TW201627009A - 製造醫藥傳遞系統之方法 - Google Patents
製造醫藥傳遞系統之方法 Download PDFInfo
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- TW201627009A TW201627009A TW104141693A TW104141693A TW201627009A TW 201627009 A TW201627009 A TW 201627009A TW 104141693 A TW104141693 A TW 104141693A TW 104141693 A TW104141693 A TW 104141693A TW 201627009 A TW201627009 A TW 201627009A
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- Prior art keywords
- calcium carbonate
- delivery system
- acid
- medical delivery
- eur
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- 238000000034 method Methods 0.000 title claims abstract description 100
- 238000004519 manufacturing process Methods 0.000 title abstract description 10
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims abstract description 325
- 229910000019 calcium carbonate Inorganic materials 0.000 claims abstract description 130
- 239000000203 mixture Substances 0.000 claims description 140
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- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 86
- 239000013543 active substance Substances 0.000 claims description 72
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- 238000005056 compaction Methods 0.000 claims description 65
- 239000002243 precursor Substances 0.000 claims description 57
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- 239000001569 carbon dioxide Substances 0.000 claims description 43
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- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 21
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Abstract
本發明係關於一種用於製造醫藥傳遞系統之方法,表面反應碳酸鈣用於提高醫藥傳遞系統之脆度以及用於提高醫藥傳遞系統之流動性的用途,以及藉由該方法獲得之醫藥傳遞系統。
Description
本發明係關於一種用於製造醫藥傳遞系統之方法,表面反應碳酸鈣用於提高醫藥傳遞系統之脆度以及用於提高醫藥傳遞系統之流動性的用途,以及藉由該方法獲得之醫藥傳遞系統。
醫藥傳遞系統經設計以向人類或動物身體釋放醫藥活性劑。此類系統中已使用許多載劑,包括蠟、油、脂肪、可溶性聚合物及其類似物。另一方法將醫藥活性劑分散於整個固體基質材料中,該活性劑藉由擴散經該固體基質材料釋放。另一方法將醫藥活性劑封閉於具有聚合壁之膠囊內,該活性劑可藉由擴散通過該聚合壁。
舉例而言,Pawar等人(Gastroretentive dosage forms:A review with special emphasis on floating drug delivery systems.Drug Delivery.2011年2月;18(2):97-110)將漂浮藥物傳遞系統(FDDS)視為關於GRDDS發展之調配物及技術態樣之一種容易及有邏輯的方法。
US 3,976,764揭示一種即刻漂浮錠劑,具有塗佈有若干下包衣之基於明膠之空心球,其中一個下包衣中包含有一種治療活性成分。
DE 35 27 852 A1揭示一種比密度低於1之醫藥調配物,其中
將在水中形成凝膠之物質與醫藥活性劑及在室溫下為固體的脂肪/油混合。凝膠形成物質為纖維素、聚葡萄糖或澱粉之衍生物。
EP 0 338 861 A2係關於一種具有較長胃滯留時間之抗酸組合物。諸如水滑石或汞齊(Amalgate)之抗酸藥形成由固體外相包圍之實心核,該固體外相含有疏水性物質,例如甘油與棕櫚酸或硬脂酸的酯、羥基化聚烯烴及非離子乳化劑。
EP 0 717 988 A1係關於一種膨脹模製件,其為具有網狀橫截面且表觀密度小於1之擴展結構,該結構主要為耐酸聚合化合物且另外含有至少一種輔助發泡劑及一種原料藥。因為其橫截面中之網狀結構,所以本發明之膨脹模製件具有大量連續或不連續之微細內孔。該耐酸聚合化合物選自例如乙酸丁二酸羥丙基甲基纖維素或鄰苯二甲酸羥丙基甲基纖維素。
US 4,451,260係關於一種包含醫藥活性成分之多層結構,其中該多層結構中包覆空氣,由此促進漂浮。
US 4,814,179係關於一種漂浮緩釋治療組合物。未壓製緩釋錠劑包含親水膠體膠凝劑、治療上可接受之黏油、經選擇之治療劑及水。
EP 2 719 376 A1係關於使用官能化碳酸鈣之胃滯留藥物調配物及傳送系統以及其製備方法。
就此而言,碳酸鈣看似有用於製備醫藥傳遞系統之前景,因為其展現將粒子有效地抓握在一起的具有片層狀表面結構之高度多孔性網狀結構,參看例如EP 2 719 373 A1。因此提供將其調配成顆粒、團塊、膠囊或將其壓實成錠劑或微錠劑的可能性。
在1998年,一種新穎類型之表面反應碳酸鈣首先描述於FR 2787802 B1中,隨後描述於WO 00/39222 A1及US 2004/0020410 A1中,且基於天然研磨碳酸鈣與氣態CO2及與一或多種中等-強至強H3O+離子提供物之反應。所獲得之產物為多孔性碳酸鈣,其具有特殊表面結構、孔隙率及比表面積,當其用作紙之顏料或塗料填充劑時,對於恆定表面積提供該紙之重量減少而不損失物理特性。
在WO 2004/083316 A1中,描述此表面反應碳酸鈣之製備中之另一有利修改,其中涉及矽酸鋁、合成二氧化矽、矽酸鈣、矽酸鹽及/或單價鹽,且其亦適用於造紙應用。另外,WO 2005/121257 A2係關於在添加有一或多種式R-X化合物的該表面反應碳酸鈣的製造中添加有利添加劑,其例如選自脂肪酸、脂肪胺或脂肪醇。WO 2009/074492 A1尤其關於在沉澱碳酸鈣方面之已知方法之最佳化,其結果為由於碳酸鈣沉澱中之特殊條件,適用於天然研磨碳酸鈣之方法未提供就合成從沉澱碳酸鈣之表面反應而言之相同良好結果。用於製備表面反應碳酸鈣之方法的若干進一步最佳化及修改遵循諸如EP 2 264 108 A1(WO 2010/146530 A1)及EP 2 264 109 A1(WO 2010/146531 A1)中所描述之彼等最佳化及修改,其涉及在表面反應碳酸鈣之製備中使用弱酸。
WO2014/001063係關於一種高固體水性無機填料懸浮液,其在低溫及酸性環境下保持其懸浮液的機械特性。
然而,前述文獻均未明確提及用於製造包含表面反應碳酸鈣之醫藥傳遞系統的有效壓實方法。
因此,持續需要如下醫藥傳遞系統及其製造方法,其比現有
醫藥傳遞系統提供更佳性能且尤其允許使用微晶纖維素代替表面反應碳酸鈣製造相較於常規醫藥傳遞系統具有提高之脆度及/或流動性之醫藥傳遞系統。此外,需要提供用於製造醫藥傳遞系統之方法,其有效且允許充分壓實該系統。
本發明之目標因此為提供一種用於製造醫藥傳遞系統之方法。另一目標亦可為提供用於製造醫藥傳遞系統之高效壓實方法。另一目標可為提供使用微晶纖維素代替表面反應碳酸鈣製造相較於常規醫藥傳遞系統具有提高之脆度及/或流動性的醫藥傳遞系統之方法。
一或多種前述及其他問題係藉由如本文在獨立的申請專利範圍中所定義的標的物來解決。本發明之有利具體實例定義於對應的申請專利範圍子項中。
本發明之第一態樣係關於一種用於製造醫藥傳遞系統之方法。該方法包含以下步驟:a)提供表面反應碳酸鈣,其為天然研磨或沉澱碳酸鈣與二氧化碳及一或多種酸在水性介質中之反應產物,其中該二氧化碳藉由酸處理原位形成及/或由外部來源供應;b)提供至少一種醫藥活性劑或其醫藥非活性前驅物;c)提供至少一種調配助劑;d)混合步驟a)之表面反應碳酸鈣、步驟b)之至少一種醫藥活性劑或其醫藥非活性前驅物及步驟c)之至少一種調配助劑;以及e)藉助於滾筒壓實機在4至20巴範圍內之壓實壓力下壓實步驟d)中
獲得之混合物;以及f)將步驟e)中獲得之滾筒壓實混合物壓實獲得醫藥傳遞系統。
圖1:基於FCC之錠劑調配物的拉伸強度隨壓製壓力之變化。錠劑含有變化量之撲熱息痛(P)且使用FCC粉末製備(虛線)或FCC顆粒藉由在5巴(短劃線/虛線且深色符號)或20巴(黑色實踐)下滾筒壓實獲得。所有顆粒均含有1wt%硬脂醯反丁烯二酸鈉。值為n=3實驗之平均值±SD。
圖2:含有撲熱息痛(P)與FCC或艾維素之混合物的顆粒的壓實。錠劑之拉伸強度隨壓製壓力之變化的比較。全部調配物均在20巴下粒化且含有1%硬脂醯反丁烯二酸鈉。值為n=3實驗之平均值±SD。
圖3:壓實後的FCC孔隙率。壓實FCC粉末(P-FCC)或FCC顆粒(G-FCC)之比較。G-FCC在5巴下粒化。使用汞壓孔率測定法分析增加之壓實壓力下FCC之孔徑分佈。值為n=2量測值之平均值。
根據本發明之另一態樣,提供表面反應碳酸鈣用於提高醫藥傳遞系統之脆度的用途,其中該表面反應碳酸鈣為天然研磨或沉澱碳酸鈣與二氧化碳及一或多種酸在水性介質中之反應產物,其中二氧化碳藉由酸處理原位形成及/或自外部來源供應,其中醫藥傳遞系統a)在100MPa下壓製的錠劑上根據Ph.Eur.4量測具有1.10%之脆度;及/或b)滿足式(II)
其中
(FRRCPh)為根據Ph.Eur.4量測的醫藥傳遞系統RCPh之脆度(以%為單位),其中步驟e)中之壓實壓力為至少15巴;(FRRCPl)為根據Ph.Eur.4量測的醫藥傳遞系統RCPl之脆度(以%為單位),其中步驟e)中之壓實壓力低於用於獲得醫藥傳遞系統RCPh之壓實壓力。
根據本發明之另一態樣,提供表面反應碳酸鈣用於提高醫藥傳遞系統之流動性的用途,其中該表面反應碳酸鈣為天然研磨或沉澱碳酸鈣與二氧化碳及一或多種酸在水性介質中之反應產物,其中二氧化碳藉由酸處理原位形成及/或自外部來源供應,其中醫藥傳遞系統滿足式(II)
其中(FLRCP)為在7mm開口直徑下根據Ph.Eur.4量測的醫藥傳遞系統之流動性(以g/s為單位);(FL參考)為在7mm開口直徑下根據Ph.Eur.4量測的同一醫藥傳遞系統之流動性(以g/s為單位),其中表面反應碳酸鈣由微晶纖維素代替。
根據本發明之另一態樣,用於製造醫藥傳遞系統之方法包含以下步驟:a)提供表面反應碳酸鈣,其為天然研磨或沉澱碳酸鈣與二氧化碳及一或多種酸在水性介質中之反應產物,其中二氧化碳藉由酸處理原位形成及/或由外部來源供應;b)不使用任何黏合劑及/或加工助劑,藉助於滾筒壓實機且在4至20巴範圍內的壓實壓力下壓實步驟a)之表面反應碳酸鈣獲得經滾筒壓實之材
料;以及c)視情況轉化步驟b)中獲得之經滾筒壓實之材料獲得包含錠劑、微錠劑、膠囊、團塊或顆粒之醫藥傳遞系統。
根據上述方法之另一具體實例,步驟b)中獲得之滾筒壓實材料進行研磨步驟及分類步驟,其中該滾筒壓實材料在分類後具有180μm至710μm之晶粒尺寸。此類分類步驟可例如藉由在不同篩孔尺寸上篩分進行。此類篩孔尺寸較佳為710μm、500μm、355μm、250μm以及180μm。
根據上述方法之另一具體實例,步驟b)之滾筒壓實材料呈顆粒形式。
本發明之另一態樣為藉由上述方法獲得之顆粒,其中該等顆粒為壓實的表面反應碳酸鈣,不具有黏合劑及/或加工助劑,粒度為180μm至710μm,且其中表面反應碳酸鈣i)使用氮氣及BET方法根據ISO 9277量測,具有20.0m2/g至200.0m2/g,較佳20.0m2/g至180.0m2/g,更佳30.0m2/g至160.0m2/g,甚至更佳40.0m2/g至150.0m2/g,且最佳50.0m2/g至140.0m2/g之BET比表面積;及/或ii)包含體積中值粒徑d50為2.0至50.0μm,較佳2.5至25.0μm,更佳2.8至20.0μm,甚至更佳3.0至10.0μm,且最佳4.0至8.0μm之粒子;及/或iii)如實驗部分所述由汞壓孔率測定法量測計算,具有在全部0.15至1.35cm3/g,較佳0.30至1.30cm3/g,且最佳0.40至1.25cm3/g範圍內之粒子內壓入之比孔隙體積。
根據本發明之另一態樣,提供藉由該方法獲得之醫藥傳遞系統,較佳錠劑、微錠劑、膠囊或糰粒。
根據本發明方法之一個具體實例,天然研磨碳酸鈣選自含有
碳酸鈣之礦物,該等礦物選自包含以下之群:大理石、白堊、白雲石、石灰石及其混合物;或該沉澱碳酸鈣選自包含具有文石、六方方解石或方解石礦物晶形或其混合物的沉澱碳酸鈣之群。
根據本發明方法之另一具體實例,表面反應碳酸鈣a)使用氮氣及BET方法根據ISO 9277所量測,具有20.0m2/g至200.0m2/g,較佳20.0m2/g至180.0m2/g,更佳30.0m2/g至160.0m2/g,甚至更佳40.0m2/g至150.0m2/g,且最佳50.0m2/g至140.0m2/g之BET比表面積;及/或b)包含體積中值粒徑d50為2.0至50.0μm,較佳2.5至25.0μm,更佳2.8至20.0μm,甚至更佳3.0至10.0μm,且最佳4.0至8.0μm之粒子;及/或c)由汞壓孔率測定法量測計算,具有在0.15至1.35cm3/g,較佳0.30至1.30cm3/g,且最佳0.40至1.25cm3/g範圍內之粒子內壓入之比孔隙體積。
根據本發明方法之另一具體實例,至少一種醫藥活性劑或其醫藥非活性前驅物選自包含合成來源、半合成來源、天然來源以及其組合的醫藥活性劑或醫藥非活性前驅物之群。
根據本發明方法之一個具體實例,至少一種調配助劑a)為至少一種相內潤滑劑及/或相外潤滑劑;及/或b)按醫藥傳遞系統之總重量計,以約0.1wt%至約10.0wt%,較佳約0.3wt%至約5.0wt%,更佳約0.5wt%至約2.5wt%之總量提供。
根據本發明方法之另一具體實例,滾筒壓實步驟e)在4至15巴範圍內,更佳4至10巴範圍內且最佳4至7巴範圍內之滾筒壓實壓力下進行。
