TWI334779B - Pharmaceutical preparation containing oxycodone and naloxone - Google Patents
Pharmaceutical preparation containing oxycodone and naloxone Download PDFInfo
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- TWI334779B TWI334779B TW092107765A TW92107765A TWI334779B TW I334779 B TWI334779 B TW I334779B TW 092107765 A TW092107765 A TW 092107765A TW 92107765 A TW92107765 A TW 92107765A TW I334779 B TWI334779 B TW I334779B
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- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
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Description
1334779 (1) 玖、發明說明 【發明所屬之技術領域】 本發明係關於一種含有涇氣可待因酮(oxycodo.ne) 及烯丙羥嗎啡酮(naloxone )之貯存安定性藥學製劑。 【先前技術】 治療由諸如癌症、風濕病及關節炎之類的疾病所造成 的嚴重疼痛,是治療這類疾病的核心。腫瘤病患所感受到 的疼痛範圍包括骨膜及骨頭本身的疼痛,以及內臟痛與軟 組織痛。所有這類疼痛使得病患日常生活難以忍受且經常 導致抑鬱狀態。因此,疼痛療法的成功可讓病人生活品質 持續改善,與理解療法(此療法係針對該疾病之正確起因 加以治療)的成功同等重要。 有關成功之疼痛療法的重要性,世界衛生組織(WHO )已經發展出治療腫瘤疼痛之病患的四步驟模式。此模式 在日常操作上已經證明是有效的,且可延伸至患有慢性疼 痛的病患、或患有癌症以外之疾病所造成之疼痛類型的病 患。根據疼痛之強度、性質及位置,此療法過程中可區分 出四步驟,且直到所使用之止·痛藥劑的效果不再有效,則 需要下一步驟(Ebell,H. J. ; Bayer A. ( Ed. ) : Die
Schmerzbehandlung von Tumorpatienten, Thieme 1 9 9 4 ( Supportive MaPnahmen in der Onkologie,Band 3) Zech, D. ; Grond, S. ; Lynch, J. ; Hertel, D. ; Lehmann, K ·:針 對癌症疼痛緩解之世界衛生組織指導方針的評估報告:未 -5- (2) 1334779 來十年硏究,Pain ( 1995),63,65— 76)。
根據WHO之這種四步驟模式,類鴉片(opioid)止 痛劑在治療疼痛上扮演著核心角色。除了代表這種藥學活 性藥劑之原型的嗎啡之外,類鴉片止痛劑也包括羥氫可待 因酮、二氫嗎啡酮(hydromorphone)、薛驗醯嗎啡( nicomorphine)、二氫可待因(dihydrocodeine)、海洛 因(diamorphine)、帕帕維屯(papaveretum)、可待因 、乙基嗎啡、苯基哌啶及其衍生物;***(methadone )、右旋普帕西芬(dextropropoxyphene)、叔丁啡( buprenorphine)、潘他哩新(pentazocine)、痛立定( tilidine )、特拉嗎寅(tramadol )及二氣可待因酮( hydrocodone) 。WHO之ATC分類法(結構治療化學分類 法)可指明一藥學活性藥劑是否代表一類鴉片止痛劑。類 鴉片止痛劑之顯著止痛作用係由於模擬內源性、類嗎啡作 用物質之作用所致,該內源性、類嗎啡作用物質之生理功 能在於控制疼痛刺激之接收與處理。 類鴉片抑制疼痛刺激之擴散。除了立即壓抑脊髓神經 內由類鴉片所引起之神經元興奮性訊息傳導作用之外,一 種自腦幹發射至脊髓神經的神經途徑活化作用也有關聯。 此活化作用導致脊髓神經內的疼痛擴散現象受到抑制。再 者,類鴉片經由對腦緣(limbic )系統發生作用而限制丘 腦接收疼痛,腦緣系統會影響情感性疼痛之估算。 類鴉片受體可於體內不同位置發現。腸與腦之受體對 於藉由類鴉片治療疼痛尤其重要,特別是當這些受體被佔 -6- (3) 1334779 據而導致不同副作用時。
若類鴉片止痛劑以高親合性結合至類鴉片受體、且誘 使疼痛之接收受到搶強烈抑制,則該類鴉片止痛劑視爲強 效之促動劑。也有高親合力而與類鴉片受體結合之物質, 則設計爲拮抗劑。根據結合行爲及所誘發的活性,類鴉片 可分類爲單純促動劑、混合型促動劑/拮抗劑、及單純拮 抗劑。舉例而言,單純拮抗劑包括下列物質:拿淬松( naltrexone )、條丙經嗎啡酮 (naloxone)、拿美芬( nalmefene )、拿洛啡(nalorphine )、拿布啡( nalbuphine)、拿洛同愛新(naloxoneazinen)、甲基拿 滓松(methylnaltrexone)、飢迪賽新(ketylcyclazocine )、若賓納芬明(norbbinaltorphimine)、納梓多( naltrindol ) 、6—β —拿龍碩(naloxol)及 6 — β —拿淬碩 (naltrexol ) ( Forth W., ; Henschler, D. ; Rummel W.
;Starke, K. : All gemeine und Spezielle Pharmakologie und T oxikologie, 7. Auflage, 1 9 9 6, Spektrum Akademischer Verlag, Heidelberg Berlin Oxford ) 〇 由於其良好之止痛功效,諸如羥氫可待因酮、痛立定 、叔丁啡及潘他唑新之化合物早已以治療疼痛之藥物形式 而使用。例如Oxigesic ®(其中羥氫可待因酮是止痛活 性之化合物)及Valoron ® (其中痛立定是止痛活性之化 合物)等藥物已經證實對治療疼痛有效。 然而,使用類鴉片止痛劑於疼痛療法上,可能一倂伴 隨著不欲之副作用。故長期使用類鴉片止痛劑可導致心理 1334779
