等の抗体を広く含有している等の理由で加熱殺菌は
施されていない。Among non-chemically modified immunoglobulins that are plasma protein components,
In particular, non-chemically modified γ-globulin preparations containing IgG as a main component have been widely used for the prevention and treatment of various infectious diseases, but lack of heat stability, various viruses,
It is not heat-sterilized because it contains a wide range of antibodies such as bacteria.
しかし、非化学修飾γ−グロブリンを血漿蛋白の分画か
ら得る場合には、肺炎ウイルス等の夾雑ウイルスの混在
を100％否定することはできない。そのため、夾雑ウイ
ルスの不活化方法として加熱殺菌を施すことは充分意義
のあることである。However, when non-chemically modified γ-globulin is obtained from a fraction of plasma proteins, it is not possible to rule out 100% contamination of contaminating viruses such as pneumonia virus. Therefore, it is sufficiently significant to perform heat sterilization as a method for inactivating the contaminating virus.
しかし、通常の生理的食塩溶液等の水溶液中でこれを行
うと短時間で白濁し、大部分の活性を失い、蛋白分子が
変性してしまうという問題点がある。However, when this is performed in an aqueous solution such as a normal physiological saline solution, there is a problem in that it becomes cloudy in a short time, loses most of its activity, and denatures protein molecules.
本発明者らは、かかる問題点を解決するために種々検討
を重ね、非化学修飾γ−グロブリンを含有する水溶液に
対して、肝炎ウイルス、エイズウイルス等を不活化する
ための加熱処理を行うに際して、ソルビトールの存在
下、特定範囲のpHおよび低イオン強度下に調整すれば加
熱処理に対する非化学修飾γ−グロブリンの熱安定性が
著しく高まることを見出した。The present inventors have conducted various studies in order to solve such problems, and when performing heat treatment for inactivating hepatitis virus, AIDS virus, etc., on an aqueous solution containing non-chemically modified γ-globulin. , It was found that the thermostability of non-chemically modified γ-globulin against heat treatment is remarkably enhanced by adjusting the pH and low ionic strength in a specific range in the presence of sorbitol.
本発明は、上記の知見に基づいて完成されたものであ
り、その要旨は非化学修飾γ−グロブリン含有水溶液に
対して、ソルビトールの存在下、pH5〜６およびイオン
強度0.01以下の低イオン強度下で加熱処理をすることを
特徴とする非化学修飾γ−グロブリン含有水溶液の加熱
処理方法である。The present invention has been completed on the basis of the above findings, and its gist is in the presence of sorbitol in a non-chemically modified γ-globulin-containing aqueous solution under a low ionic strength of pH 5 to 6 and an ionic strength of 0.01 or less. Is a heat treatment method for a non-chemically modified γ-globulin-containing aqueous solution.
本発明の非化学修飾γ−グロブリンとは、 自然のままで何らの修飾や変化も受けておらず、従
ってγ−グロブリンのフラグメイトであるFab、Ｆ（a
b′）2、Fc等を含まず、 抗体価の低下がなく、同時に抗体スペクトルの低下
もなく、 抗補体作用（補体結合性）が日本国生物学的製剤基
準で安全とみなされる20単位（CH50値）よりも十分に低
い という諸性状を備えたものをいう。The non-chemically modified γ-globulin of the present invention is a natural γ-globulin that has not undergone any modification or alteration, and thus is a fragment of γ-globulin Fab, F (a).
b ′) 2 , Fc, etc. are not included, there is no decrease in antibody titer and no decrease in antibody spectrum, and anti-complement action (complement binding) is considered to be safe according to Japanese biologic standards 20 It has various properties that are sufficiently lower than the unit (CH50 value).
本発明において使用する非化学修飾γ−グロブリンは、
自然状態のものでしかも抗補体価の低いものであれば、
いかなる方法で得たものであってもよいが、既存の設備
で製造できる、既に医薬として使用されている節注用γ
−グロブリンを用い、酸性処理でその凝集体を切り離し
て得るのが最も効率的である。しかし製造上の複雑さや
収量の低下を問題としないならば、非イオン系界面活性
剤による方法で抗補体作用の原因となるγ−グロブリン
凝集体を除去し、抗補体価の低いγ−グロブリンとした
ものを使用することが好ましい。The non-chemically modified γ-globulin used in the present invention is
If it is in a natural state and has a low anti-complementary value,
It may be obtained by any method, but it can be produced with existing equipment and is already used as a medicine.
