TW201347784A - 包含酮咯酸和曲馬朵之液相醫藥調配物 - Google Patents
包含酮咯酸和曲馬朵之液相醫藥調配物 Download PDFInfo
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- TW201347784A TW201347784A TW102114770A TW102114770A TW201347784A TW 201347784 A TW201347784 A TW 201347784A TW 102114770 A TW102114770 A TW 102114770A TW 102114770 A TW102114770 A TW 102114770A TW 201347784 A TW201347784 A TW 201347784A
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- Prior art keywords
- pain
- ketorolac
- tramadol
- effective amount
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Classifications
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
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Abstract
本發明係關於一種用於治療患有適度至嚴重疼痛之患者之液相醫藥組成物。該液相醫藥組成物包括有效量之酮咯酸或酮咯酸緩血酸胺，及有效量之曲馬朵或其醫藥學上可接受之鹽。該液相醫藥組成物有效將疼痛分數自8-9減至5.3或5.3以下。
Description
本申請案係關於包括酮咯酸(ketorolac)及曲馬朵(tramadol)之液相醫藥調配物。本申請案亦關於該醫藥調配物之用途，其用於治療適度至適度嚴重之疼痛，諸如手術後疼痛(例如在剖腹生產術或其他手術之後)、癌症疼痛、內臟疼痛及外傷疼痛。
基於身體原因，疼痛可分為三種類型：傷害型、神經型及混合型。
傷害型疼痛通常由有害刺激引起，該有害刺激諸如為熱及切口，其對身體或組織直接引起損害或損傷。基於疼痛起始部位，傷害型疼痛可進一步分成兩種類型：軀體疼痛及內臟疼痛。軀體疼痛來源於直接與外部有害刺激接觸之骨、關節、肌肉、皮膚或結締組織。內臟疼痛來源於內臟擠壓、拉伸及損傷。大多數人將症狀描述為疼痛(achy)、尖銳痛、刺痛及搏動。傷害型疼痛通常持續時間較短且當損害復原時結束。傷害型疼痛之實例包含手術後疼痛、扭傷、骨折、燒傷、腫塊、瘀傷及發炎性疼痛(除由關節炎引起之發炎以外)。
神經型疼痛來源於神經系統中在中樞或周圍之自發性異位
神經元放電。由於隱伏之病因學通常為不可逆的，因此大部分神經型疼痛為慢性疼痛。大多數人將神經型疼痛描述為射痛(shooting)、灼燒、發麻、刀刺狀痛(lancinating)、電擊品質、麻木及持續性異常疼痛。神經型疼痛之命名法係基於病因學之起始神經系統之部位；例如中風後中樞性疼痛、糖尿病性周圍神經病變、皰疹後(或帶狀皰疹後)神經痛、末期癌症疼痛、幻肢痛。
混合型疼痛之特徵在於共存傷害型疼痛與神經型疼痛。舉例而言，肌肉疼痛觸發中樞或周圍神經元敏化，從而導致慢性下腰痛、偏頭痛及肌筋膜疼痛。
臨床上疼痛強度係按0至10之標度定級；0為無疼痛，1-3為溫和疼痛，4-6為適度疼痛且7-10為嚴重疼痛。舉例而言，8-9指定為適度嚴重疼痛。
