CN105025888B - 肠溶片 - Google Patents
肠溶片 Download PDFInfo
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- CN105025888B CN105025888B CN201480009951.3A CN201480009951A CN105025888B CN 105025888 B CN105025888 B CN 105025888B CN 201480009951 A CN201480009951 A CN 201480009951A CN 105025888 B CN105025888 B CN 105025888B
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- coatel tablets
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- enteric coatel
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Classifications
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- 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
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- 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
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- A61K9/2846—Poly(meth)acrylates
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- 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
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- 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
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- 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
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Abstract
本发明提供含有大量的药效成分且在不增厚肠溶性被膜的情况下具有充分的耐冲击性的肠溶片。该肠溶片的特征在于,具有(A)含有药效成分的重量为1000mg以上的素片、位于该素片的表面的(B)含有水溶性高分子的被膜、以及位于该含有水溶性高分子的被膜的表面的(C)pH值为7以上时溶解的肠溶性被膜,被膜(B)与被膜(C)的合计量为10~18mg/cm2,被膜(B)为6~12mg/cm2,被膜(C)为3~6mg/cm2。
Description
技术领域
本发明涉及肠溶片。
背景技术
医药品的药效成分中,有些成分在酸性条件下不稳定,因而口服通常的制剂时,会被胃酸分解等而不显示充分的药效。
另一方面,对于溃疡性大肠炎、克罗恩病等炎症性肠病的治疗药,希望药效成分在作为患部的肠道内从制剂释放出来。作为配合了这样的药效成分的医药品制剂,有肠溶片等肠溶性制剂。