-It is most efficient to use globulin and to separate the aggregate by acidic treatment. However, if the complexity in production and the reduction in yield are not a problem, the γ-globulin aggregate which causes the anti-complement action is removed by a method using a nonionic surfactant, and γ- with a low anti-complement value is used. It is preferable to use a globulin.
本発明における非化学修飾γ−グロブリン水溶液として
は、非化学修飾γ−グロブリンを含む末精製な水溶液か
ら高度精製された水溶液までいかなる段階の非化学修飾
γ−グロブリン水溶液であってもよいが、有利には部分
精製または精製段階の水溶液が加熱処理の対象とされ
る。その蛋白質（非化学修飾γ−グロブリン）の含量は
0.1〜30％（w/v）のものが好ましいが、特に限定されな
い。また当該水溶液のpHは一般にpH4.5〜6.5であり、特
に適当な緩衝液によってpH5〜６に調整されていること
が好ましい。The non-chemically modified γ-globulin aqueous solution in the present invention may be a non-chemically modified γ-globulin aqueous solution at any stage from an unpurified aqueous solution containing the non-chemically modified γ-globulin to a highly purified aqueous solution. In this case, the aqueous solution in the partial purification or the purification step is subjected to heat treatment. The content of the protein (non-chemically modified γ-globulin) is
It is preferably 0.1 to 30% (w / v), but is not particularly limited. The pH of the aqueous solution is generally 4.5 to 6.5, and it is particularly preferable that the pH is adjusted to 5 to 6 with an appropriate buffer solution.
ソルビトールの添加量は非化学修飾γ−グロブリン水溶
液100ml当たり、一般に10〜70g、好ましくは30〜70g、
より好ましくは40〜60gである。The amount of sorbitol added is generally 10 to 70 g, preferably 30 to 70 g, per 100 ml of the non-chemically modified γ-globulin aqueous solution,
More preferably, it is 40 to 60 g.
加熱処理時のイオン強度は、低イオン強度であることが
好ましく、特に0.01以下、さらに好ましくは0.001以下
である。The ionic strength during the heat treatment is preferably low ionic strength, particularly 0.01 or less, and more preferably 0.001 or less.
加熱処理は、夾雑ウイルスを不活化するに十分な温度及
び時間行えばよく、具体的には50℃〜70℃、好ましくは
約60℃にて、10分〜20時間、好ましくは10時間行われ
る。The heat treatment may be carried out at a temperature and for a time sufficient to inactivate the contaminating virus, specifically at 50 ° C to 70 ° C, preferably at about 60 ° C, for 10 minutes to 20 hours, preferably 10 hours. .
本発明の加熱処理による効果を検討するため、非化学修
飾γ−グロブリン製剤に含まれる可能性が危惧される各
種ウイルスの感染性について、安化剤の添加による加熱
効果、安定化剤の無添加による加熱効果を実験した。こ
の実験は、非化学修飾γ−グロブリン試料に痘瘡ウイル
ス、おたふくかぜウイルス、はしかウイルス、水疱性口
内炎ウイルス、チクングニアイルス、ポリオウイルス、
コタサツキーウイルス、エコーウイルスを加え、60℃で
10時間の加熱処理を行い、経時的に残存するウイルス感
染性を測定したが、10時間後には安定化剤の添加、無添
加にかかわらず、感染性を完全に失っていた。この結果
は用いたウイルス以外のウイルスについても本発明の加
熱処理が施されるならば感染性は失活させうることを示
唆するものであり、また、数分間の加熱処理で感染性は
十分減少させうるものであることを示している。In order to examine the effect of the heat treatment of the present invention, regarding the infectivity of various viruses that may be contained in non-chemically modified γ-globulin preparations, the heating effect by the addition of a stabilizer and the addition of no stabilizer are The heating effect was tested. In this experiment, non-chemically modified γ-globulin samples were treated with variola virus, mumps virus, measles virus, vesicular stomatitis virus, chikungunya virus, poliovirus,
Add Kotasatsky virus and echo virus at 60 ℃
After heat treatment for 10 hours, the virus infectivity remaining with time was measured, but after 10 hours, the infectivity was completely lost regardless of the addition or non-addition of the stabilizer. This result suggests that the infectivity of viruses other than the used virus can be inactivated if the heat treatment of the present invention is applied, and the infectivity is sufficiently reduced by heat treatment for several minutes. It shows that it can be done.
