JPH01226814A - Remedy for hyperammonemia - Google Patents
Remedy for hyperammonemiaInfo
- Publication number
- JPH01226814A JPH01226814A JP5061688A JP5061688A JPH01226814A JP H01226814 A JPH01226814 A JP H01226814A JP 5061688 A JP5061688 A JP 5061688A JP 5061688 A JP5061688 A JP 5061688A JP H01226814 A JPH01226814 A JP H01226814A
- Authority
- JP
- Japan
- Prior art keywords
- biotin
- injection
- blood
- administration
- soluble
- 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
- 206010020575 Hyperammonaemia Diseases 0.000 title claims abstract description 10
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims abstract description 96
- 235000020958 biotin Nutrition 0.000 claims abstract description 49
- 239000011616 biotin Substances 0.000 claims abstract description 49
- 229960002685 biotin Drugs 0.000 claims abstract description 49
- 239000003814 drug Substances 0.000 claims abstract description 10
- 229940124597 therapeutic agent Drugs 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 abstract description 52
- 229910021529 ammonia Inorganic materials 0.000 abstract description 26
- 239000008280 blood Substances 0.000 abstract description 26
- 210000004369 blood Anatomy 0.000 abstract description 26
- 239000007924 injection Substances 0.000 abstract description 15
- 238000002347 injection Methods 0.000 abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 15
- 239000012153 distilled water Substances 0.000 abstract description 10
- 208000007386 hepatic encephalopathy Diseases 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 abstract description 8
- 206010010075 Coma hepatic Diseases 0.000 abstract description 7
- 201000001059 hepatic coma Diseases 0.000 abstract description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 6
- 239000003826 tablet Substances 0.000 abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 abstract description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000002775 capsule Substances 0.000 abstract description 3
- 238000007796 conventional method Methods 0.000 abstract description 3
- 239000003381 stabilizer Substances 0.000 abstract description 3
- 229960000583 acetic acid Drugs 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 239000012059 conventional drug carrier Substances 0.000 abstract description 2
- 239000013078 crystal Substances 0.000 abstract description 2
- 239000012362 glacial acetic acid Substances 0.000 abstract description 2
- 238000002844 melting Methods 0.000 abstract description 2
- 230000008018 melting Effects 0.000 abstract description 2
- 238000002156 mixing Methods 0.000 abstract description 2
- 239000000843 powder Substances 0.000 abstract description 2
- 239000006188 syrup Substances 0.000 abstract description 2
- 235000020357 syrup Nutrition 0.000 abstract description 2
- 238000004090 dissolution Methods 0.000 abstract 1
- 229940126701 oral medication Drugs 0.000 abstract 1
- 238000000034 method Methods 0.000 description 11
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 10
- 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 9
- 108010046334 Urease Proteins 0.000 description 9
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 208000019425 cirrhosis of liver Diseases 0.000 description 5
- 238000007912 intraperitoneal administration Methods 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 235000005152 nicotinamide Nutrition 0.000 description 4
- 239000011570 nicotinamide Substances 0.000 description 4
- 208000007788 Acute Liver Failure Diseases 0.000 description 3
- 206010000804 Acute hepatic failure Diseases 0.000 description 3
- 231100000836 acute liver failure Toxicity 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
- 235000013539 calcium stearate Nutrition 0.000 description 3
- 239000008116 calcium stearate Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 229930193140 Neomycin Natural products 0.000 description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- -1 ammonium ions Chemical class 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- XFLVBMBRLSCJAI-UHFFFAOYSA-N biotin amide Natural products N1C(=O)NC2C(CCCCC(=O)N)SCC21 XFLVBMBRLSCJAI-UHFFFAOYSA-N 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229960004927 neomycin Drugs 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000004143 urea cycle Effects 0.000 description 2
- 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 1
- 101000950981 Bacillus subtilis (strain 168) Catabolic NAD-specific glutamate dehydrogenase RocG Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 101710113083 Carbamoyl-phosphate synthase Proteins 0.000 description 1
- 206010010071 Coma Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 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
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 208000010334 End Stage Liver Disease Diseases 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 102000016901 Glutamate dehydrogenase Human genes 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000001940 Massive Hepatic Necrosis Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 208000011444 chronic liver failure Diseases 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- PGBHMTALBVVCIT-VCIWKGPPSA-N framycetin Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CN)O2)N)O[C@@H]1CO PGBHMTALBVVCIT-VCIWKGPPSA-N 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- RSAZYXZUJROYKR-UHFFFAOYSA-N indophenol Chemical compound C1=CC(O)=CC=C1N=C1C=CC(=O)C=C1 RSAZYXZUJROYKR-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000022558 protein metabolic process Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は高アンモニア血症の治療剤に関する。[Detailed description of the invention] [Industrial application field] The present invention relates to a therapeutic agent for hyperammonemia.
