TWI589305B - 用於經口投藥之包含安布索、左旋羥丙哌嗪及緩衝劑的液體調配物以及製備其之方法 - Google Patents
用於經口投藥之包含安布索、左旋羥丙哌嗪及緩衝劑的液體調配物以及製備其之方法 Download PDFInfo
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- TWI589305B TWI589305B TW102112507A TW102112507A TWI589305B TW I589305 B TWI589305 B TW I589305B TW 102112507 A TW102112507 A TW 102112507A TW 102112507 A TW102112507 A TW 102112507A TW I589305 B TWI589305 B TW I589305B
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- Prior art keywords
- liquid formulation
- sodium
- pharmaceutically acceptable
- acid
- oral administration
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- 238000000034 method Methods 0.000 title claims description 11
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Description
本發明有關一經口投藥的液體調配物，該者包含安布索、左旋羥丙哌嗪與一緩衝劑，且有關用於製備其之方法。
安布索，如下方所顯示，係為一種臨床上被證明在治療關聯於黏性或過多黏液的急性與慢性呼吸道疾病是有效的化合物，例如，急性與慢性支氣管炎、氣喘性支氣管炎、鼻竇炎、乾燥性鼻炎，及之類，且近來在該品牌Mucopect(Boehringer Ingelheim)及Wooridul Ambroxol Syr.(Wooridul Pharm)下可獲得的：
安布索係為溴克辛(bromhexine)之一代謝物，該
者刺激黏液分泌並促進黏液黏度之正常化。在最近的研究中，安布索係顯示具有化痰(secretolytic)活性、抗發炎與抗氧化活性、局部麻醉效果......等(Malerba M.等人之“Expert Opin Drug Metab Toxicol.,2008 Aug,4(8)：1119-29”)。還有，歸因於其之鎮痛效果，安布索係使用於治療急性喉嚨痛，且一般製備成一糖漿調配物，藉由此，其作用快速，並具有至少3小時的持久鎮痛效果(de Mey C.等人之“Arzneimittelforschung.,2008,58(11)：557-558”)。在5份研究之4份中，投藥含有20mg安布索之糖漿調配物的組別顯示在疼痛的顯著降低，以及快速(投藥後30分鐘)與持久的鎮痛效果(至少3個小時)。
左旋羥丙哌嗪，如下方所顯示，係為做為鎮咳劑之羥丙哌嗪的左旋異構體，該者周圍抑制有關咳嗽反射之傳入路徑：
左旋羥丙哌嗪僅在周圍神經系統中作用，在中樞神經系統中沒有作用，因此，它具有分化的機制不造成副作用，諸如便秘或呼吸抑制，該二者可以由諸如可待因及之類的阿片類鎮咳劑所產生。還有，其證明顯著降低的中樞神經系統不良反應(嗜睡)之發生；抑制發炎、支氣管收縮及黏液過度分泌；且亦稱為一安全藥物，因為它不與其他藥物交互作用，諸如β-阻斷劑、甲基黃嘌呤、黏液調
節劑(mucoregulators)、糖皮質激素、抗生素、抗組織胺......等等。在韓國，左旋羥丙哌嗪目前係於Hyundai Pharm之Levotuss、Hamni Pharm有限公司之Lebrocol Syr.及其他17種其他糖漿製劑品牌下可獲得的，且係使用於治療由急性及慢性支氣管炎造成的咳嗽。
