CN113950321A - 包含共聚物混合物和水溶性纤维素的粉末组合物 - Google Patents
包含共聚物混合物和水溶性纤维素的粉末组合物 Download PDFInfo
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Abstract
本发明涉及一种粉末组合物，其包含50至95重量％的共聚物1和共聚物2的共聚物混合物A和50至5重量％的水溶性纤维素B，所述共聚物1包含5至60重量％的甲基丙烯酸聚合单元和95至40重量％的(甲基)丙烯酸C1‑C4烷基酯，所述共聚物2包含超过95重量％且至多100重量％的(甲基)丙烯酸C1‑C4烷基酯聚合单元。所述粉末组合物源自共聚物混合物A和水溶性纤维素B通过水分散体的干燥过程的共加工，例如喷雾干燥或冷冻干燥。进一步加工产生压缩剂型。
Description
技术领域
本发明属于药物和营养品的领域，特别是压缩剂型的领域。
背景技术
Davood Hazanzadeh等人的“Thermal Treating of Acrylic Matrices as aTool for Controlling Drug Release”,Chem.Pharm.Bull.57(12)1356-1362(2009)强调了对丙烯酸基质进行热处理的要求，其中与未处理的相比，热处理会导致更加改进的释放曲线。聚合物链运动和聚合物在热处理后在片剂基质结构中的重新分布是药物释放延长的可能机制。由于热处理，聚合物的熔融和再固化显然导致了聚合物在整个基质中的重新分布以及片剂孔隙率的变化。
WO2012/171575A1描述了一种适用于药物应用的包衣组合物。该包衣组合物包含衍生自两阶段乳液聚合方法的核-壳聚合物。
FL 30D-55(Evonik Nutrition&Care GmbH,Darmstadt,Germany)是一种来自两阶段乳液聚合方法的共聚物的市售的30重量％水分散体，具有约75重量％的核和约25重量％的壳，所述核包含约70重量％的丙烯酸乙酯和30重量％的甲基丙烯酸甲酯的聚合单元，所述壳包含50重量％的丙烯酸乙酯和50重量％的甲基丙烯酸的聚合单元。
发明内容
直接压片是一种简单的口服剂量生产形式，因为它只包含几个工艺阶段，从而导致更短的工艺周期和更快的生产时间。市售的用于改进的释放的可直接压缩材料来自天然或合成来源或其组合。这两种可直接压缩的赋形剂类别都有缺点。例如，从天然来源获得的纤维素存在批次间质量差异的问题。另一方面，丙烯酸酯(最广泛使用的聚合物类别之一)的主要缺点是需要在高温下固化通常24至48小时才能获得所需的稳定释放曲线。还有人报告了关于丙烯酸酯基缓释(SR)基质的储存稳定性的问题。因此，需要配制一种克服所讨论的缺点的可直接压缩SR体系。
本发明涉及一种粉末组合物，其包含50至95重量％的共聚物1和共聚物2的共聚物混合物A和50至5重量％的水溶性纤维素B，所述共聚物1包含5至60重量％的甲基丙烯酸聚合单元和95至40重量％的(甲基)丙烯酸C1-C4烷基酯，所述共聚物2包含超过95重量％且至多100重量％的(甲基)丙烯酸C1-C4烷基酯聚合单元。所述粉末组合物可以被加工成具有稳定活性成分释放曲线的压缩剂型，而无需固化步骤。粉末组合物源自共聚物混合物A和水溶性纤维素B通过水分散体的干燥过程(例如喷雾干燥或冷冻干燥)的共加工。进一步加工产生压缩剂型。
具体实施方式
粉末组合物
本发明涉及一种粉末组合物，其包含50至95重量％的共聚物1和共聚物2的共聚物混合物A和50至5重量％的水溶性纤维素B，所述共聚物1包含5至60重量％的甲基丙烯酸聚合单元和95至40重量％的(甲基)丙烯酸C1-C4烷基酯，所述共聚物2包含超过95重量％且至多100重量％的(甲基)丙烯酸C1-C4烷基酯的聚合单元。粉末组合物可以包含50至100重量％，优选80至100重量％的共聚物混合物A和水溶性纤维素B。任选地，药物赋形剂或营养品赋形剂可以0至50重量％、优选0至20重量％的量存在。
粉末组合物的平均粒径d50可以在1至2,000μm的范围内，优选在1至1,000μm的范围内，最优选在10至600μm的范围内。平均直径可以根据美国药典36(USP)章节<429>和欧洲药典7.0(EP)章节2.9.31通过筛分或通过激光衍射而测定。
激光衍射法是基于其中强度模式取决于颗粒大小的颗粒在各个方向散射光的现象。以足够浓度分散在合适的液体或气体中的代表性样品由单色光源(通常来自激光)的光束通过。由多元件检测器测量颗粒以不同角度散射的光，然后记录与散射模式相关的数值以供后续分析。然后使用合适的光学模型和数学程序转换数值散射值，以产生总体积与离散数量的尺寸等级的比例，形成体积粒径分布(d50描述了对应于50％累积尺寸不足分布的粒径)。
共聚物混合物A
共聚物混合物A是共聚物1和共聚物2的混合物。