根據本發明方法之另一具體實例,壓實步驟f)為粒化或製
錠步驟。
根據本發明方法之一個具體實例,滾筒壓實步驟e)中獲得之滾筒壓實混合物在進行壓實步驟f)之前進行研磨步驟。
根據本發明方法之另一具體實例,滾筒壓實混合物具有藉由在不同篩孔尺寸上篩分獲得的180至710μm之晶粒尺寸,較佳使用180μm、250μm、355μm、500μm以及710μm之篩孔尺寸。
根據本發明方法之另一具體實例,醫藥傳遞系統a)在100MPa下壓製的錠劑上根據Ph.Eur.4量測具有1.10%之脆度;及/或b)滿足式(I)
其中(FRRCPh)為根據Ph.Eur.4量測的醫藥傳遞系統RCPh之脆度(以%為單位),其中步驟e)中之該壓實壓力為至少15巴;(FRRCPl)為根據Ph.Eur.4量測的醫藥傳遞系統RCPl之脆度(以%為單位),其中步驟e)中之該壓實壓力低於用於獲得該醫藥傳遞系統RCPh之壓實壓力。
根據本發明方法之一個具體實例,醫藥傳遞系統滿足式(II)
其中(FLRCP)為在7mm開口直徑下根據Ph.Eur.4量測的醫藥傳遞系統之流動性(以g/s為單位);(FL參考)為在7mm開口直徑下根據Ph.Eur.4量測的同一醫藥傳遞系統之
流動性(以g/s為單位),其中表面反應碳酸鈣由微晶纖維素代替。
根據本發明方法之另一具體實例,醫藥傳遞系統為錠劑、微錠劑、膠囊或糰粒。
應理解,出於本發明之目的,以下術語具有以下含義。
出於本發明之目的,「酸」定義為布朗斯特-勞立酸(Brnsted-Lowry acid),換言之,其為H3O+離子提供物。「酸鹽」定義為H3O+離子提供物,例如含氫鹽,其藉由正電性元素部分中和。「鹽」定義為由陰離子及陽離子形成之電中性離子化合物。「部分結晶鹽」定義為在XRD分析時呈現基本上離散之繞射圖案之鹽。
根據本發明,pKa為表示與既定酸中給定之可電離氫相關之酸解離常數的符號,且表明在既定溫度下於水中在平衡狀態下此氫自此酸自然解離的程度。此類等pKa值可發現於諸如Harris,D.C.「Quantitative Chemical Analysis:第3版」,1991,W.H.Freeman & Co.(USA),ISBN 0-7167-2170-8之參考教材中。
「天然研磨碳酸鈣」(GCC)在本發明之含義中為獲自天然來源(諸如石灰石、大理石、白雲石或白堊)且例如藉由旋風器或分類器經由濕式及/或乾式處理方法(諸如研磨、篩分及/或分餾)處理之碳酸鈣。
「沉澱碳酸鈣」(PCC)在本發明之含義中為藉由二氧化碳及石灰在水性、半乾燥或潮濕環境中之反應之後的沉澱或藉由鈣及碳酸根離子源於水中之沉澱獲得之合成材料。PCC可呈六方方解石、方解石或文石晶形。
出於本發明之目的,「表面反應碳酸鈣」為包含碳酸鈣及不
溶於水、至少部分結晶非碳酸鈣鹽(較佳自碳酸鈣之至少部分之表面擴展)之材料。形成該至少部分結晶之非碳酸鈣鹽的鈣離子大部分源自亦用以形成表面反應碳酸鈣核心之起始碳酸鈣物質。此類鹽可包括OH-陰離子及/或結晶水。
在本發明之含義中,「水不溶性」物質定義為當物質與去離子水混合且在20℃下於具有0.2μm孔徑之過濾器上過濾以回收液體濾液時,100g該液體濾液在95至100℃下蒸發之後提供小於或等於0.1g回收固體物質。「水溶性」物質定義為物質於95℃至100℃下蒸發100g該液體濾液之後回收產生大於0.1g經回收之固體物質。
在整個本發明文件中,碳酸鈣及其他物質之「粒度」藉由其粒度分佈描述。值dx表示x wt%粒子的直徑相對於其小於dx之直徑。此意謂d20值為20wt%所有粒子小於該值之粒度,且d75值為75wt%所有顆粒小於該值之粒度。d50值因此為重量中值粒度,即50wt%所有顆粒大於此粒度且其餘50wt%顆粒小於此粒度。出於本發明之目的,除非另外指出,否則將粒度規定為重量中值粒度d50。可使用Sedigraph測定重量中值粒度d50值。出於本發明之目的,表面反應碳酸鈣之「粒度」描述為體積決定之粒度分佈。可使用馬爾文粒度分析儀(Malvern Mastersizer)2000測定表面反應碳酸鈣之體積決定之粒度分佈,例如體積中值粒徑(d50),或體積決定之頂切粒度(d98)。若所有粒子之密度相同,則重量決定之粒度分佈可對應於體積決定之粒度。
在本發明之含義中,碳酸鈣之「比表面積(SSA)」定義為碳酸鈣之表面積除以其質量。如本文中所用,使用BET等溫線(ISO 9277:2010)
藉由氮氣吸附量測比表面積且以m2/g作為單位。
出於本發明之目的,「孔隙率」或「孔隙體積」係指粒子內壓入之比孔隙體積。使用Micromeritics Autopore IV 9500汞細孔計量測孔隙率或孔隙體積,該細孔計最大施加壓力為414MPa,等效於0.004μm Laplace導入口直徑。
在本發明之含義中,「懸浮液」或「漿液」包含不溶性固體及水,及視情況存在之其他添加劑,且通常含有大量固體,且因此更黏稠且可比自其形成之液體具有更高密度。
在本發明之含義中,術語「壓實」意謂孔隙率降低及在壓力下獲得之錠劑硬度提高。
當術語「包含」用於本發明說明書及申請專利範圍中時,其不排除其他要素。出於本發明之目的,術語「由……組成」視為術語「包含」之較佳具體實例。若在下文中將群組限定為包含至少某一數目之具體實例,則此亦理解為揭示較佳僅由此等具體實例組成之群組。
除非另外明確規定,否則當參考單數名詞使用不定冠詞或定冠詞,例如「一」或「該」時,此包括複數個該名詞。
如「可獲得」或「可定義」及「獲得」或「定義」之術語可互換使用。此例如意謂除非上下文明確規定,否則術語「獲得」不意謂指示例如必須藉由例如術語「獲得」之後的步驟順序獲得之具體實例,雖然術語「獲得」或「定義」始終包括此類限制理解作為較佳具體實例。
根據本發明,已發現已使用特定方式表面處理之碳酸鈣可用作醫藥傳遞系統中之賦形劑且提供有效壓實醫藥傳遞系統之可能性。
下文中,體積本發明之其他細節及尤其用於製造醫藥傳遞系統之方法的前述步驟。
根據本發明方法之步驟a),提供表面反應碳酸鈣,其為天然研磨或沉澱碳酸鈣與二氧化碳及一或多種酸在水性介質中之反應產物,其中二氧化碳藉由酸處理原位形成及/或由外部來源供應。
根據本發明使用之表面反應碳酸鈣為天然研磨或沉澱碳酸鈣與二氧化碳及至少一種酸在水性介質中之反應產物,其中二氧化碳藉由酸處理原位形成及/或由外部來源供應。
在本發明之含義中,表述「酸處理」係指天然研磨或沉澱碳酸鈣及至少一種酸在水性介質中之反應物。二氧化碳可藉由此反應在水性介質中原位形成。
天然研磨碳酸鈣(GCC)理解為天然存在之碳酸鈣形式,其開採自諸如石灰石或白堊之沉積岩或變質大理岩。已知碳酸鈣主要以三種類型之晶體多晶型物形式存在:方解石、文石及六方方解石。方解石為最常見的晶體多形體,其視為碳酸鈣之最穩定晶形。較少見的是文石,其具有分散或叢集針狀斜方晶晶體結構。六方方解石為最罕見碳酸鈣多晶型物且一般不穩定。天然碳酸鈣幾乎完全為方解石型多晶型物,其稱為三方菱面體且代表最穩定之碳酸鈣多晶型物。在本發明之含義中,術語碳酸鈣之「來源」係指自其獲得碳酸鈣之天然存在之礦物材料。碳酸鈣之來源可包含其他天然存在之組分,諸如碳酸鎂、矽酸鋁等。
根據一個具體實例,天然研磨碳酸鈣選自含有碳酸鈣之礦物,該等礦物選自由以下組成之群:大理石、白堊、白雲石、石灰石及其
混合物。
根據本發明之一個具體實例,藉由乾式研磨獲得GCC。根據本法明之另一具體實例,藉由濕式研磨及視情況存在之後續乾燥獲得GCC。
一般而言,可用任何習知研磨裝置,例如在使得粉碎主要由二級物體衝擊而產生之條件下進行研磨步驟,亦即在以下之一或多者中進行:球磨機、棒磨機、振動磨機、輥碎機、離心衝擊磨機、直立型珠粒研磨機、磨粉機、針磨機、錘碎機、磨機、粉碎機、碎料機、刀式切割機或熟習此項技術者已知之其他此類設備。在含有碳酸鈣之礦物材料包含含有經濕式研磨碳酸鈣之礦物材料的情況下,可在使得自體研磨發生之條件下及/或藉由水平式球磨研磨及/或熟習此項技術者已知之其他此類方法來進行研磨步驟。應注意,乾式研磨含有碳酸鈣之礦物材料可使用相同研磨方法。可藉由熟知方法對由此獲得的含濕式處理之經研磨碳酸鈣的礦物材料進行洗滌及脫水,例如藉由在乾燥之前絮凝、過濾或強制蒸發。可在單個步驟(諸如噴霧乾燥)或在至少兩個步驟中進行乾燥之後續步驟。亦常見此類礦物材料經受選礦步驟(諸如浮選、漂白或磁化分離步驟)以移除雜質。
在本發明之含義中,「沉澱碳酸鈣」(PCC)為一般藉由二氧化碳與石灰在水性環境中反應之後沉澱或藉由鈣及碳酸根離子源於水中之沉澱或藉由鈣及碳酸根離子(例如CaCl2及Na2CO3)自溶液之沉澱獲得的合成材料。產生PCC之其他可能方式為石灰鹼法,或索耳未法(Solvay process),其中PCC為氨產生之副產物。沉澱碳酸鈣以三種主要結晶形式存
在:方解石、霰石及六方方解石,且此等結晶形式各自存在多種不同多晶型物(晶體慣態)。方解石具有三方結構,其典型晶體慣態為諸如偏三角面體(S-PCC)、菱面體(R-PCC)、六方稜柱形、軸面、膠狀(C-PCC)、立方體及稜柱形(P-PCC)。文石為斜方晶結構,其典型晶體慣態為雙晶六方稜柱形晶體,以及不同類別之細長稜柱形、彎曲葉片狀、陡錐狀、鏨子狀晶體,分枝樹狀及珊瑚或蠕蟲樣形式。六方方解石屬於六方晶體系統。所獲得之PCC漿液可以機械方式脫水及乾燥。
根據本發明之一個具體實例,沉澱碳酸鈣選自由具有文石、六方方解石或方解石礦物晶形及其混合物的沉澱碳酸鈣組成之群。
在一較佳具體實例中,在用至少一種酸及二氧化碳處理之前,研磨天然研磨或沉澱碳酸鈣。研磨步驟可用熟習此項技術者已知之任何習知研磨裝置(諸如研磨機)來進行。
在一較佳方法中,將天然研磨或沉澱碳酸鈣懸浮於水中,其諸如藉由研磨呈細粉狀或不為細粉狀。較佳地,按漿液之重量計,漿液的天然研磨或沉澱碳酸鈣之含量在1wt%至80wt%,更佳3wt%至60wt%,且甚至更佳5wt%至40wt%範圍內。
根據本發明之一個具體實例,天然研磨或沉澱碳酸鈣之重量中值粒徑d50為0.1至50μm,較佳0.5至25μm,更佳0.8至20μm,甚至更佳1.0至10μm且最佳1.2至8μm。
在下一步驟中,向含有天然研磨或沉澱碳酸鈣之水性懸浮液添加至少一種酸。該至少一種酸在製備條件下可為產生H3O+離子之任何強酸、中強酸或弱酸,或其混合物。根據本發明,該至少一種酸亦可為在製
備條件下產生H3O+離子之酸性鹽。
根據一個具體實例,該至少一種酸為在20℃下具有0或0以下之pKa之強酸。根據另一具體實例,該至少一種酸為在20℃下具有0至2.5之pKa值之中強酸。若在20℃下pKa為0或小於0,則酸較佳選自硫酸、鹽酸或其混合物。若在20℃下pKa為0至2.5,則酸較佳選自H2SO3、H3PO4、乙二酸或其混合物。根據一較佳具體實例,該至少一種酸為H3PO4。該至少一種酸亦可為酸性鹽,例如HSO4 -或H2PO4 -,藉由諸如Li+、Na+或K+之對應陽離子至少部分中和,或HPO4 2-,藉由諸如Li+、Na+、K+、Mg2+或Ca2+之對應陽離子至少部分中和。該至少一種酸亦可為一或多種酸與一或多種酸性鹽之混合物。
根據另一具體實例,該至少一種酸為當在20℃下量測時具有大於2.5且小於或等於7的與第一可用氫之電離相關之pKa值,且具有在此第一可用氫缺失時形成之對應陰離子(其能夠形成水溶性鈣鹽)之弱酸。根據較佳具體實例,弱酸在20℃下具有2.6至5之pKa值,且弱酸更佳選自由以下組成之群:乙酸、甲酸、丙酸及其混合物。
在使用弱酸之情況下,在將該酸添加至含有天然研磨或沉澱碳酸鈣之水性懸浮液中後,另外添加至少一種水溶性鹽,在含氫鹽的情況下,當在20℃下量測時,其具有大於7的與第一可用氫之電離相關之pKa,且其鹽陰離子能夠形成水不溶性鈣鹽。該水溶性鹽之陽離子較佳選自由以下組成之群:鉀離子、鈉離子、鋰離子及其混合物。在一更佳具體實例中,該陽離子為鈉。值得重視地為可視陰離子之電荷而定,存在該等陽離子中之超過一者以得到電中性離子性化合物。該水溶性鹽之陰離子較佳選自由
以下組成之群:磷酸根、磷酸二氫根、磷酸單氫根、乙二酸根、矽酸根、其混合物及其水合物。在一更佳具體實例中,該陰離子係選自由以下組成之群:磷酸根、磷酸二氫根、磷酸單氫根、其混合物及其水合物。在一最佳具體實例中,該陰離子係選自由以下組成之群:磷酸二氫根、磷酸單氫根、其混合物及其水合物。水溶性鹽之添加可逐滴進行或在一個步驟中進行。在逐滴添加的情況下,此添加較佳發生在15分鐘之時段內。更佳在一個步驟中添加該鹽。
根據本發明之一個具體實例,該至少一種酸係選自由以下組成之群:氫氯酸、硫酸、亞硫酸、磷酸、檸檬酸、乙二酸、乙酸、甲酸及其混合物。該至少一種酸較佳選自由以下組成之群:氫氯酸、硫酸、亞硫酸、磷酸、乙二酸、H2PO4 -(藉由諸如Li+、Na+或K+之對應陽離子至少部分地中和)、HPO4 2-(藉由諸如Li+、Na+、K+、Mg2+或Ca2+之對應陽離子至少部分地中和)及其混合物,該至少一種酸更佳選自由以下組成之群:氫氯酸、硫酸、亞硫酸、磷酸、乙二酸或其混合物,且該至少一種酸最佳為磷酸。
根據本發明之另一具體實例,該至少一種酸為一或多種酸之混合物。舉例而言,該至少一種酸為磷酸與檸檬酸之混合物。一或多種酸可同時或接連添加。
該至少一種酸可以濃溶液或較稀之溶液形式添加至懸浮液中。根據一個具體實例,至少一種酸與天然研磨或沉澱碳酸鈣之莫耳比為0.01至0.6,較佳0.05至0.55且更佳0.1至0.5。作為一替代方案,亦可能在天然研磨或沉澱碳酸鈣懸浮之前將該至少一種酸添加至水中。
在下一步驟中,天然研磨或沉澱碳酸鈣用二氧化碳處理。二
氧化碳可藉由酸處理原位形成及/或可自外部來源供應。若使用諸如硫酸或鹽酸之強酸或諸如磷酸之中強酸對天然研磨或沉澱碳酸鈣進行酸處理,則自動形成足夠量之二氧化碳達到所需莫耳濃度。或者或另外,二氧化碳可由外部來源供應。
根據一個具體實例,表面反應碳酸鈣為天然研磨或沉澱碳酸鈣與二氧化碳及至少一種酸之反應產物,其中二氧化碳由於至少一種酸與天然研磨或沉澱碳酸鈣接觸而原位形成及/或自外部來源供應。
在使用強酸或中強酸之情況中,酸處理及用二氧化碳處理可同時進行。亦可能首先例如以在20℃下具有在0至2.5範圍內之pKa的中強酸進行酸處理,其中原位形成二氧化碳,且因此,二氧化碳處理將自動與酸處理同時進行,接著進行藉由自外部來源供應之二氧化碳的額外處理。
懸浮液中氣態二氧化碳之濃度較佳就體積而言為使得比率(懸浮液體積):(氣態CO2體積)為1:0.05至1:20,甚至更佳1:0.05至1:5。
在一較佳具體實例中,酸處理步驟及/或二氧化碳處理步驟重複至少一次,更佳重複若干次。
在酸處理及二氧化碳處理之後,在20℃下量測的水性懸浮液之pH自然地達到大於6.0、較佳大於6.5、更佳大於7.0、甚至更佳大於7.5之值,進而以具有大於6.0、較佳大於6.5、更佳大於7.0、甚至更佳大於7.5之pH之水性懸浮液形式製備表面反應天然研磨或沉澱碳酸鈣。若使水性懸浮液達到平衡,則pH大於7。可在不添加鹼的情況下在繼續攪拌水性懸浮液足夠時段,較佳1小時至10小時,更佳1至5小時之時將pH調整為大於6.0。
或者,在達到平衡(其在pH大於7時發生)之前,可藉由在二氧化碳處理之後添加鹼來將水性懸浮液之pH增加至大於6之值。可使用任何習知鹼,諸如氫氧化鈉或氫氧化鉀。
關於製備表面反應碳酸鈣之其他細節在WO 00/39222、WO 2004/083316、WO 2005/121257、WO 2009/074492、EP 2 264 108、EP 2 264 109以及US 2004/0020410中揭示。
