CN102958980B - 含有纤维素和无机化合物的复合粒子 - Google Patents
含有纤维素和无机化合物的复合粒子 Download PDFInfo
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- CN102958980B CN102958980B CN201180032222.6A CN201180032222A CN102958980B CN 102958980 B CN102958980 B CN 102958980B CN 201180032222 A CN201180032222 A CN 201180032222A CN 102958980 B CN102958980 B CN 102958980B
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- mierocrystalline cellulose
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Abstract
本发明的课题在于提供一种流动性优异、液体保持率高、保持液体后的粒子流动性亦高的复合粒子。另,提供一种在直接压片法中能以开放式供给进行压片、压片损伤少、成形性高的复合粒子。进一步还提供一种复合粒子与活性成分一同作成成型体时,成型体的重量及活性成分的含量均一、硬度高、磨损性低的成型体。
Description
技术领域
本发明涉及以流动性优异、液体载持性高、保持液体后亦能维持高的粒子成形性、流动性来防止压片损伤的复合粒子。
背景技术
历来医药、食品、其它化学工业领域等中,在配制含有活性成分的成型体时,广泛使用纤维素粉末作为赋形剂来实施成形。另外,当活性成分为液体成分时,通常是使无机化合物单体载持液体成分进行粉末化,对该粉末使用纤维素粉末作为赋形剂来作成成型体。
但是,无机化合物单体的表观比容过大,一次性能粉末化的量有限制。此外无机化合物亦存在飞散等操作性问题。因此,有人研究使用纤维素无机化合物多孔性复合粒子作为赋形剂。
在专利文献1中,记载有出于削减医药品赋形剂成本的目的,将微晶纤维素粒子与粒径小于30μm的碳酸钙以特定质量比进行共处理后的微粒的发明。
在专利文献2中,作为压缩性得到改善的医药品赋形剂,记载有微晶性纤维素与二氧化硅的微粒聚结物构成的赋形剂组合物的发明。
在专利文献3中,记载有一种纤维素无机化合物多孔性复合粒子的发明,其是一种特定的纤维素分散粒子与水不溶性无机化合物粒子的凝集物,特征在于粒子内孔容在0.260cm3/g以上。专利文献3中记载了通过使纤维素与无机化合物复合化,可获得粒子内孔容高、成形性、崩解性、流动性优异的粒子。
此外,在专利文献4中,记载有一种不是复合体的固形剂,其是一种无机化合物与结晶纤维素的物理混合物,是在药物、硅酸钙以及淀粉及/或结晶纤维素构成的固形剂中,相对于药物混合10~45重量%的硅酸钙,且相对于硅酸钙混合40~250重量%的淀粉及/或结晶纤维素而成。其中记载了即使是将非那西丁或对乙酰氨基酚等自身成形性差的药物直接压片,也能不产生顶裂,而混合70~90重量份的药物量。
现有技术文献
专利文献
专利文献1:USP4744987号公报
专利文献2:日本专利特表平10-500426号公报
专利文献3:日本专利特开2005-232260号公报
专利文献4:日本专利特开平3-52823号公报
发明内容
药片通常是将粉体充填于冲模中,用冲头压缩成形而进行压片的,但当药物容易附着于冲头上时,会发生所谓的成型体表面脱落的粘冲现象。通常是使用无机化合物单体作为赋形剂,但无机化合物单体不一定能防止粘冲。此外,由于无机化合物单体的表观比容大,会产生压片时粉体的喷流性增大,冲模的填充性变差,成型体的重量不均匀的问题,或者产生成型体的一部分剥离的称之为顶裂的现象。因此,无法大量添加无机化合物。
纤维素粉末虽是成形性高的赋形剂,但存在着一旦被浸湿,就成形性下降,无法发挥作为赋形剂的机能的问题,或与无机化合物相比液体保持性低的问题。此外,对于现有已知的纤维素与无机化合物的复合体,其液体保持率低、保持液体后的粒子流动性亦低。另外,同样无法充分消除粘冲或顶裂等问题。
本发明的课题在于,提供一种液体保持率高、保持液体后的粒子流动性亦高的复合粒子。另,提供一种在直接压片法中能以开放式供给进行压片、压片损伤少、成形性高的复合粒子。进一步还提供一种复合粒子与活性成分一同作成成型体时,成型体的重量及活性成分的含量均一、硬度高、磨损性低的成型体。
本发明者为了解决上述课题,发现通过使纤维素与无机化合物复合化,可提高表观比容、孔容、液体保持率,亦能提高保持液体后的粒子成形性、流动性,进而完成本发明。
即本发明如下所示。
(1)一种复合粒子,其特征在于含有纤维素和无机化合物,表观比容为7~13cm3/g。
(2)(1)所述的复合粒子,其中纤维素的平均宽度为2~30μm、平均厚度为0.5~5μm。
(3)(1)或(2)所述的复合粒子,其中纤维素含有10~60质量份、无机化合物含有40~90质量份。
(4)(1)~(3)的任意1个所述的复合粒子,其中,无机化合物是选自水合二氧化硅、轻质无水硅酸、合成硅酸铝、氢氧化铝镁、偏硅酸铝镁、硅酸铝镁、硅酸钙、含水无水晶形氧化硅、硅酸镁及含水硅酸镁构成的群中的至少1种。
(5)(1)~(4)的任意1个所述的复合粒子,其中无机化合物是硅酸钙。
(6)(1)~(5)的任意1个所述的复合粒子,孔径为0.003~1μm、孔容为1.9~3.9cm3/g。
(7)(1)~(6)的任意1个所述的复合粒子,生育酚乙酸酯保持率为500~1000%。
(8)(1)~(7)的任意1个所述的复合粒子,重量平均粒径为30~250μm。
(9)(1)~(8)的任意1个所述的复合粒子,其中进一步含有淀粉。
(10)一种成型体,含有(1)~(9)的任意1个所述的复合粒子和活性成分。
(11)(10)所述的成型体,其中活性成分为医药用成分,或健康食品用成分。
(12)一种成型体,含有复合粒子及活性成分,该复合粒子含有纤维素和无机化合物,该活性成分是25℃时的粘度为3~10000mPa·s的液体,该活性成分的混合量是每1成型体500mg中含有105~250mg。
(13)(12)所述的成型体,其中液体成分为生育酚乙酸酯。
发明效果
本发明的复合粒子的表观比容、孔容大,作为液体保持率指标的生育酚乙酸酯保持率亦高。通过复合化,飞散性得到降低,操作性变好,可作为液体成分的吸附载体使用。此外,通过复合化,可使保持液体后的流动性高、各成型体间的成型体的重量及活性成分的含量均一,故可达成成型体中的液体成分的高含量。另外,本发明的成型体可提供一种具有充分硬度,粘冲、顶裂得到抑制,磨损度低的成型体。
附图说明
[图1]是实施例2的复合粒子B放大500倍的SEM照片
[图2]是实施例4的复合粒子D放大500倍的SEM照片
[图3]是实施例7的复合粒子G放大500倍的SEM照片
[图4]是实施例9的复合粒子I放大500倍的SEM照片
[图5]是纤维素的湿饼干燥品放大200倍的SEM照片
[图6]是参考例2的硅酸钙放大500倍的SEM照片
[图7]是实施例11的复合粒子K放大500倍的SEM照片
[图8]是实施例13的复合粒子M放大500倍的SEM照片
[图9]是实施例8的复合粒子H放大200倍的SEM照片
[图10]是纤维素与硅酸钙的混合物放大100倍的SEM照片
具体实施方式
以下针对本具体实施方式(以下简称为“本实施方式”),根据需要参照附图进行详细说明。以下的本实施方式仅是用于说明本发明的例示,本发明并不被以下内容所限定。此外,附图显示的仅是一例实施方式,本实施方式不限于此。本发明在其要旨的范围内可实施适当的变形。
本实施方式的复合粒子是含有纤维素和无机化合物,复合化后具有特定表观比容的粒子。
本实施方式中,纤维素是指,含有由天然物获得的天然高分子的纤维性物质。本实施方式中,纤维素优选具有纤维素I型的结晶结构。此外,优选纤维素的平均宽度为2~30μm、平均厚度为0.5~5μm。当纤维素的平均宽度和平均厚度在上述范围内时,通过复合化可使粒子内部的细孔充分扩展故而优选。进一步优选纤维素的平均宽度为2~25μm、平均厚度为1~5μm。
本发明中的纤维素也包含结晶纤维素,本发明中使用的结晶纤维素是将由纤维性植物作为纸浆获得的α-纤维素,用无机酸进行部分性解聚,精制而成的呈白色的结晶性粉末的纤维素。此外,结晶纤维素虽有各种级别,但在本发明中,优选聚合度为100~450的结晶纤维素。市售品可使用“セオラス”PH级别、KG级别、UF级别(均为旭化成ケミカルズ(株)制)等,最优选UF级别。
纤维素的体积平均粒径优选为10~100μm。优选10~50μm、进一步优选10~40μm。
