JP4784037B2 - A therapeutic agent for tachyarrhythmia containing landiolol hydrochloride - Google Patents
A therapeutic agent for tachyarrhythmia containing landiolol hydrochloride Download PDFInfo
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、短時間型β1遮断薬である塩酸ランジオロールを含有する頻脈性不整脈の治療剤および塩酸ランジオロールを用いてなる頻脈性不整脈の治療用キットに関する。
さらに詳しく言えば、短時間型β1遮断薬である塩酸ランジオロールを含有する重症患者および／または術後患者における頻脈性不整脈の治療剤、および塩酸ランジオロールを用いてなる重症患者および／または術後患者における頻脈性不整脈の治療用キットに関する。
The present invention relates to a therapeutic agent for tachyarrhythmia containing Landiolol hydrochloride, which is a short-acting β 1 blocker, and a kit for treating tachyarrhythmia comprising Landiolol hydrochloride.
More specifically, a therapeutic agent for tachyarrhythmia in severe patients and / or post-operative patients containing the short-acting β 1 blocker landiolol hydrochloride, and severe patients and / or post-operative patients using landiolol hydrochloride The present invention relates to a kit for treating tachyarrhythmia in a patient.
（−）−［（Ｓ）−２，２−ジメチル−１，３−ジオキソラン−４−イル］メチル−３−［４−［（Ｓ）−２−ヒドロキシ−３−（２−モルホリノカルボニルアミノ）エチルアミノ］プロポキシ］フェニルプロピオン酸・１塩酸塩（CAS 登録番号：144481-98-1；以下、塩酸ランジオロールという。）は、短時間型β1遮断薬として、手術時の頻脈性不整脈（心房細動、心房粗動、洞性頻脈）に対する緊急処置に使用されている（特開平3-072475号公報（特許文献１））。 (-)-[(S) -2,2-Dimethyl-1,3-dioxolan-4-yl] methyl-3- [4-[(S) -2-hydroxy-3- (2-morpholinocarbonylamino) Ethylamino] propoxy] phenylpropionic acid monohydrochloride (CAS registration number: 144481-98-1; hereinafter referred to as landiolol hydrochloride) is a short-acting β 1 blocker and tachyarrhythmia during surgery (atrial) It is used for emergency treatment for fibrillation, atrial flutter, sinus tachycardia (Japanese Patent Laid-Open No. 3-072475 (Patent Document 1)).
不整脈とは、心臓の興奮が異所性であるもの、伝導障害があるもの、または興奮頻度が毎分６０回から１００回の範囲外にあるものを総称していう。
不整脈は、期外収縮性不整脈（心房性期外収縮、心室性期外収縮など）、徐脈性不整脈（洞不全症候群、房室ブロックなど）、および頻脈性不整脈（心房頻拍、心房細動、心房粗動、発作性上室性頻拍、心室頻拍、心室細動、ＷＰＷ症候群など）の３つに分けられ、β遮断薬が抗不整脈作用を発揮する不整脈は、心拍数が１００回を超える頻脈性不整脈である。
Arrhythmia is a generic term for cases where the heart excitement is ectopic, has conduction disturbances, or has an excitement frequency outside the range of 60 to 100 times per minute.
Arrhythmias include extrasystolic arrhythmias (such as atrial premature contraction, ventricular extrasystole), bradyarrhythmias (such as sinus insufficiency syndrome, atrioventricular block), and tachyarrhythmias (atrial tachycardia, atrial fine) Arrhythmia in which β-blocker exerts antiarrhythmic action, and has a heart rate of 100, for example, motion, atrial flutter, paroxysmal supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation, WPW syndrome) It is a tachyarrhythmia exceeding the number of times.
頻脈性不整脈は、特に心疾患を有する患者の手術時に心筋酸素消費量の増加をもたらし、予後を悪化させ、合併症や死亡の原因となる。β遮断薬は生体内の交感神経β受容体に拮抗して交感神経の興奮を抑え、心拍数および心収縮を低下させ、心筋酸素消費量の増加を抑える。また心拍数の減少に伴い、心拡張周期を延長することにより、冠血流の増大をもたらし虚血性心疾患の進展を抑制する。 Tachyarrhythmia results in increased myocardial oxygen consumption, especially during surgery for patients with heart disease, worsening prognosis and causing complications and death. Beta blockers antagonize sympathetic beta receptors in the body to suppress sympathetic excitation, reduce heart rate and contraction, and suppress increases in myocardial oxygen consumption. As the heart rate decreases, the diastole cycle is prolonged to increase coronary blood flow and suppress the development of ischemic heart disease.
手術中においては、麻酔導入、気管内挿管、皮膚切開、手術操作、気管チューブ抜管などの手術中のストレスや侵襲により一過性の強い交感神経興奮を引き起こし、生体内のエピネフリンおよびノルエピネフリンが異常レベルに達し、一過性の頻脈を生じやすい。 During surgery, transient stress and invasiveness such as induction of anesthesia, endotracheal intubation, skin incision, surgical operation, tracheal tube extubation, etc. cause transient strong sympathetic excitation, and abnormal levels of epinephrine and norepinephrine in vivo Is likely to cause transient tachycardia.
一方、手術中に限らず、重症患者（例えば、集中治療を要する患者）や、術後患者もまた頻脈性不整脈の症状を呈することがある。かかる患者における塩酸ランジオロールの有用性についてはこれまで全く知られていない。
例えば、手術後においては、心臓の器質的障害に加え、外傷や手術による炎症、カニューレ挿入等による心膜炎の発生、手術による自律神経系の崩壊、虚血性の傷害、心停止や心肺バイパス術の残留効果など、また手術後は心拍出量の減少症や体液量減少症を引き起こすことがあり、β作動薬であるドーパミンおよびドブタミンや電解質が投薬される場合もあり、非常に多数の要因が複雑に絡み合って頻脈を高頻度に発生する。手術後は安静時、伏臥時であっても、患者は術中と比べて厳重な管理下に置かれているわけではなく、またその動きが活発になることもあるため、手術を受けた際の傷跡が疼いたり、傷口が開くなど、患者の病状は大きく変わる恐れがある。
また重症患者においても、内科系、外科系など重篤な疾患を有する患者や救急外来に運ばれてきた重症患者は、心拍数の上昇が生命に影響を与える可能性がある。
On the other hand, not only during surgery, but also severe patients (for example, patients requiring intensive care) and postoperative patients may also exhibit symptoms of tachyarrhythmia. The usefulness of landiolol hydrochloride in such patients has never been known.
For example, after surgery, in addition to cardiac organ damage, inflammation due to trauma and surgery, pericarditis due to cannulation, autonomic nervous system disruption, ischemic injury, cardiac arrest and cardiopulmonary bypass There are a number of factors such as the residual effects of the drug, may cause decreased cardiac output and decreased fluid volume after surgery, and beta-agonists dopamine, dobutamine, and electrolytes may be administered. Are intertwined in a complex manner and frequently generate tachycardia. Even if the patient is resting or prone after surgery, the patient is not under strict control compared to that during surgery, and the movement may be active. The patient's medical condition may change significantly, such as a scarring or opening of a wound.
In critically ill patients, an increase in heart rate may affect life in patients with serious diseases such as internal medicine and surgery, and in critically ill patients who have been taken to an emergency department.
手術中は、主に因果関係の明確な交感神経系の興奮が関与した頻脈が発生すること、および全身麻酔薬等で管理された状況下にあることから、医師の裁量により投与量を臨機応変に調節することが有用である。
一方、重症患者および／または術後患者における頻脈性不整脈は、その原因が様々であり、複雑な要因が絡みあって頻脈が発生する。交感神経系関与の割合も様々であり、患者は必ずしも厳重な管理下におかれているわけではないので、高用量による過度の心抑制が問題となるおそれがあり、低用量から徐々に用量を上げていくことで有意に所望の心拍数を得る投与治療法が望ましい。
During surgery, tachycardia, mainly involving causal sympathetic nervous system excitement, occurs and is managed with general anesthetics. It is useful to adjust accordingly.
