TWI544936B - 包含囊封於硬膠囊中之多單位球形錠(must)的複合調配物及製備其之方法 - Google Patents
包含囊封於硬膠囊中之多單位球形錠(must)的複合調配物及製備其之方法 Download PDFInfo
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- TWI544936B TWI544936B TW102113097A TW102113097A TWI544936B TW I544936 B TWI544936 B TW I544936B TW 102113097 A TW102113097 A TW 102113097A TW 102113097 A TW102113097 A TW 102113097A TW I544936 B TWI544936 B TW I544936B
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- hard capsule
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- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 1
- 229960000620 ranitidine Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- TXHZXHICDBAVJW-UHFFFAOYSA-N rizatriptan Chemical compound C=1[C]2C(CCN(C)C)=CN=C2C=CC=1CN1C=NC=N1 TXHZXHICDBAVJW-UHFFFAOYSA-N 0.000 description 1
- 229960000425 rizatriptan Drugs 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 description 1
- 229960004796 rosuvastatin calcium Drugs 0.000 description 1
- 229960003320 roxatidine Drugs 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 1
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- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
- 229960004034 sitagliptin Drugs 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
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- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229960000835 tadalafil Drugs 0.000 description 1
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- 235000012222 talc Nutrition 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- 229960004380 tramadol Drugs 0.000 description 1
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 229960005345 trimebutine Drugs 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
- 229960000438 udenafil Drugs 0.000 description 1
- IYFNEFQTYQPVOC-UHFFFAOYSA-N udenafil Chemical compound C1=C(C=2NC=3C(CCC)=NN(C)C=3C(=O)N=2)C(OCCC)=CC=C1S(=O)(=O)NCCC1CCCN1C IYFNEFQTYQPVOC-UHFFFAOYSA-N 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 1
- 229960002381 vardenafil Drugs 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 235000019195 vitamin supplement Nutrition 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 229920003176 water-insoluble polymer Polymers 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- WJJYZXPHLSLMGE-UHFFFAOYSA-N xaliproden Chemical compound FC(F)(F)C1=CC=CC(C=2CCN(CCC=3C=C4C=CC=CC4=CC=3)CC=2)=C1 WJJYZXPHLSLMGE-UHFFFAOYSA-N 0.000 description 1
- 229960004664 xaliproden Drugs 0.000 description 1
- 229960000607 ziprasidone Drugs 0.000 description 1
- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 description 1
- ULSDMUVEXKOYBU-ZDUSSCGKSA-N zolmitriptan Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1C[C@H]1COC(=O)N1 ULSDMUVEXKOYBU-ZDUSSCGKSA-N 0.000 description 1
- 229960001360 zolmitriptan Drugs 0.000 description 1
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Description
本發明有關包含多單位球形錠(MUSTs)之一硬膠囊複合調配物,及用於製備其之方法。
在醫學領域中的進步已改善了生活品質並提高人類的預期壽命。然而,一單一的藥物學活性成分在治療帶有醫學疾病之患者的療效係有一限制。因此,同時或依序地投藥具有不同作用機制(模式)的多重藥物用於協同效果係為普遍的。
然而,二或多個分開的藥物單位之共同投藥可能降低患者服藥的順從性,從而對經受持續藥物治療的患者造成極大的不便。進一步,該患者必須一次服用如此多重的藥物單位,並隨時攜帶它們。其亦將在患者的日常生活上帶來極大的不便。
為了革除這種問題,其係已提出在一單一封裝中封裝入許多藥物的一個方法。譬如,Torrent