例如,作为炎症性肠病的治疗药的5-氨基水杨酸(美沙拉嗪)、柳氮磺胺吡啶以肠溶性制剂、灌肠剂、栓剂等制剂形式销售,被广泛使用。这样的制剂中,肠溶片在口服的服用性、携带性、品质管理等方面优异而被广泛使用。作为上述肠溶片,市场上有用溶出试验第2液(pH值6.8)溶解的一般性肠溶性包衣片和pH值为7以上时溶解的肠溶性包衣片。其中,pH值为7以上时溶解的肠溶性包衣片在到达作为患部的下消化道(回肠末端~大肠)后,释放药效成分,因而对大肠的疾病特别有用。
另外,具有胃粘膜保护作用、细胞保护作用的聚普瑞锌一直用作胃溃疡、十二指肠溃疡的治疗剂,但最近研究了将其以灌肠剂的形式用于溃疡性大肠炎、直肠粘膜损伤(非专利文献1~4)。聚普瑞锌的灌肠疗法中,内窥镜观察到的有效改善的部位是灌肠剂到达的范围,而现有的口服制剂难以到达大肠的下部。因此,聚普瑞锌对溃疡性大肠炎、直肠粘膜损伤的治疗中,从服药依从性上来讲,需要一种能可靠地到达大肠而充分作用于患部的大型的肠溶性包衣制剂。
另外,作为其它的与肠溶性包衣制剂相关的技术,报告了肠溶性包衣和pH依赖型溶解包衣的双层肠溶性包衣技术(专利文献1和2)。
现有技术文献
专利文献
专利文献1:日本特表2001-502333号公报
专利文献2:日本特表2005-510539号公报
非专利文献
非专利文献1:http://informahealthcare.com/doi/abs/10.3109/00365521.2013.863963
非专利文献2:http://ir.jikei.ac.jp/bitstream/10328/7851/1/KKN2011-89.pdf
非专利文献3:The Journal of JASTRO 21(3/4):149-1542009
非专利文献4:http://kaken.nii.ac.jp/pdf/2011/seika/C-19/34519/21591622seika.pdf
发明内容
例如,5-氨基水杨酸制剂的情况下,含有400mg的5-氨基水杨酸的肠溶片1次需要服用3片,因而期待一种1次服用1片即可的片剂。但是,想要制造出为含有大量药效成分的大型片剂且具有耐冲击性的肠溶片时,需要增厚被膜,此时,存在药物释放延迟的问题。另一方面,如果使被膜变薄或者减少赋形剂的量则存在得不到充分的耐酸性,并且耐冲击性下降这样的问题。
因此,本发明的课题在于提供一种含有大量的药效成分且在不增厚肠溶性被膜的情况下具有充分的耐冲击性的肠溶片。
因此,本发明人对配合了大量的有效成分的肠溶片的肠溶性能和耐冲击性与被膜组成的关系进行了各种研究,结果得知如果像专利文献1和2那样使肠溶性被膜为2层则在包衣操作时很多片剂破损,如果为了提高耐冲击性而使被膜层为3层则工序操作变得繁琐,工序时间增多,因此从技术或者成本方面上来看,将本技术直接用于大型的片剂在工业上是困难的。另外,需要对各肠溶性被膜分别进行适当地工序管理,难以控制肠溶性。因此,经过进一步深入研究,结果发现通过形成水溶性高分子被膜和肠溶性被膜这样的2层包衣,并使水溶性高分子被膜为内部被膜,且将这些被膜的合计量和被膜量调整成一定的范围,能够兼得在下消化道稳定释放的特性和耐冲击性,从而完成了本发明。
即,本发明提供以下的〔1〕~〔10〕。
〔1〕一种肠溶片,其特征在于,具有(A)含有药效成分的重量为1000mg以上的素片、位于该素片的表面的(B)含有水溶性高分子的被膜、和位于该含有水溶性高分子的被膜的表面的(C)pH值为7以上时溶解的肠溶性被膜,被膜(B)与被膜(C)的合计量为10~18mg/cm2,被膜(B)为6~12mg/cm2,被膜(C)为3~6mg/cm2。
〔2〕根据〔1〕所述的肠溶片,其中,素片(A)的重量为1000~1500mg。
〔3〕根据〔1〕或〔2〕所述的肠溶片,其中,药效成分的含量为700~1300mg。
