CN1886119B - 泮托拉唑多颗粒制剂 - Google Patents
泮托拉唑多颗粒制剂 Download PDFInfo
- Publication number
- CN1886119B CN1886119B CN200480035251.8A CN200480035251A CN1886119B CN 1886119 B CN1886119 B CN 1886119B CN 200480035251 A CN200480035251 A CN 200480035251A CN 1886119 B CN1886119 B CN 1886119B
- Authority
- CN
- China
- Prior art keywords
- spherical
- pantoprazole
- many granules
- coating
- spherical nuclei
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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Classifications
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- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
Abstract
本文描述了泮托拉唑钠多颗粒，它避免粘着在鼻饲管和胃管上。泮托拉唑多颗粒具有泮托拉唑或其对映体或其盐、表面活性剂和崩解剂的球形核；由羟丙基甲基纤维素(羟丙甲纤维素)和水组成的底衣，底衣上的肠溶衣，和肠溶衣上的最后隔离层，其由羟丙基甲基纤维素(羟丙甲纤维素)和水组成。
Description
发明背景
泮托拉唑，5-(二氟甲氧基)-2-[(3，4-二甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑，为H+/K+-三磷酸腺苷(ATP)抑制剂(也称为酸泵或质子泵抑制剂(PPI)，酸泵或质子泵是一种存在于胃壁细胞中的酶。可认为这些药物在壁细胞中代谢后变成活性亚磺酰胺代谢产物，该代谢产物使质子泵的巯基失去活性，从而减少氢离子分泌。PPI通常为亲脂性的弱碱，在低pH时水溶性差。多数PPI在低pH溶液中不稳定并进行快速的酸催化分解，而在中性pH或高pH时它们相对稳定。
目前可买到的泮托拉唑钠口服制剂为单一单位包衣片剂。见例如美国专利5997903，该专利描述由核、中间层和外层组成的口服形式泮托拉唑。目前的包衣有引起片剂不需要的粘在胃肠道的倾向。
与单一单位片剂相比，多颗粒制剂由于其分散于胃肠道中的性质，显示食物影响减少和胃排空时间变化减小，从而提供减少的个体间和个体内差异(Intl.Journal of Pharmaceutics 140[1996]229-235)。
在过去已进行一些开发泮托拉唑多颗粒制剂的不成功的尝试。然而，发现这些尝试所制备的多颗粒与片剂不是生物等效的，相对生物利用度仅为70％。另一尝试使用不同的non-pareil种包衣技术和挤出/滚圆法(spheronization)，所得产品在酸性条件下不能提供合适的释放。另外，于室温贮藏时，这些尝试所制备的产品不稳定，这可通过变色观察到。
发明概述
本发明提供稳定的多颗粒泮托拉唑制剂，该制剂提供减小的个体内和个体间差异。