共聚物混合物A可以包含单独的共聚物1和2的混合物形式或以核-壳共聚物形式的混合物形式的共聚物1和共聚物2。
单独的共聚物1和2
共聚物混合物A可以包含单独的共聚物1和2的混合物形式的共聚物1和共聚物2。
共聚物1
共聚物1包含5至60％重量的甲基丙烯酸聚合单元和95至40％重量的(甲基)丙烯酸C1-C4烷基酯。
合适的(甲基)丙烯酸酯共聚物1可以由40至60重量％的甲基丙烯酸和60至40重量％的甲基丙烯酸甲酯或60至40重量％的丙烯酸乙酯聚合而成。
L 100是一种由50重量％的甲基丙烯酸甲酯和50重量％的甲基丙烯酸聚合而成的共聚物。
L 100-55是一种由50重量％的丙烯酸乙酯和50重量％的甲基丙烯酸聚合而成的共聚物。
L 30D-55是一种包含30重量％
L 100-55的水分散体。
合适的(甲基)丙烯酸酯共聚物1可以由20至40重量％的甲基丙烯酸和80至60重量％的甲基丙烯酸甲酯聚合而成。
S 100是一种由70重量％的甲基丙烯酸甲酯和30重量％的甲基丙烯酸聚合而成的共聚物。
合适的(甲基)丙烯酸酯共聚物1可以由10至30重量％的甲基丙烯酸甲酯、50至70重量％的丙烯酸甲酯和5至15重量％的甲基丙烯酸聚合而成。
FS是一种由25重量％的甲基丙烯酸甲酯、65重量％的丙烯酸甲酯和10重量％的甲基丙烯酸聚合而成的共聚物。
FS 30D是一种包含30重量％
FS的水分散体。
共聚物2
共聚物2包含超过95且至多100重量％的(甲基)丙烯酸C1-C4烷基酯的聚合单元。
共聚物2可以是包含60至80重量％的丙烯酸乙酯和40至20重量％的甲基丙烯酸甲酯的聚合单元的(甲基)丙烯酸酯共聚物。
NE和
NM是包含28至32重量％的甲基丙烯酸甲酯和68至72重量％的丙烯酸乙酯的聚合单元的共聚物。优选的是根据WO 01/68767的(甲基)丙烯酸酯共聚物，其是通过使用1至10重量％的HLB值为15.2至17.3的非离子乳化剂制备成的分散体。后者提供的优点是在由乳化剂(
NM型)形成晶体结构的情况下不存在相分离。
核-壳共聚物
共聚物混合物A可以包含以核-壳共聚物形式的混合物形式的共聚物1和共聚物2。合适的核-壳共聚物例如从WO2012/171575A1已知。
共聚物混合物A可包含分别对应于共聚物1和共聚物2的两种(甲基)丙烯酸酯共聚物的核-壳聚合物形式的(甲基)丙烯酸酯共聚物的混合物。共聚物混合物A可以是包含50至90重量％，优选70至80重量％的核和50至10重量％、优选30至20重量％的壳的核-壳聚合物，所述核包含60至80重量％、优选65至75重量％的丙烯酸乙酯和40至20重量％、优选35至25重量％的甲基丙烯酸甲酯的聚合单元，所述壳包含40至60重量％、优选45至55重量％的丙烯酸乙酯和60至40重量％、优选55至45重量％的甲基丙烯酸的聚合单元。因此，在这种情况下，核对应于共聚物2，壳对应于共聚物1。
合适的核-壳聚合物是
FL 30D-55(Evonik Nutrition&Care GmbH,Darmstadt,Germany)，其是一种市售的来自两阶段乳液聚合方法的共聚物的30重量％水分散体，具有约75重量％的核和约25重量％的壳，所述核包括约70重量％的丙烯酸乙酯和30重量％的甲基丙烯酸甲酯的聚合单元，所述壳包含50重量％的丙烯酸乙酯和50重量％的甲基丙烯酸的聚合单元。
水溶性纤维素B
水溶性纤维素是在25℃的温度下以1重量％的浓度溶于水的纤维素。
水溶性纤维素B优选为甲基纤维素、羟乙基纤维素、羟乙基甲基纤维素、羟丙基纤维素和/或最优选的羟丙基甲基纤维素。
当在25℃下作为1％水溶液或胶体分散体(重量/重量)测量时，水溶性纤维素的粘度可以在约1至5,000mPa·s的范围内。
制备压缩剂型的方法
本文公开一种制备包含药物或营养组合物的压缩剂型，优选片剂的方法，该方法包括步骤i)至iv)：i)提供共聚物混合物A和水溶性纤维素B的水分散体，ii)将水分散体干燥，优选喷雾干燥或冷冻干燥以获得粉末，iii)将粉末与一种或多种生物活性成分和一种或多种药物或营养品赋形剂混合以获得用于压缩的混合物，iv)将用于压缩的混合物在模具中进行压缩以获得压缩剂型。
步骤i)
在步骤i)中，提供共聚物混合物A和水溶性纤维素B的水分散体。
步骤ii)
在步骤ii)中，将来自步骤i)的水分散体干燥以获得如要求保护的粉末组合物。
优选喷雾干燥或冷冻干燥。
喷雾干燥可以在30至60℃，优选35至55℃的入口温度下进行。
利用在350至450毫托下，从-40至-25℃开始并逐步或连续增加至15至30℃的最终温度的干燥循环步骤进行冷冻干燥4至16小时。
粉末的平均粒径d50可以在1至2,000μm的范围内，优选在1至1,000μm的范围内，最优选在10至600μm的范围内。平均直径可以根据美国药典36(USP)章节<429>和欧洲药典7.0(EP)章节2.9.31通过筛分或通过激光衍射而测定。
步骤iii)