WHO「3步」準則提供管理疼痛之準則。「3步」係由疼痛強度及藥物之止痛活性來決定。
(a)第1步溫和疼痛：乙醯胺酚、NSAID或兩者之組合。常用NSAID包含阿司匹林(aspirin)、雙氯芬酸(diclofenac)、吲哚美辛(indomethacin)、舒林酸(sulindac)、酮洛芬(ketoprofen)、依託度酸(etodolac)、酮咯酸。
(b)第2步適度疼痛：NSAID加鴉片劑(opiate)，包含阿司匹林或乙醯胺酚與可待因(codein)、氧可酮(oxycodon)、二氫可待因、氫可酮(hydrocodon)、曲馬朵
(c)第3步嚴重疼痛：強鴉片劑，包含嗎啡鹼(morphine)、氫嗎啡鹼(hydromorphine)、地美庚醇(methadol)、左啡諾(levorphanol)、芬太尼
(fentanyl)、氧可酮
充分認識到乙醯胺酚、NSAID及類鴉片均具有其固有缺陷。乙醯胺酚及NSAID經常顯示天花板效應(ceiling effect)(疼痛減輕上限)。一旦達到該上限，服用其他醫藥便不會提供進一步疼痛減輕。另外，NSAID在規則劑量下已結束心臟、肝、胃腸道及腎之器官毒性。類鴉片通常引起不可容忍之不利影響，諸如便秘、呼吸抑制、身體依賴性及濫用問題。首先，NSAID提供周圍抗傷害感受且類鴉片提供中樞抗傷害感受。
酮咯酸(分子量255.27)或酮咯酸緩血酸胺為雜環乙酸衍生物家族中之非類固醇消炎藥物(NSAID)，其經常用作止痛劑。酮咯酸藉由抑制身體合成前列腺素來起作用。酮咯酸之經口(錠劑或膠囊)及肌肉內(注射)製劑中之酮咯酸為(S)-(-)-酮咯酸(活性異構體)與(R)-(+)-酮咯酸之外消旋混合物。投予此藥物來治療適度疼痛，或與降低之類鴉片劑量組合治療嚴重疼痛。
曲馬朵(分子量263.4)，即(1R,2R)-rel-2-[(二甲胺基)甲基]-1-(3-甲氧苯基)環己醇屬於鴉片劑促效劑類別。曲馬朵分類為中樞神經系統藥物，其通常以鹽酸鹽(鹽酸曲馬朵)形式銷售。鹽酸曲馬朵為一種無消炎活性之通過中樞起作用之弱類鴉片止痛劑，其用於治療適度至嚴重疼痛。藥物具有大範圍應用，包含治療腿不寧症候群及肌肉纖維疼痛。
本發明係關於一種用於治療患有適度至嚴重疼痛之患者之液相醫藥組成物。該醫藥組成物於液相調配物中包括有效量之酮咯酸或酮咯酸緩血酸胺，及有效量之曲馬朵或其醫藥學上可接受之鹽。
在一具體實例中，酮咯酸或酮咯酸緩血酸胺之有效量為42-52.5mg，且曲馬朵或其醫藥學上可接受之鹽的有效量為28-35mg。
在另一具體實例中，酮咯酸或酮咯酸緩血酸胺之有效量為21-26.25mg，且曲馬朵或其醫藥學上可接受之鹽的有效量為70-87.5mg。
圖1為來自第一次注射液相醫藥組成物之視覺模擬標度相對於時間之散佈圖。K60=60mg酮咯酸，K60+T40=60mg酮咯酸+40mg曲馬朵，K45+T75=45mg酮咯酸+75mg曲馬朵，K30+T100=30mg酮咯酸+100mg曲馬朵，T100=100mg曲馬朵。
本發明係關於一種液相醫藥調配物，其包括(a)酮咯酸或酮咯酸緩血酸胺(在本申請案中統稱酮咯酸)及(b)曲馬朵或其醫藥學上可接受之鹽(在本申請案中統稱曲馬朵)於水溶液中。液相酮咯酸-曲馬朵調配物適於注射，例如靜脈內注射或肌肉內注射。液相酮咯酸-曲馬朵調配物亦適於經口投予。液相酮咯酸-曲馬朵調配物在室溫(約22-28℃)下穩定至少1天，較佳3天，更佳7天。如本文所用之「穩定」係指兩種藥物均維持至少80%、較佳90%其在溶液中之初始量，且溶液不顯示可見沈澱。
液相酮咯酸-曲馬朵調配物提供兩種個別藥物酮咯酸與曲馬朵之組合益處。組合之酮咯酸-曲馬朵調配物之優勢包含：(a)提供較短止痛開始及長久持續時間，(b)藉由互補性作用機制來提供中樞與周圍止痛作用，及(c)減少各藥物之劑量，因此將副作用減到最小。此外，因為NSAID