在一个实施方案中，本发明的泮托拉唑多颗粒由球形核、核上的肠溶衣组成；其中球形核包含泮托拉唑或其对映体、或其盐或水合物，至少一种表面活性剂，至少一种崩解剂和约1％至约2％W/W水；所述肠溶衣包含占球形核约15％至约45％W/W的异丁烯酸和异丁烯酸酯共聚物；其中所述多颗粒的直径平均尺寸为约1mm。
本发明的多颗粒制剂最好在室温贮藏条件下稳定至少12个月。基于对迄今所得12个月室温数据和6个月40℃/75％相对湿度(RH)数据的趋势分析，本发明的多颗粒应该具有2年以上的有效期。如果在有效期贮藏期间制剂保留90％至110％的效力，一般可认为本发明的多颗粒制剂稳定。
本发明的泮托拉唑多颗粒制剂较少粘附于肠壁、鼻饲管和胃管以及包装袋材料，从而药品可预测地传递至药物释放位点。该制剂在起效早期也提供缓解胃肠疼痛的作用，并具有延长的作用持续时间。该制剂可给予儿科患者和吞咽固体食物困难的患者。该制剂也允许经鼻饲管和胃管给药。
发明详述
本发明提供泮托拉唑多颗粒制剂，该制剂具有在碱性pH环境存在下与泮托拉唑钠相容的赋形剂和表面活性剂(如聚山梨醇酯80)的独特组合。此外，本发明提供在制粒期间使用低剪切且在干燥期间使用低温制备多颗粒的方法。该方法有助于本发明中多颗粒的核稳定。
一方面，本发明提供在胃条件下缓慢释放而在中性pH也就是在胃肠道下端快速释放的泮托拉唑多颗粒制剂。
本发明的泮托拉唑钠多颗粒制剂提供促进泮托拉唑释放至患者的系统。目前市场上的制剂为单一的单层片剂。本发明多颗粒球形制剂适用于胶囊或箔包装，可通过挤出/滚圆法加包衣技术制备。
本发明的多颗粒组合物和肠溶衣如Eudragit允许在低pH(～1)减弱释放，在中性pH(～7)快速释放。这在患者中迅速提供血药水平， 从而起效迅速。基于从狗数据得到的结果，与单一的单层(monolithic)片剂相比，多颗粒制剂的Tlag值更小，这显示多颗粒制剂起效更快。
多颗粒制剂的使用便于儿科患者和吞咽困难的患者给药，在给药之前，将球形体分散于悬浮液中或散置/分散于低pH液体如苹果酱中。该悬浮液可在给药前通过混合粉末物质与水的混合物制得。胶囊或小袋或任何其它容器中的多颗粒的尺寸较小，也可经鼻饲管或胃管给药。
与目前市场上的片剂相比，该制剂可迅速缓解GI疼痛并延长作用持续时间(延长释放)。
I.本发明的多颗粒
多颗粒合适为约0.1-2mm、0.5mm-1.5mm、0.7mm-1.25mm或0.8mm-1mm。在一个实施方案中，本发明组合物中多颗粒的平均直径为约1mm。一般本发明的多颗粒尺寸不大于约1mm，以便通过鼻饲管。
本发明的多颗粒最少由球形核与核上的肠溶衣组成。在核与肠溶衣之间可应用初始隔离层(seal coat)，如包含羟丙基甲基纤维素(羟丙甲纤维素)衣料。也可在肠溶衣上应用最后隔离层，如羟丙基甲基纤维素(羟丙甲纤维素)衣料。球形核最少由泮托拉唑或其盐和表面活性剂组成。
除非上下文另有要求，否则本文使用的术语‘泮托拉唑’指5-(二氟甲氧基)-2-[(3，4-二甲氧基-2-吡啶基)甲基亚磺酰基]-1H-苯并咪唑及其对映体，术语‘泮托拉唑化合物’包括泮托拉唑及其对映体、盐和水合物。活性化合物泮托拉唑在欧洲专利166 287中有描述，该专利描述其制备，并以商品名 
在商业上提供。其中药学上可接受的泮托拉唑盐的实例包括如钠盐、镁盐和钙盐；其它的盐还在欧洲专利166 286中有描述，该专利通过引用结合到本文中。合适盐的选择不受本发明限制。在一个实施方案中，盐为钠盐。一般存在的泮 托拉唑化合物占全部多颗粒的约5-50％w/w，更优选约20-45％w/w。