Pharmaceuticals有限公司(印度)已經發布一複合調配物“CVpill”,該者係為含有用於治療心血管疾病之膠囊與錠劑的一單一套組。CVpill係由以下所組成:一膠囊其含有10mg粉末形式的阿托伐他汀(Atorvastatin)、粉末形式的雷米普利(Ramipril)、及75mg的腸溶塗覆(enteric-coated)阿司匹林錠劑、及含50mg美托洛爾(Metoprolol)的一長效錠劑。該膠囊與錠劑必須同時每天投藥一次。但是,此種由一簡單套組組成的共封裝產品幾乎不可以改善患者服藥的順從性,然而,此者在一複合調配物中可能為預期的。所以,對於發展特定活性成分之“組合藥物或複合調配物”上的研究係有一不斷增長的需求。
該術語“複合調配物”,如於此所使用,意指二
或多種不同活性成分或藥物在一單一單位劑量,諸如錠劑或膠囊,中的組合。然而,針對特定活性成分開發一複合調配物有時係非常困難的,因為下列原因。
首先,使用於一複合調配物的特定活性成分之
組合應容易製成的。進一步,包含活性成分與藥物學可接受賦形劑之該組成物為了投藥應該在一合適的尺寸與重量。然而,開發滿足這樣要求的一複合調配物不是總是容易的。假若該所採用的藥物數量係過量或不足,其將難以調整該組成物重量至一適當水平。還有,在處理起源於藥物藥代動力學與藥物性質之各種情況的過程中,非預期的問題亦可能會遇到的。
其次,在製備一複合調配物中,該等活性成分
之間的化學交互作用可能會降低藥物的安定性。尤其是,開發對一藥物組合具有足夠的物理化學安定性的一固定組合劑型,甚至為更困難的,假若其等之安定性可能會因為它們組合時的化學交互作用而降低時。
當一錠劑複合調配物製備時,一雙重層或三重
層的壓錠機可以使用以分隔該活性成分。再者,不僅此種方法要求特殊的設備,而且完全分隔在每一層中的該主要成分亦為機械不可能的,因為在該等層之交界處可能會發生非所欲的反應。
對於膠囊,傳統的硬膠囊係充填以在粉劑、粒
劑或丸劑形式中的藥物。還有,藉由一單一充填步驟,僅有一單一活性成分充填在一硬膠囊中。還有,在粉劑、粒劑或丸劑形式中的藥物具有一密度其低於一錠劑者,由於前者沒有經受到一高壓力壓縮步驟。因此,在粉劑、粒劑或丸劑形式中充填於一膠囊中的藥物數量,其係存在一限制的。為了在一單一硬膠囊中充填高劑量的活性成分或一個以上的活性成分,膠囊尺寸必須提高,以容納這樣大數量的藥物。然而,如果該膠囊尺寸因為容納大量的藥物而變得太大,其可能會造成吞嚥困難、吞嚥障礙。特別是,具有00號(8.5mm的膠囊囊蓋直徑及23.3mm的膠囊長度)及0號(7.6mm的膠囊囊蓋直徑及21.7mm的膠囊長度)大尺寸的膠囊對老人或孩童吞嚥它們會造成困難的。由於它們的大尺寸,攜帶它們亦可能為不方便的。
相應地,本發明人已經努力解決複合調配物的
劣勢,並已開發一硬膠囊其每一主成分包含一小數目的錠劑,例如,1至3個。然而,該硬膠囊的初始溶出率(15分鐘內)係減緩的,歸因於崩解時間的延遲,且在個別的溶出試驗結果之間觀察到偏差的提高。因此,其可能難以預期源自一複合調配物之一單一劑量形式的相同生物等效性,假若其包含要求一快速吸收率的藥物,例如,1至2小時的最大藥物濃度時間(Tmax)。所以,對於開發一複合調配物其具有良好的生產率與安定性,在初始溶出率不具有延遲者依舊有一需要。
所以,本發明之一目的係為提供一複合調配物,該者在15分鐘之內在初始溶出率中不具有延遲,並展現良好的體內吸收率,歸因於在每一溶出率中的小變化,以及良好的生產力與安定性。
本發明之另一目的係為提供一種用於製備該複合調配物的方法。
根據本發明之一目的,係為提供的是一種包含二或更多藥物活性成分的硬膠囊複合調配物,其中每一藥物活性成分係含在一多單位球形錠(MUST)中且每一藥物活性成分的數個MUST係囊封在該硬膠囊中。
根據本發明之一目的,係為提供的是一種用於製備該硬膠囊複合調配物的方法,該者包含下列步驟:(1)製備包含一藥物活性成分的MUST;及(2)囊封數個該等
MUST於該硬膠囊中,藉由此,該硬膠囊複合調配物包含二或更多的藥物活性成分。
根據本發明包含多單位球形錠(MUSTs)之該硬
膠囊複合調配物可以有效地在該膠囊的有限空間中充填該MUST,該者允許在一相對小尺寸的膠囊中充填高劑量的不同藥物活性成分,從而以提高生產力並使得其容易投藥到患者。該膠囊具有一良好的溶出率,因為含在該膠囊中的藥物活性成分係彼此分隔的;所以,該等成分的溶出率係較不受到彼此的影響。其可能亦盡可能最大化該藥物活性成分的治療效果,因為該複合調配物具有良好的安定性。
圖1顯示根據本發明之一實施例的一硬膠囊複合調配物之示意圖。
圖2顯示一多單位球形錠(MUST)之示意圖,該者係充填於該硬膠囊複合調配物中。
圖3與圖4係為曲線圖,該二者分別顯示孟魯司特(montelukast)與左旋西替利嗪(levocetirizine)的溶出率,根據試驗實例1。
圖5係為一曲線圖,該者顯示根據試驗實例2中安布索(ambroxol)的溶出率。
圖6與圖7係為曲線圖,該二者分別顯示孟魯司特與左旋西替利嗪的血中濃度,根據試驗實例3。
本發明之實施例係於下文中詳細解釋。
本發明提供包含多單位球形錠(MUSTs)之一硬膠囊複合調配物。根據本發明之該硬膠囊複合調配物的示意圖係顯示於圖1中。
該術語“複合調配物”,如於此所使用,意指二或多種不同活性成分或藥物在一單一單位劑量中的組合。本發明之該複合調配物包含一膠囊,及數個多單位迷你錠劑,該者含有該等藥物學活性成分中之任一者,具有類似球體的形狀且囊封在該膠囊中。
在本發明複合調配物中,該膠囊可能為製藥工業中使用的任何常規膠囊,較佳地一硬膠囊。一硬膠囊係由一膠囊主體與一囊蓋構成,藉由此,內含物係充填於該膠囊主體的內部空間中,而該囊蓋係使用以封閉該膠囊主體而使用。該最終膠囊產品,其囊蓋封閉的,亦即實際上投藥給病人者,具有圓柱主體之形狀伴隨半球形端部,且該內含物係充填於該膠囊主體的內部空間中。一般地,常規膠囊的內部空間往往充填以一般粉劑、粒劑或丸劑,然而,本發明複合調配物之內部空間其特徵在於,係以迷你錠劑取代而充填的。該迷你錠劑之尺寸係為小的,且從而數個迷你錠劑,例如,4個或更多,可能充填於本發明複合調配物之該內部空間中。
各種尺寸號碼的膠囊係使用的,取決於該膠囊
尺寸,但具有大尺寸的膠囊,諸如00號(8.5mm的膠囊蓋直徑及23.3mm的膠囊長度)可能對老人或孩童吞嚥它們會造成困難。歸因於其巨大的尺寸,其亦可能不方便攜帶的。
所以,本發明複合調配物之膠囊尺寸較佳地係
為硬膠囊0號或更小,例如,硬膠囊0號(7.6mm的膠囊蓋直徑及21.7mm的膠囊長度)、硬膠囊1號(6.9mm的膠囊蓋直徑及19.1mm的膠囊長度)、硬膠囊2號(6.4mm的膠囊蓋直徑及17.6mm的膠囊長度)、硬膠囊3號(5.8mm的膠囊蓋直徑及15.7mm的膠囊長度)或硬膠囊4號(5.3mm的膠囊蓋膠囊直徑及14.2mm的膠囊長度),且更佳地硬膠囊1號或更小的膠囊尺寸。
在本發明複合調配物中,該MUST可能包含藥
物學活性成分及藥物學可接受的添加劑。
該MUST可以藉由將一藥物學活性成分與藥物
學可接受添加劑之一混合物或粒劑經受一壓錠機的壓縮步驟而製備。在此種事例中,該錠劑的硬度係由壓縮壓力的大小決定。
該錠劑可以在圓形、矩形或橢圓形形式中製備
的,然而,圓形形式係為較佳的,因為其允許在該硬膠囊內部空間中更容易封裝。特別地,當該圓形錠劑之直徑類似於該圓形錠劑的厚度時,其具有一球狀形狀,該者改良了錠劑的流動性,且亦最小化由形成一所欲封裝配置而在該膠囊中形成的空隙。