因此，藉由開發使用安布索及左旋羥丙哌嗪的一複合液體調配物，前者可以降低黏度並顯示祛痰活性，後者為一周圍性鎮咳劑，一增強的效果可以預期的。相應地，已經有許多安布索與左旋羥丙哌嗪係處方在一組合調配物的事例。然而，該等糖漿製劑每一者每天必須服用三次，且因此其係有一不便之處，就是患者每劑量被要求服用一比較大數量的糖漿。
本發明人已致力於開發包含安布索及左旋羥丙哌嗪的一複合液體調配物，該者具有相同的療效，即使在例如10mL或更少的一小量中，用於改善患者的順從性。然而，其係已經發現的是，當該二種成分一起存在於一液體調配物時，在安布索與左旋羥丙哌嗪之有關物質之數量中係觀察到數量的提高。
在藥物物質中的不純物可能會在患者中造成不良的副作用，且因此，活性成分的純度係為提供安全與有效的藥物調配物中的最重要因子之一。此種不純物不僅包括可以在該活性成分製造過程期間完全移除掉的化合物，但亦包括甚至在該最終產物製備之後藉由各種環境因子，例如，溫度、水分及光，產生的分解產物。
所以，本發明人已研究了當包含安布索與左旋羥丙哌嗪的液體調配物在一儲存條件中時促進相關物質產生的因子；並已發現的是該活性成分在一水性溶液中的安定性僅能在特定的pH條件下確保的。因此，本發明係藉由使用一緩衝劑調節該調配物之pH值條件而實現的。
因此，本發明之一目的係為提供一經口投藥的液體調配物，該者包含安布索或其之一藥物學可接受鹽類及左旋羥丙哌嗪或其之一藥物學可接受鹽類，並具有改良的安定性。
本發明進一步目的係為提供一種用於製備該經口投藥之液體調配物的方法。
根據本發明之一層面，其係提供一用於經口投藥的液體調配物，該者包含安布索或其之一藥物學可接受鹽類、左旋羥丙哌嗪或其之一藥物學可接受鹽類，及在水性介質中之一緩衝劑，並具有4.5到5.5之一pH值。
根據本發明之另一層面，其係提供一種用於製備該經口投藥液體調配物的方法，該方法包含下列步驟：(1)將一藥物學可接受賦形劑溶解在一水性介質中；(2)藉由使用一緩衝劑調整在步驟(1)中製備之該混合物之pH到pH在4.5至5.5該範圍中；(3)將安布索或其之一藥物學可接受鹽類，及左旋羥丙哌嗪或其之一藥物學可接受鹽類溶解於在步驟(2)中製備
之該混合物；及(4)添加一水性介質至在步驟(3)製備之該混合物。
本發明藉由採用具有不同的藥物作用機制的安布索與左旋羥丙哌嗪而製備的該液體調配物顯示改善的患者順從性及隨著時間推移而增強的儲存安定性，且因此可以安全地使用於治療急性與慢性咳嗽。
圖1係為本發明液體調配物根據其pH值於60℃時之安定性試驗的結果，其顯示安布索鹽酸產生的未知相關物質之最大數量。
圖2係為本發明液體調配物根據其pH值於60℃時之安定性試驗的結果，其顯示左旋羥丙哌嗪產生的未知相關物質之最大數量。
本發明之實施例係於下文中詳細解釋。
本發明提供了一用於經口投藥的液體調配物，該者具有4.5至5.5之一pH值，包含安布索或其之一藥物學可接受鹽類，左旋羥丙哌嗪或其之一藥物學可接受鹽類，及在一水性介質中的緩衝劑。
本發明其特徵在於，藉由在製備包含安布索與左旋羥丙哌嗪之該複合液體調配物中使用一緩衝劑調整該液體調配物至pH為4.5至5.5。在該範圍中，衍自安布索與
左旋羥丙哌嗪的未知物質的產生可以被有效地抑制，且從而顯著地改良該儲存安定性。
根據本發明之該藥物學可接受鹽類包括藉由在該技藝中已知的常規方法製備的任何鹽類。此種鹽類之例子係為酸加成鹽，該者之形成為藉由無機酸者，諸如鹽酸、氫溴酸、硫酸、硫酸氫鈉、磷酸、硝酸、碳酸、及之類；藉由有機酸者，諸如甲酸、醋酸、丙酸、草酸、琥珀酸、苯甲酸、檸檬酸、馬來酸、丙二酸、酒石酸、葡糖酸、乳酸、龍膽酸(gentisic acid)、延胡索酸(fumaric acid)、乳糖酸(lactobionic acid)、水楊酸、乙醯水楊酸(阿司匹林)、及之類；藉由胺基酸形成者，諸如甘胺酸、丙胺酸、纈胺酸、異亮胺酸、絲胺酸、半胱胺酸、胱胺酸、天門冬胺酸、麩胺酸、離胺酸、精胺酸、酪胺酸及脯胺酸；藉由磺酸形成者，諸如甲磺酸、乙磺酸、苯磺酸、對甲苯磺酸及之類；金屬鹽類其形成藉由鹼金屬者，諸如鈉、鉀及之類，及藉由銨離子及之類形成的鹽。
在本發明中，採用的活性成分係為安布索或其之一藥物學可接受鹽類、及左旋羥丙哌嗪或其之一藥物學可接受鹽類，較佳地分別為安布索鹽酸鹽與左旋羥丙哌嗪。