本领域技术人员熟知合适的表面活性剂。然而，特别理想的为十二烷基硫酸钠、聚山梨醇酯包括如聚山梨醇酯80以及这些组分的混合物。一般表面活性剂在核中存在的量占核约2％至约7％w/w，理想的为约5％w/w。在另一个实施方案中，表面活性剂存在的比例为约5∶3药物：表面活性剂(如泮托拉唑钠倍半水合物比十二烷基硫酸钠)至约10∶1药物：表面活性剂(如泮托拉唑钠倍半水合物比聚山梨醇酯80)。有利的是，已发现多颗粒制剂中的表面活性剂增加可湿性，从而增加泮托拉唑钠从本发明的多颗粒制剂释放和吸收的速度和程度。
球形核还可包含崩解剂、pH调节剂及任选的粘合剂或另外的赋形剂如羟丙基甲基纤维素(如羟丙甲纤维素2208)。崩解剂在核中存在的总量合适为约15％w/w至约80％w/w的量，或约20％w/w至约70％w/w，或约25％w/w至约45％w/w，或约30％w/w至约42％w/w。在一个实施方案中，药物的总量与粘合剂以比例表示为约50∶1至约40∶1重量药物：粘合剂。制剂中pH调节剂的总量可占多颗粒约0.1％w/w至约10％w/w，或约1％w/w至约8％w/w，或约3％w/w至约7％w/w。然而，这些百分比可按本领域技术人员所需或所希望进行调节。
崩解剂可选自其它已知的崩解剂，其中包括如纤维素和交聚维酮。在一个实施方案中，崩解剂选自微晶纤维素和交聚维酮及其混合物。粘合剂可选自已知的粘合剂，其中包括如纤维素和聚维酮。在一个实施方案中，粘合剂为羟丙基甲基纤维素(羟丙甲纤维素)。其中合适的pH调节剂包括如碳酸钠、碳酸氢钠、碳酸钾、碳酸锂。还有其它的合适组分对本领域技术人员而言是显而易见的。
在一个实施方案中，基于干的未包衣核计(w/w)，球形核包含约45％泮托拉唑钠倍半水合物(约40％游离泮托拉唑)，约25-30％并优选约27％微晶纤维素，约4-6％并优选约5％聚山梨醇酯80，约14-16％并优选约15％交聚维酮，约0.5-2％并优选约1％羟丙甲纤维素2208，约5-8％并优选约6.5％碳酸钠。在一个实施方案中，球形核包含：
在另一个实施方案中，球形核包含：
尽管在下述干燥方法期间从核中除去了水分，但核优选保留约1％至约2％w/w水。不受理论束缚，本发明人认为与尝试制备多颗粒泮托拉唑的失败的先有技术相比，该含水量有助于该多颗粒的稳定。
在用肠溶衣包衣之前，可任选直接应用初始隔离层(或底衣)至核。尽管该隔离层的组分可由本领域技术人员调节，但特别合适的初始隔离层由羟丙基甲基纤维素(羟丙甲纤维素)和水组成。例如，合适的初始隔离层可采用7.5％w/w羟丙甲纤维素溶液。一般该隔离层占未包衣核约2％w/w至约4％w/w，或占包衣多颗粒约1％w/w至约2％w/w。
在一个实施方案中，带底衣的多颗粒包含：
组分 量/胶囊 ％w/w，基于多颗粒的
总重量计
A.底衣 4.00mg 1.943
泮托拉唑钠微丸 100.00mg 48.573
(40mg泮托拉唑/100mg微丸)
羟丙基甲基纤维素2910，USP，6cps 4.00mg 1.943
纯化水，USP/BP/EP 9.33mg*
*加工期间除去
总量 104.00mg 50.516
肠溶衣施用于初始隔离层(如果存在)上，或直接施用至未包衣的球形核。应用肠溶衣以使包在核上的量合适占多颗粒约15-45％w/w，或约20％w/w至约30％w/w，或约25％w/w至30％w/w。在一个实施方案中，肠溶衣占多颗粒约27.5-32.5％w/w。肠溶衣合适包含异丁烯酸和异丁烯酸酯共聚物的产品，如可买到的Eudragit L30D-55。在一个实施方案中，肠溶衣由Eudragit L 30D-55共聚物、滑石粉、柠檬酸三乙酯、氢氧化钠和水组成。更特别是，肠溶衣可包含占多颗粒约30％w/w(以30％重量分散体应用)的Eudragit L 30D-55衣料；约15％w/w的滑石粉；约3％的柠檬酸三乙酯；pH调节剂如氢氧化钠和水。可选择其它合适的材料用于肠溶衣中，包括如邻苯二甲酸羟丙基甲基纤维素、邻苯二甲酸乙酸纤维素等。
