JPH03291234A - Drug composition for preventing rejection of transplantation - Google Patents
Drug composition for preventing rejection of transplantationInfo
- Publication number
- JPH03291234A JPH03291234A JP2093201A JP9320190A JPH03291234A JP H03291234 A JPH03291234 A JP H03291234A JP 2093201 A JP2093201 A JP 2093201A JP 9320190 A JP9320190 A JP 9320190A JP H03291234 A JPH03291234 A JP H03291234A
- Authority
- JP
- Japan
- Prior art keywords
- tnf
- administration
- rejection
- units
- transplantation
- 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.)
- Pending
Links
- 238000002054 transplantation Methods 0.000 title abstract description 11
- 239000000203 mixture Substances 0.000 title abstract description 8
- 239000003814 drug Substances 0.000 title abstract description 4
- 229940079593 drug Drugs 0.000 title abstract description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims abstract description 7
- 239000004480 active ingredient Substances 0.000 claims abstract description 6
- 102000003390 tumor necrosis factor Human genes 0.000 claims abstract 3
- 206010052779 Transplant rejections Diseases 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 abstract description 42
- 102000057041 human TNF Human genes 0.000 abstract description 23
- 102100040247 Tumor necrosis factor Human genes 0.000 abstract description 19
- 108020004511 Recombinant DNA Proteins 0.000 abstract description 8
- 210000000056 organ Anatomy 0.000 abstract description 5
- 238000007918 intramuscular administration Methods 0.000 abstract description 4
- 238000001990 intravenous administration Methods 0.000 abstract description 4
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- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、腫瘍壊死因子（以下ＴＮＦと略す）を有効成
分とする移植拒絶反応防止用医薬組成物に関する。DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a pharmaceutical composition for preventing transplant rejection containing tumor necrosis factor (hereinafter abbreviated as TNF) as an active ingredient.
（従来の技術）
臓器移植における最大の問題点は移植片の抗原に対する
宿主の免疫応答による拒絶反応である。(Prior Art) The biggest problem in organ transplantation is rejection caused by the host's immune response to antigens in the transplant.
このため臓器移植に際しては、宿主に対する免疫抑制剤
の投与が一般に実施される。しかしながら、免疫抑制剤
の投与は拒絶反応の防止において必ずしも満足のいくも
のではない。For this reason, during organ transplantation, immunosuppressants are generally administered to the host. However, administration of immunosuppressants is not always satisfactory in preventing rejection reactions.
（問題点を解決するための手段）
腫瘍壊死因子、すなわちＴＮＦは多様な生物活性を有す
る公知のサイトカインである。本発明者らはＴＮＦに対
し、その薬理作用について鋭意研究を続けていたところ
、意外にも、ＴＮＦが移植拒絶反応抑制作用を有するこ
とを発見し、該知見に基づきさらに研究を続け、本発明
を完成した。Means for Solving the Problems Tumor necrosis factor, or TNF, is a known cytokine with diverse biological activities. The present inventors have been conducting intensive research on the pharmacological effects of TNF, and have unexpectedly discovered that TNF has a suppressive effect on transplant rejection. completed.
本発明によれば、移植拒絶反応の防止に有効な量のＴＮ
Ｆと少なくとも一種の医薬投与可能な担体、希釈剤ある
いは賦形剤を含有する移植拒絶反応防止用の新規医薬組
成物が提供される。移植拒絶反応が起こると予想される
あるいは移植拒絶反応が起きた患者の治療に用いられる
本発明の医薬組成物においては、腫瘍壊死因子は、ヒト
由来の細胞から、あるいは組替えＤＮＡ技術によって製
造されるものであることが好ましい。このような組成物
には、例えば、静脈内注射用、筋肉的注射、皮下注射用
、皮肉注射用、経口投与用、直腸内投与用、外部施用用
、局所施用用、点眼用などに適合する投与形態を与える
ことができる。さらに、本発明の医薬組成物はポリペプ
チド組成物に適合する投与形態を与えることができる。According to the present invention, an amount of TN effective for preventing transplant rejection
A novel pharmaceutical composition for preventing transplant rejection is provided, which contains F and at least one pharmaceutically administrable carrier, diluent, or excipient. In the pharmaceutical composition of the present invention used for the treatment of patients who are expected to experience transplant rejection or who have experienced transplant rejection, the tumor necrosis factor is produced from human-derived cells or by recombinant DNA technology. Preferably. Such compositions may, for example, be suitable for intravenous, intramuscular, subcutaneous, subcutaneous, oral, rectal, external, topical, ophthalmic, etc. A dosage form can be provided. Furthermore, the pharmaceutical compositions of the present invention can be provided with dosage forms compatible with polypeptide compositions.
