TW201832760A - 改善凝膠化輔助劑之析出的硬質膠囊及其調製方法 - Google Patents
改善凝膠化輔助劑之析出的硬質膠囊及其調製方法 Download PDFInfo
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- TW201832760A TW201832760A TW106142327A TW106142327A TW201832760A TW 201832760 A TW201832760 A TW 201832760A TW 106142327 A TW106142327 A TW 106142327A TW 106142327 A TW106142327 A TW 106142327A TW 201832760 A TW201832760 A TW 201832760A
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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Abstract
本發明以提供一種改善硬質膠囊皮膜的凝膠化輔助劑之析出的硬質膠囊為課題。 本發明經由將非還原性之二糖類或非還原性之二糖醇添加至硬質膠囊皮膜以抑制凝膠化輔助劑之析出。
Description
本發明與一種改善凝膠化輔助劑之析出的硬質膠囊、前述硬質膠囊的調製液及前述硬質膠囊的調製方法有關。
以纖維素化合物作為基劑主成分之硬質膠囊的製造方法中,有冷凝膠法與熱凝膠法。由於冷凝膠法能夠經由和以明膠製造硬質膠囊同樣的過程製作,所以設備成本能夠降低。而且,由於冷凝膠法在乾燥時的溫度只要在室溫~40℃左右即可,從能量成本來看也是有利的,從環境保護方面來看也是理想的。
在藉由冷凝膠法將以纖維素化合物作為膠囊皮膜主成分之硬質膠囊成形的情況下,會使用凝膠化劑及凝膠化輔助劑。其中以卡帕型鹿角菜膠作為凝膠化劑,以KCl作為凝膠化輔助劑,在低溫下的凝膠化性能高且硬質膠囊的製造性(生產性)優異,對維持硬質膠囊的皮膜硬度是有效的。
所謂在低溫下的凝膠化性能高,指的是將在室溫左右的模塑針(mold pin)浸漬於硬質膠囊調製液中再取出,其後當冷卻硬質膠囊調製液時,硬質膠囊調製液隨著溫度下降而表現出快速且急遽的黏度增加,凝膠化的傾向高。僅藉由附著於模塑針表面之硬質膠囊調製液因水分蒸發造成的硬化,直到完全硬化為止需時數分鐘~數十分鐘,而且其間會由於附著於針上之皮膜物質發生滴落而無法得到均勻的膠囊皮膜。若凝膠化性能高則調製液可在短時間內硬化,因而可得到膜厚度均一的硬質膠囊。此外,藉由凝膠化而幾乎完成硬化之硬質膠囊皮膜,在之後即使加速乾燥(提高乾燥中吹送之空氣的溫度、增加空氣的數量等)以使水分自皮膜蒸發,也不易發生皺褶等缺陷。凝膠化性能高還會使乾燥時間縮短,而且可增加單位時間內的硬質膠囊製造數量。
一般來說,由於凝膠化劑添加量多則凝膠化劑的凝膠化性能高,添加過多則膠囊皮膜容易破裂,所以相對於羥丙基甲基纖維素100質量部大多以0.4質量部左右的方式添加(專利文獻1)。而且,若凝膠化劑多則凝膠化輔助劑的添加量也隨之增加,但一般來說相對於羥丙基甲基纖維素100質量部大多以0.6質量部以下的方式添加(專利文獻1)。
為了進一步提升硬質膠囊的製造性,需要提高凝膠化的性能並盡可能在短時間內使之硬化。為了提升凝膠化性能,可同時考慮凝膠化劑本身的凝膠化性能與增加凝膠化輔助劑的添加量以促進凝膠化。
另一方面,若大量添加凝膠化輔助劑,則在濕度特別高的情況下保存硬質膠囊時會有凝膠化輔助劑結晶化並析出的問題。尤其是容易在透明的硬質膠囊以目視確認發白粉末的附著,因此在外觀•美觀方面也不理想。
目前為止,有報告指出利用具有適度取代度之羥丙基甲基纖維素,具體來說是在將硬質膠囊皮膜中之羥丙基甲基纖維素全量設為100%時,以達到20~100%之範圍的方式添加取代度等級2208的羥丙基甲基纖維素,可抑制這種析出(專利文獻2)。 [先前技術文獻] [專利文獻]
[專利文獻1]日本特開2010-27003號公報 [專利文獻2]日本特開2000-297102號公報
[發明所欲解決之課題]
然而,即使可藉由專利文獻2所記載的方法觀察到凝膠化輔助劑的析出抑制效果,但仍難以更進一步增加凝膠化輔助劑添加量以使硬質膠囊的製造性提升。
本發明以提供一種即使增加凝膠化輔助劑之添加量,凝膠化輔助劑之析出仍受到抑制的硬質膠囊為課題,即以提供一種改善凝膠化輔助劑之析出的硬質膠囊為課題。 [用以解決課題之手段]
本發明者經過反覆專注研究後,發現經由將非還原性二糖類或非還原性二糖醇添加至硬質膠囊皮膜,可不損及以纖維素化合物為基劑主成分之硬質膠囊的優點如機械強度(硬度、不易破裂性)、溶出性等特性,而得到顯著的析出抑制效果。 本發明為基於該發現而完成者,並包含以下的態樣。
I. 硬質膠囊 I-1. 一種硬質膠囊,其係由包含(1)纖維素化合物、(2)凝膠化劑、(3)凝膠化輔助劑以及(4)選自由非還原性二糖類及非還原性二糖醇所成群之至少一種之皮膜所構成,在將水分以外之硬質膠囊皮膜成分合計設為100質量%的情況下,皮膜中所包含之凝膠化劑的含有量為0.05~10質量%,凝膠化輔助劑的含有量為大於0.6質量%並且5質量%以下。 I-2. 如I-1之硬質膠囊,在將水分以外之硬質膠囊的皮膜成分合計設為100質量%的情況下,皮膜中所包含之選自由非還原性二糖類及非還原性二糖醇所成群之至少一種的含有量為1~10質量%。 I-3. 如I-1或I-2之硬質膠囊,其中纖維素化合物為纖維素之羥基的氫原子被選自由烷基及羥烷基所成群之至少一個基取代之水溶性纖維素醚。 I-4. 如I-1~I-3中任一項之硬質膠囊,其中纖維素化合物為羥丙基甲基纖維素。 I-5. 如I-1~I-4中任一項之硬質膠囊,其中凝膠化劑為選自由鹿角菜膠、果膠及結蘭膠所成群之至少一種。 I-6. 如I-1~I-5中任一項之硬質膠囊,其中凝膠化劑為卡帕型鹿角菜膠。 I-7. 如I-1~I-6中任一項之硬質膠囊,其中凝膠化輔助劑為可在水溶液中產生鈉離子、鉀離子或鈣離子之化合物。 I-8. 如I-1~I-7中任一項之硬質膠囊,其中凝膠化輔助劑為氯化鉀。 I-9. 如I-1~I-8中任一項之硬質膠囊,其中非還原性二糖類為選自由海藻糖及蔗糖所成群之至少一種。 I-10. 如I-1~I-9中任一項之硬質膠囊,其中非還原性二糖醇為選自由麥芽糖醇、乳糖醇及異麥芽酮糖醇所群之至少一種。 I-11. 如第I-1~I-10中任一項之硬質膠囊,其進一步包含可塑劑及/或遮光劑。