類似地,獲得表面反應沉澱碳酸鈣。如由EP 2 070 991可詳細獲知,表面反應沉澱碳酸鈣係藉由在水性介質中使沉澱碳酸鈣與H3O+離子且與溶解於水性介質中且能夠形成水不溶性鈣鹽之陰離子接觸以形成表面反應沉澱碳酸鈣之漿液而獲得,其中該表面反應沉澱碳酸鈣包含形成於至少部分沉澱碳酸鈣之表面上之該陰離子之不溶性至少部分結晶鈣鹽。
該等溶解鈣離子對應於相對於藉由H3O+離子溶解沉澱碳酸鈣而自然產生之溶解鈣離子過量之溶解鈣離子,其中該等H3O+離子僅以陰離子之相對離子的形式(亦即經由以酸或非鈣酸鹽之形式添加陰離子)提供,且不存在任何其他鈣離子或鈣離子產生源。
該等過量溶解鈣離子較佳藉由添加可溶性中性或酸式鈣鹽,或藉由添加原位產生可溶性中性或酸式鈣鹽之酸或中性或酸式非鈣鹽來提供。
該等H3O+離子可藉由添加該陰離子之酸或酸式鹽或添加同時用以提供所有或部分該過量溶解鈣離子之酸或酸式鹽來提供。
根據本發明之一個具體實例,藉由包含以下步驟之製程獲得表面反應碳酸鈣:
a)提供天然研磨或沉澱碳酸鈣之懸浮液,b)向步驟a)之懸浮液添加在20℃下pKa值為0或0以下或pKa值為0至2.5的至少一種酸,以及c)在步驟b)之前、期間或之後用二氧化碳處理步驟a)之懸浮液。
根據一個具體實例,在步驟b)中將在20℃下具有0或0以下之pKa值的至少一種酸添加至步驟a)之懸浮液中。根據另一具體實例,在步驟b)中將在20℃下具有0至2.5之pKa值的至少一種酸添加至步驟a)之懸浮液中。
用於步驟c)中之二氧化碳可藉由步驟b)之酸處理原位形成及/或可自外部來源供應。
根據本發明之一個具體實例,藉由包含以下步驟之製程獲得表面反應碳酸鈣:A)提供天然研磨或沉澱碳酸鈣,B)提供至少一種水溶性酸,C)提供氣態CO2,D)使步驟A)之該天然研磨或沉澱碳酸鈣與步驟B)之至少一種酸及步驟C)之CO2接觸,其特徵在於:i)步驟B)之至少一種酸在20℃下具有大於2.5且小於或等於7的與其第一可用氫之電離相關之pKa,且在此第一可用氫缺失時形成能夠形成水溶性鈣鹽之對應陰離子,以及ii)在至少一種酸與天然研磨或沉澱碳酸鈣接觸之後,另外提供至少一
種水溶性鹽,其在20℃下pKa大於7之含氫鹽的情況下,與第一可用氫之電離有關,且其鹽陰離子能夠形成水不溶性鈣鹽。
根據製備表面反應天然研磨或沉澱碳酸鈣之一個具體實例,天然研磨或沉澱碳酸鈣與至少一種酸及/或二氧化碳在選自由以下組成之群的至少一種化合物存在下反應:矽酸鹽、氧化鎂、檸檬酸、硫酸鋁、硝酸鋁、氯化鋁及其混合物。此等組分可添加至包含天然研磨或沉澱碳酸鈣之水性懸浮液,隨後添加至少一種酸及/或二氧化碳。
表面反應天然或合成碳酸鈣可保持於懸浮液中。或者,可乾燥上文所描述之水性懸浮液。
將用於本發明中之表面反應天然或沉澱碳酸鈣較佳以乾粉形式提供。可藉由技術人員已知之任何方法進行隨後之乾燥步驟。舉例而言,乾燥可以單個步驟進行,諸如噴霧乾燥,或以至少兩個步驟進行,例如藉由向表面反應碳酸鈣施加第一加熱步驟來降低相關水分含量,且向表面反應碳酸鈣施加第二加熱步驟來降低剩餘水分含量。
術語「乾燥」表面反應碳酸鈣理解為表面反應碳酸鈣相對於表面反應碳酸鈣重量具有小於1.8wt%水。可藉由在乾燥腔室中使用根據ISO 787-2之方法將表面反應碳酸鈣加熱至105℃來測定水%。
本發明中打算使用之表面反應天然研磨或沉澱碳酸鈣以乾燥形式提供。表面反應碳酸鈣較佳呈粉塵或粉末形式,且最佳呈粉末形式。
根據本發明之一個具體實例,表面反應碳酸鈣包含至少一種酸之陰離子之不溶性至少部分結晶之鈣鹽,其形成於天然研磨或沉澱碳酸鈣之表面上。根據一個具體實例,至少一種酸的陰離子的不溶性至少部分
結晶鹽涵蓋天然研磨或沉澱碳酸鈣之至少部分,較佳整個表面。視所用之至少一種酸而定,陰離子可為硫酸根、亞硫酸根、磷酸根、檸檬酸根、乙二酸根、乙酸根及/或甲酸根。
根據一個較佳具體實例,表面反應碳酸鈣為天然研磨碳酸鈣與至少一種酸(較佳磷酸)之反應產物。根據另一較佳具體實例,表面反應碳酸鈣為天然研磨碳酸鈣與磷酸以及檸檬酸之反應產物。
此外,在一個較佳具體實例中,使用氮氣及BET方法根據ISO 9277 77量測,表面反應碳酸鈣具有20.0m2/g至200.0m2/g,較佳20.0m2/g至180.0m2/g,更佳30.0m2/g至160.0m2/g,甚至更佳40.0m2/g至150.0m2/g,且最佳50.0m2/g至140.0m2/g之BET比表面積。
根據一個具體實例,表面反應碳酸鈣包含體積中值粒徑d50為2.0至50.0μm,較佳2.5至25.0μm,更佳2.8至20.0μm,甚至更佳3.0至10.0μm,且最佳4.0至8.0μm之粒子。較佳地,使用Malvern Mastersizer 2000雷射繞射系統量測體積中值粒徑。方法及儀器為熟習此項技術者已知且通常用於測定填充劑及顏料之晶粒尺寸。
另外或替代地,表面反應碳酸鈣包含頂切粒度(d98)小於或等於40.0μm,較佳小於或等於30.0μm,更佳小於或等於20.0μm,更佳小於或等於17.0μm,更佳小於或等於14.0μm之粒子。較佳地,表面反應碳酸鈣包含頂切粒度(d98)在5.0至40μm,較佳6至30μm,更佳7.0至20.0μm,仍更佳8.0至17.0μm,更佳11.0至14.0μm範圍內之粒子。
較佳地,如實驗部分所述由汞壓孔率測定法量測計算,表面反應碳酸鈣之粒子內壓入之比孔隙體積在0.15至1.35cm3/g,較佳0.30至1.30
cm3/g,且最佳0.40至1.25cm3/g範圍內。累積壓入量資料中可見之總孔隙體積可分成兩個區域,其中214μm下至約1-4μm之壓入量資料顯示起重要作用的任何聚結結構之間的樣品之粗糙填充。此等直徑以下的為粒子本身之精細粒子間填充。若其亦具有粒子內的孔,則此區域呈現雙峰。此等三個區域之總和得到粉末之總全部孔隙體積,但主要視初始樣品壓製/在分佈之粗糙孔端處的粉末之沉降而定。
藉由取累積壓入量曲線之第一階導數,揭露基於等效拉普拉斯(Laplace)直徑之孔徑分佈(不可避免地包括孔隙屏蔽)。微分曲線明確顯示粗糙聚結孔結構區域、粒子間孔區域及粒子內孔區域(若存在)。知道粒子內孔直徑範圍,有可能自總孔隙體積減去剩餘粒子間及聚結物間孔隙體積以單獨以每單位質量的比孔隙體積形式提供內部孔之所需比孔隙體積。當然減除之相同原理適用於分離關注之其他孔徑區中的任一者。
藉由汞壓孔率測定法量測測定,表面反應碳酸鈣之孔徑較佳在4至500nm範圍內,更佳在20與80nm之間,尤其30至70nm的範圍內,例如50nm。
根據一較佳具體實例,表面反應碳酸鈣之粒子內及/或粒子間孔為空心的,且因此未負載表面反應碳酸鈣。換言之,表面反應碳酸鈣未用作運載劑。
較佳地,如實驗部分所述由汞壓孔率測定法量測計算,表面反應碳酸鈣之粒子間空隙在50vol%至99vol%,較佳70vol%至98vol%,尤其80vol%至95vol%範圍內。
另外或替代地,如實驗部分所述由汞壓孔率測定法量測計
算,表面反應碳酸鈣之核空隙在1vol%至30vol%,較佳5vol%至20vol%,尤其10vol%至15vol%範圍內。
表面反應碳酸鈣可呈粉塵或粉末形式,且較佳呈粉末形式。
根據一個具體實例,表面反應碳酸鈣不含有奈米等級之粒子,例如至少一個尺寸小於200nm之粒子。在本發明之含義中,「奈米等級之粒子」係指至少一個尺寸小於200nm之精細粒子。根據本發明之一個具體實例,表面反應碳酸鈣不含基於數目之中值粒徑d50小於200nm的粒子。為了測定基於數目之中值粒徑d50值,可使用Malvern Zetasizer Nano ZS採用動態光散射來測定等效球形流體動力Stokes直徑。
根據本發明方法之步驟b),提供至少一種醫藥活性劑或其醫藥非活性前驅物。
表述「至少一種」醫藥活性劑或其醫藥非活性前驅物意謂方法步驟b)中可提供一或多種醫藥活性劑或其醫藥非活性前驅物。
根據本發明之一個具體實例,方法步驟b)中提供僅一種醫藥活性劑或其醫藥非活性前驅物。根據本發明之另一具體實例,方法步驟b)中提供兩種或兩種以上醫藥活性劑或其醫藥非活性前驅物之混合物。舉例而言,方法步驟b)中提供兩種或三種醫藥活性劑或其醫藥非活性前驅物之混合物。
較佳地,方法步驟b)中提供僅一種醫藥活性劑或其醫藥非活性前驅物。
至少一種醫藥活性劑或其醫藥非活性前驅物較佳選自包含合成來源、半合成來源、天然來源以及其組合之醫藥活性劑或醫藥非活性
前驅物之群。
因此,醫藥活性劑係指合成來源、半合成來源、天然來源以及其組合之醫藥活性劑。另外,醫藥活性劑之醫藥非活性前驅物係指合成來源、半合成來源、天然來源以及其組合的醫藥非活性前驅物且將後期活化成各別醫藥活性劑。
此類醫藥非活性前驅物之活化為技術人員所已知且通常用於例如在胃及/或胃腸通道中活化,諸如酸性活化或胰蛋白酶解或胰凝乳蛋白酶解。
所提及之活化方法僅具有說明性特徵,且不打算具有限制性特徵,此在技術人員理解範圍內。
應注意,至少一種醫藥活性劑或其醫藥非活性前驅物可為技術人員已知的任何此類化合物。
當向人類及/或動物投與時,醫藥活性劑因此包括提供預防及/或治療特性之任何化合物。實例包括(但不限於)醫藥活性劑、治療活性劑、獸醫活性劑、營養製劑及生長調節劑。
舉例而言,至少一種醫藥活性劑或其醫藥非活性前驅物為抗牙垢劑。適用於本文之抗牙垢劑包括磷酸鹽。磷酸鹽包括焦磷酸鹽、聚磷酸鹽、聚膦酸鹽以及其混合物。焦磷酸鹽為用於牙齒保健產品之最佳已知磷酸鹽。傳遞至牙齒之焦磷酸根離子衍生自焦磷酸鹽。適用於本發明醫藥傳遞系統之焦磷酸鹽包括二鹼金屬焦磷酸鹽、四鹼金屬焦磷酸鹽及其混合物。非水合以及水合形式之焦磷酸二氫二鈉(Na2H2P2O7)、焦磷酸四鈉(Na4P2O7)以及焦磷酸四鉀(K4P2O7)較佳。抗結石磷酸鹽包括焦磷酸鉀及
焦磷酸鈉;三聚磷酸鈉;二膦酸鹽,諸如乙烷-1-羥基-1,I-二膦酸鹽;1-氮雜環庚烷-1,1-二膦酸鹽;以及線性烷基二膦酸鹽;線性羧酸及檸檬酸鈉及檸檬酸鋅。
可代替上述焦磷酸鹽或與上述焦磷酸鹽組合使用之試劑包括以下材料,諸如合成陰離子聚合物,包括聚丙烯酸酯及順丁烯二酸酐或酸與甲基乙烯基醚之共聚物,例如Gantrez,例如頒予Gaffar等人之美國專利第4,627,977號所述,其關於此類試劑之描述以全文引用的方式併入本文中,以及例如聚胺基丙烷磺酸(AMPS)、三水合檸檬酸鋅、聚磷酸鹽,例如三聚磷酸鹽及六偏磷酸鹽、二膦酸鹽,例如EHDP及AMP,多肽,諸如聚天冬胺酸及聚麩胺酸,及其混合物。
作為口服劑及/或全身活性劑的本發明之醫藥傳遞系統中亦可存在抗微生物劑。此類試劑可包括(但不限於)5-氯-2-(2,4-二氯苯氧基)-酚,通常稱為三氯生(triclosan)、洗必泰(chiorhexidine)、阿來西定(alexidine)、海克替啶(hexetidine)、血根鹼(sanguinarine)、苯紮氯銨、水楊醛胺、度米芬溴(domiphen bromide)、氯化乙醯吡啶(cetylpyridiurn chloride,CPC)、氯化十四烷基吡啶鎓(tetradecyl pyridiniurn chloride,TPC);氯化N-十四烷基-4-乙基吡啶鎓(TDEPC);奧替尼啶(octenidine);地莫匹醇(delmopinol)、辛哌醇(octapinol)及其他N-哌啶基衍生物,菸酸製劑;鋅/亞錫離子劑;抗生素,諸如AUGMENTIN、阿莫西林(amoxycillin)、四環素(tetracycline)、強力黴素(doxycyline)、米諾環素(minocycline)以及甲硝噠唑(metronidazole);以及上述抗微生物劑之類似物、衍生物及鹽,以及其混合物。
作為口服劑及/或全身活性劑的本發明之醫藥傳遞系統中亦可存在消炎劑。此類試劑可包括(但不限於)非類固醇消炎劑或NSAID,諸如丙酸衍生物;乙酸衍生物;芬那酸衍生物;聯苯羧酸衍生物;以及昔康(oxicam)。所有此等NSAID充分描述於頒予Sunshine等人之美國專利第4,985,459號中,其關於此類NSAID之描述以全文引用的方式併入本文中。適用NSAID之實例包括乙醯水楊酸、布洛芬(ibuprofen)、萘普生(naproxen)、苯惡洛芬(benoxaprofen)、氟比洛芬(flurbiprofen)、非諾洛芬(fenoprofen)、芬布芬(fenbufen)、酮基布洛芬(ketoprofen)、吲哚洛芬(indoprofen)、吡洛芬(pirprofen)、卡洛芬(carprofen)、奧沙普嗪(oxaprozin)、普拉洛芬(普拉洛芬)、麥布洛芬(microprofen)、硫惡洛芬(tioxaprofen)、舒洛芬(suprofen)、阿明洛芬(alminoprofen)、噻洛芬酸酸(tiaprofenic acid)、氟洛芬(fluprofen)、布氯酸(bucloxic acid)以及其混合物。
亦適用的是類固醇消炎藥,諸如氫皮質酮及其類似物,及COX-2抑制劑,諸如美洛昔康(meloxicam)、塞內昔布(celecoxib)、羅非考昔(rofecoxib)、伐地考昔(valdecoxib)、依他昔布(etoricoxib)或其混合物。可使用上述消炎劑中任一者的混合物。
可用於本發明醫藥傳遞系統中之其他材料包括通常已知之口及喉產品。此等產品包括(但不限於)上呼吸道試劑,諸如苯腎上腺素、苯海拉明、右甲嗎喃、溴己新及氯苯吡胺;胃腸試劑,諸如法莫替丁(famotidine)、洛哌丁胺(loperamide)及聚二甲矽氧烷;抗真菌劑,諸如硝酸咪康唑(miconazole nitrate)、抗生素及鎮痛劑,諸如酮基布洛芬及氟里洛芬(fluribuprofen)。
至少一種醫藥活性劑或其醫藥非活性前驅物亦可選自維生素E,即生育酚;維生素C,即抗壞血酸及其鹽、焦亞硫酸鈉、丁基羥基甲苯、丁基化羥基甲氧苯;以及防腐劑,包括尼泊金(paraben)、苯紮氯銨、氯丁醇、苯甲醇、β-苯基乙基醇、氯化十六烷基吡啶、檸檬酸、酒石酸、乳酸、蘋果酸、乙酸、苯甲酸及山梨酸及其鹽;以及螯合劑,諸如EDTA;以及沒食子酸酯,諸如沒食子酸丙酯。
至少一種醫藥活性劑或其醫藥非活性前驅物亦可選自維生素,諸如維生素B、C及E;礦物,諸如氟化物,尤其氟化鈉、單氟磷酸鈉及氟化亞錫;防氣味劑,諸如鋅及環糊精;推進劑,諸如1,1,2,2-四氟乙烷(HFC-134a)、視情況經液化,及1,1,1,2,3,3,3-七氟丙烷(HFC-227),視情況經液化。
至少一種醫藥活性劑或其醫藥非活性前驅物亦可選自麻黃素(ephedrine)、氫氧化鎂鋁(magaldrate)、假麻黃素、西地那非(sildenafil)、利多卡因(xylocaine)、氯化苯甲烷銨(benzalconium chloride)、咖啡鹼(caffeine)、苯腎上腺素(phenylephrine)安非潑拉酮(amfepramone)、羅氏鮮(orlistat)、諾美婷(sibutramine)、乙醯胺苯酚(acetaminophen)、阿司匹林(aspirin)、胺基乙酸鋁、胺基乙酸鋁以及氧化鎂、水合氧化鋁以及氧化鎂、碳酸鈣以及氫氧化鎂、碳酸鈣、二羥基碳酸鋁鈉、氧化鎂、格列酮(glitazone)、二甲雙胍(metformin)、氯丙嗪(chlorpromazine)、茶苯海明(dimenhydrinat)、多潘立酮(domperidone)、美克洛嗪(meclozine)、甲氧氯普胺(metoclopramide)、昂丹司瓊(odansetron)、潑尼龍(prednisolone)、普魯米近(promethazine)、阿伐斯丁(acrivastine)、西替利嗪(cetirizine)、辛