及生理依賴性。 特別是受疼痛所苦之病患對於類鴨片止痛劑的生理依 賴性’會導致抗藥性之發展,這表示伴隨著長期攝入藥物 ,病患爲了要獲得疼痛解除,則漸增提高止痛劑之劑量。 類鴉片止痛劑之令人心情愉快的作用,經常造成疼痛解除 劑之濫用。藥物濫用及心理依賴性是常見現象,尤其發生 在青少年之間。這些危險性的影響尤其是由強效止痛能力 之物質引起的,影響範圍由不欲的習慣到完全發展爲成瘾 。但是這些物質係合法地使用於醫療用途上,且藥物中不 能沒有這些物質。 除了上述缺點之外,使用類鴉片止痛劑於疼痛療法上 ,通常也會導致下列不欲之副作用:例如頑性便秘、 呼吸壓抑、生病及鎭靜。比較不常觀察到是,迫切需要喝 水或無法喝水。已經完成各種嘗試來對抗發生於疼痛治療 中的上癮過程及其他副作用。可利用例如傳統治療等方法 達成這類嘗試。就藥物成瘾而言,可嘗試藥物撤回療法; 就頑性便秘而言,可施用通便劑》 其他嘗試藉由施用對抗該類鴉片止痛劑之拮抗劑,其 目的在於將上癮及習慣養成傾向 '以及其他副作用,減少 至最低。這類拮抗劑可以是拿淬松或烯丙羥嗎啡酮。 目前已經有許多建議與教導,有關如何施用上述活性 化合物而能避免不欲之習慣養成及依賴性,或甚至成瘾。 美國專利案第3,773,955及3,966,940號建議,當非 經腸用藥時,將止痛劑與拿淬松組合調配,爲了要預防會 -8- (5) (5)1334779 增進依賴性之作用例如心情愉快等等。至今尙無法避免諸 如頑性便秘等副作用,。 爲了要限制經口用藥形式之非經腸濫用,美國專利案 第4,45 7,93 3號建議將嗎啡與拿淬松於特定劑量範圍內組 合。該專利案也無提及如何避免諸如頑性便秘等副作用。 同樣爲了避免濫用,美國專利案第4,5 82,83 5號描述 一種不是非經腸施用、就是經舌下施用的製劑,其含有叔 丁啡與拿淬松之組合。 德國專利申請案DE 0 352 36 1 A1係關於經口施用一 類鴉片止痛劑與一拮抗劑、藉以治療疼痛療法過程中的頑 性便秘,該拮抗劑呈拿淬松或烯丙羥嗎啡酮之前藥形式。 避免類鴉片止痛劑之濫用並非該申請案之重點。 德國專利申請案DE 43 25 465 A1也關於利用含有一 類鴉片止痛劑與一拮抗劑之製劑而治療疼痛療法過程中的 頑性便秘。該案揭示之技術特徵爲:拮抗劑(可以是烯 丙羥嗎啡酮)之劑量一定要比類鴉片止痛劑(較好是嗎啡 )之劑量更高。這是爲了確保拮抗劑可展現抗頑性便秘之 功效,但不降低促動劑之止痛活性。避免類鴉片止痛劑之 濫用並非該申請案之重點。 爲了要避免疼痛療法過程中的副作用,例如頑性便秘 及呼吸壓抑,市面上已經導入可經口施用之藥劑,其含有 類鴉片止痛劑與類鴉片拮抗劑(烯丙羥嗎啡酮)。 Windrop/Sterling公司之藥品 Talwin®含有潘他哩新與 燦丙經嗎啡酮。GSdeke公司之藥品Va】oron(®含有痛立 (6) (6)1334779 定-烯丙羥嗎啡酮之組合。 除了強效止痛功效、減少成癮可能性及避免副作用之 外,適用於疼痛療法之藥物還應該提供更多特徵。 一般而言,藥物必須調配成爲活性化合物於標準貯存 條件下盡可能長期安定之方式。藥物也必須調配成爲活性 化合物所預期之釋出圖形不隨長期貯存而改變之形式。 再者,同樣也就促動劑/拮抗劑之組合而論,每一個 單一活性化合物之釋出圖形應該可以視需要予以選擇。爲 了達到此目的,所採用的措施不應該阻擾、甚至阻止、 更多活性化合物(例如,就不同活性化合物之組合而論) 之釋出圖形可以視需要加以選擇。因此,釋出圖形應該沒 有相互依賴性。 適用於疼痛療法之藥物不是應該含有活性化合物之劑 量爲病患只有在極少情況下才必須服用者,就是應該以病 患只有在極少情況下才必須服用該藥物的方式調配。疼痛 解除劑之用藥流程愈簡單,病患愈能掌握其爲何應該且多 常應該服用哪一個錠劑,則病人更能確實遵照醫生之命令 。只是偶爾才有服用疼痛解除劑之必要,將使得病人服用 該疼痛解除劑之意願高(順從性)。 曾經嘗試經由使用所謂的緩釋配方(即,活性化合物 經過一延長的時間自藥物釋出的藥物配方)來減少止痛藥 物必須用藥之頻率,藉此增加病患之順從性。這種緩釋配 方也使得「類鴉片止痛劑之緩釋,可減少該活性化合物之 成癮可能性」乙事得以理解。 -10- (7) (7)1334779 由於一活性化合物之成癮可能性並非由該化合物本身 決定,而是經由施用該化合物之方式及所得到的藥物動力 學而定。除了類鴉片之影響精神(psychotropic )作用之 外,大腦與類鴉片接觸之頻率,比該活性化合物本身而言 ,更是產生依賴性風險之決定性關鍵(Nolte,T.: STK-Zeitschrift ftir angewandte Schmerztherapie, 2001,V〇1.2 )°
Purdue公司之藥物Oxigesic ®是一製劑,類鴉片止 痛劑羥氫可待因酮係以持續方式自該製劑釋出。由於此種 配方,降低該藥物必須服用之頻率與上癮可能性,然而副 作用仍存在,且無法排除發展成癮之危險,因爲 Oxigesic ®不含有類鴉片之拮抗劑。 根據先前提及之歐洲專利申請案EP 0 352 361 A,既 不是類鴉片止痛劑,也不是拮抗劑,被調配爲持續方式釋 出者。故此種製劑能有效作用之時間受到限制、且該製劑 必須每天施用多次。無法達到所期望之病人順從性。此專 利申請案中也無揭示該製劑之配方係以時間安定性及獨立 釋出活性化合物作爲特徵之優點。該製劑之貯存安定性也 未記載於該案之技術內容中。 德國專利申請案 DE43 25 465 A1揭示之配方可預防 疼痛療法過程中發生的頑性便秘,其係利用持續釋出類鴉 片止痛劑,超量存在之拮抗劑則一定不能以持續方式釋出 。根據烯丙羥嗎啡酮之高首要流通作用(First - Pass — Effect ),則將必須使用相當大量的該化合物。此專利申 (8) (8)1334779 請案並無揭示製劑的優點,也無該製劑之配方,該製劑係 以時間安定性及活性合物獨立釋出作爲特徵。這類製劑之 貯存安定性並非該案技術內容之重點。故醫生根據此案技 術內容而使用製劑時,每次當他想增加劑量,就必須進行 大量的滴定實驗。
Gadeke公司提供商標名爲Valoron( ®之解痛劑,其 含有痛立定-烯丙羥嗎啡酮之組合。根據產品說明,其係 使用一種配方可讓兩種活性化合物以持續方式自該配方釋 出。所使用之基質包括適當比例之水可膨脹物質(HPMC ),故該基質視爲一種可膨脹(可能有部份腐蝕性)之擴 散基質。此種習知配方的缺點爲,痛立定與烯丙羥嗎啡酮 係給予相同的質量比,但絕對含量不同,故兩種化合物會 呈現不同的釋出圖形。促動劑與拮抗劑之釋出速率彼此之 間並不依賴,可能是由所使用之持續釋出配方所致。因此 ,醫生若想要增加劑量、即使並不改變痛立定:烯丙羥嗎 啡酮之質量比時,由於他無法確定兩種組成份之釋出圖形 (release profiles)將維持不變,醫生必須對於每一位個 體病患進行大量滴定實驗,。因此,醫生對於該止痛劑可 採用之治療上有用的劑量範圍受到限制。 【發明內容】 本發明之目的之一爲提供一種提供高度止痛活性之用 於疼痛療法的藥學製劑,其特徵在於降低濫用可能性及減 少副作用,該製劑也以用藥頻率降低爲特徵,故該製劑也 -12- (9) (9)1334779 提供更高之順從性,以及每位病患獨立適應劑量的能力。 本發明之另一目的在於提供疼痛療法有效之藥學製劑的配 方,其確保該藥學製劑之活性化合物經歷一段長貯存期間 仍是安定的,且即使經過長期貯存之後,該活性化合物之 釋出可再現地保持不變且各自獨立。 本案獨立項之特徵組合足夠得知本發明之這些目的, 本發明之其他目的可參見本發明之說明內容。本發明之較 佳實施體系則定義於附屬項中。 根據本發明之目的,係藉由提供一種含有羥氫可待因 酮及烯丙羥嗎啡酮之貯存安定性藥學製劑而達成,其中該 製劑經調配而使得活性化合物以持續、穩定及各自獨立之 方式釋出。 經由羥氫可待因酮(於止痛有效之劑量)及烯丙羥嗎 啡酮之組合,確使根據本發明之製劑呈現有效之止痛活性 ,同時抑制或至少顯著降低常見的副作用,例如頑性便秘 、呼吸壓抑及發展爲成瘾。可長期安定之基質配方能長期 地確保促動劑與拮抗劑總是以預先設定的百分比釋出,且 其釋出速率彼此之間互不干擾。如此,阻止了該藥物的濫 用,蓋濫用需要羥氫可待因酮可自該配方選擇性提取出來 。根據本發明之配方使得促動劑無法由無對應量之拮抗劑 的製劑選擇性提取出來,此與所選擇之促動劑與拮抗劑的 絕對及相對含量無關。 再者,根據本發明之藥物的配方確保相對含量一樣的 活性化合物會呈現一樣的釋出圖形,與絕對含量無關。當 -13- (10) (10)1334779 設定最佳之促動劑/拮抗劑比例爲已知時,則此種獨立之 釋出行爲提供醫師一大範圍之止痛活性物質可使用之絕對 劑量。因此,每一位個別的病患有可能舒服自在地修正劑 量,逐步增加劑量,或者,若有必要,逐步降低劑量。