上記加熱処理を行った後、外観、性状はもとより、重合
体の定量、抗補体価の測定、麻疹抗体価の測定および急
性毒性実験を行った。かくして、本発明方法を経たもの
は非化学修飾γ−グロブリン製剤として医療上極めて安
全性の高い、また、有効性の高いものであることが確認
された。After the above heat treatment, not only the appearance and properties but also the amount of the polymer, the anti-complement titer, the measles antibody titer and the acute toxicity experiment were conducted. Thus, it was confirmed that the non-chemically modified γ-globulin preparations that have undergone the method of the present invention are extremely safe in terms of medical treatment and highly effective.
かくして本発明の処理を受けた製剤は、溶液状であり、
粗製品を用いた場合は公知の精製法に準じてさらに処理
を行った後、必要ならば、透析、除菌濾過を行った後、
包装単位に従って500〜10,000mgの非化学修飾γ−グロ
ブリンを含むように分注される。当該製剤の貯蔵に際し
ては、高温を避ければ特に問題ではない。望ましくは、
30℃以下にて保存される。また、当該製剤は所望により
凍結乾燥製剤としてもよい。The formulation thus treated according to the invention is in solution,
When a crude product is used, after further treatment according to a known purification method, if necessary, after dialysis and sterile filtration,
Dispense to contain 500-10,000 mg of non-chemically modified gamma-globulin according to the packaging unit. There is no particular problem in the storage of the preparation as long as high temperature is avoided. Desirably,
Stored below 30 ℃. Further, the formulation may be a freeze-dried formulation, if desired.
当該処理を経た非化学修飾γ−グロブリンは、そのま
ま、または自体公知の製剤化処理を行って、例えば注射
用蒸留水で希釈または溶解して投与される。投与量は、
通常、成人に対しては、１回に非化学修飾γ−グロブリ
ンとして2500〜5000mg量、小児に対しては、１回に非化
学修飾γ−グロブリンとして100〜150mg/kg体重が使用
される。The non-chemically modified γ-globulin that has undergone the treatment is administered as it is or after it is subjected to a formulation treatment known per se, for example, diluted or dissolved with distilled water for injection. The dosage is
Usually, 2500 to 5000 mg of non-chemically modified γ-globulin is used once for an adult, and 100 to 150 mg / kg of body weight of non-chemically modified γ-globulin is used once for a child.
本発明の加熱処理を経た非化学修飾γ−グロブリンは、
たとえば肝炎ウイルス、エイズウスルス等のウイルスが
実質的に不活化されており、かつ非化学修飾γ−グロブ
リンは高活性で存在するので、本発明の処理を経た非化
学修飾γ−グロブリンの使用によってウイルスによる感
染の可能性が極めて少ない。The non-chemically modified γ-globulin that has undergone the heat treatment of the present invention is
For example, since viruses such as hepatitis virus and AIDS-Urus are substantially inactivated, and the non-chemically modified γ-globulin is highly active, the use of the non-chemically modified γ-globulin treated by the present invention causes Very unlikely to be infected.
また、本発明の処理を経た非化学修飾γ−グロブリン
は、水に対する溶解性に優れており、水溶解物の溶状が
良好に保たれ、さらに高分子型の生成が抑制され、かつ
抗補体価の上昇が抑制されており、静脈投与製剤用の処
理法として好適である。Further, the non-chemically modified γ-globulin that has been subjected to the treatment of the present invention has excellent solubility in water, the solubility of the water-dissolved product is kept good, the generation of the polymer form is suppressed, and the anti-complement Since the increase in valency is suppressed, it is suitable as a treatment method for intravenous preparations.