那伶(cinnarizine)、氯馬斯汀(clemastine)、賽克利嗪(cyclizine)、地氯雷他定(desloratadine)、右氯菲安明(dexchlorpheniramine)、茶苯海明(dimenhydrinate)、依巴司汀(ebastine)、菲索芬那定(fexofenadine)、布洛芬、類沃普瑞新(levolevoproricin)、洛拉他定(loratadine)、美克洛嗪(meclozine)、咪唑司汀(mizolastine)、普魯米近(promethazine)、咪康唑(miconazole)、維生素B12、葉酸、鐵化合物、維生素C、二乙酸氯己定、氟、十肽KSL、氟化鋁、胺基螯合鈣、氟化銨、氟矽酸銨、單氟磷酸銨、氟化鈣、葡糖酸鈣、甘油磷酸鈣、乳酸鈣、單氟磷酸鈣、碳酸鈣、碳醯胺、氯化鯨蠟基吡啶鎓、氯己定、二葡糖酸氯己定、氯化氯己定、二乙酸氯己定、CPP酪蛋白磷酸基肽、海克特汀(hexetedine)、氟化十八烯銨、氟矽酸鉀、氯化鉀、單氟磷酸鉀、碳酸氫鈉、碳酸鈉、氟化鈉、氟矽酸鈉、單氟磷酸鈉、三聚磷酸鈉、氟化亞錫、二氫氟化硬脂基三羥乙基丙二胺、氯化鍶、焦磷酸四鉀、、焦磷酸四鈉、正磷酸三鉀、正磷酸鹽三鈉、海藻酸、氫氧化鋁、碳酸氫鈉、西地那非(sildenafil)、他達拉非(tadalafil)、伐地那非(vardenafil)、育亨賓(yohimbine)、西咪替丁(cimetidine)、尼沙替丁(nizatidine)、雷尼替丁(ranitidine)、乙醯基水楊酸(acetylsalicylic acid)、克羅匹多(clopidogrel)、乙醯半胱胺酸(acetylcysteine)、溴己新(bromhexine)、可待因(codeine)、右甲嗎喃(dextromethorphan)、苯海拉明(diphenhydramine)、諾斯卡品(noscapine)、苯丙醇胺(phenylpropanolamine)、維生素D(vitamin D)、辛伐他汀(simvastatin)、吡沙可啶(bisacodyl)、乳糖醇(lactitol)、乳酮糖(lactulose)、氧化鎂(magnesium oxide)、苉可硫酸鈉(sodium picosulfate)、番瀉苷(senna glycoside)、苯佐卡因(benzocaine)、利多卡因(lidocaine)、
四卡因(tetracaine)、阿莫曲普坦(almotriptan)、依來曲普坦(eletriptan)、那拉曲普坦(naratriptan)、利紮曲普坦(rizatriptan)、舒馬曲普坦(sumatriptan)、佐米曲普坦(zolmitriptan)、鈣、鉻、銅、碘、鐵、鎂、錳、鉬、磷光體、硒、鋅、氯胺、過氧化氫、甲硝噠唑、曲安奈德(triamcinolonacetonide)、氯化苯乙銨、氯化乙醯基吡啶、氯己定、氟、利多卡因(lidocaine)、兩性黴素(amphotericin)、咪康唑(miconazole)、製黴素(nystatin)、魚油、銀杏(ginkgo biloba)、人參、薑、紫松果菊、鋸棕櫚、西替利嗪(cetirizine)、左旋西替利嗪(levocetirizine)、洛拉他定(loratadine)、雙氯芬酸(diclofenac)、氟比洛芬(flurbiprofen)、阿伐斯丁假麻黃素(acrivastine pseudoephedrine)、洛拉他定假麻黃素(loratadine pseudoephedrine)、葡糖胺(glucosamine)、玻尿酸(hyaluronic acid)、十肽KSL-W、十肽KSL、白藜蘆醇(resveratrol)、迷索前列醇(misoprostol)、安非他酮(bupropion)鹽酸昂丹司瓊(ondansetron HCl)、埃索美拉唑(esomeprazole)、蘭索拉唑(lansoprazole)、奧美拉唑(omeprazole)、泮托拉唑(pantoprazole)、雷貝拉唑(rabeprazole)、細菌及其類似物、洛哌丁胺(loperamide)、聚二甲矽氧烷(simethicone)、乙醯水楊酸及其他、硫糖鋁(sucralfate)、維生素A、維生素B1、維生素B12、維生素B2、維生素B6、生物素、維生素C、維生素D、維生素E、醛葉酸、維生素K、菸酸、Q10、克黴唑(clotrimazole)、氟康唑(fluconazole)、伊曲康唑(itraconazole)、酮康唑(ketoconazole)、特比萘芬(terbinafine)、安樂普利諾(allopurinol)、丙磺舒(probenecid)、阿托伐他汀(atorvastatin)、氟伐他汀(fluvastatin)、洛伐他汀(lovastatin)、菸鹼酸(nicotinic acid)、普伐他汀(pravastatin)、羅素他汀(rosuvastatin)、辛伐他汀(simvastatin)、匹魯卡
品(pilocarpine)、萘普生(naproxen)、阿侖膦酸鹽(alendronate)、依替膦酸鹽(etidronate)、雷諾昔酚(raloxifene)、利塞膦酸鹽(risedronate)、苯并二氮呯(benzodiazepine)、二硫龍(disulfiram)、納曲酮(naltrexone)、丁基原啡因(buprenorphine)、可待因(codeine)、右旋丙氧吩(dextropropoxyphene)、芬太尼(fentanyl)、氫嗎啡酮(hydromorphone)、凱托米酮(ketobemidone)、酮基布洛芬(ketoprofen)、美沙酮(methadone)、嗎啡鹼(morphine)、萘普生(naproxen)、尼可嗎啡(nicomorphine)、羥考酮(oxycodone)、哌替啶(pethidine)、曲馬多(tramadol)、阿莫西林(amoxicillin)、安比西林(ampicillin)、阿奇黴素(azithromycin)、環丙沙星(ciprofloxacin)、克拉黴素(clarithromycin)、脫氧土黴素(doxycyclin)、紅黴素(erythromycin)、夫西地酸(fusidic acid)、賴甲環素(lymecycline)、甲硝噠唑(metronidazole)、莫西沙星(moxifloxacin)、氧氟沙星(ofloxacin)、土黴素(oxytetracycline)、苯氧基甲基盤尼西林、利福黴素(rifamycin)、羅紅黴素(roxithromycin)、磺胺甲二唑(sulfamethizole)、四環素(tetracycline)、甲氧苄啶(trimethoprim)、萬古黴素(vancomycin)、阿卡波糖(acarbose)、格列本脲(glibenclamide)、格列齊特(gliclazide)、格列美脲(glimepiride)、格列吡嗪(glipizide)、胰島素(insulin)、瑞格列奈(repaglinide)、甲苯磺丁尿(tolbutamide)、奧司他韋(oseltamivir)、阿昔洛韋(aciclovir)、泛昔洛韋(famciclovir)、噴昔洛韋(penciclovir)、纈更昔洛韋(valganciclovir)、胺氯地平(amlopidine)、地爾硫卓(diltiazem)、非洛地平(felodipine)、硝苯地平(nifedipine)、維拉帕米(verapamil)、非那雄安(finasteride)、敏樂定(minoxidil)、可卡因(cocaine)、丁丙諾啡(buphrenorphin)、可樂定(clonidine)、美沙酮(methadone)、納曲
酮(naltrexone)、鈣拮抗劑、可樂定(clonidine)、麥角胺(ergotamine)、β阻斷劑、醋氯芬酸(aceclofenac)、塞內昔布(celecoxib)、地昔普芬(dexiprofen)、依託度酸(etodolac)、吲哚美辛(indometacin)、酮基布洛芬、酮咯酸(ketorolac)、氯諾昔康(lornoxicam)、美洛昔康(meloxicam)、萘丁美酮(nabumetone)、奧羅昔康(oiroxicam)、帕瑞昔布(parecoxib)、苯基丁氮酮(phenylbutazone)、吡羅昔康(piroxicam)、噻洛芬酸(tiaprofenic acid)、托芬那酸(tolfenamic acid)、阿立哌唑(aripiprazole)、氯丙嗪(chlorpromazine)、氯丙硫葸(chlorprothixene)、氯氮平(clozapine)、氟哌噻噸(flupentixol)、氟非那嗪(fluphenazine)、氟哌啶醇(haloperidol)、碳酸鋰、檸檬酸鋰、美哌隆(melperone)、五氟利多(penfluridol)、哌氰嗪(periciazine)、奮乃靜(perphenazine)、哌迷清(pimozide)、匹泮哌隆(pipamperone)、丙氯拉嗪(prochlorperazine)、利培酮(risperidone)、硫醚嗪(thioridizin)、氟康唑(fluconazole)、伊曲康唑(itraconazole)、酮康唑(ketoconazole)、伏立康唑(voriconazole)、鴉片、苯并二氮呯(benzodiazepine)、氫氧化物、安寧(meprobamate)、啡噻嗪(phenothiazine)、胺基乙酸鋁、埃索美拉唑(esomeprazole)、法莫替丁(famotidine)、氧化鎂、尼紮替的(nizatide)、奧美拉唑(omeprazole)、泮托拉唑(pantoprazole)、氟康唑(fluconazole)、伊曲康唑(itraconazole)、酮康唑(ketoconazole)、甲硝噠唑(metronidazole)、安非他明(amphetamine)、阿替洛爾(atenolol)、反丁烯二酸比索洛爾(bisoprolol fumarate)、美托洛爾(metoprolol)、美曲普洛(metropolol)、品多洛爾(pindolol)、普萘洛爾(propranolol)、金諾芬(auranofin)及苄達酸(bendazac)。
至少一種適用醫藥活性劑或其醫藥非活性前驅物的其他實例包括選自包含以下之治療群組的活性成分:鎮痛劑、麻醉劑、退熱劑、抗過敏劑、抗心律不齊劑、食慾抑制劑、抗真菌劑、消炎劑、支氣管擴張劑、心血管藥物、冠狀動脈擴張劑、大腦擴張劑、周邊血管舒張劑、抗感染劑、精神藥物、抗躁狂劑、刺激劑、抗組胺劑、輕瀉劑、減充血劑、胃腸鎮靜劑、性功能障礙劑、消毒劑、抗腹瀉劑、抗心絞痛物質、血管舒張劑、抗高血壓劑、血管收縮劑、偏頭痛治療劑、抗生素、安定劑、抗精神病劑、抗腫瘤藥物、抗凝血劑、抗血栓劑、催眠劑、鎮靜劑、止吐劑、抗噁心劑、抗驚厥劑、神經肌肉劑、高血糖劑及低血糖劑、甲狀腺劑及抗甲狀腺劑、利尿劑、鎮痙劑、子宮弛緩劑、抗肥胖劑、減食慾劑、解痙劑、合成代謝劑、紅血球生成劑、抗哮喘劑、除痰劑、咳嗽抑制劑、黏液溶解劑、抗尿毒症劑、牙齒媒劑、、呼吸清新劑、抗酸藥、抗利尿劑、抗脹氣劑、β阻斷劑、牙齒增白劑、酶、輔酶、蛋白質、能量增強劑、纖維、益生菌、益生元、抗微生物劑、NSAID、鎮咳劑、解充血劑、抗組胺、祛痰劑、止瀉劑、氫拮抗劑、質子泵抑制劑、通用非選擇性CNS抑鬱劑、通用非選擇性CNS刺激劑、選擇性CNS功能改良藥物、抗帕金森病劑、麻醉性鎮痛藥、止痛性退熱劑、心理藥理學藥物及性功能障礙劑。
至少一種適用醫藥活性劑或其醫藥非活性前驅物的實例亦可包括:酪蛋白糖基巨肽(CGMP)、三氯生(Triclosan)、氯化鯨蠟基吡錠、溴化度米芬(Domiphen bromide)、四級銨鹽、鋅組分、血根鹼、氟化物、阿來西定(Alexidine)、歐克尼定(Octonidine)、EDTA、阿司匹林、乙醯胺苯酚、布洛芬、酮基布洛芬、二氟尼柳、非諾洛芬鈣、萘普生、托美丁鈉、
吲哚美辛、苯佐那酯(Benzonatate)、乙二磺酸卡拉美芬(Caramiphen edisylate)、薄荷醇、右甲嗎喃、氫溴酸鹽、鹽酸可可豆鹼、鹽酸氯苯達諾(Chlophendianol Hydrochloride)、鹽酸假麻黃素、苯腎上腺素(Phenylephrine)、苯丙醇胺、硫酸假麻黃素、順丁烯二酸溴非尼臘明(Brompheniramine maleate)、順丁烯二酸氯芬尼拉明(Chlorpheniramine maleate)、順丁烯二酸卡比沙明(Carbinoxamine maleate)、反丁烯二酸氯馬斯汀(Clemastine fumarate)、順丁烯二酸右氯菲安明(Dexchlorpheniramine maleate)、鹽酸苯海拉明(Dephenhydramine hydrochloride)、鹽酸二苯胺、順丁烯二酸阿紮他啶(Azatadine maleate)、檸檬酸苯海拉明(Diphenhydramine citrate)、丁二酸苯吡拉明(Doxylamine succinate)、鹽酸普魯米近(Promethazine hydrochloride)、順丁烯二酸吡拉明(Pyrilamine maleate)、檸檬酸三培拉明(Tripellenamine citrate)、鹽酸曲普利啶(Triprolidine hydrochloride)、阿伐斯丁(Acrivastine)、洛拉他定(Loratadine)、溴苯那敏(Brompheniramine)、德溴非明(Dexbrompheniamine)、愈創甘油醚(Guaifenesin)、吐根(Ipecac)、碘化鉀(potassium iodide)、水合萜二醇(Terpin hydrate)、洛哌丁胺(Loperamide)、法莫替丁(Famotidine)、雷尼替丁(Ranitidine)、奧美拉唑(Omeprazole)、蘭索拉唑(Lansoprazole)、脂族醇(Aliphatic alcohol)、巴比妥酸鹽(Barbiturate)、咖啡鹼(caffeine)、番木鼈鹼(strychnine)、苦味毒(Picrotoxin)、戊四氮、苯基乙內醯脲、苯巴比妥(Phenobarbital)、普里米酮(Primidone)、卡馬西平(Carbamazapine)、乙琥胺、甲琥胺、米浪丁(Phensuximide)、三甲雙酮(Trimethadione)、安定(Diazepam)、苯并二氮呯(Benzodiazepine)、苯乙醯脲、苯丁醯脲、乙醯唑胺、蘇太明(Sulthiame)、