腫瘍壊死因子、すなわちＴＮＦは、生存能力のあるマイ
クロバクテリウム ボーヴアイス（Ｍｉｃｒｏ−ｂａｃ
ｔｅｒｉｕｍ ｂｏｖｉｃｅ）のバチルスカルメットー
グヱリン（Ｂａｃｉｌｌｕｓ Ｃａｌｓｇｅｔｔｅ−Ｇ
ｕｅｒｉｎ）株（ＢＧＧ）を前投与後、細菌のエンドト
キシンを静脈内投与したマウスの血清中から初めて発見
された［プロシーデインゲス・オプ・ナショナル・アカ
デ逅−・オプ・サイエンス・ニー・ニス・ニー（Ｐｒｏ
ｃ、 Ｎａ１．Ａｃａｄ。Tumor necrosis factor, or TNF, is produced by viable Microbacterium boveis (Micro-bacillus
Bacillus Calsgette-G of Bacillus terium bovice
It was first discovered in the serum of mice that had been pre-treated with bacterial endotoxin (BGG) and then intravenously administered bacterial endotoxin. (Pro
c, Na1. Acad.
Ｓｃｉ、υ、Ｓ、Ａ、）７２巻第９号、３６６６−７０
頁（１９７５年）］。Sci, υ, S, A,) Vol. 72 No. 9, 3666-70
Page (1975)].
、ＴＮＦを含有するマウス血清は、ｉｎ ｖｉｔｒｏ
試験で多数のマウス及びヒト形質転換細胞系に対して
細胞傷害活性作用あるいは殺細胞活性を示すが、これら
の作用は正常細胞に対しては非常に弱い。, mouse serum containing TNF was tested in vitro.
Although it has shown cytotoxic or cell-killing activity against a number of mouse and human transformed cell lines in tests, these effects are very weak against normal cells.
ＴＮＦを含有するマウス血清は、マウスに移植可能な腫
瘍の壊死を生じせしめる。ＴＮＦはラット、ウサギ及び
モルモットの血清中にも産生ずる。さらに、ＴＮＦは哺
乳類由来の単核食細胞、繊維芽細胞、Ｂ細胞などによっ
てもある条件下において産生され得るものである。これ
に関しては、ロイド ジェイ・オールド（Ｌｌｏｙｄ
Ｊ、０１ｄ）によってサイエンティフィツク アメリカ
ン（Ｓｃｉｅｎｔｉｆｉｃａｍｅｒｉｃａｎ） ２５８
巻第５号５９−７５頁（１９８８年５月）の総説に引用
された文献中に多くの報告がある。Mouse serum containing TNF causes necrosis of tumors that can be implanted into mice. TNF is also produced in the serum of rats, rabbits and guinea pigs. Furthermore, TNF can also be produced under certain conditions by mononuclear phagocytes, fibroblasts, B cells, etc. of mammalian origin. Regarding this, Lloyd J. Old
J, 01d) by Scientificamerican 258
There are many reports in the literature cited in the review of Vol. 5, pp. 59-75 (May 1988).
本発明においては、哺乳類由来の血清あるいは哺乳類由
来の細胞から得られる上記ＴＮＦを活性成分として用い
ることができるが、ヒトの患者に使用するためには、免
疫適合性の点からヒ）ＴＮＦを含有する医薬組成物を用
いることが好ましい。In the present invention, the above-mentioned TNF obtained from mammalian-derived serum or mammalian-derived cells can be used as the active ingredient; Preferably, a pharmaceutical composition is used.
本発明において使用するのに適したヒトＴＮＦは、組換
えＤＮＡ技術によって製造することができる。あるいは
また、ヒトＴＮＦはヒト由来の細胞を培養することによ
っても製造することができる。Human TNF suitable for use in the present invention can be produced by recombinant DNA technology. Alternatively, human TNF can also be produced by culturing cells of human origin.