II. 硬質膠囊調製液 II-1. 一種硬質膠囊調製液,其為包含(1)纖維素化合物、(2)凝膠化劑、(3)凝膠化輔助劑以及(4)選自由非還原性二糖類及非還原性二糖醇所成群之至少一種之硬質膠囊的調製液,在將調製液之溶劑以外的成分合計設為100質量%的情況下,溶劑以外的皮膜成分合計中之凝膠化劑的含有量為0.05~10質量%,凝膠化輔助劑的含有量為大於0.6質量%並且5質量%以下。 II-2. 如II-1之硬質膠囊調製液,在將調製液之溶劑以外的成分合計設為100質量%的情況下,其溶劑以外的皮膜成分合計中選自由非還原性二糖類及非還原性二糖醇所成群之至少一種的含有量為1~10質量%。 II-3. 如II-1或II-2之硬質膠囊調製液,其中纖維素化合物為纖維素之羥基的氫原子被選自由烷基及羥烷基所成群之至少一個基取代之水溶性纖維素醚。 II-4. 如II-1~II-3中任一項之硬質膠囊調製液,其中纖維素化合物為羥丙基甲基纖維素。 II-5. 如II-1~II-4中任一項之硬質膠囊調製液,其中凝膠化劑為選自由鹿角菜膠、果膠及結蘭膠所成群之至少一種。 II-6. 如II-1~II-5中任一項之硬質膠囊調製液,其中凝膠化劑為卡帕型鹿角菜膠。 II-7. 如II-1~II-6中任一項之硬質膠囊調製液,其中凝膠化輔助劑為可在水溶液中產生鈉離子、鉀離子或鈣離子之化合物。 II-8. 如II-1~II-7中任一項之硬質膠囊調製液,其中凝膠化輔助劑為氯化鉀。 II-9. 如II-1~II-8中任一項之硬質膠囊調製液,其中非還原性二糖類為選自由海藻糖及蔗糖所成群之至少一種。 II-10. 如I-1~I-9中任一項之硬質膠囊調製液,其中非還原性二糖醇為選自由麥芽糖醇、乳糖醇及異麥芽酮糖醇所成群之至少一種。 II-11. 如II-1~II-10中任一項之硬質膠囊調製液,其進一步包含可塑劑及/或遮光劑。
III. 硬質膠囊的調製方法 III-1. 一種硬質膠囊的調製方法,其包含下述步驟: 使用如II-1~II-11中任一項之硬質膠囊調製液以調製硬質膠囊之步驟。 III-2. 如III-1之硬質膠囊的調製方法,其中前述硬質膠囊的調製方法為冷凝膠法。 III-3. 如III-1或III-2之硬質膠囊的調製方法,其中前述硬質膠囊的調製方法為用以抑制凝膠化輔助劑之析出者。 [發明之效果]
藉由本發明可提供改善凝膠化輔助劑之析出的硬質膠囊。該硬質膠囊的凝膠化性能獲得改善,而且可期待提升硬質膠囊之製造性(生產性)。
1. 硬質膠囊 本發明之硬質膠囊由包含(1)纖維素化合物、(2)凝膠化劑、(3)凝膠化輔助劑以及(4)選自由非還原性二糖類及非還原性二糖醇所成群之至少一種之皮膜所構成。
於本說明書,所謂「硬質膠囊」為先製造膠囊的皮膜、再將內容物填充至製造好的膠囊皮膜的類型之膠囊。通常由蓋部與本體部所構成,也被稱為硬膠囊或兩片式膠囊。本發明之「硬質膠囊」中不包含在兩片薄膜之間填充內容物並將薄膜彼此接著而製造之軟膠囊、將內容物和皮膜溶液一起滴進凝固液而製造之無縫膠囊、以及經由基材的析出或乳化使有效成分納入內部而調製之微膠囊。
作為本發明中所使用之纖維素化合物,可舉出纖維素之羥基的氫原子被烷基或羥烷基之至少一個基取代之水溶性纖維素醚。於此,作為上述所謂烷基或羥烷基之「烷基」,可舉出碳數1~6、以1~4為佳之直鏈或分支狀低級烷基,具體來說可舉出甲基、乙基、丙基及丁基。作為水溶性纖維素化合物,具體來說可舉出甲基纖維素等的低級烷基纖維素;羥乙基纖維素及羥丙基纖維素等的羥基低級烷基纖維素;還有羥乙基甲基纖維素、羥乙基乙基纖維素以及羥丙基甲基纖維素(於本說明書有時亦稱為羥丙基甲基纖維素或HPMC)等的羥基低級烷基烷基纖維素等。其中,從皮膜成形性及在低水分下之機械性強度優異的觀點來看,又以羥丙基甲基纖維素為最適合之纖維素化合物。此外,作為將纖維素化合物適用於硬質膠囊之例,可舉出美國專利第2526683號說明書、美國專利第2718667號說明書、美國專利第3617588號說明書、美國專利第4365060號說明書、美國專利第4993137號說明書、美國專利第5032074號說明書、美國專利第5431917號說明書、美國專利第5756123號說明書、美國專利第6517865號說明書、美國專利第6649180號說明書、美國專利第2010/0168410號說明書、美國專利第9138920號說明書、美國專利第9211659號說明書中記載之例。 本發明中所使用之羥丙基甲基纖維素中包含日本藥局方所訂定之表1中所規定之羥丙基甲基纖維素。
此外,本發明之羥丙基甲基纖維素中包含在日本國被允許使用作為食品添加劑之具有下列分子量之羥丙基甲基纖維素。 <分子量> 非取代結構單元:162.14 取代結構單元:約180(取代度1.19),約210(取代度2.37) 聚合物:約13,000(n=約70)~約200,000(n=約1000)
可從商業途徑取得之羥丙基甲基纖維素的質量平均分子量(Mw)和數目平均分子量(Mn)的比(Mw/Mn)通常在1.5~4的範圍內。再者,計算該比(Mw/Mn)時的無論質量平均分子量(Mw)或數目平均分子量(Mn)都可藉凝膠層析法(粒徑篩析層析法)求出。凝膠層析法的原理及手法並無限制,例如可參見「USP30 The United States Pharmacopeia/NF25 The National Formulary」中「Chromatography」之章「Size-Exclusion Chromatography」之項的記載。
作為可從商業途徑取得之羥丙基甲基纖維素,可舉出信越化學公司之TC-5系列、SB-4系列(註冊商標)、METOLOSE(註冊商標)系列,樂天(LOTTE)(前三星Samsung)精密化學公司之AnyCoat-C(註冊商標)系列,陶氏化學公司(The Dow Chemical Company)之METCEL(註冊商標)系列。 此外本發明中作為對象之羥丙基甲基纖維素(hypromellose)中,包含其2質量%水溶液在20℃±0.1℃下的黏度在3~50mPa•s的範圍內者。