溴化物、左旋多巴(Levodopa)、金剛胺(Amantadine)、嗎啡鹼(Morphine)、海洛因(Heroin)、氫嗎啡酮(Hydromorphone)、美托酮(Metopon)、羥嗎啡酮(Oxymorphone)、羥甲左嗎喃(Levophanol)、可待因(Codeine)、氫可酮(Hydrocodone)、羥考酮(Xycodone)、納洛芬(Nalorphine)、納洛酮(Naloxone)、納曲酮(Naltrexone)、水楊酸酯(Salicylate)、苯基丁氮酮(Phenylbutazone)、吲哚美辛(Indomethacin)、非那西汀(Phenacetin)、氯丙嗪(Chlorpromazine)、左美丙嗪(Methotrimeprazine)、氟哌啶醇(Haloperidol)、氯氮平(Clozapine)、蛇根素鹼(Reserpine)、丙咪嗪(Imipramine)、反苯環丙胺(Tranylcypromine)、苯乙肼(Phenelzine)、鋰、檸檬酸西地那非(ildenafil citrate)、他達拉非(Tadalafil)及伐地那非CL(Vardenafil CL)。
至少一種適用醫藥活性劑或其醫藥非活性前驅物的實例可包括選自以下之群的活性成分:ace抑制劑、抗心絞痛藥物、抗心律不齊劑、抗哮喘劑、鎮痛劑、麻醉劑、抗驚厥劑、抗抑鬱劑、抗糖尿病劑、抗腹瀉製劑、解毒劑、抗組胺、抗高血壓藥物、消炎劑、抗脂質劑、抗躁劑、止噁心藥、抗中風劑、抗甲狀腺製劑、抗腫瘤藥物、抗病毒劑、痤瘡藥物、生物鹼、胺基酸製劑、鎮咳劑、抗尿毒症劑、抗病毒藥物、合成代謝製劑、全身及非全身抗感染劑、抗腫瘤藥、抗帕金森病劑、抗風濕病劑、食慾刺激劑、生物學反應改性劑、血液改性劑、骨骼代謝調節劑、心血管劑、中樞神經系統刺激劑、膽鹼酯酶抑制劑、避孕藥、解充血劑、膳食補充劑、多巴胺受體促效劑、子宮內膜異位處理劑、酶、勃起功能障礙療法(諸如檸檬酸西地那非(sildenafil citrate,其目前作為ViagraTM出售)、生育劑、胃腸劑、順勢療法治療物、激素、高鈣血症處理劑及低鈣血症處理劑、免疫
調節劑、免疫抑制劑、偏頭痛製劑、動暈症處理劑、肌肉鬆弛劑、肥胖症處理劑、骨質疏鬆製劑、催產劑、副交感神經阻斷藥、擬副交感神經藥、前列腺素、心理治療劑、呼吸道劑、鎮靜劑、戒菸助劑(諸如溴麥角環肽)、交感神經劑、顫抖製劑、泌尿道劑、血管擴張劑、輕瀉劑、解酸劑、離子交換樹脂、退燒藥、食慾抑制劑、祛痰劑、抗焦慮劑、抗潰瘍劑、消炎物質、冠狀動脈擴張劑、大腦擴張劑、周邊血管擴張劑、精神藥物、刺激劑、抗高血壓藥物、血管收縮劑、偏頭痛治療劑、抗生素、安神劑、抗精神病藥、抗腫瘤藥物、抗凝集劑、抗血栓藥物、安眠藥、抗催吐藥、抗止噁心藥、抗驚厥劑、神經肌肉藥物、高血糖劑及低血糖劑、甲狀腺及抗甲狀腺製劑、利尿劑、解痙藥、子宮鬆弛劑、抗肥胖藥物、紅血球生成藥物、抗哮喘劑、咳嗽抑制劑、黏液溶解劑、DNA及遺傳學改性藥物以及其組合。
預期用於本發明醫藥傳遞系統之至少一種適用醫藥活性劑或其醫藥非活性前驅物的實例可包括解酸劑、H2拮抗劑及鎮痛劑。舉例而言,可使用單獨或與氫氧化鎂及/或氫氧化鋁組合之成分碳酸鈣製備抗酸劑配藥。此外,解酸劑可與H2拮抗劑組合使用。
鎮痛劑包括鴉片劑及鴉片劑衍生物,諸如OxycontinTM、布洛芬、阿司匹林、乙醯胺苯酚以及其可視情況包括咖啡鹼之組合。
用於具體實例之至少一種其他適用醫藥活性劑或其醫藥非活性前驅物可包括抗腹瀉劑,諸如ImmodiumTM AD、抗組胺、鎮咳劑、解充血劑、維生素及呼吸清新劑。亦預期用於本發明的是抗焦慮劑,諸如XanaxTM;抗精神病藥,諸如ClozarilTM及HaldolTM;非類固醇消炎劑(NSAID),諸如布洛芬、萘普生鈉、VoltarenTM及LodineTM;抗組胺,諸如
ClaritinTM、HismanalTM、RelafenTM及TavistTM;止吐藥,諸如KytrilTM及CesametTM;支氣管擴張劑,諸如BentolinTM、ProventilTM;抗抑鬱劑,諸如ProzacTM、ZoloftTM及PaxilTM;抗偏頭痛藥,諸如ImigraTM;ACE抑制劑,諸如VasotecTM、CapotenTM及ZestrilTM;抗阿茲海默氏劑,諸如NicergolineTM;以及CaH拮抗劑,諸如ProcardiaTM、AdalatTM及CalanTM。
預期用於本發明之通用H2拮抗劑包括西咪替丁、鹽酸雷尼替丁、法莫替丁、尼紮替丁(nizatidien)、乙溴替丁(乙溴替丁)、咪芬替丁(mifentidine)、羅沙替丁(roxatidine)、比薩替丁(pisatidine)及乙酸羅沙替丁(aceroxatidine)。
活性抗酸藥成分可包括(但不限於)以下:氫氧化鋁、胺基乙酸二羥基鋁、胺基乙酸、磷酸鋁、碳酸二羥鋁鈉、碳酸氫鹽、鋁酸鉍、碳酸鉍、次碳酸鉍、鹼式棓酸鉍、鹼式硝酸鉍、鹼式水楊酸鉍、磷酸鈣、檸檬酸根離子(酸或鹽)、胺基乙酸、水合硫酸鎂鋁、氫氧化鎂鋁、矽酸鎂鋁、碳酸鎂、甘胺酸鎂、氫氧化鎂、氧化鎂、三矽酸鎂、乳固形物、單或二鹼式磷酸鈣鋁、磷酸三鈣、碳酸氫鉀、酒石酸鈉、碳酸氫鈉、矽酸鎂鋁、酒石酸及鹽。多種營養補充劑亦可用作至少一種醫藥活性劑或其醫藥非活性前驅物,實際上包括任何維生素或礦物。舉例而言,可使用維生素A、維生素C、維生素D、維生素E、維生素K、維生素B6、維生素B12、硫胺素、核黃素、生物素、葉酸、菸酸、泛酸、鈉、鉀、鈣、鎂、磷、硫、氯、鐵、銅、碘、鋅、硒錳、膽鹼、鉻、鉬、氟、鈷以及其組合。可用作活性成分之營養補充劑之實例闡述於美國專利申請公開案第2003/0157213 A1號、第2003/0206993號及第2003/0099741 A1號,其出於所有目的以全文引
用的方式併入本文中。多種草本植物亦可用作至少一種醫藥活性劑或其醫藥非活性前驅物,諸如具有多種醫藥或膳食補充物特性的草本植物。草本植物通常為可用於醫藥學或用於調味之芳族植物或植物部分及或其提取物。適合草本植物可單獨使用或用於多種混合物中。常用草本植物包括紫錐花、白毛茛、金盞草、迷迭香、瑞香草、卡瓦胡椒(Kava Kava)、蘆薈、血根草、葡萄柚籽提取物、黑升麻、人參、瓜拉那(Guarana)、蔓越莓(Cranberry)、銀杏、聖約翰草(St.John's Wort)、月見草油、育亨賓樹皮、綠茶、麻黃(Ma Huang)、瑪咖(Maca)、覆盆子、葉黃素以及其組合。
在一些具體實例中,礦物可包括(但不限於)鈉、鎂、鉻、碘、鐵、錳、銅、氟、鉀、磷、鉬、硒、鋅以及其組合。
在一些具體實例中,至少一種醫藥活性劑或其醫藥非活性前驅物可包括(但不限於)L-肉鹼、膽鹼、輔酶Q10、α-硫辛酸、Ω-3-脂肪酸、胃蛋白酶、植酸酶、胰蛋白酶、脂肪酶、蛋白酶、纖維素酶以及其組合。
至少一種醫藥活性劑或其醫藥非活性前驅物亦可包括抗壞血酸、檸檬酸、迷迭香油、維生素A、維生素E、磷酸維生素E、生育酚、磷酸二-α-生育酚、生育三烯酚、α硫辛酸、二氫硫辛酸、葉黃素、β隱黃素、番茄紅素、葉黃素、玉米黃素、蝦青素、β-胡蘿蔔素、胡蘿蔔素、混合類胡蘿蔔素、多酚、類黃酮以及其組合。
在一些具體實例中,至少一種醫藥活性劑或其醫藥非活性前驅物可選自植物化學成分,諸如類胡蘿蔔素、葉綠素、葉綠酸、纖維、類黃酮、花青素苷、氰化物、花翠素、錦葵色素、天竺葵色素、芍藥色素、
牽牛花素、黃烷醇、兒茶素、表兒茶素、表沒食子兒茶素、沒食子兒茶素沒食子酸酯、茶黃素、茶玉紅精、原花青素、黃酮醇、槲皮素、堪非醇、楊梅素、異鼠李素、黃酮苷、柚配質、聖草酚、橘皮、黃酮、芹黃素、葉黃酮、木酚素、植物雌激素、白藜蘆醇、異黃酮、大豆黃素、染料木素、黃豆黃素、大豆異黃酮以及其組合。
在一些具體實例中,至少一種醫藥活性劑或其醫藥非活性前驅物可選自鎮痛劑/麻醉劑,諸如薄荷醇、酚類、己基間苯二酚、苯佐卡因、鹽酸達克羅寧、苯甲醇、鄰羥苄醇以及其組合。在一些具體實例中,至少一種醫藥活性劑或其醫藥非活性前驅物可選自緩和劑,諸如赤榆皮(slippery elm bark)、果膠、明膠以及其組合。在一些具體實例中,至少一種醫藥活性劑或其醫藥非活性前驅物可選自防腐劑成分,諸如氯化十六烷基吡啶、溴化度米芬、氯化地喹銨以及其組合。
在一些具體實例中,至少一種醫藥活性劑或其醫藥非活性前驅物可選自止咳成分,諸如鹽酸氯苯達諾、可待因、磷酸可待因、硫酸可待因、右甲嗎喃、氫溴酸右甲嗎喃、檸檬酸苯海拉明及鹽酸苯海拉明及其組合。
在一些具體實例中,可包括可選自喉舒緩劑之至少一種醫藥活性劑或其醫藥非活性前驅物,諸如蜂蜜、蜂膠、真蘆薈、丙三醇、薄荷醇以及其組合。在其他具體實例中,至少一種醫藥活性劑或其醫藥非活性前驅物可選自咳嗽抑制劑。此類咳嗽抑制劑可分成兩組:改變痰之紋理或產量的抑制劑,諸如黏液溶解劑及祛痰劑;以及抑制咳嗽反射之抑制劑,諸如可待因(麻醉性咳嗽抑制劑)、抗組胺、右甲嗎喃及異丙腎上腺素(非
麻醉性咳嗽抑制劑)。在一些具體實例中,可包括來自任一組或兩組之成分。
在其他具體實例中,至少一種醫藥活性劑或其醫藥非活性前驅物可為選自包含以下之群的止咳劑:可待因、右甲嗎喃、右羥嗎喃、苯海拉明、氫可酮、諾斯卡品、羥考酮、噴托維林以及其組合。在一些具體實例中,至少一種醫藥活性劑或其醫藥非活性前驅物可選自抗組胺,諸如阿伐斯丁、阿紮他啶、溴苯那敏、氯[φ]非尼拉敏、氯馬斯汀、塞庚啶、右溴苯那敏、茶苯海明、苯海拉明、苯吡拉明、安泰樂、美克利嗪、苯茚胺、苯托沙敏、普魯米近、比拉明、曲吡那明、曲普利啶以及其組合。在一些具體實例中,至少一種醫藥活性劑或其醫藥非活性前驅物可選自非鎮靜抗組胺,諸如阿司咪唑、西替利嗪、依巴司汀、菲索芬那定、氯雷他定、特非那定以及其組合。
在一些具體實例中,至少一種醫藥活性劑或其醫藥非活性前驅物可選自祛痰劑,如氯化銨、愈創甘油醚、吐根流浸提取物、碘化鉀以及其組合。在一些具體實例中,至少一種醫藥活性劑或其醫藥非活性前驅物可選自黏液溶解劑,諸如乙醯基半胱胺酸、胺溴素、溴己新以及其組合。在一些具體實例中,至少一種醫藥活性劑或其醫藥非活性前驅物可選自鎮痛劑、退熱劑及消炎劑,諸如乙醯胺苯酚、阿司匹林、雙氯芬酸、二氟尼柳、依託度酸、非諾洛芬、氟比洛芬、布洛芬、酮基布洛芬、酮咯酸、萘丁美酮、萘普生、吡羅昔康、咖啡鹼以及其混合物。在一些具體實例中,至少一種醫藥活性劑或其醫藥非活性前驅物可選自局部麻醉劑,諸如利多卡因、苯佐卡因、酚類、達克羅寧、苯佐那酯以及其混合物。在一些具體實例中,至少一種醫藥活性劑或其醫藥非活性前驅物可選自鼻解充血劑及
提供鼻部清理感覺之成分。在一些具體實例中,諸如鼻解充血劑可包括(但不限於)苯丙醇胺、假麻黃素、麻黃素、苯腎上腺素、羥甲唑啉以及其組合。在一些具體實例中,至少一種醫藥活性劑或其醫藥非活性前驅物可選自提供鼻部清理感覺之成分,諸如薄荷醇、樟腦、冰片、麻黃素、桉油、薄荷油、水楊酸甲酯、乙酸冰片酯、淡紫色油狀物、芥末提取物、辣根提取物以及其組合。在一些具體實例中,鼻部清理感覺可藉由以下提供:有氣味之精油、木材提取物、膠狀物、花及其他植物性藥材、樹脂、動物分泌物及合成芳族材料。
舉例而言,至少一種醫藥活性劑或其醫藥非活性前驅物為撲熱息痛。
應瞭解,醫藥傳遞系統可進一步包含通常用於此類系統之添加劑,諸如著色劑、調味劑、崩解劑,諸如交聯羧甲纖維素鈉、交聯聚維酮或羥基乙酸澱粉鈉、煅製二氧化矽(諸如德國Evonik Industries AG之Aerosil®,例如Aerosil® 200)等。
根據本發明方法之步驟c),提供至少一種調配助劑。
表述「至少一種」調配助劑意謂方法步驟c)中可提供一或多種調配助劑。
根據本發明之一個具體實例,方法步驟c)中僅提供一種調配助劑。根據本發明的另一個具體實例,方法步驟c)中提供兩種或兩種以上調配助劑之混合物。舉例而言,方法步驟c)中提供兩種或三種調配助劑之混合物。
較佳地,方法步驟c)中僅提供一種調配助劑。
在一個具體實例中,至少一種調配助劑為至少一種相內潤滑劑及/或相外潤滑劑。舉例而言,該至少一種調配助劑為至少一種相內潤滑劑或相外潤滑劑,較佳至少一種相內潤滑劑。或者,至少一種調配助劑為至少一種相內潤滑劑及相外潤滑劑。
該至少一種相內潤滑劑可選自包含以下之群:脂肪酸之脫水山梨糖醇酯及聚氧乙基化氫化蓖麻油(例如以商標名CREMOPHOR®出售之產品)、環氧乙烷及環氧丙烷之嵌段共聚物(例如以商標名PLURONIC®及POLOXAMER出售之產品)、聚氧乙烯脂肪醇醚、聚氧乙烯脫水山梨糖醇脂肪酸酯、脂肪酸之脫水山梨糖醇酯及聚氧乙烯硬脂酸酯、硬脂醇、二山崳酸甘油酯、硬脂醯反丁烯二酸鈉、丙三醇二硬脂酸酯以及其組合。較佳地,該至少一種相內潤滑劑為硬脂醯反丁烯二酸鈉。
該至少一種相外潤滑劑可選自包含以下之群:卵磷脂、聚氧乙烯硬脂酸酯、聚氧乙烯脫水山梨糖醇脂肪酸酯、脂肪酸鹽、可食脂肪酸之單甘油酯及二甘油酯的單乙醯基及二乙醯基酒石酸酯、可食脂肪酸之單甘油酯及二甘油酯的檸檬酸酯、脂肪酸之蔗糖酯、脂肪酸之聚甘油酯、互酯化蓖麻油酸之聚甘油酯(E476)、硬脂醯乳酸鈉、硬脂酸鎂及/或硬脂酸鈣、氫化植物油、硬脂酸、月桂基硫酸鈉、月桂基硫酸鎂、膠態二氧化矽、滑石以及其組合。較佳地,該至少一種相外潤滑劑為硬脂酸鎂及/或硬脂酸鈣,更佳硬脂酸鎂。
在一個具體實例中,按醫藥傳遞系統的總重量計,提供總量為約0.1wt.%至約10.0wt.%,較佳約0.3wt.%至約5.0wt%,更佳約0.5wt.%至約2.5wt.%的至少一種調配助劑。
根據本發明方法之步驟d),混合步驟a)之表面反應碳酸鈣、步驟b)之至少一種醫藥活性劑或醫藥非活性前驅物以及步驟c)之至少一種調配助劑。
可同時或以任何順讀各別地混合步驟a)之表面反應碳酸鈣與步驟b)之至少一種醫藥活性劑或其醫藥非活性前驅物以及步驟c)之至少一種調配助劑形成混合物。
在本發明之一個具體實例中,進行方法步驟d),其中步驟a)之表面反應碳酸鈣與步驟b)之至少一種醫藥活性劑或其醫藥非活性前驅物及步驟c)之至少一種調配助劑同時組合。舉例而言,進行方法步驟d),其中步驟a)之表面反應碳酸鈣與由步驟b)之至少一種醫藥活性劑或醫藥非活性前驅物及步驟c)之至少一種調配助劑組成的摻合物組合。亦即,可在添加至步驟a)之該表面反應碳酸鈣之前,預混步驟b)之該至少一種醫藥活性劑或其醫藥非活性前驅物與步驟c)之至少一種調配助劑。
較佳地,進行混合步驟d),其中步驟b)之至少一種醫藥活性劑或其醫藥非活性前驅物與步驟c)之至少一種調配助劑彼此獨立地添加至步驟a)之表面反應碳酸鈣中。
出於本發明之目的,可使用此項技術中已知的任何適合混合方式。然而,混合步驟d)較佳在混合器及/或摻合器,較佳諸如滾動混合器之混合器中進行。
較佳地,方法步驟d)中獲得之混合物不含聚結物。因此,在進行方法步驟e)之前,較佳例如經1000μm之篩子篩分方法步驟d)中獲得之混合物。
根據本發明方法之步驟e),藉助於滾筒壓實機,在4至20巴範圍內之壓實壓力下壓實步驟d)中獲得之混合物。
術語「滾筒壓實」係指迫使精細粉末進入兩個抗衡旋轉滾筒之間且壓成固體壓塊或帶狀物之方法。
出於本發明之目的,可使用技術人員已知之任何適合滾筒壓實機進行滾筒壓實。舉例而言,使用美國Fitzpatrick公司之Fitzpatrick® Chilsonator IR220滾筒壓實機進行滾筒壓實。
本發明方法之一個要求為在4至20巴範圍內之壓實壓力下進行方法步驟e)。較佳地,在4至15巴範圍內,更佳在4至10巴範圍內,且最佳在4至7巴範圍內之滾筒壓實壓力下進行滾筒壓實步驟e)。
另外或替代地,調整滾筒壓實步驟e)期間之饋入速率及/或滾軋速度使得獲得0.4至0.8mm,較佳0.5至0.7mm且最佳約0.6mm之帶狀物厚度。舉例而言,調整滾筒壓實步驟e)期間之饋入速率或滾軋速度使得獲得0.4至0.8mm,較佳0.5至0.7mm且最佳約0.6mm之帶狀物厚度。或者,調整滾筒壓實步驟e)期間之饋入速率及滾軋速度使得獲得0.4至0.8mm,較佳0.5至0.7mm且最佳約0.6mm之帶狀物厚度。