在本發明之一實施例中，該調配物包含安布索或其之一藥物學可接受鹽類在每100mL該液體調配物，100mg至1,000mg(例如300mg)之一數量，及左旋羥丙哌嗪或其之一藥物學可接受鹽類在100mL該液體調配物，
300mg至1,500mg(例如600mg)之一數量。
在本發明中，該緩衝劑係以用於調整該液體調配物之pH至4.5~5.5之一數量採用。在本發明之一實施例中，該調配物包含該緩衝劑在每100mL該液體調配物，100mg至1,000mg(例如300mg至600mg)之一數量。
在本發明中之該緩衝劑係選自由下列所組成之該群組：檸檬酸、檸檬酸鈉水合物、檸檬酸鉀、醋酸、醋酸鈉、碳酸鈉、碳酸鈣、磷酸三鈣、乳酸鈣、甘胺酸、馬來酸、蘋果酸、麩胺酸鈉、麩胺酸單鈉、乳酸鈉、磷酸鈉及其等之一混合物。
在本發明中，該緩衝劑較佳地選自由下列所組成之該群組：檸檬酸、檸檬酸鈉水合物、檸檬酸鉀、醋酸、醋酸鈉、蘋果酸、麩胺酸鈉、甘胺酸、碳酸鈉、馬來酸、乳酸鈉及其等之混合物；更佳地選自由下列所組成之該群組：檸檬酸與檸檬酸鈉水合物之一混合物、檸檬酸與檸檬酸鉀之一混合物、醋酸與醋酸鈉之一混合物、蘋果酸與麩胺酸鈉之一混合物、甘胺酸與碳酸鈉之一混合物、及馬來酸與乳酸鈉之一混合物；且最佳地係為檸檬酸與檸檬酸鈉水合物之一混合物。
在本發明中，該水性介質係選自由純水、乙醇及其等之一混合物所組成之該群組，較佳地純水。
根據本發明之該液體調配物可能進一步包含一藥物學可接受的賦形劑，且該藥物學可接受的賦形劑係選自由抗氧化劑、甜味劑、防腐劑、黏度改質劑及其等之一
混合物所組成之該群組。
本發明之該抗氧化劑係選自由焦亞硫酸鈉、抗壞血酸、異抗壞血酸及其等之一混合物所組成之該群組。該抗氧化劑之數量係以每100mL該液體調配物，0.1至100mg之一數量採用的，較佳地1至10mg。
本發明之甜味劑係選自由白糖、乙醯磺胺酸鉀(potassium acesulfame)、糖精、右旋葡萄糖及其等之一混合物所組成之該群組。該甜味劑之數量係以每100mL該液體調配物，5至100,000mg之一數量採用的，較佳地10至50,000mg。
本發明之防腐劑係選自由甲基對羥基苯甲酸(methyl paraoxybenzoic acid)、乙基對羥基苯甲酸(ethyl paraoxybenzoic acid)、異丙基對羥基苯甲酸(isopropyl paraoxybenzoic acid)、山梨酸、山梨酸鉀、山梨酸鈉及其等之一混合物所組成之該群組。該防腐劑之數量係以每100mL該液體調配物，5至200mg之一數量採用的，較佳地10至100mg。
本發明之該黏度改質劑選自由濃縮甘油、聚乙烯吡咯烷酮、乙基纖維素、羧甲基纖維素鈉及其等之一混合物所組成之該群組。該黏度改質劑之數量係以每100mL該液體調配物，100至20,000mg之一數量採用的，較佳地20至10,000mg。
根據本發明之該液體調配物係用於預防或治療急性與慢性呼吸道疾病，該者選自由急性與慢性支氣管
炎、氣喘性支氣管炎、鼻竇炎、乾燥性鼻炎與急性喉嚨痛所組成之該群組。
本發明提供一種用於製備該經口投藥之液體調配物的方法，該方法包含下列步驟：(1)將一藥物學可接受賦形劑溶解在一水性介質中；(2)藉由使用一緩衝劑調整在步驟(1)中製備之該混合物之pH到4.5至5.5；(3)將安布索或其之一藥物學可接受鹽類，及左旋羥丙哌嗪或其之一藥物學可接受鹽類溶解於在步驟(2)中製備之該混合物；及(4)添加一水性介質至在步驟(3)製備之該混合物。
根據本發明製備之該複合液體調配物採用在一液體調配物中具有不同藥物作用機制的安布索與左旋羥丙哌嗪，且因此降低該所要求的劑量，並藉由提高患者便利性而改善患者的順從性。此外，衍自安布索與左旋羥丙哌嗪的未知物質的產生可以藉由調整pH值在4.5至5.5該範圍內而有效地抑制，且從而改良該液體調配物的儲存安定性。所以，根據本發明製備之該液體調配物即使在一小數量中係為有效的，例如，10mL或更少，且可用於預防或治療急性及慢性呼吸道疾病。
在下文中，本發明係藉由下列實例更具體說明的，但這些係僅僅為了例示之目的而提供，且本發明並不受限於此。
根據在下方表1中描述之該組成物及數量(mg/100mL)，實例1至3之液體調配物係藉由使用安布索