〔4〕根据〔1〕~〔3〕中任一项所述的肠溶片,其中,水溶性高分子为选自水溶性纤维素醚中的1种或2种以上。
〔5〕根据〔1〕~〔4〕中任一项所述的肠溶片,其中,pH值为7以上时溶解的肠溶性被膜是由选自甲基丙烯酸共聚物中的1种或2种以上的高分子形成的被膜。
〔6〕根据〔1〕~〔5〕中任一项所述的肠溶片,其中,肠溶片的总重量为1200~1600mg。
〔7〕根据〔1〕~〔6〕中任一项所述的肠溶片,其中,药效成分为大肠疾病治疗剂。
〔8〕根据〔1〕~〔6〕中任一项所述的肠溶片,其中,药效成分为炎症性肠病治疗剂。
〔9〕根据〔1〕~〔6〕中任一项所述的肠溶片,其中,药效成分为5-氨基水杨酸。
〔10〕根据〔1〕~〔9〕中任一项所述的肠溶片,其中,被膜(B)与被膜(C)的质量比(B/C)为1.0~2.5。
本发明的肠溶片尽管在1片中含有大量的药效成分,但仍具有良好的消化道下部释放特性,且耐冲击性优异,以往需要1次服用多片的制剂现在1次服用1片就能够进行治疗。
附图说明
图1是表示包衣片的落下试验结果(高度60cm)的图。
图2是表示外侧包衣量与肠液(pH7.2)溶出试验中的制剂的滞后时间的图。
具体实施方式
本发明的肠溶片的特征在于,具有(A)含有药效成分的重量为1000mg以上的素片、位于该素片的表面的(B)含有水溶性高分子的被膜、和位于该含有水溶性高分子的被膜的表面的(C)pH值为7以上时溶解的肠溶性被膜,被膜(B)与被膜(C)的合计量为10~18mg/cm2,被膜(B)为6~12mg/cm2,被膜(C)为3~6mg/cm2。
本发明的肠溶片中的素片(A)是含有药效成分的重量为1000mg以上的素片。作为药效成分,可举出非甾体类抗炎剂、溃疡治疗剂、抗菌剂、肽、蛋白质、甾体等适合在肠道释放的药物,特别优选在下消化道(回肠末端~大肠)释放的药物。即,优选炎症性肠病治疗剂、大肠癌治疗剂等。其中,作为适合作用于大肠的药物,可举出5-氨基水杨酸(美沙拉嗪)、柳氮磺胺吡啶、泼尼松龙、倍他米松、聚普瑞锌,其中更优选5-氨基水杨酸。5-氨基水杨酸用作溃疡性大肠炎、克罗恩病等炎症性肠病治疗药。
素片(A)的重量优选为1000mg以上,从服用性、携带性的方面考虑,更优选为1000~1500mg,进一步优选为1200~1500mg。另外,从服用性、耐冲击性、携带性、用法的方面考虑,素片(A)中的药效成分的含量优选为700mg以上,更优选为900~1300mg,进一步优选为1000~1300mg。
素片(A)中除药效成分以外还可以配合通常的片剂中配合的赋形剂、崩解剂、润滑剂、粘合剂、流动剂、矫味剂、矫臭剂、增塑剂等。这些添加剂的合计含量在素片(A)中优选为100~600mg,更优选为150~400mg,进一步优选为200~400mg。作为赋形剂,可举出乳糖、白糖、葡萄糖、甘露醇等糖类、淀粉、部分糊化淀粉、结晶纤维素、碳酸钙、硫酸钙、碳酸氢钠等。优选乳糖、甘露醇、淀粉、结晶纤维素,更优选结晶纤维素。作为崩解剂,可举出淀粉、琼脂、明胶粉、结晶纤维素、羧甲基纤维素钠、羧甲基纤维素钙、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、碳酸钙、碳酸氢钠、淀粉羟基乙酸钠、羟丙基甲基纤维素、低取代羟丙基纤维素等。优选交联羧甲基纤维素钠、聚乙烯聚吡咯烷酮、淀粉羟基乙酸钠、低取代羟丙基纤维素,更优选淀粉羟基乙酸钠。作为润滑剂,可举出硬脂酸镁、硬脂酸钙、滑石、氢化植物油、聚乙二醇、硬脂富马酸钠等。优选硬脂酸钙、滑石,更优选硬脂酸镁。作为粘合剂,可举出淀粉、阿拉伯胶、明胶、海藻酸钠、甲基纤维素、乙基纤维素、聚乙烯吡咯烷酮、聚乙烯醇、羟丙基纤维素、羧甲基纤维素等。优选聚乙烯吡咯烷酮、羟丙基纤维素、羟丙甲纤维素,更优选聚乙烯吡咯烷酮、羟丙甲纤维素。另外,根据需要可以添加流动剂。作为该流动剂,可举出轻质无水硅酸等无水硅酸类。