在一个实施方案中，提供具有如下核上底衣和肠溶衣的本发明多颗粒：
组分 量/胶囊 ％w/w，基于多颗粒总
重量计
核+底衣 100.20mg 48.67
Eudragit L 30D-55 208.00mg 30.309
62.40(固体)
滑石粉，USP，Altalc 500V 31.20mg 15.155
氢氧化钠，NF 1N溶液 9.30mg 0.175
0.36(固体)
柠檬酸三乙酯，PG/NF 6.24mg 3.031
纯化水，USP/BP/EP 183.38mg*
*加工期间除去
总量 204.20mg 99.186
在一个实施方案中，包肠溶衣的多颗粒还包最后隔离层。最后隔离层合适包含羟丙基甲基纤维素，并占已包衣多颗粒约0.1％w/w至10％w/w，0.1％w/w至约5％w/w，或约0.2％w/w至约4％w/w。
在一个实施方案中，在肠溶衣上应用最后隔离层，该隔离层为量占多颗粒0.5-1％w/w的羟丙基甲基纤维素水溶液(水分在加工期间除去)。随后，可任选在最后隔离层上应用滑石粉层，用量为约0.05w/w至约1％w/w，优选0.1％w/w至0.5％w/w。
在一个实施方案中，所得本发明的多颗粒制剂达到89-94的供试品/参照品几何平均AUC比，该比值90％的置信区间为84-100，或者达到62-66的供试品/参照品几何平均Cmax比，该比值90％的置信区间为56-74，或者达到下述体外溶出曲线：
在另一个实施方案中，所得本发明的多颗粒制剂达到5451-5629ng.h/ml的平均AUC和1865-1929ng/ml的平均Cmax，或者达到下述体外溶出曲线：
*说明：酸2小时-NMT 10.0％；缓冲液45分钟-NLT 75％
然而，本发明不限于这些例举的曲线。
不受理论的束缚，认为为了药物的有效释放和吸收，羟丙基甲基纤维素的最后隔离层为减少粘液粘性Eudragit层与上胃肠道之间的接触提供物理屏障，从而让多颗粒可靠地输送至GI道中恰当的pH环境。此外，羟丙基甲基纤维素的最后隔离层使多颗粒具有抗粘的性质，从而多颗粒不会粘于包装袋材料和/或鼻饲管。本发明的多颗粒用于经鼻饲管给药和经食物媒介、尤其是酸性食物媒介给药。
II.制备本发明多颗粒制剂的方法
另一方面，本发明提供制备本发明多颗粒制剂的方法。
一般未包衣的泮托拉唑复合物可按如下方法制备。于低剪切条件下，在合适的混合器中干法混合包含至少泮托拉唑化合物和粘合剂的干燥组分。合适的低剪切条件可使用如Hobart混合器容易达到，转数在约25rpm至35rpm的范围，最理想的为32rpm。然而，本领域技术人员能够使用不同的设备，通过调节转数至所挑选设备的恰当低 剪切设置达到等同的低剪切条件。羟丙基甲基纤维素或交聚维酮可任选被取代或者另外包括在该步骤中。另外，pH调节剂可包括在该步骤中。
随后，通过在低剪切条件下混合液体组分如表面活性剂和水来提供颗粒状产品。合适的低剪切条件可使用如Hobart混合器容易达到，转数在约25rpm至35rpm的范围，最理想的为32rpm。然而，本领域技术人员能够使用不同的设备通过调节转数至所挑选设备的恰当低剪切设置达到同等的低剪切条件。然后经合适设备(如NICA挤出机/滚圆机)挤出并滚圆制粒，干燥所得球形核，过筛，并任选在贮藏之前混合。