組換えＤＮＡ技術によりヒ）ＴＮＦを製造する方法の適
例としては、たとえば、シライ ティー（Ｓｈｉｒａｉ
Ｔ、）ら、ネーチャー （Ｎａ ｔｕｒｅ） 、 ３
１３壱８ｏ３−８０６頁（１９８５年）や特開昭６０−
２５２４９６号（欧州特許出願公開第０．１５８，２８
６号に対応）に記載されている。例えば、大腸菌の培養
によって均質なヒトＴＮＦを得ることができる。精製中
のヒトＴＮＦ活性は、Ｌ−Ｍ細胞［アメリカン タイプ
カルチャーコレクション、シーシーエル１．２（Ａｍ
ｅｒｉｃａｎＴｙｐｅ Ｃｕ１ｔｕｒｅ ｃｏｒｅｃｔ
ｉｏｎ、ＣＣＬ １．２）］ を用いたウィリアムソン
等（Ｗｉｌｌｉａｍｓｏｎ ｅｌ、 ａｌ、）の方法の
変法によるマウスＬ−細胞に対する殺細胞活性によって
知ることができる。従って、必要に応じてより高純度の
ヒトＴＮＦは、ダイアン ペニカ（ＤｉａｎｅＰｅｎｎ
１ｃａ）らがネーチャー （Ｎａ ｔｕｒｅ）、３１
２巻、２〇−２７頁（１９８４年１２月）に記載した方
法や、欧州特許出願公開第１６８２１４号及び第１５５
５４９号等に記載されている他の公知の方法によっても
製造することができる。A suitable example of a method for producing human TNF using recombinant DNA technology is, for example, Shirai Tea.
T.) et al., Nature, 3
13ichi 8o3-806 pages (1985) and JP-A-1983-
No. 252496 (European Patent Application Publication No. 0.158,28
(corresponding to No. 6). For example, homogeneous human TNF can be obtained by culturing E. coli. Human TNF activity during purification was determined using LM cells [American Type Culture Collection, CCL 1.2 (Am
ericanType Culture correct
ion, CCL 1.2)] by a modification of the method of Williamson et al. (Williamson et al.). Therefore, if necessary, higher purity human TNF can be obtained from Diane Penna.
1ca) Nature, 31
2, pp. 20-27 (December 1984), and the method described in European Patent Application Publication Nos. 168214 and 155.
It can also be produced by other known methods such as those described in No. 549.
ヒトＴＮＦを構成するアミノ酸の数は、ＴＮＦを得るた
めに用いる製造方法によって異なる。たとえば、欧州特
許出願公開第０１５８２８６号に記載されている組換え
ＤＮＡ技術によって製造されるヒ）ＴＮＦは１５５個の
アミノ酸から成る。一方、上記のべ二カ（Ｐｅｎｎｉｃ
ａ）等の方法によって製造されるヒトＴＮＦは１５７個
のアミノ酸と、そのＮ末端に結合した２個のアミノ酸か
らなる配列を有する。The number of amino acids that make up human TNF varies depending on the manufacturing method used to obtain TNF. For example, human TNF produced by recombinant DNA technology as described in European Patent Application No. 0158286 consists of 155 amino acids. On the other hand, the above Benic
Human TNF produced by methods such as a) has a sequence consisting of 157 amino acids and two amino acids linked to the N-terminus.
組換えＤＮＡ技術によって製造されるＴ Ｎ ’Ｆは、
上記のアミノ酸配列のＮ末端にメチオニン残基が結合し
ているポリペプチドと、上記のアミノ酸配列のＮ末端に
ヒトＴＮＦのシグナルペプチドの一部分あるいは全部が
結合している中間体も包含する。自然の変異、あるいは
人為的変異によって、そのポリベチドの活性に有為な変
化を生しることなくポリペプチドをコードするＤＮＡの
構造の一部を変えることは可能である。TN'F produced by recombinant DNA technology is
Also included are polypeptides in which a methionine residue is bound to the N-terminus of the above amino acid sequence, and intermediates in which part or all of the signal peptide of human TNF is bound to the N-terminus of the above amino acid sequence. It is possible to change part of the structure of the DNA encoding a polypeptide by natural or artificial mutation without significantly changing the activity of the polypeptide.
本発明で用いることのできるヒトＴＮＦは、上記のアミ
ノ酸配列を有するポリペプチドの相同変異体（ｈｏｍｏ
ｌｏｇｏｕｓ ｖａｒｉａｎｔ）に相当する構造を有す
るポリペプチドを包含する。相同変異体の例として、米
国特許第４．６７７、０６３号と第４，６７７．０６４
号に記載されているペプチドが挙げられ、この開示内容
は、参照によって本明細書に記載する。これらすべての
生理活性ペプチドも、以下「ヒトＴＮＦ。Human TNF that can be used in the present invention is a homologous variant of the polypeptide having the above amino acid sequence.