On the other hand, tachyarrhythmia in severe patients and / or postoperative patients has various causes, and tachycardia occurs due to complex factors. The percentage of sympathetic nervous system involvement varies, and patients are not always under strict control, so excessive cardiac suppression with high doses can be a problem, and doses can be gradually increased from low to high. It is desirable to have an administration therapy that obtains the desired heart rate significantly by raising it.
上記に示すように、手術中の患者と重症患者や術後患者においては誘発される頻脈の要因は大きく異なることから、β遮断薬の投与量および投与方法が異なって然るべきである。 As indicated above, since the tachycardia factor induced is significantly different between patients undergoing surgery and critically ill or postoperative patients, the dose and method of administration of β-blockers should be different.
頻脈性不整脈に対しては、現在、カルシウム拮抗薬、塩酸プロプラノロールなどの既存の長時間作用型のβ遮断薬などが用いられている。しかしながら、カルシウム拮抗薬は過度の血圧低下や心抑制の遷延が懸念され、既存のβ遮断薬は半減期が２〜５時間と作用時間が長く、過度の心機能抑制作用やβ2受容体遮断作用を介した気管支収縮作用を引き起こす可能性があるため、その使用が制限されている。 Currently, existing long-acting β-blockers such as calcium antagonists and propranolol hydrochloride are used for tachyarrhythmias. However, calcium antagonists are concerned about excessive hypotension and prolonged cardiac suppression, and existing β-blockers have a long half-life of 2 to 5 hours, resulting in excessive cardiac function suppression and β 2 receptor blockade. Its use is limited because it can cause bronchoconstrictive effects via action.
塩酸ランジオロールは、血中および肝臓のエステラーゼで速やかに非活性体に分解されるため、ヒトおよびイヌにおける生体内消失半減期は各々3.96分および4.6分と、既存のβ遮断薬に比べきわめて短いものである。またそのβ1選択性（β1／β2）は約２５０（プロプラノロールは約0.8）と極めて高い心臓選択性を有し、気道系への影響は少ないことが推測される。 Landiolol hydrochloride is rapidly degraded to inactive form by blood and liver esterases, so the elimination half-life in humans and dogs is 3.96 minutes and 4.6 minutes, respectively, which is extremely short compared to existing β-blockers. It is. Further, its β 1 selectivity (β 1 / β 2 ) is estimated to be about 250 (propranolol is about 0.8) and has a very high cardiac selectivity and has little influence on the airway system.
なお、術後における頻脈性不整脈は、器質的な心臓疾患を有する患者で、特に心臓手術（冠状動脈バイパス術、僧帽弁置換術、大動脈弁置換術など）後に高頻度（術後２〜５日をピークとする。）に発生し、集中治療室での滞在を余儀なくされ、それに伴い医療費を圧迫することとなる。 In addition, tachyarrhythmia after surgery is a frequent event in patients with organic heart disease, especially after cardiac surgery (coronary artery bypass surgery, mitral valve replacement, aortic valve replacement, etc.) 5 days peak)), staying in the intensive care unit is forced, and the medical costs are reduced accordingly.
上記から、手術中のみならず集中治療を要する重症患者および／または術後患者においても、刻々と変化する生理機能に対しては、塩酸ランジオロールのように短時間型の調節性の優れた医薬品が望まれている。 From the above, not only during surgery but also in critically ill patients and / or post-operative patients, for short-term changes in physiological functions, a short-time pharmaceutical with excellent controllability such as landiolol hydrochloride is available. It is desired.
本発明者らは、上記事情を鑑み鋭意研究した結果、重症患者および／または術後患者における頻脈性不整脈の治療方法として、驚くべきことに、塩酸ランジオロールを使用することによってきわめて安全に、重症患者および／または術後患者における頻脈性不整脈の非常に優れた治療効果などが得られ、臨床上十分に有用であることを見出し、さらに、目的とする治療効果を得るのに適した投与量および投与方法を見出し、本発明を完成するに至った。 As a result of diligent research in view of the above circumstances, the present inventors have surprisingly found that, as a method for treating tachyarrhythmia in severe patients and / or postoperative patients, extremely safe and severe use of landiolol hydrochloride. Dose that is found to be very useful clinically and has a very good therapeutic effect on tachyarrhythmia in patients and / or postoperative patients, and is suitable for obtaining the desired therapeutic effect The inventors have found an administration method and completed the present invention.
すなわち本発明は、
（１）塩酸ランジオロールを含有する頻脈性不整脈の治療剤、
（２）頻脈性不整脈が重症患者および／または術後患者における頻脈性不整脈である前記１記載の治療剤、
（３）頻脈性不整脈が重症患者における頻脈性不整脈である前記２記載の治療剤、
（４）重症患者が集中治療室に入室している患者である前記３記載の治療剤、
（５）頻脈性不整脈が、術後患者における頻脈性不整脈である前記２記載の治療剤、
（６）高用量の塩酸ランジオロールを短時間投与する工程（ａ）を１回行うか、または高用量の塩酸ランジオロールを短時間投与する工程（ａ）を行い、引き続いて低用量の塩酸ランジオロールを長時間投与する工程（ｂ）の組み合わせを１〜４回行うことを特徴とする前記２記載の治療剤、
（７）高用量の塩酸ランジオロールを短時間投与する工程（ａ）を行う前記６記載の治療剤、
（８）塩酸ランジオロールを0.0625ｍｇ／ｋｇ／分を実質的に１分間投与する前記７記載の治療剤、
（９）高用量の塩酸ランジオロールを短時間投与する工程（ａ）を行い、引き続いて低用量の塩酸ランジオロールを長時間投与する工程（ｂ）を行う組み合わせを１〜４回繰り返し行う前記６記載の治療剤、
（１０）工程（ａ）が３０秒〜３分間であり、工程（ｂ）が５〜３０分間である前記９記載の治療剤、
（１１）工程（ａ）が実質的に１分間であり、工程（ｂ）が実質的に１０分間である前記９記載の治療剤、
（１２）工程（ａ）を行い、引き続いて工程（ｂ）を行う組み合わせを１回行う前記９記載の治療剤、
（１３）工程（ａ）が0.0625ｍｇ／ｋｇ／分を実質的に１分間投与する工程であり、工程（ｂ）が0.01〜0.04ｍｇ／ｋｇ／分を投与する工程である前記１２記載の治療剤、
（１４）工程（ａ）の投与量が0.015〜0.125ｍｇ／ｋｇ／分であり、工程（ｂ）の投与量が0.005〜0.04ｍｇ／ｋｇ／分である前記１２記載の治療剤、
（１５）工程（ａ）が0.015〜0.06ｍｇ／ｋｇ／分を３０秒〜３分間投与する工程であり、工程（ｂ）が0.005〜0.02ｍｇ／ｋｇ／分を５〜３０分間投与する工程である前記１２記載の治療剤、
（１６）工程（ａ）が0.03〜0.06ｍｇ／ｋｇ／分を３０秒〜３分間投与する工程であり、工程（ｂ）が0.01〜0.02ｍｇ／ｋｇ／分を５〜３０分間投与する工程である前記１２記載の治療剤、
（１７）工程（ａ）が0.03ｍｇ／ｋｇ／分を実質的に１分間投与する工程であり、工程（ｂ）が0.01ｍｇ／ｋｇ／分を実質的に１０分間投与する工程である前記１２記載の治療剤、
（１８）工程（ａ）が0.06ｍｇ／ｋｇ／分を実質的に１分間投与する工程であり、工程（ｂ）が0.02ｍｇ／ｋｇ／分を実質的に１０分間投与する工程である前記１２記載の治療剤、
（１９）工程（ａ）を行い、引き続いて工程（ｂ）を行う組み合わせを２回行うことを特徴とする前記９記載の治療剤、
（２０）１回目の工程（ａ）が0.015〜0.06ｍｇ／ｋｇ／分を３０秒〜３分間投与する工程であり、１回目の工程（ｂ）が0.005〜0.02ｍｇ／ｋｇ／分を５〜３０分間投与する工程であり、２回目の工程（ａ）が0.03〜0.125ｍｇ／ｋｇ／分を３０秒〜３分間投与する工程であり、２回目の工程（ｂ）が0.01〜0.04ｍｇ／ｋｇ／分を５〜３０分間投与する工程である前記１９記載の治療剤、
（２１）１回目の工程（ａ）が0.03〜0.06ｍｇ／ｋｇ／分を３０秒〜３分間投与する工程であり、１回目の工程（ｂ）が0.01〜0.02ｍｇ／ｋｇ／分を５〜３０分間投与する工程であり、２回目の工程（ａ）が0.06〜0.125ｍｇ／ｋｇ／分を３０秒〜３分間投与する工程であり、２回目の工程（ｂ）が0.02〜0.04ｍｇ／ｋｇ／分を５〜３０分間投与する工程である前記１９記載の治療剤、
（２２）１回目の工程（ａ）が0.03ｍｇ／ｋｇ／分を実質的に１分間投与する工程であり、１回目の工程（ｂ）が0.01ｍｇ／ｋｇ／分を実質的に１０分間投与する工程であり、２回目の工程（ａ）が0.06ｍｇ／ｋｇ／分を実質的に１分間投与する工程であり、２回目の工程（ｂ）が0.02ｍｇ／ｋｇ／分を実質的に１０分間投与する工程である前記１９記載の治療剤、