所以,充填於該膠囊中之該錠劑較佳地係在圓
形形式中,更佳地一迷你球形錠(MUST)。含括於本發明複合調配物中之該多單位球形錠係於圖2中顯示的。
為了製備球形形式中的圓形錠劑,每一MUST
的該圓形錠劑之直徑與其之厚度之比需要在1:0.7至1:1.3之一範圍內,較佳地1:0.8至1:1.2。根據本發明具有該圓形錠劑之直徑與其之厚度之比在1:0.7至1:1.3之一範圍內的MUST可以完全地填滿該硬膠囊的內部空間,而不形成任何空隙,且因此,大數量的藥物組合物可以被充填的,即使在一較小的膠囊中。
此外,當該MUST之圓柱高度與該總厚度之比
係在一特定範圍中時,該MUST的壓錠特性改良的,且由此可以改良壓錠過程的速度。
具體地,該圓柱高度係等於該錠劑之總長度減
去兩個半球形端部(頂部及底部)組合的長度,如圖2中所顯示。假若該圓柱高度在該總厚度中之比太高,該錠劑將形成一矩形形狀,該者將退化該錠劑的流動性,且從而造成封裝過程中的麻煩。假若該圓柱高度在該總厚度中之比太低,在壓錠過程期間該錠劑將容易發生碎裂。所以,根據本發明之該MUST在厚度與圓柱高度之比係於1:0.3至1:0.9之一範圍內,較佳地1:0.5至1:0.8。
進一步,MUST係為具有小尺寸的一個迷你錠
劑,且因此該膠囊之內部空間包含至少4個或更多的迷你錠劑,較佳地每一藥物學活性成分4至40個MUST。
相應地,在根據本發明之該複合調配物中的
MUST之直徑係小於該硬膠囊主體的內徑,且較佳地小於或等於該硬膠囊內徑的1/2。
如果MUST的直徑太大(例如,大於該硬膠囊主
體內徑的1/2),其變得難以在該膠囊的內部空間中充填該錠劑,且還有充填於該膠囊內部空間中的該錠劑之總數下降,從而抑制溶出率中的改良或抑制溶出率標準偏差的降低。即使在錠劑充填之後,其不允許所欲的封裝配置的形成,且因此造成空隙在該膠囊內形成。另一方面,當該MUST的直徑太小時(例如,小於1mm),在一單一錠劑中充填之該數量係限制的,且還有該錠劑的物理性質可能會在壓錠過程期間受到環境變量很大的影響。
所以,根據本發明之MUST具有1mm至4mm之
一範圍內的直徑,較佳地1.5mm至3mm之一範圍內。假若該錠劑之直徑係於該範圍內,該所欲之封裝配置可以實現,該者允許充填於一膠囊中之內含物的最大化,且其亦產生一改良的溶出率,歸因於具有多個錠劑。
本發明之該複合調配物具有一良好的充填率,
當相較於傳統充填以粒劑或丸劑的硬膠囊時。
膠囊之充填率可以藉由充填於該膠囊中的材料
重量除以膠囊主體之體積而計算出。舉例而言,當150mg的一組成物係充填於2號膠囊時(體積:0.37mL),該充填率大約為0.41g/mL。一般地,其係難以實現0.6g/mL或更大之一充填率,假若粒劑或丸劑材料係充填時,歸因於該
充填材料的低密度或在該丸劑中存在的空隙。相反的,根據本發明之該複合調配物具有0.6g/mL至1.0g/mL之一充填率,且因而具有0.6g/mL或更大之一充填率,該者使得降低硬膠囊之尺寸成為可能,使其溶意投藥至患者。
進一步,根據本發明之該複合調配物具有一顯
著較小的孔隙度(空空間之比率),當相較於充填以具有5mm或更大之一直徑的典型錠劑之常規膠囊時。由於充填率與孔隙度值之間有一反比關係,本發明之該MUST可以在一最佳水平充填於該膠囊的內部空間中。
根據本發明之一層面,其係提供包含數個
MUST的一硬膠囊複合調配物,該MUST之直徑係小於或等於該硬膠囊主體內徑的1/2,且係在1mm至4mm一範圍內。在此種調配物中,該MUST之直徑可能在1.5mm至3mm一範圍內。
根據本發明之另一層面,其係提供包含數個
MUST的一硬膠囊複合調配物,該MUST之厚度與圓柱高度比係於1:0.7至1:1.3一範圍內,且其之直徑係於1mm至4mm一範圍內。在此種調配物中,該MUST之厚度與圓柱高度比可能在1:0.8至1:1.2之一範圍內,且其之直徑可能在1.5mm至3mm一範圍內。
根據本發明之還一層面,其係提供包含數個
MUST的一硬膠囊複合調配物,該MUST之直徑係小於或等於該硬膠囊主體內徑的1/2,且該MUST之厚度與其之圓柱高度比可能在1:0.8至1:1.2之一範圍內。
在該技藝中已知的任意二或多種藥物可以採用
作為本發明該MUST的活性成分。在本發明中使用的藥物可能選自相同或不同的藥物族群。可採用之藥物之例子包括:退燒劑、止痛劑、抗發炎劑及肌肉鬆弛劑,諸如反胺苯環醇(tramadol)、萘普生(naproxen)、布洛芬(ibuprofen)、右旋布洛芬、阿司匹林、對乙醯氨基酚(acetaminophen)、吲哚美辛(indomethacin)、雙氯芬酸鈉(diclofenac sodium)、醋氯芬酸(aceclofenac)、酮洛芬(ketoprofen)、異丙安替比林(isopropyl antipyrine)、非那西丁(phenacetin)、氟比洛芬(flubiprofen)、保泰松(phenylbutazone)、依托度酸(etodolac)、塞來昔布(celecoxib)、依托昔布(etoricoxib)、乙哌立松(eperisone)、及其等之藥物學可接受鹽類;抗潰瘍劑諸如奧美拉唑(omeprazole)、埃索美拉唑(esomeprazole)、泮托拉唑(pantoprazole)、西米替丁(cimetidine)、法莫替丁(famotidine)、雷尼替丁(ranitidine)、尼扎替丁(nizatidine)、羅沙替丁(roxatidine)、及其等之藥物學可接受鹽類;心血管劑或血管擴張劑諸如氯沙坦(losartan)、伊貝沙坦(ibesartan)、坎地沙坦(candesartan)、替米沙坦(telmisartan)、纈沙坦(valsartan)、硝苯地平(nifedipine)、胺氯地平(amlodipine)、維拉帕米(verapamil)、卡托普利(captopril)、地爾硫卓鹽酸鹽(diltiazem hydrochloride)、普萘洛爾(propranolol)、氧烯洛爾(oxprenolol)、硝酸甘油、依那普利(enalapril)、及其等之藥物學可接受鹽類;抗糖
尿病劑,諸如二甲雙胍(metformin)、格列美脲(glimepiride)、西他列汀(sitagliptin)、羅格列酮(rosiglitazone)、吡格列酮(pioglitazone)、及其等之藥物學可接受鹽類;抗高血脂劑,諸如辛伐他汀(simvastatin)、羅蘇伐他汀(rosuvastatin)、阿托伐他汀、及其等之藥物學可接受鹽類;抗生素,如胺芐西林(ampicillin)、阿莫西林(amoxicillin)、頭孢氨芐(cephalexin)、頭孢氨呋肟(cefuroxime)、頭孢地尼(cefdinir)、頭孢羥氨芐(cefadroxil)、頭孢丙烯(cefprozil)、頭孢泊肟(cefpodoxime)、頭孢妥崙(cefditoren)、頭孢克洛(cefaclor)、頭孢克肟(cefixime)、頭孢拉定(cefradine)、氯碳頭孢(loracarbef)、頭孢布烯(ceftibuten)、頭孢曲秦(cefatrizine)、頭孢卡品(cefcapene)、紅黴素、四環素類、喹諾酮類(quinolones)、及其等之藥物學可接受鹽類;鎮咳劑或抗哮喘劑,諸如孟魯司特、茶鹼、胺茶鹼、磷酸可待因、鹽酸甲基麻黃鹼、右旋美沙酚(dextromethorphan)、那可汀(noscapine)、舒喘靈(salbutamol)、安布索、左旋羥丙哌嗪、克崙特羅(clenbuterol)、(tebutalin)、及其等之藥物學可接受鹽類;止吐劑或GIT調節劑諸如恩丹西酮(ondansetron)、甲氧氯普胺(metoclopramide)、多潘立酮(domperidone)、馬來酸曲美布汀(trimebutine maleate)、西沙必利(cisapride)、左旋舒必利(levosulpiride)、及其等之藥物學可接受鹽類;抗陽痿劑,例如西地那非(sildenafil)、伐地那非(vardenafil)、他達拉非(tadalafil)、