纤维素的平均聚合度优选10~450。进一步优选150~450。
本实施方式中,无机化合物只要是水不溶性、表观比容为10~50cm3/g的即无特别限制,优选例如水合二氧化硅、轻质无水硅酸、合成硅酸铝、氢氧化铝镁、偏硅酸铝镁、硅酸铝镁、硅酸钙、含水无水晶形氧化硅、硅酸镁、含水硅酸镁。基于能提高纤维素与无机化合物的分散液的浓度的点,无机化合物的体积平均粒径优选10~50μm。特别优选硅酸钙。硅酸钙优选由CaO、SiO2、H2O构成、化学式2CaO·3SiO2·mSiO2·nH2O(1<m<2、2<n<3)所示的物质。作为市售品,可购入商品名フロ一ライトR(トクヤマ制)、商品名フロ一ライトRE(CaO2在50%以上、CaO在22%以上、エ一ザイフ一ド·ケミカル株式会社销售)等。硅酸钙为白色粉体,呈水不溶性。硅酸钙是具有高吸液能力、成形性良好的物质。体积平均粒径优选10~40μm、进一步优选20~30μm。
在防止粘冲的观点上,认为无机化合物的表观比容、比表面积越大,越能发挥优异的特性,轻质无水硅酸相比于硅酸钙,其上述物性更优异,但在本发明中,对各种与纤维素一同作成的复合粒子中使用的无机化合物进行了研究之后,发现在使用硅酸钙的情况下,能发挥最优异的防粘冲效果。
本发明者将无机化合物与纤维素复合化,尽可能地增大表观比容,发现由此能将作为液体保持率的指标的生育酚乙酸酯保持率最大化。
硅酸钙单体的生育酚乙酸酯保持率为800~900%,在无机化合物中算高的,纤维素的生育酚乙酸酯保持率为200~250%。因此,单纯将两者混合的话,应该不会超过800%。但是,又发现通过复合化可使粒子内部的细孔充分扩展,进而可以得到高于单纯的算术平均值的保持率。
作为例子,将硅酸钙的混合量约为50%的与纤维素的混合物,同复合粒子进行生育酚乙酸酯保持率的比较。混合物的生育酚乙酸酯保持率的理论值约为550%。与此相对,同样的混合量时的复合粒子却为相当高的、约740%的保持率。
换言之,通过将纤维素与硅酸钙复合化,能成功提高液体保持率,进一步将纤维素的特性赋予复合粒子。由此,可得到高液体保持率的同时,还被赋予了纤维素所具有的成形性及流动性的复合粒子。
本实施方式的复合粒子优选含有纤维素10~60质量份和无机化合物40~90质量份。进一步优选纤维素为15~45质量份、无机化合物为55~85质量份。当无机化合物在40质量份以上时,获得的纤维素与无机化合物构成的复合粒子可具有大的粒子内孔容,能被赋予充分的液体保持性。此外,保持液体后的压缩成形性也得到提高。当无机化合物在90质量份以下时,喷流性得到抑制,进而成型体的重量及活性成分含量的不均匀、成形性降低能得到抑制。
在本实施方式中,复合粒子不是单纯的纤维素与无机化合物的混合物,其必须含有纤维素与无机化合物的单个粒子分别多个进行聚集、形成比单个粒子大的一个集合体。使用SEM(倍率200~500倍)对本实施方式的复合粒子的粒子表面进行观察,可观察到纤维素与无机化合物的单个粒子,这些粒子多个聚集形成集合体的状态(参照图9)。与此相比,单纯混合时见图10。此集合体大于纤维素和无机化合物的单个粒子。另一方面,纤维素与无机化合物的简单粉体之间的混合物中,纤维素及无机化合物的一次粒子一个一个单个存在,没有形成集合体。因此,单纯混合时,无法获得如本实施方式的复合粒子那样优异的成形性、流动性。至于有没有形成复合粒子,除了用SEM进行观察之外,还可以用网目75μm的筛进行筛分,通过残留在筛上的重量比例进行判别。残留在75μm筛上的粒子的比例为5~70重量%、优选10~70重量%时,可判断形成了复合粒子。复合粒子可在粒子内部形成细孔,进而可载持超过纤维素与无机化合物的单个粒子能保持的量的液体成分。随着复合化的进行,粒子内部的细孔量增加,液体成分的载持能力增强。例如,通过对比生育酚乙酸酯保持率,可衡量复合化的程度。虽然在纤维素与无机化合物的单纯物理混合物的情况下,其生育酚乙酸酯保持率停留在基于两者的构成比的算术平均值上,但随着复合化的进行,由于粒子内部的细孔增加,其生育酚乙酸酯保持率变高。
本实施方式的复合粒子的表观比容必须为7~13cm3/g。在7cm3/g以上的话,可提高液体保持率,13cm3/g以下的话可抑制喷流性的增大,抑制活性成分的含量不均匀、成形性降低。更优选为8~12cm3/g。
本实施方式的复合粒子的孔径优选0.003~1μm。此处,孔径是指复合粒子的表面的细孔的大小。更优选为0.05~0.5μm。
本实施方式的复合粒子优选孔容为1.9~3.9cm3/g。此处,孔容是指复合粒子具有的微细空孔的容积。孔容在1.9cm3/g以上的话,能提高液体保持率。此外,3.9cm3/g以下的话,可抑制喷流性的增大,进而能抑制活性成分的含量不均匀、成形性降低。更优选为2~3.5cm3/g。
孔容能赋予复合粒子以压缩成形性及成型体的液体保持性。孔容大的话,压缩时复合粒子易于压碎、塑性变形性得到提高、成型体的硬度变高。此外,孔容大的话,由于促进了液体向复合粒子内渗透,进而能提高液体保持性。
此外,本实施方式的复合粒子优选气孔率为15~50%。此处,气孔率是指孔容相对于复合粒子的体积的比例。气孔率在15%以上时,因能得到高液体保持率而优选。此外50%以下的话,能抑制喷流性的增大,进而能抑制成形性的降低,故而优选。更优选为20~40%。
本实施方式的复合粒子的重量平均粒径优选为30~250μm。基于流动性的观点,重量平均粒径优选30μm以上,基于抑制分离偏析的观点,重量平均粒径优选250μm以下。更优选40~100μm。此处,分离偏析是指,活性成分无法与复合粒子均一混合,或无法维持均一混合的状态。
本实施方式的复合粒子优选生育酚乙酸酯保持率为500~1000%。通过生育酚乙酸酯保持率高、即液体保持率高,可增加成型体中的活性成分的含量。不足500%时,能载持的液体量少。基于液体保持性的观点,虽然是越高越好,但最多不过1000%左右。进一步优选生育酚乙酸酯保持率为600~1000%、特别优选700~1000%。
本实施方式的复合粒子基于流动性的点,优选安息角在45°以下。安息角越小越好,下限虽无特别限定,但从抑制高速连续压缩时与活性成分的分离偏析的角度考虑,优选25°。更优选25~40°。液体保持后的复合粒子同样基于流动性的点,优选安息角在45°以下、优选25~40°。
本实施方式的复合粒子优选硬度为200~340N。此处,硬度是指,对0.5g通过直径1.1cm的圆形平面冲头以压力10MPa压缩而得的圆柱状成型体,使用シュロインゲル硬度计测定的值。
本实施方式的复合粒子优选进一步含有淀粉。淀粉由于具有粘结性,有助于维持纤维素与无机化合物的复合化状态,固定造粒状态,故而优选。淀粉可使用,例如糊精、可溶性淀粉、玉米淀粉、土豆淀粉、部分预胶化淀粉、预胶化淀粉等,优选具有粘结性的淀粉。作为有助于提高崩解性的、外壳为粘结性糊成分、内核为溃散粒子的淀粉,特别优选“SWELSTAR(商标)WB-1(旭化成ケミカルズ制)”。将含有淀粉的复合粒子设为100质量份时,优选含有5质量份~15质量份淀粉。此时,优选结晶纤维素与无机化合物含有85~95质量份。
本实施方式的复合粒子的表观比容大、液体保持率高、流动性优异。进一步,能很好地适用于直接压片法及湿式压片法,飞散性小操作性优异,能防止粘冲、顶裂等压片损伤。
本实施方式的复合粒子特别适用于流动性低、不易具有药片硬度的活性成分,其具体例可列举,感冒药等非处方药或中药等的提取物粉末,或经由与打压·赋形剂的摩擦容易失活的酶·蛋白等药物。
此外,同样适用于容易出现药片表面的破裂、划伤、从内部剥离、裂纹等压片损伤的药片。其具体例可列举,小型药片、具有细腰边缘等压缩压力难于均等施加的部位的非圆形的变形药片、含有多种且大量药物的药片、含有包衣颗粒的药片等。
以下对本实施方式的复合粒子的制造方法进行说明。
本实施方式的复合粒子是通过将纤维素与无机化合物分散于介质,干燥该分散液而得。此外,作为其它方法,还可以将纤维素与无机化合物以湿式强力搅拌(即所谓的复合化、协同化、Coprocessing)来获得。
纤维素的原料是含有纤维素的天然物,可列举例如木材、竹、麦秸、稻草、棉花、苎麻、甘蔗渣、洋麻、甜菜、海鞘、细菌纤维素等。原料可以是植物性或动物性,也可2种以上混合。此外,还可将原料水解。尤其是水解时,可列举酸水解、碱氧化分解、水热分解、蒸汽喷发等,可以2种以上并用。
水解时,作为分散含有纤维素的固体成分的介质,只要是工业上能使用的即无特别限制,可使用水或有机溶剂。有机溶剂可列举,例如甲醇、乙醇、异丙醇、丁醇、2-甲基丁基醇、苄醇等醇类、戊烷、己烷、庚烷、环己烷等烃类、丙酮、乙基甲基酮等酮类。特别地,有机溶剂优选医药品中使用的溶剂,可列举《医药品添加物事典》(药事日报社(株)发行)中分类为溶剂的物质。介质优选水。水、有机溶剂可以2种以上并用。此外,也可先用1种介质暂时分散后,除去该介质,再使之分散于不同的介质中。
