TW201501731A - 腸溶錠 - Google Patents
腸溶錠 Download PDFInfo
- Publication number
- TW201501731A TW201501731A TW103105940A TW103105940A TW201501731A TW 201501731 A TW201501731 A TW 201501731A TW 103105940 A TW103105940 A TW 103105940A TW 103105940 A TW103105940 A TW 103105940A TW 201501731 A TW201501731 A TW 201501731A
- Authority
- TW
- Taiwan
- Prior art keywords
- enteric
- film
- ingot
- tablet
- coating
- Prior art date
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- 239000002662 enteric coated tablet Substances 0.000 title claims abstract description 27
- 239000003826 tablet Substances 0.000 claims abstract description 45
- 229920003169 water-soluble polymer Polymers 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 17
- 238000009505 enteric coating Methods 0.000 claims abstract description 12
- 239000002702 enteric coating Substances 0.000 claims abstract description 12
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- 239000004615 ingredient Substances 0.000 claims description 20
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical group NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 claims description 10
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- 229940124597 therapeutic agent Drugs 0.000 claims description 9
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 6
- 229920000642 polymer Polymers 0.000 claims description 6
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- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 239000012528 membrane Substances 0.000 claims 1
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- 238000000576 coating method Methods 0.000 abstract description 51
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- 238000005303 weighing Methods 0.000 abstract 1