由 醫藥觀點而言,個別病患具有可修正劑量之能力是極爲有 用的。 本發明之技術特徵,包括持續的、穩定的及各自獨立 地釋出活性化合物,更可保證根據本發明所生產之藥學製 劑係以用藥頻率低爲其特徵,因此可達到高度之病患順從 性。此外,根據本發明之製劑可讓醫生針對個別病患調整 劑量。根據本發明之製劑保證可使用大範圍之活性化合物 所適用的絕對劑量,並保證活性化合物即使在長期貯存之 後仍可恢復功效、且有相同之釋出圖形。 根據本發明,活性化合物之持續釋出,表示藥學活性 物質自藥物釋出所經歷之時間比該物質由用於快速釋出之 習知配方所釋出的時間更長。較好釋出係經歷2至24小 時’ 2至2 0小時,更好是歷經2至12小時,此係根據合 乎法律與管制要件的說明。 根據本發明,能夠確保活性化合物自製劑如上所述般 持續釋出的藥物配方稱之爲阻滯((retard )配方、持續 釋出配方或延長釋出配方。本發明之技術內容中,,持續 釋出"並不表示活性化合物自配方或藥物釋出係以pH -依賴性方式。根據本發明,活性化合物之釋出反而發生不 依賴pH之方式。根據本發明,〃持續釋出〃乙詞係表 -14- (11) (11)1334779 示活性化合物歷經一延長時間而自藥物釋出。此並不意味 著在某一特定位置控制釋出,故並不表示該活性化合物不 是只在胃內釋出,就是僅在腸道釋出。當然此種在特定位 置之釋出可分別經由藥物之腸衣達成。但目前此種方式似 乎並無好處。 根據本發明,^各自獨立地釋出〃乙詞係表示,設定 至少存在兩種活性化合物,改變一種化合物之絕對含量並 不影響另一化合物之釋出圖形,故另一化合物之釋出圖形 沒有改變。根據本發明之配方,此種獨立釋出行爲不依賴 pH値,釋出之測量標的、或其製造方法。pH獨立性尤其 適用於酸性範圍,即,pH値小於7時。釋出圖形(或釋 出行爲)係定義爲活性化合物自配方釋出之量相對於時間 的變化,對所釋出之每一種活性化合物的量、係以佔活性 化合物總量的百分比表示。釋出圖形之測定係利用已知測 試方法。 詳言之,例如以乙羥氫可待因酮之釋出圖形爲例,若 具有相同配方之對應製劑中含有12毫克之羥氫可待因酮 、但含有6毫克之烯丙羥嗎啡酮,則可發現具有1 2毫克 之羥氫可待因酮與4毫克之烯丙羥嗎啡酮的羥氫可待因酮 /烯丙羥嗎啡酮一組合並不改變乙羥氫可待因酮之釋出圖 形。 各自獨立釋出之特徵較好涉及一種將具有實質上相等 組成之製劑的釋出圖形作一比較的狀況。具有實質上相等 組成之製劑具有不同含量之活性化合物,但其組成之組成 •15· (12) (12)1334779 份基本上是相同的,此組成份會實質上影響釋出行爲。 若比較上述製劑(第一製劑含有〗2毫克之徑氫可待 因酮與4毫克之烯丙羥嗎啡酮,第二製劑含有12毫克之 羥氫可待因酮與6毫克之烯丙羥嗎啡酮),假設兩種製劑 之總重相同,若烯丙羥嗎啡酮含量之差異被取代爲配方中 一種通常不會影響釋出行爲的組成份時,則將得到相同的 羥氫可待因酮與烯丙羥嗎啡酮之釋出圖形。如下文實例乙 章所示’烯丙羥嗎啡酮之含量差異可被取代爲一典型之藥 學上鈍性的塡充劑,例如乳糖,此取代不改變釋出圖形。 熟悉該技術領域之士將可了解,若兩種製劑之差異在 於活性化合物之含量,將該含量差異取代爲該配方之釋出 行爲所必須的物質時,例如乙基纖維素或脂肪醇,可產生 釋出行爲的差異。因此,各自獨立釋出特徵較好應用在下 列配方,其具有不同含量之活性化合物,而實質上影響釋 出行爲的組成份是相同的、或至少高度相似(設定此係比 較具有相同總重之配方)。 根據本發明,"穩定釋出行爲"或”穩定釋出圖形" 係定義爲,若絕對含量改變,但每單位時間所釋出之每一 種活性化合物之絕對含量百分比不明顯改變且充分地保持 固定(故不實質上改變)。充分固定之百分比’表示每單 位時間所釋出的百分比與平均値之差異不超過20% ’較 好不超過15%,更好不超過10%。平均値係由釋出圖形 之六次測量値計算出來者。當然,每單位時間之釋出量必 須符合法律與管制要件。 -16- (13) (13)1334779 詳言之,若設定一種羥氫可待因酮/烯丙羥嗎啡酮之 組合含有1 2毫克之羥氫可待因酮與4毫克之烯丙羥嗎啡 酮,於最初的4小時釋出25%羥氮可待因酮及20%烧丙 羥嗎啡酮。相反的,若該羥氫可待因酮/烯丙羥嗎啡酮之 組合含有24毫克之羥氫可待因酮及8毫克之烯丙羥嗎啡 酮,於最初的4小時也將釋出25%羥氫可待因酮及20% 烯丙羥嗎啡酮。兩種情況中,差異都將不超過平均値之 20% (此範例之平均値爲25%羥氫可待因酮及20%烯丙 羥嗎啡酮)。 如同簡要描述各自獨立釋出行爲一般,穩定釋出特徵 也較好涉及一種將具有實質上相等組成之製劑的釋出圖形 作一比較的狀況。這類製劑之活性化合物含量不同,但就 影響釋出之製劑組成分而言,這類製劑之組成相同、或至 少高度相似。 典型地,活性化合物之含量差異將以實質上不影響該 製劑之釋出行爲的藥學上鈍性賦形劑取代。這種藥學賦形 劑可以是乳糖,其爲醫藥製劑中的典型塡充劑。熟悉該項 技術者將充分理解此穩定釋出特徵不能應用在下列製劑, 其中活性化合物含量之差異被實質上影響該製劑之釋出行 爲的習知物質取代,例如乙基纖維素或脂肪醇β 本文實例乙章中,若一製劑含有20毫克之羥氫可待 因酮與1毫克之嫌丙經嗎啡酮、或含有20毫克之經氫可 待因酮與1 〇毫克之稀丙經嗎啡酮,其差異所在的條丙羥 嗎啡酮被乳糖取代,如此具有相同重量之兩種製劑提供相 -17- (14) (14)1334779 同之釋出圖形’故這兩種製劑將具有相同的持續的、穩定 的且各自獨立的釋出行爲。 根據本發明,、貯存安定的〃或''貯存安定性〃表示 在標準條件下(於室溫及一般溼度下至少2年),藥物 配方中的活性化合物含量與最初含量之差異不超過一般藥 典之說明或指導方針所不的數値。根據本發明,貯存安定 性也表示根據本發明製備的製劑可在標準條件下(6 〇 %相 對溼度,25 °C )貯存,如同獲得上市許可所需之條件。 根據本發明,、貯存安定的〃或"時間安定的〃用詞 也表示在標準條件下貯存之後,活性化合物呈現之釋出圖 形如同該化合物將要立即使用而不貯存一般。根據本發明 ’釋出圖形有關之可接受的變化特徵在於,每單位時間的 釋出量變化(相對於平均値)不超過20%,較好不超過 15%,且更好不超過10%β平均値係由釋出圖形之六次 測量値計算出來者。 較好’測定活性化合物自一持續釋出配方釋出的情形 係採用根據美國藥典(USP)之藥籃(Basket)方法,於 pH 1.2或pH 6.5、利用高效液相層析儀(HPLC)進行。 測定貯存安定性較好係採用遵照USP之藥籃方法, 於pH 1 .2、利用HPLC進行。 根據本發明,"非可膨脹性"或"實質上非可膨脹性 〃擴散基質是一種基質配方,藉由膨脹該基質(尤其是在 病人體內有關標的位置之生理液體內),活性化合物之釋 出不受影響(至少有相當程度不受影響),。 -18- (15) (15)1334779 根據本發明, >實質上非可膨脹性〃擴散基質乙詞也 意指一種基質,其體積於水溶液中(尤其是在病人體內有 關標的位置之生理液體內)將增加約3 00 %,較好約200 %,更好約100% '約75%或約50%,甚至更好約3.0% 或約20%,且最好約15%、約10%、約5%或約1%。 本發明之技術內容中,^促動劑〃或^止痛劑"總是 意指羥氫可待因酮。本發明之技術內容中,^拮抗劑〃總 是意指烯丙羥嗎啡酮。 根據本發明所製造的製劑可經口、經鼻、經直腸及/ 或藉由吸入而施用於疼痛療法。根據本發明,非經腸用藥 並未設想。特佳的是經口施用的配方。 儘管並未詳細說明,"促動劑〃或*拮抗劑〃之用語 總是包括藥學上可接受且同等作用之衍生物、鹽類等等。 