本发明中所述的纤维素,优选平均宽度为2~30μm、平均厚度为0.5~5μm。只要是将纤维素主要沿垂直方向撕裂的方法,即无特别限定,可以通过用高压均化器对木浆进行处理等、根据需要进行磨碎等机械处理或分离处理,或适当将两者组合的方法等,来将纤维素的平均宽度、平均厚度控制在特定范围内。此外例如,也可以选取纤维素的平均宽度为2~30μm、平均厚度为0.5~5μm的木浆来使用。水分散状态的纤维素的体积平均粒径优选为10~100μm。优选10~50μm、进一步优选10~40μm。专利文献3中,虽记载了水分散状态的10~100μm留分的L/D在2.0以上的纤维素作为复合化纤维素,但如专利文献3的实施例中所示,无法达成本发明的高表观比容。进一步地,在孔容、生育酚乙酸酯保持率方面也劣于本发明的复合体。特定的平均宽度、平均厚度的纤维素因能增加粒子内部的细孔量而优选。
作为获得水分散状态下的体积平均粒径为10~100μm的纤维素的方法,具有以下方法。
i)对纤维素进行剪切、磨碎、压碎、粉碎来调整粒径的方法。
ii)对纤维素实施爆碎处理等高压处理,将纤维素粒子沿长轴方向分割,根据需要施予剪切力来调整粒径的方法。
iii)对纤维素进行化学处理来调整的方法。
上述中的任意方法均可,也可2种以上并用上述方法。上述的i)及ii)的方法可以以湿式进行,也可以以干式进行,也可干湿并用。
作为上述的i)及ii)中的方法,可列举,例如移动式搅拌器、立体搅拌器、侧面搅拌器等单方向旋转式、多轴旋转式、往复反转式、上下移动式、旋转+上下移动式、管路式等使用搅拌翼的剪切方法、管路搅拌器等喷流式搅拌剪切方法、使用高剪切均化器、高压均化器、超声波均化器等的处理方法、捏合机那样的轴旋转挤压式剪切方法等。
特别地,粉碎方法可列举,筛磨、锤式粉碎机等筛式粉碎方法、快速搅拌器等旋转翼剪切筛式粉碎方法、喷射式粉碎机等气流式粉碎方法、球磨机、振动球磨机等球式粉碎方法、搅拌翼式粉碎方法等。上述方法也可以2种以上并用。
通过调整纤维素的水解或分散工序的条件、特别是对含纤维素溶液的搅拌力,也可将纤维素的体积平均粒径控制在所期望的范围内。一般地,增加水解溶液的酸及碱浓度,或反应温度,纤维素的聚合度会下降,分散液中的纤维素的体积平均粒径具有减小的倾向,此外,增强溶液的搅拌力,具有减小纤维素粒子的体积平均粒径的倾向。
接着,对含有纤维素和无机化合物的分散液的制造方法进行说明。可以将纤维素、无机化合物分散于介质中进行制造。具体地可列举下述方法。
i)将纤维素与无机化合物混合后添加到介质中作成分散液的方法。
ii)向纤维素分散液中添加无机化合物作成分散液的方法。
iii)向混合了淀粉等第3成分和纤维素粒子的分散液中添加无机化合物作成分散液的方法。
iv)将淀粉等第3成分与纤维素分散液混合后,向其中添加无机化合物作成分散液的方法。
v)向添加了无机化合物的分散液中,添加纤维素作成分散液的方法。
作为各成分的添加方法,只要是通常使用的方法的话,即无特别限制。具体地可列举,使用小型吸引输送装置、空气输送装置、斗式输送机、压送式输送装置、真空输送机、振动式定量送料器、喷雾器、漏斗等的添加方法。可以连续添加,也可以一起投入。
作为混合方法,只要是通常使用的方法即无特别限制。具体地,可以使用V型、W型、双锥型、罐型混合机等容器旋转式混合机、高速搅拌型、万能搅拌型、带型、揉捏型、圆锥型螺旋混合机等搅拌式混合机、高速流动式混合机、滚筒式混合机、流动层式混合机。此外也可以使用摇动筛等容器振动式混合机、移动式搅拌器、立体搅拌器、侧面搅拌器等单方向旋转式、多轴旋转式、往复反转式、上下移动式、旋转+上下移动式、管路式等使用搅拌翼的分散方法、管路搅拌器等喷流式搅拌分散方法、使用高剪切均化器、高压均化器、超声波均化器等的处理方法,例如捏合机那样的轴旋转挤压式剪切方法,也可以2种以上并用。
通过上述操作获得的分散液中的纤维素和无机化合物及淀粉的浓度,优选为5~40质量%。基于通过干燥分散液而获得的复合粒子的流动性的点,优选5质量%以上,基于压缩成形性的点,优选40质量%以下。更优选5~30质量%,进一步优选5~20质量%。
对由上述操作获得的分散液进行干燥,可获得本实施方式的复合粒子。干燥方法无特别限制,可列举例如冷冻干燥、喷雾干燥、滚筒干燥、晾晒架干燥、气流干燥、真空干燥等。也可2种以上并用。喷雾干燥时的喷雾方法可以是圆盘式、加压喷嘴、加压二流体喷嘴、加压四流体喷嘴等的任意的喷雾方法,也可以2种以上并用。
在进行上述喷雾干燥时,基于降低分散液的表面张力的目的,可添加微量的水溶性高分子、表面活性剂,基于促进介质的气化速度的目的,可添加发泡剂或能产生气体的物质,此外也可向分散液中添加气体。水溶性高分子、表面活性剂、发泡剂、能产生气体的物质、气体的具体例如下所示。另,上述的水溶性高分子、表面活性剂、能产生气体的物质可在干燥前添加,其添加顺序无特别限制。此外,也可各自2种以上并用。
水溶性高分子可列举,羟基丙基纤维素、羟基丙基甲基纤维素、聚丙烯酸、羧基乙烯基聚合物、聚乙二醇、聚乙烯醇、聚乙烯基吡咯烷酮、甲基纤维素、阿拉伯胶、淀粉糊等《医药品添加物事典》(药事日报社(株)发行)中所记载的水溶性高分子类。
表面活性剂可列举,磷脂质、丙三醇脂肪酸酯、聚乙二醇脂肪酸酯、脱水山梨糖醇脂肪酸酯、聚氧乙烯氢化蓖麻油、聚氧乙烯十六烷基醚、聚氧乙烯十八烷基醚、聚氧乙烯壬基苯基醚、聚氧乙烯聚氧基丙二醇、聚氧乙烯失水山梨醇单月桂酸酯、聚山梨酸酯、单油酸脱水山梨糖醇酯、单硬脂酸甘油酯、单氧化乙烯失水山梨醇单棕榈酸酯、单氧化乙烯失水山梨醇单硬脂酸酯、单油酸聚氧乙烯脱水山梨糖醇、单棕榈酸脱水山梨糖醇、月桂基硫酸钠等《医药品添加剂事典》(药事日报社(株)发行)中归类为表面活性剂的物质。
发泡剂可列举,酒石酸、碳酸氢钠、土豆淀粉、柠檬酸酐、药用皂、月桂基硫酸钠、月桂酸二乙醇酰胺、聚桂醇等《医药品添加剂事典》(药事日报社(株)发行)中记载的发泡剂类。
能产生气体的物质可列举,碳酸氢钠、碳酸氢铵等热分解产生气体的碳酸氢盐类、碳酸钠、碳酸铵等与酸反应产生气体的碳酸盐类等。其中,在使用上述碳酸盐类时,优选与酸同时使用。酸可列举柠檬酸、乙酸、抗坏血酸、己二酸等有机酸类、盐酸、硫酸、磷酸、硝酸等质子酸、氟化硼等路易斯酸等。特别优选作为医药品·食品所使用的物质。
作为气体,可将氮、二氧化碳、液化石油气体、二甲基醚等气体类浸渗于分散液中。
本实施方式的复合粒子是以无机化合物存在于含有上述纤维素的分散液中的状态,将它们同时干燥而形成。在纤维素与无机化合物均匀地缔合的状态中,如使介质蒸发,会产生毛细凝结作用,纤维素与无机化合物会紧密凝集。由于在单独干燥纤维素或单独干燥无机化合物之后,即使向其中添加及混合无机化合物或纤维素,也不会进行复合化,故无法获得该凝集物结构。此外,对于分散液中的纤维素,当其为特定的平均宽度、平均厚度时,抑制干燥时毛细凝结所引起的粒子过度凝集的效果大,可在复合粒子内形成大的孔容。另,在制造本实施方式的复合粒子时,纤维素粒子及无机化合物粒子也会残留在干燥的粉体中,不用将它们进行分离,直接使用也无大碍。
本实施方式的成型体是本实施方式的复合粒子与活性成分的成形物。以下对本实施方式的成型体进行说明。
成型体中,活性成分可在0.001~99%的范围、复合粒子可在1~99.999%的范围内使用。基于确保有效治疗量的点,优选活性成分0.001%以上,基于实用性硬度、磨损度、崩解性的点,优选99%以下。更优选成型体中含有1~90%的复合粒子。当活性成分为液状时,由于会发生粘冲或顶裂等压片损伤,故一直以来在成型体中的含量受到限制,但本发明的复合体由于兼备高液体保持性和高成形性,故液体成分可混合超过20%。优选21~50%、特别优选21~30%。现在市售的成型体中,生育酚乙酸酯含量最大的是100mg/药片总量500mg,没有发现混合超过20%的量。通过使用本发明的复合体,液体成分的混合量为21~50%的话,成型体可小型化在250~480mg的范围,此外药片重量为500mg的话,可将液体成分增加到105~250mmg范围的量。优选120~200mg、进一步优选120~150mg。
本实施方式的成型体可用造粒、整粒、压片等公知的方法进行加工。特别地,本实施方式的复合粒子适于通过压片进行成形。通过含有上述范围的本实施方式的复合粒子和活性成分,在直接压片法中,可制造出具有充分硬度的成型体。此外,本实施方式的复合粒子除了直接压片法以外,同样适用干式颗粒压缩法、湿式颗粒压缩法、粉末法(後末法)、将预先压缩成形的药片作为内核来制造多核药片的方法、将预先压缩的多个成型体重叠进行再次压缩来制造多层药片的方法等。
