JPH0651641B2 - Gamma interferon composition - Google Patents
Gamma interferon compositionInfo
- Publication number
- JPH0651641B2 JPH0651641B2 JP58157560A JP15756083A JPH0651641B2 JP H0651641 B2 JPH0651641 B2 JP H0651641B2 JP 58157560 A JP58157560 A JP 58157560A JP 15756083 A JP15756083 A JP 15756083A JP H0651641 B2 JPH0651641 B2 JP H0651641B2
- Authority
- JP
- Japan
- Prior art keywords
- ifn
- freeze
- units
- drying
- gamma interferon
- 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
Links
- 108010074328 Interferon-gamma Proteins 0.000 title claims description 41
- 239000000203 mixture Substances 0.000 title claims description 11
- 102000008070 Interferon-gamma Human genes 0.000 title claims description 6
- 229940044627 gamma-interferon Drugs 0.000 title claims description 6
- 150000001720 carbohydrates Chemical class 0.000 claims description 10
- 235000000346 sugar Nutrition 0.000 claims description 4
- 150000002016 disaccharides Chemical class 0.000 claims description 3
- 150000002772 monosaccharides Chemical class 0.000 claims description 3
- 150000008163 sugars Chemical class 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 2
- 102100037850 Interferon gamma Human genes 0.000 description 35
- 239000000243 solution Substances 0.000 description 13
- 238000004108 freeze drying Methods 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 210000000265 leukocyte Anatomy 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 3
- 229930091371 Fructose Natural products 0.000 description 3
- 239000005715 Fructose Substances 0.000 description 3
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 3
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 229930182830 galactose Natural products 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000000087 stabilizing effect Effects 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 229920002684 Sepharose Polymers 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000013329 compounding Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000012812 general test Methods 0.000 description 2
- 239000000411 inducer Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 102100026720 Interferon beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 108010047620 Phytohemagglutinins Proteins 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000012931 lyophilized formulation Substances 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 230000001885 phytohemagglutinin Effects 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012475 sodium chloride buffer Substances 0.000 description 1
- IBUIVNCCBFLEJL-UHFFFAOYSA-M sodium;phosphoric acid;chloride Chemical compound [Na+].[Cl-].OP(O)(O)=O IBUIVNCCBFLEJL-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000004753 textile Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
【発明の詳細な説明】 技術分野 本発明は、安定なガンマ・インターフェロン（以下、Ｉ
ＦＮ−γという）組成物に関する。TECHNICAL FIELD The present invention relates to a stable gamma interferon (hereinafter, referred to as I
FN-γ) composition.
技術水準 ＩＦＮ−γはヒト白血球にPhytohemagglutinin（ＰＨ
Ａ）やConcanavarin A(Con-A)等のマイトージェン(mito
gen)をインデューサーとして刺激することによって産生
される分子量約２万〜４万の糖蛋白質である。State of the art IFN-γ is found in human leukocytes with Phytohemagglutinin (PH
A) and Concanavarin A (Con-A) etc.
(gen) is stimulated as an inducer to produce a glycoprotein having a molecular weight of about 20,000 to 40,000.
ＩＦＮーγは顕著な免疫抑制作用、抗ウイルス作用、抗
細胞作用を有するほか、ＩＦＮーαおよびＩＦＮ−βの
活性に相乗効果を与え、さらに腫瘍細胞に対する抗増殖
効果はＩＦＮ−α、ＩＦＮ−βに比べて10〜100倍の効
果がある。このため、ＩＦＮ−γの医薬としての臨床効
果に期待がかけられるところは広大なものである。IFN-γ has a remarkable immunosuppressive action, antiviral action, and anti-cell action, and also has a synergistic effect on the activities of IFN-α and IFN-β. Furthermore, the antiproliferative effect on tumor cells is IFN-α, IFN- It is 10 to 100 times more effective than β. Therefore, there are vast expectations for the clinical effects of IFN-γ as a medicine.
ところで、ＩＦＮ−γは酸性条件（たとえば、ph２程
度）、熱に対して不安定である。また、ＩＦＮ−γは溶
液中での保存安定性にも欠けるので医薬品とする場合、
凍結乾燥品とすることが望ましいが、凍結乾燥時にもそ
の活性が失われるのが実情である。従って、ＩＦＮ−γ
はなんらかの形で安定化させておくことが要求される。By the way, IFN-γ is unstable to acidic conditions (for example, about ph2) and heat. In addition, since IFN-γ lacks storage stability in solution, when it is used as a drug,
It is desirable to use a freeze-dried product, but the fact is that its activity is lost during freeze-drying. Therefore, IFN-γ
Is required to be stabilized in some way.