例如’若提及羥氫可待因酮或烯丙羥嗎啡酮,此除了游離 鹼之外’也包括其鹽酸鹽、硫酸鹽 '硫酸氫鹽、酒石酸鹽 、硝酸鹽、檸檬酸鹽、酒石酸氫鹽、磷酸鹽、蘋果酸鹽、 馬來酸鹽、氫溴酸鹽、氫碘酸鹽、富馬酸鹽、琥珀酸鹽等 等。 根據本發明,促動劑及拮抗劑以一種方式調配,使得 彼等係以持續、各自獨立且穩定之方式由所製得之藥學製 劑釋出。此並不意味著拮抗劑會比促動劑過量。相反的, 在含有促動劑/拮抗劑之組合的配方中(其顯示根據本發 明之釋出圖形),較好促動劑比拮抗劑過量。 促動劑之過量與否係根據組合製劑中存在之拮抗劑單 -19- (16) (16)1334779 位劑量的含量而定。類鴉片促動劑之過量程度通常以促動 劑相對於拮抗劑的重量比表示。 羥氫可待因酮及烯丙羥嗎啡酮之範例中,促動劑相對 於拮抗劑之較佳重量比在重量比範圍最大爲25: 1之範圍 內,特佳重量比範圍爲15:1、 10:1、5:1、4:1、3 :1、2 : 1 及 1 : 1。 所欲使用之促動劑與拮抗劑的絕對含量,係根據活性 化合物的選擇。根據本發明,必須注意到促動劑與拮抗劑 係以各自獨立且穩定之方式、由已經調配爲穩定釋出之藥 學製劑釋出。 若使用羥氫可待因酮與烯丙羥嗎啡酮來調配組合製劑 ,較好使用每單位劑量介於10至150毫克、更好是10 至80毫克之羥氫可待因酮(應用之典型劑量),及每單 位劑量較好介於 1至 5 0毫克的烯丙羥嗎啡酮。 本發明之其他較佳實施體系中,該製劑可含有5至 50毫克之羥氫可待因酮、10至40毫克之羥氫可待因酮、 10至30毫克之羥氫可待因酮、或約20毫克之羥氫可待 因酮。本發明之較佳實施體系也可包括每單位劑量具有j 至4 0毫克之烯丙羥嗎啡酮、1至3 〇毫克之烯丙羥嗎啡酮 、1至20毫克之烯丙羥嗎啡酮、或丨至10毫克之烯丙羥 嗎啡酮的製劑。 根據本發明,選擇羥氫可待因酮與烯丙羥嗎啡酮之比 例’必須可保證得到根據本發明之兩種活性物質之釋出圖 形’且促動劑可發揮其止痛功效;並採取可減少或消除促 -20- (17) (17)1334779 動劑之習慣成型或成癮增進作用及副作用的方式來選擇拮 抗劑之劑量’但不(實質上)影響促動劑之止痛作用。根 據本發明’形成習慣及成癮,以及頑性便秘與呼吸壓抑, 皆視爲具有止痛作用之類鴨片促動劑的副作用。 根據本發明,可使用普遍常用的配方,只要這些配方 能確保活性化合物係以持續、各自獨立且穩定的方式自該 製劑釋出。根據本發明,必須選擇可讓活性化合物貯存安 定的配方。 較好使用基於基質之阻滯(retardation)配方,作爲 提供根據本發明之促動劑與拮抗劑釋出的配方。根據本發 明’基於實質上非可膨脹性擴散基質的配方尤其佳。此時 ’具有腐蝕性基質、或可膨脹之擴散基質的配方不被喜好 〇 根據本發明,必須選擇可提供持續釋出活性化合物的 基質,如此可讓該活性化合物以持續、各自獨立且穩定之 方式釋出。較好此種基質含有基於乙基纖維素之聚合物, 而乙基纖維素是一特佳的聚合物。含有市面上可獲得之聚 合物,商標名爲 Surelease ®,的基質更佳。使用 Surelease ® E - 7 — 7050 者尤其佳。 根據本發明釋出行爲的配方,特別包括下列基質,其 含有乙基纖維素與至少一種脂肪醇,作爲實質上影響該基 質之釋出特性的組成份。乙基纖維素及至少一種脂肪醇之 含量可明顯不同,如此可得到具有不同釋出圖形之製劑。 儘管創新的製劑通常會含有上述兩種組成份,有些情況下 -21 - (18) 1334779 ’較好製劑只含有乙基纖維素或脂肪醇作爲決定釋 成份。 根據本發明’目前較好避免下列基質:基於 丙嫌酸醋之基質(例如,Eudragit ®RS30D及 Eudragit ® RL30D)、或含有適量水可膨脹材質之 尤其是由羥烷基纖維素衍生物,例如HPMC。 根據本發明之基質可用來生產以持續、各自獨 定之方式釋出活性化合物、且每單位時間釋出等量 合物的製劑。特言之,此乃意指,就含有12毫克 可待因酮及4毫克之烯丙羥嗎啡酮之羥氫可待因酮 羥嗎啡酮組合而言,於最初4小時內釋出2 5 %羥 因酮及2 5 %烯丙羥嗎啡酮;相同地,就含有24毫 氫可待因酮及8毫克之烯丙羥嗎啡酮之羥氫可待因 丙羥嗎啡酮組合而言,於最初4小時內釋出2 5 % 待因酮及2 5 %烯丙羥嗎啡酮;此兩種情況下的變 超過平均値(此範例爲25%羥氫可待因酮或烯丙 酮)之20%。 於醫藥觀點上,兩種活性化合物有這種相同的 爲是企求的。 本發明之較佳實施體系係關於15分鐘之後, %至40%、較好5%至35%、更好10%至30%、 1%至40%之羥氫可待因酮及/或烯丙羥嗎啡酮的 本發明之其他實施體系中,15%至20%、20%至 約15% '約20%、或約25%之羥氫可待因酮及/ 出之組 聚甲基 基質, 立且穩 活性化 之羥氫 /烯丙 氫可待 克之羥 酮/烯 羥氫可 化皆不 羥嗎啡 釋出行 釋出1 且特好 製劑。 25%、 或烧丙 -22- (19) (19)1334779 羥嗎啡酮於1 5分鐘之後釋出β 本發明之另一較佳實施體系係關於1小時之後’釋出 25%至.65%、較好30%至60%、更好35%至55%、且 特好40%至50%之羥氫可待因酮及/或烯丙羥嗎啡酮的 製劑。本發明之其他實施體系中,40%至45% ' 45%至 50%、約40%、約45%、或約50%之羥氫可待因酮及/ 或烯丙羥嗎啡酮於1小時之後釋出。 本發明又一較佳實施體系係關於2小時之後’釋出 40%至80%、較好45%至75%、更好45%至70%、且 特好 45% 至 50%、50% 至 55%、55% 至 60% '60% 至 65%或65%至70%之羥氫可待因酮及/或烯丙羥嗎啡酮 的製劑。較佳實施體系也包括約45%、約50%、約55% 、約60%、約65%或約70%之羥氫可待因酮及/或烯丙 羥嗎啡酮於2小時之後釋出的製劑。 本發明之一較佳實施體系係關於4小時之後’釋出 70%至100%、較好75%至95%、更好80%至95%、且 特好80%至90%之羥氫可待因酮及/或烯丙羥嗎啡酮的 製劑。本發明之較佳實施體系也關於80%至85%、85% 至90%、約80%、約85%、或約90%之羥氫可待因酮及 /或烯丙羥嗎啡酮於4小時之後釋出的製劑。 本發明之一較佳實施體系也關於7小時之後’釋出 70% 至 100%、較好 75% 至 100% ' 更好 80% 至 95%、 且特好80%至85%、85%至90%、或90%至95%之羥 氫可待因酮及/或烯丙羥嗎啡酮的製劑。本發明之較佳實 -23- (20) (20)1334779 施體系也關於約80%、約85%、約90%或約95%之羥氫 可待因酮及/或烯丙羥嗎啡酮於7小時之後釋出的製劑^ 本發明又一較佳實施體系係關於12小時之後,釋出 85% 至 100%、較好 90% 至 100%、更好 95% 至 100%、 且特好約95%、或1〇〇%之羥氫可待因酮及/或烯丙羥嗎 啡酮的製劑。 根據本發明,提供基於本發明而釋出活性化合物之配 方’除了形成基質之聚合物之外,可含有塡充劑及添加物 ’例如粒化輔助劑、潤滑劑、染劑、流動劑及增塑劑。 乳糖' 葡萄糖或蔗糖、澱粉類及其水解產物、微晶纖 維素、cell at ose、例如山梨糖醇或甘露糖醇之糖醇類,多 溶性鈣鹽例如磷酸氫鈣、磷酸二鈣或隣酸三鈣,可用來作 爲塡充劑。 波維東(povidone)可用來作爲粒化輔助劑。 較好使用高度分散性矽石(Aerosil ® )、滑石、玉 米澱粉、氧化鎂及硬脂酸鎂或硬脂酸鈣作爲流動劑或潤滑 劑。 可優先使用硬脂酸鎂及/或硬脂酸鈣作爲潤滑劑。也 可優先使用脂肪酸類(例如硬脂酸)、或脂肪類(諸如氫 化蓖麻油)。 也可使用聚乙二醇及脂肪醇[例如鯨臘醇、及/或硬 脂醇、及/或鯨硬脂(cet〇stearyl )醇],作爲影響阻滯作 用(retardation)之添加物。 