更に詳しくは、本発明はビオチンを有効成分として含有
することからなる高アンモニア血症の治療剤に関する。More specifically, the present invention relates to a therapeutic agent for hyperammonemia containing biotin as an active ingredient.
現在、ビオチンを有効成分として含有する治療剤として
の適応は、急・慢性湿疹、小児湿疹、接触皮膚炎等の皮
膚疾患を対象として使用されている。Currently, biotin is used as a therapeutic agent containing biotin as an active ingredient for skin diseases such as acute and chronic eczema, childhood eczema, and contact dermatitis.
高アンモニア血症の治療剤として、従来は非吸収性の抗
生物質、例えばフラジオマイシン(fura−dioa
+aicin)、ネオマイ、シン(neomycin)
などの経口投与や、合成二糖類製剤の経口、浣腸投与に
よる治療が行なわれ、効果を挙げている。Conventionally, non-absorbable antibiotics such as fradiomycin (fura-dioa
+aicin), neomycin, neomycin
Oral administration of synthetic disaccharide preparations and enema administration have been used successfully.
血中のアンモニアは、腸管から吸収されたもの、体内の
蛋白代謝においてアミノ酸転移酵素とグルタミン酸脱水
素酵素の共役反応によって産生されたもの、および体細
胞でアミノ酸から直接離脱したものである。これら血液
中でのアンモニアは、遊離アンモニアと解離平衡により
生成するアンモニウムイオンの状態で存在している。ア
ンモニアは、生体において有毒であることから、健常者
においては、尿素回路などで処理され、血中、組織中と
も遊離アンモニアはきわめて低い一定のレベルに保たれ
ている。Ammonia in the blood is absorbed from the intestinal tract, produced by the coupled reaction of amino acid transferase and glutamate dehydrogenase during protein metabolism in the body, and directly separated from amino acids in body cells. Ammonia in the blood exists in the form of ammonium ions generated by dissociation equilibrium with free ammonia. Ammonia is toxic to living bodies, so in healthy people it is processed through the urea cycle, and free ammonia is kept at a constant, extremely low level in both blood and tissues.
一方、重症肝障害(劇症肝炎、肝硬変など)の場合、ア
ンモニア産生の増加に加え、肝臓でのアンモニア処理能
力が低下するため、高アンモニア血症をきたし、それが
肝性脳症の主因の一つであるとされている。このような
場合、上記従来の治療方法では、患者にしばしば下痢、
菌交代症、腸内組菌叢の変化、胃腸障害等の副作用を惹
起するという欠点を有している。On the other hand, in cases of severe liver damage (fulminant hepatitis, cirrhosis, etc.), in addition to increased ammonia production, the liver's ability to process ammonia decreases, resulting in hyperammonemia, which is one of the main causes of hepatic encephalopathy. It is said that there is one. In such cases, the above conventional treatment methods often leave patients with diarrhea,
It has the disadvantage of causing side effects such as bacterial alternation, changes in intestinal bacterial flora, and gastrointestinal disorders.
本発明は上記従来の治療方法の欠点を克服した、人を含
む温血動物の高アンモニア血症に対するすぐれた治療剤
を提供することを目的とする。An object of the present invention is to provide an excellent therapeutic agent for hyperammonemia in warm-blooded animals including humans, which overcomes the drawbacks of the conventional therapeutic methods described above.
本発明のその他の目的は以後の詳細な説明及び実施例か
ら明らかであろう。Other objects of the invention will become apparent from the detailed description and examples below.
