Japan Chemical Research Co., Ltd.

Jcr Pharmaceuticals Co., Ltd.

Noda Shokukin Kogyo Co., Ltd.

Ajinomoto Co., Ltd.

Zeria-shinyaku Kogyo Kabushiki Kaisha

Hajime Hiratani

Koichiro Nakanishi

Yoshikazu Yuki

Toyohiko Nishimura

Kazuo Kato

Junichi Koga

Naomi Uchida

Yasuhiro Ohashi

Kenji Takezawa

Koji Sasaki

Hiroshi Sato

Mitsuo Shimizu

Hiroshi Matsumoto

Hiroyuki Shirono

Tetsuyuki Kitamoto

Akio Matsuo

Kaname Takagi

Satoshi Nishimuro

Masaichi Ota

Motoko Baba

Jun Tateishi

Yoshiyuki Nakano

A modified superoxide dismutase represented by the formula: ##STR1## (wherein R is as defined below; SOD is a residue of superoxide dismutase) is produced, in a shortened period of reaction with a high and constant modification ratio, by reacting a polymeric carbonyldiimidazole derivative represented by the formula: ##STR2## (wherein R is a residue of a water soluble polymer having an average molecular weight of about 2,000 to 10,000) with superoxide dismutase in the presence of a buffer having a pH of 9.0 to 11.0 and a concentration of 0.1 M to 0.5 M, preferably 0.2 M to 0.4 M, at a temperature of 30.degree. to 70.degree. C., preferably 45.degree. to 60.degree. C. The modified superoxide dismutase thus produced exhibits a suitably prolonged blood half-life.

Process of producing modified superoxide dismutase

Secretory immunoglobulin A preparations substantially not containing virus are produced by a process wherein secretory immunoglobulin A which might be contaminated with viruses is (1) heated about 60.degree. C. for about 10 hours, or (2) subjected to the reaction with tri-n-butyl phosphate and a surfactant and the heating as mentioned above, as liquidized form in an aqueous medium, and then polymerized matters are precipitated from the resulting solution by adding polyethyleneglycol thereto.

Process for producing secretory immunoglobulin A preparations

There are provided thrombolytic agents suited for oral administration. The agent comprises a proteolytic enzyme of subtilisin family, such as subtilisin BPN', subtilisin Carsberg, subtilisin amylosacchariticus, etc., produced by microorganisms belonging to genus Bacillus, such as Bacillus subtilis, Bacillus licheniformis, Bacillus amyloliquefaciens, etc. and, even when administered orally, exhibits thrombolytic activity.

Subtilisin as an oral thrombolytic agent

LEM which is an aqueous extract of a mycelial culture of Lentinus Edodes and has a sugar composition composed of arabinose, xylose, glucose, mannose, galasctose, fucose and rhamnose, as well as a fraction of LEM which corresponds to molecular weights of 10,000 to 1,000,000 daltons and has a sugar composition composed of arabinose, xylose, glucose, mannose and galactose are provided as agents for inhibiting the adsorption of herpesviruses such as herpes simplex to the cells.

Inhibitor of herpesvirus absorption

An inhibitor of the proliferation of herpesviruses and of the recurrence of affections caused by their latent infection, which is an active material obtained by fractional purification of the aqueous extract from cultured Lentinus edodes mycelia.

Inhibitor of the proliferation of herpes viruses and inhibitor of the

Antiserum which can recognize all subtypes of human leukocyte interferon is prepared from the blood of an animal immunized with partially purified human leukocyte interferon obtained from a culture of human leukocyte stimulated with Sendai virus. The antiserum is added to a column whereon concentrated culture broth of human leukocyte has been immobilized to adsorb impurities, the effluent is added to a column whereon partially purified human leukocyte interferon has been immobilized to adsorb anti-human leukocyte interferon antibody and then the antibody is eluted from the column. The antibody thus obtained recognizes all subtypes of human leukocyte interferon and can be separated by a chromatography to each monoclonal antibody which recognizes a single subtype. Employing these antibodies, the subtypes of human leukocyte interferon or their antibodies in a sample can be analized or assayed.