发明人已发现当本发明的多颗粒在低温干燥时提供化合物稳定性的显著优势。本发明的泮托拉唑多颗粒的球形核理想地干燥至干燥失重(LOD)百分比(％)为3.4％-4.3％。本文使用的低温干燥指温度不超过约40℃干燥10-12小时。当干燥条件超过该温度和时间期限时，观察到引起不稳定的杂质。在一个实施方案中，在35℃-40℃或约37℃-39℃范围内对核进行干燥约8-72小时。在另一个实施方案中，在约40℃干燥核10-12小时。当如所述应用包衣层时，各包衣层的合适干燥温度也在该范围内。
可任选应用亲水性聚合物的初始隔离层至未包衣的多颗粒。例如，由羟丙基甲基纤维素和纯化水组成的初始隔离层可在流化床包衣机上应用，如通过喷雾。
肠溶衣可直接施用至未包衣的球形核上，也就是未包衣的多颗粒上，或者可施用至初始隔离层上。如上所述，肠溶衣一般在流化床wurster包衣机上应用。
在一个实施方案中，最后隔离层施用至肠溶衣上，在将多颗粒填充至合适的包装单位之前，最后步骤中可任选使用滑石粉。
本发明的多颗粒根据所需释药途径可为任何合适的形式，包括如颗粒、微丸、珠、小片、小球、珠形片(beadlets)、微胶囊、毫球 (millispheres)、纳米胶囊、微球、板形片(platelets)、片和胶囊。
III.制剂、药剂盒和释放方法
在另一个实施方案中，本发明提供包含本发明的泮托拉唑多颗粒的产品。
本发明的多颗粒组合物适宜配制成使患者接受适量的泮托拉唑，如5mg-200mg，约10mg至约100mg或约40mg(基于游离泮托拉唑计算)。优选制剂以单一剂量单位释放合适剂量。这些剂量可每天给予，持续合适的一段时间，如4周至8周，但可释放较短的一段时间，如3天至3周、1周至3个月，或经过一段较长时间，如超过6个月或更长时间。这些组合物可单独释放或者与抗酸剂或其他合适组合物联合释放。
在一个实施方案中，本发明提供通过给予有效剂量的泮托拉唑多颗粒治疗人的方法，所述多颗粒的曲线下面积(AUC)至少与 
片剂生物等效且达到表VI中所列Cmax。
在一个实施方案中，包装泮托拉唑多颗粒供患者或其护理给药者使用。例如，多颗粒可包装在箔或其它合适的包装中，并适用于混合在食品(如苹果酱及其它酸性食品媒介)中或混合在饮料中供患者使用。
本发明泮托拉唑多颗粒制剂用于治疗胃食管返流疾病(GERD)、胃溃疡和十二指肠溃疡及佐林格-埃利森综合征(Zollinger-Ellisonsyndrome)。
在另一个实施方案中，泮托拉唑多颗粒混悬于生理上相容的悬浮液体中。
在还另一个实施方案中，泮托拉唑多颗粒填充在胶囊、囊形片等中用于经口释放。
在还再一个实施方案中，本发明提供通过给予有效剂量本发明的泮托拉唑多颗粒治疗有需要的患者的方法。
如下实施例举例说明本发明具体的实施方案，但并不限制本发明。
实施例1-泮托拉唑钠多颗粒制剂
在最初的制剂发展期间，使用NICA挤出机/滚圆机制备几种原型的未包衣多颗粒，以获得即释曲线类似于或快于泮托拉唑钠未包衣片剂的目标，未包衣片剂目前以Protonix(20mg和40mg)片剂提供。在制备四批未包衣多颗粒期间评价5-28.5％崩解剂交聚维酮和0.5-1％粘合剂羟丙基甲基纤维素的水平。
A.未包衣泮托拉唑钠多颗粒的制备
更特别是，将泮托拉唑钠倍半水合物、微晶纤维素、羟丙基甲基纤维素(羟丙甲纤维素2208)、交聚维酮和碳酸钠在Hobart混合器中干混。然后，向Hobart混合器加入聚山梨醇酯80、NF(植物源)和纯化水(USP)。在 挤出机/滚圆机中挤出并滚圆所得颗粒状产物，于不超过40℃的温度下盘式干燥球形体，过筛，接着转移至PK混合机中。将最后的球形体贮藏在圆桶中。
选择含有15％崩解剂交聚维酮和1％羟丙基甲基纤维素(羟丙甲纤维素2208)的一批作为具有相似释放曲线的原型。从该批筛选出的未包衣球形体在500-1000微米之间。