本発明者らは、高アンモニア血症ラットにおいてビオチ
ンを投与することにより、血中アンモニアの有意な低下
を認めた。また、高アンモニア血症を伴う慢性肝不全患
者の血中アンモニア値を低下させ、同時に患者の臨床症
状を著しく改善することを知り、本発明を完成した。The present inventors observed a significant decrease in blood ammonia by administering biotin to hyperammonemic rats. Furthermore, the present invention was completed based on the knowledge that the present invention lowers the blood ammonia level of patients with chronic liver failure accompanied by hyperammonemia, and at the same time significantly improves the clinical symptoms of the patients.
本発明において活性成分として使用するビオチンは次式
によって示される。:
(CHz)9COOH
この化合物は白色の結晶又は結晶性の粉末で、におい及
び味はない。融点は約231℃ (分解)であり、氷酢
酸に溶けに<<、水、エタノール、又はn−ブタノール
に極めて溶けにくく、エーテル又はクロロホルムにほと
んど溶けない。水酸化ナトリウム試液にとける。Biotin used as an active ingredient in the present invention is represented by the following formula. : (CHz)9COOH This compound is a white crystal or crystalline powder with no odor or taste. It has a melting point of about 231° C. (decomposed), is soluble in glacial acetic acid, extremely sparingly soluble in water, ethanol, or n-butanol, and almost insoluble in ether or chloroform. Dissolves in sodium hydroxide test solution.
本発明のビオチンを含有する通常の医薬剤型としてはた
とえば経口剤として錠剤、被覆錠剤、カプセル剤、シロ
ップ剤等、非経口剤としては注射剤等である。投薬単位
形においてはビオチン約0.1ないし50■を含有しう
る。Typical pharmaceutical dosage forms containing the biotin of the present invention include, for example, oral preparations such as tablets, coated tablets, capsules, and syrups, and parenteral preparations such as injections. The dosage unit form may contain about 0.1 to 50 μg of biotin.
固体製剤は通常の医薬担体たとえば乳糖、ショ糖、ソル
ビトール、マンニトール、デンプン類、セルロース誘導
体、ステアリン酸カルシウムおよびマグネシウム、カー
ボワックス、PvP等を包含しうる。経口用水性製剤は
必要により溶解補助剤たとえばニコチン酸アミド、矯味
料例えばショ糖、あるいは安定化剤、香料、着色料等を
包含しうる。Solid formulations may include conventional pharmaceutical carriers such as lactose, sucrose, sorbitol, mannitol, starches, cellulose derivatives, calcium and magnesium stearate, carbowaxes, PvP, and the like. Oral aqueous preparations may optionally contain solubilizing agents such as nicotinamide, flavoring agents such as sucrose, or stabilizers, flavoring agents, coloring agents, and the like.
注射用水性製剤はビオチンと注射用蒸留水からなり、必
要により溶解補助剤、安定化剤、無痛化剤のような他の
成分を含有することができる。これらの医薬製剤はこの
技術分野においてよく知られている技術に従って容易に
製造することができる。The aqueous preparation for injection consists of biotin and distilled water for injection, and may contain other ingredients such as solubilizers, stabilizers, and soothing agents, if necessary. These pharmaceutical formulations can be readily manufactured according to techniques well known in the art.
本発明のビオチンの治療における使用量は患者の症状に
よって可変であるが、成人の場合1日あたりビオチン0
.5ないし100■、好ましくは1ないし30■である
。注射剤の場合1日1ないし2回、内服剤の場合1日数
回、好ましくは3ないし4回に分けて投与するのが推奨
される。The amount of biotin used in the treatment of the present invention varies depending on the patient's symptoms, but for adults, the amount of biotin used per day is 0.
.. It is 5 to 100 square meters, preferably 1 to 30 square meters. In the case of injections, it is recommended to administer the drug once or twice a day, and in the case of oral preparations, it is recommended to administer the drug several times a day, preferably in 3 or 4 divided doses.