在步骤iii)中，将来自步骤ii)的粉末与一种或多种生物活性成分和一种或多种药物或营养品赋形剂混合以获得用于压缩的混合物。
步骤iv)
在步骤iv)中，将来自步骤iii)的用于压缩的混合物在模具中进行压缩以获得压缩剂型，优选压缩片剂。
压缩片剂的重量可以为2至2,000mg，优选30至1,200mg，最优选100至800mg。
在压缩过程中施加的力可以在1到20kN的范围内，优选地在2至10kN的范围内。所得片剂硬度可以在10至250N，优选50至150N的范围内。用于测定片剂的硬度的方法和设备是药学、盖伦派医学或营养技术领域的技术人员公知的。
压缩剂型
所公开的压缩剂型，优选片剂，包含一种或多种药物或营养活性成分和粉末组合物以及一种或多种药物或营养品赋形剂。
优选地，压缩剂型可包含1至50重量％的一种或多种生物活性成分、10至70重量％的粉末组合物和10至89重量％的一种或多种药物或营养品赋形剂。所述一种或多种生物活性成分、粉末组合物和一种或多种药物或营养品赋形剂可以加起来高达100％。
所公开的压制剂型的特征可以在于，相同尺寸、形式和组成的压缩剂型在40℃下固化24小时的情况下以及没有此固化的情况下显示出50或更大的来自在pH 6.8下的药物溶出试验的它们的比较活性成分释放曲线的相似因子f2。
所公开的压制剂型的特征可以在于，相同尺寸、形式和组成的压缩剂型在和没有在40℃和75％相对湿度下存储在HDPE容器中一个月的情况下显示出50或更大的来自在pH6.8下的药物溶出试验的比较活性成分释放曲线的相似因子f2。
根据USP(例如USP 31)，在pH 6.8下的溶出试验中，所公开的压缩剂型在24小时内显示出60％或更多的活性成分释放。
F2-值
f2-值是本领域技术人员从美国食品和药物管理局(FDA)定义的生物等效性研究的要求中已知的。例如，这些值可以在文件如“行业指南；基于生物药剂学分类系统的速释固体口服剂型的体内生物利用度和生物等效性研究的豁免(Guidance for Industry；Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on Biopharmaceutics ClassificationSystem)”(美国卫生与公共服务部(U.S.Department of Health and Human Services)，食品和药物管理局(Food and Drug Administration)，药品评价与研究中心(Center forDrug Evaluation and Research)(CDER)，2000年8月)或者该文件的其他版本，或FDA或CDER关于生物利用度和生物等效性研究的其他文件或指南中找到。所有这些文件都可在因特网上获得并且是药学和盖伦派医学领域的技术人员所熟知的。在上述2000年8月的文件中，在第7页定义了相似因子(f2)的计算：
在比较试验产品和参照产品时，应使用相似因子(f2)比较溶出曲线。相似因子是平方误差总和的对数倒数平方根变换，并且是两条曲线之间的溶出百分比(％)相似性的度量。
f2＝50·log{[1+(1/n)Σt＝1n(Rt-Tt)2]-0.5·100}
当f2值≥50时，两个溶出曲线被认为是相似的。
生物活性成分
生物活性成分优选为药物活性成分和/或营养活性成分。
一种或多种生物活性成分可以选自以下组中：镇痛药、抗生素或抗感染药、抗体、抗癫痫药、植物抗原、抗风湿药、苯并咪唑衍生物、β-受体阻滞剂、心血管药物、化疗药物、CNS药物、洋地黄糖苷、胃肠药物(例如质子泵抑制剂、酶、激素、液体或固体天然提取物、寡核苷酸、肽类激素蛋白质、治疗性细菌、肽、蛋白质及其(金属)盐，即天冬氨酸、氯化物、原酸盐)、泌尿科药物和疫苗。生物活性成分的其他实例可以是例如阿坎酸(acamprosat)、七叶皂甙、淀粉酶、乙酰水杨酸、肾上腺素、5-氨基水杨酸、金霉素、杆菌肽(bacitracin)、巴沙拉嗪(balsalazine)、β胡萝卜素、比卡鲁胺(bicalutamid)、比沙可啶(bisacodyl)、菠萝蛋白酶(bromelain)、布地奈德(budesonide)、降钙素(calcitonin)、carbamacipine、卡铂(carboplatin)、头孢菌素(cephalosporin)、西曲瑞克(cetrorelix)、克拉霉素(clarithromycin)、氯霉素、西咪替丁(cimetidine)、西沙必利(cisapride)、克拉屈滨(cladribine)、氯氮卓(clorazepate)、色甘酸(cromalyn)、1-去氨半胱氨酸-8-D-精氨酸-加压素(vasopressin)、德伦环烷(deramciclane)、地肽瑞里(detirelix)、右兰索拉唑(dexlansoprazole)、双氯芬酸(diclofenac)、去羟肌苷(didanosine)、洋地黄毒苷(digitoxin)和其它洋地黄糖苷、双氢链霉素(dihydrostreptomycin)、二甲硅油(dimethicone)、双丙戊酸钠(divalproex)、屈螺酮(drospirenone)、度洛西汀(duloxetine)、酶、红霉素、艾美拉唑(esomeprazole)、雌激素类、依托泊苷(etoposide)、法莫替丁(famotidine)、氟化物、蒜油、高血糖素(glucagon)、粒细胞集落刺激因子(G-CSF)、肝素(heparin)、氢化可的松(hydrocortisone)、人生长素(hGH)、布洛芬(ibuprofen)、艾普拉唑(ilaprazole)、胰岛素(insulin)、干扰素(interferon)、白介素、内含子A、酪洛芬(ketoprofen)、兰索拉唑(lansoprazole)、醋酸亮丙瑞林(leuprolidacetat)脂肪酶、硫辛酸、锂、激肽(kinin)、美金刚(memantine)、美沙拉秦(mesalazine)、乌洛托品(methenamine)、米拉美林(milameline)、矿物质、minoprazole、萘普生(naproxen)、那他霉素(natamycin)、呋喃妥因(nitrofurantion)、新生霉素(novobiocin)、奥沙拉秦(olsalazine)、奥美拉唑(omeprazole)、乳清酸酯(orothates)、胰酶素(pancreatin)、泮托拉唑(pantoprazole)、甲状旁腺激素、帕罗西汀(paroxetine)、盘尼西林、吡帕拉唑(perprazol)、吲哚洛尔(pindolol)、多粘菌素(polymyxin)、钾、普伐他汀(pravastatin)、强的松(prednisone)、preglumetacin普罗加胺(progabide)、原生长抑素(pro-somatostatin)、蛋白酶、喹那普利(quinapril)、雷贝拉唑(rabeprazole)、雷尼替丁(ranitidine)、雷诺嗪(ranolazine)、瑞波西汀(reboxetine)、芦丁(rutosid)、生长抑素(somatostatin)链霉素(streptomycin)、枯草菌素(subtilin)、柳氮磺胺吡啶(sulfasalazine)、对氨基苯磺酰胺、坦洛新(tamsulosin)、替那拉唑(tenatoprazole)、胰蛋白酶、丙戊酸(valproic acid)、加压素(vasopressin)、维生素类、锌，包括它们的盐、衍生物、多晶型物、同形体(isomorphs)、或任何种类的混合物或组合。
对技术人员明显的是，术语药物和营养活性成分、赋形剂和组合物(分别是药物或营养剂型)之间存在广泛的重叠。许多列为营养品的物质也可用作药物活性成分。根据具体的应用和地方当局的立法和分类，相同的物质可能被列为药物或营养活性成分，分别是药物或营养组合物，甚至两者。
营养品是技术人员众所周知的。营养品通常被定义为声称对人类健康有医学作用的食物提取物。因此，营养活性成分也可能具有药物活性：营养活性成分的实例可以是作为抗氧化剂的来自葡萄产品的白藜芦醇、可溶性膳食纤维产品，例如用于降低高胆固醇血症的车前子壳、作为癌症预防剂的西兰花(硫烷)以及用于改善动脉健康的大豆或三叶草(异黄酮)。因此，明显的是，许多列为营养品的物质也可用作药物活性成分。
典型的营养品或营养活性成分可包括益生菌和益生元。益生菌是活的微生物，据信在食用时支持人类或动物的健康。益生元是营养品或营养活性成分，其诱导或促进人或动物肠道中有益微生物的生长或活性。
营养品的实例是作为抗氧化剂的来自葡萄产品的白藜芦醇、ω-3-脂肪酸或例如来自越橘、蓝莓或黑醋栗的前花青素，可溶性膳食纤维产品，如用于降低高胆固醇血症的车前子壳，作为癌症预防剂的西兰花(硫烷)以及用于改善动脉健康的大豆或三叶草(异黄酮)。其他营养品的实例是类黄酮、抗氧化剂、来自亚麻籽的α-亚油酸、来自万寿菊花瓣的β-胡萝卜素或各种来源的花青素。有时，保健品或营养药被用作营养品的同义词。优选的生物活性成分是例如美托洛尔。
药物或营养品赋形剂
药物或营养品赋形剂可选自抗氧化剂、增白剂、粘合剂、缓冲剂、调味剂、流动助剂、助流剂、渗透促进剂、颜料、增塑剂、赋形剂聚合物(不同于聚合物混合物A或水溶性纤维素B，例如是诸如微晶纤维素或PVP的聚合物)、成孔剂和稳定剂或其任何组合。
优选地，药物或营养品赋形剂可包括微晶纤维素、甘油单硬脂酸酯、乳糖、二氧化硅、硬脂酸镁、交联羧甲基纤维素钠和/或硬脂酰富马酸钠。
实施例
实施例中使用的聚合物：
所使用的水溶性纤维素是羟乙基纤维素(HEC)、羟丙基纤维素(HPC-LM)和羟丙基甲基纤维素(HPMC K4M和6CPS)。乙基纤维素(EC)是一种水不溶性纤维素。PVP是聚乙烯吡咯烷酮，PVA是聚乙烯醇。
1.