（２３）１回目の工程（ａ）が0.06ｍｇ／ｋｇ／分を実質的に１分間投与する工程であり、１回目の工程（ｂ）が0.02ｍｇ／ｋｇ／分を実質的に１０分間投与する工程であり、２回目の工程（ａ）が0.125ｍｇ／ｋｇ／分を実質的に１分間投与する工程であり、２回目の工程（ｂ）が0.04ｍｇ／ｋｇ／分を実質的に１０分間投与する工程である前記１９記載の治療剤、
（２４）工程（ａ）を行い、引き続いて工程（ｂ）を行う組み合わせを３回行うことを特徴とする前記９記載の治療剤、
（２５）１回目の工程（ａ）が0.015〜0.03ｍｇ／ｋｇ／分を３０秒〜３分間投与する工程であり、１回目の工程（ｂ）が0.005〜0.01ｍｇ／ｋｇ／分を５分〜３０分間投与する工程であり、２回目の工程（ａ）が0.03〜0.06ｍｇ／ｋｇ／分を３０秒〜３分間投与する工程であり、２回目の工程（ｂ）が0.01〜0.02ｍｇ／ｋｇ／分を５分〜３０分間投与する工程であり、３回目の工程（ａ）が0.06〜0.125ｍｇ／ｋｇ／分を３０秒〜３分間投与する工程であり、３回目の工程（ｂ）が0.02〜0.04ｍｇ／ｋｇ／分を５分〜３０分間投与する工程である前記２４記載の治療剤、
（２６）１回目の工程（ａ）が0.015ｍｇ／ｋｇ／分を実質的に１分間投与する工程であり、１回目の工程（ｂ）が0.005ｍｇ／ｋｇ／分を実質的に１０分間投与する工程であり、２回目の工程（ａ）が0.03ｍｇ／ｋｇ／分を実質的に１分間投与する工程であり、２回目の工程（ｂ）が0.01ｍｇ／ｋｇ／分を実質的に１０分間投与する工程であり、３回目の工程（ａ）が0.06ｍｇ／ｋｇ／分を実質的に１分間投与する工程であり、３回目の工程（ｂ）が0.02ｍｇ／ｋｇ／分を実質的に１０分間投与する工程である前記２４記載の治療剤、
（２７）１回目の工程（ａ）が0.03ｍｇ／ｋｇ／分を実質的に１分間投与する工程であり、１回目の工程（ｂ）が0.01ｍｇ／ｋｇ／分を実質的に１０分間投与する工程であり、２回目の工程（ａ）が0.06ｍｇ／ｋｇ／分を実質的に１分間投与する工程であり、２回目の工程（ｂ）が0.02ｍｇ／ｋｇ／分を実質的に１０分間投与する工程であり、３回目の工程（ａ）が0.125ｍｇ／ｋｇ／分を実質的に１分間投与する工程であり、３回目の工程（ｂ）が0.04ｍｇ／ｋｇ／分を実質的に１０分間投与する工程である前記２４記載の治療剤、
（２８）工程（ａ）を行い、引き続いて工程（ｂ）を行う組み合わせを４回行うことを特徴とする前記９記載の治療剤、
（２９）１回目の工程（ａ）が0.015ｍｇ／ｋｇ／分を実質的に１分間投与する工程であり、１回目の工程（ｂ）が0.005ｍｇ／ｋｇ／分から0.02ｍｇ／ｋｇ／分を実質的に１０分間投与する工程であり、２回目の工程（ａ）が0.03ｍｇ／ｋｇ／分を実質的に１分間投与する工程であり、２回目の工程（ｂ）が0.01ｍｇ／ｋｇ／分を実質的に１０分間投与する工程であり、３回目の工程（ａ）が0.06ｍｇ／ｋｇ／分を実質的に１分間投与する工程であり、３回目の工程（ｂ）が0.02ｍｇ／ｋｇ／分を実質的に１０分間投与する工程であり、４回目の工程（ａ）が0.125ｍｇ／ｋｇ／分を実質的に１分間投与する工程であり、４回目の工程（ｂ）が0.04ｍｇ／ｋｇ／分を実質的に１０分間投与する工程である前記２８記載の治療剤、
（３０）（ｉ）高含量の塩酸ランジオロールを含有するバイアルおよび（ii）低含量の塩酸ランジオロールを含有するバイアルを組み合わせてなる頻脈性不整脈の治療用キット、
（３１）頻脈性不整脈の治療剤を製造するための塩酸ランジオロールの使用、
（３２）高用量の塩酸ランジオロールを短時間投与する工程（ａ）を行い、引き続いて低用量の塩酸ランジオロールを長時間投与する工程（ｂ）を行う組み合わせを１〜４回行う前記３１記載の使用、
（３３）有効量の塩酸ランジオロールを哺乳動物に投与することを特徴とする頻脈性不整脈の治療方法、
（３４）高用量の塩酸ランジオロールを短時間投与する工程（ａ）を行い、引き続いて低用量の塩酸ランジオロールを長時間投与する工程（ｂ）を行う組み合わせを１〜４回行う前記３３記載の治療方法、
（３５）静脈注射剤である前記１乃至５のいずれかに記載の治療剤、および
（３６）工程（ａ）が静脈内急速投与であり、工程（ｂ）が静脈内持続投与である前記１乃至５のいずれかに記載の治療剤に関する。
That is, the present invention
(1) A therapeutic agent for tachyarrhythmia containing landiolol hydrochloride,
(2) The therapeutic agent according to 1 above, wherein the tachyarrhythmia is tachyarrhythmia in a severe patient and / or a postoperative patient,
(3) The therapeutic agent according to 2 above, wherein the tachyarrhythmia is tachyarrhythmia in a severe patient,
(4) The therapeutic agent according to 3 above, wherein the critical patient is a patient entering the intensive care unit,
(5) The therapeutic agent according to 2 above, wherein the tachyarrhythmia is tachyarrhythmia in a postoperative patient,
(6) The step (a) of administering a high dose of landiolol hydrochloride for a short time is performed once, or the step (a) of administering a high dose of landiolol hydrochloride for a short time is carried out, followed by the low dose of landiolol hydrochloride. 3. The therapeutic agent according to 2 above, wherein the combination of the step (b) for time administration is performed 1 to 4 times,
(7) The therapeutic agent according to 6 above, wherein the step (a) of administering a high dose of landiolol hydrochloride for a short time is performed,
(8) The therapeutic agent according to 7 above, wherein landiolol hydrochloride is administered at 0.0625 mg / kg / min for substantially 1 minute,
(9) The combination according to 6 above, wherein the step (a) of administering a high dose of landiolol hydrochloride for a short time and then the step (b) of administering a low dose of landiolol hydrochloride for a long time is repeated 1 to 4 times. Therapeutic agent,
(10) The therapeutic agent according to 9 above, wherein the step (a) is from 30 seconds to 3 minutes, and the step (b) is from 5 to 30 minutes,
(11) The therapeutic agent according to 9 above, wherein the step (a) is substantially 1 minute and the step (b) is substantially 10 minutes,
(12) The therapeutic agent according to 9 above, wherein the combination of performing step (a) and subsequently performing step (b) is performed once,
(13) The treatment according to 12 above, wherein step (a) is a step of substantially administering 0.0625 mg / kg / min for 1 minute, and step (b) is a step of administering 0.01 to 0.04 mg / kg / min. Agent,
(14) The therapeutic agent according to the above 12, wherein the dose in step (a) is 0.015 to 0.125 mg / kg / min, and the dose in step (b) is 0.005 to 0.04 mg / kg / min,
(15) The step (a) is a step of administering 0.015-0.06 mg / kg / min for 30 seconds to 3 minutes, and the step (b) is a step of administering 0.005-0.02 mg / kg / min for 5-30 minutes. 13. The therapeutic agent according to the above 12,
(16) Step (a) is a step of administering 0.03 to 0.06 mg / kg / min for 30 seconds to 3 minutes, and Step (b) is a step of administering 0.01 to 0.02 mg / kg / min for 5 to 30 minutes. 13. The therapeutic agent according to the above 12,
(17) Step 12 (a) is a step of substantially administering 0.03 mg / kg / min for 1 minute, and step (b) is a step of substantially administering 0.01 mg / kg / min for 10 minutes. The therapeutic agent described,
(18) The step (a) is a step of substantially administering 0.06 mg / kg / min for 1 minute, and the step (b) is a step of substantially administering 0.02 mg / kg / min for 10 minutes. The therapeutic agent described,
(19) The therapeutic agent according to 9 above, wherein the combination of performing step (a) and subsequently performing step (b) is performed twice.
