TWI436763B - 有效成分具有分界而成之醫藥固形製劑 - Google Patents
有效成分具有分界而成之醫藥固形製劑 Download PDFInfo
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- TWI436763B TWI436763B TW098129783A TW98129783A TWI436763B TW I436763 B TWI436763 B TW I436763B TW 098129783 A TW098129783 A TW 098129783A TW 98129783 A TW98129783 A TW 98129783A TW I436763 B TWI436763 B TW I436763B
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- 238000002360 preparation method Methods 0.000 title claims description 45
- 239000007787 solid Substances 0.000 title claims description 30
- 239000004480 active ingredient Substances 0.000 title claims description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 88
- 239000008187 granular material Substances 0.000 claims description 54
- 239000011668 ascorbic acid Substances 0.000 claims description 43
- 235000010323 ascorbic acid Nutrition 0.000 claims description 43
- 229960005070 ascorbic acid Drugs 0.000 claims description 43
- 229960000401 tranexamic acid Drugs 0.000 claims description 43
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 claims description 43
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 claims description 36
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 claims description 35
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 29
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims description 24
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 claims description 21
- 229940011671 vitamin b6 Drugs 0.000 claims description 21
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 claims description 20
- 239000011726 vitamin B6 Substances 0.000 claims description 20
- 235000019158 vitamin B6 Nutrition 0.000 claims description 20