FL 30D-55和纤维素聚合物组合的实验
1.1配方
1.1.1实施例I-1至I-8(根据本发明)的配方
表1：组成(％/w/w)
#对于每个批次，标有*的成分在单个喷雾干燥步骤中一起共同加工。
缩写：FD＝冷冻干燥；SD＝喷雾干燥；PM＝物理混合；HPMC＝羟丙基甲基纤维素；HPC＝羟丙基纤维素；HEC＝羟乙基纤维素；EC＝乙基纤维素；API＝活性药物成分；MCC＝微晶纤维素
1.1.2实施例I-9至I-16(根据本发明)的配方
表1(续)：组成(％/w/w)
#对于每个批次，标有*的成分在单个喷雾干燥步骤中一起共同加工。对于每个批次，标有**的成分在单个冷冻干燥中一起共同加工。标有***的成分仅通过与同一批次中的喷雾干燥粉末进行物理混合来共同加工。
缩写：FD＝冷冻干燥；SD＝喷雾干燥；PM＝物理混合；HPMC＝羟丙基甲基纤维素；HPC＝羟丙基纤维素；HEC＝羟乙基纤维素；EC＝乙基纤维素；API＝活性药物成分；MCC＝微晶纤维素
1.1.3实施例I-17至I-20(根据本发明)的配方
表1(续)：组成(％/w/w)
#对于每个批次，标有*的成分在单个喷雾干燥步骤中一起共同加工。
缩写：FD＝冷冻干燥；SD＝喷雾干燥；PM＝物理混合；HPMC＝羟丙基甲基纤维素；HPC＝羟丙基纤维素；HEC＝羟乙基纤维素；EC＝乙基纤维素；API＝活性药物成分；MCC＝微晶纤维素
1.1.4实施例C-1至C-7(比较)的配方
表1(续)：组成(％/w/w)
#对于每个批次，标有*的成分在单个喷雾干燥步骤中一起共同加工。
缩写：FD＝冷冻干燥；SD＝喷雾干燥；PM＝物理混合；HPMC＝羟丙基甲基纤维素；HPC＝羟丙基纤维素；HEC＝羟乙基纤维素；EC＝乙基纤维素；API＝活性药物成分；MCC＝微晶纤维素
1.2实施例C-1至C-7和I-1至I-8和I-17至I-20的过程详述
a)喷雾干燥步骤：
·在连续搅拌下将纤维素组分(如果配方中有的话)缓慢添加到水中以形成胶体分散体。
·将
FL 30D-55缓慢添加到来自上述步骤的胶体分散体中。
·然后将分散体通过60#ASTM筛(250μm)，然后使用实验室规模的Buchi喷雾干燥器将其用于喷雾干燥。
喷雾干燥的工艺参数：
| 实验编号 | C-1和C-4至C-7 | C-2、I-1至I-8和I-17至I-20 |
| 入口温度(℃) | 50-55 | 65-75 |
| 抽吸器(％) | 90-95 | 90-95 |
b)片剂压制步骤
·所有成分均通过30#ASTM筛(590μm)。
·将来自以上的喷雾干燥的聚合物粉末与表1中提到的API和其他压片赋形剂(硬脂酸镁除外)进行几何混合。
·在将硬脂酸镁通过80#ASTM筛(180μm)后结束时将硬脂酸镁添加到来自上述步骤的共混物中并混合均匀。
·使用安装在旋转压制机上的D模具将共混物压制成片剂。
片剂压制的工艺参数：
| 实验编号 | C-1和C-4至C-7 | C-2、I-1至I-8和I-17至I-20 |
| 冲头尺寸(mm) | 9 | 12.5 |
| 重量(mg) | 230 | 650-655 |
| 硬度(N) | 80-90 | 70-90 |
1.3实施例I-9、I-10和C-3的过程详述
a)喷雾干燥步骤：
·在连续搅拌下将纤维素组分缓慢添加到水中以形成胶体分散体。
·在搅拌下将
NM 30D缓慢添加到
L 30D-55(如果有)中以混合在一起。
·在搅拌下将来自上述步骤的
分散体添加到胶体纤维素分散体中。
·然后将分散体通过60#ASTM筛(250μm)，然后使用实验室规模的Buchi喷雾干燥器将其用于喷雾干燥。
喷雾干燥的工艺参数：
| 实验编号 | I-9、I-10和C-3 |
| 入口温度(℃) | 40-50 |
| 抽吸器(％) | 90-95 |
b)片剂压制步骤
·所有成分均通过30#ASTM筛(590μm)。