若使用塡充劑及添加物,例如染劑及上述潤滑劑、流 -24- (21) (21)1334779 動劑及增塑劑’則必須注意到,根據本發明,只可使用上 述組合倂用基質形成物質者、及/或保證得到根據本發明 之活性化合物的釋出圖形之基質形成物質。 若要選擇配方之任一添加組成份,其係以一種可讓釋 出用基質獲得一種實質上非水可膨脹、或非緩衝液可膨脹 且非腐蝕性之擴散基質的特性之方式。 根據本發明,特佳配方含有乙基纖維素或 Sublease ® E— 7—7050作爲基質構築物質,硬脂醇作爲 脂肪醇,硬脂酸鎂作爲潤滑劑,乳糖作爲塡充劑,及波維 東(povidone )作爲粒化輔助劑。 根據本發明之製劑可以製造成任何常見用藥形式,原 則上’此用藥形式適合阻滞配方並保證活性化合物係根據 本發明之方式釋出_。尤其適合者是旋劑、多層旋劑及膠囊 。可使用其他用藥形式’例如粒劑或粉劑,但只有提供足 夠阻滯作用及根據本發明之釋出行爲的用藥形式是可接受 的。 藥學製劑也可包括薄膜塗料。然而’必須要保證該薄 膜塗料不會負面影響活性化合物自基質釋出的性質,及活 性化合物於基質中的貯存安定性。此種薄膜塗料可以染色 、若有需要’或者可含有活性化合物之最初劑量。具有該 最初劑量之活性化合物將立刻釋出,如此可非常快速地達 到治療有效之血漿濃度。 可利用累加式(build — up )或削減式(build - down )成粒法(granulation)製造根據本發明之藥學製劑或其 -25- (22) (22)1334779 前軀物。較佳實施體系是採用噴霧成粒且隨後乾燥顆粒的 製法。另一較佳實施體系係於滾筒中、或粒化圓盤上,利 用累加式成粒法製造顆粒。然後利用適合之添加物與製程 ,將該顆粒擠壓成,例如錠劑。 熟悉該項技術者熟知應用在製藥技術上的成粒技術。 實施例(參見下文)揭示本發明之明確實施體系。然而, 爲了要達到特定目的而修改該製法之參數,此乃屬於熟悉 該項技術者可充分理解的範疇之內。 根據本發明,利用擠壓技術製造藥學製劑或其前軀物 之方法特別有利。於一較佳實施體系中,利用熔解擠壓法 製造藥學製劑或其前軀物,其係使用配備同向或反向轉動 之擠壓器(包含兩個螺旋)。另一較佳實施體系是藉由擠 壓製造的方法,其利用含有一個或一個以上螺旋之擠壓器 。這些擠壓器也可包括揉捏元件。 擠壓法也是製藥技術上一種充分建立的生產方法,爲 熟悉該項技術者熟知者。熟悉該項技術者可充分理解,爲 了要生產具有所欲特性之產物,於擠壓製法過程中可改變 各式各樣的參數,例如進料速率、旋進速度、不同擠壓器 區域之加熱溫度(若可以做到的話)、水含量等等。下文 實例乙章提供根據本發明之製劑的多種實例,其係利用擠 壓法製得者。 上述參數將由所使用之擠壓器的特殊種類而決定。擠 壓過程中,加熱區(本發明配方之組成份於其中熔解)之 溫度可由40至120°C、較好由50至100°C、更好由50至 (23) (23)1334779 9 0t、特好由50至70°C '及最好由50至65°C,特別是 使用反向轉動雙螺旋擠壓器(例如 Leistritz Micro 18 GGL )之情況。熟悉該項技術者將可充分理解’並非每一 個加熱區都必須加熱。特別是位於進料器(將組成分混合 之處)的後面,可能有必要冷卻爲約2 5 °C。旋進速度可 以是每分鐘1〇〇至500次旋轉(rpm)、較好由100至 250 rpm'更好由100至200 rpm、且最好約150 rpm,特 別是使用反向轉動雙螺旋擠壓器(例如Leistritz Micro 18 GGL )之情況。噴嘴之幾何構形及直徑可視所需加以選擇 。常用擠壓器之噴嘴直徑通常是1至毫米、較好是2 至8毫米、最好是3至5毫米。可用來生產本發明製劑之 擠壓器,其螺旋長度相對於直徑的比率通常約40: 1。 —般而言,加熱區的溫度必須加以選擇,如此不會產 生破壞該藥學活性化合物的溫度。選擇之進料速率與旋進 速度,可使得藥學活性化合物係以持續、各自獨立且穩定 之方式、自利用擠壓法所製得之製劑釋出,且該藥學活性 化合物於基質中可安定貯存。例如,若增加進料速率,則 旋進速度必須相對地增加以確保得到相同的阻滯作用。 熟悉該項技術者知悉上述全部參數皆取決於特殊生產 條件(擠壓器種類、螺旋幾何構形、組成份之數目等等) ,可能有必要加以修飾,如此可讓經由擠壓法製得之製劑 提供持續、各自獨立且穩定的釋出,及上述貯存安定性。 熟悉該項技術者可由實施例(參見下文)推知,藉由 改變擠壓過程中的參數,以及改變實質上負責該製劑之釋 -27- (24) 1334779 出行爲之化合物的組成關係,可得到 製劑。故本發明首先使得具有所欲之 羥嗎啡酮之釋出圖形的製劑得以製造 變脂肪醇或基質形成聚合物乙基纖維 參數,例如溫度、旋進速度(擠壓過 過程中的壓力。 —旦獲得具有所欲釋出圖形的製 創新製劑可允許熟悉該項技術者改變 之活性化合物之含量。含有不同量之 實質上相同組成的製劑,將可提供持 釋出之特性》 因此,實例乙章中揭示多種實施 用量(例如乙基纖維素)而得具有不 其他實例證實一旦建立了某一製劑具 若活性化合物之含量差異被藥學鈍性 取代,則改變烯丙羥嗎啡酮之含量並 行爲。 展現本發明極爲有利之實施體系 &提供其他實例驗證本發明之製劑與 Ιέ。這些實例不應該被解釋成限制本 【實施方式】 實例1 :利用噴霧成粒法、生產 具有不同釋出圖形的 羥氫可待因酮及烯丙 出來,例如,藉由改 素的含量,以及製法 程中)、或製造錠劑 劑,則根據本發明之 該製劑中於上文列示 活性化合物、但具有 續、穩定且各自獨立 例,證實可經由改變 同釋出圖形之製劑。 有所欲之釋出圖形, 賦形劑(例如乳糖) 不影響該製劑之釋出 的實例列示於下文。 常見配方比較下之優 發明之可能實施體系 非可膨脹性擴散基質 -28- (25) 1334779 中含有不同量之羥氫可待因酮/烯丙羥嗎啡酮之錠劑 下表列出之組成份含量係用來製造根據本發明之羥氫 可待因酮/烯丙羥嗎啡酮錠劑。 製劑 0 X y/N a1 - 0 Oxy/N al-5 Oxy/Nal -1 0 (名稱) 羥氫可待因酮 20.0毫克 20.0毫克 20.0毫克 鹽酸鹽 烯丙羥嗎啡酮 — 5.0毫克 10.0毫克 鹽酸鹽 乳糖 Flow Lac 59.25毫克 5 4.2 5毫克 49.25毫克 100 波維東3 0 5.0毫克 5.0毫克 5.0毫克 Surelease ® 10.0毫克 10.0毫克 1〇.〇毫克固 固體物 固體物 體物 硬脂醯醇 25.0毫克 25.0毫克 25.0毫克 滑石 2.5毫克 2.5毫克 2.5毫克 硬脂酸鎂 1.25毫克 1.25毫克 1-25毫克
所使用之Surelease ® E- 7 - 705 0聚合物混合物具 有下列組成。 -29- (26) 1334779
Sur e 1 e a s e ® 乙基纖 維素 2 0 cps 癸二 酸二 丁酯 氫 氧化 錢 _ 油酸 二 氧化 矽 _ 水