因天花板效應而僅可管理溫和至適度疼痛，所以酮咯酸-曲馬朵調配物優於一種單一藥物，因為添加曲馬朵消除酮咯酸之天花板效應。因此，酮咯酸-曲馬朵調配物可用來治療具有適度嚴重強度之疼痛。此等改良向患者提供更多治療選擇。
液相酮咯酸-曲馬朵溶液較佳為透明溶液，但其亦可為懸浮液形式及乳液形式。
液相酮咯酸-曲馬朵調配物之有效劑量一般為約7.5-60mg酮咯酸及10-100mg曲馬朵。
酮咯酸及曲馬朵之有效量亦可為42-59mg酮咯酸及14-71mg曲馬朵；較佳為42-52.5mg酮咯酸及28-35mg曲馬朵；或45-52.5mg酮咯酸及30-35mg曲馬朵。
酮咯酸及曲馬朵之有效量亦可為9-42mg酮咯酸及71-99mg曲馬朵；較佳為18.75-26.25mg酮咯酸及62.5-87.5mg曲馬朵；或21-26.25mg酮咯酸及70-87.5mg曲馬朵。
劑量通常調配為1-20ml以用於靜脈內注射及0.5-2ml以用於肌肉內注射。醫藥組成物中各藥物之濃度(mg/ml)可藉由量(mg)除以體積(ml)來計算。
液相醫藥調配物含有酮咯酸或酮咯酸緩血酸胺及曲馬朵或其醫藥學上可接受之鹽於水中，pH值為5.0-8.0，較佳為pH 6-8。液相醫藥調配物可含有鹽水。液相醫藥調配物亦可含有緩衝劑以使pH值穩定。液相醫藥調配物可含有熟習該項技術者已知之醫藥學上可接受之載劑。舉例而言，可將用於注射形式或經口形式之已知的醫藥學上可接受之載劑添加至
液相醫藥調配物中。除酮咯酸及曲馬朵以外，液相醫藥調配物較佳不含有任何其他藥物或任何其他活性成分。舉例而言，液相醫藥調配物不含有甲氧氯普胺(metoclopramide)或MgSO4。
基於已知之止痛相關作用機制及所報導之臨床可能，本發明之酮咯酸-曲馬朵調配物適用於管理適度至適度嚴重強度(標度4-9或6-9)之疼痛，較佳適用於管理適度嚴重強度(標度8-9)之疼痛。酮咯酸-曲馬朵調配物尤其適用於管理手術後疼痛、癌症疼痛、內臟疼痛及外傷疼痛。
本發明係關於一種用於治療患有適度至適度嚴重疼痛(疼痛標度4-9，較佳為6-9，更佳為8-9)之患者的方法。方法包括：鑒別罹患疼痛之患者，及向該患者投予有效量之液相酮咯酸-曲馬朵調配物。如本文所用之「有效量」係指有效減少或減輕患者疼痛之量。本發明將疼痛分數減至5.3。
在一具體實例中，酮咯酸或酮咯酸緩血酸胺之有效量為42-52.5mg，且曲馬朵或其醫藥學上可接受之鹽的有效量為28-35mg。較佳地，酮咯酸或酮咯酸緩血酸胺之有效量為45-52.5mg，且曲馬朵或其醫藥學上可接受之鹽的有效量為30-35mg。
在另一具體實例中，酮咯酸或酮咯酸緩血酸胺之有效量為18.75-26.25mg，且曲馬朵或其醫藥學上可接受之鹽的有效量為62.5-87.5mg。較佳地，酮咯酸或酮咯酸緩血酸胺之有效量為21-26.25mg，且曲馬朵或其醫藥學上可接受之鹽的有效量為70-87.5mg。
液相酮咯酸/曲馬朵調配物可藉由靜脈內注射、肌肉內注射
或經口投予來投予。
靜脈內注射可藉由快速注射或連續輸注來投予；1、2、3或4次大丸劑為較佳。一般而言，靜脈內注射之總體積為1-20ml或2-10ml，且肌肉內注射之總體積<2ml，例如0.5-1.5ml。
本發明之方法適用於治療疼痛強度為8-9之適度嚴重疼痛。該方法亦適用於治療手術後疼痛，諸如剖腹生產後疼痛、其他手術後之手術後疼痛、嚴重癌症疼痛、內臟疼痛或外傷疼痛。