·将来自以上的喷雾干燥的聚合物粉末与表1中提到的API和其他压片赋形剂(硬脂酸镁除外)进行几何混合。对于实验I-10，在与其他成分混合之前，将
L 100粉末与喷雾干燥的粉末均匀混合。
·在将硬脂酸镁通过80#ASTM筛(180μm)后结束时将硬脂酸镁添加到来自上述步骤的共混物中并混合均匀。
·使用安装在旋转压制机上的D模具将共混物压制成片剂。
片剂压制的工艺参数：
| 实验编号 | I-9、I-10和C-3 |
| 冲头尺寸(mm) | 12.5 |
| 重量(mg) | 650-655 |
| 硬度(N) | 70-90 |
1.4实施例I-11和I-13的过程详述
a)冷冻干燥步骤：
·在连续搅拌下将纤维素组分(如果配方中有的话)缓慢添加到水中以形成胶体分散体。
·在搅拌下将
NM 30D缓慢添加到
L 30D-55(如果有)中以混合在一起。
·在搅拌下将来自上述步骤的
分散体添加到胶体纤维素分散体中。
·然后将分散体通过60#ASTM筛(250μm)，接着使用实验室规模的Vertis冷冻干燥器将其用于冷冻干燥。
冷冻干燥的工艺参数：
b)片剂压制步骤
·所有成分均通过30#ASTM筛(590μm)。
·将来自以上的喷雾干燥的聚合物粉末与表1中提到的API和其他压片赋形剂进行几何混合。
·在将硬脂酸镁通过80#ASTM筛(180μm)后结束时将硬脂酸镁添加到来自上述步骤的共混物中并混合均匀。
·使用安装在旋转压制机上的D模具将共混物压制成片剂。
片剂压制的工艺参数：
| 实验编号 | I-11至I-13 |
| 冲头尺寸(mm) | 12.5 |
| 重量(mg) | 650-655 |
| 硬度(N) | 70-90 |
1.5实验I-14至I-16的过程详述
a)喷雾干燥和物理混合步骤：
·用水将
FL 30D稀释至15％(w/w)的固含量。
·然后将分散体通过60#ASTM筛(250μm)，接着使用实验室规模的Buchi喷雾干燥器将其用于喷雾干燥。
喷雾干燥的工艺参数：
| 实验编号 | I-14至I-16 |
| 入口温度(℃) | 50-55 |
| 抽吸器(％) | 90-95 |
·将来自上述步骤的喷雾干燥的聚合物粉末与纤维素混合均匀并通过30#ASTM筛(590μm)
b)片剂压制步骤
·所有成分均通过30#ASTM筛(590μm)。
·将来自以上的喷雾干燥并物理混合的聚合物粉末与表1中提到的API和其他压片赋形剂(硬脂酸镁除外)进行几何混合。
·在将硬脂酸镁通过80#ASTM筛(180μm)后结束时将硬脂酸镁添加到来自上述步骤的共混物中并混合均匀。
·使用安装在旋转压制机上的D模具将共混物压制成片剂。
片剂压制的工艺参数：
| 实验编号 | I-14至I-16 |
| 冲头尺寸(mm) | 12.5 |
| 重量(mg) | 650-655 |
| 硬度(N) | 70-90 |
1.6压缩片剂的分析：
a)溶出：使用推荐的溶出设备和介质研究所有样品的溶出曲线(24小时)。
b)固化研究：通过将所有压缩片剂样品暴露于40-50℃持续24小时来研究其固化效果。使用f2值比较固化前后的溶出曲线。
c)稳定性：将未固化的样品装在HDPE容器中并装入保持在40℃/75％RH下的稳定箱中。至少在储存1个月后对样品进行分析，并使用f2检验研究溶出曲线的任何变化。
1.7a)根据本发明的样品(I-1至I-20)的结果
1.7b)比较例(C-1至C-7)的结果
1.8来自以上实验的重要发现
a)
FL 30D–55(粉末形式)在单独用于直接压片时，不能提供无固化的溶出曲线。
b)
FL 30D-55在与水溶性纤维素结合使用时，给出所需的无固化、稳定溶出性质。
c)
FL 30D-55在与水不溶性纤维素(例如乙基纤维素)组合时给出所需的无固化曲线，但无法保持溶出曲线的稳定性，其中f2值在储存1个月内降至50以下。
2.