発明の開示 かかる実情下に本発明者らは鋭意研究を重ねて来たとこ
ろ、ＩＦＮ−γに一定量の糖類を共存させておいく、Ｉ
ＦＮ−γが安定化されること、ＩＦＮ−γ含有水溶液の
凍結乾燥に際してＩＦＮ−γの不活性化もなく、凍結乾
燥後の乾燥製材としての保存安定性も高まることを見い
だして本発明を完成した。DISCLOSURE OF THE INVENTION Under such circumstances, the inventors of the present invention have conducted extensive studies and found that a certain amount of saccharides coexist in IFN-γ.
The present invention has been completed by finding that FN-γ is stabilized, IFN-γ is not inactivated during freeze-drying of an aqueous solution containing IFN-γ, and storage stability as dry lumber after freeze-drying is increased. did.
即ち、本発明は糖類を含有するＩＦＮ−γ組成物であっ
て、ＩＦＮ−γと糖類との配合比率が、ＩＦＮ−γが１
×１０４〜１×１０６単位に対して糖類が５〜１０mgと
なるに相当する比率であることを特徴とする、凍結乾燥
された安定なＩＦＮ−γ組成物に関する。That is, the present invention is an IFN-γ composition containing a saccharide, wherein the blending ratio of IFN-γ and the saccharide is 1 for IFN-γ.
It relates to a freeze-dried stable IFN-γ composition, characterized in that the ratio is 5 to 10 mg of saccharide per x10 4 to 1 x 10 6 units.
本発明に関するＩＦＮ−γとしては、一般にヒト白血球
をＰＨＡやCon-A等のマイトージエン(mitogen)をインデ
ューサーとして刺激することによって得られたものを抗
体カラム等によるクロマトグラフィーにより精製したも
のなどが使用されるが、その他遺伝子工学で大腸菌、酵
母等によって生産されたものなどその由来を問わずひろ
く使用可能である。As the IFN-γ relating to the present invention, generally used is one obtained by stimulating human leukocytes with a mitogen such as PHA or Con-A as an inducer and purified by chromatography using an antibody column or the like. However, it can be widely used regardless of its origin such as those produced by Escherichia coli or yeast by genetic engineering.
本発明に使用される糖類としては、単糖類、二糖類、こ
れらの混合物が好適である。単糖類としては、例えばグ
ルコース、マンノース、ガラクトース、果糖等が列挙さ
れ、二糖類としては蔗糖、麦芽糖、乳糖等が列挙され
る。The saccharides used in the present invention are preferably monosaccharides, disaccharides and mixtures thereof. Examples of monosaccharides include glucose, mannose, galactose, and fructose, and examples of disaccharides include sucrose, maltose, and lactose.
ＩＦＮ−γと糖類との配合比は、ＩＦＮ−γが１×１０
４〜１×１０６単位に対して糖類が５〜１０mgとなるに
相当する比率である。この配合比は固形状のＩＦＮ−
γ、水溶液状のＩＦＮ−γ等の安定化等のいずれの場合
にも適用されるものである。なおＩＦＮ−γ水溶液の凍
結乾燥に当たってはＩＦＮ−γの含有量にかかわりなく
ＩＦＮ−γ水溶液中に少なくとも5mg／ml、好ましくは1
0mg／mlの濃度に糖類を添加しておけばＩＦＮ−γの安
定化が達成される。The compounding ratio of IFN-γ and saccharide was 1 × 10 6 for IFN-γ.
It is a ratio corresponding to 5 to 10 mg of saccharide with respect to 4 to 1 × 10 6 units. This compounding ratio is solid IFN-
It is applicable to any of the cases of stabilizing γ, IFN-γ in the form of an aqueous solution, and the like. In the freeze-drying of the IFN-γ aqueous solution, regardless of the content of IFN-γ, at least 5 mg / ml, preferably 1
If saccharides are added at a concentration of 0 mg / ml, stabilization of IFN-γ can be achieved.
糖類による凍結乾燥処理は例えば次のようにして行われ
る。即ち、精製ＩＦＮ−γを含有する水溶液をph５〜９
に調整し、これに糖類を前記安定化量添加し、この水溶
液の除菌濾過をおこなった後、分注し、常法によって凍
結乾燥に付すことによって行われる。Freeze-drying treatment with sugars is performed as follows, for example. That is, an aqueous solution containing purified IFN-γ was added to a ph5-9 solution.