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 2
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—Poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/606—Salicylic acid; Derivatives thereof having amino groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
本發明提供一種腸溶錠，其含有大量藥效成分，且在不增厚腸溶性覆膜之情況下具有充分之耐衝擊性。
本發明之腸溶錠之特徵在於：其係具有(A)含有藥效成分之重量1000mg以上之素錠、位於該素錠之表面的(B)含水溶性高分子之覆膜、及位於該含水溶性高分子之覆膜之表面的(C)於pH值7以上之條件下溶解之腸溶性覆膜者，並且覆膜(B)與覆膜(C)之合計量為10~18mg/cm2，覆膜(B)為6~12mg/cm2，覆膜(C)為3~6mg/cm2。
Description
本發明係關於一種腸溶錠。
醫藥品之藥效成分中，有由於在酸性條件下不穩定，故而於經口投予通常之製劑之情形時因被胃酸分解等而變得不再顯示充分之藥效的成分。
另一方面，關於潰瘍性大腸炎或克隆氏病等炎症性腸疾病之治療藥，較理想為藥效成分於作為患部之腸道內自製劑釋出。作為調配有此種藥效成分之醫藥品製劑，有腸溶錠等腸溶性製劑。
例如，作為炎症性腸疾病之治療藥的5-胺基水楊酸(美沙拉，mesalazine)及柳氮磺胺吡啶係作為腸溶性製劑、灌腸劑、栓劑等製劑市售而廣泛使用。此種製劑中，腸溶錠於經口投予之服用性、攜帶性、品質管理等方面優異而被通用。作為該腸溶錠，市售有於溶出試驗第2液(pH值6.8)中溶解之一般腸溶性包衣錠及於pH值7以上之條件下溶解之腸溶性包衣錠。其中，於pH值7以上之條件下溶解之腸溶性包衣錠係於到達作為患部之下消化道(回腸末端~大腸)後釋出藥效成分，因此對大腸之疾病特別有用。
又，具有胃黏膜保護作用、細胞保護作用之聚普瑞鋅係用作胃潰瘍、十二指腸潰瘍之治療劑，最近正研究用於潰瘍性大腸炎或直腸黏膜損傷之灌腸劑(非專利文獻1~4)。於聚普瑞鋅之灌腸療法中，於灌腸劑達到之範圍以內窺鏡可見有意義之改善，而先前之經口投予製
劑難以到達大腸之下部。因此，於聚普瑞鋅之潰瘍性大腸炎或直腸黏膜損傷之治療中，就服藥適應性方面而言，亦期待確實地到達大腸而對患部充分發揮作用之大型腸溶性包衣製劑。
又，作為其他關於腸溶性包衣製劑之技術，報告有腸溶性包衣與pH值依賴性溶解包衣之雙重腸溶性包衣技術(專利文獻1及2)。
[專利文獻1]日本專利特表2001-502333號公報
[專利文獻2]日本專利特表2005-510539號公報
[非專利文獻1] http://informahealthcare.com/doi/abs/10.3109/00365521.2013.863963
[非專利文獻2] http://ir.jikei.ac.jp/bitstream/10328/7851/1/KKN2011-89.pdf
[非專利文獻3] The Journal of JASTRO 21(3/4): 149-154 2009
[非專利文獻4] http://kaken.nii.ac.jp/pdf/2011/seika/C-19/34519/21591622seika.pdf
例如，於5-胺基水楊酸製劑之情形時，由於需要1次服用3錠含有400mg之腸溶錠，故而期待1次投予1錠便可之錠劑。但是，於欲製造出為含有大量藥效成分之大型錠劑且具有耐衝擊性之腸溶錠之情形時，需增厚覆膜，此時有藥物釋出延遲之問題。另一方面，若減薄覆膜，或減少賦形劑之量，則有無法獲得充分之耐酸性，又，耐衝擊性降低之問題。
因此，本發明之課題在於提供一種腸溶錠，其含有大量藥效成
分，且在不增厚腸溶性覆膜之情況下具有充分之耐衝擊性。
