JP2000290179A - Stable 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt preparation and its production - Google Patents
Stable 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt preparation and its productionInfo
- Publication number
- JP2000290179A JP2000290179A JP11092089A JP9208999A JP2000290179A JP 2000290179 A JP2000290179 A JP 2000290179A JP 11092089 A JP11092089 A JP 11092089A JP 9208999 A JP9208999 A JP 9208999A JP 2000290179 A JP2000290179 A JP 2000290179A
- Authority
- JP
- Japan
- Prior art keywords
- amidino
- guanidinobenzoate
- naphthyl
- addition salt
- acid addition
- 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.)
- Granted
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 21
- MQQNFDZXWVTQEH-UHFFFAOYSA-N nafamostat Chemical compound C1=CC(N=C(N)N)=CC=C1C(=O)OC1=CC=C(C=C(C=C2)C(N)=N)C2=C1 MQQNFDZXWVTQEH-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 239000002253 acid Substances 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 5
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000004108 freeze drying Methods 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000001384 succinic acid Substances 0.000 claims abstract description 5
- 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 claims description 8
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 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 claims 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 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- 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 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 abstract description 6
- 238000004090 dissolution Methods 0.000 abstract description 4
- 239000000243 solution Substances 0.000 abstract description 3
- 238000000354 decomposition reaction Methods 0.000 abstract description 2
- 238000001035 drying Methods 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 108090000631 Trypsin Proteins 0.000 description 3
- 102000004142 Trypsin Human genes 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 230000008014 freezing Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000012588 trypsin Substances 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 108090000190 Thrombin Proteins 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000023555 blood coagulation Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 229960004072 thrombin Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- ZIIUUSVHCHPIQD-UHFFFAOYSA-N 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)NC1=CC=CC(C(F)(F)F)=C1 ZIIUUSVHCHPIQD-UHFFFAOYSA-N 0.000 description 1
- FCEQRBOTYXIORK-UHFFFAOYSA-N 2-(diaminomethylideneamino)benzoic acid Chemical compound NC(=N)NC1=CC=CC=C1C(O)=O FCEQRBOTYXIORK-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- -1 6-amidino-2-naphthyl Chemical group 0.000 description 1
- 102000004411 Antithrombin III Human genes 0.000 description 1
- 108090000935 Antithrombin III Proteins 0.000 description 1
- 241000206601 Carnobacterium mobile Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108060005987 Kallikrein Proteins 0.000 description 1
- 102000001399 Kallikrein Human genes 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 102000015439 Phospholipases Human genes 0.000 description 1
- 108010064785 Phospholipases Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 101000605527 Rattus norvegicus Kallikrein-1 Proteins 0.000 description 1
- 102000057032 Tissue Kallikreins Human genes 0.000 description 1
- SRXKIZXIRHMPFW-UHFFFAOYSA-N [4-[6-[amino(azaniumylidene)methyl]naphthalen-2-yl]oxycarbonylphenyl]-(diaminomethylidene)azanium;methanesulfonate Chemical compound CS([O-])(=O)=O.CS([O-])(=O)=O.C1=CC(N=C([NH3+])N)=CC=C1C(=O)OC1=CC=C(C=C(C=C2)C([NH3+])=N)C2=C1 SRXKIZXIRHMPFW-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229960005348 antithrombin iii Drugs 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000004154 complement system Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229940012957 plasmin Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、安定な６−アミジ
ノ−２−ナフチル ４−グアニジノベンゾエート酸付加
塩製剤ならびにその製造方法に関する。The present invention relates to a stable 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt preparation and a method for producing the same.
【０００２】[0002]
【従来の技術】６−アミジノ−２−ナフチル ４−グア
ニジノベンゾエートの酸付加塩は、蛋白分解酵素阻害作
用をもち、血液凝固・線溶系（トロンビン、ＸIIａ、Ｘ
ａ、ＶIIａ、プラスミン）、カリクレイン−キニン系
（カリクレイン）、補体系（Ｃ1r、Ｃ1s、Ｂ、Ｄ）およ
び膵酵素（トリプシン、膵カリクレイン）に対する強力
な阻害作用を有することが知られている。2. Description of the Related Art An acid addition salt of 6-amidino-2-naphthyl 4-guanidinobenzoate has a proteolytic enzyme inhibitory action, and has a blood coagulation / fibrinolysis system (thrombin, XIIa, XII).
a, VIIa, plasmin), kallikrein-kinin system (kallikrein), complement system ( C1r , C1s , B, D) and pancreatic enzymes (trypsin, pancreatic kallikrein). .