本实施方式中,活性成分可列举医药品用成分、健康食品用成分、农药成分、肥料成分、饲料成分、食品成分、化妆品成分、色素、香料、金属、陶瓷、催化剂、表面活性剂等。合适的活性成分有医药品用成分、健康食品用成分。
医药品用成分可使用解热镇痛消炎药、催眠镇静药、抗嗜睡药、镇晕药、小儿镇痛药、健胃药、抗酸剂、助消化药、强心药、心律不齐用药、降压药、血管扩张药、利尿药、抗溃疡药、肠道疏通药、骨质疏松症治疗药、镇咳去痰药、抗哮喘药、抗菌剂、尿频改善剂、滋养强壮剂、维他命剂等口服药物。药效成分可单独使用,也可2种以上并用。具体地,可列举例如乙酰水杨酸、乙酰水杨酸铝、对乙酰氨基酚、乙柳酰胺、双水杨酸酯、水杨酰胺、乳酰氨基苯乙醚、盐酸氮异丙嗪、盐酸二苯吡咯素、盐酸苯海拉明、二苯特罗、盐酸苯丙烯啶、盐酸曲吡那敏、盐酸嘧啶二胺、盐酸芬乙嗪、盐酸甲地嗪、水杨酸苯海拉明、二苯基二磺酸氯苯吡醇胺、酒石酸阿利马嗪、丹宁酸苯海拉明、茶氯酸二苯吡咯素、美海屈林萘二磺酸盐、异丙嗪亚甲基二水杨酸盐、马来酸氯苯吡醇胺、dl-马来酸扑尔敏、d-马来酸扑尔敏、磷酸二苯特罗、盐酸阿洛拉胺、盐酸氯苯息定、柠檬酸喷托维林(枸橼酸喷托维林)、柠檬酸替培啶、地布酸钠、氢溴酸右美沙芬、右美沙芬·酚酞盐、海苯酸替培啶、氯苄哌醚联苯酰苯酸盐、磷酸可待因、磷酸二氢可待因、盐酸那可丁、那可丁、dl-盐酸甲基麻黄碱、dl-甲基麻黄碱糖精盐、愈创木酚磺酸钾、愈创甘油醚、苯甲酸钠咖啡因、咖啡因、无水咖啡因、维他命B1及其衍生物以及它们的盐类、维他命B2及其衍生物以及它们的盐类、维他命C及其衍生物以及它们的盐类、橙皮苷及其衍生物以及它们的盐类、维他命B6及其衍生物以及它们的盐类、烟酰胺、泛酸钙、氨基乙酸、硅酸镁、合成硅酸铝、合成水滑石、氧化镁、二羟基铝·氨基乙酸盐(甘氨酸铝)、氢氧化铝凝胶(作为干燥氢氧化铝凝胶)、干燥氢氧化铝凝胶、氢氧化铝·碳酸镁混合干燥凝胶、氢氧化铝·碳酸氢钠的共沉淀产物、氢氧化铝·碳酸钙·碳酸镁的共沉淀产物、氢氧化镁·硫酸铝钾的共沉淀产物、碳酸镁、偏硅酸铝镁、盐酸雷尼替丁、西米替丁、法莫替丁(famotidine)、萘普生、双氯芬酸(diclofenac)钠、吡罗昔康、薁、吲哚美辛、酮洛芬、布洛芬、盐酸地芬尼、盐酸二苯吡咯素、苯海拉明、盐酸异丙嗪、盐酸氯苯甲嗪、茶苯海明、丹宁酸苯海拉明、丹宁酸芬乙嗪、异丙嗪茶氯酸二苯吡咯素、富马酸苯海拉明、异丙嗪亚甲基二水杨酸盐、溴氢酸东莨菪碱、盐酸奥西克利平、盐酸双环维林、盐酸美噻吨、溴甲阿托品、溴甲辛托品、溴化甲基东莨菪碱、溴化甲基-1-莨菪碱、溴甲贝那替秦、颠茄提取物、异丙胺碘、碘化二苯基哌啶子基甲基二氧戊环、盐酸罂粟碱、氨基苯甲酸、草酸铯、哌啶基乙酰氨基苯甲酸乙酯、氨茶碱、二羟丙茶碱、茶碱、碳酸氢钠、呋喃硫胺、硝酸异山梨醇酯、麻黄碱、氨苄青霉素、头孢氨苄、磺胺异恶唑、硫糖铝、烯丙基异丙基乙酰脲、溴异戊酰脲等、麻黄、白南天、樱桃树皮、远志、甘草、桔梗、车前子、车前草、美远志、贝母、小茴香、软木树皮、黄连、莪术、德国洋甘菊、肉桂、龙胆、牛黄、动物胆(包括熊胆)、沙参、生姜、苍术、丁香、芹壁、白术、蚯蚓、三七根茎、胡萝卜、缬草、牡丹皮片、花椒及它们的提取物等、胰岛素、加压素、干扰素、尿激酶、沙雷菌蛋白酶、生长抑素等“日本药局方”、“局外规(日本药局方外医药品规格)”、“USP”、“NF”、“EP”中所述的医药品用成分等,可以从上述中选择1种单独使用,也可2种以上并用。
作为健康食品用成分,只要是以增强健康为目的而混合的成分,即无限定,可列举例如青汁粉、苷元、姬松茸、南非醉茄、虾青素、针叶、氨基酸(缬氨酸、亮氨酸、异亮氨酸、赖氨酸、蛋氨酸、苯丙氨酸、苏氨酸、色氨酸、组氨酸、胱氨酸、酪氨酸、精氨酸、丙氨酸、天门冬氨酸、海藻粉末、谷氨酰胺、谷氨酸、甘氨酸、脯氨酸、丝氨酸等)、海藻酸、银杏叶提取物、沙丁鱼肽、姜黄、糖醛酸、紫锥花、西伯利亚人参、寡糖、油酸、核蛋白、鲣鱼肽、儿茶素、钾、钙、类胡萝卜素、藤黄、L-肉碱、壳聚糖、共轭亚油酸、芦荟、匙羹藤提取物、柠檬酸、猫须草、甘油酯、甘油、胰高血糖素、姜黄素、氨基葡萄糖、L-谷氨酰胺、小球藻、蔓越莓提取物、猫爪草、锗、酶、高丽人参提取物、辅酶Q10、胶原蛋白、胶原蛋白肽、毛喉鞘蕊花、软骨素、洋车前子壳粉、山楂提取物、皂甙、类脂物、L-半胱氨酸、紫苏提取物、藤黄果、脂肪酸、植物甾醇、种子提取物、螺旋藻、角鲨烯、西洋白柳、神经酰胺、硒、贯叶连翘提取物、大豆异黄酮、大豆皂甙、大豆肽、大豆卵磷脂、单糖、蛋白质、淡紫花牡荆提取物、铁、铜、二十二碳六烯酸、生育三烯酚、纳豆激酶、纳豆菌培养提取物、烟碱酸钠、烟酸、二糖、乳酸菌、大蒜、锯棕榈、发芽糙米、薏仁提取物、草药提取物、缬草提取物、泛酸、透明质酸、生物素、吡啶甲酸铬、维他命A、A2维他命B1、B2、B6、维他命B12、维他命C、维他命D、维他命E、维他命K、羟基酪醇、双歧杆菌、啤酒酵母、低聚果糖类、黄酮类、假叶树提取物、黑升麻、蓝莓、梅干红提取物、原花青素、蛋白质、蜂胶、菠萝、益生菌、磷脂酰胆碱、磷脂酰丝氨酸、β-胡萝卜素、肽、红花提取物、舞茸提取物、南美秘鲁根菜提取物、镁、乳蓟、锰、线粒体、矿物质、粘多糖、褪黑激素、桑树菇、木樨提取粉末、钼、野菜粉末、叶酸、乳糖、番茄红素、亚油酸、硫辛酸、燐(磷)、叶黄素、卵磷脂、迷迭香、蜂王浆、DHA、EPA等。
此外,活性成分可以是粉体状、结晶状、液体状、半固态等任意形态,液体活性成分合适。此外,出于控制溶出、降低苦味等目的实施了包衣或胶囊化的活性成分也可。也可使用溶解、悬浮、乳化在介质中的活性成分。活性成分可以多种并用。
液体的活性成分可列举,替普瑞酮、吲哚美辛四烯甲萘醌、法尼基、植物甲萘醌、维他命A油、苯戊醇、维他命D、维他命E等维他命类、DHA(二十二碳六烯酸)、EPA(二十碳五烯酸)、肝油等高级不饱和脂肪酸类、辅酶Q类、橙油、柠檬油、薄荷油等油溶性香味料等“日本药局方”、“局外规”、“USP”、“NF”、“EP”中所述的医药品用成分等。此外,维他命E还具有多种同族体、衍生物,可列举例如dl-α-生育酚、乙酸dl-α-生育酚、生育酚乙酸酯、乙酸d-α-生育酚等,虽然25℃下为液状的话,即无特别限定,但优选粘度在3~10000mPa·s范围的物质。在具有合适粘度的情况下,因液体成分向复合体载持后的复合粒子的成形性、流动性的平衡优异而优选。特别优选生育酚乙酸酯。
半固态的活性成分可列举,蚯蚓、甘草、肉桂、牡丹、牡丹皮片、缬草、花椒、生姜、芹壁、麻黄、白南天、樱桃树皮、远志、桔梗、车前子、车前草、石蒜、美远志、贝母、小茴香、软木树皮、黄连、莪术、德国洋甘菊、龙胆、牛黄、动物胆、沙参、生姜、苍术、丁香、芹壁、白术、三七根茎、胡萝卜、葛根汤、桂枝汤、香苏散、紫胡桂枝汤、小紫胡汤、小青龙汤、麦门冬汤、半夏厚朴汤、麻黄汤等汉方或生药提取物类、牡蛎肉提取物、蜂胶及蜂胶提取物、辅酶Q类等。
另,成型后的活性成分的结晶的形状可以与成形前的状态相同,也可不同,但基于稳定性的点,优选为相同。
本实施方式的成型体除了活性成分、复合粒子之外,也可根据需要自由添加赋形剂、崩解剂、粘合剂、助流剂、润滑剂、矫味剂、香料、着色剂、甜味剂等添加剂。添加剂可以2种以上并用。
赋形剂可列举,丙烯酸淀粉、L-天门冬氨酸、氨基乙基磺酸、氨基乙酸、糖(粉)、阿拉伯橡胶、阿拉伯橡胶末、藻酸、藻酸钠、阿尔法化淀粉、肌醇、乙基纤维素、乙烯·乙酸乙烯共聚物、氯化钠、橄榄油、高岭土、可可脂、酪蛋白、果糖、轻石粒、羧甲基纤维素、羧甲基纤维素钠、水合二氧化硅、干燥酵母、干燥氢氧化铝凝胶、干燥硫酸钠、干燥硫酸镁、寒天、寒天末、木糖醇、柠檬酸、柠檬酸钠、柠檬酸二钠、丙三醇、甘油磷酸钙、葡糖酸钠、L-谷氨酰胺、粘土、粘土粒、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、硅酸铝镁、硅酸钙、硅酸镁、轻质无水硅酸、轻质流动石蜡、肉桂末、结晶纤维素、结晶纤维素·羧甲基纤维素钠、结晶纤维素(粒)、玄米曲(ゲンマイコウジ)、合成硅酸铝、合成水滑石、香油、小麦粉、小麦淀粉、小麦胚芽粉、米粉、大米淀粉、乙酸钾、乙酸钙、乙酸酞酸纤维素、红花油、蜂蜡、氧化锌、氧化钛、氧化镁、β-环糊精、二羟基铝氨基乙酸酯、2,6-二-丁基-4-甲基苯酚、二甲基聚硅氧烷、酒石酸、酒石酸氢钾、煅烧石膏、蔗糖脂肪酸酯、氢氧化铝镁、氢氧化铝·凝胶、氢氧化铝·碳酸氢钠共沉淀物、氢氧化镁、角鲨烷、十八烷基醇、硬脂酸、硬脂酸钙、聚氧乙烯硬脂酸酯、硬脂酸镁、精制明胶、精制虫胶、精制白糖、精制白糖球状颗粒、十六十八醇、聚乙二醇1000单十六烷基醚、明胶、山梨糖醇酐脂肪酸酯、D-山梨糖醇、磷酸三钙、大豆油、大豆不皂化物、大豆卵磷脂、脱脂粉乳、滑石粉、碳酸铵、碳酸钙、碳酸镁、中性无水硫酸钠、低取代度羟基丙基纤维素、葡聚糖、糊精、天然硅酸铝、玉米淀粉、黄蓍末、二氧化硅、ニュ一カルゲン204、乳酸钙、乳糖、パ一フィラ一101、白色虫胶、白色凡士林、白土、白糖、白糖·淀粉球状颗粒、裸麦绿叶提取物粉末、裸麦芽叶青汁干燥粉末、蜂蜜、石蜡、土豆淀粉、半消化体淀粉、人血清白蛋白、羟丙基淀粉、羟丙基纤维素、羟丙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、植酸、葡萄糖、葡萄糖水和物、部分阿尔法化淀粉、支链淀粉、丙二醇、粉末还原麦芽糖浆、粉末纤维素、果胶、澎润土、聚丙烯酸钠、聚氧乙烯烷基醚、聚氧乙烯固化蓖麻油、聚氧乙烯(105)聚氧丙烯(5)乙二醇、聚氧乙烯(160)聚氧丙烯(30)乙二醇、聚苯乙烯磺酸钠、聚山梨酸、聚乙烯基缩醛二乙基氨基乙酸酯、聚乙烯基吡咯烷酮、聚乙二醇(分子量1500~6000)、麦芽糖醇、麦芽糖、D-甘露糖醇、糖浆、肉豆蔻酸异丙酯、无水乳糖、无水磷酸氢钙、无水磷酸钙造粒物、偏硅酸铝镁、甲基纤维素、棉子粉、棉子油、木蜡、单硬脂酸铝、单硬脂酸丙三醇、单硬脂酸山梨糖醇酐、药用碳、花生油、硫酸铝、硫酸钙、粒状玉米淀粉、流动石蜡、dl-苹果酸、磷酸-氢钙、磷酸氢钙、磷酸氢钙造粒物、磷酸氢钠、磷酸二氢钾、磷酸二氢钙、磷酸二氢钠等《医药品添加物事典》(药事日报社(株)发行)中分类为赋形剂的物质。