因此，本發明者對調配有大量有效成分之腸溶錠之腸溶性能及耐衝擊性、與覆膜組成之關係進行了各種研究，結果若如專利文獻1及2般將腸溶性覆膜設為2層，則於包衣操作時會大量發生錠劑破損，若為了提高耐衝擊性而將覆膜層設為3層，則步驟操作變得煩雜，步驟時間增加，就技術性或成本方面而言，於工業上難以將本技術直接應用於大型錠劑。又，需要分別對各腸溶性覆膜適當地進行步驟管理，腸溶性之控制困難。因此，本發明者進一步反覆研究，結果發現：藉由設為水溶性高分子覆膜與腸溶性覆膜之2層包衣，並將水溶性高分子覆膜設為內部覆膜，將該等覆膜之合計量與覆膜量調整為一定範圍，可兼具於下消化道中之穩定之釋出特性及耐衝擊性，從而完成本發明。
即，本發明係提供以下之[1]~[10]者。
[1]一種腸溶錠，其特徵在於：其係具有(A)含有藥效成分之重量1000mg以上之素錠、位於該素錠之表面的(B)含水溶性高分子之覆膜、及位於該含水溶性高分子之覆膜之表面的(C)於pH值7以上之條件下溶解之腸溶性覆膜者，並且覆膜(B)與覆膜(C)之合計量為10~18mg/cm2，覆膜(B)為6~12mg/cm2，覆膜(C)為3~6mg/cm2。
[2]如[1]之腸溶錠，其中素錠(A)之重量為1000~1500mg。
[3]如[1]或[2]之腸溶錠，其中藥效成分之含量為700~1300mg。
[4]如[1]至[3]中任一項之腸溶錠，其中水溶性高分子係選自水溶性纖維素醚中之1種或2種以上。
[5]如[1]至[4]中任一項之腸溶錠，其中於pH值7以上之條件下溶解之腸溶性覆膜係由選自甲基丙烯酸共聚物中之1種或2種以上之高分子所形成之覆膜。
[6]如[1]至[5]中任一項之腸溶錠，其中腸溶錠之總重量為1200~1600mg。
[7]如[1]至[6]中任一項之腸溶錠，其中藥效成分為大腸疾病治療劑。
[8]如[1]至[6]中任一項之腸溶錠，其中藥效成分為炎症性腸疾病治療劑。
[9]如[1]至[6]中任一項之腸溶錠，其中藥效成分為5-胺基水楊酸。
[10]如[1]至[9]中任一項之腸溶錠，其中覆膜(B)與覆膜(C)之質量比(B/C)為1.0~2.5。
本發明之腸溶錠雖然於1錠中含有大量藥效成分，但具有良好之消化道下部釋出特性，且耐衝擊性優異，對於先前需1次服用多錠之製劑，可1次服用1錠而進行治療。
圖1係表示包衣錠之跌落試驗結果(高度60cm)的圖。
圖2係表示外側包衣量與腸液(pH值7.2)溶出試驗中之製劑之延遲時間的圖。
本發明之腸溶錠之特徵在於：其係具有(A)含有藥效成分之重量1000mg以上之素錠、位於該素錠之表面的(B)含水溶性高分子之覆膜、及位於該含水溶性高分子之覆膜之表面的(C)於pH值7以上之條件下溶解之腸溶性覆膜者，並且覆膜(B)與覆膜(C)之合計量為10~18mg/cm2，覆膜(B)為6~12mg/cm2，覆膜(C)為3~6mg/cm2。
本發明之腸溶錠中之素錠(A)係含有藥效成分之重量1000mg以上之素錠。作為藥效成分，可列舉：非類固醇系抗炎劑、潰瘍治療劑、
抗菌劑、胜肽、蛋白質、類固醇等較佳為於腸道釋出之藥物，尤佳為於下消化道(回腸末端~大腸)釋出之藥物。即，較佳為炎症性腸疾病治療劑、大腸癌治療劑等。其中，作為較佳為對大腸發揮作用之藥物，可列舉：5-胺基水楊酸(美沙拉)、柳氮磺胺吡啶、潑尼松龍、倍他米松、聚普瑞鋅，其中更佳為5-胺基水楊酸。5-胺基水楊酸係用作潰瘍性大腸炎、克隆氏病等炎症性腸疾病之治療藥。
素錠(A)之重量較佳為1000mg以上，就服用性、攜帶性之方面而言，更佳為1000~1500mg，進而較佳為1200~1500mg。又，就服用性、耐衝擊性、攜帶性、用法之方面而言，素錠(A)中之藥效成分之含量較佳為700mg以上，更佳為900~1300mg，進而較佳為1000~1300mg。
於素錠(A)中，可調配除藥效成分以外之通常調配至錠劑中之賦形劑、崩解劑、潤滑劑、結合劑、流動化劑、矯味劑、矯臭劑、塑化劑等。該等添加劑之合計含量於素錠(A)中較佳為100~600mg，更佳為150~400mg，進而較佳為200~400mg。作為賦形劑，可列舉：乳糖、白糖、葡萄糖、甘露糖醇等糖類，澱粉、部分α化澱粉、結晶纖維素、碳酸鈣、硫酸鈣、碳酸氫鈉等。較佳為乳糖、甘露糖醇、澱粉、結晶纖維素，進而較佳為結晶纖維素。作為崩解劑，可列舉：澱粉、瓊脂、明膠粉末、結晶纖維素、羧甲基纖維素鈉、羧甲基纖維素鈣、交聯羧甲基纖維素鈉、交聯聚乙烯吡咯啶酮、碳酸鈣、碳酸氫鈉、羧甲基澱粉鈉、羥丙基甲基纖維素、低取代羥丙基纖維素等。較佳為交聯羧甲基纖維素鈉、交聯聚乙烯吡咯啶酮、羧甲基澱粉鈉、低取代羥丙基纖維素，進而較佳為羧甲基澱粉鈉。作為潤滑劑，可列舉：硬脂酸鎂、硬脂酸鈣、滑石、氫化植物油、聚乙二醇、反丁烯二酸硬脂酯鈉等。較佳為硬脂酸鈣、滑石，進而較佳為硬脂酸鎂。作為結合劑，可列舉：澱粉、阿拉伯膠、明膠、海藻酸鈉、甲基纖維素、