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 claims description 18
- 239000011713 pantothenic acid Substances 0.000 claims description 18
- 229940055726 pantothenic acid Drugs 0.000 claims description 18
- 235000019161 pantothenic acid Nutrition 0.000 claims description 18
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 claims description 15
- 229960002079 calcium pantothenate Drugs 0.000 claims description 15
- 235000013878 L-cysteine Nutrition 0.000 claims description 14
- 239000004201 L-cysteine Substances 0.000 claims description 14
- 229960002433 cysteine Drugs 0.000 claims description 14
- 239000004615 ingredient Substances 0.000 claims 1
- 235000008160 pyridoxine Nutrition 0.000 claims 1
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- 235000010980 cellulose Nutrition 0.000 description 35
- 238000002845 discoloration Methods 0.000 description 28
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 26
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- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 4
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- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 206010064127 Solar lentigo Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
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Description
本發明為有關凝血酸(tranexamic acid)和抗壞血酸經由互相隔著分界而存在,而不易發生製劑變色之內服用固形製劑。
凝血酸為作為抗血纖維蛋白溶酶劑具有抗出血、抗過敏、抗炎症效果等,廣泛使用作為醫療用醫藥品,也配合於OTC醫藥品。於1979年對慢性蕁麻疹患者投與凝血酸,竟有併發之肝斑消退之報告,以此為機對肝斑治療習將凝血酸為處方(以上參照例如非專利文獻1)。
抗壞血酸早已知不僅抑制黑色素色素之產生,且由分解既蓄積之黑色素色素之作用,而抑制色素之沈著,於OTC醫藥品,對維生素C主藥製劑之承認效能,承認因污垢、肝斑、日晒‧斑疹之色素沈著(參照非專利文獻2)。
又有掲示含有凝血酸和抗壞血酸之色素沈著症治療用製劑,而比投與凝血酸單劑或抗壞血酸單劑之場合,其色素沈著症之改善度更佳之報告(參照專利文獻1)。
更由本發明者等掲示含有凝血酸、抗壞血酸及L-半胱胺酸之美白用組成物,比併用凝血酸和抗壞血酸更抑制色素沈著(參照專利文獻2)。
但至今未知於凝血酸和抗壞血酸有配合變化。