ビオチンが血中アンモニア値を低下させる機序は未だ確
立されていないが、尿素回路の初期段階であるカルバモ
イルリン酸合成酵素の炭酸固定に関与している可能性が
考えられるゆ
〔効 果〕
本発明のビオチンのすぐれた血中アンモニア値の上昇抑
制効果は以下に示すラットを使用した試験の結果から実
証される。:
ビオチンの腹腔内投与実験
この実験には、ウィスター系ラット(雄性、平均体重2
00 g )をビオチン投与群に9匹、対照群に9匹の
合計18匹使用した。ビオチン投与実験は血中アンモニ
ア値を上げるために、生理食塩水に溶かしたウレアーゼ
(濃度25単位/−、シグマ社)を25j#位/kg投
与した。ウレアーゼを投与する12時間前に、下記実施
例4に従って製造した注射剤を使用してビオチン1■/
匹(濃度1■/2−)を腹腔的投与し、ウレアーゼ投与
直前に採血を行った。ウレアーゼを腹腔内に投与した後
、2時間、4時間、6時間、9時間目に採血し、これら
の血液試料のアンモニア値を、奥田、藤井の方法〔最新
医学21.622−627(1966)) 、即ち、除
蛋白上清に直接インドフェノール試薬を加えて発色させ
、アンモニアを定量する方法に従い測定した(本実験)
。対照群実験は、ビオチンの代りに生珪素塩水2mlを
腹腔的投与し、上記実験と全く同じ方法で行なった。結
果をそれぞれ次の表1及び表2に示す。Although the mechanism by which biotin lowers blood ammonia levels has not yet been established, it is thought that biotin may be involved in carbon dioxide fixation by carbamoyl phosphate synthase, which is an early step in the urea cycle. The excellent effect of the biotin of the invention on suppressing the rise in blood ammonia levels is demonstrated by the results of the test using rats shown below. : Intraperitoneal administration experiment of biotin This experiment involved Wistar rats (male, average weight 2
00 g) was used for a total of 18 animals, 9 animals in the biotin administration group and 9 animals in the control group. In the biotin administration experiment, in order to increase the blood ammonia level, urease (concentration 25 units/-, Sigma) dissolved in physiological saline was administered at a dose of about 25j#/kg. 12 hours before administering urease, inject biotin 1/2 hours using an injection prepared according to Example 4 below.
The mice (concentration 1/2-) were administered intraperitoneally, and blood was collected immediately before administration of urease. After intraperitoneal administration of urease, blood was collected at 2 hours, 4 hours, 6 hours, and 9 hours, and the ammonia levels of these blood samples were determined using the method of Okuda and Fujii [Modern Medicine 21.622-627 (1966). ), that is, indophenol reagent was directly added to the deproteinized supernatant to develop color, and ammonia was measured according to the method of quantifying it (this experiment).
. A control group experiment was conducted in exactly the same manner as the above experiment, with 2 ml of raw silicon saline being intraperitoneally administered instead of biotin. The results are shown in Tables 1 and 2 below.
上記表1、表2からビオチン投与群の、ウレアーゼ投与
4時間後及び6時間後の血中アンモニア値の上昇の平均
がそれぞれ126.4μg/d!、104.8μg/d
!であるのに対し、対照群のウレアーゼ投与4時間後及
び6時間後の血中アンモニア値の上昇の平均はそれぞれ
257.0μg/dl、278.1 μg/d1であり
、ビオチンを投与することによりウレアーゼ負荷によっ
て生ずる血中アンモニア値の上昇をウレアーゼ投与後4
ないし6時間にわたって著しく抑制する事が認められる
。また上記表1および表2の数値につき、それぞれに対
応する平均値の差のt検定を行なったところ、ウレアー
ゼ投与後4時間および9時間でp<0.02.6時間で
p<0.01と明らかな差をもって本発明のビオチンは
血中アンモニア値を低下せしめることを示した。From Tables 1 and 2 above, the average increase in blood ammonia levels in the biotin-administered group 4 and 6 hours after urease administration was 126.4 μg/d, respectively! , 104.8μg/d
! On the other hand, the average increase in blood ammonia levels in the control group 4 hours and 6 hours after administration of urease was 257.0 μg/dl and 278.1 μg/d1, respectively; Increase in blood ammonia levels caused by urease loading after urease administration4
Significant suppression was observed for up to 6 hours. In addition, when a t-test was conducted on the difference between the corresponding mean values for the values in Tables 1 and 2 above, it was found that p<0.02.6 hours and p<0.01 at 4 hours and 9 hours after urease administration. It was shown that the biotin of the present invention lowers blood ammonia levels with a clear difference.