The amount of the saccharide is added to the above stabilizing amount, the aqueous solution is sterilized and filtered, then dispensed and freeze-dried by a conventional method.
かくして調整されたＩＦＮ−γの凍結乾燥製剤の好まし
い組成は、ＩＦＮ−γ１万〜５０万単位（好ましくは、
５万〜５０万単位）、糖類５〜２０mg（好ましくは、１
０〜２０mg）、食塩９〜１８mg程度に対応する比率の組
成より成るものである。The preferred composition of the freeze-dried preparation of IFN-γ thus prepared is 10,000 to 500,000 units of IFN-γ (preferably,
50,000 to 500,000 units), sugars 5 to 20 mg (preferably 1)
0 to 20 mg) and 9 to 18 mg of sodium chloride.
本発明の方法によって提供されたＩＦＮ−γ製剤は、経
口あるいは非経口的に投与され、その投与量は、対象と
する疾患、投与ルートなどにより異なるが、例えば注射
剤の場合は、通常注射用蒸留水によってＩＦＮ−γの約
１〜10％ｗ／ｖ溶液に調整し、症状に応じてＩＦＮ−γ
の２×１０３〜１×１０４単位／kgを静脈内、筋肉内に
投与する。The IFN-γ preparation provided by the method of the present invention is orally or parenterally administered, and its dose varies depending on the target disease, administration route, etc. Adjust to about 1-10% w / v solution of IFN-γ with distilled water, and adjust IFN-γ depending on symptoms.
2 × 10 3 to 1 × 10 4 units / kg of i.v. are administered intravenously and intramuscularly.
以下に実施例・実験例を挙げて本発明を具体的に説明す
るが、本発明はこれらにより何ら限定されるものでな
い。Hereinafter, the present invention will be specifically described with reference to Examples and Experimental Examples, but the present invention is not limited thereto.
実施例１ 白血球にＰＨＡを刺激剤として産生したＩＦＮ−γをモ
ノクローナルＩＦＮ−γ抗体−sepharoseカラムにより
比活性10６Ｕ／mg以上に精製したＩＦＮ−γをリン酸ー
塩化ナトリウム緩衝液（ph７）に対して透析した。その
後、このＩＦＮ−γを１×１０４単位／ml、１×１０５
単位／ml、１×１０６単位／ml含む各種力価の溶液群を
調整し、それぞれの溶液群にグルコース、マンノース、
ガラクトース、果糖、蔗糖、麦芽糖、乳糖を各々10mg／
ml量づつ加えた。これらの溶液を除菌濾過し、2mlずつ1
0ml容の管瓶に分注し、最終到達温度２５℃の乾燥条件
で凍結乾燥した。Example 1 IFN-γ produced by using PHA as a stimulant in leukocytes was purified to a specific activity of 10 6 U / mg or more by a monoclonal IFN-γ antibody-sepharose column. A phosphate-sodium chloride buffer solution (ph7). It was dialyzed against. Thereafter, this IFN-γ was added at 1 × 10 4 units / ml, 1 × 10 5
Units / ml, 1 × 10 6 units / ml of various titer solution groups were prepared, and glucose, mannose, and
Galactose, fructose, sucrose, maltose, lactose 10 mg / each
ml volume was added. These solutions are sterilized and filtered, and 2 ml each
The mixture was dispensed into a 0 ml tube bottle and freeze-dried under the drying conditions such that the final reached temperature was 25 ° C.
得られた乾燥品の含湿度を生物学的製剤基準、一般試験
法に準じて試験したところ、いずれも約0.2％であっ
た。いずれの乾燥品についても2mlの注射用蒸留水を加
えると直ちに溶解し、溶解液は無色透明であった。これ
らの溶解液についてＩＦＮ−γ残存率を求めたところ、
いずれも凍結乾燥前と何ら変化なかった。When the moisture content of the obtained dried product was tested according to the biological standard and the general test method, all were about 0.2%. All the dried products were immediately dissolved when 2 ml of distilled water for injection was added, and the solutions were colorless and transparent. When the IFN-γ residual rate was obtained for these lysates,
None of them changed from before freeze-drying.