(專利文獻1)特開平4-243825號公報
(專利文獻2)特開2004-217655號公報
(非專利文獻1)PharmaciaVol.44No.52008p.437-442
(非專利文獻2)一般用醫藥品製造(輸入)承認基準時報2008年版
發明欲解決之課題
本發明者等於專利文獻1之實施例1掲示之將含有凝血酸與抗壞血酸之顆粒劑實際試作之際,發現經時保存(溫度40℃、相對濕度75%之加速試驗)而有漸次變色(紅變)之問題。
故本發明之課題為提供含有凝血酸和抗壞血酸之製劑中,無變色等而安定性優異之內服用固形製劑。
本發明者等為解決上述課題反覆製劑之試行錯誤之結果,發現如下事實,終於完成本發明。
1.將(a)含有凝血酸之顆粒,與(b)含有抗壞血酸之顆粒分別製劑來製造則可抑制製劑變色。
2.於1.記載之製劑進一步含有「維生素B6(pyridoxine)」時,於含有維生素B6之顆粒中含有L-半胱胺酸,則可抑制製劑變色。
3.於1.記載之製劑進一步含有「L-半胱胺酸(cystein)」時,於含有L-半胱胺酸之顆粒中含有泛酸(pantothenic acid),則可抑制製劑變色。
4.於1.記載之製劑進一步配合「維生素B6及泛酸」時,於含有維生素B6及泛酸之顆粒中含有L-半胱胺酸,則可抑制製劑變色。
也即本發明為如下示發明。
(1)由凝血酸及抗壞血酸作為有效成分而成,此等於製劑中隔著分界存在而成為特徵之內服用固形製劑。
(2)(a)由凝血酸作為有效成分而成之成分,和(b)由抗壞血酸作為有效成分而成之成分,係隔著分界而含有為特徵之內服用固形製劑。
(3)於(2)記載之成分為顆粒之(2)記載之固形製劑。
(4)於(a)、(b)之任一方或雙方含有L-半胱胺酸及維生素B6之(2)或(3)記載之固形製劑。
(5)於(a)、(b)之任一方或雙方含有L-半胱胺酸及泛酸之(2)或(3)記載之固形製劑。
(6)於(a)、(b)之任一方或雙方、含有L-半胱胺酸、泛酸及維生素B6之(2)或(3)記載之固形製劑。
(7)維生素B6為維生素B6鹽酸鹽之(4)或(6)記載之內服用固形製劑。
(8)泛酸為泛酸鈣之(5)或(6)記載之內服用固形製劑。
本發明為即使配合凝血酸和抗壞血酸亦抑制製劑變色之安定的內服用固形製劑而為有用的。再者,含有L-半胱胺酸、維生素B6或/及泛酸,也抑制製劑變色之安定內服用固形製劑而為有用的。
本發明之「維生素B6」為維生素B6及其鹽,宜為維生素B6鹽酸鹽。
本發明之「泛酸」為泛酸及其鹽,宜為泛酸鈣。
本發明之「固形製劑」為記載於第15改正日本藥典之顆粒劑、丸劑、散劑、錠劑、膠囊劑等。
本發明之內服用固形製劑宜為顆粒劑、散劑、膠囊劑或錠劑。
又本發明之顆粒劑或錠劑之適宜態樣可為施予糖衣或膜衣者。也即糖衣顆粒、膜衣顆粒、糖衣錠、膜衣錠等。
本發明之內服用固形製劑為錠劑之場合,可為將組成相異之粉末或顆粒以2層或3層以上重疊壓縮成型之多層錠也為適宜之態樣。
本發明之「互相隔著分界存在」乃指固形製劑中有複數之藥劑等存在時,這些藥劑等不均勻混合存在,無直接藥劑彼此反應,而於同一固形製劑中存在之狀態。例如各藥劑之間有結合劑或賦形劑等不與藥劑反應之物質存在,或各藥劑存於相異之顆粒的複數之顆粒存在之固形製劑。
由於如此藥劑乃「互相隔著分界存在」,故即使有複數之藥劑於同一固形製劑中存在,因實質上藥劑彼此不接觸,而能抑制固形製劑之變色。
本發明之固形製劑之製造方法可為經如下工程之方法:
(1)將(a)含有凝血酸之顆粒,和(b)含有抗壞血酸之顆粒個別製造、
(2)若為錠劑之場合,將各顆粒混合後,壓縮成型。
本發明使用之凝血酸、抗壞血酸、泛酸鈣、維生素B6鹽酸鹽收載於第15改正日本藥典。
又L-半胱胺酸收載於醫藥品添加物規格2003。
作為本發明之固形製劑,含有凝血酸、抗壞血酸、L-半胱胺酸、維生素B6鹽酸鹽及泛酸鈣時,其含有比為凝血酸每1重量份,抗壞血酸、L-半胱胺酸、維生素B6鹽酸鹽及泛酸鈣之含有比率各如下:宜為0.01~10重量份、0.01~10重量份、0.001~1重量份及0.001~1重量份,更宜為0.1~2重量份、0.1~2重量份、0.001~0.5重量份及0.01~0.5重量份。