乙基纖維素、聚乙烯吡咯啶酮、聚乙烯醇、羥丙基纖維素、羧甲基纖維素等。較佳為聚乙烯吡咯啶酮、羥丙基纖維素、羥丙基甲基纖維素，進而較佳為聚乙烯吡咯啶酮、羥丙基甲基纖維素。又，亦可視需要添加流動化劑。作為該流動化劑，可列舉輕質無水矽酸等無水矽酸類。
素錠(A)藉由常法製造即可，可為直接粉末壓縮法、乾式顆粒壓縮法、半乾式顆粒壓縮法、濕式顆粒壓縮法任一者。較佳為於濕式造粒後以乾式進行壓縮之方法。
就耐衝擊性之方面而言，素錠(A)之硬度於長徑方向較佳為160N以上，更佳為170N以上，進而較佳為180N以上，進而較佳為160~300N，進而較佳為170~300N。硬度可利用硬度計(PHARMA TEST公司製造，PTB302等)進行測定。
本發明之腸溶錠於上述素錠(A)之表面具有(B)水溶性高分子覆膜。該覆膜(B)係水溶性高分子覆膜，並非腸溶性，係以通常之水溶性高分子為主成分之覆膜。作為覆膜(B)所使用之水溶性高分子，可列舉：羥丙基纖維素、羥丙基甲基纖維素(hypromellose)、羥乙基纖維素等水溶性纖維素醚，聚乙二醇、明膠、海藻酸鹽、糊精，聚乙烯醇-丙烯酸-甲基丙烯酸甲酯共聚物、聚乙烯醇-聚乙二醇接枝共聚物等水溶性聚乙烯醇衍生物等。其中，較佳為水溶性纖維素醚，較佳為選自羥丙基纖維素及羥丙基甲基纖維素中之1種或2種以上。
形成覆膜(B)時，只要將含有上述水溶性高分子之溶液噴霧於素錠(A)後，使之乾燥即可。此處，於含有水溶性高分子之溶液中，可添加檸檬酸三乙酯、聚山梨糖醇酯、聚乙二醇等塑化劑等。又，作為溶劑，可使用水、乙醇、水-乙醇混合液等。
本發明之腸溶錠於上述覆膜(B)之表面具有(C)於pH值7以上之條件下溶解之腸溶性覆膜。該覆膜(C)係用以藉由於pH值7以上之條件下
溶解而使本發明之腸溶錠中之藥效成分於下消化道溶出之覆膜。作為覆膜(C)所使用之構成於pH值7以上之條件下溶解之腸溶性覆膜的高分子，較佳為甲基丙烯酸共聚物，更佳為甲基丙烯酸-甲基丙烯酸甲酯共聚物，進而較佳為選自甲基丙烯酸共聚物L、甲基丙烯酸共聚物S及甲基丙烯酸共聚物LD中之1種或2種以上。進而較佳為選自甲基丙烯酸共聚物S及甲基丙烯酸共聚物L中之1種或2種以上。
形成覆膜(C)時，只要將含有上述於pH值7以上之條件下溶解之高分子的溶液噴霧於形成有覆膜(B)之錠劑後，使之乾燥即可。此處，於含有於pH值7以上之條件下溶解之高分子的溶液中，可添加檸檬酸三乙酯等塑化劑、滑石等潤滑劑、色素等。又，作為溶劑，可使用水、乙醇、異丙醇、丙酮、及該等之混合液等。
於本發明之腸溶錠中，就獲得良好之腸溶性及耐衝擊性之方面而言，重要的是覆膜(B)與覆膜(C)之合計量為10~18mg/cm2，覆膜(B)為6~12mg/cm2，覆膜(C)為3~6mg/cm2。
於覆膜(B)與覆膜(C)之合計量未達10mg/cm2時，無法獲得充分之耐衝擊性，若超過18mg/cm2，則步驟時間增加，溶出時間變得過長，變得無法獲得適當之釋出。該合計量更佳為10~16mg/cm2，進而較佳為10~15mg/cm2。
於覆膜(B)之量未達6mg/cm2時，無法獲得充分之耐衝擊性，若超過12mg/cm2，則覆膜(C)之量相對減少，因此釋出特性之控制變得困難。更佳之覆膜(B)之量為6~11mg/cm2，進而較佳為6~10mg/cm2。
於覆膜(C)之量未達3mg/cm2時，釋出特性之控制困難，若超過6mg/cm2，則覆膜(B)之量相對減少，因此無法獲得充分之耐衝擊性。更佳之覆膜(C)之量為4~6mg/cm2。
就工業性、耐衝擊性與釋出性之控制之方面而言，覆膜(B)與覆
膜(C)之質量比(B/C)較佳為1.0~2.5，進而較佳為1.5~2.5。
又，就服用性之方面而言，本發明之腸溶錠之總重量較佳為1060~1650mg，更佳為1300~1600mg，進而較佳為1350~1550mg。