素片(A)只要利用常规方法制造即可,可以为直接粉末压片法、干式颗粒压片法、半干式颗粒压片法、湿式颗粒压片法中的任一种。优选在湿式造粒后进行干式压片的方法。
从耐冲击性方面考虑,素片(A)的硬度在长径方向优选为160N以上,更优选为170N以上,进一步优选为180N以上,进一步优选为160~300N,更进一步优选为170~300N。硬度可以利用硬度计(PHARMA TEST公司制,PTB302等)测定。
本发明的肠溶片在上述素片(A)的表面具有(B)水溶性高分子被膜。该被膜(B)为水溶性高分子被膜,并非肠溶性,而是以通常的水溶性高分子为主成分的被膜。作为被膜(B)中使用的水溶性高分子,可举出羟丙基纤维素、羟丙基甲基纤维素(羟丙甲纤维素)、羟乙基纤维素等水溶性纤维素醚,聚乙二醇、明胶、海藻酸盐、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,优选水溶性纤维素醚,优选选自羟丙基纤维素和羟丙基甲基纤维素中的1种或2种以上。
形成被膜(B)时,只要向素片(A)喷雾含有上述水溶性高分子的溶液后,进行干燥即可。这里,可以向含有水溶性高分子的溶液中添加柠檬酸三乙酯、聚山梨酸酯、聚乙二醇等增塑剂等。另外,作为溶剂,使用水、乙醇、水-乙醇混合液等。
本发明的肠溶片在上述被膜(B)的表面具有(C)pH值为7以上时溶解的肠溶性被膜。该被膜(C)是用于通过在pH值为7以上时溶解而使本发明的肠溶片中的药效成分在下消化道溶出的被膜。作为构成被膜(C)使用的pH值为7以上时溶解的肠溶性被膜的高分子,优选甲基丙烯酸共聚物,更优选甲基丙烯酸-甲基丙烯酸甲酯共聚物,进一步优选选自甲基丙烯酸共聚物L、甲基丙烯酸共聚物S和甲基丙烯酸共聚物LD中的1种或2种以上。更进一步优选选自甲基丙烯酸共聚物S和甲基丙烯酸共聚物L中的1种或2种以上。
形成被膜(C)时,只要向形成有被膜(B)的片剂喷雾含有上述pH值为7以上时溶解的高分子的溶液后,进行干燥即可。这里,可以向含有pH值为7以上时溶解的高分子的溶液中添加柠檬酸三乙酯等增塑剂、滑石等润滑剂、色素等。另外作为溶剂,使用水、乙醇、异丙醇、丙酮和它们的混合液等。
本发明的肠溶片中,从得到良好的肠溶性和耐冲击性的方面考虑,重要的是被膜(B)与被膜(C)的合计量为10~18mg/cm2、被膜(B)为6~12mg/cm2、被膜(C)为3~6mg/cm2。
被膜(B)与被膜(C)的合计量低于10mg/cm2时得不到充分的耐冲击性,如果超过18mg/cm2,则工序时间增加,溶出时间变得过长,得不到适当的释放。更优选的该合计量为10~16mg/cm2,进一步优选为10~15mg/cm2。
被膜(B)的量低于6mg/cm2时得不到充分的耐冲击性,如果超过12mg/cm2则被膜(C)的量相对减少而难以控制释放特性。更优选的被膜(B)的量为6~11mg/cm2,进一步优选为6~10mg/cm2。
被膜(C)的量低于3mg/cm2时难以控制释放特性,如果超过6mg/cm2则被膜(B)的量相对减少而得不到充分的耐冲击性。更优选的被膜(C)的量为4~6mg/cm2。
从工业性、耐冲击性和释放性的控制的方面考虑,被膜(B)与被膜(C)的质量比(B/C)优选为1.0~2.5,进一步优选为1.5~2.5。
另外,从服用性方面考虑,本发明肠溶片的总重量优选为1060~1650,更优选为1300~1600mg,进一步优选为1350~1550mg。
从耐冲击性方面考虑,本发明肠溶片的硬度在长径方向优选为250N以上,更优选为260N以上,更优选为250~500N,进一步优选为260~450N。硬度可以利用硬度计(PHARMATEST公司制,PTB502等)测定。