以下の実施例において、試験は次の方法によって行っ
た。In the following examples, the test was conducted by the following method.
（試験方法） 外観性状としては、濁りが問題となることからO.D600nm
の吸光度を測定した。(Test method) As for appearance, turbidity is a problem, so OD 600 nm
The absorbance of was measured.
重合体の定量は高速液体クロマトグラフィーで分析し
た。The quantification of the polymer was analyzed by high performance liquid chromatography.
抗補体価の測定は、カパットとマイヤーの方法〔Experi
mental Immunochemistry,225（1961）〕および西岡、岡
田の方法〔免疫の生化学、103、昭46（共立出版）〕に
準じた。即ち、100単位の補体が試料を加えることによ
って何単位に減少するかを測定し、その減少単位を抗補
体価として表わした。The anti-complement value is measured by Kapat and Meyer's method [Experiment
mental Immunochemistry, 225 (1961)] and the method of Nishioka and Okada [Immune Biochemistry, 103, Sho 46 (Kyoritsu Shuppan)]. That is, it was measured how many units 100 units of complement were reduced by adding a sample, and the reduction unit was expressed as an anti-complement number.
麻疹抗体価はHemagglutination Inhibition Test法によ
り測定し、国際単位（IU/150mg）で表わした。The measles antibody titer was measured by the Hemagglutination Inhibition Test method and expressed in international units (IU / 150 mg).
実施例１ コーン画分II＋III 1kgに0.001Mの塩化ナトリウム溶液1
0lを加え、pHを5.0に調整した後、PEG＃4000を終濃度が
８％になるように添加し、２℃で遠心分離を行った。Example 1 1 kg of Cohn Fraction II + III 0.001 M sodium chloride solution 1
0 l was added to adjust the pH to 5.0, PEG # 4000 was added so that the final concentration was 8%, and the mixture was centrifuged at 2 ° C.
得られた上清を1N−水酸化ナトリウムを用いてpHを8.0
とした後、PEG＃4000を終濃度が12％になるように加
え、２℃で遠心分離を行い、IgG画分を集めた。The pH of the obtained supernatant was adjusted to 8.0 with 1N sodium hydroxide.
After that, PEG # 4000 was added so that the final concentration was 12%, centrifugation was performed at 2 ° C., and IgG fractions were collected.
このIgG画分を、水を用いIgG濃度が７％になるように溶
解せしめ、pHを6,5に調整した。この溶液をDEAE−セフ
ァデックス（その1ml当たり50ml溶液量）で０〜４℃の
条件下約１時間接触処理し、処理後上清を遠心分離で回
収した。This IgG fraction was dissolved in water so that the IgG concentration was 7%, and the pH was adjusted to 6.5. This solution was contact-treated with DEAE-Sephadex (50 ml solution volume per 1 ml) at 0 to 4 ° C. for about 1 hour, and the supernatant after the treatment was collected by centrifugation.
このIgG溶液100mlを別途調整したベンズアミジンセファ
ロース（登録商標、ファルマシア社製）カラム5mlおよ
びヒト血液型物質フォルミルセルロファインカラム3ml
を通過させ血液型抗体を吸着除去した。この工程での吸
着により血液型抗体（1:32）から（1:2）に低下した。Benzamidine Sepharose (registered trademark, manufactured by Pharmacia) column 5 ml and human blood group substance formyl cellulofine column 3 ml prepared by separately preparing 100 ml of this IgG solution
To remove the blood group antibody by adsorption. The blood group antibody (1:32) decreased to (1: 2) due to adsorption in this step.