鹽酸鹽(Hwail Pharm.,Korea)及左旋羥丙哌嗪(Sungwoo Chemical,Korea)、濃縮甘油(Seojin Chemical)、白糖(CheilJedang)、D-山梨醇溶液(Roquette)、乙醯磺胺酸鉀(Nutrinova)、焦亞硫酸鈉(Riedel-de Haen)、檸檬酸(DSM Nutritional)、檸檬酸鈉水合物(Jungbunzlauer)、甲基對羥基苯甲酸(Sanfu Chemical)及乙基對羥基苯甲酸(Sanfu Chemical)而製備的。
具體地，純水、甲基對羥基苯甲酸、丙基對羥基苯甲酸、乙醯磺胺酸鉀及焦亞硫酸鈉係置於一製造罐中，且該混合物係藉由於95℃攪拌達30分鐘完全溶解，以完全溶解該混合物。該所得到之溶液係冷卻至50℃，依序加入白糖、D-山梨醇溶液、檸檬酸及檸檬酸鈉水合物，並攪拌計60分鐘，以完全溶解該混合物。每一溶液之pH值係根據下方表1調整的。該製造槽之溫度係降低到35至40℃，且安布索鹽酸鹽與左旋羥丙哌嗪係加入其中，繼之攪拌以完全溶解該混合物。該製造槽之溫度係降低到30℃或以下，且於室溫的無菌純水係加入以使得該水平成一彎月形，繼之攪拌達20分鐘。該最終混合物係通過一1μm過濾器過濾，並儲存在一儲存罐或一合適容器中。
根據在下方表2中描述之該組成物及數量(mg/100mL)，比較實例1至3之液體調配物係藉由重複實例1之程序而製備，使用安布索鹽酸鹽與左旋羥丙哌嗪、濃縮甘油、白糖、D-山梨醇溶液、乙醯磺胺酸鉀、焦亞硫酸鈉、檸檬酸、檸檬酸鈉水合物、甲基對羥基苯甲酸及丙基對羥基苯甲酸。
為了評估隨著時間推移之儲存安定性，一測試係於實例1至3與比較實例1至3中製備的該等液體調配物上執行。
具體地，每一液體調配物係含在一高密度聚乙烯(HDPE)瓶中，並在60℃加速條件下儲存在一腔室中。4週之後，源自其等每一分解產物的鹽酸安布索與左旋羥丙哌嗪之未知相關物質的最高數量係依據下面條件使用HPLC方法評估的。該等結果係顯示於表4與表5中，及圖1與圖2中。
吸收：248nm
管柱：不銹鋼管柱(內徑：大約4.6mm；長度：大約250mm)填充5μm的C18
洗提液：乙腈及磷酸鹽緩衝液(5：5(v/v%))
吸收：254nm
管柱：不銹鋼管柱(內徑：大約4.6mm；長度：大約150mm)填充5μm的C8
洗提液：甲醇及磷酸鹽緩衝液(4：6(v/v%))
還有，根據由FDA發出的‘工業指南；藥品物質與藥品產品之安定性試驗’，根據實例1與比較實例1製備之液體調配物係於加速條件之下測試的。該加速試驗係藉由放置每一液體調配物在單獨的HDPE瓶中並儲存在於40℃、相對濕度75%的容器中。在1個月與3個月之後，樣品係取出並調查任何顯著的變化。該等結果係顯示於下方表6中。
如表4至表6及圖1與圖2中所顯示，當包含安布索鹽酸鹽與左旋羥丙哌嗪作為主要成分的該複合液體調配物之pH值藉由使用緩衝劑保持在4.5至5.5該範圍中時，衍自於該主要成分之未知物質的產生係有效地抑制。特別的，在加速條件下，安布索鹽酸鹽相關物質之產生係降低
大約12到15倍(最大)，而該左旋羥丙哌嗪之產生降低大約約25到35倍或更多。所以，該等結果指出，本發明之該液體調配物的儲存安定性係顯著增強的。
還有，根據國際醫藥法規協合會(ICH)的規範，其應分別不超過0.2%與0.5%重量份的未知與已知的不純物。本發明實例1之液體調配物在40℃加速條件下顯示小於0.5%令人滿意的結果，甚至直到初始期後3個月。相反地，比較實例1之液體調配物，該者不採用用於調整該pH至4.5到5.5的一緩衝劑，遠遠超過了ICH指南所預決定的限制，即使從該初始期後1個月後。
Claims (7)
- 一種經口投藥的液體調配物，其具有4.5至5.5之一pH值，其包含：安布索(ambroxol)或其藥學上可接受的鹽類；左旋羥丙哌嗪(levodropropizine)或其藥學上可接受的鹽類；及在一水性介質中的一緩衝劑，其中每100mL該液體調配物中有100mg至1,000mg之量的該安布索或其藥學上可接受的鹽類，且每100mL該液體調配物中有300mg至1,500mg之量的該左旋羥丙哌嗪或其藥學上可接受的鹽類。