爲了要製造錠劑,於翻滾式攪拌器(Bohle )中混合 羥氫可待因酮鹽酸鹽、烯丙羥嗎啡酮鹽酸鹽、波維東30 及乳糖Flow Lac 100,然後在流化浴成粒裝置(GPCG3 ) 中使用Surelease® E— 7- 7050進行噴霧粒化。令此原料 通過Comill 1.4毫米篩網而篩選。於強力切割攪拌器中( Collette ) '與經熔解之脂肪醇進行另一粒化步驟。經由 上述方法製得的全部錠劑核心具有123毫克之重量(按乾 物重計)。 實例2 :利用擠壓法、生產含有羥氫可待因酮/烯丙羥 嗎啡酮於非可膨脹性擴散基質中之錠劑 下表列出之組成份含量係用來製造根據本發明之羥氫 可待因酮/烯丙羥嗎啡酮錠劑。 -30- (27) (27)1334779 製劑 Oxy/N al — Extr (名稱) 羥氫可待因酮鹽酸鹽 20毫克 烯丙羥嗎啡酮鹽酸鹽 10毫克 Kollidon 30 6毫克 乳糖 Flow Lac 100 49.25毫克 乙基纖維素 45cpi 10毫克 硬脂醇 24毫克 滑石 2.5毫克 硬脂酸鎂 1 .25毫克 將上表列示用量之羥氫可待因酮鹽酸鹽、乙基纖維素 45cpi、波維東30、硬脂醇及乳糖Flow Lac 100混合於翻 滾式攪拌器(Bohle )中。隨後利用反向轉動雙螺旋擠壓 器,機型爲 Micro 18 GGL ( Leistritz AG, Nurnberg,德 國),擠壓該混合物。加熱區1之溫度是25 °C,加熱區2 之溫度是50°C,加熱區3至5之溫度是60°C,加熱區6 至8之溫度是55°C,加熱區9之溫度是6(TC,加熱區10 之溫度是65°C。螺旋轉動速度是每分鐘150轉(rpm), 所得之熔解溫度是8 7 °C ,進料速率是1 . 5公斤/小時, 噴嘴開口之直徑是3毫米。使用Frewitt 0.68x1.00毫米 之篩網過濾經擠壓之原料。然後混合輾磨後之擠壓物與滑 石及硬脂酸鎂(其事先經過添加至1毫米手動式篩網之上 的處理)’隨後壓製成錠劑。擠壓器有一螺旋幾何構造, -31 - (28) (28)1334779 如圖1所示。 與同樣含有以Surelease ®爲底之非可膨脹性擴散基 質、但利用噴霧成粒法(參見實例Ο生產的羥氫可待因 酮/烯丙羥嗎啡酮錠劑作一比較,經擠壓之製劑含有較少 組成份。 實例3 :實例1製得之羥氫可待因酮 /烯丙羥嗎啡酮錠 劑的釋出圖形 於pH 1 .2、使用高效液相層析儀(HPLC )測量歷經 1 2小時期間之活性化合物的釋出情形,此係採用根據 USP之藥籃方法。測試了錠劑Ox/Nal— 0、Ox/Nal—5 及 Ox/Nal — 10。 由圖 2與下表所列數値可確認一事實,就基於 Surelease®之非可膨脹性擴散基質而言,不同含量之羥氫 可待因酮的釋出速率仍能維持相同(穩定),不受烯丙羥 嗎啡酮含量之影響。相同地,在羥氫可待因酮含量不同時 ,也觀察到烯丙羥嗎啡酮有穩定的釋出圖形。 -32- (29) 1334779 時間 Ox/Nal- Ox/Nal- Ox/Nal - Ox/Nal- 0 x/Nal -1 0 - (分鐘) 0 5-0 5-N 10- 0 N 0 xy 0 x y Nal Oxy Nal 0 0 0 0 0 0 15 26.1 24.9 23.5 22.8 24.1 120 62.1 63 6 1 57. 5 60.2 420 9 1.7 94.5 9 1.9 89. 4 93.5 720 98.1 99.6 96.6 95 . 7 100.6
釋出數値涉及羥氫可待因酮或烯丙羥嗎啡酮(第2列 ),其係以百分比表示。例如,烯丙羥嗎啡酮於420分 鐘之釋出平均値爲92·7%。於420分鐘之最大偏差是1% 。〇xy及Nal分別表示羥氫可待因酮及烯丙羥嗎啡酮,且 指明所測定之活性化合物。
實例4 : 實例2製得之羥氫可待因酮/烯丙羥嗎啡酮錠 劑於不同pH値的釋出圖形 活性化合物自錠劑釋出之情形係於pH 1.2、歷經12 小時測量者;或者,於pH 1 ·2、歷經1小時測量,然後於 pH 6.5、歷經1 1小時測量者。根據USP之藥籃方法,利 用HPLC測定釋出速率。 下表之釋出速率係於pH 1 ·2、歷經12小時測量者。 -33- (30) 1334779 時間 Oxy/Nal-Extr-1 , 2-0 Oxy/Nal-Extr-1,2-N (分鐘) 〇xy Nal 0 0 0 15 24.1 24.0 120 62.9 63.5 420 92.9 93.9 720 96.9 98.1 下表 於 pH 6.. 之釋出速率係於pH 1.2、 5、歷經1 1小時測量者。 歷經1小時測量,然後 時間 Oxy/Nal-Extr-6, 5-0 Oxy/Nal-Extr-6, 5-N (分鐘) Oxy Nal 0 0 0 60 48.1 49.2 120 65.0 64.7 240 83.3 8 1.8 420 94.1 92.3
釋出數値涉及羥氫可待因酮或烯丙羥嗎啡酮(第2列 ),其係以百分比表示。〇xy及Nal分別表示羥氫可待因 酮及烯丙羥嗎啡酮,且指明所測定之活性化合物。 將實例4表格與實例3表格中的數値作一比較,明確 -34- (31) (31)1334779 得知活性化合物以等量自製劑釋出,不受製造方法的影響 。例如,420分鐘時,89.4%之羥氫可待因酮自噴霧成粒 型錠劑釋出(Ox/ Nal — 10 —錠劑,參見實例3 ),而420 分鐘時,92.9%之羥氫可待因酮自經擠壓之錠劑釋出( Oxy/Nal- Extr- 1.2- 0,實例4)。羥氫可待因酮自擠 壓型錠劑釋出之數値、與羥氫可待因酮自噴霧成粒型錠劑 釋出之平均値(420分鐘時,91.9%)相差1.1%。420 分鐘時,93.5%之烯丙羥嗎啡酮自噴霧成粒型錠劑釋出( Ox/Nal—ΙΟ -錠劑,參見實例 3),而420分鐘時, 93.9%之烯丙羥嗎啡酮自擠壓型錠劑釋出(0\7/1^1-Extr— 1.2— Ο,實例4)。烯丙羥嗎啡酮自擠壓型錠劑釋 出之數値、與烯丙羥嗎啡酮自噴霧成粒型錠劑釋出之平均 値(420分鐘時,92.7%)相差1.3%。 再者,由實例4表格之數値比較及圖3a及 3b,吾 等可推論,釋出速率不受PH之影響,羥氫可待因酮烯丙 羥嗎啡酮之釋出情形維持相同且穩定。 實例5 :比較性實例:Valoron ®錠劑之釋出行爲 檢視7小時期間之活性物質自銳劑釋出的情形。根據 USP之藥籃方法’於pH 1.2測定Valoron ®錠劑1小時’ 然後利用 HPLC、於pH 6.5另外再測試6小時’該 Valoron®錠劑含有50毫克之痛立定與4毫克之烯丙羥嗎 啡酮(Ti/Nal-50/4)、或含有100毫克之痛立定與8 毫克之烯丙羥嗎啡酮(Ti/ Nal - 100 / 8 )、或含有150 -35- (32) (32)1334779 毫克之痛立定與12毫克之烯丙羥嗎啡酮(Ti/Nal-150 / 12 )。 吾等由圖4A及4B、以及下表所示數値[就具有適量 HPMC之可膨脹的(且可能是腐蝕性)擴散基質而言], 不同含量之痛立定的釋出情形明顯不同,且不同含量之烯 丙羥嗎啡酮的釋出情形不是穩定的。此適用於烯丙羥嗎啡 酮》這表示在該pH時,活性化合物之釋出情形並非互不 依賴的。 時間 (分鐘) Ti/Nal- 50/4-T Ti/Nal- 50/4-N Ti/Nal- 100/8-T Ti/Nal- 100/8-N Ti/Nal- 150/12-T Ti/Nal- 150/12-N Til Nal Til Nal Til Nal 0 0 0 0 0 0 0 60 37.2 27.6 33.9 27.3 29.9 23.3 120 47.6 31.7 46.5 33.4 41.5 28.5 180 54.7 37.4 55 41.2 48.2 35 240 59.7 44 68.2 59.5 54.5 40.1 300 65.2 50.6 82.6 72.9 60.5 47.5 360 70.3 58 85.7 82.7 67.2 56.4 420 74.2 60.8 93.1 90.9 84.9 78.9 釋出數値涉及痛立定或烯丙羥嗎啡酮(第2列),其 係以百分比表示。烯丙羥嗎啡酮之釋出平均値,例如於 420分鐘時,爲7 8.87 %。於420分鐘之最大偏差是20.4 (33) (33)1334779 %。