(udenafil)、及其等之藥物學可接受鹽類;及抗癡呆劑,諸如多奈哌齊(donepezil)、加蘭他敏(galantamine)、利伐斯的明(rivastigmine)、乙醯肉毒鹼(acetyl carnitine)、美金剛(memantine)、紮利羅登(xaliproden)、及其等之藥物學可接受鹽類。
此外,抗前列腺增生(anti-BPH)劑諸如坦索羅辛
(tamsulosin);抗偏頭痛藥諸如佐米曲坦(zolmitriptan)、利扎曲坦抗(rizatriptan);興奮劑;抗菌劑;抗組織胺劑諸如西替利嗪(cetirizine),左旋西替利嗪及氯雷他定(loratadine);抗糖尿病劑;抗過敏劑;避孕劑;維生素補充劑;抗凝劑諸如氯吡格雷(clopidogrel);肌肉鬆弛劑;腦代謝增強劑;利尿劑諸如托塞米(torsemide)及速尿(furosemide);及抗癲癇藥物諸如加巴噴丁(gabapentin)、普瑞巴林(pregabalin)、丙戊酸鈉(valproate)、托吡酯(topiramate)、卡馬西平(carbamazepine)、拉莫三嗪(lamotrigine)、奧卡西平(oxcarbazepine);及抗帕金森藥物諸如司來吉蘭(selegiline);抗精神病藥物諸如利培酮(risperidone)、齊拉西酮(ziprasidone)、喹硫平(quetiapine)、奧氮平(olanzapine)、氯氮平(clozapine)、帕利哌酮(paliperidone)、及其等之藥物學可接受鹽類在本發明中亦可能採用的。還有,生物製劑諸如口服疫苗在本發明中亦可能採用的。
較佳地,該活性成分可能選自由下列所組成之
該群組:左旋西替利嗪;孟魯司特;安布索;左旋羥丙哌
嗪(levodropropizine);氯沙坦;伊貝沙坦;胺氯地平;瑞舒伐他汀;阿托伐他汀;阿司匹林;氯吡格雷;醋氯芬酸;乙哌立松;埃索美拉唑;萘普生;及其等之藥物學可接受鹽類。
在本發明複合調配物中,該MUST可能進一步
包含藥物學可接受添加劑,該者選自由下列所組成之該群組:藥物學可接受的稀釋劑、崩解劑、黏合劑、安定劑、潤滑劑、著色劑、及其等之一混合物。
該稀釋劑可能選自下列所組成之該群組:微晶
纖維素、乳糖、Ludipress®、甘露糖醇、磷酸二氫鈣、澱粉、低取代羥丙基纖維素、及其等之一混合物。該所採用的稀釋劑數量可能為約1至99wt%,較佳地約5至90wt%,以該錠劑之總重量為基準。
該崩解劑可能為在液體環境中安全膨脹的任何
材料,該者係選自由下列所組成之該群:交聯聚維酮(crospovidone)、羧甲基澱粉鈉、交聯羧甲基纖維素鈉、低取代羥丙基纖維素、澱粉、藻酸鹽、或其之鈉鹽、或其等之一混合物。在本發明之一較佳實施例中,該崩解劑係選自由低取代羥丙基纖維素、交聯聚維酮、羧甲基澱粉鈉、交聯羧甲基纖維素鈉、及其等之一混合物所組成之該群組。該所採用的崩解劑數量可能為約1至30wt%,較佳地約2至15wt%,以該錠劑之總重量為基準。
該黏合劑可能選自由下列所組成之該群組:羥
丙基纖維素、羥丙基甲基纖維素、聚乙烯基吡咯烷酮、共
聚維酮(copovidone)、聚乙二醇(macrogol)、輕質無水矽酸、合成矽酸鋁、諸如矽酸鈣或偏矽酸鋁鎂(magnesium metasilicate aluminate)的矽酸鹽衍生物、諸如磷酸氫鈣的磷酸鹽、諸如碳酸鈣的碳酸鹽、及其等之一混合物,且該所採用之黏合劑數量可能從約1至30wt%,較佳地約2至15wt%,以該錠劑之總重量為基準。
該安定劑可能為抗氧化劑、酸化劑或鹼化劑。
抗氧化劑之具體實例包括丁基羥基甲苯
(BHT)、丁基羥基茴香醚(BHA)、抗壞血酸、抗壞血酸棕櫚酸酯、乙二胺四乙酸(EDTA)、焦亞硫酸鈉、及其等之一混合物;特別地,丁基羥基甲苯係為較佳的。酸化劑之具體實例包括有機酸,諸如富馬酸、檸檬酸、酒石酸、琥珀酸、乳酸、蘋果酸、甲苯磺酸(tosylic acid)、草酸、抗壞血酸、麩胺酸、藻酸、馬來酸、己二酸及之類;無機酸,諸如鹽酸、硫酸、硝酸、磷酸、醋酸、硼酸及之類,以及其等之一混合物,較佳地富馬酸、檸檬酸、酒石酸與磷酸。鹼化劑之實例包括精胺酸、離胺酸、組胺酸、美洛明(meglumine)、矽酸鋁鎂、偏矽酸鎂鋁(aluminum magnesium metasilicate),或基本礦物質,諸如NaHCO3、CaCO3、MgCO3、KH2PO4、K2HPO3、磷酸三鈣及之類,較佳地NaHCO3、CaCO3、MgCO3或其等之一混合物。
該安定劑可以取決於該藥物學活性成分的天性
而選擇,且該所採用之安定劑數量可能為約0.01至10wt%,以該所選擇之藥物學活性成分之總數量為基準。
該潤滑劑可能選自由下列所組成之該群組:硬
脂酸、諸如硬脂酸鈣與硬脂酸鎂的硬脂酸金屬鹽、滑石、膠態二氧化矽(colloidal silica)、脂肪酸蔗糖酯、氫化植物油、高熔點的蠟、甘油脂肪酸酯、甘油二十二酸酯(glycerol dibehenate)及其等之一混合物中,且該所採用之潤滑劑數量可能為約0.02至5wt%之一範圍內,較佳地約0.3至3wt%,以該錠劑之總重量為基準。
該著色劑可能選自由下列所組成之該群組:紅
色氧化鐵顏料、黃色氧化鐵顏料、二氧化鈦、藍色1號、藍色2號、以及其等之一混合物,且該所採用之著色劑數量可能在約0.001至2wt%之一範圍內,較佳地約0.01至1.5wt%,以該錠劑之總重量為基準。
本發明複合調配物包含數個MUST,且因此具
有一非常快的溶出率,而不會羥歷在初始溶出中之一降低。一般地,一傳統硬膠囊調配物要求該膠囊的崩解時間,因此歸因於該初始溶出率(15分鐘之內)的放緩,其係有一缺點為在該溶出試驗結果之偏差中的提高。因此,其可能難以預期源自一複合調配物之一單一劑量形式的相同生物等效性,假若其包含要求一快速吸收率的藥物,例如,1至2小時的最大藥物濃度時間(Tmax)。然而,本發明複合調配物包含數個具有小尺寸的錠劑,該等可以同時快速地崩解,且從而在初始溶出率沒有延遲。
相應地,本發明複合調配物之一或多種活性成
分係為立即釋放藥物,一種或多種活性成分在投藥後5分
鐘內具有30%或更高之一體外初始溶出率,及在投藥後10分鐘內80%或更高之一體外初始溶出率(參閱圖3至5)。
進一步,本發明複合調配物完全分隔每一活性成分,確保改良的溶出率與長期儲存時一良好的安定性。這種有利的效果可以進一步藉由塗覆該MUST而增強的。相應地,本發明之該MUST可能塗覆以一聚合物薄膜塗佈層,以為了物理上防止該二或更多活性成分之間任何可能的交互作用。