Method of assaying or analyzing subtypes of human leukocyte interferons

A membrane filter of 0.025 to 0.05 .mu. in pore size is treated by passing the solution of a water-soluble high molecular substance such as albumin, dextran, polyvinylpyrrolidone, polysorbate 80, gelatin or the like through the membrane filter. Employing the filter thus treated, the solution of a physiologically active substance of human origin such as human growth hormone, kallikrein, trypsin inhibitor, epidermal growth factor, leucocyte interferon etc. is filtered at high recovery rate of the active substance avoiding the adsorption of the active substance onto the filter. By the filtration, harmful viruses such as Creutzfeldt-Jacob disease pathogen which may exist in the physiologically active substance can be removed.

Process for removal of viruses from solutions of physiologically active

The thermal degradation of urokinase in an aqueous solution is suppressed by heating an aqueous solution containing urokinase in the presence of citric acid or a water-soluble salt thereof such as sodium, potassium or lithium citrate at about 60.degree. C. for about 10 hours.

Method of suppressing the thermal degradation of urokinase

Two components, trypsin and kallidinogenase, in human urine are concentrated simultaneously by allowing human urine at neutral pH, collecting bubbles thus formed to obtain the concentrate of the two components, adjusting the concentrate to weak acidity, contacting the acidified concentrate with chitosan to allow the two components to be adsorbed onto chitosan, eluting the components from the adsorbent with aqueous ammonia solution, and neutralizing and heating the eluate at about 60.degree. C. for about 10 hours to make the eluate virus-free, followed by separating the components from the eluate.

Process for concentrating and separating trypsin inhibitor and

A tumor cytostatic-cytocidal factor is produced by disrupting platelets, extracting the disrupted platelets with an acidic aqueous solution or an acidic water-organic solvent mixture, and, after gel filtration, if desired, to separate a fraction having an estimated molecular weight of 10,000 to 20,000 and having tumor cell growth inhibiting activity, subjecting said extract or said fraction to chromatography to isolate a cytostatic fraction having a molecular weight of 10,000 to 20,000 and an isoelectric point of 9.0 to 10.0, giving a positive nihidrin reaction and being such that it is deactivated by trypsin but not deactivated by heating in physiological saline solution at 60.degree. C. for 30 minutes or contacting at room temperature with 0.2N hydrochloric acid for 60 minutes or 70% formic acid for 30 minutes.

Tumor cytostatic-citocidal factor from blood platelets

Crude HCG is purified by extracting with a neutral or weakly basic aqueous solution containing lower aliphatic alcohol and soluble salt, adding lower aliphatic alcohol to the extracted solution to form precipitates and the precipitates containing high purity of HCG are collected. This precipitates can be further purified by dissolving in a buffer solution, contacting the solution with a weak anion exchanger and eluting the exchanger with said buffer solution containing added salt.

Process for producing highly purified HCG

A composition wherein a physiologically active polypeptide or a glycoprotein of human origin, for instance, urokinase, kallikrein or leukocyte interferon, is coupled to a polyoxyethylene-polyoxypropylene copolymer. The composition is effective in the human body for a prolonged period of time.

Long-acting composition

A method for producing a human epidermal growth factor in high yield and high purity by adding particles of an aluminum or magnesium silicate of the formula z.2 (or 6) SiO.sub.2.xH.sub.2 O where Z is Al.sub.2 O.sub.3 or 2MgO and x is the number of water molecules in each molecule of the compound, to human urine under neutral to acid conditions to adsorb the factor on the particles and then eluting the factor with an alkaline solution.

Method of producing human epidermal growth factor

Human urinary kallikrein is concentrated and purified by the following procedures; (a) Human urine is contacted with chitosan, a high molecular agglutinant obtained from chitin, at a pH from 4.0 to 7.0, thereby kallikrein is adsorbed on the chitosan and (b) kallikrein is eluted from the chitosan with an aqueous alkaline solution having a pH from 8.0 to 12.0.

Process for concentrating and purifying human urinary kallikrein

Human urine kallikrein dissolved in water is made heat-stable by the addition of a citric acid salt such as sodium citrate, so that an aqueous solution containing the kallikrein and the citric acid salt can be sterilized at 60.degree. to 70.degree. C.

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Sennan, Japan

Hajime Hiratani