JP6858729B2 - New acetaminophen complex composition with no side effects on the liver - Google Patents
New acetaminophen complex composition with no side effects on the liver Download PDFInfo
- Publication number
- JP6858729B2 JP6858729B2 JP2018100209A JP2018100209A JP6858729B2 JP 6858729 B2 JP6858729 B2 JP 6858729B2 JP 2018100209 A JP2018100209 A JP 2018100209A JP 2018100209 A JP2018100209 A JP 2018100209A JP 6858729 B2 JP6858729 B2 JP 6858729B2
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- mannitol
- acetaminophen
- sucralose
- content
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Description
本発明は、肝臓に対する副作用がない、新しいアセトアミノフェン（Acetaminophen、APAP）複合組成、特に、アセトアミノフェン、細胞色素であるシトクロムP450 2E1（CYP2E1）の酵素活性を抑制する、安全で、薬学的に許容可能なひとつ以上の賦形剤とを組み合わせ、アセトアミノフェンが起こす肝毒性の副作用を降下させる、新しいアセトアミノフェン複合組成に関するものである。 The present invention is safe and pharmaceutical, suppressing the enzymatic activity of a novel acetaminophen (APAP) complex composition that has no side effects on the liver, in particular acetaminophen, the cytochrome P450 2E1 (CYP2E1). It relates to a new acetaminophen composite composition that, in combination with one or more acceptable excipients, reduces the hepatotoxic side effects of acetaminophen.
アセトアミノフェン（Acetaminophen，俗称「普拿疼」）、別名パラセタモール（paracetamol）またはN-アセチル-P-アミノフェノール（N-acetyl-para-aminophenol）、略称APAPは、最もよく知られている解熱鎮痛剤である。アセトアミノフェンの不当な使用を原因とする中毒や、これを自殺に用いる事件が毎年発生しており、アセトアミノフェンがもたらす肝障害はかなり深刻であり、死亡することも珍しくない。アセトアミノフェンの肝毒性は予防可能であることは、すでに多くの臨床経験によって証されており、早期の診断及び適時の解毒剤N-アセチルシステイン（N-acetylcysteine、NAC）投与によって、肝毒性の発生を防ぐことができる。 Acetaminophen, also known as paracetamol or N-acetyl-para-aminophenol, abbreviated APAP, is the most well-known antipyretic analgesia. It is an agent. Poisoning caused by improper use of acetaminophen and cases of using it for suicide occur every year, and the liver damage caused by acetaminophen is quite serious, and it is not uncommon to die. Much clinical experience has already demonstrated that acetaminophen's hepatotoxicity is preventable, with early diagnosis and timely administration of the antidote N-acetylcysteine (NAC) to prevent hepatotoxicity. It can be prevented from occurring.
アセトアミノフェンを過度に服用した場合、早期の発見が大事である。中毒後8時間以内に解毒剤を投与すれば、最も効果的だからである。初期における薬物中毒の兆候は、身体の不快感、悪心、吐き気だが、一部の患者の場合、血液中のアセトアミノフェン濃度が中毒であることを示す濃度に達し、肝機能も異常なのだが、初期においては症状が現れず（第一期）、腹痛、嘔吐の繰り返し、黄疸、右上腹部の痛みといった肝毒性の兆候は、大量摂取から24〜48時間（第二期）で明らかになってくる。血清中のトランスアミナーゼは、服用から16時間後に上昇しはじめ、これにともなって臨床症状が現れてくる。服用後、3〜4日が第三期であり、このとき、肝障害の程度、今後の症状が予想できるようになる。肝毒性の症状は、軽微な状態から、肝機能を表す指数ASTが、AST＞1,000IU/Lになると、激しい肝炎に代謝性アシドーシス、黄疸、低血糖をともない、AST＞10,000IU/Lになると、血液凝固異常、肝脳疾患などをともない、第四期になると、腎不全による乏尿が起こり、深刻な場合には死に至る。 Early detection is important when acetaminophen is taken excessively. It is most effective to administer the antidote within 8 hours after poisoning. Early signs of drug addiction are physical discomfort, nausea, and nausea, but in some patients, acetaminophen levels in the blood reach levels that indicate addiction and liver function is abnormal. Symptoms do not appear in the early stage (first stage), and signs of hepatotoxicity such as abdominal pain, repeated vomiting, jaundice, and pain in the upper right abdomen become apparent 24-48 hours (second stage) after high intake. .. Transaminase in serum begins to rise 16 hours after administration, and clinical symptoms appear with this. Three to four days after taking the drug is the third stage, at which time the degree of liver damage and future symptoms can be predicted. The symptom of hepatotoxicity is that when the index AST, which indicates liver function, becomes AST> 1,000 IU / L from a slight state, severe hepatitis is accompanied by metabolic acidosis, jaundice, and hypoglycemia, and AST> 10,000 IU / L. In the fourth stage, with abnormal blood coagulation, hepato-brain disease, etc., jaundice due to renal failure occurs, and in severe cases, death occurs.
一部のアセトアミノフェン中毒患者は、肝障害の程度は軽いが、深刻な腎毒性を有しており、それはアセトアミノフェンが腎細管上のシトクロムP450s（cytochrome P450s、略称CYPs）において代謝することによってもたらされた腎毒性である。しかし、急性肝不全が急性腎不全をもたらす肝腎症候群の可能性もあり、この場合、尿中ナトリウム排泄率（fraction excretion of Na、略称FeNa）によって、腎性腎不全（FeNa＞1）と肝腎症候群（FeNa ＜1）を区別する。FeNaの計算式：（尿中ナトリウム濃度Sodiumurinary ÷ 尿中クレアチニン濃度Creatinineurinary）÷（血漿ナトリウム濃度Sodiumplasma ÷ 血漿クレアチニン濃度Creatinineplasma）× 100、である。 Some patients with acetaminophen poisoning have mild but severe nephrotoxicity, which is that acetaminophen is metabolized in cytochrome P450s (cytochrome P450s, abbreviated CYPs) on the renal tubules. Nephrotoxicity brought about by. However, there is also the possibility of hepato-renal syndrome in which acute hepatic failure results in acute renal failure. In this case, depending on the urinary sodium excretion of Na (abbreviated as FeNa), renal renal failure (FeNa> 1) and hepato-renal syndrome Distinguish (FeNa <1). Formula for calculating FeNa: (Urine sodium concentration Sodiumurinary ÷ Urinary creatinine concentration Creatinineurinary) ÷ (Plasma sodium concentration Sodiumplasma ÷ Plasma creatinine concentration Creatinineplasma) × 100.
アセトアミノフェンを経口で服用後、1〜2時間で血液中濃度がピークに達し、そのほとんどが肝臓で代謝される。つまり、90%はグルクロン酸（glucuronide）及びスルフェート（sulfate）と結合して無毒の代謝物が形成される。わずかだが5%未満は、CYP2E1、CYP1A2及びCYP3A4といった異なるシトクロム（CYPs）によって代謝されるが、そのうちCYP2E1及びCYP1A2が主な代謝酵素である。これらの酵素の代謝により発生するアセトイミドキノン（N-acetyl-p-benzoquinoneimine、略称 NAPQI（図1参照））は、活性度の高い求電子試薬（electrophile）である。正常な状況においては、NAPQIはすぐに細胞内のグルタチオン（glutathione）と反応して、無毒のメルカプチド化合物（mercaptide）を形成する。アセトアミノフェンが過度に投与されると、細胞内におけるグルタチオンの消耗が、その合成の速度を上回るため、細胞内グルタチオン含有量が正常の30%を割ったとき、NAPQIは、細胞内でシステイン（cysteine）を含む大分子、またはヌクレオチドと結合し、肝細胞が障害される。細胞組織の染色観察から、肝細胞が壊死する前、NAPQIは、肝子葉の中央部で、システインのメルカプチドと共有結合することがわかっている。 Blood levels peak 1 to 2 hours after taking acetaminophen orally, most of which is metabolized in the liver. That is, 90% binds to glucuronide and sulfate to form non-toxic metabolites. A small but less than 5% is metabolized by different cytochromes (CYPs) such as CYP2E1, CYP1A2 and CYP3A4, of which CYP2E1 and CYP1A2 are the major metabolic enzymes. Acetimidequinone (N-acetyl-p-benzoquinoneimine, abbreviated as NAPQI (see Fig. 1)) generated by metabolism of these enzymes is a highly active electrophile. Under normal circumstances, NAPQI immediately reacts with intracellular glutathione to form a non-toxic mercaptide compound. When acetaminophen is overdosed, intracellular glutathione depletion exceeds the rate of its synthesis, so when the intracellular glutathione content falls below 30% of normal, NAPQI is called intracellular cysteine ( It binds to large molecules or nucleotides containing (cysteine) and damages hepatocytes. Staining observations of cell tissues indicate that NAPQI covalently binds to cysteine mercaptide in the central part of the hepatic lobule before hepatocyte necrosis.