可以形成一薄膜塗層的任何常規聚合物可能在本發明之薄膜塗佈層中使用。具體實例包括水溶性聚合物,諸如聚乙烯醇、羥乙基纖維素、羥丙甲纖維素(hypromellose)、聚乙烯吡咯烷酮、以及其等之一混合物;水不溶性聚合物,諸如羥丙甲纖維素酞酸酯(HPMCP)、聚乙酸乙烯酯(例如,Kollicoat®SR30D)、水不溶性聚甲基丙烯酸酯共聚物[諸如,聚(丙烯酸乙酯-甲基丙烯酸甲酯)共聚物(例如,Eudragit®NE30D)、聚(丙烯酸乙酯-甲基丙烯酸甲酯-氯化甲基丙烯酸三甲基胺基乙酯(trimethylaminoethyl methacrylate chloride))共聚物(例如Eudragit®RSPO),及之類]、乙基纖維素、纖維素酯、纖維素醚、纖維素醯化物、纖維素二醯化物、纖維素三醯化物、纖維素乙酸酯、纖維素二乙酸酯、纖維素三乙酸酯、及其等之一混合物,但不限於此。
此種聚合物之採用不僅作用以將活性成分彼此分隔開,但亦作用以允許在該相同膠囊中形成具不同溶出
率的MUST(例如,立即/持續或立即/腸溶)。在此種事例中,該MUST係塗覆以該聚合物,且然後可以如該藥物設計者意欲的所欲比率充填的,以便於調控相同藥物族群之間或不同藥物族群之間的溶出率。此種有利的效果可能藉由採用數個迷你錠劑作為本發明中之MUST而成為可能。
聚合物數量可能調整的,以在一有效方式中提
供具有一合適尺寸與溶出率的錠劑,該者較佳地約為1至50wt%,更佳地約1至20wt%,以該錠劑之總重量為基準。每一錠劑係完全分隔並形成一獨立的劑型,防止錠劑之間任何的交互作用。還有,在根據本發明製備之活性成分的安定性分析中,其將足夠藉由用於分析單一藥品的常規方法,而不是為此之任何特殊方法,分析含在膠囊中每一錠劑的安定性。
還有,本發明提供了一種用於製備該硬膠囊複
合調配物的方法,該者包含下列步驟:(1)製備包含一藥物活性成分的MUST;及(2)囊封數個該等MUST於該硬膠囊中,藉由此,該硬膠囊複合調配物包含二或多個藥物活性成分。該方法可能進一步包含在上文該方法之步驟(1)期間以一聚合物薄膜塗覆該MUST的一額外步驟。
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。
- 旋西替利嗪層-
- 孟魯司特層-
該含有左旋西替利嗪的錠劑層係如下文描述般
製備。左旋西替利嗪二鹽酸鹽、Ludipress®(BASF)、微晶纖維素、檸檬酸、交聯羧甲基纖維素鈉、輕質無水矽酸與
硬酯酸鎂係過篩且混合,且然後將所得得到之混合物使用一錠劑壓製機伴隨2.0mm之模具直徑壓製成錠劑,以產生10個MUST,其中每一錠劑具有8.3mg的重量,約2.0mm的厚度,以及1.3mm的圓柱高度。
分別地,一塗佈溶液係藉由將Opadry® Y-1-7000
溶解在蒸餾水中而製備,且該塗佈液係施用於上文製備之該含有左旋西替利嗪的MUST上。由此獲得之該10個MUST的總重量為85mg,且在其中之該左旋西替利嗪的總重量為為5mg。
與此同時,該含有孟魯司特的錠劑層係如下文
描述般製備。孟魯司特鈉、D-甘露糖醇、微晶纖維素、輕質無水矽酸、羥丙基纖維素、羧甲基澱粉鈉與硬酯酸鎂係過篩且摻合,然後將所得得到之混合物使用一錠劑壓製機伴隨2.0mm之模具直徑壓製成錠劑,以產生20個MUST,其中每一錠劑具有8.3mg的重量,約2.0mm的厚度,以及1.3mm的圓柱高度。
分別地,一塗佈溶液係藉由將羥丙甲纖維素、
羥丙基纖維素、二氧化鈦、紅色氧化鐵及黃色氧化鐵溶解於蒸餾水中而製備,且該塗佈液係施用於上文製備之該含有孟魯司特的MUST上。由此獲得之該20個MUST的總重量為170mg,且在其中之該孟魯司特的總重量為為10mg。
上文製備之該兩個不同的MUSTs,10個含有左旋
西替利嗪的MUSTs及20個含有孟魯司特的MUSTs,係充填於
主要由明膠製成之1號硬膠囊的膠囊主體中,以產生一硬膠囊調配物其包含10mg的孟魯司特與5mg的左旋西替利嗪。
- 安布索層-
- 左旋羥丙哌嗪層-
該含有安布索的錠劑層係如下文描述般製備。
安布索鹽酸鹽、乳糖水合物與預膠化澱粉係摻合,加入藉由將聚維酮K-30溶解於蒸餾水中而製備的一黏合劑溶液,且該混合物係濕式造粒的。輕質無水矽酸與硬酯酸鎂係添加到該者中,且該混合物係使用一錠劑壓製機伴隨2.0mm之模具直徑壓製成錠劑,以產生10個MUST,其中每一錠劑具有7.8mg的重量,及約2.0mm的厚度,以及1.3mm的圓柱高度。由此獲得之該10個MUST的總重量為78mg,且
在其中之該安布索鹽酸鹽的總重量為為30mg。
與此同時,該含有左旋羥丙哌嗪的錠劑層係如
下文描述般製備。該左旋羥丙哌嗪、乳糖水合物、微晶纖維素、羧甲基澱粉鈉及硬酯酸鎂係過篩且摻合,且然後將所得到之混合物使用一錠劑壓製機伴隨2.0mm之模具直徑壓製成錠劑,以產生20個MUST,其中每一錠劑具有8.0mg的重量,約2.0mm的厚度,以及1.4mm的圓柱高度。
由此獲得之該20個MUST的總重量為160mg,且在其中之該左旋羥丙哌嗪的總重量為為60mg。
上文製備之該兩個不同的MUSTs,10個含有安
布索鹽酸鹽的MUSTs及20個含有左旋羥丙哌嗪的MUSTs,係充填於主要由明膠製成之1號硬膠囊的膠囊主體中,以產生一硬膠囊調配物其包含30mg的安布索鹽酸鹽與60mg的左旋羥丙哌嗪。
- 氯沙坦層-
- 胺氯地平層-
該含有氯沙坦的錠劑層係如下文描述般製備。
該氯沙坦鉀、Ludipress®(BASF)、共聚維酮、交聯羧甲基纖維素鈉、輕質無水矽酸及硬酯酸鎂係過篩且摻合,且然後將該混合物使用一錠劑壓製機伴隨2.0mm之模具直徑壓製成錠劑,以產生12個MUST,其中每一錠劑具有8.3mg的重量,約2.0mm的厚度,以及1.2mm的圓柱高度。
分別地,一塗佈溶液係藉由將Opadry® Y-1-7000
溶解於蒸餾水中而製備,且該塗佈液係施用於上文製備之該含有氯沙坦的MUST上。由此獲得之該12個MUST的總重量為102mg,且在其中之該氯沙坦的總重量為為50mg。
與此同時,該含有胺氯地平的錠劑層係如下文
描述般製備。該胺氯地平樟腦磺酸鹽(Amlodipine camsylate)、甘露糖醇、微晶纖維素、羧甲基澱粉鈉、羥丙基纖維素及硬酯酸鎂係過篩且摻合,然後將該所得到之混合物使用一錠劑壓製機伴隨2.0mm之模具直徑壓製成錠
劑,以產生12個MUST,其中每一錠劑具有8.3mg的重量,約2.0mm的厚度,以及1.3mm的圓柱高度。
分別地,一塗佈溶液係藉由將Opadry® Y-1-7000
溶解於蒸餾水中而製備,且該塗佈液係施用於上文製備之該含有胺氯地平的MUST上。由此獲得之該12個MUST的總重量為102mg,且在其中之該胺氯地平的總重量為為10mg。
上文製備之該兩個不同的MUSTs,12個含有氯
沙坦的MUSTs及12個含有胺氯地平的MUSTs,係充填於主要由明膠製成之2號硬膠囊的膠囊主體中,以產生一硬膠囊調配物其包含50mg的氯沙坦與10mg的胺氯地平。
- 瑞舒伐他汀層-
- 阿司匹林層-
該含有瑞舒伐他汀的錠劑層係如下文描述般製
備。該瑞舒伐他汀鈣、乳糖水合物、微晶纖維素、交聯聚維酮及硬酯酸鎂係過篩且摻合,且然後將該混合物使用一錠劑壓製機伴隨2.0mm之模具直徑壓製成錠劑,以產生10個MUST,其中每一錠劑具有8.3mg的重量,約2.0mm的厚度,以及1.3mm的圓柱高度。
分別地,一塗佈溶液係藉由將Opadry® Y-1-7000
溶解於蒸餾水中而製備,且該塗佈液係施用於上文製備之該含有瑞舒伐他汀的MUST上。由此獲得之該10個MUST的總重量為86mg,且在其中之該胺氯地平的總重量為為10mg。
與此同時,該含有阿司匹林的錠劑層係如下文