手術後疼痛係由軀體疼痛及內臟疼痛引起。軀體疼痛來源於在損傷部位(切口)之直接有害脈衝。在損傷部位之傳入纖維敏化推動中樞敏化。內臟疼痛來源於內臟擠壓、拉伸及發炎。液相酮咯酸-曲馬朵調配物向疼痛由發炎(COX1/C0X2)及內臟疼痛引起之患者提供益處。其亦藉由調節μ受體及血清素及去甲腎上腺素含量來增強來自中樞之抗傷害反應
液相酮咯酸-曲馬朵調配物因以下原因而尤其有效地管理剖腹生產後之手術後疼痛：
(a)由子宮收縮引起之內臟疼痛為剖腹生產術後疼痛之主要分量。酮咯酸在減輕內臟疼痛中高度有效。
(b)前列腺素涉及於組織損傷與子宮收縮中。酮咯酸抑制PGE2比單獨之乙醯胺酚提供更佳之消炎及止痛作用。
(c)液相酮咯酸-曲馬朵調配物負責剖腹生產疼痛減輕之作用機制包含抑制COX1及COX2、鈉電流、血清素及去甲腎上腺素再攝取及g受體活化。
一半以上手術後疼痛患者在現行治療下仍經歷不足之疼痛
減輕。液相酮咯酸-曲馬朵調配物適用於其他類型手術後之疼痛控制，其他類型手術諸如為冠狀動脈繞道移植術(CABG)、腰椎間盤手術(lumbar disc surgery)、整形外科手術(orthopaedia)及扁桃體切除術。
手術後疼痛主要地為急性且嚴重的。管理手術後疼痛通常在手術後一小時開始且再持續48-72小時。因為大多數患者在重大手術之後住烷，所以認為非經腸投予止痛劑是容易且便利的。非經腸投予液相酮咯酸-曲馬朵調配物在增加藥物暴露及較短髮作方面提供益處。另外，藥物吸收可在手術後前24小時內變化。針對手術後疼痛之較佳投藥途徑為靜脈內注射或肌肉內注射。
癌症疼痛為由腫瘤引起之組織損傷、化學療法、輻射或手術之影響的結果。癌症疼痛可在任何癌症階段發生。疼痛強度介於適度至嚴重疼痛之範圍內。癌症患者在末期經常經歷不可容忍之嚴重嚴重，其中常用如嗎啡鹼之高度強效類鴉片。
在癌症及傷害感受惡化過程中，前列腺素誘發性發炎及傷害感受器敏化係以不同程度做貢獻。視癌症過程而定，癌症疼痛可為傷害型、神經型或兩者。液相酮咯酸-曲馬朵調配物向疼痛係由嚴重發炎(前列腺素)及鈉通道異常興奮性引起之癌症患者提供益處。其亦藉由調節μ受體及血清素及去甲腎上腺素含量來增強來自中樞之抗傷害性反應。
液相酮咯酸-曲馬朵調配物因以下原因而適用於管理癌症疼痛：
(a)癌症疼痛主要為發炎性及神經性。提供消炎與神經阻斷活性之液
相酮咯酸-曲馬朵調配物有效管理具有適度嚴重強度之癌症疼痛。
(b)液相酮咯酸-曲馬朵調配物可用於末期癌症患者來減少疼痛減輕中之嗎啡鹼使用。
患有嚴重疼痛之末期癌症患者可為急性及慢性的，具有偶然
之適度至嚴重強度之爆發性疼痛。為管理急性及爆發性疼痛，IM或IV非經腸投藥提供快速且有效之疼痛減輕。
本發明進一步由以下實施例說明，該等實施例不被視為將本發明的範疇限於其中所述之特定程序。
a.酮咯酸緩血酸胺之穩定性
自Yung Shin Pharmaceuticals獲得酮咯酸緩血酸胺(30mg/ml，pH 6-8)。用HCl或NaOH將酮咯酸緩血酸胺溶液調節至不同pH值(pH 5、6、7、8及9)且儲存在室溫下。在第0、1、3及7天測試具有不同pH值之溶液以藉由HPLC量測酮咯酸緩血酸胺之含量。
結果顯示酮咯酸緩血酸胺(30mg/ml)在室溫下在pH5-9下穩定7天；在7天後，酮咯酸緩血酸胺含量為98.4-101.7%。
b.曲馬朵之穩定性
自Grunenthal GMBH Products獲得曲馬朵(50mg/ml，pH 6-8)。用HCl或NaOH將曲馬朵溶液調節至不同pH值(pH5、6、7、8及9)且儲存在室溫下。在第0、1、3及7天測試具有不同pH值之溶液以藉由HPLC量測曲馬朵含量。
結果顯示曲馬朵在室溫下在pH 5-8下穩定7天；在7天後，曲馬朵含量為97.4-102.4%。在pH 9下，曲馬朵沈澱出且在第0天，70.4%初始量保留於溶液中，且在第1、3、7天後，56.4%初始量保留於溶液中。