(20) The first step (a) is a step of administering 0.015-0.06 mg / kg / min for 30 seconds to 3 minutes, and the first step (b) is a step of 0.005-0.02 mg / kg / min from 5 It is a step of administering for 30 minutes, the second step (a) is a step of administering 0.03 to 0.125 mg / kg / min for 30 seconds to 3 minutes, and the second step (b) is 0.01 to 0.04 mg / kg. 19. The therapeutic agent according to 19 above, which is a step of administering 5 min / min for 5 min / min,
(21) The first step (a) is a step of administering 0.03 to 0.06 mg / kg / min for 30 seconds to 3 minutes, and the first step (b) is 0.01 to 0.02 mg / kg / min from 5 to 5. It is a step of administering for 30 minutes, the second step (a) is a step of administering 0.06 to 0.125 mg / kg / min for 30 seconds to 3 minutes, and the second step (b) is 0.02 to 0.04 mg / kg 19. The therapeutic agent according to 19 above, which is a step of administering 5 min / min for 5 min / min,
(22) The first step (a) is a step of substantially administering 0.03 mg / kg / min for 1 minute, and the first step (b) is a dose of 0.01 mg / kg / min for substantially 10 minutes. The second step (a) is a step of substantially administering 0.06 mg / kg / min for 1 minute, and the second step (b) is substantially 10% of 0.02 mg / kg / min. 20. The therapeutic agent according to 19 above, which is a step of administering for a minute.
(23) The first step (a) is a step of substantially administering 0.06 mg / kg / min for 1 minute, and the first step (b) is a dose of 0.02 mg / kg / min for substantially 10 minutes. The second step (a) is a step of substantially administering 0.125 mg / kg / min for 1 minute, and the second step (b) is substantially 10% of 0.04 mg / kg / min. 20. The therapeutic agent according to 19 above, which is a step of administering for a minute.
(24) The therapeutic agent according to 9 above, wherein the combination of performing step (a) and subsequently performing step (b) is performed three times.
(25) The first step (a) is a step of administering 0.015-0.03 mg / kg / min for 30 seconds to 3 minutes, and the first step (b) is 0.005-0.01 mg / kg / min for 5 minutes The second step (a) is a step of administering 0.03 to 0.06 mg / kg / min for 30 seconds to 3 minutes, and the second step (b) is a step of 0.01 to 0.02 mg / kg. The step of administering kg / min for 5 minutes to 30 minutes, the third step (a) is the step of administering 0.06-0.125 mg / kg / min for 30 seconds to 3 minutes, and the third step (b) 25. The therapeutic agent according to 24 above, which is a step of administering 0.02 to 0.04 mg / kg / min for 5 to 30 minutes,
(26) The first step (a) is a step of substantially administering 0.015 mg / kg / min for 1 minute, and the first step (b) is a dose of 0.005 mg / kg / min for substantially 10 minutes. The second step (a) is a step of administering 0.03 mg / kg / min substantially for 1 minute, and the second step (b) is substantially 0.01 mg / kg / min of 10 The third step (a) is substantially a step of administering 0.06 mg / kg / min for 1 minute, and the third step (b) is substantially a dose of 0.02 mg / kg / min. 25. The therapeutic agent according to the above 24, which is a step of administering to
(27) The first step (a) is a step of substantially administering 0.03 mg / kg / min for 1 minute, and the first step (b) is a dose of 0.01 mg / kg / min for substantially 10 minutes. The second step (a) is a step of substantially administering 0.06 mg / kg / min for 1 minute, and the second step (b) is substantially 10% of 0.02 mg / kg / min. The third step (a) is a step of substantially administering 0.125 mg / kg / min for 1 minute, and the third step (b) is substantially a step of 0.04 mg / kg / min. 25. The therapeutic agent according to the above 24, which is a step of administering to
(28) The therapeutic agent according to 9 above, wherein the combination of performing step (a) and subsequently performing step (b) is performed 4 times,
(29) The first step (a) is a step of substantially administering 0.015 mg / kg / min for 1 minute, and the first step (b) is from 0.005 mg / kg / min to 0.02 mg / kg / min. A step of substantially administering for 10 minutes, a second step (a) of substantially administering 0.03 mg / kg / min for 1 minute, and a second step (b) of 0.01 mg / kg / min. The step (a) for the third time is a step for substantially administering 0.06 mg / kg / min for 1 minute, and the step (b) for the third time is 0.02 mg / min. kg / min is substantially administered for 10 minutes, and the fourth step (a) is a step of substantially administering 0.125 mg / kg / min for 1 minute, and the fourth step (b) is 0.04. 29. The therapeutic agent according to the above 28, which is a step of administering mg / kg / min for substantially 10 minutes,
(30) A kit for treating tachyarrhythmia comprising a combination of (i) a vial containing a high content of landiolol hydrochloride and (ii) a vial containing a low content of landiolol hydrochloride,
(31) Use of landiolol hydrochloride for producing a therapeutic agent for tachyarrhythmia,
(32) The use according to 31 above, wherein the step (a) for administering a high dose of landiolol hydrochloride for a short time is performed, and the step (b) for subsequently administering a low dose of landiolol hydrochloride for a long time is performed 1 to 4 times. ,
(33) A method for treating tachyarrhythmia, comprising administering an effective amount of landiolol hydrochloride to a mammal,
(34) The treatment according to the above-mentioned 33, wherein the step (a) of administering a high dose of landiolol hydrochloride for a short time is performed, and the step of subsequently administering the low dose of landiolol hydrochloride (b) for a long time is performed 1 to 4 times. Method,
(35) The therapeutic agent according to any one of 1 to 5 above, which is an intravenous injection, and (36) Step 1 (a) is intravenous rapid administration, and Step (b) is intravenous continuous administration The therapeutic agent according to any one of 5 to 5.