為更詳細說明本發明,以下記載實施例及比較例。
於流動層造粒機投入‧混合凝血酸96.2g、抗壞血酸38.5g、適量結晶纖維素,將羥丙基纖維素水溶液噴霧,得顆粒劑。
於該顆粒混合滑石而作為試驗用顆粒。殘餘之顆粒與結晶纖維素、交聯羧甲醚纖維素鈉、硬脂酸鎂混合後,打錠而得錠劑。
於流動層造粒機投入‧混合凝血酸96.2g、抗壞血酸38.5g、L-半胱胺酸30.8g、維生素B6鹽酸鹽0.8g、適量結晶纖維素,將羥丙基纖維素水溶液噴霧,得顆粒劑。
於該顆粒混合滑石,作為試驗用之顆粒。殘餘之顆粒與結晶纖維素、交聯羧甲醚纖維素鈉、硬脂酸鎂混合後,打錠而得錠劑。
於流動層造粒機投入‧混合凝血酸750mg、抗壞血酸300mg、L-半胱胺酸240mg、泛酸鈣37mg、維生素B6鹽酸鹽6mg及適量結晶纖維素,將羥丙基纖維素水溶液噴霧,得顆粒劑。
於該顆粒混合滑石,而作為試驗用顆粒。殘餘之顆粒與結晶纖維素、交聯羧甲醚纖維素鈉、硬脂酸鎂混合後,打錠而得錠劑。
於流動層造粒機投入‧混合凝血酸96.2g、抗壞血酸38.5g、適量結晶纖維素,將羥丙基纖維素水溶液噴霧,得顆粒1。又混合L-半胱胺酸30.8g、泛酸鈣4.7g、維生素B6鹽酸鹽0.8g、適量結晶纖維素,將羥丙基纖維素水溶液噴霧,得顆粒2。
於該顆粒混合滑石,而作為試驗用顆粒。殘餘之顆粒與結晶纖維素、交聯羧甲醚纖維素鈉、硬脂酸鎂混合後,打錠而得錠劑。
於流動層造粒機投入‧混合凝血酸96.2g、L-半胱胺酸30.8g、適量結晶纖維素,將羥丙基纖維素水溶液噴霧,而作為顆粒a。又混合抗壞血酸38.5g、泛酸鈣4.7g、維生素B6鹽酸鹽0.8g、適量結晶纖維素,將羥丙基纖維素水溶液噴霧,得顆粒b。
於該顆粒混合滑石,而作為試驗用顆粒。殘餘之顆粒與結晶纖維素、交聯羧甲醚纖維素鈉、硬脂酸鎂混合後,打錠而得錠劑。
於流動層造粒機投入‧混合凝血酸96.2g、維生素B6鹽酸鹽0.8g、適量結晶纖維素,將羥丙基纖維素水溶液噴霧,得顆粒a。又混合抗壞血酸38.5g、L-半胱胺酸30.8g、泛酸鈣4.7g、適量結晶纖維素,將羥丙基纖維素水溶液噴霧,得顆粒b。
於該顆粒混合滑石,而作為試驗用顆粒。殘餘之顆粒與結晶纖維素、交聯羧甲醚纖維素鈉、硬脂酸鎂混合後,打錠而得錠劑。
於流動層造粒機投入‧混合凝血酸96.2g、泛酸鈣4.7g、維生素B6鹽酸鹽0.8g、適量結晶纖維素,將羥丙基纖維素水溶液噴霧,得顆粒a。又混合L-半胱胺酸30.8g、抗壞血酸38.5g、適量結晶纖維素,將羥丙基纖維素水溶液噴霧,得顆粒b。
於該顆粒混合滑石,而作為試驗用顆粒。殘餘之顆粒與結晶纖維素、交聯羧甲醚纖維素鈉、硬脂酸鎂混合後,打錠而得錠劑。
於流動層造粒機投入‧混合凝血酸96.2g、L-半胱胺酸30.8g、泛酸鈣4.7g、適量結晶纖維素,將羥丙基纖維素水溶液噴霧,得顆粒a。又混合抗壞血酸38.5g、維生素B6鹽酸鹽0.8g、適量結晶纖維素,將羥丙基纖維素水溶液噴霧,得顆粒b。
於該顆粒混合滑石,而作為試驗用顆粒。殘餘之顆粒與結晶纖維素、交聯羧甲醚纖維素鈉、硬脂酸鎂混合後,打錠而得錠劑。
於流動層造粒機混合凝血酸96.2g和適量結晶纖維素,將羥丙基纖維素水溶液噴霧,得顆粒a。又投入‧混合抗壞血酸38.5g和適量結晶纖維素,將羥丙基纖維素水溶液噴霧,得顆粒b。
於該顆粒混合滑石,而作為試驗用顆粒。殘餘之顆粒與結晶纖維素、交聯羧甲醚纖維素鈉、硬脂酸鎂混合後,打錠而得錠劑。
於流動層造粒機混合凝血酸96.2g和適量結晶纖維素,將羥丙基纖維素水溶液噴霧,得顆粒a。又投入‧混合抗壞血酸38.5g、L-半胱胺酸30.8g、維生素B6鹽酸鹽0.8g、適量結晶纖維素,將羥丙基纖維素水溶液噴霧,得顆粒b。
於該顆粒混合滑石,而作為試驗用顆粒。殘餘之顆粒與結晶纖維素、交聯羧甲醚纖維素鈉、硬脂酸鎂混合後,打錠而得錠劑。
於流動層造粒機投入‧混合凝血酸96.2g和適量結晶纖維素,將羥丙基纖維素水溶液噴霧,得顆粒a。又混合抗壞血酸38.5g、L-半胱胺酸30.8g、泛酸鈣4.7g、維生素B6鹽酸鹽0.8g、適量結晶纖維素,將羥丙基纖維素水溶液噴霧,得顆粒b。