- 如申請專利範圍第1項之經口投藥的液體調配物，其中該緩衝劑係選自由下列所組成之群組：檸檬酸；檸檬酸鈉水合物；檸檬酸鉀；醋酸；醋酸鈉；碳酸鈉；碳酸鈣；磷酸三鈣(calcium phosphate tribasic)；乳酸鈣；甘胺酸；馬來酸；蘋果酸；麩胺酸鈉；麩胺酸單鈉；乳酸鈉；磷酸鈉及其等之混合物。
- 如申請專利範圍第2項之經口投藥的液體調配物，其中該緩衝劑係選自由下列所組成之群組：檸檬酸；檸檬酸鈉水合物；檸檬酸鉀；醋酸；醋酸鈉；蘋果酸；麩胺酸鈉；甘胺酸；碳酸鈉；馬來酸；乳酸鈉及其等之混合物。
- 如申請專利範圍第2項之經口投藥的液體調配物，其中該緩衝劑係為檸檬酸與檸檬酸鈉水合物之一混合物。
- 如申請專利範圍第1項之經口投藥的液體調配物，其中該水性介質係選自由純水、乙醇及其等之一混合物所組 成之群組。
- 如申請專利範圍第1項之經口投藥的液體調配物，其進一步包含一藥學上可接受的賦形劑，其選自由抗氧化劑、甜味劑、防腐劑、黏度改質劑(viscosity modifying agent)及其等之混合物所組成之群組。
- 一種用於製備如申請專利範圍第1項之該經口投藥之液體調配物的方法，包含下列步驟：(1)將一藥學上可接受的賦形劑溶解在一水性介質中；(2)藉由使用一緩衝劑，將步驟(1)中所製得之該混合物之pH調整到4.5至5.5；(3)將安布索或其藥學上可接受的鹽類，及左旋羥丙哌嗪或其藥學上可接受的鹽類溶解於步驟(2)中所製得之該混合物；及(4)添加一水性介質至步驟(3)所製得之該混合物中。
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| TW201345563A TW201345563A (zh) | 2013-11-16 |
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| Application Number | Title | Priority Date | Filing Date |
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| TW102112507A TWI589305B (zh) | 2012-04-10 | 2013-04-09 | 用於經口投藥之包含安布索、左旋羥丙哌嗪及緩衝劑的液體調配物以及製備其之方法 |
Country Status (3)
| Country | Link |
|---|---|
| KR (1) | KR101915056B1 (zh) |
| TW (1) | TWI589305B (zh) |
| WO (1) | WO2013154347A1 (zh) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105193707A (zh) * | 2014-06-30 | 2015-12-30 | 南京瑞尔医药有限公司 | 一种盐酸氨溴索口服溶液及其制备方法 |
| WO2017091165A1 (en) * | 2015-11-26 | 2017-06-01 | Pharmacti̇ve İlaç San. Ve Ti̇c. A.Ş. | Liquid formulation of levodropropizine and method for preparation thereof |
| EP3600275A1 (en) | 2017-03-27 | 2020-02-05 | Ilko Ilaç Sanayi Ve Ticaret Anonim Sirketi | Stabilized pharmaceutical syrup composition comprising terbutaline sulphate and ambroxol hydrochloride |
| MX2017014725A (es) * | 2017-11-16 | 2019-05-17 | Productos Farm S A De C V | Dropropizina en combinacion con ambroxol en la forma farmaceutica de jarabe y tabletas. |