另外,本发明肠溶片的形状只要为通常的圆盘或者椭圆状且为具有1个或2个以上的曲率半径的发圆的片剂即可,从耐冲击性方面考虑,其长宽比优选为1:1~22:9,更优选为20~21:9~10。另外,片剂厚度优选为6~8mm,更优选为6.5~8mm,进一步优选为6.5~7.8mm,更进一步优选为7.2~7.6mm。
实施例
接下来举出实施例对本发明进行详细说明,但本发明不限于这些实施例。
(参考例1)
将5-氨基水杨酸(活性成分)85.7%、结晶纤维素约8.5~9.5%、淀粉羟基乙酸钠3%和羟丙甲纤维素1.5~2.5%进行湿式造粒后,干燥,并与硬脂酸镁约0.3%混合。用旋转压片机将该混合物压缩成型为含有1200mg活性成分的约1400mg的片剂。形状为长径20.5mm×短径9.5mm。素片的硬度(利用硬度计即PHARMA TEST公司制PTB302或502进行测定)为约240N。
(比较例1)
对参考例1中记载的素片喷雾如下配方的包衣液而实施甲基丙烯酸共聚物S的外侧包衣层。
[表1]
将用滚筒容积约10L的包衣锅包衣的结果示于(表2)。
[表2]
无内侧包衣的试验结果(合格品数/试验数)
破损片:素片露出的片剂缺损、膜龟裂
由于甲基丙烯酸共聚物的被膜牢固,缺乏弹性、可塑性,所以为非常大型的片剂的情况下,由于在包衣锅内片剂转动时片剂间或者片剂与装置碰撞时的冲击大,所以即便为少量规模也存在产生大量素片露出的缺损片或膜龟裂等这样的破损片的问题。
另外,用pH值1.2的日本药典崩解试验第1液对得到的包衣片的外观合格品进行2小时崩解试验,观察试验后的片剂,结果4mg/cm2包衣品3片中3片均开口,就连8mg/cm2包衣品3片中也有1片开口,确认了无法满足肠溶性制剂所要求的耐酸性。这表明对大型的素片直接包衣甲基丙烯酸共聚物的肠溶性被膜时,不能形成均匀的被膜,品质的偏差大,并且混入外观上没有问题但不满足品质基准的片剂的风险高。另外,同时表示难以将专利文献2中记载的技术直接用于大型的片剂。
另一方面,使10片该片剂从30cm的高度反复落至不锈钢制容器中10次,观察落下后的外观,结果合格率为10~20%左右,确认了为非常脆的片剂,因此从实际生产规模下的包衣工序、包装工序中的机械应力、搬运、日常的操作方面考虑,认为对素片直接包衣甲基丙烯酸共聚物层的方法不适合实际应用。
(参考例2)
对参考例1中记载的素片喷雾如下配方的包衣液而实施羟丙甲纤维素的内侧包衣层。
[表3]
(实施例1)
对参考例2中记载的实施了羟丙甲纤维素的内侧包衣层的片剂喷雾(表1)的配方的包衣液而实施甲基丙烯酸共聚物S的外侧包衣层。
使在滚筒容积约10L的包衣锅包衣的片剂从规定的高度反复落至不锈钢制容器中10次,观察落下后的外观,结果确认了内侧包衣量在羟丙甲纤维素量相对于素片的表面积为4~8mg/cm2的范围时,耐冲击性随着包衣量增加而增大,外侧层的甲基丙烯酸共聚物S的量为4mg、内侧层的羟丙甲纤维素量为6mg/cm2以上时,以及外侧层的甲基丙烯酸共聚物S量为3mg、内侧层的羟丙甲纤维素为8mg/cm2以上时显示充分的耐冲击性(表4)和(图1)。此时,片剂的硬度(利用硬度计即PHARMA TEST公司制PTB502进行测定)分别为约370N和约400N。
[表4]
另外,用pH值1.2的日本药典崩解试验第1液对得到的包衣片进行2小时崩解试验,观察试验后的片剂,结果确认通过羟丙甲纤维素4mg/cm2内侧包衣品中甲基丙烯酸共聚物S的量为4mg/cm2,羟丙甲纤维素6mg/cm2内侧包衣品中甲基丙烯酸共聚物S的量为3mg/cm2,满足肠溶性制剂所要求的耐酸性(表5)。
[表5]
耐酸性试验结果(pH值1.2、2小时、合格品数/试验数)