【０００３】そのトロンビンに対する阻害はアンチトロ
ンビンIIIに依存せず、血液凝固時間も強力に延長し、
さらに血小板凝集に対する強い抑制効果を有する。この
ことから、汎発性血管内血液凝固症（ＤＩＣ）に対する
強い有用性が認められている。[0003] Its inhibition on thrombin is not dependent on antithrombin III, the blood coagulation time is prolonged strongly,
Furthermore, it has a strong inhibitory effect on platelet aggregation. From this, a strong utility against generalized intravascular coagulation (DIC) has been recognized.
【０００４】また、トリプシンおよびα２−マクログロ
ブリン結合トリプシンの双方に対する強力な阻害作用、
及びホスホリパーゼＡ２に対する阻害作用から、膵炎の
急性症状の改善への高い有用性が確認されている。A strong inhibitory effect on both trypsin and α 2 -macroglobulin-bound trypsin;
And the inhibitory effect on phospholipase A 2, highly useful for improvement of acute symptoms of pancreatitis has been confirmed.
【０００５】６−アミジノ−２−ナフチル ４−グアニ
ジノベンゾエート酸付加塩は水溶液中では不安定である
ことから、用時溶解の製剤として用いられている。The 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt is unstable in an aqueous solution, and is therefore used as a preparation which is dissolved when used.
【０００６】[0006]
【発明が解決しようとする課題】本発明の目的は、水溶
液中で不安定な６−アミジノ−２−ナフチル ４−グア
ニジノベンゾエート酸付加塩を、溶解後長期にわたって
安定に保存できる６−アミジノ−２−ナフチル ４−グ
アニジノベンゾエート酸付加塩製剤およびその製造方法
を提供することにある。SUMMARY OF THE INVENTION It is an object of the present invention to provide a 6-amidino-2 salt which can stably store 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt which is unstable in an aqueous solution for a long time after dissolution. -Naphthyl 4-guanidinobenzoate acid addition salt preparation and a method for producing the same.
【０００７】[0007]
【課題を解決するための手段】上記問題点を解決すべく
鋭意研究を重ねた結果、６−アミジノ−２−ナフチル４
−グアニジノベンゾエート酸付加塩と共にコハク酸を水
に溶解し、この水溶液を凍結乾燥することによって、安
定な凍結乾燥製剤が得られることを見出した。As a result of intensive studies to solve the above problems, 6-amidino-2-naphthyl 4
-It has been found that a stable lyophilized preparation can be obtained by dissolving succinic acid in water together with a guanidinobenzoate acid addition salt and freeze-drying this aqueous solution.
【０００８】本発明において、６−アミジノ−２−ナフ
チル ４−グアニジノベンゾエート酸付加塩としては、
６−アミジノ−２−ナフチル ４−グアニジノベンゾエ
ート１モルに対して、塩酸、硫酸、リン酸等の無機酸、
または、酢酸、乳酸、クエン酸、メタンスルホン酸、４
−トルエンスルホン酸、コハク酸、フマル酸、マレイン
酸等の有機酸等の医薬として使用可能な酸が、２当量付
加したものが用いられる。In the present invention, 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt includes
6-amidino-2-naphthyl 4-guanidinobenzoate per mole of inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid,
Or acetic acid, lactic acid, citric acid, methanesulfonic acid, 4
-An acid which can be used as a medicament such as an organic acid such as toluenesulfonic acid, succinic acid, fumaric acid and maleic acid to which 2 equivalents are added is used.
【０００９】本発明においては、このような６−アミジ
ノ−２−ナフチル ４−グアニジノベンゾエート酸付加
塩とコハク酸を、重量比で１５〜５：１の割合、より好
ましくは１０：１の割合で加えて凍結乾燥をする。In the present invention, such a 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt and succinic acid are used in a weight ratio of 15 to 5: 1, more preferably 10: 1. In addition, freeze-dry.
【００１０】この凍結乾燥に際しては、Ｄ−マンニトー
ル、乳糖および白糖の１種または２種以上を、６−アミ
ジノ−２−ナフチル ４−グアニジノベンゾエート酸付
加塩の１〜３倍量、より好ましくは約２倍量程度、配合
することが望ましい。In the freeze-drying, one or more of D-mannitol, lactose and sucrose are used in an amount of 1 to 3 times, more preferably about 1 to 3 times the amount of 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt. It is desirable to mix about twice the amount.
【００１１】これらは適当量の水に溶解して、ガラスバ
イアルに分注し、凍結乾燥するのがよい。この時、用い
る水の量は、通常６−アミジノ−２−ナフチル ４−グ
アニジノベンゾエート酸付加塩重量の２０〜２００倍程
度である。These are preferably dissolved in an appropriate amount of water, dispensed into glass vials, and lyophilized. At this time, the amount of water used is usually about 20 to 200 times the weight of the 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt.