急性肝不全モデルラットにおけるビオチンの腹腔的投与
実験
この実験にはウィスター系ラット(雄性、平均体重24
0 g )を20匹使用した。急性肝不全モデルを作る
ためにオリーブ油と1対1に混合した四塩化炭素を2
d / kgを腹腔内投与した。ビオチン投与群は四塩
化炭素投与48時間前、24時間前、6時間前に下記実
施例4に従って製造した注射溶液を使用してビオチン各
1■(1■/2w11)を腹腔内投与し、四塩化炭素投
与直前に採血を行なった。Experiment on intraperitoneal administration of biotin in acute liver failure model rats.
0 g) were used. Carbon tetrachloride mixed 1:1 with olive oil was used to create an acute liver failure model.
d/kg was administered i.p. For the biotin-administered group, 48 hours, 24 hours, and 6 hours before the administration of carbon tetrachloride, each dose of biotin (1/2 w11) was intraperitoneally administered using an injection solution prepared according to Example 4 below. Blood was collected immediately before carbon chloride administration.
四塩化炭素を腹腔内投与した後、24時間、48時間目
にそれぞれ5匹ずつ頚静脈より採血した。これらの血液
試料のアンモニア値を奥田、藤井の前記の方法に従い測
定した(本実験)。After intraperitoneal administration of carbon tetrachloride, blood was collected from the jugular vein of five animals each at 24 hours and 48 hours. The ammonia levels of these blood samples were measured according to the method described by Okuda and Fujii (this experiment).
対照実験はビオチンの代りに生理食塩水を21R1腹腔
内投与し、上記実験と全く同じ方法で行なった。結果を
次の表3及び表4に示す。A control experiment was conducted in exactly the same manner as the above experiment, with physiological saline being intraperitoneally administered to 21R1 instead of biotin. The results are shown in Tables 3 and 4 below.
上記表3、表4からビオチンは四塩化炭素負荷による急
性肝不全モデルでの血中アンモニア値の上昇を抑制する
傾向であることが認められる。また対照群において四塩
化炭素投与24時間後及び48時間後にラットがそれぞ
れ2匹ずつ死亡しているのに対し、ビオチン投与群は死
亡例が無い。これらの死亡率についてカッブランマイヤ
ー法で検定をおこなったところビオチン投与群のほうが
明らかに延命効果を示した。From Tables 3 and 4 above, it is recognized that biotin tends to suppress the increase in blood ammonia level in the acute liver failure model caused by carbon tetrachloride loading. Furthermore, in the control group, two rats each died 24 hours and 48 hours after carbon tetrachloride administration, whereas there were no deaths in the biotin administration group. When these mortality rates were tested using the Kabran-Meier method, the biotin-administered group clearly showed a survival benefit.
本発明のビオチンを各種投与経路でマウス及びラットに
投与した場合の急性毒性(LD、。)を次の表5 〔フ
レグランス ジャーナル、61−64 (1980)、
フレグランスジャーナル社〕に示す。The acute toxicity (LD,.) when the biotin of the present invention is administered to mice and rats via various administration routes is shown in Table 5 below [Fragrance Journal, 61-64 (1980),
Fragrance Journal Co.].
表 5
〔ビオチンの急性毒性〕
〔実施例〕
本発明の化合物を投薬するための有用な医薬製剤の例を
次の実施例に示す。Table 5 Acute Toxicity of Biotin Examples Examples of useful pharmaceutical formulations for administering compounds of the invention are provided in the following examples.