It includes polypeptides having a structure corresponding to a logous variant). Examples of homologous variants include US Pat. Nos. 4.677,063 and 4,677.064.
, the disclosure of which is incorporated herein by reference. All these bioactive peptides are also referred to as "human TNF".
と称する。It is called.
天然のヒ）ＴＮＦは、生化学的修飾あるいは化学的修飾
を受は易く、また、２量体や３量体のような会合体の形
になり易い。天然に産生されるこれらのＴＮＦポリペプ
チドもまた、以下「ヒトＴＮＦ、と称し、本発明の医薬
組成物の活性成分として使用できる。Natural human TNF is easily subject to biochemical or chemical modification, and is also likely to form aggregates such as dimers and trimers. These naturally produced TNF polypeptides, hereinafter referred to as "human TNF," can also be used as active ingredients in the pharmaceutical compositions of the present invention.
ＴＮＦは現在、抗癌剤としての臨床研究が進められてい
るほか、抗炎症・鎮痛作用（日本公開特許公報間６２−
２９２７２７ ） 、免疫複合体病として定義される自
己免疫疾患抑制作用（日本公開特許公報間６３−３０４
２６） 、等をも有することが報告されている。しかし
、ＴＮＦが移植拒絶反応を抑制するという報告はいっさ
いなされていない。その反対に、ＴＮＦは移植片拒絶反
応の原因物質の１つではないか、という推測すらなされ
ていたＥロウリ−（Ｌｏｗｒｙ） ら、トランスプラ
ンテーション・プロシーデインゲス（丁ｒａｎｓｐｌａ
ｎｔａｔｉｏｎ Ｐｒｏｃｅｅｄｉｎｇｓ）、第２０巻
、２４５頁、（１９８８年）］、ところが発明者らはマ
ウスを用いた移植拒絶反応の実験モデルにおいて、意外
にもＴＮＦを投与すると移植拒絶反応の発症を抑制する
ことを見出した。すなわち、本発明は既に知られている
作用のいずれとも異なった新しいＴＮＦの作用の発見に
基づくものである。以下にその具体的な実験例をしめす
。TNF is currently undergoing clinical research as an anticancer agent, and has anti-inflammatory and analgesic effects (Japanese Patent Publication No. 62-62-
292727), suppressive effect on autoimmune diseases defined as immune complex diseases (Japanese Patent Publication No. 63-304)
26), etc. have also been reported. However, there have been no reports that TNF suppresses transplant rejection. On the other hand, it was even speculated that TNF might be one of the causative agents of graft rejection.
Proceedings), Vol. 20, p. 245 (1988)] However, in an experimental model of transplant rejection using mice, the inventors unexpectedly found that administering TNF suppressed the onset of transplant rejection. I found out. That is, the present invention is based on the discovery of a new effect of TNF that is different from any previously known effects. A specific experimental example is shown below.
１簾班
移植拒絶反応のモデルとして、マウスの同種異型皮膚移
植拒絶反応について検討した。５週齢のＢＡＬＢ／ｃマ
ウス（Ｈ−２ｄ）の腹部皮膚をＣ５７ＢＬ／６マウス（
Ｈ−２ｂ）側背部に藤井の方法（皮膚移植法、免疫学実
験操作法、５６６頁）に従って移植した。移植皮膚を毎
日観察し、移植皮膚拒絶までの日数を生着日数として記
録した。ヒトＴＮＦは、欧州特許出願公開第０．１５８
．２８６号に記載の方法に従って組換えＤＮＡ技術によ
って製造したものを用い、移植の１週間前から１０．０
００単位／匹を１日１回、隔日毎に移植１日前まで計４
回尾静脈内投与した。対照群には、ヒ）ＴＮＦを溶解す
るのに用いた溶液（０，，１２セラチン含有リン酸緩衝
液）をヒトＴＮＦ投与群と同しスケジュール、同し投与
法で投与した。As a model of skin graft rejection, allogeneic skin graft rejection in mice was investigated. The abdominal skin of a 5-week-old BALB/c mouse (H-2d) was injected into a C57BL/6 mouse (
H-2b) It was transplanted to the lateral dorsal region according to Fujii's method (Skin Grafting Method, Immunology Experimental Procedures, p. 566). The grafted skin was observed every day, and the number of days until rejection of the grafted skin was recorded as the number of days for engraftment. Human TNF is European Patent Application Publication No. 0.158
．． 10.0 from one week before transplantation using a product produced by recombinant DNA technology according to the method described in No. 286.