肝臓病、アルコール依存症、または、カルバマゼピン（Carbamazepine）、エタノール（Ethanol）、イソニアジド（Isoniazid）、フェノバルビタール（Phenobarbital）（おそらく他のバルビツール酸誘導体（barbiturates））、フェニトイン（Phenytoin）、スルフィンピラゾン（Sulfinpyrazone）、スルホニル尿素誘導体（Sulfonylureas）、リファンピン（Rifampin）、プリミドン（Primidone）など、肝臓のシトクロムP450酵素を活性化させる薬物を服用している患者は、アセトアミノフェンによる深刻な肝毒性がもたらされるリスクが高い。患者が、成人呼吸窮迫症候群、水頭症、止血不能、感染症または複数の臓器不全といった合併症を患っている場合には、死に至ることも多い。アルコールを例にとると、アルコールは肝臓のCYP2E1によって代謝されるが、この過程でアセトアミノフェン中毒が誘発されるメカニズムは三段階に分かれる。第一段階は、アルコールとアセトアミノフェンが肝臓のCYP2E1で競合する段階で、このときNAPQIの濃度はまず降下する。第二段階は、アルコールがCYP2E1の半減期を7時間から37時間まで延長し、肝臓におけるCYP2E1含有量を増加させる段階で、このときNAPQIの濃度はしだいに上昇する。第三段階は、アルコールが断たれたとき、肝臓の中で増えたCYP2E1がアセトアミノフェンを代謝する段階で、アセトアミノフェンの毒性代謝物が著しく増加し、肝細胞の障害をまねく。最近の研究によると、ジアリルスルフィド（diallyl sulfide）を用いると、アセトアミノフェンがラット体内で引き起こす肝障害を予防でき、これを一歩進めて、ジアリルスルフィドがCYP2E1酵素の活性を抑制することがわかっており、ジアリルスルフィドはアセトアミノフェンが引き起こす肝毒性の障害を予防できると推論できる。その保護メカニズムは、アセトアミノフェンが活性中間代謝産物であるアセトイミドキノンを抑制する、というものであり、肝細胞中の還元性グルタチオン（glutathione）の消費を抑制することにより、アセトイミドキノンがもたらす酸化ストレス、ミトコンドリア機能障害、DNA損傷を軽減し、サンシチニンジン（Panax notoginseng）、アデノシン（Adenosine）、及びアデノシン一リン酸、アデノシン二リン酸、アデノシン三リン酸といった誘導体など、アセトアミノフェンによる肝障害を軽減することであり、いずれの場合もこの保護メカニズムを通して、アセトアミノフェンのもたらす肝障害を防止できる。 Liver disease, alcohol dependence, or carbamazepine, Ethanol, Isoniazid, phenobarbital (probably other barbiturates), phenytoin, sulfinpyrazone Patients taking drugs that activate hepatic cytochrome P450 enzymes, such as (Sulfinpyrazone), sulfonylurea derivatives (Sulfonylureas), Rifampin, and Primidone, have severe hepatotoxicity due to acetaminophen. There is a high risk of being affected. Patients often die if they suffer from complications such as adult respiratory distress syndrome, hydrocephalus, hemostasis, infections or multiple organ failure. Taking alcohol as an example, alcohol is metabolized by CYP2E1 in the liver, and the mechanism by which acetaminophen poisoning is induced in this process is divided into three stages. The first step is when alcohol and acetaminophen compete for CYP2E1 in the liver, at which time the concentration of NAPQI drops first. The second step is when alcohol extends the half-life of CYP2E1 from 7 hours to 37 hours, increasing the CYP2E1 content in the liver, at which time the concentration of NAPQI gradually increases. The third stage is when CYP2E1 increased in the liver metabolizes acetaminophen when alcohol is cut off, and the toxic metabolites of acetaminophen increase significantly, leading to hepatocyte damage. Recent studies have shown that diallyl sulfide can prevent liver damage caused by acetaminophen in rats and takes this one step further, showing that diallyl sulfide suppresses the activity of the CYP2E1 enzyme. Therefore, it can be inferred that diallyl sulfide can prevent the damage of hepatotoxicity caused by acetaminophen. The protective mechanism is that acetaminophen suppresses the active intermediate metabolite, acetimidequinone, which is brought about by suppressing the consumption of reducing glutathione in hepatocytes. Reduces oxidative stress, mitochondrial dysfunction, DNA damage, and acetaminophen-induced livers such as panax notoginseng, adenosine, and derivatives such as adenosine monophosphate, adenosine diphosphate, and adenosine triphosphate. It is to reduce the disorder, and in any case, through this protection mechanism, the liver damage caused by acetaminophen can be prevented.
侵襲式及び非侵襲式の方法で、ラットの肝機能を測定し、肝障害の推移をモニタリングして肝臓疾患をスクリーニングする。もっともよく用いられる方法は、血清中のアスパラギン酸アミノ基転移酵素（aspartate aminotransferase、AST）、アラニンアミノ基転移酵素（alanine aminotransferase、ALT）、アルカリホスファターゼ（alkaline phosphatase）の数値測定、及び、ビリルビン（bilirubin）、アルブミン（albumin）といった肝細胞の産物の測定、プロトロンビン時間（prothrombin time）の計測による凝固因子（coagulation factors）の検査などがある。肝機能定量測定は、ほとんど肝臓代謝だけしか受けない基質の血清中濃度に基づいており、これらの基質の除去は、肝門静脈、肝動脈の血液流量、及びこれらの基質に対する肝細胞の作用によって決まり、肝臓の血液流量は肝臓に提供される基質の量と関係しており、これに反して、これらの基質の除去は肝臓の代謝能力によって決まる。 Liver function in rats is measured by invasive and non-invasive methods, and the transition of liver damage is monitored to screen for liver disease. The most commonly used methods are numerical measurement of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (alkaline phosphatase) in serum, and bilirubin. ), Measurement of hepatocyte products such as albumin, and examination of coagulation factors by measurement of prothrombin time. Quantitative hepatic function measurements are based on serum concentrations of substrates that undergo almost exclusively hepatic metabolism, and removal of these substrates is by the blood flow of the hilar vein, hepatic artery, and the action of hepatic cells on these substrates. Determined, the blood flow of the liver is related to the amount of substrates provided to the liver, whereas the removal of these substrates is determined by the metabolic capacity of the liver.
ガラクトース（galactose）は抽出比（extraction ratio）が高く、90%肝臓中で代謝される糖類である。肝臓の中でガラクトースは、ガラクトキナーゼ（galactokinase）のエピメリ化（epimerization）を経て、グルコース-1-リン酸（Glucose-1-phosphate）に転換される。ガラクトキナーゼの作用は、肝細胞中におけるガラクトース代謝過程の律速段階（rate-limiting step）に当たる。ガラクトースは抽出比が高いので、肝臓の血液流量と肝臓機能に依頼するガラクトース代謝作用をもって、肝機能を測定することが可能である。今のところ、ラットの残存肝機能（residual liver function）を測定する方法は規定されていないが、ひとつの化合物（例：ガラクトース）の代謝能力から、肝臓中のひとつの代謝作用の律速段階を推測することもまた、残存肝機能を数値化するひとつの方法であろう。 Galactose is a saccharide that has a high extraction ratio and is 90% metabolized in the liver. In the liver, galactose is converted to glucose-1-phosphate via epimerization of galactokinase. The action of galactokinase corresponds to the rate-limiting step of the galactose metabolism process in hepatocytes. Since galactose has a high extraction ratio, it is possible to measure liver function with the blood flow rate of the liver and the galactose metabolism that depends on the liver function. At present, the method for measuring the residual liver function of rats has not been specified, but the rate-determining stage of one metabolic action in the liver is estimated from the metabolic capacity of one compound (eg, galactose). Doing would also be one way to quantify residual liver function.