根據本發明方法之步驟f),壓實步驟e)中獲得之滾筒壓實混合物獲得醫藥傳遞系統。
可使用技術人員已知的任何習知壓實機進行壓實。舉例而言,使用製錠機(諸如來自法國Medel'Pharm之Styl'One 105ml製錠機)進行壓實。
較佳地,壓實步驟f)為粒化或製錠步驟。
術語「粒化」在本發明之含義中係指將材料壓實或成型為糰粒形狀之方法。術語「製錠」在本發明之含義中係指將材料壓實或成型為錠劑形狀之方法。
方法步驟f)較佳在5至500MPa範圍內之壓製壓力下進行。應注意,步驟f)中所用之壓製壓力視步驟b)中所提供之具體至少一種醫藥活性劑或其醫藥非活性前驅物而定。技術人員因此將相應地調適壓製壓力。較佳地,在6至400MPa範圍內,且最佳10至400MPa範圍內之壓製壓力下進行壓實步驟f)。舉例而言,在50至300MPa範圍內,且最佳50至200MPa或100至200MPa範圍內之壓製壓力下進行壓實步驟f)。
在一個具體實例中,在進行壓實步驟f)之前,對滾筒壓實步驟e)中獲得之滾筒壓實混合物進行研磨步驟。
可使用技術人員已知之任何習知研磨機進行研磨。舉例而言,使用來自美國Fitzpatrick公司之FitzMill®進行研磨。
另外或替代地,在進行壓實步驟f)之前,對滾筒壓實步驟e)中獲得之滾筒壓實混合物進行篩分步驟。
在進行壓實步驟f)之前,若該方法包含研磨及篩分滾筒壓實步驟e)中獲得之混合物,則該混合物較佳首先進行研磨步驟,隨後進行篩分步驟。亦即,藉由篩分獲得之材料進行壓實步驟f)。
可使用技術人員已知之任何習知篩分方式進行篩分。舉例而言,使用瑞士Vibro Retsch之振動篩板塔進行篩分。
為了接收穩定醫藥傳遞系統,進行壓實步驟f)之滾筒壓實混合物較佳具有特殊穩定性。該穩定性較佳在穩定性測試中確定。
進行壓實步驟f)之滾筒壓實混合物之穩定性較佳由滾筒壓實混合物的剩餘部分決定。較佳地,進行壓實步驟f)之滾筒壓實混合物在500μm篩孔尺寸之篩上篩分滾筒壓實混合物後具有至少60wt%剩餘部分,剩餘比率藉由式(III)計算
其中m tot為最初施加於篩上之總質量(g)且m res為震盪10分鐘後篩上之殘餘量(g)。
在本發明之一個具體實例中,若進行壓實步驟f)之滾筒壓實混合物具有特殊晶粒尺寸分佈,則獲得有利醫藥傳遞系統。因此,進行壓實步驟f)之滾筒壓實混合物較佳具有藉由在不同篩孔尺寸上篩分獲得的180至710μm之晶粒尺寸,較佳使用約180μm、250μm、355μm、500μm以及710μm之篩孔尺寸篩分。更佳地,藉由使用約180μm、250μm、355μm、500μm及710μm之篩孔尺寸篩分及合併經篩分之滾筒壓實混合物,使得小於180μm及超過710μm之晶粒尺寸排除在外。
因此,用於製造醫藥傳遞系統之方法較佳包含如上文所述在具有500μm篩孔尺寸之篩上篩分滾筒壓實混合物之後具有至少60%剩餘部分的穩定滾筒壓實混合物進行研磨及篩分使得所獲得之滾筒壓實混合物具有藉由在不同篩孔尺寸上篩分獲得180至710μm之晶粒尺寸。在此情形下,在進行壓實步驟f)之前,步驟e)中獲得之滾筒壓實混合物較佳首先如上文所述進行穩定性測試,隨後研磨及篩分穩定滾筒壓實混合物使得滾筒壓實混合物具有藉由在不同篩孔尺寸上篩分獲得180至710μm之晶粒尺寸。
亦即,藉由篩分獲得之材料使得具有藉由在不同篩孔尺寸上篩分獲得的180至710μm之晶粒尺寸的滾筒壓實混合物進行壓實步驟f)。
所得醫藥傳遞系統為錠劑、微錠劑、膠囊或糰粒。
因此可製備廣泛尺寸範圍之醫藥傳遞系統,其中可藉由習知方式(諸如篩分)分離不同尺寸部分。
一般而言,醫藥傳遞系統可具有0.1至20.0mm,較佳0.2至15.0mm且更佳0.3至10.0mm之重量中值粒度。
藉由本發明方法獲得之醫藥傳遞系統會具有低脆度。較佳地,在100MPa下壓製之錠劑上根據Ph.Eur.4量測,醫藥傳遞系統具有1.10%之脆度。更佳地,在100MPa下壓製之錠劑上根據Ph.Eur.4量測,醫藥傳遞系統的脆度1.0%,甚至更佳0.8%且最佳0.6%,如0.4%至0.6%。
另外或替代地,醫藥傳遞系統滿足式(I)
其中(FRRCPh)為根據Ph.Eur.4量測的醫藥傳遞系統RCPh之脆度(以%為單位),其中步驟e)中之該壓實壓力為至少15巴;(FRRCPl)為根據Ph.Eur.4量測的醫藥傳遞系統RCPl之脆度(以%為單位),其中步驟e)中之該壓實壓力低於用於獲得該醫藥傳遞系統RCPh之壓實壓力。
較佳地,醫藥傳遞系統滿足式(Ia),更佳(Ib)且最佳(Ic)
其中(FRRCPh)為根據Ph.Eur.4量測的醫藥傳遞系統RCPh之脆度(以%為單位),其中步驟e)中之該壓實壓力為至少15巴;(FRRCPl)為根據Ph.Eur.4量測的醫藥傳遞系統RCPl之脆度(以%為單位),其中步驟e)中之該壓實壓力低於用於獲得該醫藥傳遞系統RCPh之壓實壓力。
另外或替代地,藉由本發明方法獲得之醫藥傳遞系統會具有高流動性。較佳地,醫藥傳遞系統滿足式(II)
其中(FLRCP)為在7mm開口直徑下根據Ph.Eur.4量測的該醫藥傳遞系統之流動性(以g/s為單位);(FL參考)為在7mm開口直徑下根據Ph.Eur.4量測的同一醫藥傳遞系統之流動性(以g/s為單位),其中表面反應碳酸鈣由微晶纖維素代替。
較佳地,醫藥傳遞系統滿足式(IIa),更佳(IIb)且最佳(IIc)
其中(FLRCP)為在7mm開口直徑下根據Ph.Eur.4量測的該醫藥傳遞系統之流動性(以g/s為單位);
(FL參考)為在7mm開口直徑下根據Ph.Eur.4量測的同一醫藥傳遞系統之流動性(以g/s為單位),其中表面反應碳酸鈣由微晶纖維素代替。
本發明獲得之良好結果在另一態樣中係指藉由該方法獲得之醫藥傳遞系統,較佳錠劑、微錠劑、膠囊或糰粒。
另一態樣係指表面反應碳酸鈣用於提高醫藥傳遞系統之脆度的用途,其中表面反應碳酸鈣為天然研磨或沉澱碳酸鈣與二氧化碳及一或多種酸在水性介質中之反應產物,其中二氧化碳藉由酸處理原位形成及/或由外部來源供應,其中醫藥傳遞系統a)在100MPa下壓製的錠劑上根據Ph.Eur.4量測具有1.10%之脆度;及/或b)滿足式(II)
其中(FRRCPh)為根據Ph.Eur.4量測的醫藥傳遞系統RCPh之脆度(以%為單位),其中步驟e)中之該壓實壓力為至少15巴;(FRRCPl)為根據Ph.Eur.4量測的醫藥傳遞系統RCPl之脆度(以%為單位),其中步驟e)中之該壓實壓力低於用於獲得該醫藥傳遞系統RCPh之壓實壓力。
關於表面反應碳酸鈣,醫藥傳遞系統及其較佳具體實例之定義,參考上文論述本發明之表面反應碳酸鈣及醫藥傳遞系統的技術細節時提供之陳述。
在一個實施例中,在100MPa下壓製之錠劑上根據Ph.Eur.4
量測,醫藥傳遞系統的脆度1.0%,甚至更佳0.8%且最佳0.6%,如0.4至0.6%。
另外或替代地,醫藥傳遞系統滿足式(Ia),更佳(Ib)且最佳(Ic)
其中(FRRCPh)為根據Ph.Eur.4量測的醫藥傳遞系統RCPh之脆度(以%為單位),其中步驟e)中之該壓實壓力為至少15巴;(FRRCPh)為根據Ph.Eur.4量測的醫藥傳遞系統RCPl之脆度(以%為單位),其中步驟e)中之該壓實壓力低於用於獲得該醫藥傳遞系統RCPh之壓實壓力。
本發明之另一態樣係指表面反應碳酸鈣用於提高醫藥傳遞系統之流動性的用途,其中表面反應碳酸鈣為天然研磨或沉澱碳酸鈣與二氧化碳及一或多種酸在水性介質中之反應產物,其中二氧化碳藉由酸處理原位形成及/或自外部來源供應,其中醫藥傳遞系統滿足式(II)
其中(FLRCP)為在7mm開口直徑下根據Ph.Eur.4量測的醫藥傳遞系統之流動性(以g/s為單位);(FL參考)為在7mm開口直徑下根據Ph.Eur.4量測的同一醫藥傳遞系統之
流動性(以g/s為單位),其中表面反應碳酸鈣由微晶纖維素代替。
關於表面反應碳酸鈣,醫藥傳遞系統及其較佳具體實例之定義,參考上文論述本發明之表面反應碳酸鈣及醫藥傳遞系統的技術細節時提供之陳述。
在本發明之一個具體實例中,醫藥傳遞系統滿足式(IIa),更佳(IIb)且最佳(IIc)
其中(FLRCP)為在7mm開口直徑下根據Ph.Eur.4量測的醫藥傳遞系統之流動性(以g/s為單位);(FL參考)為在7mm開口直徑下根據Ph.Eur.4量測的同一醫藥傳遞系統之流動性(以g/s為單位),其中表面反應碳酸鈣由微晶纖維素代替。
以下實施例及測試將說明本發明,但並不打算以任何方式限制本發明。
材料及方法
1.1 材料
官能化碳酸鈣(FCC)(來自瑞士Omya International AG)與微晶纖維素(Avicel® PH 102,愛爾蘭FMC BioPolymer)比較。官能化碳酸鈣之其他細節概述於下表1中:
選擇撲熱息痛作為醫藥活性劑(Acetaminophen USP/Paracetamol Ph Eur Powder,Mallinckrodt,美國)。
使用硬脂醯反丁烯二酸鈉(SSF,LubriSanaq®,Pharmatrans Sanaq AG,瑞士)作為滾筒壓實期間之相內潤滑劑,而使用硬脂酸鎂(MgSt,Sandoz,瑞士)作為製錠期間之相外潤滑劑。
汞(Sigma-Aldrich,德國)作為非潤濕液體用於汞壓孔率測定法量測。
1.2 方法
1.2.1 滾筒壓實及研磨
在滾筒壓實之前,將各粉末經1000μm篩篩分破壞聚結物。賦形劑與撲熱息痛摻合獲得24.75wt%、49.50wt%、74.25wt%及99wt%之相對撲熱息痛含量。另外,製備不具有撲熱息痛之參考調配物。出於比較原因,全部調配物均含有1wt%硬脂醯反丁烯二酸鈉作為內潤滑劑。在滾動混合器(Turbula T2C,Willy A.Bachofen AG,瑞士)中,在32rpm下混合粉末10分鐘。使用Fitzpatrick® Chilsonator IR220滾筒壓實機(The Fitzpatrick公司,美國)進行粒化。壓力設為5巴或20巴。調整饋入速率及滾軋速度獲得0.6mm之帶狀物厚度。在滾筒壓實之後,使用FitzMill® L1A(The Fitzpatrick公司,美國)在500rpm下研磨帶狀物。
1.2.2 篩選
進行篩選。對於各調配物,將10g各別帶狀物置於具有500μm篩孔尺寸的篩上。藉助於振動篩板塔(Vibro Retsch,瑞士)在1.5mm振盪位移下振盪篩10分鐘。藉助於以下等式計算剩餘部分(RF):
其中m tot為最初施加於篩上之總質量(g)且m res為震盪10分鐘後篩上之殘餘量(g)。
剩餘部分超過60%之調配物視為對製錠方法而言足夠穩定。
1.2.3 顆粒分析
為了測定使用滾筒壓實方法獲得之精細部分,收集滾筒壓實方法之產物(包括細粒之帶狀物),稱量(m tot)且經具有180μm篩孔尺寸的篩篩分。進行篩分,其中將獲自滾筒壓實方法之相應產物置於具有180μm篩孔尺寸的篩上。藉助於振動篩板塔(Vibro Retsch,瑞士)在1.5mm振盪位移下振盪篩10分鐘。
使用振動篩板塔(Vibro Retsch,瑞士)進行粒度分佈分析。篩板塔在1.5mm振盪位移下振盪10分鐘。使用篩孔尺寸為約180μm、250μm、355μm、500μm及710μm之鋼絲篩網(Vibro Retsch,200×25mm,德國)。稱量各篩上剩餘之粉末的量。尺寸小於180μm或大於710μm之顆粒排除在外。
藉助於以下等式計算精細部分(FF):
其中mtot為最初施加於篩上之質量(g)且mres為震盪10分鐘後篩上之
殘餘量(g)。
合併尺寸為180μm至710μm之顆粒部分且對其進行以下測試:根據Ph Eur(European Pharmacopeia.第7版.Strasbourg(France):Council of Europe;2011)量測所選顆粒部分之流動性以及容積密度及敲緊密度。使用Mettler PM460天平(Mettler Toledo,瑞士)進行流動性量測。選擇三種不同開口(5mm、7mm及9mm)。
使用STAV 2003體積計(J.Engelsmann,德國)量測容積密度及敲緊密度。
根據Ph Eur(European Pharmacopeia.第7版.Strasbourg(France):Council of Europe;2011)量測豪斯內比(Hausner ratio)(敲緊密度/容積密度)。
1.2.4 錠劑製備
對於錠劑製備,使用尺寸介於180μm與710μm之間的全部顆粒。顆粒在氮氣流下在KVTS 11型真空乾燥箱(Salvis,瑞士)中乾燥隔夜(12-15小時),隨後將其在滾動混合器(Turbula T2C,Willy A.Bachofen AG,瑞士)中在32rpm混合10分鐘。使用10mm圓形平坦工具,使用Styl'One 105ml製錠機(Medel'Pharm,法國)壓製顆粒。製錠機配備有Analis軟體2.01版(Medel'Pharm,法國)。在壓實期間,由於原料之高度可變孔隙率,錠劑體積在最低壓製壓力下保持恆定。調整各調配物之衝頭間隙在6.37MPa(0.50kN)壓製壓力下獲得6mm之錠劑高度。各調配物之衝頭間隙在整個壓製壓力範圍上保持恆定。調配物在6MPa至500MPa範圍內的10個不同
壓製壓力下重複壓實三次。若在低於500MPa時發生分層,則停止進一步提高壓製壓力。使用硬脂酸鎂手動潤滑衝頭及模具。藉由將最低衝頭之上升及降落設定為750ms且「維持」相設為0ms,在最小可能停留時間下壓製錠劑。
錠劑製備及分析期間之溫度及相對濕度分別介於22.3℃與25.9℃之間以及28.5%與50.0%之間。
1.2.5 錠劑分析(重量、尺寸、高度、擠壓力、拉伸強度及脆度)
在錠劑壓製之後,重複直接量測錠劑重量、尺寸、高度及擠壓力三次。使用Delta Range AX204天平(Mettler Toledo,瑞士)測定重量。使用CD-15CPX型之測微螺旋(Mitutoyo,日本)量測直徑及高度。使用錠劑硬度測試儀(8M,Dr.Schleuniger Pharmatron,瑞士)在1mm/s之衝擊速度下量測低於400N之擠壓力。如Stirnimann T等人,Compaction of functionalized calcium carbonate,a porous and crystalline microparticulate material with a lamellar surface.International Journal of Pharmaceutics.2014年5月15日;466(1-2):266-75.中所述使用Styl'One製錠機(Medel'Pharm,法國)測試較硬錠劑(>400N)。
使用以下等式計算拉伸強度:
其中σ t為徑向拉伸強度(MPa),F為擠壓力(N),d為錠劑直徑(mm),且h為錠劑厚度(mm)。
根據Ph Eur(European Pharmacopeia.第7版Strasbourg (France):Council of Europe;2011)使用轉鼓(Erweka,德國)量測在100MPa下壓製之錠劑的脆度。
1.2.6 赫克爾(Heckel)及改良赫克爾等式