FL 30D-55和非纤维素聚合物组合的实验
2.1配方
2.1.1实施例C-8至C-14(比较)的配方
表1(续)：组成(％/w/w)
#对于每个批次，标有*的成分在单个喷雾干燥步骤中一起共同加工。对于每个批次，标有**的成分在单个冷冻干燥步骤中一起共同加工。对于每个批次，标有***的成分仅通过物理混合在一起共同加工。
缩写：FD＝冷冻干燥；SD＝喷雾干燥；PM＝物理混合；API＝活性药物成分；MCC＝微晶纤维素；PVP＝聚乙烯吡咯烷酮；PVA＝聚乙酸乙烯酯
2.2实验C-8、C-9和C-12的过程详述
a)喷雾干燥步骤：
·在连续搅拌下在水中缓慢添加除
以外的非纤维素组分(如果配方中有的话)以形成胶体分散体。
·将
FL 30D-55缓慢添加到来自上述步骤的胶体分散体中。
·单独制备其他
分散体，然后向其中添加
FL 30D-55。
·然后将分散体通过60#ASTM筛(250μm)，接着使用实验室规模的Buchi喷雾干燥器将其用于喷雾干燥。
喷雾干燥的工艺参数：
| 实验编号 | C-8、C-9和C-12 |
| 入口温度(℃) | 70-73 |
| 抽吸器(％) | 85-90 |
b)片剂压制步骤
·所有成分均通过30#ASTM筛(590μm)。
·将来自以上的喷雾干燥的聚合物粉末与表1中提到的API和其他压片赋形剂(硬脂酸镁除外)进行几何混合。
·在将硬脂酸镁通过80#ASTM筛(180μm)后结束时将硬脂酸镁添加到来自上述步骤的共混物中并混合均匀。
·使用安装在旋转压制机上的D模具将共混物压制成片剂。
片剂压制的工艺参数：
2.3实验C-13的过程详述
a)冷冻干燥步骤：
·制备
FL 30D分散体并将其保持在搅拌下。
·单独制备实验中提到的其他
的分散体。
·在搅拌下将来自上述步骤的
分散体加入到
FL 30D分散体中。
·然后将分散体通过60#ASTM筛(250μm)，接着使用实验室规模的Vertis冷冻干燥器将其用于冷冻干燥。
冻干工艺参数：
b)片剂压制步骤
·所有成分均通过30#ASTM筛(590μm)。
·将来自以上的冷冻干燥的聚合物粉末与表1中提到的API和其他压片赋形剂(硬脂酸镁除外)进行几何混合。
·在将硬脂酸镁通过80#ASTM筛(180μm)后于结束时将硬脂酸镁添加到来自上述步骤的共混物中并混合均匀。
·使用安装在旋转压制机上的D模具将共混物压制成片剂。
片剂压制的工艺参数：
| 实验编号 | C-13 |
| 冲头尺寸(mm) | 12.5 |
| 重量(mg) | 650-655 |
| 硬度(N) | 70-90 |
2.4实验C-10、C-11和C-14的过程详述
a)喷雾干燥和物理混合步骤：
·用水将
FL 30D稀释至15％(w/w)的固含量。
·然后将分散体通过60#ASTM筛(250μm)，接着使用实验室规模的Buchi喷雾干燥器将其用于喷雾干燥。
喷雾干燥的工艺参数：
| 实验编号 | C-10、C-11和C-14 |
| 入口温度(℃) | 50-55 |
| 抽吸器(％) | 90-95 |
·将来自上述步骤的喷雾干燥的聚合物粉末与纤维素混合均匀并通过30#ASTM筛(590微米)
b)片剂压制步骤
·所有成分均通过30#ASTM筛(590μm)。
·将来自以上的喷雾干燥并物理混合的聚合物粉末与表1中提到的API和其他压片赋形剂(硬脂酸镁除外)进行几何混合。
·在将硬脂酸镁通过80#ASTM筛(180μm)后结束时将硬脂酸镁添加到来自上述步骤的共混物中并混合均匀。
·使用安装在旋转压制机上的D模具将共混物压制成片剂。
片剂压制的工艺参数：
| 实验编号 | C-10、C-11和C-14 |
| 冲头尺寸(mm) | 12.5 |
| 重量(mg) | 650-655 |
| 硬度(N) | 70-90 |
2.5压缩片剂的分析：
a)溶出：使用推荐的溶出设备和介质研究所有样品的溶出曲线(24小时)。
b)固化研究：通过将所有压缩片剂样品暴露于40℃持续24小时来研究其固化效果。使用f2值比较固化前后的溶出曲线。
c)稳定性：将未固化的样品装在HDPE容器中并装入保持在40℃/75％RH下的稳定箱中。至少在储存1个月后对样品进行分析，并使用f2检验研究溶出曲线的任何变化。
2.6所有实验(C-8至C-14)的结果
2.7来自以上实验(C-8至C-14)的重要发现
a)
FL 30D-55在与各种非纤维素聚合物组合时，没有一种组合能够满足所有的验收标准。
b)所有与
FL 30D-55的非纤维素组合都是比较例。
Claims (15)
1.一种粉末组合物，其包含50至95重量％的共聚物1和共聚物2的共聚物混合物A和50至5重量％的水溶性纤维素B，所述共聚物1包含5至60重量％的甲基丙烯酸聚合单元和95至40重量％的(甲基)丙烯酸C1-C4烷基酯，所述共聚物2包含超过95重量％且至多100重量％的(甲基)丙烯酸C1-C4烷基酯的聚合单元。