本発明は、ガラクトース単一点法で慢性肝炎、肝硬化及び肝臓癌を計測し、ガラクトース単一点法がこれらの肝臓疾患を正確に表せることを発見した。ガラクトース単一点法は、肝臓病患者がプロマジン（promazine）やセフォペラゾン（cefoperazone）といった薬物を排除するための残存肝機能の測定に応用されている。このほか、ガラクトース単一点法は、米国食品医薬品局（FDA）の出版物である『産業界のためのガイダンス』（Guidance for Industry）において、肝機能測定方法のひとつとして推奨されている。 The present invention measures chronic hepatitis, cirrhosis and liver cancer with the galactose single point method and found that the galactose single point method can accurately represent these liver diseases. The galactose single point method has been applied to measure residual liver function for patients with liver disease to eliminate drugs such as promazine and cefoperazone. In addition, the galactose single point method is recommended as one of the liver function measurement methods in the US Food and Drug Administration (FDA) publication Guidance for Industry.
以上により、従来のアセトアミノフェン使用には数多くの欠点があり、多くの製剤技術を用い、さまざまな医薬品添加物（excipient）を加えてアセトアミノフェンに改良を加えている。たとえば、矯味物質を添加して風味を改善したアセトアミノフェンの経口服用液などの製剤方法があるが、アセトアミノフェンの肝毒性という副作用については、副作用のないアセトアミノフェン医薬組成物というものはまだ存在しない。世に出て半世紀の長きにわたるアセトアミノフェン医薬組成物も、設計は優良とは言えないのが現状である。よって、アセトアミノフェン医薬組成物に関して、用量を変えて、アセトアミノフェン毒性代謝物を除去する添加物と組み合わせ、適切な用量を動物の体内に投与する試験を実施し、最終的に副作用をなくす、というのが本発明が解決しようとする課題である。 Based on the above, the conventional use of acetaminophen has many drawbacks, and many formulation techniques are used to improve acetaminophen by adding various pharmaceutical additives (excipients). For example, there is a formulation method such as an oral solution of acetaminophen whose flavor is improved by adding a flavoring substance, but regarding the side effect of acetaminophen hepatotoxicity, an acetaminophen pharmaceutical composition having no side effect is available. It doesn't exist yet. The design of acetaminophen pharmaceutical compositions, which has been around for half a century, is not good at present. Therefore, for the acetaminophen pharmaceutical composition, a test was conducted in which the dose was changed, combined with an additive for removing acetaminophen toxic biotransforms, and an appropriate dose was administered into the animal body, and finally the side effects were eliminated. , Is the problem to be solved by the present invention.
本発明は、アセトアミノフェンの従来の用法には肝毒性をもたらす副作用があるという欠点を改良し、長年の研究を経て、肝臓に対する副作用のない、新しいアセトアミノフェン複合組成を開発した。
The present invention has improved the drawbacks of conventional uses of acetaminophen that have side effects that cause hepatotoxicity, and after many years of research, has developed a new acetaminophen composite composition that has no side effects on the liver.
本発明の目的は、肝毒性を抑えて副作用のない、新しいアセトアミノフェン（Acetaminophen、APAP）複合組成を提供することにあり、（a）薬学的に有効な用量のアセトアミノフェンとアセトアミノフェン前駆薬としての構造類似物、及び（b）肝臓酵素CYP2E1代謝薬物がもたらす肝毒性を降下させる化合物、を含んでいる。 An object of the present invention is to provide a novel acetaminophen (APAP) composite composition that suppresses hepatotoxicity and has no side effects, and (a) pharmaceutically effective doses of acetaminophen and acetaminophen. It contains structural analogs as precursors and (b) compounds that reduce the hepatotoxicity of the hepatic enzyme CYP2E1 metabolizing drug.
前記目的を達成するため、この化合物は以下のグループからの一個以上の任意の組合せとする。モノラウリン酸ソルビタンポリエチレングリコール（ツイン20）（Polyethylene glycol sorbitan monolaurate；Tween 20)、結晶セルロース（Microcrystalline cellulose）、リン酸二カルシウム二水和物（Dicalcium phosphate dihydrate）、ポリオキシエチレン（23）ラウリルエーテル（Brij 35）、サッカリン（Saccharin）、マンニトール（Mannitol）、ポリオキシエチレン硬化ヒマシ油 (40) （Cremophor RH40）、スクラロース（Sucralose）、クロスポビドン（Crospovidone）、デンプングリコール酸ナトリウム（Sodium starch glycolate）、メタクリル酸コポリマーS（Eudragit S100）、クロスカルメロースナトリウム（Croscarmellose sodium）、ポリオキシエチレン（160）ポリオキシプロピレン（30）グリコール（Pluronic F68）、メンソール（Menthol）、低置換度ヒドロキシプロピルセルロース（Low-substituted hydroxypropyl cellulos）、アルファでん粉（Pregelatinized starch）、デキストレートNF水和物（Dextrates NF hydrated）、クエン酸（Citric acid）、ポリオキシアルキレン(C 24)ヒマシ油脂肪酸エステル（Cremophor EL）、アエロジル200（Aerosil 200）、ステアリン酸2-(2-ヒドロキシエトキシ)エチル（Myrj 52）、ソルビン酸（Sorbic acid）、レモンオイル（Lemon oil）、ヒドロキシプロピルセルロース（Hydroxypropyl cellulose）、ソルビトール（Sorbitol）、アセスルファムカリウム（Acesulfame potassium）、ヒドロキシプロピルメチルセルロース（Hydroxypropyl methylcellulose）、ラクトース一水和物（Lactose monohydrate）、マルトデキストリン（Maltodextrin）、ポリオキシエチレンセチルエーテル（Brij 58）、デカエチレングリコールモノオクタデシルエーテル（Brij 76）、ポリオキシエチレンソルビタンモノオレアート（ツイン80）（Tween 80）、ポリオキシエチレンソルビタンモノパルミタート（ツイン40）（Tween 40）、ポリエチレングリコール400（PEG 400）、ポリエチレングリコール4000（PEG 4000）、ポリエチレングリコール8000（PEG 8000）、モノステアリン酸ソルビタン（Span 60）、安息香酸ナトリウム（Sodium benzoate）、ヒドロキシエチルメチルセルロース（Hydroxy ethylmethylcellulose）、メチルセルロース（Methylcellulose）、モノオレイン酸ソルビタン（Span 80）、シクラミン酸ナトリウム（Sodium cyclamate）、ベヘン酸グリセリル（Glyceryl behenate）、赤色酸化鉄（Oxide red）、モノステアリン酸グリセリン（Glycerin monostearate）、コポビドンK28（Copovidone K28）、酢酸デン粉（Starch acetate）、ステアリン酸マグネシウム（Magnesium stearate）、ラウリル硫酸ナトリウム（Sodium lauryl sulfate）、プロビドンK30（Providone K30）、及びポリエチレングリコール2000（PEG 2000）。 To achieve the above objectives, the compounds will be any combination of one or more from the following groups. Polyethylene glycol sorbitan monolaurate (Tween 20), Microcrystalline cellulose, Dicalcium phosphate dihydrate, Polyoxyethylene (23) Lauryl ether (Brij) 35), Saccharin, Mannitol, Polyoxyethylene hydrogenated castor oil (40) (Cremophor RH40), Sucralose, Crospovidone, Sodium starch glycolate, Methacrylate Copolymer S (Eudragit S100), Croscarmellose sodium, polyoxyethylene (160) polyoxypropylene (30) glycol (Pluronic F68), menthol, low-substituted hydroxypropyl cellulos), pregelatinized starch, Dextrates NF hydrated, citric acid, polyoxyalkylene (C 24) castor oil fatty acid ester (Cremophor EL), Aerosil 200 ), 2- (2-Hydroxyethoxy) ethyl stearate (Myrj 52), Sorbic acid, Lemon oil, Hydroxypropyl cellulose, Sorbitol, Acesulfame potassium ), Hydroxypropyl methylcellulose, Lactose monohydrate, Maltodextrin, Polyoxyethylene cetyl ether (Brij 58), Decaethylene glycol monooctadecyl ether ( Brij 76), Polyoxyethylene sorbitan monooleate (Twin 80) (Tween 80), Polyoxyethylene sorbitan monopalmitate (Twin 40), Polyethylene glycol 400 (PEG 400), Polyethylene glycol 4000 (PEG 4000) ), Polyethylene glycol 8000 (PEG 8000), sorbitan monostearate (Span 60), Sodium benzoate, Hydroxy ethylmethylcellulose, Methylcellulose, sorbitan monooleate (Span 80), cyclamine Sodium cyclamate, Glyceryl behenate, Oxide red, Glycerin monostearate, Copovidone K28, Starch acetate, magnesium stearate (Magnesium stearate), Sodium lauryl sulfate, Providone K30, and Polyethylene Glycol 2000 (PEG 2000).