本發明中羥丙基甲基纖維素可單獨使用一種,亦可任意組合兩種以上使用,但無論何者皆可使用「羥丙基甲基纖維素黏度值」為300~5000,以300~1500的範圍為佳,以300~960的範圍為較佳者。於此,所謂「羥丙基甲基纖維素黏度值」,代表用以製造膠囊薄膜之羥丙基甲基纖維素的2質量%水溶液在20℃±0.1℃下的黏度(mPa•s)乘以相對於羥丙基甲基纖維素總量100質量部之該比例(質量部)所得值的總和。具體來說,在單獨使用2質量%水溶液的黏度為6mPa•s之羥丙基甲基纖維素以製造膠囊薄膜的情況下,「羥丙基甲基纖維素黏度值」為「6mPa•s´100質量部」等於600。而在使用2質量%水溶液的黏度為4mPa•s之羥丙基甲基纖維素30質量部、以及6mPa•s之羥丙基甲基纖維素70質量部以製造膠囊薄膜的情況下,「羥丙基甲基纖維素黏度值」為「4mPa•s´30質量部+6mPa•s´70質量部」等於540。
一般來說,分子量越低黏度值越低。此外,在分子量低,即黏度值低的情況下,雖然硬質膠囊的溶解性變好,卻反而有容易破裂的傾向。
因此,對於溶解性受到重視之口服投與醫藥品來說,通常以300~960為佳。另一方面,對於吸入製劑醫藥品及食品用途來說,不易破裂性受到重視,以500~1500為佳。
作為凝膠化劑,可舉例鹿角菜膠、果膠及結蘭膠等能與凝膠化輔助劑組合以使硬質膠囊調製液凝膠化者。此等可單獨使用一種,亦可任意組合兩種以上使用。
上述凝膠化劑之中又以鹿角菜膠的凝膠強度高,而且在與特定離子共存下只要少量使用即表現出優異的凝膠化性,所以是最適合的凝膠化劑。再者,鹿角菜膠一般來說已知有卡帕型(kappa)鹿角菜膠、阿歐塔型(iota)鹿角菜膠及萊姆達型(lambda)鹿角菜膠3種。本發明中可適宜地使用硬度相對較高之具有凝膠化能的卡帕型鹿角菜膠及阿歐塔型鹿角菜膠,可更適宜地使用卡帕型鹿角菜膠。此外可依照酯化度的差異將果膠分類為LM果膠與HM果膠,並且可依照醯化的有無將結蘭膠分類為醯化結蘭膠(天然結蘭膠)與脫醯化結蘭膠,但本發明中無論何者皆可不加以區別地使用。
本發明之硬質膠囊皮膜中所包含之凝膠化劑的含有量,只要是能以冷凝膠法將硬質膠囊皮膜成形即無限制。作為凝膠化劑的含有量,在將水分以外之硬質膠囊的皮膜成分合計設為100質量%的情況下,可舉出為0.05~10質量%,以0.1~9.5質量%為佳,以0.2~9質量%為較佳,以0.3~8質量%為更佳。
凝膠化輔助劑可視使用之凝膠化劑的種類做選擇。凝膠化輔助劑有促進凝膠化劑之凝膠化的效果。或者,有時也會直接作用於纖維素化合物使凝膠化溫度或濁點溫度升高或降低,而有助於促進凝膠化。作為在使用鹿角菜膠作為凝膠化劑的情況下可組合使用之凝膠化輔助劑,有關卡帕型鹿角菜膠可舉出可在水溶液中產生鈉離子、鉀離子、銨離子及鈣離子之一種或兩種以上的化合物,例如氯化鈉、氯化鉀、磷酸鉀、氯化銨、醋酸銨、氯化鈣。以在水中產生鈉離子、鉀離子或鈣離子之化合物為佳。此外,有關阿歐塔型鹿角菜膠可舉出可在水中提供鈣離子之例如氯化鈣。此外,作為在使用結蘭膠作為凝膠化劑的情況下可組合使用之凝膠化輔助劑,可舉出可在水中提供鈉離子、鉀離子、鈣離子及鎂離子之一種或兩種以上的化合物,例如氯化鈉、氯化鉀、氯化鈣、硫酸鎂。此外還可使用檸檬酸或檸檬酸鈉作為有機酸或其水溶性鹽。
本發明之硬質膠囊皮膜中所包含之凝膠化輔助劑的含有量,亦可視凝膠化劑的含有量設定。在將水分以外之硬質膠囊皮膜成分合計設為100質量%的情況下,可將凝膠化輔助劑的含有量設為至少比0.6質量%高,並且為10質量%以下的範圍。作為凝膠化輔助劑的含有量的下限值,可舉出以0.65質量%以上為佳,以0.7質量%以上為較佳,以1質量%以上為更佳,以2.6質量%以上為進一步更佳。作為凝膠化輔助劑的含有量的上限值,可舉出以5質量%以下為佳,以4質量%以下為較佳,以3.5質量%以下為更佳。該上限值與下限值可適當組合。
在使用羥丙基甲基纖維素作為纖維素化合物的情況下,可適宜地舉出鹿角菜膠,特別是卡帕型鹿角菜膠作為合併使用之凝膠化劑,而且可適宜地舉出氯化鉀作為與此合併使用之凝膠化輔助劑。
於本說明書,作為「二糖類」,代表蔗糖、海藻糖、麥芽糖、乳糖、松二糖、纖維二糖等兩個單糖類結合的糖。於本發明,作為二糖類以非還原性之二糖類為佳。還原性的有無,取決於分子內有無醛基。作為非還原性之二糖類,以選自由蔗糖及海藻糖所成群之至少一種為佳。蔗糖及海藻糖的化學式皆為C12
H22
O11
,作為二糖類是例外的非還原性二糖。
於本說明書,所謂「二糖醇」,為包含作為二糖類構成要件之醛糖或酮糖的羰基被還原而生成之糖醇者。本發明中作為二糖醇以非還原性二糖醇為佳。作為非還原性二糖醇,以選自由麥芽糖醇、乳糖醇及異麥芽酮糖醇所成群之至少一種為佳。 糖類或糖醇類的還原性,可在水溶液中依照第16日本藥局方的一般試驗法,4.03消化力試驗法中所記載之以斐林反應來判定。惟,糖類或糖醇類的還原性來自於其在水溶液中所能形成之化學結構中所包含之醛基的還原性。
本發明者們群針對各種單糖、二糖類及二糖醇等糖質,專注研究其對以纖維素化合物為主成分之膠囊皮膜的添加效果後,結果發現於非還原性的二糖類或二糖醇可得到顯著的凝膠化輔助劑析出抑制效果。特別是,還發現到非還原性二糖類幾乎不會因為添加而造成膠囊皮膜硬度降低,並且可得到凝膠化輔助劑析出抑制效果,所以較佳。
專利文獻2中所記載之使用取代度2208羥丙基甲基纖維素所帶來的效果,雖然不及選自由非還原性二糖類及非還原性二糖醇所成群之至少一種糖質所發揮之凝膠化輔助劑析出抑制效果,但仍可能藉由合併兩者使用而達到更顯著的凝膠化輔助劑析出抑制效果。
硬質膠囊皮膜中所包含之選自由非還原性二糖類及非還原性二糖醇所成群之至少一種的含有量,只要能抑制凝膠化輔助劑的析出即無限制。此外,在使用選自由非還原性二糖類及非還原性二糖醇所成群之兩種以上糖質的情況下,所使用之前述糖質的總量以達到下述含有量範圍的方式設定。選自由非還原性二糖類及非還原性二糖醇所成群之至少一種的含有量,在將水分以外之硬質膠囊的皮膜成分合計設為100質量%的情況下,可設為1質量%~ 10質量%之範圍。作為前述含有量的下限值,可舉出以2質量%以上為佳,以3質量%以上為較佳。作為前述含有量的上限值,可舉出以9質量%以下為佳,以8質量%以下為較佳。由於選自由非還原性二糖類及非還原性二糖醇所成群之至少一種的含有總量一旦超過10質量%,硬質膠囊的硬度即會下降,因此該含有量以不超過10質量%為佳。
本發明之硬質膠囊皮膜,亦可視需要包含可塑劑、潤滑劑、螯合劑、著色劑、遮光劑、殘留水分(亦簡稱為水分)等作為硬質膠囊的皮膜成分。