2.根据权利要求1所述的粉末组合物，其中所述共聚物混合物A包含单独的共聚物1和聚合物2的混合物形式或以核-壳共聚物形式的混合物形式的共聚物1和共聚物2。
3.根据权利要求1或2所述的粉末组合物，其中共聚物1包含40至60重量％的甲基丙烯酸和60至40重量％的丙烯酸乙酯或甲基丙烯酸甲酯的聚合单元。
4.根据权利要求1至3中任一项所述的粉末组合物，其中共聚物2包含60至80重量％的丙烯酸乙酯和40至20重量％的甲基丙烯酸甲酯的聚合单元。
5.根据权利要求1至4中任一项所述的粉末组合物，其中所述共聚物混合物A以核-壳聚合物的形式存在，所述核-壳聚合物具有50至90重量％的共聚物2的核和50至10重量％的共聚物1的壳。
6.根据权利要求1至5中任一项所述的粉末组合物，其中所述水溶性纤维素B为甲基纤维素、羟乙基纤维素、羟乙基甲基纤维素、羟丙基纤维素和/或羟丙基甲基纤维素。
7.根据权利要求1至6中任一项所述的粉末组合物，其中当在25℃下作为1％(重量/重量)水溶液或胶体分散体测量时，所述水溶性纤维素的粘度为约1至5,000mPa·s。
8.一种制备包含根据权利要求1至7中任一项的药物或营养组合物的压缩剂型，优选片剂的方法，所述方法包括步骤i)至iv)：
i)提供所述共聚物混合物A和所述水溶性纤维素B的水分散体，
ii)将所述水分散体干燥，优选喷雾干燥或冷冻干燥，以获得粉末组合物，
iii)将所述粉末组合物与一种或多种生物活性成分和一种或多种药物或营养品赋形剂混合，以获得用于压缩的混合物，
iv)将所述用于压缩的混合物在模具中进行压缩，以获得所述压缩剂型。
9.根据权利要求8所述的方法，其中在步骤ii)中，喷雾干燥在30至60℃、优选35至55℃的入口温度下进行。
10.根据权利要求8所述的方法，其中在步骤ii)中，利用在350至450毫托下，从-40至-25℃开始并逐步或连续升高至15至30℃的最终温度的干燥循环步骤进行冷冻干燥4至16小时。
11.一种压缩剂型，优选片剂，其包含一种或多种药物或营养活性成分、根据权利要求1至7中任一项所述的粉末组合物和一种或多种药物或营养品赋形剂。
12.根据权利要求11所述的压缩剂型，其包含1至50重量％的所述一种或多种生物活性成分、10至70重量％的根据权利要求1至7中任一项所述的粉末组合物和10至89重量％的所述一种或多种药物或营养品赋形剂。
13.根据权利要求11或12所述的压缩剂型，其中相同尺寸、形式和组成的压缩剂型在40℃下固化24小时的情况下和没有所述固化的情况下显示出50或更大的来自在pH 6.8下的药物溶出试验的比较活性成分释放曲线的相似因子f2。
14.根据权利要求11至13中任一项所述的压缩剂型，其中相同尺寸、形式和组成的压缩剂型在40℃和75％相对湿度下存储在HDPE容器中一个月的情况下和没有所述存储的情况下显示出50或更大的来自在pH 6.8下的药物溶出试验的比较活性成分释放曲线的相似因子f2。
15.根据权利要求11至14中任一项所述的压缩剂型，其在pH 6.8下的溶出试验中，在24小时内显示出60％或更多的活性成分释放。
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| CN103608001A (zh) * | 2011-06-17 | 2014-02-26 | 赢创罗姆有限公司 | 适用于药物或营养制品剂型的包衣组合物 |
| WO2017076987A1 (en) * | 2015-11-03 | 2017-05-11 | Ratiopharm Gmbh | Composition comprising apremilast in amorphous form |
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| DE102005024614A1 (de) * | 2005-05-25 | 2006-11-30 | Röhm Gmbh | Verwendung von Polymermischungen zur Herstellung von überzogenen Arzneiformen sowie Arzneiform mit polymerem Mischüberzug |
| CN103608001A (zh) * | 2011-06-17 | 2014-02-26 | 赢创罗姆有限公司 | 适用于药物或营养制品剂型的包衣组合物 |
| WO2017076987A1 (en) * | 2015-11-03 | 2017-05-11 | Ratiopharm Gmbh | Composition comprising apremilast in amorphous form |
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