就耐衝擊性之方面而言，本發明腸溶錠之硬度於長徑方向上較佳為250N以上，更佳為260N以上，更佳為250~500N，進而較佳為260~450N。硬度可利用硬度計(PHARMA TEST公司製造，PTB502等)進行測定。
又，本發明之腸溶錠之形狀只要為通常之圓盤或橢圓狀且為具有1種或2種以上之曲率半徑的帶弧度之錠劑即可，就耐衝擊性之方面而言，其縱橫比較佳為1：1~22：9，更佳為20~21：9~10。又，錠劑厚度較佳為6~8mm，更佳為6.5~8mm，進而較佳為6.5~7.8mm，進而較佳為7.2~7.6mm。
其次，列舉實施例詳細地說明本發明，但本發明並不限定於該等實施例。
將5-胺基水楊酸(活性成分)85.7%、結晶纖維素約8.5~9.5%、羧甲基澱粉鈉3%及羥丙基甲基纖維素1.5~2.5%濕式造粒後，使之乾燥，並與硬脂酸鎂約0.3%混合。利用旋轉壓錠機，將該混合物壓縮成形為包含活性成分1200mg之約1400mg之錠劑。形狀為長徑20.5mm×短徑9.5mm。素錠之硬度(利用硬度計、PHARMA TEST公司製造之PTB302或502進行測定)為約240N。
對參考例1中記載之素錠噴霧如下配方之包衣液，而施加甲基丙烯酸共聚物S之外側包衣層。
將利用滾筒容積約10L之包衣鍋進行包衣之結果示於(表2)。
甲基丙烯酸共聚物之覆膜由於強固且缺乏彈力性或可塑性，故而於為非常大型之錠劑之情形時，錠劑在包衣鍋內滾動時，錠劑間或向裝置之碰撞時之衝擊較大，因此產生即便為少量規模，亦大量產生素錠露出之缺損錠或膜龜裂等之破損錠之問題。
又，針對所獲得之包衣錠之外觀良品，利用pH值1.2之日本藥典崩解試驗第1液進行2小時崩解試驗，並觀察試驗後之錠劑，結果確認：4mg/cm2包衣品3錠中3錠均開口，8mg/cm2包衣品3錠中亦有1錠開口，不滿足腸溶性製劑所要求之耐酸性。該情況顯示，於直接對大型素錠包衣甲基丙烯酸共聚物之腸溶性覆膜之情形時，未形成均勻之覆膜而品質偏差增大，及混入外觀上似無問題但不滿足品質基準之錠
劑之風險較高。又，同時提示，難以將專利文獻2中記載之技術直接應用於大型之錠劑。
另一方面，使該錠劑10錠自30cm之高度反覆跌落至不鏽鋼製容器中10次，並觀察跌落後之外觀，結果確認其係良品率為10~20%左右之非常易碎之錠劑，因此認為若考慮實際生產規模中之包衣步驟或包裝步驟中之機械應力、輸送、日常之操作，則直接對素錠包衣甲基丙烯酸共聚物層之方法實際使用上並不適合。
對參考例1中記載之素錠噴霧如下配方之包衣液，而施加羥丙基甲基纖維素之內側包衣層。
對施加有參考例2中記載之羥丙基甲基纖維素之內側包衣層之錠劑噴霧(表1)之配方之包衣液，而施加甲基丙烯酸共聚物S之外側包衣層。
使利用滾筒容積約10L之包衣鍋進行包衣之錠劑自特定之高度反覆跌落至不鏽鋼製容器中10次，並觀察跌落後之外觀，結果確認：關於內側包衣量，於羥丙基甲基纖維素相對於素錠之表面積為4~8mg/cm2之範圍內，耐衝擊性隨著包衣量增加而增大，於外側層之甲基丙烯酸共聚物S之量為4mg時之內側層之羥丙基甲基纖維素量為6mg/cm2以上時，於外側層之甲基丙烯酸共聚物S之量為3mg時之內側
層之羥丙基甲基纖維素為8mg/cm2以上時，顯示出充分之耐衝擊性(表4)及(圖1)。此時，錠劑之硬度(利用硬度計、PHARMA TEST公司製造之PTB502進行測定)分別為約370N、及約400N。
又，針對所獲得之包衣錠，利用pH值1.2之日本藥典崩解試驗第1液進行2小時崩解試驗，並觀察試驗後之錠劑，結果為根據羥丙基甲基纖維素4mg/cm2內側包衣品中，甲基丙烯酸共聚物S之量為4mg/cm2，羥丙基甲基纖維素6mg/cm2內側包衣品中，甲基丙烯酸共聚物S之量為3mg/cm2，滿足腸溶性製劑所要求之耐酸性(表5)。
另一方面，於為藉由消化道之pH值變化而控制消化道內之藥物
釋出部位的pH值依賴型之釋出調節製劑之情形時，要求到達作為目標之消化道部位之pH值區域後，覆膜立即迅速地溶解而釋出藥物。將pH值7.2之較稀之McIlvine緩衝液之溶出試驗中之製劑之延遲時間(溶出所需之時間)示於圖2。確認製劑之延遲時間係較大地取決於甲基丙烯酸共聚物S之量而延遲，於本劑之情形時，若超過6mg/cm2，則延遲時間變為60分鐘以上，因此認為外側包衣層之甲基丙烯酸共聚物S之量較理想為3~6mg/cm2。