c.酮咯酸及曲馬朵之穩定性
將酮咯酸緩血酸胺(30mg/ml)及曲馬朵(50mg/ml)與鹽水混合在一起以提供含有酮咯酸緩血酸胺(2mg/ml)及曲馬朵(20mg/ml)之混合物溶液。用HCl或NaOH將混合物溶液調節至不同pH值(pH 5、6、7、8及9)且儲存在室溫下。在第0、1、3及7天觀察混合物溶液之外觀。
在pH 5.0及6.0下，混合物溶液在第0天為透明的，但具有極少懸浮固體，在第1、3及7天無顯著變化。在pH 7.0及8.0下，混合物溶液在第0-7天為透明的。在pH 9下，在第0天立即觀察到劇烈沈澱，且在第1-7天見到針狀晶體。
結果顯示混合物溶液在室溫下在pH 5-8下穩定7天，但在pH 9下不穩定。
本研究之目標在於測試預混合之酮咯酸與曲馬朵液態調配物對於手術後疼痛治療之安全概況及功效。
總共63名受試者隨機化於本研究中。大多數受試者(>90%)經歷選擇性重大腹部手術或婦科手術(包含腹腔鏡手術)。其他受試者(<10%)經歷乳房切除術。
自Yung Shin Pharmaceuticals Ind有限公司獲得酮咯酸緩血酸胺(Keto，30mg/ml)。自Grunenthal GMBH Products獲得鹽酸曲馬朵(50mg/ml)。將兩種藥物與鹽水預混合在一起至12.0ml或12.5ml之總體積以提供如下5種不同濃度。
第1組. 僅6mg/ml酮咯酸(最大劑量60mg於10ml中)，n=12
第2組. 6mg/ml酮咯酸，4mg/ml曲馬朵(最大劑量60mg酮咯酸及40mg曲馬朵於10ml中)，n=13
第3組. 4.5mg/ml酮咯酸，7.5mg/ml曲馬朵(最大劑量45mg酮咯酸及75mg曲馬朵於10ml中)，n=13
第4組. 3mg/ml酮咯酸，10mg/ml曲馬朵(最大劑量30mg酮咯酸及100mg曲馬朵於10ml中)，n=12
第5組. 僅10mg/ml曲馬朵(最大劑量100mg曲馬朵於10ml中)，n=13
在零時刻藉由靜脈內注射給予各患者2.5ml之初始劑量(最大劑量之四分之一)，接著每10分鐘藉由靜脈內注射給予患者2.5ml之劑量，直至患者之疼痛分數<5或劑量用盡為止。
自手術中醒來之後，將最嚴重疼痛分數定級為>5之受試者隨機化至五組酮咯酸及/或曲馬朵之一。給予患者四分之一體積(2.5ml)之初始劑量治療，且若受試者之最嚴重疼痛程度仍為適度至嚴重(疼痛分數
5)，則隨後在約10分鐘、20分鐘及30分鐘時給予2.5ml。在各劑量之後每5分鐘評估疼痛分數及生命徵象。若受試者之最嚴重疼痛分數定級為<5或受試者已接受最大劑量，則受試者停止服用液相酮咯酸及曲馬朵調配物且使受試者直接接至嗎啡鹼PCA泵。
使用視覺模擬標度(Visual Analog Scale；VAS)評分系統來評估患者疼痛強度(0-10)。10意謂最嚴重疼痛且0意謂無疼痛。藉由字描述符錨定長10cm(100mm)之水平線，各端為「無疼痛」及「極嚴重疼痛」。藉由自該線左手端量測至受試者所標記之點(毫米)來確定VAS分數。研究護士量測自0點(無疼痛)至標記之長度且將其抄錄為0.0cm至10.0cm之間的數字。記錄各患者在0、5、10、15、20、35、30、35及40分鐘時之疼痛分數。
所有測試均基於雙側備擇假設(two-sided alternative hypotheses)且在5%顯著性程度下達成。
對於功效終點，對組合酮咯酸與曲馬朵之累積總單位劑量進行凡德瓦登檢驗(Van Der Waerden test)。(en.wikipedia.org/wiki/Van_der_Waerden_test)另外，適當時藉由回歸法來模型化組合比率(酮咯酸劑量：曲馬朵劑量)與用於疼痛減輕之酮咯酸與曲馬朵之組合的累積總單位劑量之間的相關性。