崩解剂可列举,交联羧甲基纤维素钠、羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠、低取代度羟基丙基纤维素等纤维素类、羧甲基淀粉钠、羟丙基淀粉、大米淀粉、小麦淀粉、玉米淀粉、土豆淀粉、部分阿尔法化淀粉等淀粉类、交联聚乙烯吡咯烷酮、交联聚乙烯吡咯烷酮共聚物等合成高分子等《医药品添加物事典》(药事日报社(株)发行)中分类为崩解剂的物质。
粘结剂可列举,白糖、葡萄糖、乳糖、果糖等糖类、甘露糖醇、木糖醇、麦芽糖醇、丁四醇、山梨糖醇等糖醇类、明胶、支链淀粉、卡拉胶、刺槐豆胶、寒天、葡甘露聚糖、黄原胶、罗望子胶、果胶、藻酸钠、阿拉伯胶等水溶性多糖类、结晶纤维素、粉末纤维素、羟基丙基纤维素、甲基纤维素等的纤维素类、玉米淀粉、土豆淀粉、阿尔法化淀粉、淀粉糊等淀粉类、聚乙烯基吡咯烷酮、羧基乙烯基聚合物、聚乙烯醇等合成高分子类、磷酸氢钙、碳酸钙、合成水滑石、硅酸铝镁等无机化合物类等《医药品添加物事典》(药事日报社(株)发行)中分类为粘合剂的物质。
助流剂可列举,水合二氧化硅、轻质无水硅酸等硅化合物类等或硅酸钠类湿式二氧化硅、硅酸钙、富马酸十八烷基钠(商品名“PRUV”JRS制)等《医药品添加物事典》(药事日报社(株)发行)中分类为助流剂的物质。
润滑剂可列举,硬脂酸镁、硬脂酸钙、硬脂酸、蔗糖脂肪酸酯、滑石粉、Fujicalin(フジカリン)、富马酸十八烷基钠(商品名“PRUV”JRS制)等《医药品添加物事典》(药事日报社(株)发行)中归类为润滑剂的物质。
矫味剂可列举,谷氨酰胺酸、富马酸、琥珀酸、柠檬酸、柠檬酸钠、酒石酸、苹果酸、抗坏血酸、氯化钠、1-薄荷脑等《医药品添加物事典》(药事日报社(株)发行)中分类为矫味剂的物质。
香料可列举,橙、香草、草莓、酸乳酪、薄荷脑、茴香油、肉桂油、云杉油、薄荷油等油类、绿茶末等《医药品添加物事典》(药事日报社(株)发行)中分类为调味剂、香料的物质。
着色剂可列举,食用红色3号、食用黄色5号、食用蓝色1号等食用色素、叶绿酸铜钠、氧化钛、核黄素等《医药品添加物事典》(药事日报社(株)发行)中分类为着色剂的物质。
甜味剂可列举,阿斯巴甜、糖精、甘草酸二钾、斯特维亚菊、麦芽糖、麦芽糖醇、糖浆、甘茶末等《医药品添加物事典》(药事日报社(株)发行)中分类为甜味剂的物质。
作为成型体的形态,在用于医药品时,可列举药片、散剂、细粒剂、颗粒剂、丸剂的固形制剂等。
以下对适合本实施方式的成型体的药片具体例进行说明。
药片是指,含有本实施方式的复合粒子、活性成分、根据需要添加的其它添加剂,经由压片而获得的成型体。由于本实施方式的复合粒子具有优异的压缩成形性,故在较低的压缩压下,也能获得具有实用性的药片。由于可在低压缩压下进行成形压片,故能维持药片内的空隙(导水管),适合在口腔内能迅速崩解的口腔内崩解药片。另外,本实施方式的复合粒子同样适用于将数种组成成分在一个步骤或其它步骤进行压缩成型的多层药片或有核药片,能赋予成型体优异的硬度,抑制压片损伤、抑制层间的剥离及裂纹的效果高。进一步,本实施方式的复合粒子由于粒子本身的分割性优异,易于对药片进行均一分割,故也适用于有分割线的药片等。
此外,本实施方式的复合粒子由于具有多孔性结构,复合粒子自身的微粒状药物、悬浮液状药物、溶液状成分等液体成分的保持性优异,故本实施方式的复合粒子的成型体也具有优异的液体成分保持性。因此,在将悬浮液状或溶液状成分于药片进行成层及包衣时,同样具有防止包衣层等外层剥离的效果。因此,本实施方式的复合粒子同样适用于成层药片或具有包衣层的药片(糖衣药片、层积了碳酸钙等成分的药片等)。
以下对含有活性成分和本实施方式的复合粒子的成型体的制造方法进行说明。其仅为一个例子,本发明并不受下述记载所限制。
成型体的成形方法可列举,在混合活性成分和本实施方式的复合粒子后,进行压缩成型的方法。此时,除了活性成分以外,可根据需要混合上述添加剂。添加顺序无特别限制,可列举下述成形方法。
1)将活性成分、本实施方式的复合粒子和根据需要添加的添加剂一起进行混合的压缩成型方法。
2)将活性成分、助流剂或润滑剂等添加剂混合后,再进一步混合本发明的复合粒子和根据需要添加的添加剂后,进行压缩成型的方法。
3)向1)或2)中所得的压缩成型用混合粉末中,进一步添加润滑剂进行混合后,再进行压缩成型的方法。
各成分的添加方法只要是通常进行的方法即无特别限制,可以使用小型吸引输送装置、空气输送装置、斗式输送机、压送式输送装置、真空输送机、振动式定量送料器、喷雾器、漏斗等进行连续性添加,也可一起投入。
混合方法只要是通常进行的方法即无特别限制,可以使用V型、W型、双锥型、罐型混合机等容器旋转式混合机、或高速搅拌型、万能搅拌型、带型、揉捏型、圆锥型螺旋混合机等搅拌式混合机、高速流动式混合机、滚筒式混合机、流动层式混合机。此外也可使用摇动筛等容器振动式混合机。
压缩成形方法只要是通常进行的方法即无特别限制,可以是使用冲模和冲头压缩成形为期望形状的方法,或预先压缩成形为片状后,再切割为期望形状的方法。压缩成形机可使用,例如静压机、压块辊压机、平滑辊压机等辊压机、单冲式压片机、旋转式压片机等压缩机。
在使用难溶于水的活性成分时,一般可列举下述压缩成形方法。
A)将活性成分粉碎后,与本实施方式的复合粒子和根据需要添加的其它成分进行混合的压缩成型方法。
B)将活性成分于水、有机溶剂或助溶剂等中溶解或分散后,与本实施方式的复合粒子和根据需要添加的其它添加剂混合,根据需要馏去水或有机溶剂,再进行压缩成型的方法。
本实施方式的复合粒子在上述B)的方法中合适。B)的方法中,由于要经过先将难溶于水或不溶性活性成分进行溶解或分散的工序,故能使活性成分很好地载持于复合粒子上。由此,可防止压缩成形时活性成分分离、渗出,抑制粘冲。本实施方式的复合粒子由于具有高压缩成形性及流动性,即使在上述B)的情况下,也能作成压缩成形引起的重量偏差小的药片。
上述B)的方法在活性成分为医药品中使用的药物、作为进行分散的介质并用聚乙二醇等液状介质时,更加合适。使用聚乙二醇等是出于以下目的:当活性成分被体内吸收时,血液中,活性成分通过被聚乙二醇包覆,能使具有易被肝脏代谢的性质的活性成分的药效得到持续。
上述B)的方法中,为了辅助溶解,可并用水溶性高分子或表面活性剂作为助溶剂,使其分散于介质后使用,非常有效。
有机溶剂只要是医药品中使用的物质,即无特别限制,可列举例如甲醇、乙醇等醇类、丙酮等酮类等《医药品添加剂事典》(药事日报社(株)发行)中分类为溶剂的物质,可以2种以上自由并用。
上述B)的方法中,作为助溶剂的水溶性高分子可列举,例如羟丙基纤维素、羟丙基甲基纤维素、聚丙烯酸、羧基乙烯基聚合物、聚乙二醇、聚乙烯醇、聚乙烯基吡咯烷酮、甲基纤维素、乙基纤维素、阿拉伯胶、淀粉糊等《医药品添加剂事典》(药事日报社(株)发行)中记载的水溶性高分子,可以2种以上自由并用。
作为助溶剂的油脂可列举,例如硬脂酸单甘油酯、硬脂酸三甘油酯、硬脂酸蔗糖酯、液体石蜡等石蜡类、巴西棕榈蜡、氢化蓖麻油等氢化油类、蓖麻油、硬脂酸、十八烷基醇、聚乙二醇等《医药品添加剂事典》(药事日报社(株)发行)中记载的油脂,可以2种以上自由并用。
助溶剂中的表面活性剂可列举,例如磷脂、丙三醇脂肪酸酯、聚乙二醇脂肪酸酯、脱水山梨糖醇脂肪酸酯、聚氧乙烯氢化蓖麻油、聚氧乙烯十六烷基醚、聚氧乙烯十八烷基醚、聚氧乙烯壬基苯基醚、聚氧乙烯聚氧基丙二醇、聚氧乙烯失水山梨醇单月桂酸酯、聚山梨酸酯、单油酸脱水山梨糖醇酯、单硬脂酸甘油酯、单氧化乙烯失水山梨醇单棕榈酸酯、单氧化乙烯失水山梨醇单硬脂酸酯、单油酸聚氧乙烯脱水山梨糖醇、单棕榈酸脱水山梨糖醇、月桂基硫酸钠等《医药品添加剂事典》(药事日报社(株)发行)中分类为表面活性剂的物质,可以2种以上自由并用。