| WO2019208898A1 (ko) * | 2018-04-24 | 2019-10-31 | 한국유나이티드제약 주식회사 | 콜린알포세레이트를 함유하는 액상 시럽제제 |
| CN116327696A (zh) * | 2023-03-30 | 2023-06-27 | 山东京卫制药有限公司 | 一种稳定的氨溴特罗口服溶液 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1417961A1 (en) * | 2002-11-08 | 2004-05-12 | Boehringer Ingelheim International GmbH | New pharmaceutical compositions containing a combination of ambroxol or bromhexine and isopropamide iodide |
| ITMI20032463A1 (it) * | 2003-12-16 | 2005-06-17 | Advance Holdings Ltd | Soluzione acquosa concentrata a base di ambroxolo |
| BRPI0614887A2 (pt) | 2005-08-25 | 2011-04-19 | Boehringer Ingelheim Int | uso de ambroxol para o tratamento de infecções por rinovìrus |
| WO2007047576A1 (en) | 2005-10-14 | 2007-04-26 | The Board Of Trustees Of The University Of Illinois | Pharmacological treatments for sleep disorders |
| US8158152B2 (en) * | 2005-11-18 | 2012-04-17 | Scidose Llc | Lyophilization process and products obtained thereby |
| WO2009018280A2 (en) | 2007-07-30 | 2009-02-05 | Auspex Pharamaceuticals, Inc. | Substituted indoles |
| CA2706440C (en) * | 2007-11-21 | 2014-03-25 | The Procter & Gamble Company | Preparations, methods and kits useful for treatment of cough |
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2012
- 2012-04-10 KR KR1020120037409A patent/KR101915056B1/ko active IP Right Grant
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2013
- 2013-04-09 TW TW102112507A patent/TWI589305B/zh not_active IP Right Cessation
- 2013-04-10 WO PCT/KR2013/002999 patent/WO2013154347A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| KR20130114948A (ko) | 2013-10-21 |
| TW201345563A (zh) | 2013-11-16 |
| WO2013154347A1 (en) | 2013-10-17 |
| KR101915056B1 (ko) | 2018-11-07 |
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