假定實際生產時，利用滾筒容積約550L之包衣鍋實施包衣，結果為各層之包衣所需之時間如(表6)所示。若考慮包衣液之製備時間或噴霧後之乾燥操作所需之作業，則為於1天以內結束包衣作業，噴霧時間較理想為最長6小時左右。因此，內側包衣量之上限值以羥丙基甲基纖維素計設為12mg/cm2。
綜合上述之耐衝擊性、耐酸性、腸溶性及噴霧時間而得知：覆膜(B)(內側包衣(水溶性高分子))與覆膜(C)(外側包衣(於pH值7以上之條件下溶解之覆膜))之合計量較佳為10~18mg/cm2，覆膜(B)較佳為6~12mg/cm2，覆膜(C)較佳為3~6mg/cm2。
於滾筒容積約550L之包衣鍋內添加參考例1中記載之素錠約140kg，噴霧(表7)之配方之包衣液，以羥丙基甲基纖維素相對於素錠之表面積成為8mg/cm2之方式施加內側包衣層。
繼而，對施加有上述羥丙基甲基纖維素之內側包衣層之錠劑噴霧(表1)之配方之包衣液，以甲基丙烯酸共聚物S相對於素錠之表面積成為4mg/cm2之方式施加外側包衣層。此時，所獲得之錠劑之硬度(利用硬度計、PHARMA TEST公司製造之PTB502進行測定)為約405N。
所獲得之包衣錠之試驗結果如(表8)所示，確認其係具有腸溶性製劑所要求之耐酸性，且藉由改善耐衝擊性，包衣後之錠劑破損即便於實際生產規模中不良率亦未達0.1%而生產性優異之製劑。
將5-胺基水楊酸(活性成分)85.7%及羥丙基甲基纖維素約2%濕式造粒後，使之乾燥，並與結晶纖維素約9.2%、羧甲基澱粉鈉約3%及
硬脂酸鎂約0.5%混合。利用旋轉壓錠機，將該混合物壓縮成形為包含活性成分1200mg之約1400mg之錠劑。形狀為長徑21mm×短徑10mm。素錠之硬度(利用硬度計、PHARMA TEST公司製造之PTB302進行測定)為約170N。
對參考例1中記載之素錠噴霧(表3)之配方之包衣液，以羥丙基甲基纖維素相對於素錠之表面積成為6mg/cm2之方式施加內側包衣層。
繼而，對施加有上述羥丙基甲基纖維素之內側包衣層之錠劑噴霧(表9)之配方之包衣液，以甲基丙烯酸共聚物S及L之總量相對於素錠之表面積成為6mg/cm2之方式施加外側包衣層。此時，所獲得之錠劑之硬度(利用硬度計、PHARMA TEST公司製造之PTB502進行測定)為約280N~約320N。
所獲得之包衣錠之試驗結果如(表10)所示，具有腸溶性製劑所要求之耐酸性，且顯示出耐衝擊性。
對參考例1中記載之素錠噴霧(表11)之配方之包衣液，以聚乙烯醇-聚乙二醇接枝共聚物相對於素錠之表面積成為8mg/cm2之方式施加內側包衣層。
繼而，對施加有上述聚乙烯醇-聚乙二醇接枝共聚物之內側包衣層之錠劑噴霧(表1)之配方之包衣液，以甲基丙烯酸共聚物S相對於素錠之表面積成為3~6mg/cm2之方式施加外側包衣層。此時，所獲得之錠劑之硬度(利用硬度計、PHARMA TEST公司製造之PTB502進行測定)為約270N~約300N。
所獲得之包衣錠之試驗結果如(表12)所示，具有腸溶性製劑所要求之耐酸性，且顯示出耐衝擊性。
將聚普瑞鋅(活性成分)60%、結晶纖維素24%、甘露糖醇10%、交聯聚乙烯吡咯啶酮3%及羥丙基纖維素約2%濕式造粒後，使之乾燥，並與硬脂酸鎂約1%混合。利用旋轉壓錠機，將該混合物壓縮成形為包含活性成分700mg之約1167mg之錠劑。形狀為長徑20.5mm×短徑9.5mm。素錠之硬度(利用硬度計、PHARMA TEST公司製造之PTB502進行測定)為約220N。
對參考例4中記載之素錠噴霧(表3)之配方之包衣液，以羥丙基甲基纖維素相對於素錠之表面積成為8mg/cm2之方式施加內側包衣層。
繼而，對施加有上述羥丙基甲基纖維素之內側包衣層之錠劑噴霧(表1)之配方之包衣液，以甲基丙烯酸共聚物S相對於素錠之表面積成為4mg/cm2、6mg/cm2之方式施加外側包衣層。此時，所獲得之錠劑之硬度(利用硬度計、PHARMA TEST公司製造之PTB502進行測定)分別為約380N、約430N。
所獲得之包衣錠之試驗結果如(表13)所示，具有腸溶性製劑所要求之耐酸性，且顯示出耐衝擊性。
Claims (10)