本発明において、重症患者とは、特に限定されないが、例えば、集中治療を要する患者、例えば集中治療室に入室した患者を表わす。
集中治療を要する患者とは、特に限定されないが、例えば、急性循環器疾患、急性消化器疾患、急性呼吸器疾患、急性末梢性疾患、急性中枢性疾患、急性傷害、急性アレルギー疾患、急性泌尿器系疾患が挙げられ、また心不全、脱水、脳血管障害、虚血性心疾患、消化性潰瘍、感染症、発熱、蕁麻疹、炎症などの疾患に罹患した患者が挙げられる。
In the present invention, the severe patient is not particularly limited, but represents, for example, a patient requiring intensive care, for example, a patient who has entered an intensive care unit.
Examples of patients requiring intensive care include, but are not limited to, for example, acute cardiovascular disease, acute digestive organ disease, acute respiratory disease, acute peripheral disease, acute central disease, acute injury, acute allergic disease, acute urological system Examples include diseases, and patients suffering from diseases such as heart failure, dehydration, cerebrovascular disorder, ischemic heart disease, peptic ulcer, infection, fever, urticaria and inflammation.
術後患者の受けた手術の種類としては特に限定されないが、例えば、細胞移植、臓器移植、開腹術、開胸術、癌手術、神経手術などが挙げられる。術後の症状としては、特に限定されないが、例えば、重症疾患（例えば、幹細胞移植後敗血症、食道癌術後症例、開腹術後成人呼吸促拍症候群症例、開胸術後症例など）が挙げられる。 The type of surgery performed by the patient after surgery is not particularly limited, and examples include cell transplantation, organ transplantation, laparotomy, thoracotomy, cancer surgery, and neurosurgery. Examples of postoperative symptoms include, but are not limited to, severe diseases (eg, post-stem cell transplant sepsis, post-esophageal cancer surgery, post-laparotomy adult respiratory stimulation syndrome, post-thoracotomy, etc.) .
本発明において、工程（ａ）における短時間静脈内急速（ボーラス）投与のための高用量とは、塩酸ランジオロールの導入にあたり定常の血中濃度を速やかに得るのに必要な投与量をいう。 In the present invention, the high dose for short-term intravenous rapid (bolus) administration in the step (a) refers to a dose necessary for promptly obtaining a steady blood concentration upon introduction of landiolol hydrochloride.
重症患者における頻脈性不整脈に対して、工程（ａ）における高用量としては、例えば、患者体重１ｋｇあたり0.04〜0.12ｍｇ／分の範囲内の投与量が好ましく、特に0.0625ｍｇ／分が好ましい。
術後患者における頻脈性不整脈に対して、工程（ａ）における高用量としては、例えば、患者体重１ｋｇあたり0.015〜0.125mｇ／分の投与量が好ましい。0.03〜0.125ｍｇ／分が特に好ましい。
For tachyarrhythmia in critically ill patients, the high dose in step (a) is preferably, for example, a dose in the range of 0.04 to 0.12 mg / min per kg of patient body weight, particularly preferably 0.0625 mg / min.
For a tachyarrhythmia in a postoperative patient, the high dose in step (a) is preferably, for example, a dose of 0.015-0.125 mg / min per kg of patient weight. 0.03-0.125 mg / min is particularly preferred.
工程（ａ）における短時間とは、塩酸ランジオロールの導入にあたり定常の血中濃度を速やかに得るのに必要な時間をいう。
重症患者および／または術後患者における頻脈性不整脈に対して、工程（ａ）における短時間とは、塩酸ランジオロールの導入にあたり定常の血中濃度を速やかに得るのに必要な時間をいう。具体的には、約３０秒〜約５分間が好ましく、より好ましくは約３０秒〜約３分間である。最も好ましくは約１分間である。
The short time in the step (a) refers to a time necessary for promptly obtaining a steady blood concentration for the introduction of landiolol hydrochloride.
For tachyarrhythmias in critically ill patients and / or post-operative patients, the short time in step (a) refers to the time required to rapidly obtain a steady blood concentration upon introduction of landiolol hydrochloride. Specifically, it is preferably about 30 seconds to about 5 minutes, more preferably about 30 seconds to about 3 minutes. Most preferably about 1 minute.
工程（ｂ）における長時間静脈内持続（インフュージョン）投与のための低用量とは、不整脈患者が定常的に正常な脈拍数（例えば、５０〜１００回／分）を得るのに十分な投与量をいう。
重症患者における頻脈性不整脈に対して、工程（ｂ）における低用量としては、例えば、患者体重１ｋｇあたり0.01〜0.04ｍｇ／分の範囲内の投与量が好ましい。術後患者における頻脈性不整脈に対して、工程（ｂ）における低用量としては、例えば、患者体重１ｋｇあたり0.005〜0.04ｍｇ／分の投与量が好ましく、0.005〜0.02ｍｇ／分が特に好ましい。
A low dose for long-term intravenous (infusion) administration in step (b) is sufficient administration for an arrhythmic patient to constantly obtain a normal pulse rate (eg, 50-100 times / min). Say quantity.
For tachyarrhythmia in critically ill patients, the low dose in step (b) is preferably, for example, a dose within the range of 0.01 to 0.04 mg / min per kg of patient weight. For tachyarrhythmia in postoperative patients, the low dose in step (b) is preferably, for example, a dose of 0.005 to 0.04 mg / min per kg of patient body weight, particularly preferably 0.005 to 0.02 mg / min.
工程（ｂ）における長時間とは、不整脈患者が定常的に正常な脈拍数（例えば、５０〜１００回／分）を得るのに十分な時間をいう。
術後患者における頻脈性不整脈に対して、工程（ｂ）における長時間としては、例えば、約５分〜約２４時間が好ましく、より好ましくは約５分〜約６時間である。更に好ましくは約５分〜約３０分間であり、最も好ましくは約１０分間である。
The long time in the step (b) refers to a time sufficient for the arrhythmic patient to obtain a normal pulse rate (for example, 50 to 100 times / minute).
For tachyarrhythmia in postoperative patients, the long time in step (b) is, for example, preferably about 5 minutes to about 24 hours, more preferably about 5 minutes to about 6 hours. More preferably, it is about 5 minutes to about 30 minutes, and most preferably about 10 minutes.
工程（ａ）における静脈内急速投与とは、上記の投与量を短時間投与することをいい、例えばインフュージョンポンプや輸液ポンプなどの機器を使った投与または手動での投与をいう。
工程（ｂ）における静脈内持続投与とは、上記の投与量を長時間投与することをいい、例えばインフュージョンポンプや輸液ポンプなどの機器を使った投与または手動での投与をいう。
Intravenous rapid administration in step (a) refers to administration of the above dose for a short time, for example, administration using a device such as an infusion pump or an infusion pump, or manual administration.
Intravenous continuous administration in step (b) means administration of the above-mentioned dose for a long time, for example, administration using a device such as an infusion pump or an infusion pump or manual administration.
本発明において、工程（ａ）で高用量を静脈内急速投与するのは、迅速に塩酸ランジオロールの血中濃度を上げることを目的とし、一方、工程（ｂ）で低用量を静脈内持続投与するのは、半減期の短い薬物である塩酸ランジオロールの血中濃度を一定に保つことを目的とする。 In the present invention, the rapid intravenous administration of a high dose in step (a) is aimed at rapidly increasing the blood concentration of landiolol hydrochloride, while the low dose is continuously administered intravenously in step (b). The purpose of this is to keep the blood concentration of landiolol hydrochloride, a drug with a short half-life, constant.
「静脈内急速投与」とは、上記の高用量を短時間投与することをいい、ボーラス投与と同じ意味を表わす。「静脈内持続投与」とは、上記の低用量を長時間投与することをいい、インフュージョン投与と同じ意味を表わす。 “Intravenous rapid administration” refers to administration of the above-mentioned high dose for a short time, and represents the same meaning as bolus administration. “Intravenous continuous administration” refers to administration of the above-mentioned low dose for a long time, and represents the same meaning as infusion administration.