上述B)的方法中,作为溶解或分散方法只要是通常进行的溶解、分散方法即无特别限制,可以使用移动式搅拌器、立体搅拌器、侧面搅拌器等单方向旋转式、多轴旋转式、往复反转式、上下移动式、旋转+上下移动式、管路式等使用搅拌翼的搅拌混合方法、管路搅拌器等喷流式搅拌混合方法、气体吹入式搅拌混合方法、使用高剪切均化器、高压均化器、超声波均化器等的混合方法,也可采用使用摇动筛的容器振动式混合方法等。
此外,本实施方式的复合粒子由于具有多孔性结构,复合粒子自身的药物保持性优异,可以将药物载持于细孔内的粒子直接作为细粒使用,也可造粒作成颗粒后使用,也可将它们进行压缩成形。
载持药物的方法只要是公知的方法即无特别限制,可列举以下方法等。
i)通过与微粒状药物混合,使其载持于本实施方式的复合粒子的细孔内的方法。
ii)通过与粉末状药物高速混合,强制性进行载持的方法。
iii)与暂时作成溶液或分散液的药物混合、使其载持后,根据需要进行干燥的方法。
iv)通过与升华性药物混合、进行加热及/或减压,使其升华吸附于细孔内的方法。
v)在加热前或加热中与药物进行混合,使其熔融的方法。
上述的方法可以2种以上并用。
除了如上所述的进行压缩成形、作成药片使用之外,本实施方式的复合粒子由于固体、液状成分的保持性亦优异,出于改善尤其是流动性、耐结块性、耐凝集性的目的,可以作成颗粒剂或散剂使用。另,上述细粒、颗粒可进一步进行包衣。
作为颗粒剂、散剂的制造方法,使用例如干式造粒、湿式造粒、加热造粒、喷雾干燥、微胶囊化的任意,均能获得同样的效果。
此外,本实施方式的复合粒子由于具有适当的保水性、保油性,除了赋形剂之外,还可作为成层、包衣用的核粒子使用,在成层、包衣工序中,具有抑制粒子间凝集的效果。成层、包衣可以是干式方法,也可以是湿式方法。
本实施方式的复合粒子同样可用于点心、健康食品、口感改良剂、食物纤维强化剂等食品、固体粉底、浴用剂、动物药、诊断药、农药、肥料、陶瓷催化剂等。
实施例
基于实施例对本发明进行说明。但本发明的实施方式不被这些实施例的记载所限定。另,实施例、比较例中的各物性的测定方法如下。
(1)纤维素的平均宽度(μm)
将由天然纤维素构成的纤维素一次粒子,根据需要进行干燥,放置在贴好碳带的试料台上,真空蒸镀铂钯(此时的蒸镀膜的膜厚为20nm以下),使用日本分光(株)制JSM-5510LV(商品名),以加速电压6kV、倍率250倍进行观察,将纤维素粒子的长轴的中央附近的短轴作为代表宽度测定大小。对有代表性的3个纤维素初始粒子进行宽度测定,以其平均值作为纤维素的平均宽度。
(2)纤维素的平均厚度(μm)
将由天然纤维素构成的纤维素一次粒子,根据需要进行干燥,放置在贴好碳带的试料台上,真空蒸镀金后,使用聚焦离子束加工装置(日立制作所(株)制、FB-2100(商品名)),通过Ga离子束切出纤维素一次粒子的截面后,以加速电压6kV、倍率1500倍进行观察,将纤维素粒子截面的较短的轴的值作为厚度进行测定(使较长的轴的值相当于纤维素粒子的短轴进行切出)。对有代表性的3个纤维素一次粒子进行厚度测定,以其平均值作为纤维素的厚度。
(3)纤维素或者无机化合物的体积平均粒径(μm)
将纤维素或者无机化合物用水分散后的分散液,以使用激光衍射式粒度分布计(堀場制作所制、LA-910(商品名)),选择搅拌4及循环5作为测定模式,于透过率85%附近、超声波处理1分钟、以折射率1.20下测定的累积体积50%的粒子表示。但是,由于该测定值与以下转动轻敲式获得的干燥粒子的粒度分布的测定原理完全不同,所以未必相关。由激光衍射测定的体积平均粒径,是由依赖于纤维状粒子的长轴的体积频率测定而得的值,而与此相对,转动轻敲式所获得的重量平均粒径,是将获得的粉末置于筛上使之振动而划分,故其依赖于纤维状粒子的短轴。因此,依赖于纤维状粒子的长轴的激光衍射式的测定值有时会大于依赖纤维状粒子的短轴的转动轻敲式的值。
(4)复合粒子的重量平均粒径(μm)
粉体试料(干燥后的复合粒子)的重量平均粒径是使用转动轻敲式筛振荡机(平工作所制、商品名“シ一ブシェ一カ一A型”)、使用JIS标准筛(Z8801-1987),将10g试料筛分10分钟,由此测定粒度分布,以累积重量50%的粒径表示。粒度分布是使用300μm、212μm、177μm、150μm、106μm、75μm、38μm作为筛的大小求得。
(5)孔径(μm)、粒子内孔容(cm3/g)、气孔率(%)
使用岛津制作所(株)制、商品名“オ一トポア9520型”,通过水银孔率法求得细孔分布。采取约0.03g至0.05g测定所使用的各试料粉体至标准膨胀节,在初期压力7kPa(约1psia、细孔直径约相当于18μm)的条件下测定2次。由获得的细孔分布,计算出特定孔径范围0.003~1.0μm时的容积,作为孔容。此外,气孔率是指,初气压下,孔容相对于汞被压入直径约180μm的细孔时试料体积的比例。
(6)安息角(°)
使用杉原式安息角测定器(槽尺寸深度10x宽50x高140mm、宽50mm的位置上设置量角器),通过电磁式送料器(MF-1型/筒井理化)将试料一点一点少量地(大致3g/分)连续堆积在测定部位,作成斜面。当剩余的试料开始滑落、几乎成直线状时,立即关闭送料器的开关,用设置好的量角器测定斜面的角度,作为安息角。
(7)试料的压缩成型方法
称取各试料0.5g,装入冲模(使用菊水制作所制、材质SUS2,3),用直径1.1cm的圆形平面冲头(使用菊水制作所制、材质SUS2,3)进行压缩,直至压力变为10MPa(アイコ一エンジニアリング制、商品名“PCM-1A”、压缩速度1cm/分钟),在目标压力下保持10秒,即可作成圆柱状成型体。
(8)药片硬度(N)
使用シュロインゲル硬度计(フロイント产业(株)制、商品名“8M型”)对圆柱状成型体或药片沿圆柱状成型体或药片的直径方向施加负重,测定破坏时的负重。以10个试料的平均值表示。
(9)表观比容(cm3/g)
将25cm3的容器设置于斯科特容量计(スコットボリュメ一タ)(VWR SCIENTIFIC社制、S64985型)。接着,使用电磁式送料器(MF-1型/筒井理化),以10~20g/分钟的速度投入各试料。当试料从设置好的容器中溢出时,取出容器,抖掉多余的量,测定试料质量。用容器的体积(25cm3)除以试料质量的值(cm3/g)即为表观比容。以测定2次试料的平均值表示。
(10)生育酚乙酸酯保持率(%)
称取各试料2g,揉捏试料的同时,一点点少量地滴加生育酚乙酸酯(25℃的粘度:3300mPa·s),以表面渗出液体时为终点。生育酚乙酸酯保持率由下式所示。
生育酚乙酸酯保持率(%)=滴加的液量g/试料2g×100
测定值以2个试料的平均值表示。
(11)顶裂发生个数(个)
任意抽取50个压片后的药片样品,数出有裂纹或部分剥离的药片的个数。
(12)粘冲发生率(%)
目视检查50个药片,数出药片表面有剥离等、有缺损的药片个数。以发现粘冲的药片的个数的比例为粘冲发生率(%)。
(13)重量CV值
测定任意抽取的10个压片后的药片样品的重量,根据该测定值的平均值及标准偏差,定义重量CV值=(标准偏差/平均值)×100[%]。重量CV值越大,重量偏差越大,进而药物的含量不均匀量增加、制品产率低。重量CV值大于1.0%时,实用上存在问题。
(14)扫描电子显微镜照片(以下简称SEM)
使用电子显微镜(日本电子(株)制、JSM-551OLV型)进行测定。将试料装配到试料移动台上,经由金蒸镀法(AUTO FINE COATER、日本电子(株)制、JFC-1600型)使试料表面均薄薄地覆盖金属粒子。其后,装配到试料室,使试料室内为真空,以电子束照射试料位置,输出需要观察的部分的放大图像。
(15)平均聚合度
通过第14改正日本药局方、结晶纤维素的确认试验(3)中记载的铜乙二胺溶液粘度法测定的值。
(16)水分散状态的纤维素粒子的L/D
水分散状态的纤维素粒子的平均L/D按如下进行测定。使用JIS标准筛(Z8801-1987),使纤维素的水分散液通过75μm筛,对残留在38μm筛上的粒子,进行粒子的光学显微镜像的图像解析处理((株)インタ一クエスト制、装置:Hyper700,软件:Imagehyper),将与粒子外接的长方形之中的面积最小的长方形的长边与短边的比(长边/短边)作为粒子的L/D。粒子的平均L/D使用至少100个粒子的平均值。
(实施例1)