描述般製備。該阿司匹林、微晶纖維素、預膠化澱粉及輕質無水矽酸係摻合。硬酯酸係添加至該所得到之混合物作為一潤滑劑,且然後將該混合物使用一錠劑壓製機伴隨2.0mm之模具直徑壓製成錠劑,以產生20個MUST,其中每一錠劑具有7.05mg的重量,約2.0mm的厚度,以及1.2mm的圓柱高度。
分別地,一塗佈溶液係藉由將羥丙甲纖維素酞
酸酯、二氧化鈦及乙醯化單甘油酯溶解於乙醇及丙酮之一混合溶劑中而製備,且該塗佈液係施用於上文製備之該含有阿司匹林的MUST上。由此獲得之該20個MUST的總重量為160mg,且在其中之該阿司匹林的總重量為為100mg。
上文製備之該兩個不同的MUSTs,10個含有瑞舒
伐他汀的MUSTs及20個含有阿司匹林的MUSTs,係充填於主要由明膠製成之1號硬膠囊的膠囊主體中,以產生一硬膠囊調配物其包含10mg的瑞舒伐他汀與100mg的阿司匹林。
- 氯吡格雷層-
- 阿司匹林層-
該含有氯吡格雷的錠劑層係如下文描述般製
備。該氯吡格雷硫酸鹽、D-甘露糖醇、低取代羥丙基纖維素及脂肪酸蔗糖酯係過篩且摻合,且然後將該混合物使用一錠劑壓製機伴隨2.0mm之模具直徑壓製成錠劑,以產生20個MUST,其中每一錠劑具有8.0mg的重量,約2.0mm的厚度,以及1.3mm的圓柱高度。
分別地,一塗佈溶液係藉由將Opadry®
32K-14834溶解於蒸餾水中而製備,且該塗佈液係施用於上文製備之該含有氯吡格雷的MUST上。由此獲得之該20個MUST的總重量為164mg,且在其中之該氯吡格雷的總重量為為75mg。
與此同時,該含有阿司匹林的錠劑層係如下文
描述般製備。該阿司匹林、微晶纖維素、預膠化澱粉及輕質無水矽酸係摻合。硬酯酸係添加至該所得到之混合物作為一潤滑劑,且然後將該混合物使用一錠劑壓製機伴隨2.0mm之模具直徑壓製成錠劑,以產生20個MUST,其中每一錠劑具有7.05mg的重量,約2.0mm的厚度,以及1.2mm的圓柱高度。
分別地,一塗佈溶液係藉由將羥丙甲纖維素酞
酸酯、二氧化鈦及乙醯化單甘油酯溶解於乙醇及丙酮之一混合溶劑中而製備,且該塗佈液係施用於上文製備之該含有阿司匹林的MUST上(腸溶塗層enteric coating)。由此獲得之該20個MUST的總重量為160mg,且在其中之該阿司
匹林的總重量為為100mg。
上文製備之該兩個不同的MUSTs,20個含有氯
吡格雷的MUSTs及20個含有阿司匹林的MUSTs,係充填於主要由明膠製成之1號硬膠囊的膠囊主體中,以產生一硬膠囊調配物其包含75mg的氯吡格雷與100mg的阿司匹林。
- 左旋西替利嗪層-
- 孟魯司特層-
該含有左旋西替利嗪的錠劑層係如下文描述般
製備。左旋西替利嗪二鹽酸鹽、Ludipress®、微晶纖維素、檸檬酸、交聯羧甲基纖維素鈉、輕質無水矽酸與硬酯酸鎂係過篩且混合,然後將該混合物使用一錠劑壓製機伴隨5.0mm之模具直徑壓製成錠劑,以產生一錠劑。然後,藉由將Opadry® Y-1-7000溶解在蒸餾水中而製備的一塗佈溶液係施用於該錠劑上以產生該左旋西替利嗪錠劑。由此獲得之該錠劑之總重量為85mg,且在其中之該左旋西替利嗪的總重量為5mg。
與此同時,該含有孟魯司特的錠劑層係如下文
描述般製備。孟魯司特鈉、D-甘露糖醇、微晶纖維素、輕質無水矽酸、羥丙基纖維素、羧甲基澱粉鈉與硬酯酸鎂係過篩且摻合,然後將所得到之混合物使用一錠劑壓製機伴隨5.0mm之模具直徑壓製成錠劑,以產生2個錠劑。分別地,一塗佈溶液係藉由將羥丙甲纖維素、羥丙基纖維素、二氧化鈦、紅色氧化鐵及黃色氧化鐵溶解於蒸餾水中而製備,且該塗佈液係施用於上文製備之該錠劑上以產生該孟魯司特錠劑。由此獲得之該錠劑之總重量為170mg,且在其中之該孟魯司特的總重量為為10mg。
上文製備之該兩個不同的錠劑,1個左旋西替利
嗪錠劑及2個孟魯司特錠劑,係充填於主要由明膠製成之1
號硬膠囊的膠囊主體中,以產生一硬膠囊調配物其包含5mg的左旋西替利嗪與10mg的孟魯司特。
- 安布索層-
- 左旋羥丙哌嗪層-
該含有安布索的錠劑層係如下文描述般製備。
安布索鹽酸鹽、乳糖水合物與預膠化澱粉係摻合,加入藉由將聚維酮K-30溶解於蒸餾水中而製備的一黏合劑溶液,且然後該混合物係濕式造粒的。輕質無水矽酸與硬酯酸鎂係添加到該者中,且該混合物係使用一錠劑壓製機伴隨5.0mm之模具直徑壓製成錠劑,以產生一錠劑。由此獲得之該錠劑的總重量為78mg,且在其中之該安布索鹽酸鹽的總重量為為30mg。
與此同時,該含有左旋羥丙哌嗪的錠劑層係如
下文描述般製備。該左旋羥丙哌嗪、乳糖水合物、微晶纖維素、羧甲基澱粉鈉及硬酯酸鎂係過篩且摻合,然後將所得到之混合物使用一錠劑壓製機伴隨5.0mm之模具直徑壓製成錠劑,以產生兩個錠劑。由此獲得之該錠劑的總重量為160mg,且在其中之該左旋羥丙哌嗪的總重量為為60mg。
上文製備之該兩個不同錠劑,1個安布索錠劑及
2個左旋羥丙哌嗪錠劑,係充填於主要由明膠製成之1號硬膠囊的膠囊主體中,以產生一硬膠囊調配物其包含30mg的安布索鹽酸鹽與60mg的左旋羥丙哌嗪。
在實例1與比較實例1中製備的包含孟魯司特與左旋西替利嗪之該等複合調配物及分別作為孟魯司特與左旋西替利嗪參照藥物的Singulair®錠劑(MSD,10mg)與Xyzal®錠劑(韓國UCB公司,5mg),係羥受藥物溶出試驗,該試驗係於下面條件下對每一藥物使用6個試驗容器。其結果係顯示於表1及圖3與圖4中。
對孟魯司特=0.5%月桂基硫酸鈉(SLS)溶液,900mL
對左旋西替利嗪=蒸餾水,900mL
- 溶出試驗系統:槳式攪拌器,75rpm
- 溫度:37℃
- 柱:不銹鋼柱其填充以5μm十八烷基矽烷凝膠用於液相
色層分析(Inertsil C8,4.6 x 150mm,5μm)
- 動相:0.025M磷酸二氫鉀(pH為6.6)、乙腈(40:60,v/v)
- 測器:紫外分光光度計(225nm)
- 動速率:1.0mL/min
- 射體積:10μL
- 柱溫度:45℃
如表1及圖3與圖4中所顯示,在實例1中製備包
含MUST之該複合調配物展現較高的初始溶出率(在10分鐘之內),較諸包含傳統錠劑的比較實例1,甚至類似於該等參照藥物Singulair®錠劑(孟魯司特)與Xyzal®錠劑(左旋西替利嗪)。
此外,實例1之孟魯司特與左旋西替利嗪的溶出
試驗結果較諸比較實例1的溶出試驗結果表現顯著較小的標準偏差值,且從而在身體吸收率中的較小變化可以從本發明複合調配物預期的。所以,其亦可能預期的是,對本發明包含MUST的硬膠囊複合調配物與其等之參照藥物Singulair®與Xyzal®為生物等效性將會更容易些。
在實例2與比較實例2中製備的包含安布索與左
旋羥丙哌嗪之該等複合調配物及作為安布索之參照藥物的Mucopect®錠劑(Boehringer Ingelheim,30mg),係經受藥物溶出試驗,該試驗係於下面條件下對每一藥物使用6個試驗容器。其結果係顯示於表2及圖5中。
- 溶出介質:pH 1.2人工胃液,900mL
- 溶出試驗系統:槳式攪拌器,75rpm
- 溫度:37℃
- 柱:不銹鋼管柱其填充以5μm十八烷基矽烷凝膠用於
液相色層分析(Waters ODS-2,4.6mm x 50mm,5μm)
- 動相:0.05M磷酸二氫鉀(使用磷酸調整pH至3.0)、甲醇
(88:12,v/v)
- 測器:紫外分光光度計(254nm)
- 動速率:1.0mL/min
- 射體積:10μL
- 柱溫度:30℃
如表2及圖5中所顯示,在實例2中製備包含MUST之該複合調配物展現遠遠較高的初始溶出率(在10分
鐘之內),及遠遠較小的標準偏差值的變化,較諸填充以傳統錠劑的比較實例2。