この未吸着画分（非化学修飾γ−グロブリン）を５％濃
度に調整し、安定化剤ソルビトールを20％濃度（γ−グ
ロブリン溶液100mlに対しソルビトールを20g加えたも
の）に添加後、60℃、１時間の加熱処理を行い、溶液の
濁り、重合体の定量及び抗補体価を調べた。この結果、
イオン強度を０〜0.01、特に0.001以下に調整し、安定
化剤を添加し、PHを4.5〜6.5、特に５〜６に調整するこ
とによって非化学修飾γ−グロブリンの加熱安定性は増
大した（表１）。This non-adsorbed fraction (non-chemically modified γ-globulin) was adjusted to a concentration of 5%, and the stabilizer sorbitol was added to a concentration of 20% (100 ml of the γ-globulin solution to which 20 g of sorbitol was added). After heat treatment for 1 hour, turbidity of the solution, quantification of polymer and anti-complement number were examined. As a result,
The thermal stability of non-chemically modified γ-globulin was increased by adjusting the ionic strength to 0 to 0.01, particularly 0.001 or less, adding a stabilizer and adjusting PH to 4.5 to 6.5, especially 5 to 6 ( Table 1).
実施例２ 実施例１で得た非化学修飾γ−グロブリン溶液、即ち未
吸着画分に各種濃度にソルビトールを添加、非化学修飾
γ−グロブリン濃度を５％に調整したものにつき60℃加
熱処理を行い、重合体定量、抗補体価、麻疹抗体価等の
測定を行い、その結果を表２に示した。Example 2 The non-chemically modified γ-globulin solution obtained in Example 1, that is, the non-adsorbed fraction to which sorbitol was added at various concentrations, and the non-chemically modified γ-globulin concentration was adjusted to 5%, was subjected to heat treatment at 60 ° C. The amount of polymer, anti-complement value, measles antibody value, etc. were measured, and the results are shown in Table 2.
ソルビトールを10g/dlしか含まない系は、pH値によって
は１時間以内に白濁し、変性、重合体の生成、抗補体価
の上昇を示していることが見られるのに対し、ソルビト
ールを15g/dl加えた系は、非化学修飾γ−グロブリンの
安定性が高まった（表２）。A system containing only 10 g / dl of sorbitol was found to become cloudy within 1 hour depending on the pH value, showing denaturation, formation of a polymer, and an increase in anti-complement number, whereas sorbitol contained 15 g / dl. The system with / dl increased the stability of non-chemically modified γ-globulin (Table 2).
実施例１ 安全性試験として急性毒性実験を行った。Example 1 An acute toxicity experiment was conducted as a safety test.
実施例１において、pH5.0で60℃、１時間加熱処理を施
したサンプルにつき、無菌生理的食塩水で十分透析した
後、マウスの尾静脈から１匹当たり総量0.5mlおよび1.0
mlをそれぞれ１群５匹に投与し、７日間観察したが、異
常は認められなかった。The sample heat-treated at pH 5.0 at 60 ° C. for 1 hour in Example 1 was thoroughly dialyzed against sterile physiological saline, and then 0.5 ml and 1.0 per mouse from the tail vein of the mouse.
5 ml of each group was administered and observed for 7 days, but no abnormality was observed.
───────────────────────────────────────────────────── フロントページの続き (56)参考文献 特開 昭51−118825（ＪＰ，Ａ) 特開 昭55−3721（ＪＰ，Ａ) 特開 昭56−139422（ＪＰ，Ａ) 特開 昭58−43914（ＪＰ，Ａ) Ｔｈｅ Ｌａｎｃｅｔ，Ｎｏｖｅｍｂｅ ｒ 19，1983 Ｐ．1198〜1199 ─────────────────────────────────────────────────── ─── Continuation of front page (56) Reference JP-A-51-118825 (JP, A) JP-A-55-3721 (JP, A) JP-A-56-139422 (JP, A) JP-A-58- 43914 (JP, A) The Lancet, November 19, 1983 P.M. 1198 ~ 1199
Claims (4)
して、ソルビトールの存在下、pH5〜６およびイオン強
度0.01以下の低イオン強度下で加熱処理をすることを特
徴とする非化学修飾γ−グロブリン含有水溶液の加熱処
理方法。1. A non-chemically modified γ-globulin characterized by heat-treating an aqueous solution containing a non-chemically modified γ-globulin in the presence of sorbitol at a low ionic strength of pH 5 to 6 and an ionic strength of 0.01 or less. Method for heat treatment of aqueous solution containing globulin.