実施例２ ＰＨＡで刺激した人白血球から、ｍ−ＲＮＡを得、その
ｍ−ＲＮＡを鋳型として、0kayama and Berg法により、
ｃＤＮＡを合成した。これをｐＢＲ３２２誘導体である
ｐＹＮ６に挿入し、これにより大腸菌を形質転換した。
この形質転換体を培養し、菌体内に産生させたＩＦＮ−
γを溶菌して得た。この粗製ＩＦＮ−γ溶液をモノクロ
ーナルＩＦＮ−γ抗体ーSepharoseカラム（溶出液２Ｍ
ＫＳＣＮ〔ph８〕）により精製した。さらに、リン酸
ー塩化ナリトウム緩衝液（ph７）に対して透析し、比活
性10６Ｕ／mg以上のＩＦＮ−γを得た。その後、このＩ
ＦＮ−γを１×１０４単位／ml、１×１０５単位／ml、
１×１０６単位／ml含む各種力価の溶液群を調整し、そ
れぞれの溶液群にグルコース、マンノース、ガラクトー
ス、果糖、蔗糖、麦芽糖、乳糖、マンニット、キシリッ
トを各々10mg/ml量づつ加えた。これらの溶液を除菌濾
過し、2mlずつ10ml容の管瓶に分注し、最終到達温度25
℃の乾燥条件で凍結乾燥した。Example 2 m-RNA was obtained from human leukocytes stimulated with PHA, and the m-RNA was used as a template according to the 0kayama and Berg method.
cDNA was synthesized. This was inserted into pBR322 which is a pBR322 derivative, and E. coli was transformed with it.
IFN- produced by culturing this transformant in the cells
It was obtained by lysing γ. This crude IFN-γ solution was applied to a monoclonal IFN-γ antibody-Sepharose column (eluent 2M
It was purified by KSCN [ph8]). Further, it was dialyzed against a phosphate-narridium chloride buffer solution (ph7) to obtain IFN-γ having a specific activity of 10 6 U / mg or more. Then this I
FN-γ is 1 × 10 4 units / ml, 1 × 10 5 units / ml,
A solution group having various titers containing 1 × 10 6 units / ml was prepared, and glucose, mannose, galactose, fructose, sucrose, maltose, lactose, mannitol, and xylite were added to the respective solution groups in an amount of 10 mg / ml each. . These solutions are sterilized and filtered, and 2 ml each is dispensed into a 10 ml tube bottle.
It was freeze-dried under a drying condition of ° C.
得られた乾燥品の含湿度を生物学的製剤基準、一般試験
法に準じて試験したところ、いずれも約0.2％であっ
た。いずれの乾燥品についても2mlの注射用蒸留水を加
えると直ちに溶解し、溶解液は無色透明であった。これ
らの溶解液についてＩＦＮ−γ残存立を求めたところ、
いずれも凍結乾燥前と何ら変化なかった。When the moisture content of the obtained dried product was tested according to the biological standard and the general test method, all were about 0.2%. All the dried products were immediately dissolved when 2 ml of distilled water for injection was added, and the solutions were colorless and transparent. IFN-γ residual standing was determined for these lysates,
None of them changed from before freeze-drying.
実施例１ 本発明による安定化効果を確認するための実験を行っ
た。精製ＩＦＮ−γの溶液（１×10４単位／ml：力価の
測定はＦＬ−Sindvis virus系のＣＰＥ阻止法によっ
た。）にグルコース、蔗糖（１mg／ml、５mg／ml、10mg
／ml）を各々添加し、次いで凍結乾燥を行った。凍結乾
燥品の力価は凍結乾燥直前、凍結乾燥直後および室温に
て６カ月保存後に測定し、糖類添加直後の力価に対する
活性残存率を第１表に示した。Example 1 An experiment was conducted to confirm the stabilizing effect according to the present invention. Glucose and sucrose (1 mg / ml, 5 mg / ml, 10 mg) were added to a solution of purified IFN-γ (1 × 10 4 units / ml; titer was determined by FL-Sindvis virus CPE inhibition method).
/ Ml) respectively, followed by freeze-drying. The titer of the freeze-dried product was measured immediately before freeze-drying, immediately after freeze-drying, and after storage at room temperature for 6 months, and the activity residual ratio relative to the titer immediately after the addition of sugar is shown in Table 1.