実施例 l
ビオチン 2■乳
糖 55コーン
スターチ 16微結晶セルロース
30ポリビニルピロリドンに−3
05
ステアリン酸カルシウム 2全量110
■
乳糖の一部でビオチン倍散を予製し、コーンスターチ、
微結晶セルロース、残りの乳糖を混合した中にビオチン
倍散を添加混合する。次にポリビニルピロリドンに−3
0の水溶液を結合剤として加え、以下常法に従って組粒
を製造し、ステアリン酸カルシウムを加えて混合した後
1錠110■の錠剤に打錠する。Example l Biotin 2 ■ Milk
Sugar 55 Corn starch 16 Microcrystalline cellulose 30 Polyvinylpyrrolidone -3
05 Calcium stearate 2 total amount 110
■ Pre-prepared biotin trichloride with a portion of lactose, cornstarch,
Add the biotin suspension to the mixture of microcrystalline cellulose and remaining lactose and mix. Next, -3 to polyvinylpyrrolidone
An aqueous solution of No. 0 is added as a binder, followed by preparing aggregated granules according to a conventional method. After adding calcium stearate and mixing, the mixture is compressed into 110 square tablets.
実施例 2
エンテリツクコーティング錠
実施例1に従い得られた錠剤の表面に下記組成のコーテ
イング液を常法に従い噴霧し、乾燥物として1錠あたり
10■の被膜を形成させる。Example 2 Enteric Coated Tablets A coating solution having the following composition is sprayed on the surface of the tablets obtained according to Example 1 according to a conventional method to form a coating of 10 cm per tablet as a dry product.
エンテリツクコーティング′100■の几オイドラギッ
トL30D −5545,0マクロゴール6000
1 、5タルク
3.0精製水
50.5全量100.0■
実施例 3
ビオチン 2.0■注射用
蒸留水 通量全量 10.0d
ビオチンを注射用蒸留水に溶解し、常法に従い濾過した
後アンプルに10.0−充填する。続いてアンプルを溶
閉後滅菌する。Enteric coating '100■'s Eudragit L30D -5545,0 Macrogol 6000
1.5 talc
3.0 Purified water
50.5 Total amount 100.0 ■ Example 3 Biotin 2.0 ■ Distilled water for injection Total amount 10.0 d Biotin is dissolved in distilled water for injection, filtered according to the usual method, and then filled into ampules with 10.0 d. . The ampoule is then fused and sterilized.
実施例 4
ビオチン 5.0 ■ニ
コチン酸アミド 0.15ベンジル
アルコール 0.2注射用蒸留水
適量全量 10.oIlll
ビオチン及びニコチン酸アミド(溶解補助剤)をビオチ
ンが溶解しうる適量容量の加温した注射用蒸留水に加え
、ついで攪拌溶解後常温まで冷却した後ベンジルアルコ
ール(無痛化剤)と注射用蒸留水を加え全量とする。Example 4 Biotin 5.0 ■Nicotinic acid amide 0.15 Benzyl alcohol 0.2 Distilled water for injection
Appropriate amount of whole amount 10. oIlll Add biotin and nicotinic acid amide (solubilizing agent) to an appropriate volume of warmed distilled water for injection in which biotin can be dissolved, then stir and dissolve, cool to room temperature, and add benzyl alcohol (soothing agent) and distilled water for injection. Add water to make the total volume.
以後、常法に従い濾過した後アンプルに10.0Pnl
充填し、溶閉後滅菌する。Thereafter, after filtering according to the usual method, 10.0Pnl was added to the ampoule.
Fill, seal and sterilize.
実施例 5
梗旦里之ユヱIM
ユ並4主
ビオチン 10 zニコ
チン酸アミド 300D−ソルビット
2000渾留水
適量全量100M1
約374容量の温蒸留水中にビオチンとニコチン酸アミ
ドを加え、撹拌溶解後D−ソルビ・ノドを徐々に加える
。溶解後、常温まで冷却し残りの蒸留水を規定量まで加
える。Example 5 Kotan Satoyuki IM Yu average 4 main biotin 10 z Nicotinic acid amide 300D-Sorvit 2000 water distilled water
Add biotin and nicotinic acid amide to approximately 374 volumes of hot distilled water (100 M1 total volume), stir and dissolve, and then gradually add D-Sorbi Nod. After dissolving, cool to room temperature and add the remaining distilled water to the specified amount.