另一方面,为根据消化道的pH值变化控制在消化道内的药物释放部位的pH值依赖型的释放调节制剂时,要求其在到达作为靶标的消化道部位的pH值区域后,被膜立即迅速溶解而释放出药物。将制剂在pH值为7.2的稀McIlvine缓冲液中的溶出试验中的滞后时间(溶出所需时间)示于图2。确认了制剂的滞后时间很大程度上依赖于甲基丙烯酸共聚物S的量而延迟,本剂的情况下,若超过6mg/cm2则滞后时间为60分钟以上,因此认为外侧包衣层中的甲基丙烯酸共聚物S的量优选为3~6mg/cm2。
假定实际生产时,用滚筒容积约550L的包衣锅实施包衣,结果各层的包衣所需时间如(表6)所示。若考虑包衣液的制备时间、喷雾后的干燥操作所需的作业,则在1天以内结束包衣作业时,喷雾时间优选最长为6小时左右。因此,内侧包衣量的上限值以羟丙甲纤维素计为12mg/cm2。
[表6]
*1:以羟丙甲纤维素或甲基丙烯酸共聚物S计
若综合上述的耐冲击性、耐酸性、肠溶性和喷雾时间考虑,可知被膜(B)(内侧包衣(水溶性高分子))与被膜(C)(外侧包衣(pH值值为7以上时溶解的被膜))的合计量优选为10~18mg/cm2,被膜(B)优选为6~12mg/cm2,被膜(C)优选为3~6mg/cm2。
(实施例2)
向滚筒容积约550L的包衣锅中投入参考例1中记载的素片约140kg,并喷雾(表7)的配方的包衣液,以羟丙甲纤维素相对于素片的表面积为8mg/cm2的方式实施内侧包衣层。
[表7]
接着,对上述的实施了羟丙甲纤维素的内侧包衣层的片剂喷雾(表1)的配方的包衣液,以甲基丙烯酸共聚物S相对于素片的表面积为4mg/cm2的方式实施外侧包衣层。此时,得到的片剂的硬度(利用硬度计即PHARMA TEST公司制PTB502进行测定)为约405N。
得到的包衣片的试验结果如(表8)所示,确认了具有肠溶性制剂所要求的耐酸性,且通过改善耐冲击性,包衣后的片剂破损即便在实际生产规模中不合格率也低于0.1%,为生产率优异的制剂。
[表8]
包衣片的试验结果
合格品数/试验数、破损片:素片露出的片剂缺损、膜龟裂
(参考例3)
将5-氨基水杨酸(活性成分)85.7%和羟丙甲纤维素约2%进行湿式造粒后,干燥,并与结晶纤维素约9.2%、淀粉羟基乙酸钠约3%和硬脂酸镁约0.5%混合。用旋转压片机将该混合物压缩成型为含有1200mg活性成分的约1400mg的片剂。形状为长径21mm×短径10mm。素片的硬度(利用硬度计即PHARMA TEST公司制PTB302进行测定)为约170N。
(实施例3)
对参考例1中记载的素片喷雾(表3)的配方的包衣液,以羟丙甲纤维素相对于素片的表面积为6mg/cm2的方式实施内侧包衣层。
接着,对实施了上述的羟丙甲纤维素的内侧包衣层的片剂喷雾(表9)的配方的包衣液,以甲基丙烯酸共聚物S和L的总量相对于素片的表面积为6mg/cm2的方式实施外侧包衣层。此时,得到的片剂的硬度(利用硬度计即PHARMA TEST公司制PTB502进行测定)为约280N~约320N。
得到的包衣片的试验结果如(表10)所示,具有肠溶性制剂所要求的耐酸性,且显示了耐冲击性。
[表9]
[表10]
包衣片的试验结果
合格品数/试验数
(实施例4)
对参考例1中记载的素片喷雾(表11)的配方的包衣液,以聚乙烯醇·聚乙二醇·接枝共聚物相对于素片的表面积为8mg/cm2的方式实施内侧包衣层。
[表11]
接着,对实施了上述的聚乙烯醇·聚乙二醇·接枝共聚物的内侧包衣层的片剂喷雾(表1)的配方的包衣液,以甲基丙烯酸共聚物S相对于素片的表面积为3~6mg/cm2的方式实施外侧包衣层。此时,得到的片剂的硬度(利用硬度计即PHARMA TEST公司制PTB502进行测定)为约270N~约300N。
得到的包衣片的试验结果如(表12)所示,具有肠溶性制剂所要求的耐酸性,且显示了耐冲击性。
[表12]
包衣片的试验结果
合格品数/试验数
(参考例4)