Til及Nal分別表示痛立定及烯丙羥嗎啡酮,且指明 所測定之活性化合物。 實例 6 :利用電子顯微鏡進行實例1及 2之錠劑與 Valoron ® N錠劑之結構比較。 爲了要進行電子顯微鏡,使用含有20毫克之羥氫可 待因酮及1 〇毫克之烯丙羥嗎啡酮的錠劑,此錠劑不是根 據實例1之噴霧成粒法製造者(Ox/Nal— 10)、就是利 用實例2之擠壓法製造者(Oxy/Nal - Extr )。再者,使 用含有1〇〇毫克之痛立定及8毫克之烯丙羥嗎啡酮的 Valoron®N 旋劑。圖5A及5B顯示Ox/Nal — 10 —錬劑 之掃描式電子顯微鏡照片的不同放大倍數,該錠劑含有本 發明配方,且係利用噴霧成粒法生產者。圖6A及6B顯 示Oxy/ Nal- Extr-錠劑之掃描式電子顯微鏡照片的不 同放大倍數,該錠劑含有本發明配方,且係利用擠壓法生 產者。圖7A及7B顯示Valoron ® N-錠劑之掃描式電 子顯微鏡照片的不同放大倍數。 由這些圖示之比較,吾等可淸楚看見、含有本發明之 配方的錠劑具有實質上比較細緻且比較均質結構的表面, 比Valoron ®錠劑之裂痕更少,無論該錠劑是否是以噴霧 成粒法或擠壓法生產的。結構上的差異可能就是不同製劑 有不同釋出行爲的原因。 實例7: 利用擠壓法、生產非可膨脹性擴散基質中含有 -37- (34) 1334779 不同羥氫可待因酮/烯丙羥嗎啡酮含量的錠劑 下表列出之含量係用來生產根據本發明之羥氫可待因 酮/烯丙羥嗎啡酮錠劑。 製劑 OxN20/ OxN20/ OxN20/ OxN20/ (名稱) 1-Extr-A 1-Extr-B 1-Extr-C 10-Extr-A 羥氫可待因酮 20毫克 20毫克 20毫克 20毫克 鹽酸鹽 烯丙羥嗎啡酮 1毫克 1毫克 1毫克 10毫克 鹽酸鹽 乳糖 Flow Lac 58.25毫克 58.25毫克 58.25毫克 49.25毫克 100 Kollidone 30 6毫克 6毫克 6毫克 6毫克 乙基纖維素 10毫克 10毫克 10毫克 10毫克 硬脂醇 24毫克 24毫克 24毫克 24毫克 滑石 1.25毫克 1.25毫克 1.25毫克 1.25毫克 硬脂酸鎂 2.5毫克 2.5毫克 2.5毫克 2.5毫克
如上所述(實例2)進行擠壓法,其具有下列參數: Ο X N 2 0 /1 - Ex t r - A :溫度: 55— 63 °C
rpm(螺旋):1 5 0 rpm 進料速率: 1.5公斤/小時 OxN20/l-Extr-B :溫度: 5 5 — 63 °C 15 5 rpm rpm(螺旋): 1334779 進料速率: 1.5 公斤/小時 OxN20/l-Extr-C :溫度: 55 - 6 3〇C rpm(螺旋): 1505 rpm 進料速率: 1.5 公斤/小時 OxN20/l O-Extr-A :溫度: 55 - 6 3〇C rpm(螺旋): 160 rpm 進料速率: 1.75 公斤/小時 利用常見之壓錠裝置進行錠劑生產,其具有下列
OxN20/ — Extr— A : rpm : 40 rpm 壓力: 9 kN OxN20/ 1 - Extr - B : rpm: 42 rpm 壓力: 8.9 kN OxN20/ 1 - Extr - C : rpm : 3 6 rpm 壓力: 9 kN OxN20/ 10— Extr— A : rpm : 3 6 rpm 壓力: 7.5 kN
應用根據USP之藥籃方法,於pH 1.3、使用HPLC 測量歷經1 2小時之活性化合物釋出情形。測試了下列錠 劑:OxN20/l-Extr-A、OxN20/i_Extr—B、OxN20 /1— Extr— C 及 OxN20/10_Extr— a。 由下表所列之數値’吾等將了解到,就以乙基纖維素 -39- (36) 1334779 爲底之非可膨脹性擴散基質而言’不同含量之烯丙經嗎啡 酮的釋出速率實質上維持相同’不受到羥氫可待因酮含量 之影響。同樣的’這些製劑提供該活性化合物一種各自獨 立且穩定的釋出。 時間 (分鐘 OxN20/l -Extr A OxN20/l -Extr-B OxN20/l -Extr-C OxN20/l 0-Extr-A ) Oxy Nal Oxy Nal Oxy Nal Oxy Nal 0 0 0 0 0 0 0 0 0 15 2 1.2 25.8 2 1.7 2 1.1 19.7 19.3 23.3 24.3 1 20 56.6 53.8 58.8 5 7.3 57.7 56.2 64.5 66.9 420 87.2 84.5 94.2 92.6 93.7 91.5 92.7 96.3 720 99.7 96.8 100.1 98 100.6 97.5 93.6 97.4
釋出數値涉及羥氫可待因酮或烯丙羥嗎啡酮(第2列 ),其係以百分比表示。烯丙羥嗎啡酮之釋出平均値,例 如於42G分鐘時,爲92.3%。於420分鐘之最大偏差是 7.4%。Oxy及Nal分別表示羥氫可待因酮及烯丙羥嗎啡 酮,且指明所測定之活性化合物。 因此’一旦具有所欲釋出圖形之製劑發展出來,則吾 等可改變該活性化合物之含量,但不顯著改變活性化合物 之釋出圖形。含有不同量之活性化合物的製劑仍可提供一 種持續的、各自獨立的、及穩定的釋出。 -40- (37) (37)1334779 實例8: 利用擠壓法、生產非可膨脹性擴散基質中含有 羥氫可待因酮/烯丙羥嗎啡酮的錠劑 此實例中展示,利用本發明之配方、可製得含有羥氫 可待因酮及烯丙羥嗎啡酮、並具有特別釋出行爲的製劑。 下表列出組成份之含量係用來生產根據本發明之羥氫 可待因酮/烯丙羥嗎啡酮錠劑。 製劑 OxN20/l- OxN20/l- OxN20/10 OxN20/10 OxN20/10 OxN20/10 (名稱) Extr-D Extr-E -Extr-B -Extr-C -Extr-D -Extr-E 羥氫可待因 20毫克 20毫克 20毫克 20毫克 20毫克 20毫克 酮.鹽酸鹽 烯丙羥嗎啡 1毫克 1毫克 10毫克 10毫克 10毫克 10毫克 酮.鹽酸鹽 乳糖now 56.2毫克 56.25 毫 54.25 毫 65.25 毫 60.25 毫 55.25 毫 Lac 100 克 克 克 克 克 Kollidone® 7毫克 6毫克 6毫克 7.25毫克 7.25毫克 7.25毫克 30 乙基纖維素 11毫克 12毫克 10毫克 12毫克 12毫克 12毫克 硬脂醇 24毫克 24毫克 24毫克 28.75 毫 28.75 毫 28.75 毫 克 克 克 滑石 1.25毫克 1.25毫克 1.25毫克 1.25毫克 1.25毫克 1.25毫克 硬脂酸鎂 2.5毫克 2.5毫克 2.5毫克 2.5毫克 2.5毫克 2.5毫克 如上所述(實例2)進行擠壓法,其具有下列參數: -41 - 1334779
OxN20/ 1 - Extr - D : 溫度: 5 5 - 6 3 °C rpm(螺旋) : 15 0 rpm 進料速率: 1.5公斤/小時 OxN20/ 1 - Extr - E : 溫度: 5 5 - 6 3 °C r p m (螺旋) : 15 0 rpm 進料速率: 1.5公斤/小時 0 x N 2 0 / 1 0 — E x t r — B : 溫度: 5 5 - 6 3 °C rpm(螺旋) : 16 0 rpm 進料速率: 1.75公斤/小時 OxN20/ 1 0 - Extr — C : 溫度: 5 5 - 6 3 °C r p m (螺旋) : 16 0 rpm 進料速率: 1.75公斤/小時 OxN20/ 1 0 - Extr - D : 溫度: 5 5 - 6 3 °C rpm(螺旋) 15 0 rpm 進料速率: 1.5公斤/小時 OxN20/ 1 0 - Extr- E : 溫度: 5 5 - 6 3 °C r p m (螺旋) 15 0 rpm 進料速率: 1.5 公斤/小時 利用常見之壓錠裝置進行錠劑生產 9 其具有下列參數 OxN20/ 1 - Extr - D : rpm : 39 rpm 壓力: 11 kN OxN20/ 1 - Extr - E : rpm : 39 rpm