前記目的を達成するため、この化合物は以下のグループからの一個以上の任意の組合せとし、その組成物の用量を以下のように限定する。モノラウリン酸ソルビタンポリエチレングリコール（ツイン20）（Polyethylene glycol sorbitan monolaurate；Tween 20）の含有量0.1〜5.5g、結晶セルロース（Microcrystalline cellulose）の含有量100〜1000mg、リン酸二カルシウム二水和物（Dicalcium phosphate dihydrate）の含有量10〜1000mg、ポリオキシエチレン（23）ラウリルエーテル（Brij 35）の含有量0.1〜5.5g、サッカリン（Saccharin）の含有量10〜2000mg、マンニトール（Mannitol）の含有量0.01〜5.5g、ポリオキシエチレン硬化ヒマシ油 (40) （Cremophor RH40）の含有量0.1〜5.5g、スクラロース（Sucralose）の含有量0.1〜5.5g、クロスポビドン（Crospovidone）の含有量0.1〜5.5g、デンプングリコール酸ナトリウム（Sodium starch glycolate）の含有量0.1〜5.5g、メタクリル酸コポリマーS（Eudragit S100）の含有量0.17〜5.5g、クロスカルメロースナトリウム（Croscarmellose sodium）の含有量0.1〜5.5g、ポリオキシエチレン（160）ポリオキシプロピレン（30）グリコール（Pluronic F68）の含有量1.0〜5.5g、メンソール（Menthol）の含有量10〜1000mg、低置換度ヒドロキシプロピルセルロース（Low-substituted hydroxypropyl cellulos）の含有量0.1〜1.0g、アルファでん粉（Pregelatinized starch）の含有量1.0〜5.5g、デキストレートNF水和物（Dextrates NF hydrated）の含有量0.1〜5.5g、クエン酸（Citric acid）の含有量0.01〜8.0g、ポリオキシアルキレン(C 24)ヒマシ油脂肪酸エステル（Cremophor EL）の含有量1.0〜5.5g、アエロジル200（Aerosil 200）の含有量0.1〜5.5g、ステアリン酸2-(2-ヒドロキシエトキシ)エチル（Myrj 52）の含有量1.0〜5.5g、ソルビン酸（Sorbic acid）の含有量5〜1000mg、レモンオイル（Lemon oil）の含有量0.1〜5.5g、ヒドロキシプロピルセルロース（Hydroxypropyl cellulose）の含有量0.1〜5.5g、ソルビトール（Sorbitol）の含有量0.1〜5.5g、アセスルファムカリウム（Acesulfame potassium）の含有量1.0〜5.5g、ヒドロキシプロピルメチルセルロース（Hydroxypropyl methylcellulose）の含有量0.1〜5.5g、ラクトース一水和物（Lactose monohydrate）の含有量0.006〜6.0g、マルトデキストリン（Maltodextrin）の含有量0.1〜5.5g、ポリオキシエチレンセチルエーテル（Brij 58）の含有量0.1〜5.5g、デカエチレングリコールモノオクタデシルエーテル（Brij 76）の含有量0.1〜5.5g、ポリオキシエチレンソルビタンモノオレアート（ツイン80）（Tween 80）の含有量0.1〜5.5g、ポリオキシエチレンソルビタンモノパルミタート（ツイン40）（Tween 40）の含有量1.0〜5.5g、ポリエチレングリコール400（PEG 400）の含有量1.0〜5.5g、ポリエチレングリコール4000（PEG 4000）の含有量1.0〜5.5g、ポリエチレングリコール8000（PEG 8000）の含有量1.0〜5.5g、モノステアリン酸ソルビタン（Span 60）の含有量1.0〜5.5g、安息香酸ナトリウム（Sodium benzoate）の含有量0.01〜15.0g、ヒドロキシエチルメチルセルロース（Hydroxy ethylmethylcellulose）の含有量0.1〜5.5g、メチルセルロース（Methylcellulose）の含有量0.1〜5.5g、モノオレイン酸ソルビタン（Span 80）の含有量1.0〜5.5g、シクラミン酸ナトリウム（Sodium cyclamate）の含有量0.003〜72.0g、ベヘン酸グリセリル（Glyceryl behenate）の含有量10〜1000mg、赤色酸化鉄（Oxide red）の含有量10〜1000mg、モノステアリン酸グリセリン（Glycerin monostearate）の含有量1.0〜5.5g、コポビドンK28（Copovidone K28）の含有量0.170〜5.5g、酢酸デン粉（Starch acetate）の含有量0.170〜5.5g、ステアリン酸マグネシウム（Magnesium stearate）の含有量0.1〜5.5g、ラウリル硫酸ナトリウム（Sodium lauryl sulfate）の含有量0.1〜5.5g、プロビドンK30（Providone K30）の含有量100〜3000mg、及びビポリエチレングリコール2000（PEG 2000）の含有量1.0〜5.5g。
To achieve the above objectives, the compound should be any combination of one or more from the following groups and the dose of the composition is limited as follows. Polyethylene glycol sorbitan monolaurate (Tween 20) content 0.1-5.5 g, Microcrystalline cellulose content 100-1000 mg, Dicalcium phosphate Dihydrate) content 10-1000 mg, polyoxyethylene (23) lauryl ether (Brij 35) content 0.1-5.5 g, saccharin content 10-2000 mg, mannitol content 0.01-5.5 g, Polyoxyethylene hydrogenated castor oil (40) (Cremophor RH40) content 0.1-5.5 g, Sucralose content 0.1-5.5 g, Crospovidone content 0.1-5.5 g, starch glycol Sodium starch glycolate content 0.1-5.5 g, methacrylic acid copolymer S (Eudragit S100) content 0.17-5.5 g, Croscarmellose sodium content 0.1-5.5 g, polyoxyethylene (160) Polyoxypropylene (30) glycol (Pluronic F68) content 1.0-5.5 g, menthol content 10-1000 mg, low-substituted hydroxypropyl cellulos content 0.1 ~ 1.0 g, pregelatinized starch content 1.0 ~ 5.5 g, Dextrates NF hydrated content 0.1 ~ 5.5 g, citric acid content 0.01 ~ 8.0 g , Polyoxyalkylene (C 24) castor oil fatty acid ester (Cremophor EL) content 1.0-5.5 g, Aerosil 200 (Aerosil 200) content 0.1-5.5 g, 2- (2-hydroxyethoxy) ethyl stearate ( Myrj 52) content 1.0-5.5g,
前記目的を達成するため、その化合物はマンニトール（Mannitol）とスクラロース（Sucralose）の組み合わせが最良である。 To achieve the above objectives, the best compound is a combination of mannitol and sucralose.
前記目的を達成するため、その組み合わせは、別個に、同時に、または順序を定めて用いる。 To achieve the above objectives, the combinations may be used separately, simultaneously or in order.
前記目的を達成するため、アセトアミノフェン及び/または同一経路で発生する毒性や副作用薬物の肝毒性を降下させる化合物は、ゲル剤、エアゾール剤、軟錠剤、カプセル剤、散剤、液剤、懸濁剤、乳剤、芳香水剤、シロップ剤、エリキシル剤、チンキ剤、流エキス剤、軟膏剤、ローション剤、貼付剤、注射剤、坐剤、錠剤、または分散性錠剤及び薬学的に許容可能な方式で投与する。 To achieve the above objectives, acetaminophen and / or compounds that reduce the hepatotoxicity of toxic or side-effect drugs generated by the same route are gels, aerosols, ointments, capsules, powders, liquids, suspensions. , Emulsions, aromatics, syrups, elixirs, tinctures, flow extracts, ointments, lotions, patches, injections, suppositories, tablets, or dispersible tablets and in pharmaceutically acceptable manners. Administer.
前記目的を達成するため、その組合せは、医薬品キット、医薬品パックまたは患者用パックに含まれている。 To achieve the above objectives, the combination is included in a drug kit, drug pack or patient pack.
本発明の別の目的として、アセトアミノフェンの肝毒性を抑え、肝臓への副作用をなくした薬剤を製造する際の組合せを提供することがある。 Another object of the present invention is to provide a combination for producing a drug that suppresses hepatotoxicity of acetaminophen and eliminates side effects on the liver.
以下において、実施例を示して本発明を説明するが、実施例は具体例を挙げて説明するためであり、本発明に制限を加えると解釈されるべきではない。 Hereinafter, the present invention will be described with reference to examples, but the examples are for the purpose of giving specific examples and should not be construed as imposing restrictions on the present invention.