作為可塑劑,只要是能使用於醫藥品或食品組成物者即無特殊限制,但例如可舉出己二酸二辛酯、己二酸聚酯、環氧化大豆油、環氧六氫鄰苯二甲酸二酯、高嶺土、檸檬酸三乙酯、甘油、甘油脂肪酸酯、芝麻油、二甲基聚矽氧烷•二氧化矽混合物、D-山梨糖醇、中鏈脂肪酸甘油三酯、來自玉米澱粉之糖醇液、三乙酸甘油酯、濃甘油、蓖麻油、植物固醇、鄰苯二甲酸二乙酯、鄰苯二甲酸二辛酯、鄰苯二甲酸二丁酯、鄰苯二甲醯丁基乙醇酸丁酯、丙二醇、聚氧乙烯(105)聚氧丙烯(5)二醇、聚山梨醇酯80、聚乙二醇1500、聚乙二醇400、聚乙二醇4000、聚乙二醇600、聚乙二醇6000、肉豆蔻酸異丙酯、棉實油•大豆油混合物、單硬脂酸甘油酯、亞油酸異丙酯等。再者,使用可塑劑時,在將水分以外之硬質膠囊的皮膜成分合計設為100質量%的情況下,通常可舉出15質量%以下的範圍。可在以13質量%以下為佳,以11質量%以下為較佳,以8質量%以下為更佳的範圍內添加。
作為螯合劑,可舉出乙二胺四乙酸、醋酸、硼酸、檸檬酸、葡萄糖酸、乳酸、磷酸、酒石酸或此等之鹽,偏磷酸鹽、二羥乙基甘胺酸、卵磷脂、b-環糊精或此等之組合。
作為潤滑劑,只要是能使用於醫藥品或食品組成物者即無特殊限制。例如可舉出硬脂酸鈣、硬脂酸鎂、硬脂醯反丁烯二酸鈉、棕櫚蠟、澱粉、蔗糖脂肪酸酯、輕質無水矽酸、聚乙二醇、滑石、氫化植物油等。
作為著色劑、遮光劑,只要是能使用於醫藥品或食品組成物者即無特殊限制。作為著色劑,例如可舉出兒茶鞣酸末、薑黃萃取液、氯化甲基薔薇苯胺、黃色氧化鐵、黃色三氧化二鐵、Opaspray K-1-24904、橘子香精、褐色氧化鐵、炭黑、焦糖、胭脂紅、胡蘿蔔素液、β-胡蘿蔔素、感光素201號、甘草萃取物、金箔、山白竹萃取物、黑色氧化鐵、輕質無水矽酸、血竭、氧化鋅、氧化鈦、三氧化二鐵、雙偶氮黃、食用藍色1號及其鋁色澱、食用藍色2號及其鋁色澱、食用黃色4號及其鋁色澱、食用黃色5號及其鋁色澱、食用綠色3號及其鋁色澱、食用紅色2號及其鋁色澱、食用紅色3號及其鋁色澱、食用紅色102號及其鋁色澱、食用紅色104號及其鋁色澱、食用紅色105號及其鋁色澱、食用紅色106號及其鋁色澱、氫氧化鈉、滑石、銅葉綠素鈉、銅葉綠酸、裸麥綠茶萃取物末、裸麥綠茶萃取物、酚紅、螢光素鈉、d-龍腦、孔雀石綠、肉荳蔻酸辛基月桂酯、亞甲藍、藥用碳、丁酸核黃素、核黃素、綠茶末、磷酸錳銨、磷酸核黃素鈉、玫瑰油、薑黃色素、葉綠素、胭脂紅酸色素、食用紅色40號及其鋁色澱、水溶性胭脂樹紅、葉綠酸鐵鈉、杜氏鹽藻胡蘿蔔素、辣椒色素、胡蘿蔔胡蘿蔔素、降胭脂樹素鉀、降胭脂樹素鈉、棕櫚油胡蘿蔔素、甜菜紅、葡萄果皮色素、黑醋栗色素、紅麴色素、紅花紅色素、紅花黃色素、金盞花色素、核黃素磷酸酯鈉、茜草色素、紫草色素、鋁、甘藷胡蘿蔔素、蝦色素、磷蝦色素、橘子色素、可可色素、可可炭末色素、牡蠣色素、螃蟹色素、長角豆色素、魚鱗箔、銀、海州常山色素、梔子藍色素、梔子紅色素、梔子黃色素、薯莨色素、葉綠酸、高粱色素、骨炭色素、竹子色素、牛油樹果色素、紫根色素、紫檀色素、植物炭末色素、蘇木色素、螺旋藻色素、洋蔥色素、羅望子色素、玉米色素、蕃茄色素、花生色素、法夫酵母(Phaffia)色素、胡桃色素、紅麴黃色素、胭脂樹末色素、紅球藻色素、紫甘藷色素、紫玉米色素、紫山芋色素、油煙色素、紫膠色素、芸香苷、槐花萃取物、蕎麥全株萃取物、蘇木色素、紫甘藍色素、紅米色素、紅色蘿蔔色素、紅豆色素、甘茶(Amacha)萃取物、烏賊黑汁色素、藍靛果忍冬色素、接骨木莓色素、橄欖茶、越橘色素、鵝莓色素、蔓越莓色素、鮭莓色素、草莓色素、黑色甜櫻桃色素、櫻桃色素、果實樹莓色素、露珠莓色素、鳳梨果汁、酸越橘色素、葡萄果汁色素、黑醋栗色素、黑莓色素、李子色素、藍莓色素、漿果果汁、伯森莓色素、鳥嘴莓色素、桑椹色素、歐洲酸櫻桃色素、覆盆子色素、紅醋栗色素、檸檬果汁、羅甘莓色素、綠藻末、可可、番紅花色素、紫蘇色素、菊苣色素、海苔色素、洛神花色素、麥芽萃取物、紅椒粉末、甜菜汁、胡蘿蔔汁等。
作為遮光劑,例如可舉出氧化鈦、三氧化二鐵、黃色三氧化二鐵、黑色氧化鐵、食用藍色1號及其鋁色澱、食用藍色2號及其鋁色澱、食用黃色4號及其鋁色澱、食用黃色5號及其鋁色澱、食用綠色3號及其鋁色澱、食用紅色2號及其鋁色澱、食用紅色3號及其鋁色澱、食用紅色102號及其鋁色澱、食用紅色104號及其鋁色澱、食用紅色105號及其鋁色澱、食用紅色106號及其鋁色澱、食用紅色40號及其鋁色澱。 於醫藥用硬質膠囊,為了防止內容物因紫外線等而劣化,有時會添加氧化鈦作為遮光劑。
於調製後之膠囊皮膜,通常以包含數%之殘留水分為佳。通常,若將成形後的膠囊在從30℃至100℃的範圍內進行乾燥處理,即會穩定至對應於膠囊之固體含量及其組成之預定飽和殘留水分值。當然,穩定至飽和水分值為止的時間以在高溫下進行乾燥處理者較短。殘留水分也取決於保存膠囊時的環境濕度,但幾乎是可逆地發生變化。即,在30~100℃的條件下充分進行乾燥處理後的飽和水分值,若更進一步在一定的溫度、相對溼度下保管數日後,即會收斂至一定的值。於本發明,使用在室溫且相對濕度43%的條件下保管數日後的飽和水分值。
包含少量的殘留水分對於維持不易破裂性反而是好的。作為殘留水分在室溫、43%相對濕度下的飽和水分值,相對於膠囊皮膜全質量以至少1%以上為佳,以2%以上為較佳,以3%以上為更佳。另一方面,若殘留水分過多,則在長期保存的情況下有時會引發和內部填充藥物的反應,因此以8%以下為佳,以6%以下為較佳。
殘留飽和水分量能以乾燥損失的含水率表示,其測定能按以下的方式進行。 <以乾燥損失法測定膠囊皮膜中之含水率的方法>
於乾燥器,在置入碳酸鉀飽和水溶液以呈現恆濕狀態的環境中放入樣品(硬質膠囊或薄膜)並密閉,在25℃下調濕一星期。再者,在碳酸鉀飽和水溶液的存在下,可製造相對溼度約43%的環境。測定調濕後之樣品的質量(濕質量)之後,接著在105℃下加熱乾燥該樣品2小時,並再次測定樣品的質量(乾燥質量)。依照下列算式,從乾燥前的質量(濕質量)與乾燥後的質量(乾燥質量)的差算出因在105℃下加熱乾燥2小時而減少之水分量的比例(含水率)。
2. 硬質膠囊調製液 用以調製本態樣之硬質膠囊之膠囊調製液包含溶劑與上述1.中所述之皮膜成分。溶劑,只要是水性溶劑即無特殊限制。作為溶劑以水、乙醇及此等之混合物為佳,以水為較佳。
硬質膠囊調製液中所包含之上述皮膜成分的含有量,只要是能以冷凝膠法將硬質膠囊皮膜成形即無限制。作為凝膠化劑的含有量,在將該調製液之溶劑以外的皮膜成分合計設為100質量%的情況下,溶劑以外的皮膜成分合計中的凝膠化劑含有量可舉出為0.05~10質量%,以0.1~9.5質量%為佳,以0.2~9質量%為較佳,以0.3~8質量%為更佳。