実施例 6
カプセル
1カプセル中
ビオチン 2 ■乳
糖 298全量3
00■
乳糖の約1710量にビオチンを加えて混合した後、残
りの乳糖を加えて均一に混合する。これをゼラチン硬カ
プセルに充填する。Example 6 Biotin in 1 capsule 2 ■Milk
Sugar 298 total amount 3
00■ Add biotin to about 1710 ml of lactose and mix, then add the remaining lactose and mix uniformly. This is filled into hard gelatin capsules.
本発明のビオチン含有製剤を主に肝硬変に基づ(高アン
モニア血症の患者に投与した臨床成績、即ち血中アンモ
ニア値及び高アンモニア血症に付随して発症する肝性昏
睡の改善効果を以下に示す。尚、此等の患者は、他の高
アンモニア血症治療薬を投与しても、改善が見られなか
った例である。The clinical results of administering the biotin-containing preparation of the present invention to patients with hyperammonemia, mainly due to liver cirrhosis, are as follows: These patients are examples in which no improvement was seen even after administration of other hyperammonemia therapeutics.
患者 1 男 67歳 肝硬変+胃癌
患者 2 女 65歳 肝硬変
患者 3 男 51歳 肝硬変
ビオチンは実施例4に従って製造した注射液(0,5■
/−)を1日5■ないし10■静脈内投与を行なった。Patient 1: Male, 67 years old, liver cirrhosis + gastric cancer patient 2: Female, 65 years old, liver cirrhosis patient 3: Male, 51 years old Liver cirrhosis biotin was an injection prepared according to Example 4 (0.5
/-) was administered intravenously 5 to 10 times a day.
投与期間は各患者の状態によって異なっている。The administration period varies depending on each patient's condition.
各患者の血液試料は1日1回又は数回はぼ同時刻に採血
したものを微量拡散法(患者l、患者2)及び奥田・藤
井の前記方法(患者3)により血中アンモニア値を測定
し、また、肝性昏睡の度合をしらべた。Blood samples from each patient were collected once or several times a day at approximately the same time, and blood ammonia levels were measured using the microdiffusion method (patients 1 and 2) and the method described by Okuda and Fujii (patient 3). The degree of hepatic coma was also determined.
肝性昏睡の度合は、表6〔昏睡度分類表〕に基づいて定
めた。これについての診断基準となる分類表は、日本医
師会雑誌第92巻第7号(昭和59年10月1日発行)
第78頁及び第12回犬山シンポジウム110゜198
2、中外医学社に所載されている。The degree of hepatic coma was determined based on Table 6 [Coma Degree Classification Table]. The classification table that serves as the diagnostic standard for this is published in the Journal of the Japan Medical Association, Vol. 92, No. 7 (published October 1, 1980).
Page 78 and 12th Inuyama Symposium 110°198
2. Published in Chugai Igakusha.
各患者のビオチン投与の間隔、投与前後の血中アンモニ
ア値及び肝性昏睡の度合を表7〜9にそれぞれ示す。Tables 7 to 9 show the biotin administration interval, blood ammonia level before and after administration, and degree of hepatic coma for each patient.
支−ユ
C恒者 3〕
a)血中アンモニア値:ビオチン投与前の血中アンモニ
ア濃度を表わす
(単位μg/di)
b)肝 性 昏 睡 度二表6に従った肝性昏睡度を表
わす。3) a) Blood ammonia level: Represents the blood ammonia concentration before biotin administration (unit: μg/di) b) Hepatic coma level 2 Represents the hepatic coma level according to Table 6 .
ただし、■−■は、mと■との中間状態を示す(以下同
様)。However, ■-■ indicates an intermediate state between m and ■ (the same applies hereinafter).
m<nに近い中間状態を示す(以下同 様)。Indicates an intermediate state close to m<n (hereinafter the same) Mr).
Oは正常状態を表わす。O represents a normal state.
C)ビオチン投与量 :1日(24時間)のビオチン投
与量を表わす。C) Biotin dose: represents the biotin dose per day (24 hours).
上記表7〜9の結果は、全ての例において本発明のビオ
チンを投与することにより血中アンモニア値の低下及び
肝性昏睡度を改善せしめることを示している。The results in Tables 7 to 9 above show that administration of the biotin of the present invention reduces blood ammonia levels and improves the degree of hepatic coma in all cases.