【００１２】また、凍結乾燥は常法によって行う。凍結
乾燥条件としては、例えば、予備凍結；−５０〜−５℃
で５〜２０時間、次に一次乾燥；−１０℃〜１０℃で２
０〜５０時間、二次乾燥；１０〜３０℃で１０〜３０時
間の順に行うのが望ましい。具体的には、−４５℃で８
時間の予備凍結の後、一次乾燥として０℃で４０時間、
二次乾燥として２５℃、１５時間程度処理するのがよ
い。The freeze-drying is carried out by a conventional method. Freeze-drying conditions include, for example, pre-freezing;
For 5-20 hours, then primary drying;
It is preferable to perform secondary drying in the order of 0 to 50 hours and 10 to 30 hours at 10 to 30 ° C. Specifically, 8 at −45 ° C.
After pre-freezing for hours, primary drying at 0 ° C. for 40 hours,
The secondary drying is preferably performed at 25 ° C. for about 15 hours.
【００１３】このように凍結乾燥の際にも長時間を有す
ることから、水溶液中で不安定な６−アミジノ−２−ナ
フチル ４−グアニジノベンゾエート酸付加塩を、本発
明方法で凍結乾燥すると、製造工程中の分解を最小限に
止めることが可能となり、安定な製剤を提供できる。さ
らに、本発明によって製造した６−アミジノ−２−ナフ
チル ４−グアニジノベンゾエート酸付加塩製剤は用時
溶解後も２４時間以上安定に保つことができる。As described above, since 6-amidino-2-naphthyl 4-guanidinobenzoate acid salt which is unstable in an aqueous solution is freeze-dried by the method of the present invention because it has a long time in freeze-drying, Decomposition during the process can be minimized, and a stable preparation can be provided. Furthermore, the 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt preparation produced by the present invention can be kept stable for 24 hours or more even after dissolution at the time of use.
【００１４】次に、実施例をあげて、本発明をさらに詳
細に説明する。Next, the present invention will be described in more detail with reference to examples.
【００１５】[0015]
【実施例】６−アミジノ−２−ナフチル ４−グアニジ
ノベンゾエート ジメタンスルフォネート（Ｃ19Ｈ17Ｎ
5Ｏ2・２ＣＨ3ＳＯ3Ｈ）２０ｇ、Ｄ−マンニトール４０
ｇ及びコハク酸２ｇを水に溶かし、正確に２Ｌとした。
この液を０．４５μｍのフィルターでろ過し、１ｍＬず
つガラスバイアルに分注した後、凍結乾燥（−４５℃で
８時間の予備凍結の後、一次乾燥として０℃で４０時
間、二次乾燥として２５℃で１５時間）を行った。終了
後、打栓し、アルミキャップで巻き締めをした。EXAMPLE 6-Amidino-2-naphthyl 4-guanidinobenzoate dimethanesulfonate (C 19 H 17 N
5 O 2 · 2CH 3 SO 3 H) 20 g, D-mannitol 40
g and 2 g of succinic acid were dissolved in water to make exactly 2 L.
This solution was filtered through a 0.45 μm filter, dispensed in 1 mL portions into glass vials, and then lyophilized (after preliminary freezing at −45 ° C. for 8 hours, primary drying was performed at 0 ° C. for 40 hours, and secondary drying was performed. At 25 ° C. for 15 hours). After completion, the stopper was stoppered and the tube was tightly wound with an aluminum cap.
【００１６】このようにして製造した６−アミジノ−２
−ナフチル ４−グアニジノベンゾエート−ジメタンス
ルフォネート凍結乾燥製剤を、水１０ｍＬで溶解し、こ
の液２μＬを正確にとり、次の条件で液体クロマトグラ
フ法により、６−アミジノ−２−ナフチル ４−グアニ
ジノベンゾエートのピーク面積を測定し、６−アミジノ
−２−ナフチル ４−グアニジノベンゾエートの残存率
を求めた。The 6-amidino-2 thus prepared
-Naphthyl 4-guanidinobenzoate-dimethanesulfonate Lyophilized preparation is dissolved in 10 mL of water, 2 μL of this solution is accurately taken, and 6-amidino-2-naphthyl 4-guanidinobenzoate is obtained by liquid chromatography under the following conditions. Was measured, and the residual ratio of 6-amidino-2-naphthyl 4-guanidinobenzoate was determined.