00 units/mouse once a day, every other day until 1 day before transplantation for a total of 4
It was administered intravenously. To the control group, the solution used to dissolve human TNF (phosphate buffer containing 0, 12 seratin) was administered on the same schedule and in the same administration method as the human TNF administration group.
移植片拒絶反応の観察によると別表に示すごとく、対照
群では移植１０日前後で移植皮膚の拒絶が起こったのに
対して、ヒトＴＮＦ投与群では移植２０日後から３０日
後に拒絶が観察され、結果として生着日数の１０日から
２０日の延長がみられた。According to the observation of graft rejection, as shown in the attached table, rejection of the grafted skin occurred around 10 days after transplantation in the control group, whereas rejection was observed in the human TNF-administered group 20 to 30 days after transplantation. As a result, the survival time was extended by 10 to 20 days.
別表
以上の結果より明らかなる如く、ヒトＴＮＦの投与は移
植拒絶反応の発症を抑制する作用を有していることを示
している。As is clear from the results shown in the attached table, it is shown that administration of human TNF has the effect of suppressing the onset of transplant rejection.
本発明の移植拒絶反応の治療用医薬組成物は静脈内、筋
肉内、皮下及び皮肉注射剤として、または経口剤、外用
剤、全開、点眼剤として投与することが出来る。The pharmaceutical composition for treatment of transplant rejection of the present invention can be administered as an intravenous, intramuscular, subcutaneous, or subcutaneous injection, or as an oral preparation, external preparation, dilatation, or eye drops.
製剤例としては、溶液または凍結乾燥品が挙げられる。Examples of formulations include solutions or lyophilized products.
その製剤化にあったでは、賦形剤として、バレイショデ
ンプン、トウモロコシデンプン、デキストリン、小麦、
デン粉等のデンプン類、ヒドロキシプロピルスターチ等
のデンプン誘導体、乳糖、ブドウ糖、ショ糖、マントニ
トール、ソルビトール等の糖類、メチルセルロース、カ
ルボキシメチルセルロース、ヒドロキシプロピルセルロ
ース等のセルロース類、塩化ナトリウム、ホウ酸、硫酸
カルシウム、リン酸カルシウム類、沈降炭酸カルシウム
等の無機物質、流動化剤としては、重質酸化マグネシウ
ム、合成ケイ酸アルミン酸マグネシウム、含水ケイ酸、
タルク、ステアリン酸マグネシウム、無水ケイ酸、カオ
リン（にａｏｌｉｎ）等、結合剤としては、ポリエチレ
ングリコール、ポリビニルピロリドン、ポリビニルアル
コール等の合成高分子及びこれらの誘導体、アラビアゴ
ム、トラガント、アルギン酸ナトリウム、ゼラチン、グ
ルテン等の天然物、安定化剤としては、アルブミン、ゼ
ラチン、グロブリン、プロタミン、プロタミン塩等の蛋
白質、及びアミノ酸類、ｐＨ調節剤としては、塩酸、水
酸化ナトリウム、リン酸塩類、クエン酸塩、炭酸塩等を
使用する事が出来る。In its formulation, excipients include potato starch, corn starch, dextrin, wheat,
Starches such as starch, starch derivatives such as hydroxypropyl starch, sugars such as lactose, glucose, sucrose, mantonitol, sorbitol, celluloses such as methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, sodium chloride, boric acid, calcium sulfate , calcium phosphates, precipitated calcium carbonate, and other inorganic substances; as fluidizing agents, heavy magnesium oxide, synthetic magnesium aluminate silicate, hydrated silicic acid,
Talc, magnesium stearate, silicic anhydride, kaolin, etc. Binders include synthetic polymers such as polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, and derivatives thereof, gum arabic, tragacanth, sodium alginate, gelatin, Natural products such as gluten, stabilizers include albumin, gelatin, globulin, protamine, proteins such as protamine salts, and amino acids; pH regulators include hydrochloric acid, sodium hydroxide, phosphates, citrates, Carbonates etc. can be used.