凝膠化輔助劑的含有量,亦可視凝膠化劑的含有量設定。在將該調製液之溶劑以外的皮膜成分合計設為100質量%的情況下,可將溶劑以外的皮膜成分合計中之凝膠化輔助劑的含有量設為至少比0.6質量%高,並且為10質量%以下的範圍。作為凝膠化輔助劑的含有量的下限值,可舉出以0.65質量%以上為佳,以0.7質量%以上為較佳,以1質量%以上為更佳,以2.6質量%以上為進一步更佳。作為凝膠化輔助劑的含有量的上限值,可舉出以5質量%以下為佳,以4質量%以下為較佳,以3.5質量%以下為更佳。該上限值與下限值可適當組合。
硬質膠囊調製液中所包含之選自由非還原性二糖類及非還原性二糖醇所成群之至少一種的含有量,只要能抑制凝膠化輔助劑的析出即無限制。選自由非還原性二糖類及非還原性二糖醇所成群之至少一種的含有量,在將該調製液之溶劑以外的皮膜成分合計設為100質量%的情況下,在溶劑以外的皮膜成分合計中可設為1質量%~10質量%之範圍。作為前述含有量的下限值,可舉出以2質量%以上為佳,以3質量%以上為較佳。作為前述含有量的上限值,可舉出以9質量%以下為佳,以8質量%以下為較佳。
此外,在使用選自由非還原性二糖類及非還原性二糖醇所成群之兩種以上糖質的情況下,所使用之前述糖質的總量以達到上述含有量範圍的方式設定。
例如,可舉出下述濃度作為膠囊調製液中的終濃度。再者,終濃度代表最終完成之溶液中的濃度,即在實際調製膠囊時所使用之溶液中的濃度。該調製液之溶劑以外的皮膜成分總量在全調製液中的濃度,可舉出10~30質量%,以12~25質量%為佳,以14~20質量%為較佳之範圍作為終濃度的範圍。
關於作為主成分之纖維素化合物,可舉出10~30質量%,以12~25質量%為佳,以14~20質量%為較佳之範圍作為終濃度的範圍。而且,凝膠化劑,可舉出0.005~0.5質量%,以0.01~0.45質量%為佳,以0.015~0.4質量%為較佳之範圍作為終濃度的範圍。此外,凝膠化劑輔助劑,可舉出0.06~3質量%之範圍作為終濃度的範圍作為該濃度。凝膠化輔助劑的含有量的下限值,以0.07質量%以上為佳,以0.1質量%以上為較佳;凝膠化輔助劑的含有量的上限值,以1.8質量%以下為佳,以1.5質量%以下為較佳,以1.2質量%以下為更佳。該上限值與下限值可適當組合。
選自由非還原性二糖類及非還原性二糖醇所成群之至少一種,可將0.03~2.5質量%設為終濃度之範圍。作為該含有量的下限值,可舉出以0.1質量%以上為佳,以0.2質量%以上為較佳。作為該含有量的上限值,可舉出以3.5質量%以下為佳,以3質量%以下為較佳,以2.5質量%以下為更佳。 在包含潤滑劑、著色劑、遮光劑、螯合劑、香料等的情況下,其含有量可分別在0.5質量%以下的範圍內適當設定。
3. 硬質膠囊的調製方法 膠囊調製液(浸漬液)的調製方法並無特殊限制。可任意使用例如將凝膠化劑和凝膠化輔助劑、非還原性二糖類及非還原性二糖醇分散、溶解於加熱至約70~90℃左右的純水中,然後使水溶性纖維素化合物分散,將此冷卻至期望的浸漬液溫度(通常為35~60℃,以40~60℃為較佳)以使水溶性纖維素化合物溶解並調製均勻膠囊調製液(浸漬液)的方法;以及將水溶性纖維素化合物分散於約70~90℃左右的熱水中,暫時將之冷卻以使水溶性纖維素化合物溶解,然後再次加熱並調製至30~60℃左右,進一步添加並溶解凝膠化劑及凝膠化輔助劑,調製均勻膠囊調製液(浸漬液),並調整至期望之浸漬液溫度的方法等。膠囊調製液的黏度並無特殊限制。膠囊調製液的黏度能以下述方式調製為佳:在浸漬膠囊成形用針時所採用之溫度(浸漬液的溫度)的條件下(30~80℃,以40~60℃為佳),膠囊調製液的黏度達到100~20000mPa•s,以300~10000mPa•s為佳。作為膠囊調製液的溶劑含有量,通常可舉出為60~90質量%,以70~85質量為佳。
本發明中規定的黏度,代表以B型旋轉黏度計,在黏度不滿500mPa•s的情況下使用轉子號碼2,在黏度500mPa•s以上、不滿2000mPa•s的情況下使用轉子號碼3,在黏度2000mPa•s以上的情況下使用轉子號碼4,在預定溫度下,以旋轉數60rpm,測定時間1分鐘的條件下進行測定時的黏度。 膠囊調製液中所包含之各成分的濃度稍後再述。
硬質膠囊的調製(成形)方法,只要包含使用本發明之膠囊調製液以調製膠囊之步驟即無特殊限制。硬質膠囊,一般來說,使作為膠囊鑄模之模塑針浸漬於溶解有膠囊皮膜成分之水溶液中,藉由使取出時附著的皮膜硬化並乾燥而得到期望之膠囊形狀與厚度(浸漬法)。具體來說,硬質膠囊的調製方法是經由下述步驟製造:以上述方法調製膠囊調製液或購買膠囊調製液等的準備步驟,與將成形用針浸漬於該膠囊調製液後取出,將附著於膠囊成形用針的溶液凝膠化,然後在20~80℃下將凝膠化了的皮膜乾燥之調製步驟。 更具體地來說,本發明中所使用之硬質膠囊可經由下述之成形步驟製造。
(1)將膠囊成形用針浸漬於含有纖維素化合物、凝膠化劑、凝膠化輔助劑以及選自由非還原性二糖類及非還原性二糖醇所成群之至少一種之膠囊調製液(浸漬液)之步驟(浸漬步驟), (2)將膠囊成形用針從膠囊調製液(浸漬液)中取出,並將附著於該針之外表面的膠囊調製液凝膠化之步驟(凝膠化步驟), (3)將在膠囊成形用針之外表面包覆成形之凝膠化膠囊薄膜(凝膠化皮膜)乾燥之步驟(乾燥步驟), (4)使乾燥了的膠囊薄膜(皮膜)脫離膠囊成形用針之步驟(脫離步驟)。 再者,亦可視需要在上述(4)的步驟之後進行下述加熱步驟。 (5)在上述凝膠化步驟(2)之後的乾燥步驟(3)的前後或同時,或是在脫離步驟(4)之後,在30~150℃下對凝膠化膠囊薄膜(凝膠化皮膜)進行加熱處理之步驟(加熱步驟)。
再者,在使用摻合卡帕型鹿角菜膠作為凝膠化劑之溶液作為膠囊調製液(浸漬液)的情況下,可利用該凝膠化劑會在約40℃以下的溫度凝膠化的現象,將膠囊製造機周圍的溫度通常設定在35℃以下,以30℃以下為佳,以室溫下為佳,經由將附著於膠囊成形用針之外表面的膠囊調製液放涼以進行上述凝膠化步驟(2)(冷凝膠法)。具體來說,在浸漬步驟(1),將視膠囊調製液(浸漬液)液溫而調整至10~30℃,以15~25℃為佳之膠囊成形用針,浸漬於調整至35~60℃,以40~60℃為佳之一定溫度的膠囊調製液(浸漬液),接著在凝膠化步驟(2),將膠囊成形用針從膠囊調製液(浸漬液)中取出,並將附著於該針之外表面的膠囊調製液凝膠化。