「工程（ａ）での高用量」と「工程（ｂ）での低用量」の比は、工程（ａ）を行った後工程（ｂ）を行うにあたり、その比が２：１〜５：１の比であることが好ましい。術後患者における頻脈性不整脈においてはさらに好ましくは、２：１〜４：１の比であり、特に好ましくは３：１の比である。
重症患者における頻脈性不整脈においては好ましくは３：２〜６：１の比である。
The ratio of “high dose in step (a)” and “low dose in step (b)” is 2: 1 to 5: when step (b) is performed after step (a) is performed. A ratio of 1 is preferred. In tachyarrhythmia in postoperative patients, a ratio of 2: 1 to 4: 1 is more preferable, and a ratio of 3: 1 is particularly preferable.
For tachyarrhythmias in critically ill patients, the ratio is preferably 3: 2 to 6: 1.
１回目の工程（ａ）および工程（ｂ）の投与量に対して、それに引き続いて行われる２回目の工程（ａ）および工程（ｂ）の投与量は、それぞれ１回目の（ａ）および（ｂ）よりも高用量である。３回目および４回目の工程も同様である。
特に好ましい投与態様としては、以下が挙げられる。
With respect to the dose of the first step (a) and step (b), the dose of the second step (a) and step (b) to be performed subsequently is the same as that of the first step (a) and (b), respectively. higher dose than b). The same applies to the third and fourth steps.
Particularly preferred modes of administration include the following.
工程（ａ）と工程（ｂ）の組み合わせ投与を１回行う場合として、
１）（ａ）0.015ｍｇ／ｋｇ／分、続いて（ｂ）0.005ｍｇ／ｋｇ／分、
２）（ａ）0.03ｍｇ／ｋｇ／分、続いて（ｂ）0.01ｍｇ／ｋｇ／分、
３）（ａ）0.06ｍｇ／ｋｇ／分、続いて（ｂ）0.02ｍｇ／ｋｇ／分、
４）（ａ）0.125ｍｇ／ｋｇ／分、続いて（ｂ）0.04ｍｇ／ｋｇ／分
の投与方法が好ましく、特に２）および３）が好ましい。
As a case where the combined administration of step (a) and step (b) is performed once,
1) (a) 0.015 mg / kg / min, followed by (b) 0.005 mg / kg / min,
2) (a) 0.03 mg / kg / min, followed by (b) 0.01 mg / kg / min,
3) (a) 0.06 mg / kg / min, followed by (b) 0.02 mg / kg / min,
4) (a) 0.125 mg / kg / min followed by (b) 0.04 mg / kg / min administration method is preferred, especially 2) and 3).
工程（ａ）と工程（ｂ）の組み合わせ投与を２回行う場合として、
１）（ａ）0.015ｍｇ／ｋｇ／分、続いて（ｂ）0.005ｍｇ／ｋｇ／分、続いて（ａ）0.03ｍｇ／ｋｇ／分、続いて（ｂ）0.01ｍｇ／ｋｇ／分、
２）（ａ）0.03ｍｇ／ｋｇ／分、続いて（ｂ）0.01ｍｇ／ｋｇ／分、続いて（ａ）0.06ｍｇ／ｋｇ／分、続いて（ｂ）0.02ｍｇ／ｋｇ／分、
３）（ａ）0.06ｍｇ／ｋｇ／分、続いて（ｂ）0.02ｍｇ／ｋｇ／分、続いて（ａ）0.125ｍｇ／ｋｇ／分、続いて（ｂ）0.04ｍｇ／ｋｇ／分
の投与方法が好ましく、特に２）および３）が好ましい。
As a case where the combined administration of step (a) and step (b) is performed twice,
1) (a) 0.015 mg / kg / min, followed by (b) 0.005 mg / kg / min, followed by (a) 0.03 mg / kg / min, followed by (b) 0.01 mg / kg / min,
2) (a) 0.03 mg / kg / min followed by (b) 0.01 mg / kg / min followed by (a) 0.06 mg / kg / min followed by (b) 0.02 mg / kg / min
3) (a) 0.06 mg / kg / min followed by (b) 0.02 mg / kg / min followed by (a) 0.125 mg / kg / min followed by (b) 0.04 mg / kg / min And 2) and 3) are particularly preferable.
工程（ａ）と工程（ｂ）の組み合わせ投与を３回行う場合として、
１）（ａ）0.015ｍｇ／ｋｇ／分、続いて（ｂ）0.005ｍｇ／ｋｇ／分、続いて（ａ）0.03ｍｇ／ｋｇ／分、続いて（ｂ）0.01ｍｇ／ｋｇ／分、続いて（ａ）0.06ｍｇ／ｋｇ／分、続いて（ｂ）0.02ｍｇ／ｋｇ／分、
２）（ａ）0.03ｍｇ／ｋｇ／分、続いて（ｂ）0.01ｍｇ／ｋｇ／分、続いて（ａ）0.06ｍｇ／ｋｇ／分、続いて（ｂ）0.02ｍｇ／ｋｇ／分、続いて（ａ）0.125ｍｇ／ｋｇ／分、続いて（ｂ）0.04ｍｇ／ｋｇ／分
の投与方法が好ましく、特に２）が好ましい。
As a case where the combined administration of step (a) and step (b) is performed three times,
1) (a) 0.015 mg / kg / min followed by (b) 0.005 mg / kg / min followed by (a) 0.03 mg / kg / min followed by (b) 0.01 mg / kg / min followed (A) 0.06 mg / kg / min, followed by (b) 0.02 mg / kg / min,
2) (a) 0.03 mg / kg / min followed by (b) 0.01 mg / kg / min followed by (a) 0.06 mg / kg / min followed by (b) 0.02 mg / kg / min followed The administration method is preferably (a) 0.125 mg / kg / min, followed by (b) 0.04 mg / kg / min, particularly 2).
工程（ａ）と工程（ｂ）の組み合わせ投与を４回行う場合として、
（ａ）0.015ｍｇ／ｋｇ／分、続いて（ｂ）0.005ｍｇ／ｋｇ／分、続いて（ａ）0.03ｍｇ／ｋｇ／分、続いて（ｂ）0.01ｍｇ／ｋｇ／分、続いて（ａ）0.06ｍｇ／ｋｇ／分、続いて（ｂ）0.02ｍｇ／ｋｇ／分、続いて（ａ）0.125ｍｇ／ｋｇ／分、続いて（ｂ）0.04ｍｇ／ｋｇ／分
の投与方法が好ましい。
なお、重症患者に対する投与として好ましくは、
（ａ）0.0625ｍｇ／ｋｇ／分、続いて（ｂ）0.01〜0.04ｍｇ／ｋｇ／分
の投与方法である。
As a case where the combined administration of step (a) and step (b) is performed four times,
(A) 0.015 mg / kg / min followed by (b) 0.005 mg / kg / min followed by (a) 0.03 mg / kg / min followed by (b) 0.01 mg / kg / min followed by (a The administration method is preferably 0.06 mg / kg / min, followed by (b) 0.02 mg / kg / min, followed by (a) 0.125 mg / kg / min, followed by (b) 0.04 mg / kg / min.
In addition, preferably for administration to severe patients,
(A) 0.0625 mg / kg / min followed by (b) 0.01 to 0.04 mg / kg / min.
本発明において、（ｉ）高含量の塩酸ランジオロールを含有するバイアルおよび（ii）低含量の塩酸ランジオロールを含有するバイアルを組み合わせてなる重症患者における頻脈性不整脈の治療用キットとは、１０ｍｇ〜１００ｍｇの塩酸ランジオロールを含有するバイアルおよび３０ｍｇ〜３００ｍｇの塩酸ランジオロールを含有するバイアルの組み合わせである治療用キットをいう。 In the present invention, (i) a kit for treating tachyarrhythmia in a critically ill patient comprising a combination of a vial containing a high content of landiolol hydrochloride and (ii) a vial containing a low content of landiolol hydrochloride is 10 mg to 100 mg. A therapeutic kit that is a combination of a vial containing 1 mg of landiolol hydrochloride and a vial containing 30 mg to 300 mg of landiolol hydrochloride.