-42 (39) (39)1334779
壓力·· 1 0.5 kN
OxN20/10-Extr— B: rpm: 3 6 rpm
壓力: 9.5 kN
OxN2 0 / 1 0 — Ex tr — C : rpm : 3 6 rpm
壓力: 7.8 kN O xN 2 0 / 1 0 — E x tr — D : rpm : 39 rpm
壓力: 9 kN
OxN20/ 1 0 - Extr — E : rpm : 39 rpm
壓力: 7·5 kN 應用根據USP之藥籃方法,於pH 1.2、使用HPLC 測量歷經1 2小時之活性化合物釋出情形。測試了下列錠 劑: OxN20/l — Extr — D、OxN20/l — Extr — E、O xN 2 0 / 10- Extr- B、OxN20 / 1 0 - Extr - C、OxN20 /10-Extr— D 及 O x N 2 0 / 1 0 — E x t r — E 0 -43-
Claims (1)
1334779 拾、申請專利範圍 附件5 A : 第0 9 2 1 0 7 7 6 5號專利申請案 恭. η -ι 年月日 年9月2袼 正 中文申請專利範圍替換本 民國99
1. 一種含有羥氫可待因酮及烯丙羥嗎啡酮之貯存安 定性藥學製劑’其特徵在於活性化合物係以持續、穩定及 各自獨立之方式自該製劑釋出,且其中該製劑含有一實質 上非可膨脹性且非腐蝕性之擴散基質,該擴散基質至少含 有乙基纖維素及至少一種脂肪醇,以作爲實質上影響活性 化合物釋出行爲的組成份。 2.如申請專利範圍第1項之製劑,其特徵在於羥氫 可待因酮及/或烯丙羥嗎啡酮係以藥學上可接受且同等活 性之衍生物的形式存在,該衍生物例如游離鹼、鹽及類似 者。 3 .如申請專利範圍第2項之製劑,其特徵在於羥氫 可待因酮及/或烯丙羥嗎啡酮係爲其鹽酸鹽、硫酸鹽、硫 酸氫鹽、酒石酸鹽、硝酸鹽、檸檬酸鹽、酒石酸氫鹽、磷 酸鹽、蘋果酸鹽、馬來酸鹽、氫溴酸鹽、氫碘酸鹽、富馬 酸鹽或琥珀酸鹽。 4. 如申請專利範圍第1至3項中任一項之製劑,其 特徵在於羥氫可待因酮之劑量超過烯丙羥嗎啡酮之單位劑 量。 5. 如申請專利範圍第1至3項中任一項之製劑,其 特徵在於烯丙羥嗎啡酮之劑量範圍爲1至5 0毫克。 1334779 6 ·如申請專利範圍第1至3項中任一項之製劑,其 特徵在於羥氫可待因酮之劑量範圍爲1〇至15〇毫克。 7.如申請專利範圍第6項之製劑,其特徵在於羥氫 可待因酮之劑量範圍爲10至80毫克。 8 _如申請專利範圍第1至3項中任一項之製劑,其 特徵在於羥氫可待因酮與烯丙羥嗎啡酮之重量比範圍爲i :8 至 25 : 1。 9.如申請專利範圍第8項之製劑,其特徵在於羥氫 可待因酮與烯丙羥嗎啡酮之重量比係選自2 0 : 1、1 5 : 1 '5:1、4:1、3:1、2:1 或 1:卜 1 〇.如申請專利範圍第1至3項中任一項之製劑,其 特徵在於該製劑不含有鹼可膨脹及/或水可膨脹物質的相 關含量。 1 1 ·如申請專利範圍第1 0項之製劑,其特徵在於該 製劑不含有丙烯酸衍生物及/或羥烷基纖維素的相關含量 〇 1 2 _如申請專利範圍第1至3項中任一項之製劑,其 特徵在於該製劑含有習知塡充物及添加物。 1 3 ·如申請專利範圍第1 2項之製劑,其特徵在於該 製劑含有潤滑劑' 流動劑、增塑劑及類似者。 1 4 .如申請專利範圍第1 2項之製劑,其特徵在於該 製劑含有作爲潤滑劑的硬脂酸鎂、硬脂酸鈣及/或月桂酸 鈣及/或脂肪酸。 1 5 .如申請專利範圍第丨2項之製劑,其特徵在於該 -2 - 1334779 製劑含有作爲潤滑劑的硬脂酸鎂、硬脂酸鈣及/或月桂酸 鈣及/或硬脂酸。 1 6 ·如申請專利範圍第1 2項之製劑,其特徵在於該 製劑含有作爲流動劑之高度分散性矽石,滑石、玉米澱粉 、氧化鎂及硬脂酸鎂及/或硬脂酸鈣。 17. 如申請專利範圍第1 2項之製劑,其特徵在於該 製劑含有作爲流動劑之Aerosil ®,滑石、玉米澱粉、氧 化鎂及硬脂酸鎂及/或硬脂酸鈣。 18. 如申請專利範圍第1項之製劑,其特徵在於商業 上可獲得之含有乙基纖維素的聚合物混合物係用來取代乙 基纖維素。 1 9 ·如申請專利範圍第丨8項之製劑,其特徵在於商 業上可獲得之聚合物混合物Surelease ® E-7-7050係用來 取代乙基纖維素。 2〇.如申請專利範圍第1項之製劑,其特徵在於該製 劑被調配爲經口、經鼻、經直腸施用或吸入用藥。 2 1 _如申請專利範圍第1項之製劑,其特徵在於該製 劑是錠劑、九劑、膠囊、粒劑及/或粉劑。 22.申請專利範圍第1項之製劑,其特徵在於該製劑 或其前驅藥係利用成累加式(build-up)或削減式(break down )粒法製造。 23·如申請專利範圍第1項之製劑,其特徵在於該製 劑或其前驅藥係利用擠壓法製造。 24.如申請專利範圍第1項之製劑,其特徵在於,根 -3- 1334779 據藥物許可指導方針,該製劑可於標準條件下(60%相對 溼度,2 5 °C )貯存至少兩年。
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DE10215067A DE10215067A1 (de) | 2002-04-05 | 2002-04-05 | Lagerstabiles pharmazeutisches Präparat, das Oxycodon und Naloxon umfasst |
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NO330672B1 (no) | 2009-11-12 | 2011-06-06 | Proxdynamics As | Rotormekanisme for helikoptere |
WO2012020097A2 (en) | 2010-08-13 | 2012-02-16 | Euro-Celtique S.A. | Use of binders for manufacturing storage stable formulations |
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2005
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2006
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2011
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2012
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2013
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2014
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2017
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