乾燥步驟(3)可在室溫下進行。通常,經由送風室溫的空氣來進行。脫離步驟(4)經由將在膠囊成形用針的表面形成的乾燥膠囊薄膜從膠囊成形用針拔出來進行。
作為選擇性步驟之加熱步驟(5),可在凝膠化步驟(2)之後,即膠囊調製液凝膠化(固化)之後進行。加熱處理的時期,只要是在凝膠化步驟(2)之後無論任何階段皆可,可在乾燥步驟(3)的前或後進行,或者亦可同時進行加熱與乾燥。此外亦可在脫離步驟(4)之後。以在凝膠化步驟(2)之後,將凝膠化膠囊薄膜送往室溫下的乾燥步驟,且在乾燥後或半乾的階段進行加熱處理為佳。加熱處理通常可經由送風20~150℃的空氣來進行。只要加熱溫度在20~150℃的範圍即無特殊限制,但以25~80℃為佳,以30~50℃的範圍為較佳。
將以這種方式調製之膠囊薄膜切割調整成預定之長度後,可在蓋部與本體部成對嵌合的狀態或不嵌合的狀態下提供作為硬質膠囊。
硬質膠囊的皮膜厚度通常被設定在50~ 200mm的範圍。特別是,膠囊側壁部分的厚度在目前市售膠囊中通常設為70~150mm,以80~120mm為較佳。作為硬質膠囊的尺寸,雖有00號、0號、1號、2號、3號、4號、5號等,但本發明中無論哪個尺寸的硬質膠囊皆可使用。
此外,硬質膠囊的調製方法,亦為用以抑制調製後之硬質膠囊中凝膠化輔助劑之析出的方法。
4. 硬質膠囊之內容物的填充、及用途 將內容物填充至硬質膠囊的方法並無特殊限制。 要將內容物填充至硬質膠囊內,可利用記載於日本特開2007-14401號公報、日本特開2000-226097號公報等之為公眾所知的膠囊填充機,例如全自動膠囊填充機(型號名稱:LIQFILsuper80/150,Qualicaps Co.Ltd.製)、膠囊填充•密封機(型號名稱:LIQFILsuperFS,Qualicaps Co. Ltd.製)等來實施。
於上述填充方法,硬膠囊的暫時結合與正式結合經由美國專利第3508678號說明書、美國專利第3823843號說明書、美國專利第4040536號說明書、美國專利第4822618號說明書、美國專利第5769267號說明書等所示之鎖緊裝置來確保。硬膠囊的硬度對於用以穩定地維持上述鎖緊裝置而言也是重要的。
除了上述蓋部與本體部互相磨合的鎖緊裝置之外,為了進行更確實的密封以防止惡意開封與混入異物,以及為了確實防止液體填充物滲漏,亦可經由日本特開2005-187412號公報或日本特開2009-504630號公報所記載之帶式密封將嵌合部封口。 本發明之硬質膠囊的用途並無特殊限制。可舉出以口服製劑及吸入製劑等為佳。
口服製劑以在胃或腸中快速溶解為理想。為了使膠囊皮膜在腸中溶解並將藥劑釋放至腸中,亦可製成在膠囊皮膜表面附加腸溶性基材塗層之腸溶性膠囊。膠囊皮膜本身亦可全部或部分使用腸溶性基材以製成腸溶性膠囊。所謂腸溶性膠囊只要是具有不在胃中溶解而在腸中溶解的性質者即無特殊限制,但所指的例如是在pH1.2之稀鹽酸溶液中(日本藥局方1液)中經過兩小時以上幾乎不溶解,而在pH6.8之緩衝溶液(日本藥局方2液)中溶解者。
此外亦可使藥劑從硬質膠囊中緩緩釋放。若要使藥劑緩緩地溶出,亦可在膠囊皮膜表面塗覆緩釋性的皮膜。
吸入製劑是預先在硬質膠囊中封入一次投與份量的藥劑,並安裝在如美國專利4069819、美國專利4210140、美國專利7669596、美國專利2010-0300440號公報等所揭示之裝置。可藉由用小針穿孔或破壞膠囊而以適切的流量吸入內部的藥劑。
硬質膠囊劑的內容物並無特殊限制,可沒有限制地舉出人類或動物的醫藥品、準醫藥品、化妝料及食品。 內容物的形狀亦無特殊限制。例如為液狀物、凝膠狀物、粉末狀、顆粒狀、錠劑狀、顆粒狀、或者亦可為此等之混合形狀(複合狀)。
作為硬質膠囊劑之內容物,在醫藥品的情況下例如可舉出選自滋養強壯保健藥、解熱鎮痛消炎藥、精神科藥物、抗焦慮藥、抗憂鬱藥、催眠鎮靜藥、鎮痙藥、中樞神經作用藥、腦代謝改善劑、腦循環改善劑、抗癲癇劑、交感神經興奮劑、胃腸藥、制酸劑、抗潰瘍劑、鎮咳祛痰劑、止吐劑、呼吸促進劑、支氣管擴張劑、過敏用藥、牙科口腔用藥、抗組織胺劑、強心劑、心律不整用劑、利尿藥、降血壓劑、血管收縮藥、冠狀血管擴張劑、末梢血管擴張藥、抗高血脂症用劑、利膽劑、抗生素、化學療法劑、糖尿病治療藥、骨質疏鬆症用劑、抗風濕症藥、骨骼肌鬆弛藥、鎮痙劑、荷爾蒙劑、生物鹼系麻醉藥、磺胺劑、痛風治療藥、抗凝血劑、抗惡性腫瘤劑等之一種或兩種以上的藥物成分。再者,此等藥效成分可無特殊限制地廣泛舉出為公眾所知之成分,但具體來說可舉出WO2006/070578號手冊中段落[0055]~[0060]中記載之各成分為例。
此外,在食品的情況下,例如可舉出二十二碳六烯酸、二十碳五烯酸、a-硫辛酸、蜂王漿、異黃酮、姬松茸、西印度櫻桃、蘆薈、吉拉索蘆薈、薑黃、L-肉鹼、寡糖、可可、兒茶素、辣椒素、洋甘菊、洋菜、生育酚、蘇子油酸、木糖醇、甲殼素、GABA、檸檬酸、綠藻、葡糖胺、人參、輔酶Q10、黑糖、膠原蛋白、軟骨素、多孔菌科、角鯊烯、甜菊、神經醯胺、牛磺酸、皂素、卵磷脂、糊精、魚腥草、菸鹼酸、納豆菌、鹽鹵、乳酸菌、沙巴棕、蜂蜜、薏米、梅肉萃取物、泛酸、玻尿酸、維生素A、維生素K、維生素C、維生素D、維生素B1、維生素B2、維生素B6、維生素B12、槲皮素、蛋白質、蜂膠、長蒴黃麻、葉酸、蕃茄紅素、亞油酸、芸香苷、靈芝等的功能性成分等。但並非受限於此等者。
5. 凝膠化輔助劑之析出的評價 硬質膠囊皮膜中凝膠化輔助劑之析出的評價,例如可經由在調製上述膠囊調製液之後使用流延薄膜塗佈器製作薄膜,並評價該薄膜之凝膠化輔助劑的析出來進行。以薄膜厚度達100mm±5mm的方式製作薄膜,將製作好的薄膜切割為10mm´50mm的大小之後,可在25℃、相對溼度60% (在硝酸銨飽和水溶液存在下)的條件下,每隔一星期以目視觀察接下來有無白濁以評價膠囊化輔助劑之析出。 若無法以目視觀察到白濁,則凝膠化輔助劑之析出可評價為「無析出」。
6. 硬度的評價 硬質膠囊之硬度的評價,例如可經由在製作上述膠囊調製液之後使用流延薄膜塗佈器製作薄膜,並評價該薄膜之硬度來進行。將製作好的薄膜製成薄膜厚度100mm±5mm,並切割為10mm´50mm的大小之後,可在25℃、相對溼度43%(碳酸鉀飽和水溶液)的條件調濕下,例如每隔一星期以壓縮測試評價接下來的硬度。