使用費雪爾精確檢驗(Fisher exact test)來比較治療組中分數小於5之受試者的比例。(en.wikipedia.org/wiki/Fisher's_exact_test)
對於安全性變數，由治療組提供不利事件之概述頻率表。將
描述統計學用於生命徵象資料。
相對於自初始注射之時間繪製各組在0、5、10、15、20、35、30、35及40分鐘時之平均VAS分數的圖，且展示為圖1。
如圖1中所示，用組I(僅酮咯酸)、III(最大劑量45mg酮咯酸及75mg曲馬朵於10ml中)及V(僅曲馬朵)治療之患者未減小其疼痛分數使其降至小於6。
相反地，用組II(最大劑量60mg酮咯酸及40mg曲馬朵於10ml中)治療之患者在約28-35分鐘或30-35分鐘時疼痛分數減至5。在28-35分鐘時之累積劑量經計算為42-52.5mg酮咯酸及28-35mg曲馬朵。在30-35分鐘時之累積劑量經計算為45-52.5mg酮咯酸及30-35mg曲馬朵。
另外，用組IV(最大劑量30mg酮咯酸及100mg曲馬朵於10ml中)治療之患者在約25-35分鐘或28-35分鐘時疼痛分數減至5.3，且在40分鐘時疼痛分數甚至更低。在考慮高劑量曲馬朵之不利影響時，達至5.3之疼痛分數之較低劑量曲馬朵為較佳的。在25-35分鐘時之累積劑量經計算為18.75-26.25mg酮咯酸及62.5-87.5mg曲馬朵。在28-35分鐘時之累積劑量經計算為21-26.25mg酮咯酸及70-87.5mg曲馬朵。
Claims (12)
- 一種用於治療患有適度至嚴重疼痛之患者的液相醫藥組成物，其於水性調配物中包括有效量之酮咯酸或酮咯酸緩血酸胺及有效量之曲馬朵或其醫藥學上可接受之鹽，其中酮咯酸或酮咯酸緩血酸胺之該有效量為42-52.5mg，且曲馬朵或其醫藥學上可接受之鹽之該有效量為28-35mg。
- 如申請專利範圍第1項之液相醫藥組成物，其中酮咯酸或酮咯酸緩血酸胺之該有效量為45-52.5mg，且曲馬朵或其醫藥學上可接受之鹽之該有效量為30-35mg。
- 一種用於治療患有適度至嚴重疼痛之患者的液相醫藥組成物，其於水性調配物中包括有效量之酮咯酸或酮咯酸緩血酸胺及有效量之曲馬朵或其醫藥學上可接受之鹽，其中酮咯酸或酮咯酸緩血酸胺之該有效量為18.75-26.25mg，且曲馬朵或其醫藥學上可接受之鹽之該有效量為62.5-87.5mg。
- 如申請專利範圍第3項之液相醫藥組成物，其中酮咯酸或酮咯酸緩血酸胺之該有效量為21-26.25mg，且曲馬朵或其醫藥學上可接受之鹽之該有效量為70-87.5mg。
- 如申請專利範圍第1或3項之液相醫藥組成物，其中該患者之疼痛強度為6-9。
- 如申請專利範圍第1或3項之液相醫藥組成物，其中該患者之疼痛強度為8-9。
- 如申請專利範圍第6項之液相醫藥組成物，其用於使該患者之疼痛分 數自8-9減至5.3或5.3以下。
- 如申請專利範圍第1或3項之液相醫藥組成物，其中該組成物呈溶液形式、懸浮液形式或乳液形式。
- 如申請專利範圍第1或3項之液相醫藥組成物，其pH值為5-8。
- 如申請專利範圍第1或3項之液相醫藥組成物，其中該疼痛為手術後疼痛、癌症疼痛、內臟疼痛或外傷疼痛。
- 如申請專利範圍第1或3項之液相醫藥組成物，其藉由靜脈內注射來投予。
- 如申請專利範圍第1或3項之液相醫藥組成物，其藉肌肉內注射來投予。
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