本発明は、アセトアミノフェンの従来の用法には肝毒性をもたらす副作用があるという欠点を改良し、長年の研究を経て、肝臓に対する副作用のない、新しいアセトアミノフェン複合組成を開発した。 The present invention has improved the drawbacks of conventional uses of acetaminophen that have side effects that cause hepatotoxicity, and after many years of research, has developed a new acetaminophen composite composition that has no side effects on the liver.
肝臓に対する副作用のない、新しいアセトアミノフェン複合組成を提供するという、前記目的を達成するため、本発明はまず、新しいアセトアミノフェン複合組成によってラットに肝毒性を誘発させ、ひとつ以上のCYP2E1抑制剤と組み合わせて、ラット体内のアセトアミノフェン誘発肝毒性に対する影響を観察した。一般的な肝毒性の表記、病理組織の切片採取だけでなく、ガラクトース単一点法（GSP）によりラットの残存肝機能を定量化測定して評価を行った。 In order to achieve the above object of providing a new acetaminophen complex composition without side effects on the liver, the present invention first induces hepatotoxicity in rats by the new acetaminophen complex composition, and one or more CYP2E1 inhibitors. In combination with, the effect on acetaminophen-induced hepatotoxicity in rats was observed. In addition to the general notation of hepatotoxicity and sectioning of pathological tissue, the residual liver function of rats was quantified and measured by the galactose single point method (GSP) for evaluation.
本文書に用いる技術的、科学的用語は、別途定義されている場合を除き、その用語が属する領域で通常の技能を有する者が共通して保持する認識に基づいて解釈する。 Unless otherwise defined, the technical and scientific terms used in this document shall be construed on the basis of the common understanding of those with ordinary skills in the area to which the term belongs.
本文書に用いている用語「組成物」（combination）とは、二種類以上の化合物及び/または薬剤（本文書においては、成分ともいう）を用いる際、二種類以上の化合物/薬剤を結合させた材料を指す。用語「組合せ」（“ｃｏｍｂｉｎｅｄ”及び“ｃｏｍｂｉｎｉｎｇ”）もまた、本文書においてはこのように解釈する。 The term "combination" as used in this document refers to the combination of two or more compounds / or drugs (also referred to as components in this document) when two or more compounds and / or drugs (also referred to as components in this document) are used. Refers to the material used. The terms "combination" ("combined" and "combining") are also interpreted in this way in this document.
医薬品キット（pharmaceutical kits）、医薬品パック（pharmaceutical packs）、患者用パック（patient packs）とは、二種類以上の化合物/薬剤が包装されている、または用意されている（与薬を準備する部門向け）ものを指す。 Pharmaceutical kits (pharmaceutical kits), pharmaceutical packs (pharmaceutical packs), and patient packs (patient packs) are two or more compounds / drugs that are packaged or prepared (for departments that prepare medications). ) Refers to things.
以下に本発明の実施例を記述するが、本発明は実施例によって制限を受けてはならない。本発明に用いる薬物、生物材料はいずれも市販されており、次に示す例は代表的な取得経路に過ぎない。 Examples of the present invention will be described below, but the present invention shall not be limited by the examples. Both the drug and the biomaterial used in the present invention are commercially available, and the following examples are merely typical acquisition routes.
実施例1 Example 1
アセトアミノフェンと、安全で薬学的に許容可能な一種類以上の賦形剤化合物とを組み合わせて、薬物による肝毒性を抑える動物試験を実施する。
材料と方法
1. 試験材料
すべての有機溶剤はHPLC（高速液体クロマトグラフ）クラスで、テディア社（米国オハイオ州フェアフィールド）製を購入。アセトアミノフェンは、シグマアルドリッチ社（米国セントルイス）製を購入。ガラクトース注射液は南光化学製薬股▲フン▼有限公司製を用い、ガラクトース（シグマ社製）400gを、適切なバッファー液と等張食塩液を含む蒸留水1リットルに溶かし、注射液とする。
2. 試験動物
体重175-280gのオスSDラット（スプラグ・ドーレイ、Sprague-Dawley）を国家実験動物中心（台湾）から購入し、国家衛生研究院動物実験ガイドに従って試験を実施する。すべてのラットは温度湿度調整環境におき、明暗サイクル12時間、水と飼料は無制限に供給、試験期間中にラット体重を持続的に計測し、水分は通常どおり供給した。
3. 試験プロセス
体外でスクリーニングしたCYP2E1抑制剤を選び、抑制剤を併用したアセトアミノフェンと併用しないアセトアミノフェンで、アセトアミノフェン肝毒性抑制の動物試験を行う。肝毒性試験の動物に対しては、ラット体重1kg当たり、アセトアミノフェン単一用量1000mgをチューブで投与して肝毒性を起こさせる。肝保護実験動物に対しては、いずれもラット体重1kg当たり、リン酸二カルシウム二水和物1.67mg、またはマンニトール1.67mg、またはメンソール1.67mg、またはHUEXC041 1.67mg、またはマンニトール1.67mg＋スクラロース1.67mg、またはマンニトール0.83mg＋スクラロース0.83mg、またはマンニトール0.42mg＋スクラロース0.42mg、またはマンニトール0.17mg＋スクラロース0.17mgと、いずれもラット体重1kg当たりアセトアミノフェン単一用量1000mgを併用して、チューブで投与する。結晶中のアスパラギン酸アミノ基転移酵素（AST）及びアラニンアミノ基転移酵素（ALT）を計測して肝炎の指標とし、薬剤投与の前後各16時間の時点でガラクトース単一点法（GST）を測定してラットの残存肝機能を定量分析するとともに、群ごとにラットの肝臓組織病理変化を観察して、肝障害または保護メカニズムを評価する。
4. 血液サンプル
試験プロセスの終了後、ラットをエーテル麻酔で安楽死させ、ラットの尾の動脈から血液を採取し、エチレンジアミン四酢酸（EDTA）を含む試験管に入れ、13,000gを4℃で15分間遠心分離機にかけて血漿（plasma）を分離し、分離後の血漿をエッペンチューブ（Eppendorf tube）に入れて、-80℃で保存する。
5. 生化学分析
肝細胞の損傷は、アスパラギン酸アミノ基転移酵素（AST）及びアラニンアミノ基転移酵素（ALT）活性をもって定量化する。AST及びALTは肝毒性を表すのによく用いられる指標であり、Synchron LXi 725（米国ベックマン・インスツルメンツ社製）で計測する。
6. 光学顕微鏡
ラットを安楽死させた後、病理組織学的分析を行う。肝臓サンプルを、10%リン酸バッファー液で調合したホルマリン（phosphate-buffered formalin）で固定し、脱水してからパラフィン（paraffin）に包埋し、5μm厚の切片を採取し、この切片サンプルをヘマトキシリン（hematoxylin）とエオジン（eosin）で染色し、PAS染色試験（Periodic acid Schiff stain）を行って、光学顕微鏡で染色後の組織学的観察を行う。
7. 肝機能の定量測定
試験の終了後、すべてのラットに対してガラクトース単一点法（GSP）計測を行う。ラットに対し30秒以内で、濃度0.4g/mlのBWガラクトース溶液を0.5g/kgで迅速に静脈注射し、注射後、5、10、15、30、45及び60分経過した時点で、血液サンプルを尾の静脈から採取し、ガラクトースデヒドロゲナーゼ比色分析法（colorimetric galactose dehydrogenase）でガラクトース含有量を測定する。計測する濃度範囲は50から1,000μｇ／ｍｌ、各濃度の日内変動（within-day variation）は標準偏差（standard deviation）と変動係数（coefficient of variation、CV）の比で計算し、最大許容変動係数は10% CV、逐日変動（day-to-day variation）は検量線（calibration curves）の勾配と切片により検証する。ガラクトース単一点法（GSP）は、30秒間の注射を停止してから60分経過時の血液中のガラクトース濃度を計測することである。
8. 統計学的分析
すべてのデータは平均±標準偏差（SD）で表し、試験結果は分散分析（ANOVA）によって統計学上の有意差の有無を、「社会科学のための統計パッケージ」（Statistical Package of the Social Science program）（Version 13, SPSS Inc.）を使って計算する。その後、事後検定（post hoc test）、最小有意差検定（least significant difference）を用いて多重比較し、実験群間の有意確率を確認し、有意水準がp < 0.05となることを確認する。
結果
1. 生化学的分析結果
試験終了後、試験動物の体重と相対的な肝重量を計測したところ、正常対照群と比較しても、顕著な差はなかった。血液の生化学的分析結果を表1に示した。アセトアミノフェン肝毒性群においては、血漿中のアスパラギン酸アミノ基転移酵素（AST）とアラニンアミノ基転移酵素（ALT）活性は、正常対照群と較べて著しく高く（正常対照群の血漿中AST活性は202±34 IU/L、アセトアミノフェン肝毒性群の血漿中AST活性は499±112 IU/L、p < 0.005；正常対照群の血漿中のALT活性は56±14 IU/L、アセトアミノフェン肝毒性群の血漿中のALT活性は368± 71 IU/L、p < 0.005）、アセトアミノフェン毒性群では生化学でいう肝障害が進んでいることを示している。リン酸二カルシウム二水和物試験群が予期されたほどでもなかったのを除き、肝障害の現象は、併用されたマンニトール、メンソール、スクラロースといった安全な常用賦形剤によって抑制され、肝炎指標のAST、ALT、GSP、及び病理組織切片における肝臓病変の程度を表すトータルHAIスコアも顕著に低く、表1に示された実験データのように、マンニトールとスクラロースの組合せが最良の結果を得ており、正常対照群と比しても遜色ない。