硬度的評價是在高壓釜(例如Shimadzu Corporation AGS-J)中將上述調濕後的薄膜彎曲成拱形並設置在固定器(如圖1a所示,設置好的薄膜寬度為2cm,設置好的薄膜高度為2cm),以金屬壓頭壓迫薄膜頂部5~8mm (圖2b),並求出薄膜壓縮測試力的峰值(圖2c)。再經由將該值與標準品(糖質以外的成分與測試品成分相同,增量與糖質含有份量等量之基劑而製成的薄膜)之壓縮測試力的值比較來進行。壓縮速度例如為50mm/min,金屬製壓頭的直徑例如為9mm(圖2b)。
在例如將不含下述糖質之標準品的壓縮測試力設為100的情況下,可將90評價為硬度「無硬度變化」。此外,不滿90可評價為「脆弱化」。 [實施例]
以下舉出實施例將本發明做更具體地說明。但本發明並非受實施例限定解釋者。
1. 膠囊皮膜的調製 評價硬質膠囊皮膜中凝膠化輔助劑之析出及硬質膠囊硬度時,測定值會隨膠囊皮膜的厚度,特別是壓入金屬壓頭之膠囊主體部之皮膜厚度而變化。特別是硬度的評價,先統一被測試皮膜的厚度再比較是重要的。因此,取決於硬質膠囊各成分組成之凝膠化輔助劑之析出及硬質膠囊硬度的評價,是以硬質膠囊皮膜各成分分別經由塗佈法製作和硬質膠囊各成分組成同樣成分組成之薄膜,取代經由浸漬法而成形之硬質膠囊,使用該薄膜而進行的。以下,製作和硬質膠囊各成分組成相同成分組成之薄膜取代經由浸漬法而成形之硬質膠囊並進行評價,該薄膜的厚度均一性優異且評價的重現性優異,並且為良好反應作為膠囊皮膜的凝膠化輔助劑之析出抑制效果及硬度者。
1-1. 膠囊調製液的調製 於以下的實施例,如表2所示,使用混合取代度2910中的兩種或三種分子量的HPMC作為用作基劑的HPMC。再者,另外確認凝膠化輔助劑的析出性及膠囊薄膜的硬度並不取決於羥丙基甲基纖維素黏度值。用於實驗的取代度2910羥丙基甲基纖維素適當使用Samsung(現為LOTTE) Fine Chemicals(三星(現為樂天)精密化學公司)製,AnyCoat-C系列黏度等級4及6的AW4及AW6,Shin-Etsu Chemical Co., Ltd.(信越化學公司)製,TC-5系列黏度6的TC-5R。於相同黏度等級值(黏度值),並無觀察到因羥丙基甲基纖維素製造商不同而對凝膠化輔助劑之析出性及硬度造成影響。
膠囊調製液中之溶劑以外的硬質膠囊皮膜成分濃度,可在10~25質量%的範圍內以得到期望膜厚之流延薄膜的方式適當調整。在將水分以外之硬質膠囊皮膜成分合計設為100質量%的情況下,各成分的含有量如表2及表3所示。
將卡帕型鹿角菜膠及作為凝膠化輔助劑之氯化鈉或氯化鉀投入純水中並攪拌使之分散,升溫至80℃後確認溶解,然後使選自由非還原性二糖類及非還原性二糖醇所成群之至少一種溶解。其後在將液溫保持在80℃的狀態下投入HPMC使之分散並靜置30分鐘,並以真空脫泡去除氣泡。 接著,一邊用三一電動機攪拌一邊使之降溫至50℃~60℃,並以三一電動機攪拌一小時以調製膠凍狀之膠囊調製液。
1-2. 薄膜的形成方法 流延薄膜是在保持室溫的玻璃面上或PET膜上設置金屬性之塗佈器,澆注50℃~60℃的膠囊調製液並以一定速度移動以製成100mm的均勻薄膜。為了得到均勻的100mm膜厚,適當運用間隙0.4mm~1.5mm之塗佈器。其後,在室溫~30℃下乾燥10小時左右。
2. 膠囊輔助劑之析出的評價 將製作好的薄膜切割為10mm´50mm的大小之後,在25℃、相對溼度60%(在硝酸銨飽和水溶液存在下)的條件下,每隔一星期以目視觀察接下來有無白濁以評價凝膠化輔助劑之析出。 若無法以目視觀察到白濁,則凝膠化輔助劑之析出可評價為「無析出」。
3. 硬度的評價 將調製好的薄膜並切割為10mm´50mm的條狀之後,在25℃、相對溼度43%(碳酸鉀飽和水溶液)的條件調濕下,每隔一星期以壓縮測試評價調濕後的硬度。
硬度的評價是在高壓釜(Shimadzu Corporation AGS-J)中將上述調濕後的薄膜彎曲成拱形並設置在固定器(如圖1a所示,設置好的薄膜寬度為2cm,設置好的薄膜高度為2cm),以金屬壓頭壓迫薄膜頂部5~8mm(圖2b),並求出薄膜壓縮測試力的峰值(圖2c)。壓縮速度例如為50mm/min,金屬製壓頭的直徑為9mm(圖2b)。藉此擬似地重現壓縮測試力對硬膠囊主體部的施加狀態。
經由比較測得的之各薄膜壓縮應力與標準品(硬度改善劑以外的成分與測試品成分相同,增量與硬度改善劑含有份量等量之基劑而製成的薄膜)之壓縮測試力的值來評價硬度。評價在將標準品的壓縮測試力設為100的情況下的相對壓縮應力。
4. 結果 將製成之薄膜的組成與凝膠化輔助劑之析出抑制效果及硬度的評價結果示於表2及表3。表2及表3中的「○」代表薄膜調製後即使經過1星期也沒有觀察到凝膠化輔助劑之析出。表2的參考例1為凝膠化輔助劑氯化鉀之含有量與傳統硬質膠囊皮膜的含有量相同程度之薄膜。因為參考例1沒有觀察到凝膠化輔助劑之析出,所以表示若是傳統凝膠化輔助劑之含有量,即沒有膠囊調製後凝膠化輔助劑析出的問題。此外,如表2之參考例2所示,一旦將凝膠化輔助劑氯化鉀的含有量增加至0.8質量%,氯化鉀即會析出。此傾向在添加0.8質量%氯化鉀作為凝膠化輔助劑之表3的參考例3也相同,在薄膜調製後第五天觀察到氯化鉀之析出。
另一方面,於增加凝膠化輔助劑含有量的條件中,在確認各種單糖類、二糖類、二糖醇之凝膠化輔助劑的析出抑制效果時發現,僅在添加非還原性二糖類之海藻糖及蔗糖、以及非還原性二糖醇之麥芽糖醇、乳糖醇及異麥芽酮糖醇的情況下即使經過1星期也沒有觀察到氯化鉀之析出。而在其他糖質方面,即使是以和非還原性二糖類及非還原性二糖醇等量的方式添加至薄膜中仍無法抑制凝膠化輔助劑之析出。於表2的比較例3的乳糖,膠囊的透明性喪失。
同樣地,在使用氯化鈉作為凝膠化輔助劑的情況下,氯化鈉的析出也經由添加海藻糖而受到抑制。由此判斷非還原性二糖類及非還原性二糖醇對於抑制凝膠化輔助劑之析出是有效的。
此外,在添加非還原性二糖類及非還原性二糖醇的情況下,亦幾乎沒有觀察到薄膜硬度的下降,但在添加作為單糖之糖醇的木糖醇或赤藻糖醇的情況下則觀察到薄膜硬度略為下降。由此判斷,從維持硬質膠囊之適當硬度並且同時抑制凝膠化輔助劑之析出的觀點來看,非還原性二糖類及非還原性二糖醇也是有效的。
[圖1]圖示被設置在高壓釜中的薄膜。(a)正視圖,(b)立體圖。 [圖2]圖示金屬壓頭壓縮薄膜頂部的樣子。(a)壓縮前,(b)壓縮後。(c)圖示壓縮深度與壓縮測試力的關係。壓頭的直徑為9mm。
Claims (24)