将聚普瑞锌(活性成分)60%、结晶纤维素24%、甘露醇10%、交联聚乙烯吡咯烷酮3%和羟丙基纤维素约2%进行湿式造粒后,干燥,并与硬脂酸镁约1%混合。用旋转压片机将该混合物压缩成型为含有700mg活性成分的约1167mg的片剂。形状为长径20.5mm×短径9.5mm。素片的硬度(利用硬度计即PHARMA TEST公司制PTB502进行测定)为约220N。
(实施例5)
对参考例4中记载的素片喷雾(表3)的配方的包衣液,以羟丙甲纤维素相对于素片的表面积为8mg/cm2的方式实施内侧包衣层。
接着,对实施了上述的羟丙甲纤维素的内侧包衣层的片剂喷雾(表1)的配方的包衣液,以甲基丙烯酸共聚物S相对于素片的表面积为4mg/cm2、6mg/cm2的方式实施外侧包衣层。此时,得到的片剂的硬度(利用硬度计即PHARMA TEST公司制PTB502进行测定)分别为约380N、约430N。
得到的包衣片的试验结果如(表13)所示,具有肠溶性制剂所要求的耐酸性,且显示了耐冲击性。
[表13]
包衣片的试验结果
合格品数/试验数。
Claims (14)
1.一种肠溶片,其特征在于,具有(A)含有药效成分的重量为1000mg以上的素片、位于该素片的表面的(B)并非肠溶性的含有水溶性高分子的被膜、以及位于该含有水溶性高分子的被膜的表面的(C)pH值为7以上时溶解的肠溶性被膜,被膜B与被膜C的合计量为10~18mg/cm2,被膜B为6~12mg/cm2,被膜C为3~6mg/cm2,被膜B与被膜C的质量比B/C为1.0~2.5,
水溶性高分子是选自水溶性纤维素醚中的1种或2种以上,
pH值为7以上时溶解的肠溶性被膜是由选自甲基丙烯酸共聚物中的1种或2种以上的高分子形成的被膜。
2.根据权利要求1所述的肠溶片,其中,素片A的重量为1000~1500mg。
3.根据权利要求1或2所述的肠溶片,其中,药效成分的含量为700~1300mg。
4.根据权利要求1或2所述的肠溶片,其中,肠溶片的总重量为1200~1600mg。
5.根据权利要求3所述的肠溶片,其中,肠溶片的总重量为1200~1600mg。
6.根据权利要求1或2所述的肠溶片,其中,药效成分为大肠疾病治疗剂。
7.根据权利要求3所述的肠溶片,其中,药效成分为大肠疾病治疗剂。
8.根据权利要求4所述的肠溶片,其中,药效成分为大肠疾病治疗剂。
9.根据权利要求1或2所述的肠溶片,其中,药效成分为炎症性肠疾病治疗剂。
10.根据权利要求3所述的肠溶片,其中,药效成分为炎症性肠疾病治疗剂。
11.根据权利要求4所述的肠溶片,其中,药效成分为炎症性肠疾病治疗剂。
12.根据权利要求1或2所述的肠溶片,其中,药效成分为5-氨基水杨酸。
13.根据权利要求3所述的肠溶片,其中,药效成分为5-氨基水杨酸。
14.根据权利要求4所述的肠溶片,其中,药效成分为5-氨基水杨酸。
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- 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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CN1314390C (zh) * | 2001-11-23 | 2007-05-09 | 宝洁公司 | 具有多重包衣的药物剂型 |
CN101732280A (zh) * | 2009-10-23 | 2010-06-16 | 天津力生制药股份有限公司 | 一种新型结肠定位释药的口服制剂 |
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5-氨基水杨酸结肠定位双层包衣微丸的制备;陈宇洲,等;《中国药学杂志》;20100831;第45卷(第15期);第1154-1158页 * |
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