製剤例 実施例に準じて以下の組成から成る凍結乾燥製剤を調整
した。 Formulation Example A lyophilized formulation having the following composition was prepared according to the examples.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 須山 忠和 京都府綴喜郡田辺町松井ケ丘４丁目３―７ (56)参考文献 特開 昭58−92619（ＪＰ，Ａ) 特開 昭59−181223（ＪＰ，Ａ) 欧州特許公開82481（ＥＰ，Ａ) 根井外喜男編「凍結・乾燥と保護物質」 （1972−３−20），東京大学出版会発行第 １頁〜第39頁 生科学，54［11］，（1982），第1255〜 1259頁 ＳＥＮ−Ｉ ＧＡＫＫＡＩＳＨＩ（繊維 と工業）37［12］，（1981）上平初穂 第 436〜443頁 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Tadakazu Suyama 4-3-7 Matsuigaoka, Tanabe-cho, Tsuzuki-gun, Kyoto Prefecture (56) References JP-A-58-92619 (JP, A) JP-A-59-181223 (JP, A) European Patent Publication 82481 (EP, A) "Freeze / Dry and Protective Substances" edited by Yoshio Nei (1972-3-20), published by The University of Tokyo Press, pages 1-39 Bioscience, 54 [11], (1982), pp. 1255-1259 SEN-I GAKKAISHI (textile and industry) 37 [12], (1981) Hatsumi Uehira, pp. 436-443
Claims (1)
ンターフェロン組成物であって、ガンマ・インターフェ
ロンと糖類との配合比率が、ガンマ・インターフェロン
が１×１０４〜１×１０６単位に対して糖類が５〜１０
mgとなるに相当する比率であることを特徴とする、凍結
乾燥された安定なガンマ・インターフェロン組成物。1. A gamma interferon composition containing a monosaccharide or a disaccharide, wherein the mixing ratio of gamma interferon and saccharide is 1 × 10 4 to 1 × 10 6 units of gamma interferon. 5-10 sugars
Freeze-dried stable gamma-interferon composition, characterized in a proportion corresponding to mg.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58157560A JPH0651641B2 (en) | 1983-08-29 | 1983-08-29 | Gamma interferon composition |
| DE8484304992T DE3484374D1 (en) | 1983-08-04 | 1984-07-23 | GAMMA INTERFERON COMPOSITION. |
| EP19840304992 EP0133767B1 (en) | 1983-08-04 | 1984-07-23 | Gamma interferon composition |
| CA000459960A CA1223207A (en) | 1983-08-04 | 1984-07-30 | Gamma interferon composition |
| ES534815A ES8505545A1 (en) | 1983-08-04 | 1984-08-02 | Gamma interferon composition. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58157560A JPH0651641B2 (en) | 1983-08-29 | 1983-08-29 | Gamma interferon composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6048933A JPS6048933A (en) | 1985-03-16 |
| JPH0651641B2 true JPH0651641B2 (en) | 1994-07-06 |
Family
ID=15652344
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58157560A Expired - Lifetime JPH0651641B2 (en) | 1983-08-04 | 1983-08-29 | Gamma interferon composition |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0651641B2 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4797388A (en) * | 1984-05-21 | 1989-01-10 | Cetus Corporation | Pharmaceutical compositions with galactitol as carrier |
| JP2577743B2 (en) * | 1986-07-18 | 1997-02-05 | 中外製薬株式会社 | Stable granulocyte colony-stimulating factor containing preparation |
| CA2564679C (en) | 2004-03-22 | 2015-06-23 | Osiris Therapeutics, Inc. | Mesenchymal stem cells and uses therefor |
| ES2643076T3 (en) * | 2004-03-22 | 2017-11-21 | Mesoblast International Sàrl | Mesenchymal stem cells and their uses |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5892619A (en) * | 1981-11-28 | 1983-06-02 | Sunstar Inc | Stable composition containing interferon |
| EP0082481B2 (en) * | 1981-12-23 | 1990-09-12 | Schering Corporation | Stabilised alpha-interferon formulations and their preparation |
| JPS59181223A (en) * | 1983-03-29 | 1984-10-15 | Sumitomo Chem Co Ltd | Stabilization of interferon |
-
1983
- 1983-08-29 JP JP58157560A patent/JPH0651641B2/en not_active Expired - Lifetime
Non-Patent Citations (3)
| Title |
|---|
| ＳＥＮ−ＩＧＡＫＫＡＩＳＨＩ（繊維と工業）３７［１２，（１９８１）上平初穂第４３６〜４４３頁 |
| 根井外喜男編「凍結・乾燥と保護物質」（１９７２−３−２０），東京大学出版会発行第１頁〜第３９頁 |
| 生科学，５４［１１，（１９８２），第１２５５〜１２５９頁 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6048933A (en) | 1985-03-16 |
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