表1 正常対照群、アセトアミノフェン肝毒性群、及びリン酸二カルシウム二水和物、マンニトール、メンソール、スクラロースなどの肝保護試験群に対し、チューブで単一用量を投与して試験を行った後の、ガラクトース単一点法（GSP）分析、アスパラギン酸アミノ基転移酵素（AST）、アラニンアミノ基転移酵素（ALT）活性、病理組織切片に対するトータルHAIスコア（数値の計算は平均±SD）
抑制の結果は肝臓組織そのものにも反映されており、チューブで単一用量1000 mg/kgのアセトアミノフェンを経口投与されたラットは、体内に肝毒性が起こり、アセトアミノフェン肝毒性群ラットの肝臓組織切片は、中央静脈周囲の細胞が破裂し、空胞化が著しく、細胞核も少なくなり、部分的に壊死（necrosis）も見られるが、正常対照群ラット体内の肝臓は構造も正常で、細胞に損傷なく、整然としており、空胞化はみられない（図2A参照）。マンニトール、メンソール、スクラロースなどの肝保護試験群ラットの肝組織切片観察の結果によると、肝細胞は比較的整然としており、細胞核もはっきりとしており、空胞化も少なく（図2C、D、F、G、H参照）、マンニトール、メンソール、スクラロースなどの肝保護試験群ラットの肝組織は、正常なラットの肝組織に近く、特にマンニトールとスクラロースの組合せによる保護効果が最良で、しかも投与量に正比例しており、投与量が多いほど効果的である。
3. 残存肝機能の測定
表1によると、正常対照群とアセトアミノフェン肝毒性群のラットのガラクトース単一点法（GSP）値はかなりの差があり（正常対照群ラットのGSP値は289±38 mg/L、アセトアミノフェン肝毒性群ラットのGSP値は848±123 mg/L、p < 0.005）。一方、リン酸二カルシウム二水和物、マンニトール、メンソール、スクラロースの肝保護群ラットの場合、GSP値はそれぞれ、444±60 mg/L、253±29 mg/L、289±20 mg/L、218±31 mg/Lであり、アセトアミノフェン肝毒性群と比較して、マンニトール、メンソール、スクラロースの肝保護群ラットのGSP値は、アセトアミノフェン肝毒性群ラットと較べて、かなりの差がある（p < 0.005）。アセトアミノフェンを単独で用いるとGSP値が顕著に増加するが、アセトアミノフェンにマンニトール、メンソール、スクラロースといった賦形剤を併用した肝保護試験群ラットには顕著な変化は起きていない。
Animal studies are performed in which acetaminophen is combined with one or more safe and pharmaceutically acceptable excipient compounds to reduce drug-induced hepatotoxicity.
Materials and methods
1. Test materials All organic solvents are HPLC (High Performance Liquid Chromatograph) class and purchased from Tedia (Fairfield, Ohio, USA). Acetaminophen was purchased from Sigma-Aldrich (St. Louis, USA). The galactose injection solution is manufactured by Nanko Chemical Pharmaceutical Co., Ltd., and 400 g of galactose (manufactured by Sigma Co., Ltd.) is dissolved in 1 liter of distilled water containing an appropriate buffer solution and isotonic saline solution to prepare an injection solution.
2. Test animals A male SD rat (Sprague-Dawley) weighing 175-280 g will be purchased from the National Center for Laboratory Animals (Taiwan) and tested according to the National Health Research Institute Animal Care and Use Guide. All rats were placed in a temperature-humidity controlled environment, with a 12-hour light-dark cycle, unlimited supply of water and feed, continuous weighting of the rats during the test period, and normal supply of water.
3. Test process Select an in vitro screened CYP2E1 inhibitor and conduct an animal test on acetaminophen hepatotoxicity suppression with acetaminophen with and without the inhibitor. For animals tested for hepatotoxicity, a single dose of 1000 mg of acetaminophen per kg of rat body weight is administered by tube to cause hepatotoxicity. For liver protection laboratory animals, dicalcium phosphate dihydrate 1.67 mg, or mannitol 1.67 mg, or menthol 1.67 mg, or HUEX C041 1.67 mg, or mannitol 1.67 mg + sucralose 1.67 mg, per 1 kg of rat body weight, Alternatively, mannitol 0.83 mg + sucralose 0.83 mg, or mannitol 0.42 mg + sucralose 0.42 mg, or mannitol 0.17 mg + sucralose 0.17 mg, both of which are administered in a tube in combination with a single dose of acetaminophen 1000 mg per 1 kg of rat body weight. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the crystal were measured and used as an index of hepatitis, and galactose single point method (GST) was measured 16 hours before and after drug administration. Quantitative analysis of residual liver function in rats and observation of changes in liver histology of rats in each group are performed to evaluate liver damage or protective mechanism.
4. After completion of the blood sample testing process, rats are euthanized with ether anesthesia, blood is drawn from the rat's tail artery and placed in a test tube containing ethylenediaminetetraacetic acid (EDTA), 13,000 g at 4 ° C. 15 Plasma (plasma) is separated by centrifuge for minutes, and the separated plasma is placed in an Eppendorf tube and stored at -80 ° C.
5. Biochemical analysis Hepatocyte damage is quantified by aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. AST and ALT are commonly used indicators of hepatotoxicity and are measured with Synchron LXi 725 (manufactured by Beckman Instruments, USA).
6. After euthanizing the light microscope rat, perform histopathological analysis. The liver sample was fixed with formalin (phosphate-buffered formalin) prepared with a 10% phosphate buffer solution, dehydrated and then embedded in paraffin, and a 5 μm-thick section was taken, and this section sample was taken as hematoxylin. Stain with (hematoxylin) and eosin, perform a PAS staining test (Periodic acid Schiff stain), and perform histological observation after staining with an optical microscope.
7. Quantitative measurement of liver function After completion of the test, galactose single point method (GSP) measurement will be performed on all rats. Within 30 seconds, a 0.4 g / ml concentration of BW galactose solution was rapidly intravenously injected into the rat at 0.5 g / kg, and blood was injected 5, 10, 15, 30, 45 and 60 minutes after the injection. Samples are taken from the tail vein and the galactose content is measured by colorimetric galactose dehydrogenase. The concentration range to be measured is 50 to 1,000 μg / ml, and the within-day variation of each concentration is calculated by the ratio of the standard deviation and the coefficient of variation (CV), and the maximum allowable variation coefficient. Is 10% CV, and day-to-day variation is verified by the gradient and section of the calibration curves. The galactose single point method (GSP) is to measure the galactose concentration in the blood 60 minutes after stopping the injection for 30 seconds.