- 一種硬質膠囊,其係由包含(1)纖維素化合物、(2)凝膠化劑、(3)凝膠化輔助劑以及(4)選自由非還原性二糖類及非還原性二糖醇所成群之至少一種之皮膜所構成,在將水分以外之硬質膠囊皮膜成分合計設為100質量%的情況下,皮膜中所包含之凝膠化劑的含有量為0.05~10質量%,凝膠化輔助劑的含有量為大於0.6質量%並且5質量%以下。
- 如申請專利範圍第1項之硬質膠囊,其中在將水分以外之硬質膠囊的皮膜成分合計設為100質量%的情況下,其選自皮膜中所包含之選自由非還原性二糖類及非還原性二糖醇所成群之至少一種的含有量為1~10質量%。
- 如申請專利範圍第1項或第2項之硬質膠囊,其中纖維素化合物為纖維素之羥基的氫原子被選自由烷基及羥烷基所成群之至少一個基取代之水溶性纖維素醚。
- 如申請專利範圍第1項~第3項中任一項之硬質膠囊,其中纖維素化合物為羥丙基甲基纖維素。
- 如申請專利範圍第1項~第4項中任一項之硬質膠囊,其中凝膠化劑為選自由鹿角菜膠、果膠及結蘭膠所成群之至少一種。
- 如申請專利範圍第1項~第5項中任一項之硬質膠囊,其中凝膠化劑為卡帕型鹿角菜膠。
- 如申請專利範圍第1項~第6項中任一項之硬質膠囊,其中凝膠化輔助劑為可在水溶液中產生鈉離子、鉀離子或鈣離子之化合物。
- 如申請專利範圍第1項~第7項中任一項之硬質膠囊,其中凝膠化輔助劑為氯化鉀。
- 如申請專利範圍第1項~第8項中任一項之硬質膠囊,其中非還原性二糖類為選自由海藻糖及蔗糖所成群之至少一種。
- 如申請專利範圍第1項~第9項中任一項之硬質膠囊,其中非還原性二糖醇為選自由麥芽糖醇、乳糖醇及異麥芽酮糖醇所成群之至少一種。
- 如申請專利範圍第1項~第10項中任一項之硬質膠囊,其進一步包含可塑劑及/或遮光劑。
- 一種硬質膠囊調製液,其為包含(1)纖維素化合物、(2)凝膠化劑、(3)凝膠化輔助劑以及(4)選自由非還原性二糖類及非還原性二糖醇所成群之至少一種之硬質膠囊的調製液,在將調製液之溶劑以外的成分合計設為100質量%的情況下,溶劑以外的皮膜成分合計中之凝膠化劑的含有量為0.05~10質量%,凝膠化輔助劑的含有量為大於0.6質量%並且5質量%以下。
- 如申請專利範圍第12項之硬質膠囊調製液,其中在將調製液之溶劑以外的成分合計設為100質量%的情況下,溶劑以外的皮膜成分合計中選自非還原性二糖類及非還原性二糖醇所成群之至少一種的含有量為1~10質量%。
- 如申請專利範圍第12項或第13項之硬質膠囊調製液,其中纖維素化合物為纖維素之羥基的氫原子被選自由烷基及羥烷基所成群之至少一個基取代之水溶性纖維素醚。
- 如申請專利範圍第12項~第14項中任一項之硬質膠囊調製液,其中纖維素化合物為羥丙基甲基纖維素。
- 如申請專利範圍第12項~第14項中任一項之硬質膠囊調製液,其中凝膠化劑為選自由鹿角菜膠、果膠及結蘭膠所成群之至少一種。
- 如申請專利範圍第12項~第16項中任一項之硬質膠囊調製液,其中凝膠化劑為卡帕型鹿角菜膠。
- 如申請專利範圍第12項~第17項中任一項之硬質膠囊調製液,其中凝膠化輔助劑為可在水溶液中產生鈉離子、鉀離子或鈣離子之化合物。
- 如申請專利範圍第12項~第18項中任一項之硬質膠囊調製液,其中凝膠化輔助劑為氯化鉀。
- 如申請專利範圍第12項~第19項中任一項之硬質膠囊調製液,其中非還原性二糖類為選自由海藻糖及蔗糖所成群之至少一種。
- 如申請專利範圍第12項~第20項中任一項之硬質膠囊調製液,其中非還原性二糖醇為選自由麥芽糖醇、乳糖醇及異麥芽酮糖醇所成群之至少一種。
- 如申請專利範圍第12項~第21項中任一項之硬質膠囊調製液,其進一步包含可塑劑及/或遮光劑。
- 一種硬質膠囊的調製方法,其包含下述步驟: 使用如申請專利範圍第12項~第22項中任一項之硬質膠囊調製液以調製硬質膠囊之步驟。
- 如申請專利範圍第23項之硬質膠囊的調製方法,其中前述硬質膠囊的調製方法為冷凝膠法。
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US (1) | US11318102B2 (zh) |
EP (1) | EP3552629A4 (zh) |
JP (1) | JP7039486B2 (zh) |
KR (1) | KR102406542B1 (zh) |
CN (1) | CN110191723B (zh) |
BR (1) | BR112019011253A2 (zh) |
CA (1) | CA3044929A1 (zh) |
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BR112019000111A2 (pt) * | 2016-07-06 | 2019-04-09 | Qualicaps Co., Ltd. | cápsula sólida tendo resistência melhorada, e método para a sua fabricação |
CN109771285B (zh) * | 2019-01-16 | 2021-03-16 | 温州大学 | 基于药用植物材料来源的粉末和药机 |
WO2021024930A1 (ja) | 2019-08-02 | 2021-02-11 | クオリカプス株式会社 | タグを含むバンドシールにより封緘された硬質カプセル製剤 |
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CN110191723B (zh) | 2023-03-10 |
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JP7039486B2 (ja) | 2022-03-22 |
EP3552629A1 (en) | 2019-10-16 |
US20190282509A1 (en) | 2019-09-19 |
JPWO2018105339A1 (ja) | 2019-10-24 |
CN110191723A (zh) | 2019-08-30 |
US11318102B2 (en) | 2022-05-03 |
KR20190093201A (ko) | 2019-08-08 |
EP3552629A4 (en) | 2020-02-05 |
BR112019011253A2 (pt) | 2019-10-08 |
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