所以,其可以預期的是假若安布索,該者之初始
溶出率被係認為關鍵於一給定的0.25至1hr之Tmax,係在本發明包含MUST的硬膠囊複合調配物形式中製備的,然後對本發明複合調配物與其之參照藥物Mucopect®錠劑為生物等效性將會更容易些,且身體吸收率中的較小變化亦為預期的。
包含孟魯司特與左旋西替利嗪、在實例1中製備的複合調配物,及分別作為孟魯司特與左旋西替利嗪的參照藥物的Singulair®錠劑10mg與Xyzal®錠劑5mg,係在下面條件下經口投藥至用於生物可用率試驗的試驗動物。
該試驗動物係為健康、雄性、體重12±2kg的20月齡的米格魯犬,且每一試驗組係配發5隻狗。這些狗係安置在一個籠子裡,允許自由地接近商業狗飼料(每天400g),且然後在實驗前14小時禁食一段時間。這些狗係分成兩組:第1組(實例1)及第2組(Singulair®錠劑+Xyzal®錠劑)。每一隻狗係經口投藥以該對應的調配物,並強迫投以40mg的水。血液樣本(2mL)係使用具抗凝血劑(1,000 IU/mL,肝素5μl)的管子,從頭靜脈採樣,於經口投藥後0(初始)、0.25、0.5、1、2、3、4、8、10、24及48小時後。所有的血液樣本係離心(12,000rpm,2分鐘,Eppendorf)成血漿,並含在-20℃的冰箱中,用於稍後在下列條件下藉由LC-MS分析每一樣品:
管柱:Halo C18(2.1×50mm,2.7μm)
移動相:甲醇、10mM甲酸銨(85:15,v/v)
注射數量:10μL
偵測:渦輪離子噴霧電離模式(正)
Cmax與Tmax係從血中濃度對時間曲線圖獲得的,且在投藥後0到24小時的AUC係根據根據梯形規則使用該曲線計算。該等結果係顯示於表3及圖6與圖7中。
如表3及圖6與圖7中所顯示,實例1之複合調配
物較諸同時服用該兩個單一調配物參照錠劑具有等同或較優的生物可用率。
根據實例1之該複合調配物引致孟魯司特與左旋
西替利嗪的AUC及Cmax類似於其等之參照藥物,Singulair®錠劑與Xyzal®錠劑,且在Tmax值中顯示沒有延遲,而是稍微小的Tmax值。
Claims (11)
- 一種包含二或多種藥物學活性成分的硬膠囊複合調配物,其中每單一種藥物學活性成分係被包含在一具有直徑在1至4mm之範圍內的多單位球形錠(MUST)中,且每一藥物學活性成分有4至40個MUST係被囊封在該硬膠囊中,以及其中每一MUST具有範圍在1:0.8至1:1.2內之一直徑與厚度比,及範圍在1:0.5至1:0.8內之一厚度與圓柱高度比。
- 如申請專利範圍第1項之硬膠囊複合調配物,其中每一MUST之直徑係小於或等於該硬膠囊之內徑的1/2。
- 如申請專利範圍第1項之硬膠囊複合調配物,其中該硬膠囊係為硬膠囊0號、硬膠囊1號、硬膠囊2號、硬膠囊3號或硬膠囊4號。
- 如申請專利範圍第1項之硬膠囊複合調配物,其中每一藥物學活性成分係選自由下列所組成之群組:左旋西替利嗪(levocetirizine);孟魯司特(montelukast);安布索(ambroxol);左旋羥丙哌嗪(levodropropizine);氯沙坦(losartan);伊貝沙坦(ibesartan);胺氯地平(amlodipine);瑞舒伐他汀(rosuvastatin);阿托伐他汀(atorvastatin);阿司匹林;氯吡格雷(clopidogrel);醋氯芬酸(aceclofenac);乙哌立松(eperisone);埃索美拉唑(esomeprazole);萘普生(naproxen);及其等之藥物學可接受鹽類。
- 如申請專利範圍第1項之硬膠囊複合調配物,其中每一MUST包含一藥物學可接受的添加劑。
- 如申請專利範圍第5項之硬膠囊複合調配物,其中該藥物學可接受添加劑係選自由下列所組成之該群組:藥物學可接受的稀釋劑、崩解劑、黏合劑、安定劑、潤滑劑、著色劑、及其等之一混合物。
- 如申請專利範圍第1項之硬膠囊複合調配物,其中每一MUST係塗覆以一聚合物薄膜塗佈層。
- 如申請專利範圍第1項之硬膠囊複合調配物,其中一或多個藥物學活性成分係立即釋放的。
- 如申請專利範圍第8項之硬膠囊複合調配物,其中一或多個藥物學活性成分具有距投藥5分鐘內30%或更大之一體外初始溶出率,及距投藥10分鐘內80%或更大之一體外初始溶出率。
- 一種用於製備如申請專利範圍第1項之硬膠囊複合調配物的方法,該者包含:(1)製備具有直徑在1至4mm之範圍內的一MUST,其包含有一藥物活性成分,其中每一MUST具有範圍在1:0.8至1:1.2內之一直徑與厚度比,及範圍在1:0.5至1:0.8內之一厚度與圓柱高度比;及(2)囊封每一藥物學活性成分4-40個MUST於該硬膠囊中,藉此使得該硬膠囊複合調配物包含二或多個藥物學活性成分。
- 如申請專利範圍第10項之方法,該者進一步包含在步驟(1)期間以一聚合物薄膜塗覆每一MUST。
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UA (1) | UA116102C2 (zh) |
WO (1) | WO2013154390A1 (zh) |
ZA (1) | ZA201408285B (zh) |
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KR101910901B1 (ko) | 2013-11-29 | 2018-10-24 | 한미약품 주식회사 | 암로디핀, 로자탄 및 로수바스타틴을 포함하는 약제학적 복합 제제 |
EP3209285A1 (en) * | 2014-10-21 | 2017-08-30 | Reckitt Benckiser LLC | Pharmaceutical capsule containing at least two tablets |
CN108156807A (zh) * | 2015-06-30 | 2018-06-12 | 韩美药品株式会社 | 含有氨氯地平、氯沙坦和瑞舒伐他汀的药物复合制剂 |
BE1023011B1 (nl) * | 2015-08-05 | 2016-11-04 | Nordic Specialty Pharma Bvba | Acetylsalicylzuur tablet met onmiddellijke afgifte |
CA3001337C (en) | 2015-10-09 | 2023-12-12 | Reckitt Benckiser Llc | Pharmaceutical formulation |
KR101625344B1 (ko) * | 2015-12-21 | 2016-06-08 | 주식회사 유영제약 | 세레콕시브 및 둘록세틴을 함유하는 약제학적 조성물 |
PL3222279T3 (pl) | 2016-03-21 | 2022-05-09 | Invest Bielany Spółka Z Ograniczoną Odpowiedzialnością | Doustny preparat farmaceutyczny montelukastu i lewocetyryzyny oraz sposób jego wytwarzania |
KR101920996B1 (ko) * | 2017-04-26 | 2018-11-22 | 알보젠코리아 주식회사 | HMG-CoA 환원효소 저해제 및 칼슘채널 차단제를 포함하는 복합제제 |