グロブリン含有水溶液100ml当たり、10〜70gである特許
請求の範囲第（１）項記載の加熱処理方法。2. The amount of sorbitol added is non-chemically modified γ-
The heat treatment method according to claim (1), wherein the amount is 10 to 70 g per 100 ml of the globulin-containing aqueous solution.
範囲第（１）項記載の加熱処理方法。3. The heat treatment method according to claim 1, wherein the ionic strength is 0.001 or less.
ある特許請求の範囲第（１）項記載の加熱処理方法。4. The heat treatment method according to claim 1, wherein the heat treatment is a treatment at about 60 ° C. for 10 minutes to 20 hours.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000541146A CA1310267C (en) | 1986-07-09 | 1987-07-02 | Process for heat treating chemically unmodified _-globulin |
| KR1019870007233A KR960015104B1 (en) | 1986-07-09 | 1987-07-07 | How to heat treat chemically unmodified γ-globulin |
| ES198787109927T ES2034999T3 (en) | 1986-07-09 | 1987-07-09 | PROCEDURE FOR THERMAL TREATMENT OF GAMMA-GLOBULIN CHEMICALLY NOT MODIFIED. |
| US07/071,685 US4845199A (en) | 1986-07-09 | 1987-07-09 | Process for heat treating chemically unmodified gamma-globulin |
| DE8787109927T DE3781962T2 (en) | 1986-07-09 | 1987-07-09 | METHOD FOR HEATING TREATMENT OF CHEMICALLY UNMODIFIED GAMMA GLOBULIN. |
| EP87109927A EP0253313B1 (en) | 1986-07-09 | 1987-07-09 | Process for heat treating chemically unmodified gamma-globulin |
| KR1019970034234A KR100263005B1 (en) | 1986-07-09 | 1997-07-18 | Chemically unmodified ñ -globulin preparation |
| KR1019990064500A KR100276155B1 (en) | 1986-07-09 | 1999-12-29 | Chemically unmodified γ-globulin preparation |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16158986 | 1986-07-09 | ||
| JP61-161589 | 1986-07-09 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63146832A JPS63146832A (en) | 1988-06-18 |
| JPH07103045B2 true JPH07103045B2 (en) | 1995-11-08 |
Family
ID=15738004
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61204760A Expired - Lifetime JPH07103045B2 (en) | 1986-07-09 | 1986-08-30 | Method for heat treatment of non-chemically modified γ-globulin |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPH07103045B2 (en) |
| KR (1) | KR960015104B1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2547556B2 (en) * | 1987-02-06 | 1996-10-23 | 株式会社 ミドリ十字 | Liquid formulation of r-globulin |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5840532B2 (en) * | 1975-04-08 | 1983-09-06 | カブシキガイシヤ ミドリジユウジ | IGA Oyobi IGM Nonetsu Antei Kahou |
| JPS553721A (en) * | 1978-06-21 | 1980-01-11 | Morinaga Milk Ind Co Ltd | Production of powder of colostrum |
| EP0035204B2 (en) * | 1980-03-05 | 1991-05-22 | Miles Inc. | Pasteurized therapeutically active protein compositions |
| US4396608A (en) * | 1981-08-24 | 1983-08-02 | Cutter Laboratories | Intravenously injectable immune serum globulin |
-
1986
- 1986-08-30 JP JP61204760A patent/JPH07103045B2/en not_active Expired - Lifetime
-
1987
- 1987-07-07 KR KR1019870007233A patent/KR960015104B1/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| ＴｈｅＬａｎｃｅｔ，Ｎｏｖｅｍｂｅｒ１９，１９８３Ｐ．１１９８〜１１９９ |
Also Published As
| Publication number | Publication date |
|---|---|
| KR880001298A (en) | 1988-04-22 |
| JPS63146832A (en) | 1988-06-18 |
| KR960015104B1 (en) | 1996-10-28 |
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