本発明に使用される塩酸ランジオロールは、特許2,004,651号および特許3,302,647号に記載された化合物であり、その化学名は（−）−［（Ｓ）−２，２−ジメチル−１，３−ジオキソラン−４−イル］メチル−３−［４−［（Ｓ）−２−ヒドロキシ−３−（２−モルホリノカルボニルアミノ）エチルアミノ］プロポキシ］フェニルプロピオン酸・１塩酸塩である。 Landiolol hydrochloride used in the present invention is a compound described in Patent No. 2,004,651 and Patent No. 3,302,647, and its chemical name is (−)-[(S) -2,2-dimethyl-1,3-dioxolane- 4-yl] methyl-3- [4-[(S) -2-hydroxy-3- (2-morpholinocarbonylamino) ethylamino] propoxy] phenylpropionic acid monohydrochloride.
塩酸ランジオロールは、それ自体公知の方法、たとえば特許2,004,651号または特許3,302,647号公報に記載された方法に従って、医薬組成物として種々の剤形に用いることができる。例えば静脈投与できる剤形であればいずれでも良いが、とりわけ液剤および用時溶剤に溶解して用いる凍結乾燥剤が好ましい。かかる剤形においては、塩酸ランジオロールを１バイアルあたり１ｍｇから1,000ｍｇ含有する剤形が好ましい。より好ましくは１０ｍｇから１００ｍｇであり、更に好ましくは５０ｍｇ含有する剤形である。
医薬組成物に使用されるものとしては、一般的に使用されている賦形剤、結合剤、潤沢剤などから適宜選択して用いられる。
Landiolol hydrochloride can be used in various dosage forms as a pharmaceutical composition according to a method known per se, for example, the method described in Japanese Patent No. 2,004,651 or Japanese Patent No. 3,302,647. For example, any dosage form that can be administered intravenously may be used, but a lyophilized agent used by dissolving in a solution and a solvent for use is particularly preferred. In such a dosage form, a dosage form containing 1 mg to 1,000 mg of landiolol hydrochloride per vial is preferable. The dosage form is more preferably 10 mg to 100 mg, and still more preferably 50 mg.
As a pharmaceutical composition, it is appropriately selected from commonly used excipients, binders, lubricants and the like.
塩酸ランジオロールは、その投与量および投与方法を最適化することにより、重症患者および／または術後患者における頻脈性不整脈の治療剤として有用である。 Landiolol hydrochloride is useful as a therapeutic agent for tachyarrhythmia in critically ill and / or postoperative patients by optimizing its dosage and method of administration.
以下に、本発明の塩酸ランジオロールの投与による重症患者および術後患者における頻脈性不整脈患者の臨床効果を、実施例および製剤例を挙げて詳しく述べるが、本発明はこれらの例に限定されるものではない。また、本発明の範囲を逸脱しない範囲で変化させた態様も本発明に含まれる。 Hereinafter, the clinical effects of tachyarrhythmia patients in severe patients and postoperative patients by administration of landiolol hydrochloride of the present invention will be described in detail with reference to examples and formulation examples, but the present invention is limited to these examples. It is not a thing. Moreover, the aspect changed in the range which does not deviate from the scope of the present invention is also included in the present invention.
実施例１：重症患者に対する塩酸ランジオロールの作用
対象患者：
集中治療を要する重症患者症例10例（幹細胞移植後敗血症３例、食道癌手術後症例２例、開腹手術後成人呼吸促拍症候群症例３例、開胸術後症例症例２例；対象患者の平均年齢65.8歳）を対象に、各症例で心拍数が120以上になった時点で通常の頻脈発作への治療を施行してもなお頻脈が持続する場合に以下の投与方法に従って塩酸ランジオロールを投与した。
Example 1: Patients subject to the effect of landiolol hydrochloride on critically ill patients:
10 severely ill patients requiring intensive care (3 cases of sepsis after stem cell transplantation, 2 cases after esophageal cancer surgery, 3 cases of adult respiratory stimulation syndrome after laparotomy, 2 cases of cases after thoracotomy; average of target patients If the tachycardia still persists after treatment for a normal tachycardia attack at the time when the heart rate in each case reaches 120 or more, the administration of landiolol hydrochloride according to the following administration method Administered.
方法：
初期投与量0.0625ｍｇ／ｋｇ／分を単回投与し、続けて0.01ｍｇ／ｋｇ／分で持続投与を開始し、目的とする心拍数が得られるまで随時0.04ｍｇ／ｋｇ／分まで増量した。この間の血圧変動、心拍数の変動、効果発現までの時間と0.0625ｍｇ／ｋｇ／分の単回投与の効果持続時間、塩酸ランジオロールの総投与量等を検討した。
結果：
・心拍数
対象患者に対して0.0625ｍｇ／ｋｇ／分の単回投与後、約１分で心拍数の低下を認めた。単回投与の効果持続は平均１２分であった。
Method:
The initial dose of 0.0625 mg / kg / min was administered once, followed by continuous administration at 0.01 mg / kg / min, and increased to 0.04 mg / kg / min as needed until the desired heart rate was obtained. During this period, blood pressure fluctuations, heart rate fluctuations, time to effect onset, duration of effect of a single administration of 0.0625 mg / kg / min, total dose of landiolol hydrochloride, etc. were examined.
result:
-Heart rate After a single dose of 0.0625 mg / kg / min to the subject patient, a decrease in heart rate was observed in about 1 minute. The sustained effect of a single dose averaged 12 minutes.
実施例２：臨床試験例
術後頻脈性不整脈患者を対象にして、以下の条件で比較試験を行った。
用法：
(1)被験薬（塩酸ランジオロール）投与群、
(2)偽薬（プラセボ）投与群。
治験薬の剤型・含有量：
(1)被験薬：塩酸ランジオロールを１バイアル中に５０ｍｇ含有する白色凍結乾燥品、
(2)偽薬：塩酸ランジオロール５０ｍｇと外観上識別不能なプラセボバイアル。
Example 2: Clinical Test Example A comparative test was conducted on postoperative tachyarrhythmia patients under the following conditions.
Usage:
(1) Study drug (landiolol hydrochloride) administration group,
(2) Placebo administration group.
Study drug dosage form and content:
(1) Test drug: white lyophilized product containing 50 mg of landiolol hydrochloride in one vial,
(2) Placebo: A placebo vial that is visually indistinguishable from landiolol hydrochloride 50 mg.
被験薬投与群および偽薬投与群の投与方法・投与量（工程（ａ）および工程（ｂ））を表１に示す。
被験薬または偽薬各４バイアルを治験薬溶解用生理食塩水（２０ｍｌ）に溶解し、インフュージョンポンプを用いて投与を行った。患者に対し、１分間の急速静注後に１０分間の静脈内持続投与を行った（第一段階）。投与後１１分時点で徐拍目標に達した場合は投与を終了した。投与後１１分時点で徐脈目標に達しない場合には用量を漸増し、さらに１分間の急速静注後に１０分間の静脈内持続投与を行った（第二段階）。第二段階の途中で徐脈目標に達した場合は投与を終了した。 4 vials each of the test drug or placebo were dissolved in physiological saline for study drug dissolution (20 ml) and administered using an infusion pump. Patients received continuous intravenous administration for 10 minutes after rapid intravenous infusion for 1 minute (first stage). The administration was terminated when the bradycardia target was reached at 11 minutes after administration. When the bradycardia target was not reached at 11 minutes after administration, the dose was gradually increased, followed by continuous intravenous administration for 10 minutes after rapid intravenous infusion for 1 minute (second stage). Administration was terminated if the bradycardia target was reached during the second stage.
徐脈目標は投与直前心拍数に対する２０％以上の徐脈化かつ心拍数１００回／分未満とした。
なお、徐脈目標は、投与直前心拍数に対する２０％以上の徐拍化かつ心拍数１００回／分未満、ただし、心拍数１００回／分以上を徐脈目標とする場合は投与前に予め設定した。
The bradycardia target was a bradycardia of 20% or more with respect to the heart rate immediately before administration and a heart rate of less than 100 times / min.