JP2020535113A (ja) * | 2017-09-28 | 2020-12-03 | ハンミ ファーマシューティカルズ カンパニー リミテッド | エソメプラゾール、及びその薬学的に許容可能な塩を含むマルチユニット球状錠剤を含む薬剤学的組成物、並びにその製造方法 |
KR102026982B1 (ko) * | 2018-02-02 | 2019-09-30 | 주식회사 씨티씨바이오 | 캡슐 충진 장치 |
KR102612984B1 (ko) * | 2019-04-02 | 2023-12-13 | 한미약품 주식회사 | 에스오메프라졸 또는 이의 약학적으로 허용 가능한 염을 포함하고 이중방출 프로파일을 갖는 약학적 조성물 |
KR20210052281A (ko) * | 2019-10-29 | 2021-05-10 | 신에쓰 가가꾸 고교 가부시끼가이샤 | 캡슐 충전용 조성물 및 이것을 사용한 캡슐 제제의 제조 방법 그리고 캡슐 제제 |
US20210275531A1 (en) * | 2020-03-04 | 2021-09-09 | VK Research Associates Inc | Phosphodiesterase-5 inhibitor combinations, methods of making, and methods of use thereof |
BR112022021011A2 (pt) | 2020-04-17 | 2022-12-27 | Honeybrains Llc | Composições e métodos para tratamento de distúrbios neuropsiquiátricos |
EP4085903A1 (de) * | 2021-05-07 | 2022-11-09 | Midas Pharma GmbH | Minitablette enthaltend losartan für pädiatrische anwendungen |
CA3229117A1 (en) * | 2021-08-19 | 2023-02-23 | Dorit MIMROD | Method of treating parkinson's disease |
KR20240045586A (ko) | 2022-09-30 | 2024-04-08 | 주식회사 제뉴원사이언스 | 레보세티리진 또는 이의 약학적으로 허용가능한 염 및 몬테루카스트 또는 이의 약학적으로 허용가능한 염을 포함하는 안정성이 향상된 이층정 정제 및 그의 제조방법 |
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BR0012869A (pt) * | 1999-07-30 | 2002-05-21 | Smithkline Beecham Plc | Forma de dosagem farmacêutica de componentes múltiplos |
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KR100949273B1 (ko) * | 2008-02-22 | 2010-03-25 | 한올제약주식회사 | 복합제제 |
WO2009127974A2 (ko) * | 2008-02-22 | 2009-10-22 | 한올제약주식회사 | 심혈관계 질환 치료용 약제학적 제제 |
WO2009118359A2 (en) * | 2008-03-28 | 2009-10-01 | Ferrer Internacional S.A. | Capsule for the prevention of cardiovascular diseases |
TR201005325A2 (tr) * | 2010-06-30 | 2012-01-23 | Bi̇lgi̇ç Mahmut | Atorvastatin ve aspirin içeren farmasötik formülasyonlar |
KR101298788B1 (ko) | 2011-03-15 | 2013-08-22 | 보령제약 주식회사 | 안정성이 개선된 복합제제 |
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Also Published As
Publication number | Publication date |
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PT2836207T (pt) | 2020-03-26 |
JP6129295B2 (ja) | 2017-05-17 |
TW201345568A (zh) | 2013-11-16 |
PH12014502271B1 (en) | 2014-12-10 |
BR112014024964A8 (pt) | 2021-06-15 |
CN110051642B (zh) | 2021-12-31 |
CN104220050A (zh) | 2014-12-17 |
PE20142035A1 (es) | 2014-12-24 |
ES2778864T3 (es) | 2020-08-12 |
CL2014002717A1 (es) | 2015-01-09 |
KR101378973B1 (ko) | 2014-03-28 |
RU2014145557A (ru) | 2016-06-10 |
CO7131367A2 (es) | 2014-12-01 |
KR20130115864A (ko) | 2013-10-22 |
SG11201406298RA (en) | 2014-11-27 |
JP2015517998A (ja) | 2015-06-25 |
US20150098992A1 (en) | 2015-04-09 |
MY171703A (en) | 2019-10-23 |
MX2014012144A (es) | 2014-12-05 |
EP2836207B1 (en) | 2020-02-19 |
BR112014024964B1 (pt) | 2022-03-15 |
MX354328B (es) | 2018-02-27 |
ZA201408285B (en) | 2016-09-28 |
HK1204959A1 (zh) | 2015-12-11 |
BR112014024964A2 (pt) | 2017-06-20 |
CN110051642A (zh) | 2019-07-26 |
EP2836207A1 (en) | 2015-02-18 |
PL2836207T3 (pl) | 2020-07-27 |
WO2013154390A1 (en) | 2013-10-17 |
EP2836207A4 (en) | 2015-08-19 |
PH12014502271A1 (en) | 2014-12-10 |
UA116102C2 (uk) | 2018-02-12 |
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