8. Statistical analysis All data are represented by mean ± standard deviation (SD), and test results are analyzed by analysis of variance (ANOVA) to determine the presence or absence of statistically significant differences in the "Statistical Package for Social Sciences" (Statistical). Calculated using the Package of the Social Science program (Version 13, SPSS Inc.). After that, multiple comparisons are performed using a post hoc test and a least significant difference test to confirm the significance probability between the experimental groups and confirm that the significance level is p <0.05.
result
1. Biochemical analysis results After the test was completed, the body weight of the test animals and the liver weight relative to the body weight were measured, and there was no significant difference even when compared with the normal control group. The results of biochemical analysis of blood are shown in Table 1. In the acetoaminophen hepatotoxic group, the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities in plasma are significantly higher than those in the normal control group (AST activity in plasma in the normal control group). 202 ± 34 IU / L, acetaminophen hepatotoxic group plasma AST activity 499 ± 112 IU / L, p <0.005; normal control group plasma ALT activity 56 ± 14 IU / L, acetamino The ALT activity in plasma of the phen hepatotoxic group is 368 ± 71 IU / L, p <0.005), indicating that the acetoaminophen toxic group has advanced hepatotoxicity in biochemistry. Except for the less than expected dicalcium phosphate dihydrate test group, the phenomenon of liver damage was suppressed by the concomitantly used safe excipients such as mannitol, menthol, and sclarose, which were indicators of hepatitis. The total HAI score, which indicates the degree of liver lesions in AST, ALT, GSP, and histopathological sections, was also significantly lower, and the combination of mannitol and sclarose gave the best results, as shown in the experimental data shown in Table 1. , It is not inferior to the normal control group.
Table 1 Tests were performed by administering a single dose in a tube to the normal control group, acetaminophen hepatotoxicity group, and hepatoprotection test group such as dicalcium phosphate dihydrate, mannitol, menthol, and sclarose. Later, galactose single point method (GSP) analysis, aspartate aminotransferase (AST), alanine aminotransferase (ALT) activity, total HAI score for histopathological sections (numerical calculation is average ± SD)
3. Measurement of residual liver function According to Table 1, there is a considerable difference in galactose single-point method (GSP) values between the normal control group and the acetaminophen hepatotoxic group (the GSP value of the normal control group rats is 289 ±). The GSP value of 38 mg / L, acetaminophen hepatotoxic group rats was 848 ± 123 mg / L, p <0.005). On the other hand, in the case of hepatoprotective rats of dicalcium phosphate dihydrate, mannitol, menthol, and sclarose, the GSP values were 444 ± 60 mg / L, 253 ± 29 mg / L, and 289 ± 20 mg / L, respectively. It was 218 ± 31 mg / L, and the GSP values of mannitol, menthol, and sclarose hepatoprotective group rats were significantly different from those of the acetaminophen hepatotoxic group. There is (p <0.005). The GSP level increased significantly when acetaminophen was used alone, but no significant change occurred in rats in the hepatoprotection test group in which acetaminophen was used in combination with excipients such as mannitol, menthol, and sucralose.
実施例２ Example 2
シトクロムP450 2E1（CYP2E1）抑制剤のスクリーニング-ラット肝ミクロソーム及びヒト肝ミクロソーム
材料と方法
1. 試験材料
この実施例では、ラットとヒトの肝臓を用いてミクロソームを調製し、CYP2E1抑制剤としての体外スクリーニングを行う。安全で食用可能な一般賦形剤55種類に対して、シトクロムP450 2E1（CYP2E1）抑制剤としてのスクリーニングを実施し、ラットまたはヒト由来肝臓のCYP2E1抑制剤を選ぶ。このCYP2E1抑制剤スクリーニングの原理は、ラット肝またはヒト肝から調製したミクロソームの中で、CYP2E1はクロルゾキサゾン（Chlorzoxazone、CZX）に対して作用するが、試験サンプルを加えてから、CYP2E1代謝標準物である6-ヒドロキシクロルゾキサゾン（6-OH-CZX、6-Hydroxy-Chlorzoxazone）の生成量を測定し、対照群（control）の6-OH-CZX生成量を基準にして、試験サンプルのCYP2E1抑制率を計算する。
試験サンプルはいずれも、10%エタノール（methanol）液または二次処理水に溶かし、賦形剤の濃度を変えて（66uM、33uM、16.5uM；0.167%、0.08%、0.042%、w/v）、それぞれのCYP2E1抑制率を計算した結果を表2に示す。
この実施例では、ラット肝またはヒト肝から調製したミクロソームを用い、シトクロムCYP2E1抑制剤に必要な薬剤をスクリーニングした（以下参照）。
（１）CYP2E1：100mMリン酸カリウム（pH 7.4）、P450酵素濃度10mg/mL
（２）対照群：10mg/mL P450酵素を100mMリン酸カリウム（pH 7.4）に溶かす
（３）バッファー液：0.5M リン酸カリウム（pH 7.4）
（４）反応停止液：冷凍アセトニトリル
（５）捕因子：100mMニコチンアミドアデニンジヌクレオチドリン酸（NADP）+10 mM グルコース-6-リン酸
（６）グルコース-6-リン酸デヒドロゲナーゼ：2000 units/mlを無菌水に溶かす
（７）クロルゾキサゾン：基質（substrate）、16mM クロルゾキサゾンを10%エタノール（methanol）液に溶かす
（８）DDTC（ジエチルジチオカルバミン酸）：CYP2E1選択性抑制剤（陽性対照群）、20mM DDTCを10%エタノール（methanol）液に溶かす
（９）NADPH（還元型ニコチンアミドアデニンジヌクレオチドリン酸）-リジェネレーションシステム：3.42 mLの中に、530 uL 捕因子、40 uL G6PDH（グルコース-6-リン酸デヒドロゲナーゼ溶液）、及び100 uL 対照群を加える
2. シトクロムP450 2E1（CYP2E1）抑制剤のスクリーニング
ラット肝またヒト肝のミクロソームを用いてシトクロムCYP2E1抑制剤をスクリーニングする実験の手順は以下のとおり。
（１）4℃氷浴環境で、0.1Mリン酸バッファー液（pH 7.4）に、0.5 mg/mLラット肝またはヒト肝のミクロソーム、5 mM 塩化マグネシウムMgCl2を入れて15分間置く。
（２）このとき実験群には、シトクロムP450 2E1反応基質薬物である16 mM クロルゾキサゾン（Chlorzoxazone）を加え、対照群には「メタノール：無菌水＝1：1」を加え、陽性対照群にはDDTC（ジエチルジチオカルバミン酸）を加える。
（３）最後に、捕因子1 mM酸化型ニコチンアミドアデニンジヌクレオチドリン酸（NADP+）、10 mMグルコース-6-リン酸（G6P）、2 IUグルコース-6-リン酸デヒドロゲナーゼ（G6PD）を加える。反応液を37℃水浴前保温（pre-incubation）1分間に移し、活性実験の反応時間は30分間とする。
（４）反応終了後、500 μLアセトニトリルで反応を停止させ、サンプルを1分間安置してから内部標準品（5 ug/mL 4-ヒドロキシ-トルブタミド）を加え、遠心分離機にかけてから上層液20 uLを取り、「メタノール：無菌水」で十倍に希釈してから、5 uLの溶液を取ってLC/MS/MS装置に入れて分析する。
（５）分析結果：LC/MS/MS装置で測定して得た数値を、CYP2E1代謝物標準品である6-ヒドロキシクロルゾキサゾン（6-OH-CZX、6-Hydroxy-Chlorzoxazone）の生成量（pmol）に換算した後、対照群を基準に、すなわち対照群のCYP 2E1抑制率を0％とし、次の式で陽性対照群及び実験群のCYP 2E1抑制率を計算する。
1. 陽性対照群
陽性対照群（DDTC、ジエチルジチオカルバミン酸）で測定されたCYP 2E1抑制率を表2に示す。表2より、DDTC濃度100μMのとき、CYP 2E1抑制率が89.2%に達するのがわかる。
2. 実験群CYP 2E1抑制率
ラット肝ミクロソームにおける賦形剤のCYP 2E1抑制率を表2に示す。この結果により、賦形剤の濃度が異なれば（66μM、33μM、16.5μM；0.167%、0.08%、0.042%、w/v）、シトクロムP450 2E1に対する抑制効果も異なるのがわかり、そのうち0.167% ポリオキシエチレンセチルエーテル（Brij 58）の抑制效果が最良（100.0±0.00%）である。
表2、ラット肝ミクロソームにおける賦形剤のCYP 2E1抑制率によるスクリーニング
表2、ヒト肝ミクロソームにおける賦形剤のCYP 2E1抑制率によるスクリーニング
1. Test material In this example, microsomes are prepared using rat and human livers and in vitro screened as a CYP2E1 inhibitor. Screen for 55 safe and edible general excipients as cytochrome P450 2E1 (CYP2E1) inhibitors and select rat or human-derived liver CYP2E1 inhibitors. The principle of this CYP2E1 inhibitor screening is that CYP2E1 acts on chlorzoxazone (CZX) in microsomes prepared from rat liver or human liver, but after adding a test sample, it is a CYP2E1 metabolic standard. The amount of 6-hydroxychlorzoxazone (6-OH-CZX, 6-Hydroxy-Chlorzoxazone) produced was measured, and the amount of 6-OH-CZX produced in the control group was used as a reference to suppress CYP2E1 in the test sample. Calculate the rate.