- 一種腸溶錠，其特徵在於：其係具有(A)含有藥效成分之重量1000mg以上之素錠、位於該素錠之表面的(B)含水溶性高分子之覆膜、及位於該含水溶性高分子之覆膜之表面的(C)於pH值7以上之條件下溶解之腸溶性覆膜者，並且覆膜(B)與覆膜(C)之合計量為10~18mg/cm2，覆膜(B)為6~12mg/cm2，覆膜(C)為3~6mg/cm2。
- 如請求項1之腸溶錠，其中素錠(A)之重量為1000~1500mg。
- 如請求項1或2之腸溶錠，其中藥效成分之含量為700~1300mg。
- 如請求項1或2之腸溶錠，其中水溶性高分子係選自水溶性纖維素醚中之1種或2種以上。
- 如請求項1或2之腸溶錠，其中於pH值7以上之條件下溶解之腸溶性覆膜係由選自甲基丙烯酸共聚物中之1種或2種以上之高分子所形成之覆膜。
- 如請求項1或2之腸溶錠，其中腸溶錠之總重量為1200~1600mg。
- 如請求項1或2之腸溶錠，其中藥效成分為大腸疾病治療劑。
- 如請求項1或2之腸溶錠，其中藥效成分為炎症性腸疾病治療劑。
- 如請求項1或2之腸溶錠，其中藥效成分為5-胺基水楊酸。
- 如請求項1或2之腸溶錠，其中覆膜(B)與覆膜(C)之質量比(B/C)為1.0~2.5。
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- 2014-02-21 WO PCT/JP2014/054104 patent/WO2014129568A1/ja active Application Filing
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- 2014-02-21 SG SG11201506653WA patent/SG11201506653WA/en unknown
- 2014-02-21 KR KR1020157022571A patent/KR102167265B1/ko active IP Right Grant
- 2014-02-21 HU HUE14754975A patent/HUE052167T2/hu unknown
- 2014-02-21 BR BR112015020237-3A patent/BR112015020237B1/pt not_active IP Right Cessation
- 2014-02-21 EP EP14754975.2A patent/EP2959892B1/en active Active
- 2014-02-21 JP JP2015501510A patent/JP6237760B2/ja active Active
-
2015
- 2015-08-13 IL IL240575A patent/IL240575B/en active IP Right Grant
- 2015-09-07 ZA ZA2015/06585A patent/ZA201506585B/en unknown
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2018
- 2018-09-20 US US16/136,377 patent/US20190015345A1/en not_active Abandoned
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2020
- 2020-11-12 HR HRP20201808TT patent/HRP20201808T1/hr unknown
- 2020-12-08 CY CY20201101162T patent/CY1123908T1/el unknown
- 2020-12-11 US US17/118,824 patent/US20210093577A1/en not_active Abandoned
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2023
- 2023-08-01 US US18/363,001 patent/US20230372250A1/en active Pending
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