本発明の医薬ｍ放物は、底入に対するヒトＴＮＦの一日
投与量として、一般に約５０からｉｏｏ、 ｏｏｏ、
ｏｏｏ単位の用量で、好ましくは、局所投与の場合には
、約５０からｓｏｏ、ｏｏｏ単位の用量で、静脈内投与
や筋肉内投与のような一般的な投与のばあい、約１ 、
０００から１０，０００，０００単位の用量で、そして
経口投与の場合には、約１０，０００から１００．００
０，０００単位の用量で移植拒絶反応が起こると予想さ
れるあるいは移植拒絶反応が起きた患者に投与すること
ができる。−日の投与量は患者の年齢や症状によって異
なる。上記のように本発明の医薬組成物は、通常、数日
から数週間にわたり、−日５０から１００．０００．０
００単位の用量で投与することができる。この−日投与
量は、−度に、あるいは数回に分けて患者に投与するこ
とができる。The pharmaceutical formulations of the present invention generally have a daily dose of human TNF for nadir of about 50 to ioo, ooo,
ooo doses, preferably from about 50 to soo for topical administration, ooo doses for common administration such as intravenous or intramuscular administration, from about 1.
000 to 10,000,000 units, and for oral administration, about 10,000 to 100.00 units.
A dose of 0,000 units can be administered to a patient who is expected to experience transplant rejection or who has experienced transplant rejection. - The daily dosage varies depending on the patient's age and symptoms. As mentioned above, the pharmaceutical compositions of the present invention are generally administered for a period of several days to several weeks.
It can be administered in doses of 0.00 units. This daily dose can be administered to the patient in multiple doses or in divided doses.
本発明の医薬組成物は、連日、あるいは、間隔をおいて
投与することができる。その代表的な投与方法の例を次
に示す。The pharmaceutical composition of the present invention can be administered daily or at intervals. Examples of typical administration methods are shown below.
ａ）１週間から４週間の連日投与
ｂ）６日間毎日投与した後、７日間から数週間の体薬を
はさむ間歇的投与
ｃ）１週間に１回投与
ｄ）５日間毎日投与した後、１ケ月の体薬期間をはさむ
間歇投与。a) Daily administration for 1 to 4 weeks b) Daily administration for 6 days, followed by intermittent administration with body medications in between for 7 days to several weeks c) Once a week administration d) Daily administration for 5 days, then 1 Intermittent administration with a period of several months of physical therapy.
以上のように本発明によれば、移植拒絶反応防止用医薬
組成物の提供が可能となる。As described above, according to the present invention, it is possible to provide a pharmaceutical composition for preventing transplant rejection.
以下に実施例にて本発明の一実施態様を具体的に説明す
る。An embodiment of the present invention will be specifically described below in Examples.
（実施例）
ヒ）ＴＮＦを上記組換えＤＮＡ技術によって調製し、得
られるヒトＴＮＦを用いて下記のＭ戒を持つ注射用凛結
乾燥製剤を調製する。(Example) h) TNF is prepared by the above-mentioned recombinant DNA technology, and the obtained human TNF is used to prepare a dried preparation for injection having the following M precepts.
組成 ヒトＴＮＦ Ｄ−マンニトール 正常血清アルブミン（ヒト） 塩化ナトリウム リン酸二水素ナトリウム （水酸化ナトリウムでｐＨ８，０ ５００，０００単位 ０ ｖｓｇ ０ ｍｇ ２、ＯＢ ３．９ ｍｇ に調製） 以 上composition human TNF D-mannitol Normal serum albumin (human) sodium chloride Sodium dihydrogen phosphate (pH 8.0 with sodium hydroxide) 500,000 units 0 vsg 0 mg 2.OB 3.9 mg (prepared to) Below Up
Claims (1)
用医薬組成物。(1) A pharmaceutical composition for preventing transplant rejection containing tumor necrosis factor as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2093201A JPH03291234A (en) | 1990-04-10 | 1990-04-10 | Drug composition for preventing rejection of transplantation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2093201A JPH03291234A (en) | 1990-04-10 | 1990-04-10 | Drug composition for preventing rejection of transplantation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH03291234A true JPH03291234A (en) | 1991-12-20 |
Family
ID=14075961
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2093201A Pending JPH03291234A (en) | 1990-04-10 | 1990-04-10 | Drug composition for preventing rejection of transplantation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH03291234A (en) |
-
1990
- 1990-04-10 JP JP2093201A patent/JPH03291234A/en active Pending
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