藉助於軟體OriginPro 8.5版(OriginLab Corporation,USA),根據以下等式擬合赫克爾表達(亦參看赫克爾RW.Density-pressure relationships in powder compaction.Trans Metall Soc AIME.1961;221:671-5及赫克爾RW.An analysis of powder compaction phenomena.Trans Metall Soc AIME.1961;221:1001-8):
其中ρ為錠劑密度(g/cm3),k為赫克爾參數(MPa-1),s為壓製壓力(MPa),且A為常數。赫克爾分析考慮50MPa與200MPa之間的4個資料點。
根據以下等式計算密度(ρ):
其中m為錠劑質量(g),r為錠劑半徑(cm),h為錠劑高度(cm)且ρ 真實為多孔性錠劑內骨架形成物質之真實密度(g/cm3)。
使用以下等式計算平均屈服壓力(σy,MPa):
其中k為赫克爾參數(MPa-1)。
根據以下等式擬合改良之赫克爾等式(亦參看M.Kuentz等人,Pressure susceptibility of polymer tablets as a critical property:A modified Heckel equation.Journal of Pharmaceutical Sciences.1999;88(2):174-9):
其中σ為壓製壓力(MPa),C為常數(MPa-1),ρ rc為相對臨界密度且ρ為錠劑之相對密度。改良赫克爾分析考慮5MPa與200MPa之間的6個資料點。
1.2.7 錠劑中之孔徑分佈
為了量測孔徑分佈,如1.2.4部分中所述製備錠劑。使用Auto Pore IV 9500汞細孔計(Micromeritics,美國)進行分析。低壓及高壓汞壓分別在3.59kPa至206.64kPa範圍內及206.78kPa至206.78MPa範圍內。整個壓力範圍上之平衡時間設為10s。
結果及論述
2.1 篩選
對於製錠,顆粒較佳應小時針對進一步處理之特定剛度。精細部分(<500μm)給出帶狀物剛度之線索。使用18種調配物之篩選獲得10中所關注調配物,因為其均顯示剩餘部分(>500μm)超過60wt%。此意謂僅40%固體(帶狀物形式)在振盪10分鐘之後崩塌成尺寸小於500μm之細粒。
具有SSF之FCC在滾筒壓實期間顯示與所施加之滾軋壓力無關(在20巴下製備之顆粒的剩餘部分之值在5巴下的值的標準差內)的極高剩餘部分(約90%)。此結果顯示由FCC製成之剛性帶狀物可甚至在低壓(5巴)下經滾筒壓實。一般而言,觀測到較高剩餘部分;因此,在較高壓力(20巴)下滾筒壓實之粉末摻合物的剛性帶狀物更多。此作用對於含有微晶纖維素艾維素之混合物更明顯。在5巴滾軋壓力下處理的具有SSF摻合物之艾維素顯示僅10wt%剩餘部分,此為極脆弱帶狀物之標誌。因此
假設與FCC相比,5巴之壓力不足以使艾維素形成充分數目之粒子間結合。在20巴下,艾維素及SSF粉末摻合物未進入壓製區且在滾輪壓實機之饋入區內導致故障。
2.2 顆粒特性
表2顯示所製備調配物在滾筒壓實期間之精細部分。可搜集到FCC混合物顯示在將滾筒壓實期間之壓製壓力從5巴提高至20巴之後,精細部分減少50%。與現有技術之微晶纖維素(艾維素)相當,藉由提高混合物中之撲熱息痛的量觀測到FCC具有較高精細部分。然而,74.25%藥物負載下的精細部分比現有技術微晶纖維素(艾維素)觀測到的低得多。
藉由採用滾筒壓實FCC,可顯著提高FCC之流動性。關於流動性,表1顯示在滾筒壓實期間的相同藥物負載及相同壓製壓力下,FCC混合物始終比現有技術之混合物(包含艾維素)快。
表2進一步顯示5巴壓實之顆粒相較於20巴壓實之顆粒顯示較低密度,因為滾筒壓實期間較低施加壓力產生的較鬆散填充。一般而言,FCC混合物之密度相較於艾維素混合物始終較高。
全部混合物之豪斯內比均介於1.04與1.11之間,意謂敲緊期間之固結最小。應注意,藉由提高撲熱息痛之量使豪斯內比變得較小。可能原因是撲熱息痛之結構及平整表面紋理,此不允許初始填充後發生重排。FCC之薄層及艾維素之纖維可互鎖且防止粒子形成緻密填充。調配物中撲熱息痛之量越高,艾維素及FCC之互鎖作用越小,因此降低豪斯內比。
2.3 錠劑特性
表2顯示不同調配物之所得錠劑重量。在5巴下滾筒壓實之
顆粒相較於20巴下之顆粒獲得較輕錠劑,此因為滾筒壓實期間緻密化較少。在20巴下處理撲熱息痛混合物時,在相同藥物-賦形劑比率下,FCC-撲熱息痛混合物相較於艾維素-撲熱息痛混合物產生較重錠劑,此由於相較於現有技術之微晶纖維素艾維素(約0.57g/cm3)較高之FCC容積密度(約0.64g/cm3)。
表2亦顯示FCC-撲熱息痛混合物之錠劑脆度相較於艾維素-撲熱息痛摻合物大大降低。在微晶纖維素艾維素調配物中,可僅量測49.50%藥物負載之錠劑的脆度。假設撲熱息痛之彈性特性可能未經艾維素補償,且因此錠劑不顯示足以通過脆度測試之物理強度。
具有硬脂醯反丁烯二酸鈉摻合物之FCC(與滾筒壓實期間施加之壓力無關)及與低藥物負載組合之FCC(在5巴下滾筒壓實)的脆度值低於1%。此外,在5巴下獲得之FCC顆粒產生的錠劑脆度顯著低於在20巴下壓製之錠劑。此結果亦解釋於圖1中。
圖1顯示基於FCC之錠劑調配物的錠劑拉伸強度隨壓製壓力變化。高達250MPa壓力,全部調配物之拉伸強度在增加之壓製壓力下幾乎呈直線升高加。具體而言,脆度視錠劑拉伸強度而定,錠劑拉伸強度隨可供用於接觸之表面而變化。滾筒壓實期間之壓力越高,粒子填充越緻密且表面積損失越高。
在極高壓力(約400MPa)下,由5巴顆粒及20巴顆粒製成之錠劑的拉伸強度相當。在此類壓力下,顆粒(及亦顆粒內之粒子)可破裂且因此提供用於形成結合之接觸的額外表面積。對於在20巴下壓製之顆粒,粒子破裂所需之壓製壓力相較於在5巴下獲得之顆粒更高。與粉末
摻合物製成之錠劑相比,使用FCC顆粒的錠劑分層風險在較高壓製壓力下降低。
FCC-撲熱息痛及艾維素-撲熱息痛混合物之錠劑拉伸強度結果支持高比表面積對錠劑穩定性的積極作用。
圖2顯示拉伸強度隨具有FCC及艾維素之撲熱息痛混合物的壓製壓力而變化。具有FCC之混合物達到的拉伸強度值比艾維素與撲熱息痛之混合物高得多,但具有24.75% FCC之調配物除外。對於具有74.25%撲熱息痛之混合物,FCC已在50MPa下達到最大拉伸強度(0.16MPa)。具有相同藥物負載之艾維素調配物在施加150MPa壓製壓力之後達到此值。具有74.25%藥物負載之艾維素調配物達到的拉伸強度比FCC與撲熱息痛之組合高3.4倍,但需要高10倍之壓力來達到此值。在較高藥物負載下,FCC相較於艾維素顯示優良特性,在較低壓力範圍內尤其如此。
表3顯示赫克爾及改良赫克爾分析之值。滾筒壓實期間之壓力越高,錠劑之赫克爾參數(k)值越低。低「k」值指示獲得相同拉伸強度之穩定錠劑所需的壓力越高。相對臨界密度(ρ rc)之值(即可首先形成穩定壓實物之錠劑密度)支持赫克爾分析之結果。
2.4 汞壓孔率測定法
圖3顯示使用粉末及顆粒製成之FCC錠劑的孔徑分佈的汞壓孔率測定法曲線。錠劑在三種不同壓製壓力下壓製。藉由提高壓製壓力,特徵峰由於FCC緻密化及粒子表面上之薄層塌陷而移位至較小孔直徑(圖3)。對於所有類型之主要材料(粉末或顆粒),在相同壓製壓力下壓製之錠劑的曲線幾乎疊合。僅提及之差異為在較大孔直徑下,顆粒之孔隙體積高
於粉末。FCC之顆粒內(intraparticular)結構(直徑小於0.02μm之孔)既不受滾筒壓實方法影響,亦不受製錠方法影響。
結論
FCC之滾筒壓實揭示低精細部分下,甚至在滾筒壓實期間之低壓力下之剛性帶狀物。由FCC及醫藥活性劑製成之所得顆粒顯示流動性比相應基於微晶纖維素(艾維素)之調配物更佳。另外,由粒化FCC及醫藥活性劑構成之錠劑在整個壓力範圍上顯示顯著高於基於微晶纖維素(艾維素)之調配物的之拉伸強度。因此,FCC之粒化調配物相較於基於微晶纖維素(艾維素)之調配物或非粒化FCC調配物具有優良流動性及壓實性特性。
Claims (15)
- 一種用於製造醫藥傳遞系統之方法,其包含以下步驟:a)提供表面反應碳酸鈣,其為天然研磨或沉澱碳酸鈣與二氧化碳及一或多種酸在水性介質中之反應產物,其中該二氧化碳藉由酸處理原位形成及/或由外部來源供應;b)提供至少一種醫藥活性劑或其醫藥非活性前驅物;c)提供至少一種調配助劑;d)混合步驟a)之該表面反應碳酸鈣、步驟b)之該至少一種醫藥活性劑或其醫藥非活性前驅物及步驟c)之該至少一種調配助劑;以及e)藉助於滾筒壓實機在4至20巴範圍內之壓實壓力下壓實步驟d)中獲得之該混合物;以及f)將步驟e)中獲得之該滾筒壓實混合物壓實以獲得該醫藥傳遞系統。
- 如申請專利範圍第1項所述之方法,其中該天然研磨碳酸鈣選自含有碳酸鈣之礦物,該等礦物選自包含以下之群:大理石、白堊、白雲石、石灰石及其混合物;或該沉澱碳酸鈣選自包含具有文石、六方方解石或方解石礦物晶形及其混合物的沉澱碳酸鈣之群。
- 如申請專利範圍第1項或第2項中任一項所述之方法,其中該表面反應碳酸鈣a)根據ISO 9277使用氮氣及BET方法量測,具有20.0m2/g至200.0m2/g,較佳20.0m2/g至180.0m2/g,更佳30.0m2/g至160.0m2/g,甚至更佳40.0m2/g至150.0m2/g,且最佳50.0m2/g至140.0m2/g之BET比表面積;及/或 b)包含體積中值粒徑d 50為2.0至50.0μm,較佳2.5至25.0μm,更佳2.8至20.0μm,甚至更佳3.0至10.0μm,且最佳4.0至8.0μm之粒子;及/或c)由汞壓孔率測定法量測計算,具有在0.15至1.35cm3/g,較佳0.30至1.30cm3/g,且最佳0.40至1.25cm3/g範圍內之粒子內壓入之比孔隙體積。
- 如申請專利範圍第1項至第3項中任一項所述之方法,其中該至少一種醫藥活性劑或其醫藥非活性前驅物選自包含合成來源、半合成來源、天然來源以及其組合之醫藥活性劑或醫藥非活性前驅物之群。
- 如申請專利範圍第1項至第4項中任一項之方法,其中該至少一種調配助劑a)為至少一種相內潤滑劑及/或相外潤滑劑;及/或b)按該醫藥傳遞系統之總重量計,以約0.1wt%至約10.0wt%,較佳約0.3wt%至約5.0wt%,更佳約0.5wt%至約2.5wt%之總量提供。
- 如申請專利範圍第1項至第5項中任一項所述之方法,其中滾筒壓實步驟e)在4至15巴範圍內,更佳4至10巴範圍內且最佳4至7巴範圍內之滾筒壓實壓力下進行。
- 如申請專利範圍第1項至第6項中任一項所述之方法,其中壓實步驟f)為粒化或製錠步驟。
- 如申請專利範圍第1項至第7項中任一項所述之方法,其中滾筒壓實步驟e)中獲得之該滾筒壓實混合物在進行壓實步驟f)之前先進行研磨步驟。
- 如申請專利範圍第1項至第8項中任一項所述之方法,其中該滾筒壓 實混合物具有藉由在不同篩孔尺寸上篩分獲得的180至710μm之晶粒尺寸,較佳使用180μm、250μm、355μm、500μm以及710μm之篩孔尺寸。
- 如申請專利範圍第1項至第9項中任一項所述之方法,其中該醫藥傳遞系統a)在100MPa下壓製的錠劑上根據Ph.Eur.4量測具有1.10%之脆度;及/或b)滿足式(I)
- 如申請專利範圍第1項至第10項中任一項所述之方法,其中該醫藥傳遞系統滿足式(II)
- 如申請專利範圍第1項至第11項中任一項所述之方法,其中該醫藥傳遞系統為錠劑、微錠劑、膠囊或糰粒。
- 一種表面反應碳酸鈣的用途,其係用於提高醫藥傳遞系統之脆度,其中該表面反應碳酸鈣為天然研磨或沉澱碳酸鈣與二氧化碳及一或多種酸在水性介質中之反應產物,其中該二氧化碳藉由酸處理原位形成及/或由外部來源供應,其中該醫藥傳遞系統a)在100MPa下壓製的錠劑上根據Ph.Eur.4量測具有1.10%之脆度;及/或b)滿足式(II)
- 一種表面反應碳酸鈣的用途,其係用於提高醫藥傳遞系統之流動性,其中該表面反應碳酸鈣為天然研磨或沉澱碳酸鈣與二氧化碳及一或多種酸在水性介質中之反應產物,其中該二氧化碳藉由酸處理原位形成及/或由外部來源供應,其中該醫藥傳遞系統滿足式(II)
- 一種醫藥傳遞系統,較佳錠劑、微錠劑、膠囊或糰粒,其藉由如申請專利範圍第1項至第12項中任一項所述之方法獲得。
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EP14199037.4A EP3034070A1 (en) | 2014-12-18 | 2014-12-18 | Method for the production of a pharmaceutical delivery system |
US201462095865P | 2014-12-23 | 2014-12-23 | |
US201562232516P | 2015-09-25 | 2015-09-25 |
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EP (2) | EP3034070A1 (zh) |
JP (1) | JP2017538733A (zh) |
KR (1) | KR20170098894A (zh) |
CN (1) | CN107106498A (zh) |
AR (1) | AR103077A1 (zh) |
AU (1) | AU2015367524B2 (zh) |
BR (1) | BR112017012665A2 (zh) |
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CO (1) | CO2017005500A2 (zh) |
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PH (1) | PH12017501035A1 (zh) |
RU (1) | RU2693491C2 (zh) |
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TW (1) | TW201627009A (zh) |
UY (1) | UY36444A (zh) |
WO (1) | WO2016096997A1 (zh) |
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EP3069713A1 (en) * | 2015-03-20 | 2016-09-21 | Omya International AG | Dispersible dosage form |
EP3260114A1 (en) | 2016-06-21 | 2017-12-27 | Omya International AG | Method for the production of a dosage form |
EP3260115A1 (en) | 2016-06-21 | 2017-12-27 | Omya International AG | Method for the production of a dosage form |
EP3269361A1 (en) | 2016-07-14 | 2018-01-17 | Omya International AG | Dosage form |