【００１７】以下に液体クロマトグラフ法の操作条件を
示した。 検出器：紫外吸光光度計（測定波長：２６１ｎｍ） カラム：ＹＭＣ−Ｐａｃｋ ＯＤＳ−ＡＭ ＡＭ−３０
３（５μｍ、４．６ｍｍ×２５０ｍｍ、（株）ＹＭＣ
製） カラム温度：３５℃付近の一定温度 移動相：薄めたリン酸（１→１０００）／アセトニトリ
ル混液（９：１） 注入量：２μＬ 流量：毎分１ｍＬThe operating conditions of the liquid chromatography method are shown below. Detector: UV absorption spectrophotometer (measurement wavelength: 261 nm) Column: YMC-Pack ODS-AM AM-30
3 (5 μm, 4.6 mm × 250 mm, YMC Corporation)
Column temperature: constant temperature around 35 ° C. Mobile phase: diluted phosphoric acid (1 → 1000) / acetonitrile mixed solution (9: 1) Injection volume: 2 μL Flow rate: 1 mL per minute
【００１８】その結果、溶解直後は９９．９０％、１時
間後９９．８５％、２時間後９９．８６％、２４時間後
９９．６２％であり、安定であった。As a result, it was stable immediately after dissolution: 99.90% after 1 hour, 99.85% after 2 hours, 99.86% after 2 hours and 99.62% after 24 hours.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ テーマコート゛(参考） Ａ６１Ｋ 47/26 Ａ６１Ｋ 9/14 ──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 7 Identification symbol FI theme coat ゛ (Reference) A61K 47/26 A61K 9/14
Claims (3)
ニジノベンゾエート（Ｃ19Ｈ17Ｎ5Ｏ2）酸付加塩１５〜
５部に対し、コハク酸１部を含有する安定な６−アミジ
ノ−２−ナフチル ４−グアニジノベンゾエート酸付加
塩凍結乾燥製剤。1. A 6-amidino-2-naphthyl 4-guanidinobenzoate (C 19 H 17 N 5 O 2 ) acid addition salt 15 to
A freeze-dried 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt lyophilized preparation containing 1 part of succinic acid per 5 parts.
種または２種以上を３５〜５部、さらに含有してなる請
求項１の凍結乾燥製剤。2. One of D-mannitol, lactose and sucrose.
The lyophilized preparation according to claim 1, further comprising 35 to 5 parts of a seed or two or more kinds.
ニジノベンゾエート酸付加塩１５〜５部に対し、コハク
酸１部、要すればＤ−マンニトール、乳糖および白糖の
１種または２種以上を３５〜５部、水に溶解し、凍結乾
燥することを特徴とする安定な６−アミジノ−２−ナフ
チル ４−グアニジノベンゾエート酸付加塩製剤の製造
方法。3. To 15 to 5 parts of 6-amidino-2-naphthyl 4-guanidinobenzoate addition salt, 1 part of succinic acid, if necessary, one or more of D-mannitol, lactose and sucrose is added to 35 parts. A method for producing a stable 6-amidino-2-naphthyl 4-guanidinobenzoate addition salt preparation, characterized by dissolving in 5 to 5 parts in water and freeze-drying.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP09208999A JP4557098B2 (en) | 1999-03-31 | 1999-03-31 | Stable 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt preparation and method for producing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP09208999A JP4557098B2 (en) | 1999-03-31 | 1999-03-31 | Stable 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt preparation and method for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2000290179A true JP2000290179A (en) | 2000-10-17 |
| JP4557098B2 JP4557098B2 (en) | 2010-10-06 |
Family
ID=14044728
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP09208999A Expired - Fee Related JP4557098B2 (en) | 1999-03-31 | 1999-03-31 | Stable 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt preparation and method for producing the same |
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| Country | Link |
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| JP (1) | JP4557098B2 (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS51144717A (en) * | 1975-05-27 | 1976-12-13 | Mallinckrodt Chemical Works | Preparation of radioactive medicine |
| JPS5753454A (en) * | 1980-09-16 | 1982-03-30 | Torii Yakuhin Kk | Guanidinobenzoate and anticomplementary agent |
| JPH09136836A (en) * | 1995-09-13 | 1997-05-27 | Nippon Shinyaku Co Ltd | Pge1-containing lyophilizing preparation |
| JPH11510170A (en) * | 1995-07-27 | 1999-09-07 | ジェネンテック インコーポレーテッド | Protein Formula |
| JP2000510813A (en) * | 1995-02-06 | 2000-08-22 | ジェネテイックス・インスティテュート・インコーポレイテッド | Formulation for IL-12 |
-
1999
- 1999-03-31 JP JP09208999A patent/JP4557098B2/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS51144717A (en) * | 1975-05-27 | 1976-12-13 | Mallinckrodt Chemical Works | Preparation of radioactive medicine |
| JPS5753454A (en) * | 1980-09-16 | 1982-03-30 | Torii Yakuhin Kk | Guanidinobenzoate and anticomplementary agent |
| JP2000510813A (en) * | 1995-02-06 | 2000-08-22 | ジェネテイックス・インスティテュート・インコーポレイテッド | Formulation for IL-12 |
| JPH11510170A (en) * | 1995-07-27 | 1999-09-07 | ジェネンテック インコーポレーテッド | Protein Formula |
| JPH09136836A (en) * | 1995-09-13 | 1997-05-27 | Nippon Shinyaku Co Ltd | Pge1-containing lyophilizing preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| JP4557098B2 (en) | 2010-10-06 |
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