将阔叶树实施公知的制浆处理、漂白处理后的木浆(纤维素一次粒子的平均宽度约19μm、平均厚度约3μm)切碎,将该切碎品4.5kg与0.2%的盐酸水溶液30L装入低速型搅拌机(池袋琺瑯工业(株)制、商品名、30LGL反应器)进行搅拌,同时在124℃下水解1小时,获得酸不溶解性残渣(以下记为湿饼)。纤维素粒子的体积平均粒径由激光衍射/散射式粒度分布测定装置((株)堀场制作所制、商品名“LA-910”)以折射率1.20测定,结果其值为25μm。
向合成树脂水桶中装入纯水,以3-1马达搅拌的同时,加入湿饼进行混合,接着,加入硅酸钙(トクヤマ(株)制、商品名:フロ一ライトR、体积平均粒径25μm)进行混合。质量比是,纤维素/硅酸钙为28.6/71.4(基于固体成分),总固体成分浓度约为8.5质量%。将其喷雾干燥(分散液供给速度6kg/hr、入口温度180~220℃、出口温度70~95℃、喷雾器转速15000rpm)后获得复合粒子A。复合粒子A的各种物性见表1。
(实施例2、3)
将阔叶树实施公知的制浆处理、漂白处理后的木浆(纤维素一次粒子的平均宽度约19μm、平均厚度约3μm)切碎,将该切碎品4.5kg与0.2%的盐酸水溶液30L装入低速型搅拌机(池袋琺瑯工业(株)制、商品名、30LGL反应器)进行搅拌,同时在124℃下水解1小时,获得酸不溶解性残渣(以下记为湿饼)。纤维素粒子的体积平均粒径由激光衍射/散射式粒度分布测定装置((株)堀场制作所制、商品名“LA-910”)以折射率1.20测定,结果其值为25μm。
向合成树脂水桶中装入纯水,以3-1马达搅拌的同时,加入淀粉(旭化成ケミカルズ制、商品名“SWELSTAR”WB-1)进行混合,接着,加入湿饼进行混合,再加入硅酸钙(トクヤマ(株)制、商品名:フロ一ライトR、体积平均粒径25μm)进行混合。质量比是,淀粉/纤维素/硅酸钙为10/20/70(基于固体成分),总固体成分浓度约为8.5质量%(pH10.2)。将其喷雾干燥(分散液供给速度6kg/hr、入口温度180~220℃、出口温度70~95℃、喷雾器转速15000rpm、30000rpm)后获得复合粒子B(喷雾器转速15000rpm)、C(喷雾器转速30000rpm)。复合粒子B、C的各种物性见表1。
(实施例4、5)
将阔叶树实施公知的制浆处理、漂白处理后的木浆(纤维素一次粒子的平均宽度约19μm、平均厚度约3μm)切碎,将该切碎品4.5kg与0.2%的盐酸水溶液30L装入低速型搅拌机(池袋琺瑯工业(株)制、商品名、30LGL反应器)进行搅拌,同时在124℃下水解1小时,获得酸不溶解性残渣(以下记为湿饼)。纤维素粒子的体积平均粒径由激光衍射/散射式粒度分布测定装置((株)堀场制作所制、商品名“LA-910”)以折射率1.20测定,结果其值为25μm。
向合成树脂水桶中装入纯水,以3-1马达搅拌的同时,加入湿饼进行混合,接着,加入硅酸钙(トクヤマ(株)制、商品名:フロ一ライトR、体积平均粒径25μm)进行混合。质量比是,纤维素/硅酸钙为20/80(基于固体成分),总固体成分浓度约为8.5质量%。将其喷雾干燥(分散液供给速度6kg/hr、入口温度180~220℃、出口温度70~95℃、喷雾器转速15000rpm、30000rpm)后获得复合粒子D(喷雾器转速15000rpm)、E(喷雾器转速30000rpm)。复合粒子D、E的各种物性见表1。
(实施例6、7)
将质量比改为淀粉/纤维素/硅酸钙=5/40/55(基于固体成分),除此之外,与实施例2、3相同地获得复合粒子F(喷雾器转速15000rpm)、G(喷雾器转速30000rpm)。复合粒子F、G的各种物性见表1。
(实施例8、9)
将质量比改为淀粉/纤维素/硅酸钙=7/43/50(基于固体成分)、总固体成分浓度改为9.3质量%,除此之外,与实施例2、3相同地获得复合粒子H(喷雾器转速15000rpm)、I(喷雾器转速30000rpm)。复合粒子H、I的各种物性见表1。
(实施例10、11)
将质量比改为纤维素/硅酸钙=60/40(基于固体成分)、总固体成分浓度改为11.7质量%,除此之外,与实施例4、5相同地获得复合粒子J(喷雾器转速15000rpm)、K(喷雾器转速30000rpm)。复合粒子J、K的各种物性见表1。
(实施例12、13)
将质量比改为淀粉/纤维素/硅酸钙=3/60/37(基于固体成分)、总固体成分浓度改为11.7质量%、喷雾器转速改为8000rpm、30000rpm,除此之外,与实施例2、3相同地获得复合粒子L(喷雾器转速8000rpm)、M(喷雾器转速30000rpm)。复合粒子L、M的各种物性见表1。
(实施例14)
将质量比改为淀粉/纤维素/硅酸钙=2.5/72.5/25(基于固体成分)、总固体成分浓度改为11.7质量%,除此之外,与实施例2相同地获得复合粒子N(喷雾器转速15000rpm)。复合粒子N的各种物性见表1。
(实施例15)
将质量比改为纤维素/轻质无水硅酸=50/50(基于固体成分)、总固体成分浓度改为4质量%,除此之外,与实施例5相同地获得复合粒子O(喷雾器转速30000rpm)。复合粒子O的各种物性见表1。
(实施例16)
将质量比改为纤维素/偏硅酸铝镁=30/70(基于固体成分)、总固体成分浓度改为5质量%,除此之外,与实施例4相同地获得复合粒子P(喷雾器转速15000rpm)。复合粒子P的各种物性见表1。
(实施例17)
将质量比改为纤维素/含水硅酸镁=50/50(基于固体成分)、总固体成分浓度改为5质量%,除此之外,与实施例4相同地获得复合粒子Q(喷雾器转速15000rpm)。复合粒子Q的各种物性见表1。
[表1]
(参考例1)
向不锈钢壶中装入纯水100g,以3-1马达搅拌的同时,边用药匙一点点少量地加入硅酸钙(トクヤマ(株)制、商品名:フロ一ライトR、体积平均粒径25~30μm)边搅拌。添加到10.7g时变得无法再搅拌。
(参考例2)
向不锈钢壶中装入纯水,以3-1马达搅拌的同时,加入实施例1中获得的湿饼进行混合,接着边用药匙一点点少量地加入SiO2(商品名:アエロジル200、日本アエロジル(株)制)、体积平均粒径0.016μm)边搅拌混合。质量比为纤维素/轻质无水硅酸=29.3/70.7(基于固体成分),总固体成分浓度为8.5质量%(pH10.2)。变为浆糊状,无法进行喷雾干燥。
(参考例3)
向不锈钢壶中装入纯水,以3-1马达搅拌的同时,加入实施例1中获得的湿饼进行混合,接着混合偏硅酸铝镁(商品名:ノイシリン、富士化学工业(株)制)。质量比为纤维素/偏硅酸铝镁=31.0/69.0(基于固体成分),总固体成分浓度为11.7质量%(pH10.2)。变为乳状,无法进行喷雾干燥。
(比较例1)
硅酸钙(トクヤマ(株)制、商品名:フロ一ライトR、体积平均粒径25μm)单体的物性见表2。
(比较例2)
将质量比改为淀粉/纤维素/硅酸钙=2.5/72.5/25(基于固体成分)、总固体成分浓度改为11.7质量%,除此之外,与实施例4相同地获得复合粒子R。复合粒子R的各种物性见表2。
(比较例3)
将市售溶解木浆(针叶树木浆、纤维素一次粒子的平均宽度约为39μm、平均厚度约为8μm)切碎,将该切碎品2kg与0.4%的盐酸水溶液30L装入低速型搅拌机(池袋琺瑯工业(株)制、商品名、30LGL反应器)进行搅拌,同时在116℃下水解1小时,获得酸不溶解性残渣(纤维素分散粒子的体积平均粒径为51μm、L/D为3.4)。将获得的酸不溶解性残渣及水不溶解性无机化合物的二氧化硅(トクヤマ制、商品名、ファインシ一ル、体积平均粒径5μm)以量比30/70(基于固体成分)装入90L的合成树脂水桶中,加入纯水直至总固体成分浓度变为20重量%,用3-1马达进行搅拌的同时,加入氨水进行中和(中和后的pH为7.5~8.0),将其进行喷雾干燥(分散液供给速度6kg/hr、入口温度180~220℃、出口温度50~70℃、喷雾器转速30000rpm),获得复合粒子S(相当于专利文献3的实施例2)。复合粒子S的各种物性见表2。
(比较例4)
将市售的木浆(针叶树木浆、纤维素一次粒子的平均宽度约为39μm、平均厚度约为8μm)切碎,将该切碎品2kg与0.2%的盐酸水溶液30L装入低速型搅拌机(池袋琺瑯工业(株)制、商品名、30LGL反应器)进行搅拌,同时在116℃下水解1小时,获得酸不溶解性残渣(纤维素分散粒子的体积平均粒径为72μm、L/D为4.0)。将获得的酸不溶解性残渣及滑石粉(和光纯药制、配制成体积平均粒径为5μm)以量比98/2(基于固体成分)装入90L的合成树脂水桶中,加入纯水直至总固体成分浓度变为10重量%,用3-1马达进行搅拌的同时,加入氨水进行中和(中和后的pH为7.5~8.0),将其与比较例3同样地进行喷雾干燥,获得复合粒子T(相当于专利文献3的实施例6)。复合粒子T的各种物性见表2。
(比较例5)