The bradycardia target is 20% or more of the heart rate immediately before administration and less than 100 heartbeats / minute. However, if the heartbeat rate is 100 heartbeats / minute or more, it is set in advance before administration. did.
症例数：偽薬投与群 患者数４８
塩酸ランジオロール投与群 患者数４８
成績：
最終用量における血圧の改善率の結果を表２に示す。
Landiolol hydrochloride group 48 patients
Grade:
The results of the improvement rate of blood pressure at the final dose are shown in Table 2.
心拍数の変化率の結果を表３に示す。
投与直前と投与終了時（または中止時）における心拍数を評価した。投与終了後において、プラセボ投与群よりも塩酸ランジオロール投与の両群が、プラセボ群に対して有意な改善を示した。
Heart rate was evaluated immediately before administration and at the end of administration (or at the time of discontinuation). After administration, both groups receiving landiolol hydrochloride showed a significant improvement over the placebo group over the placebo group.
上記に示した投与量以外でも、工程（ａ）と工程（ｂ）の組み合わせ投与を１回行う場合として、
１）（ａ）0.015ｍｇ／ｋｇ／分、続いて（ｂ）0.005ｍｇ／ｋｇ／分、
２）（ａ）0.06ｍｇ／ｋｇ／分、続いて（ｂ）0.02ｍｇ／ｋｇ／分、
３）（ａ）0.125ｍｇ／ｋｇ／分、続いて（ｂ）0.04ｍｇ／ｋｇ／分、
In addition to the doses shown above, the combination of step (a) and step (b) is performed once,
1) (a) 0.015 mg / kg / min, followed by (b) 0.005 mg / kg / min,
2) (a) 0.06 mg / kg / min, followed by (b) 0.02 mg / kg / min,
3) (a) 0.125 mg / kg / min, followed by (b) 0.04 mg / kg / min,
工程（ａ）と工程（ｂ）の組み合わせ投与を２回行う場合として、
１）（ａ）0.015ｍｇ／ｋｇ／分、続いて（ｂ）0.005ｍｇ／ｋｇ／分、続いて（ａ）0.03ｍｇ／ｋｇ／分、続いて（ｂ）0.01ｍｇ／ｋｇ／分、
２）（ａ）0.06ｍｇ／ｋｇ／分、続いて（ｂ）0.02ｍｇ／ｋｇ／分、続いて（ａ）0.125ｍｇ／ｋｇ／分、続いて（ｂ）0.04ｍｇ／ｋｇ／分、
As a case where the combined administration of step (a) and step (b) is performed twice,
1) (a) 0.015 mg / kg / min, followed by (b) 0.005 mg / kg / min, followed by (a) 0.03 mg / kg / min, followed by (b) 0.01 mg / kg / min,
2) (a) 0.06 mg / kg / min followed by (b) 0.02 mg / kg / min followed by (a) 0.125 mg / kg / min followed by (b) 0.04 mg / kg / min
工程（ａ）と工程（ｂ）の組み合わせ投与を３回行う場合として、
１）（ａ）0.015ｍｇ／ｋｇ／分、続いて（ｂ）0.005ｍｇ／ｋｇ／分、続いて（ａ）0.03ｍｇ／ｋｇ／分、続いて（ｂ）0.01ｍｇ／ｋｇ／分、続いて（ａ）0.06ｍｇ／ｋｇ／分、続いて（ｂ）0.02ｍｇ／ｋｇ／分、
２）（ａ）0.03ｍｇ／ｋｇ／分、続いて（ｂ）0.01ｍｇ／ｋｇ／分、続いて（ａ）0.06ｍｇ／ｋｇ／分、続いて（ｂ）0.02ｍｇ／ｋｇ／分、続いて（ａ）0.125ｍｇ／ｋｇ／分、続いて（ｂ）0.04ｍｇ／ｋｇ／分、
As a case where the combined administration of step (a) and step (b) is performed three times,
1) (a) 0.015 mg / kg / min followed by (b) 0.005 mg / kg / min followed by (a) 0.03 mg / kg / min followed by (b) 0.01 mg / kg / min followed (A) 0.06 mg / kg / min, followed by (b) 0.02 mg / kg / min,
2) (a) 0.03 mg / kg / min followed by (b) 0.01 mg / kg / min followed by (a) 0.06 mg / kg / min followed by (b) 0.02 mg / kg / min followed (A) 0.125 mg / kg / min, followed by (b) 0.04 mg / kg / min,
工程（ａ）と工程（ｂ）の組み合わせ投与を４回行う場合として、
（ａ）0.015ｍｇ／ｋｇ／分、続いて（ｂ）0.005ｍｇ／ｋｇ／分、続いて（ａ）0.03ｍｇ／ｋｇ／分、続いて（ｂ）0.01ｍｇ／ｋｇ／分、続いて（ａ）0.06ｍｇ／ｋｇ／分、続いて（ｂ）0.02ｍｇ／ｋｇ／分、続いて（ａ）0.125ｍｇ／ｋｇ／分、続いて（ｂ）0.04ｍｇ／ｋｇ／
のいずれの場合でも術後頻脈性不整脈の症状を改善した。
As a case where the combined administration of step (a) and step (b) is performed four times,
(A) 0.015 mg / kg / min followed by (b) 0.005 mg / kg / min followed by (a) 0.03 mg / kg / min followed by (b) 0.01 mg / kg / min followed by (a ) 0.06 mg / kg / min followed by (b) 0.02 mg / kg / min followed by (a) 0.125 mg / kg / min followed by (b) 0.04 mg / kg / min
In both cases, the symptoms of postoperative tachyarrhythmia were improved.
製剤例１：塩酸ランジオロール５０ｍｇ含有製剤の製造
以下の各成分を常法により混合した後、溶液を常法により滅菌し、５ｍｌずつバイアルに充填し、常法により凍結乾燥し、１バイアル中５０mgの活性成分を含有するバイアル10000本を得た。
・塩酸ランジオロール ………５００ｇ
・Ｄ−マンニトール ………５００ｇ
・水酸化ナトリウム ………４２０ｍｇ
・蒸留水 ………全量で6000ｍｌ
Formulation Example 1: Production of a preparation containing 50 mg of landiolol hydrochloride After the following components were mixed by a conventional method, the solution was sterilized by a conventional method, filled in 5 ml vials, freeze-dried by a conventional method, and 50 mg in one vial. 10000 vials containing the active ingredient were obtained.
・ Landiolol hydrochloride: 500g
・ D-mannitol ……… 500g
・ Sodium hydroxide ……… 420mg
・ Distilled water ……… 6000ml in total
製剤例２：偽薬剤の製造
以下の各成分を常法により混合した後、ろ過滅菌法により滅菌し、0.6ｍｌずつバイアルに充填し、常法により凍結乾燥し、偽薬のバイアル10000本を得た。
・Ｄ−マンニトール ………９６９ｇ
・塩化ナトリウム ………２５ｇ
・グリチルリチン酸モノアンモニウム ………6.0ｇ
・リン酸水素２ナトリウム・１２水塩 ………8.0ｇ
・クエン酸 ………２２５ｍｇ
・注射用水 ………全量で6000ｍｌ
Formulation Example 2: Manufacture of placebo The following components were mixed by a conventional method, then sterilized by a filtration sterilization method, filled into vials each 0.6 ml, and freeze-dried by a conventional method to obtain 10,000 vials of placebo .
・ D-mannitol ......... 969g
・ Sodium chloride: 25g
・ Monoammonium glycyrrhizinate …… 6.0g
・ Disodium hydrogen phosphate ・ 12 hydrate ……… 8.0g
・ Citric acid ... 225mg
・ Water for injection ……… 6000ml in total
塩酸ランジオロールは短時間型β1遮断薬として、重症患者および／または術後患者における頻脈性不整脈の治療剤として有用である。
Landiolol hydrochloride is useful as a short-acting β 1 blocker and as a therapeutic agent for tachyarrhythmia in critically ill and / or postoperative patients.
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