EP3275537A1 (en) * | 2016-07-25 | 2018-01-31 | Omya International AG | Surface-modified calcium carbonate as carrier for transition metal-based catalysts |
EP3520798A1 (en) * | 2018-01-31 | 2019-08-07 | Omya International AG | Use of functionalized calcium carbonate as active ingredient |
BR112021025200A2 (pt) | 2019-06-17 | 2022-02-01 | Dsm Ip Assets Bv | Composição compreendendo metformina hcl, vitamina b12 e pelo menos um aditivo de fluxo |
US20210059932A1 (en) * | 2019-08-28 | 2021-03-04 | Vincent Langlois | Multi-layer edible strip containing active medicinal ingredients |
CN111419815B (zh) * | 2020-04-23 | 2022-03-11 | 永信药品工业(昆山)股份有限公司 | 依托考昔片及其优化方法 |
TW202200206A (zh) | 2020-04-28 | 2022-01-01 | 瑞士商歐米亞國際公司 | 包含表面反應碳酸鈣作為賦形劑之顆粒 |
EP3928859A1 (en) | 2020-06-23 | 2021-12-29 | Omya International AG | Surface-reacted calcium carbonate in a process for the production of a loaded microcapsule |
CN113413388B (zh) * | 2021-06-30 | 2022-11-15 | 上海奥全生物医药科技有限公司 | 含有枸橼酸西地那非的药物组合物、制备方法及其应用 |
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JPS6143108A (ja) | 1984-08-03 | 1986-03-01 | Nippon Shinyaku Co Ltd | 医薬品製剤及びその製造法 |
DK162986A (da) | 1985-04-12 | 1986-10-13 | Forest Laboratories | Terapeutisk middel i enhedsdosisform |
US4627977A (en) | 1985-09-13 | 1986-12-09 | Colgate-Palmolive Company | Anticalculus oral composition |
GB8809421D0 (en) | 1988-04-21 | 1988-05-25 | Fordonal Sa | Antacid compositions with prolonged gastric residence time |
EP0717988B1 (en) | 1993-08-20 | 2001-10-17 | Nippon Shinyaku Company, Limited | Gastric remaining preparation, swollen molding, and production process |
FR2787802B1 (fr) | 1998-12-24 | 2001-02-02 | Pluss Stauffer Ag | Nouvelle charge ou pigment ou mineral traite pour papier, notamment pigment contenant du caco3 naturel, son procede de fabrication, compositions les contenant, et leurs applications |
US6582738B2 (en) | 1999-09-13 | 2003-06-24 | Deseret Laboratories, Inc. | Process for preparing chewing gum containing a nutritional supplement |
ATE371439T1 (de) * | 2000-07-27 | 2007-09-15 | Roquette Freres | Granulat bestehend aus stärke und laktose |
AU8444401A (en) * | 2000-09-06 | 2002-03-22 | Tanabe Seiyaku Co | Preparations for oral administration |
US7494669B2 (en) * | 2001-02-28 | 2009-02-24 | Carrington Laboratories, Inc. | Delivery of physiological agents with in-situ gels comprising anionic polysaccharides |
US20030157213A1 (en) | 2002-02-19 | 2003-08-21 | Jeffrey Jenkins | Nutrient chewing gum |
FR2852600B1 (fr) | 2003-03-18 | 2005-06-10 | Nouveau pigment mineral contenant du carbonate de calcium, suspension aqueuse le contenant et ses usages | |
FR2871474B1 (fr) | 2004-06-11 | 2006-09-15 | Omya Development Ag | Nouveau pigment mineral sec contenant du carbonate de calcium, suspension aqueuse le contenant et ses usages |
FR2881957B1 (fr) * | 2005-02-16 | 2008-08-08 | Solvay | Comprimes comprenant une substance biologiquement active et un excipient |
PL2070991T3 (pl) | 2007-12-12 | 2011-02-28 | Omya Int Ag | Sposób wytwarzania strącanego węglanu wapnia o powierzchni zmodyfikowanej chemicznie |
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ES2384017T3 (es) | 2009-06-15 | 2012-06-28 | Omya Development Ag | Proceso para preparar carbonato de calcio que reacciona en la superficie y su uso |
PL2264108T3 (pl) | 2009-06-15 | 2012-07-31 | Omya Int Ag | Sposób wytwarzania przereagowanego powierzchniowo węglanu wapnia, z wykorzystaniem słabego kwasu |
SI2679638T1 (sl) | 2012-06-28 | 2015-11-30 | Omya International Ag | Vodna mineralna in/ali polnilna in/ali pigmentna suspenzija z visoko vrednostjo trdnih delcev v kislinskem ph okolju |
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RS54024B1 (en) | 2012-10-12 | 2015-10-30 | Omya International Ag | GASTRORETENCY FORMULATION OF MEDICINES AND SYSTEMS FOR DELIVERY AND METHODS OF THEIR PREPARATION USING FUNCTIONALIZED CALCIUM CARBONATE |
ES2645223T3 (es) * | 2013-06-06 | 2017-12-04 | Zentiva, K.S. | Formulaciones de agomelatina que comprenden agomelatina en forma de co-cristales |
RU2646113C1 (ru) * | 2016-09-06 | 2018-03-01 | Федеральное государственное бюджетное учреждение науки Институт химической биологии и фундаментальной медицины Сибирского отделения Российской академии наук (ИХБФМ СО РАН) | Способ получения системы доставки фрагментов нуклеиновых кислот в клетки млекопитающих |
-
2014
- 2014-12-18 EP EP14199037.4A patent/EP3034070A1/en not_active Withdrawn
-
2015
- 2015-12-11 TW TW104141693A patent/TW201627009A/zh unknown
- 2015-12-16 EP EP15813352.0A patent/EP3233062A1/en not_active Withdrawn
- 2015-12-16 CN CN201580069007.1A patent/CN107106498A/zh active Pending
- 2015-12-16 BR BR112017012665A patent/BR112017012665A2/pt not_active IP Right Cessation
- 2015-12-16 SG SG11201704513VA patent/SG11201704513VA/en unknown
- 2015-12-16 UY UY0001036444A patent/UY36444A/es not_active Application Discontinuation
- 2015-12-16 RU RU2017125320A patent/RU2693491C2/ru not_active IP Right Cessation
- 2015-12-16 CR CR20170236A patent/CR20170236A/es unknown
- 2015-12-16 JP JP2017532816A patent/JP2017538733A/ja active Pending
- 2015-12-16 MX MX2017007880A patent/MX2017007880A/es unknown
- 2015-12-16 CA CA2969763A patent/CA2969763A1/en not_active Abandoned
- 2015-12-16 AU AU2015367524A patent/AU2015367524B2/en not_active Ceased
- 2015-12-16 WO PCT/EP2015/080016 patent/WO2016096997A1/en active Application Filing
- 2015-12-16 KR KR1020177020103A patent/KR20170098894A/ko not_active IP Right Cessation
- 2015-12-16 US US15/534,145 patent/US20190022012A1/en not_active Abandoned
- 2015-12-17 AR ARP150104151A patent/AR103077A1/es unknown
-
2017
- 2017-05-31 CO CONC2017/0005500A patent/CO2017005500A2/es unknown
- 2017-06-05 PH PH12017501035A patent/PH12017501035A1/en unknown
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AU2015367524B2 (en) | 2018-03-15 |
RU2693491C2 (ru) | 2019-07-03 |
RU2017125320A (ru) | 2019-01-18 |
UY36444A (es) | 2016-04-29 |
WO2016096997A1 (en) | 2016-06-23 |
RU2017125320A3 (zh) | 2019-01-18 |
MX2017007880A (es) | 2017-09-05 |
SG11201704513VA (en) | 2017-07-28 |
AU2015367524A1 (en) | 2017-07-20 |
US20190022012A1 (en) | 2019-01-24 |
CO2017005500A2 (es) | 2017-09-29 |
JP2017538733A (ja) | 2017-12-28 |
CA2969763A1 (en) | 2016-06-23 |
AR103077A1 (es) | 2017-04-12 |
PH12017501035A1 (en) | 2018-03-05 |
CR20170236A (es) | 2017-09-26 |
CN107106498A (zh) | 2017-08-29 |
KR20170098894A (ko) | 2017-08-30 |
BR112017012665A2 (pt) | 2017-12-26 |
EP3034070A1 (en) | 2016-06-22 |
EP3233062A1 (en) | 2017-10-25 |
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