特許出願人 三生製薬株式会社Patent applicant: Sansei Pharmaceutical Co., Ltd.
Claims (1)
ンモニア血症治療剤。A therapeutic agent for hyperammonemia containing biotin as an active ingredient.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5061688A JPH0788304B2 (en) | 1988-03-05 | 1988-03-05 | Hyperammonemia treatment |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5061688A JPH0788304B2 (en) | 1988-03-05 | 1988-03-05 | Hyperammonemia treatment |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH01226814A true JPH01226814A (en) | 1989-09-11 |
JPH0788304B2 JPH0788304B2 (en) | 1995-09-27 |
Family
ID=12863908
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP5061688A Expired - Lifetime JPH0788304B2 (en) | 1988-03-05 | 1988-03-05 | Hyperammonemia treatment |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0788304B2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3275439A1 (en) * | 2016-07-29 | 2018-01-31 | Medday Pharmaceuticals | Method for treating hepatic encephalopathy |
-
1988
- 1988-03-05 JP JP5061688A patent/JPH0788304B2/en not_active Expired - Lifetime
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3275439A1 (en) * | 2016-07-29 | 2018-01-31 | Medday Pharmaceuticals | Method for treating hepatic encephalopathy |
WO2018020010A1 (en) | 2016-07-29 | 2018-02-01 | Medday Pharmaceuticals | Method for treating hepatic encephalopathy |
US10117854B2 (en) | 2016-07-29 | 2018-11-06 | Medday Pharmaceuticals | Method for treating hepatic encephalopathy |
US10328059B2 (en) | 2016-07-29 | 2019-06-25 | Medday Pharmaceuticals | Method for treating hepatic encephalopathy |
JP2019522030A (en) * | 2016-07-29 | 2019-08-08 | メッドデイ、ファーマシューティカルズMedday Pharmaceuticals | Treatment for hepatic encephalopathy |
Also Published As
Publication number | Publication date |
---|---|
JPH0788304B2 (en) | 1995-09-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
BRPI0818118B1 (en) | Pharmaceutical composition in the form of a stabilized aqueous suspension of carisbamate and its formation process | |
CN106659711A (en) | Durable preparation of an injectable of melatonin exhibiting long-term stability | |
BR112013020424A2 (en) | REPLACED NITROCATECOL, USES OF THE SAME, COMBINATION AND COMPOSITION THAT UNDERSTAND IT | |
JPH0367045B2 (en) | ||
JPH06507382A (en) | Molecular correction in the treatment of sickle cell disease | |
CH655009A5 (en) | USEFUL COMPOSITIONS FOR PROPHYLAXIS OF HYPERLACTACIDEMIA. | |
US4027017A (en) | Method of treating alcoholism | |
JP2526059B2 (en) | Anti-ulcer agent | |
JPH07507288A (en) | Desferrioxamine-B salts and their use as orally effective iron chelators | |
JP3872834B2 (en) | Maillard reaction inhibitor | |
JPH0352815A (en) | Remedy for intravascular blood coagulation syndrome | |
WO2007143895A1 (en) | Supersaturated solution of gemcitabine hydrochloride and prepraration method thereof | |
EP0448029B1 (en) | Novel pharmaceutical uses of forskolin derivatives | |
JPH03135918A (en) | Immune-activating agent | |
JPH01226814A (en) | Remedy for hyperammonemia | |
JP3125083B2 (en) | TNF overproduction inhibitor | |
EA006776B1 (en) | Medical composition for treating diabetic neuropathy | |
US3459854A (en) | Tetracycline cyclohexyl sulphamate and process for preparation | |
US3961064A (en) | Pharmaceutical composition for remedy of hyperammoniemia | |
JP2720165B2 (en) | Glucose electrolyte compounding agent | |
US3906107A (en) | Aminoalkyl sulfate esters with diuretic activity | |
JPH05504130A (en) | Tumor necrosis factor antagonist | |
US4271150A (en) | Urokinase preparation for oral administration | |
US4766126A (en) | Process for treatment of nephritis with imidazoquinazolines | |
US5747495A (en) | Method for treating hypertension using pyrazolopyrimidine derivatives |