将使用セオラスPH-101(旭化成ケミカルズ制)作为结晶纤维素、质量比改为纤维素/硅酸钙=28.6/71.4的物质装入塑料袋中,充分混合3分钟,获得纤维素/硅酸钙的混合物U(专利文献4中硅酸混合量最大者)。混合物U的各种物性见表2。
(比较例6)
将使用セオラスPH-101(旭化成ケミカルズ制)作为结晶纤维素、质量比改为纤维素/硅酸钙=71.4/28.6的物质装入塑料袋中,充分混合3分钟,获得纤维素/硅酸钙的混合物V(专利文献4中硅酸混合量最小者)。混合物V的各种物性见表2。
[表2]
<SEM照片>
使用日本电子(株)制“JSM-5510LV型”电子显微镜,以SEM观察复合粒子B,D,G,I,K,M的状态。
可知实施例2的复合粒子B(参照图1)、实施例4的复合粒子D(参照图2)、实施例7的复合粒子G(图3参照)、实施例9的复合粒子I(参照图4),相对来说表面无凹凸,呈近似球状的形状。此外,还可知纤维素湿饼(参照图5)和参考例2的硅酸钙(参照图6)复合化后,具有空隙。由于具有该空隙,可做成液保持率高、硬度高的成型体。
另一方面,实施例11的复合粒子K(图7)、实施例13的复合粒子M(图8参照)表面具有凹凸。
<防粘冲的评价>
布洛芬(异丁苯丙酸)是易粘冲药物的代表例。使用它对防粘冲效果进行比较。评价所使用的混合布洛芬的造粒颗粒按下述方法作成。
称量相对于总量1000g的、布洛芬((株)エ一ピ一アイコ一ポレ一ション制)45%、乳糖水和物(商品名:乳糖200M、DMV制)38%、玉米淀粉(GRDE:ST-C、日澱化学(株)制)17%,用聚乙烯袋混合3分钟后,加入到立式造粒机(バ一チカルグラニュレ一タ一)((株)パウレック制、FM-VG-10P型)中混合(叶片200rpm、切刀2100rpm),历时30秒投入羟丙基纤维素(商品名:HPCーL、日本曹達(株)制)6%的溶液200g后,进一步混合3分钟(造粒)后,取出。接着,用マルチフレックス((株)パウレック制、MP-01型)进行干燥,当排气温度变为40℃时结束干燥,取出造粒物。将造粒物用筛的网目710μm筛过后,作为试验样品(以下将其记为造粒颗粒)。
(实施例18)
将造粒颗粒88质量%、交联羧甲基纤维素钠(ニチリン化学(株)制、“キッコレ一ト”ND-2HS)2质量%、实施例3的复合粒子C10质量%在聚乙烯袋中混合3分钟。接着,相对于该混合粉体的总重量,加入0.5质量%的硬脂酸镁(太平化学产业(株)制)进一步缓慢混合30秒。将该混合粉体用旋转式压片机((株)菊水制作所制、CLEANPRESS CORRECT 12HUK),使用直径0.8cm、12R的杵,在转台转速54rpm、压片压5~15kN、开放式给料的条件下进行压片,制得重量180mg的药片。该药片物性见表3。
(实施例19)
将实施例18的复合粒子C改为实施例8的复合粒子H,除此之外进行与实施例18相同的操作。药片物性见表3。
(比较例7)
将实施例18的复合粒子C改为轻质无水硅酸(日本アエロジル(株)制、アエロジル200),除此之外进行与实施例18相同的操作。药片物性见表3。
(比较例8)
将实施例18的复合粒子C改为比较例3的复合粒子S,除此之外进行与实施例18相同的操作。药片物性见表3。
(比较例9)
将实施例18的复合粒子C改为比较例4的复合粒子T,除此之外进行与实施例18相同的操作。药片物性见表3。
(比较例10)
将实施例18的复合粒子C改为比较例5的混合物U,除此之外进行与实施例18相同的操作。药片物性见表3。
(比较例11)
将实施例18的复合粒子C改为比较例6的混合物V,除此之外进行与实施例18相同的操作。药片物性见表3。
[表3]
实施例18及19中,获得了实用硬度50N以上、重量CV值1.0%以下,且无压片损伤(粘冲、顶裂)的药片。另一方面,在比较例7中,发生了压片损伤(虽无粘冲,但顶裂有2个),此外重量CV值也超过1.0%,无法供于实用。此外比较例8~11中,重量CV值超过1.0%,压片损伤(粘冲、顶裂)明显,无法供于实用。
比较例9的打压15kN虽在实用硬度50N以上,但磨损度为0.8%,不在实用标准的0.5%以下。
此外,对各自的药片的崩解时间进行了测定,但均无显著差异。
<乳化液作成方法>
称量液体活性成分理研生育酚乙酸酯(理研维他命)360g,以及吐温80(和光纯药)、纯水1000g,使用TK高速混合搅拌机(プライミクスMARK2 2.5型),以10000rpm搅拌混合15分钟,作成乳化液。
(实施例20)
将实施例3的复合粒子C360g投入立式造粒机(バ一チカルグラニュレ一タ一)((株)パウレック社制、FM-VG-10P)中,以叶片200rpm、切刀2100rpm的条件下混合的同时,用30秒投入上述作成的乳化液360g后,造粒6分钟后排出。接着,烘箱(タバイ社制、エスペックオ一ブンPV-211)干燥后,将通过网目710μm的筛(イイダ制作所制、试验用筛网)后的干燥品作为试验样品(以下记为VE颗粒)。VE颗粒的安息角为35°,良好。
将VE颗粒35质量%、结晶纤维素(旭化成ケミカルズ(株)制、UF-711)45质量%、无水磷酸氢钙(富士化学药品(株)制、フジカリン)18质量%、交联羧甲基纤维素钠(ニチリン化学(株)制、“キッコレ一ト”ND-2HS)2质量%,在聚乙烯袋中混合3分钟。接着,相对于混合粉体的总重量,加入2.0质量%的硬脂酸镁(太平化学产业(株)制),进一步缓慢混合30秒。将该混合粉体用旋转式压片机((株)菊水制作所制、LIBRA2),使用直径0.8cm、12R的冲头,在转台转速30rpm、压片压2~7kN、开放式给料的条件下进行压片,制得重量200mg的药片。该药片物性见表4。
(比较例12)
将复合粒子C改为硅酸钙(トクヤマ(株)制、商品名:フロ一ライトGrade(R)、体积平均粒径(凝集状态下进行的测定)25~30μm),除此之外进行与实施例20相同的操作。该药片物性见表4。VE颗粒的安息角为41°,相比于使用复合粒子C时,流动性变差。
(比较例13)
将复合粒子C改为复合粒子S,除此之外进行与实施例20相同的操作。该药片物性见表4。
(比较例14)
将复合粒子C改为混合物U,除此之外进行与实施例20相同的操作。该药片物性见表4。
[表4]
表4
实施例20中,获得了实用硬度50N以上、重量CV值1.0%以下,且无压片损伤(粘冲、顶裂)的药片。另一方面,比较例12中,在所有的压片压中,粘冲发生率不为0,无法供于实用。此外,比较例13、14中的生育酚乙酸酯保持率低、无法进行粉末化。
产业上的利用可能性
本发明的复合粒子,由于成形性、流动性非常优异,故在含有各种活性成分的成型体的制造中,主要作为医药品领域中的赋形剂使用时,与活性成分的混合均一性优异,此外,由于能维持高的液体保持后的粒子成形性、流动性,进而能防止压片损伤。另外,本发明的成型体的重量偏差少、活性成分的含量均一性优异,具有充分的硬度,磨损度低。
Claims (11)
1.一种复合粒子,其特征在于,含有纤维素和无机化合物,表观比容为7~13cm3/g,生育酚乙酸酯保持率为500~1000%,100质量份复合粒子中,含有10~60质量份的纤维素,所述纤维素的平均宽度为2~30μm,平均厚度为0.5~5μm,体积平均粒径为10~40μm。
2.根据权利要求1所述的复合粒子,其含有10~60质量份纤维素、40~90质量份无机化合物。
3.根据权利要求1或2所述的复合粒子,其中无机化合物是选自由水合二氧化硅、轻质无水硅酸、合成硅酸铝、氢氧化铝镁、偏硅酸铝镁、硅酸铝镁、硅酸钙、含水无水晶形氧化硅、硅酸镁及含水硅酸镁构成的群组之中的至少1种。
4.根据权利要求3所述的复合粒子,其中无机化合物为硅酸钙。
5.根据权利要求1或2所述的复合粒子,其孔径为0.003~1μm,孔容为1.9~3.9cm3/g。
6.根据权利要求1或2所述的复合粒子,其重量平均粒径为30~250μm。
7.根据权利要求1或2所述的复合粒子,其进一步含有淀粉。
8.一种成型体,其含有权利要求1~7任意一项所述的复合粒子和活性成分。
9.根据权利要求8所述的成型体,其中活性成分为医药用成分,或健康食品用成分。
10.一种成型体,其含有复合粒子及活性成分,该复合粒子含有纤维素和无机化合物,该复合粒子的表观比容为7~13cm3/g,生育酚乙酸酯保持率为500~1000%,100质量份的该复合粒子中,含有10~60质量份的纤维素,所述纤维素的平均宽度为2~30μm,平均厚度为0.5~5μm,体积平均粒径优选10~40μm,
该活性成分是25℃时的粘度为3~10000mPa·s的液体,该活性成分的含量是每个500mg的成型体中含有105~250mg。
11.根据权利要求10所述的成型体,其中该活性成分为生育酚乙酸酯。
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