All test samples were dissolved in 10% ethanol solution or secondary treated water and the concentration of excipients was changed (66uM, 33uM, 16.5uM; 0.167%, 0.08%, 0.042%, w / v). Table 2 shows the results of calculating the respective CYP2E1 suppression rates.
In this example, microsomes prepared from rat liver or human liver were used to screen for agents required for cytochrome CYP2E1 inhibitors (see below).
(1) CYP2E1: 100 mM potassium phosphate (pH 7.4), P450 enzyme concentration 10 mg / mL
(2) Control group: 10 mg / mL P450 Enzyme dissolved in 100 mM potassium phosphate (pH 7.4) (3) Buffer solution: 0.5 M potassium phosphate (pH 7.4)
(4) Reaction terminator: Frozen acetonitrile (5) Catch factor: 100 mM nicotinamide adenine dinucleotide phosphate (NADP) + 10 mM Glucose-6-phosphate (6) Glucose-6-phosphate dehydrogenase: 2000 units / ml (7) Chlorzoxazone: substrate, 16 mM chlorzoxazone in 10% ethanol solution (8) DDTC (diethyldithiocarbamic acid): CYP2E1 selectivity inhibitor (positive control group), 20 mM DDTC (9) NADPH (reduced nicotinamide adenine dinucleotide phosphate) -regeneration system: 530 uL catcher, 40 uL G6PDH (glucose-6-phosphate) in 3.42 mL. Acid dehydrogenase solution), and 100 uL control group is added.
2. Screening for cytochrome P450 2E1 (CYP2E1) inhibitors The procedure for an experiment to screen cytochrome CYP2E1 inhibitors using microsomes from rat liver or human liver is as follows.
(1) In a 4 ° C ice bath environment, put 0.5 mg / mL rat liver or human liver microsomes and 5 mM magnesium chloride MgCl 2 in 0.1 M phosphate buffer (pH 7.4) and leave for 15 minutes.
(2) At this time, 16 mM chlorzoxazone, which is a cytochrome P450 2E1 reaction substrate drug, was added to the experimental group, "methanol: sterile water = 1: 1" was added to the control group, and DDTC was added to the positive control group. (Diethyldithiocarbamic acid) is added.
(3) Finally, the catching factor 1 mM oxidized nicotinamide adenine dinucleotide phosphate (NADP + ), 10 mM glucose-6-phosphate (G6P), and 2 IU glucose-6-phosphate dehydrogenase (G6PD) are added. .. The reaction solution is transferred to 37 ° C. pre-incubation for 1 minute, and the reaction time of the activity experiment is 30 minutes.
(4) After completion of the reaction, stop the reaction with 500 μL acetonitrile, leave the sample for 1 minute, add the internal standard (5 ug / mL 4-hydroxy-torbutamide), centrifuge, and then centrifuge 20 uL of the upper layer solution. After diluting with "methanol: sterile water" tenfold, take a 5 uL solution and place it in an LC / MS / MS device for analysis.
(5) Analysis result: The value obtained by measuring with the LC / MS / MS device was used to generate 6-hydroxychlorzoxazone (6-OH-CZX, 6-Hydroxy-Chlorzoxazone), which is a standard product of CYP2E1 biotransformer. After conversion to the amount (pmol), the CYP 2E1 inhibition rate of the positive control group and the experimental group is calculated based on the control group, that is, the CYP 2E1 inhibition rate of the control group is set to 0% by the following formula.
1. Positive control group Table 2 shows the CYP 2E1 inhibition rate measured in the positive control group (DDTC, diethyldithiocarbamic acid). From Table 2, it can be seen that the CYP 2E1 inhibition rate reaches 89.2% when the DDTC concentration is 100 μM.
2. Experimental group CYP 2E1 inhibition rate Table 2 shows the CYP 2E1 inhibition rate of excipients in rat liver microsomes. The results show that different excipient concentrations (66 μM, 33 μM, 16.5 μM; 0.167%, 0.08%, 0.042%, w / v) have different inhibitory effects on cytochrome P450 2E1, of which 0.167% poly. The inhibitory effect of oxyethylene cetyl ether (Brij 58) is the best (100.0 ± 0.00%).
Table 2, screening by CYP 2E1 inhibition rate of excipients in rat liver microsomes
Table 2, screening by CYP 2E1 inhibition rate of excipients in human liver microsomes
本発明が提供する、肝臓への副作用がないアセトアミノフェン新複合組成は、アセトアミノフェン単独使用時の試験結果と比較すると、生化学的分析（ALT、AST値）、病理学的分析及び残存肝機能（GSP値）といった分析結果は、アセトアミノフェンが起こす肝毒性の副作用を低減させる効果が顕著である。 The new complex composition of acetaminophen provided by the present invention without side effects on the liver is biochemical analysis (ALT, AST value), pathological analysis and residual when compared with the test results when acetaminophen is used alone. Analysis results such as liver function (GSP value) show a remarkable effect of reducing the hepatotoxic side effects caused by acetaminophen.
上述の詳細説明は本発明における実現可能な実施例の具体的説明であり、これらの実施例は本発明請求項に制限を加えるものではなく、本発明の趣旨に従い、適度な修飾や変化を加えることで同等の効果を得た場合、たとえば、アセトアミノフェン、シトクロムP450 2E1抑制剤の選択の種類、濃度及び比率を置き換えて、同等の効果を得るような実施例は、いずれも本発明請求項の保護範囲内とする。 The above-mentioned detailed description is a concrete description of feasible examples in the present invention, and these examples do not impose restrictions on the claims of the present invention, but appropriately modify or change according to the gist of the present invention. When the same effect is obtained, for example, examples in which the same effect is obtained by substituting the selection type, concentration and ratio of acetaminophen and cytochrome P450 2E1 inhibitor are all claimed in the present invention. Within the protection range of.
以上を総合すると、本発明はアセトアミノフェンの応用という点で独自性があり、且つ安全な一般賦形剤を用いて、アセトアミノフェン使用時に起こる肝毒性副作用を確実に抑制している。本発明を順調に完遂できたのは、研究開発チームの熊正輝博士、何欣恬博士、蔡昌晏博士、許翔恩、胡希賢、黄俐瑛、分析チームの黄北緯、劉為煬、楊蘋、唐熙卉、楊▲エン▼鈴、林軍伯、林文豪、及び臨床チームの朱凱民医師、楊東和医師、田巧怡、邱鴻傑、李▲シ▼▲テイ▼らの人たちのおかげであり、この場を借りて感謝の意を表しておく（敬称略）。 Taken together, the present invention is unique in terms of application of acetaminophen and uses safe general excipients to reliably suppress hepatotoxic side effects that occur when acetaminophen is used. The invention was successfully completed by Dr. Masateru Kuma, Dr. Huang Xin, Dr. Cai Chang-Akira, Xu Xiang-on, Hu Ki-Ken, Huang Bao-Ei, Analysis Team Huang Hoku Wei, Liu Tao-Hu, Yang 蘋, Tang Hee-Soo, Yang ▲ En ▼ Bell, We would like to take this opportunity to express our gratitude to Dr. Hayashi, Wengo Hayashi, and Dr. Zhu Kaimin, Dr. Yang Dongwa, Dr. Takumi Ta, Jie Hong, and Lee ▲ Shi ▼ ▲ Tay. (Titles omitted).
Claims (26)
前記組成物は、微結晶セルロース、リン酸二カルシウム二水和物、マンニトール、スクラロース、クロスポビドン、デンプングリコール酸ナトリウム、メンソール、Aerosil（登録商標）200、プロビドンK30およびそれらの任意の組み合わせからなるグループから選択される化合物を含む、使用。 Use of a composition to produce a drug for reducing or eradicating hepatotoxicity caused by acetaminophen (APAP) poisoning.
The composition comprises a group consisting of microcrystalline cellulose, dicalcium phosphate dihydrate, mannitol, sclarose, crospovidone, sodium starch glycolate, menthol, Aerosil® 200, Providone K30 and any combination thereof. Use, including compounds selected from.
該組成物は、スクラロース、メンソール及びそれらの任意の組み合わせからなるグループから選択される化合物を含む、使用。 Use of a composition to produce a drug for reducing or eradicating hepatotoxicity caused by acetaminophen (APAP) poisoning.
The composition comprises a compound selected from the group consisting of sucralose, menthol and any combination thereof.
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