於該顆粒混合滑石,而作為試驗用顆粒。殘餘之顆粒與結晶纖維素、交聯羧甲醚纖維素鈉、硬脂酸鎂混合後,打錠而得錠劑。
於流動層造粒機投入‧混合凝血酸2403.8g、L-半胱胺酸769.2g、泛酸鈣118.6g、維生素B6鹽酸鹽19.2g、適量結晶纖維素,將羥丙基纖維素水溶液噴霧,而作為顆粒a。又混合抗壞血酸961.5g、適量結晶纖維素,將羥丙基纖維素水溶液噴霧,而作為顆粒b。
於該顆粒混合滑石,而作為試驗用顆粒。殘餘之顆粒與結晶纖維素、交聯羧甲醚纖維素鈉、硬脂酸鎂混合後,打錠而得錠劑。
於流動層造粒機投入‧混合凝血酸2403.8g、泛酸鈣118.6g、適量結晶纖維素,將羥丙基纖維素水溶液噴霧,而作為顆粒a。又與抗壞血酸961.5g、L-半胱胺酸769.2g、維生素B6鹽酸鹽19.2g、適量結晶纖維素混合,將羥丙基纖維素水溶液噴霧,而作為顆粒b。
於該顆粒混合滑石,而作為試驗用顆粒。殘餘之顆粒與結晶纖維素、交聯羧甲醚纖維素鈉、硬脂酸鎂混合後,打錠而得錠劑。
就實施例1-5及比較例1-8之顆粒、及用該顆粒打錠之錠劑,於50℃放置4日(僅比較例3逕行室溫2週),以冰箱保存品為對照,將各顆粒及錠劑之變色依目視觀察。目視之評價乃用以下之基準。
A:無變色
B:少許變色
C:有變色
D:顯著變色
由表1之結果,得知凝血酸和抗壞血酸不隔著分界分離時,於製劑出現變色。他方面,凝血酸和抗壞血酸隔著分界分離時,得知製劑之變色顯被抑制。
由表2-3之結果,凝血酸和抗壞血酸隔著分界分離時,更含有維生素B6時,可發生變色。
由如此場合得知,也於(a)含有凝血酸之顆粒同時含有維生素B6和L-半胱胺酸,則可顯著抑制變色、或於(b)含有抗壞血酸之顆粒同時含有維生素B6和L-半胱胺酸,則可顯著抑制變色。
又於(a)含有凝血酸之顆粒,及於(b)含有抗壞血酸之顆粒之雙方,同時含有維生素B6和L-半胱胺酸,則可顯著抑制變色。
由表4之結果,將凝血酸和抗壞血酸隔著分界分離之場合,更含有L-半胱胺酸時,可發生變色。
即使如此場合得知,(a)於含有凝血酸之顆粒,同時含有L-半胱胺酸和泛酸,則可顯著抑制變色,或(b)於含有抗壞血酸之顆粒,同時含有L-半胱胺酸和泛酸,則可顯著抑制變色。
由表5之結果得知,凝血酸與抗壞血酸隔著分界分離之場合,更將維生素B6和泛酸同一顆粒中存在之場合,發生變色。
即使如此場合得知,(a)於含有凝血酸之顆粒,同時含有維生素B6和泛酸及L-半胱胺酸,則可顯著抑制變色,或(b)於含有抗壞血酸之顆粒,同時含有維生素B6和泛酸及L-半胱胺酸,則可顯著抑制變色。
綜合以上表2-5之結果得知,將凝血酸和抗壞血酸隔著分界分離之場合,更為抑制含有藥劑場合之變色,可施行如下:
(1)更含有維生素B6時,於同一成分中同時含有L-半胱胺酸。
(2)更含有L-半胱胺酸時,於同一成分中同時含有泛酸。
(3)更含有維生素B6和泛酸時,於同一成分中含有L-半胱胺酸。
Claims (8)
- 一種內服用固形製劑,其特徵為由凝血酸(tranexamic acid)及抗壞血酸構成有效成分,此等成分於製劑中隔著分界存在。
- 一種內服用固形製劑,其特徵為(a)作為有效成分之由凝血酸而成之成分,和(b)作為有效成分之由抗壞血酸而成之成分,係隔著分界而含有。
- 如申請專利範圍第2項之固形製劑,其中之成分為顆粒。
- 如申請專利範圍第2或3項之固形製劑,其中於(a)、(b)之任一方或雙方含有L-半胱胺酸及維生素B6(pyridoxine)。
- 如申請專利範圍第2或3項之固形製劑,其中於(a)、(b)之任一方或雙方含有L-半胱胺酸及泛酸。
- 如申請專利範圍第2或3項之固形製劑,其中於(a)、(b)之任一方或雙方含有L-半胱胺酸、泛酸及維生素B6。
- 如申請專利範圍第4或6項之內服用固形製劑,其中維生素B6為維生素B6鹽酸鹽。
- 如申請專利範圍第5或6項之內服用固形製劑,其中泛酸為泛酸鈣。
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