B.原型实验室批(批A)
将约100克的这些未包衣球形体在3″Wurster流化床包衣机中用Eudragit L30D-55和羟丙甲纤维素包衣得到包肠溶衣的多颗粒。
在对该批包衣期间，羟丙基甲基纤维素(HPMC)初始隔离层的水平以未包衣多颗粒重量计为4％。所用干聚合物Eudragit L30D-55的w/w百分比为22.16％。在对批包衣过程中，以干粉将滑石粉加至包衣室中，而不是将滑石粉作为悬浮液的一部分。这是由于对100g批产品包衣时所使用喷嘴的尺寸小(0.5mm)，可能被阻塞。与随后制备的临床批相比，实验室批用到的滑石粉和柠檬酸三乙酯的百分比较 小。将多颗粒手工填充至#2 HPMC胶囊中，填充重量为206mg。在体外0.1N HCl和pH6.8磷酸盐缓冲液中检测胶囊。与希望的一样，在酸性介质中2小时内释放小于1％，在碱性介质中45分钟内释放大于80％。
在狗中检验这些胶囊。将Cmax和AUC与目前市场上的Protonix20mg片剂进行比较(并且将值外推至40mg含量)。如希望的那样，发现这些多颗粒在pH6.8磷酸盐缓冲液中的释药速度快于当前的Protonix片剂。最后隔离层包含羟丙基甲基纤维素(羟丙甲纤维素)和水。将该批以球形体包装在透明玻璃小瓶中，并于加速条件(30℃/65％相对湿度(RH)和40℃/75％RH)下放置观察其稳定性。监控其稳定性3个月。其效力和溶出结果在表I中列出。多颗粒经三个月后稳定，填充至胶囊中的40mg相等剂量的多颗粒在各稳定性时间点完全符合溶出和稳定性标准。
通过将贮藏的球形体填充至胶囊壳中并在0.1N HCl中溶出(在2小时目标释放：不超过(NMT)10％)，接着在pH6.8磷酸盐缓冲液中溶出(在45分钟目标释放：不小于(NLT)75％)测定溶出度。接收标准还需要标示的90-110％浓度。
表I.多颗粒在透明玻璃小瓶中的稳定性
1一粒胶囊-释放78％。
实施例2-包衣的泮托拉唑钠多颗粒制剂(批B)
根据实验室批A，使用7″wurster流化床包衣机制备更大规模的1400g批量。在对该批包衣时，与未包衣批A的4％相比，该批的羟丙基甲基纤维素的初始隔离层水平以未包衣多颗粒重量计为2％。使用的干聚合物Eudragit L30D-55的w/w百分比为22.16％w/w。而且因使用较大尺寸(1mm)的喷嘴，滑石粉直接加入包衣悬浮液中。
包衣多颗粒在0.1N酸中的初始释放高(9.0％)，非常接近于10％的限度。当于加速条件(30℃/60％相对湿度(RH)和40℃/75％RH)下检测时，该批(B)不符合稳定性和溶出度标准。该批的试验显示占未包衣多颗粒大于2％的初始隔离层提高多颗粒的稳定性。另外，当方法按比例放大时，更多的肠溶聚合物填充剂可有利于控制在酸性介质中的释放。
实施例3-泮托拉唑多颗粒放大批的制备
A.工艺批
用NICA挤出机/滚圆机制备36kg工艺批的未包衣多颗粒，在Glatt GPCG-15机器中将20kg该批多颗粒包肠溶衣，得到32kg该批 的包衣多颗粒。使用的干聚合物Eudragit L30D-55的w/w百分比为22.16％w/w。将该批多颗粒填充在3号HPMC胶囊中，填充重量为156mg。在0.1N HCl中2小时内释放大于所需的10％。根据该结果，考虑放大的影响，对处方做少许调整并加工临床批。
B.临床批
将两12kg子批湿颗粒状团从NICA挤出机/滚圆机挤出并滚圆，得到湿的多颗粒。于40℃将多颗粒在托盘上干燥10-12小时至所需3.4％-4.3％的LOD百分比。该批过筛，仅有16kg未包衣的多颗粒用于包衣以确保在GPCG-15机器中包衣的均匀和完全。将过筛的未包衣多颗粒包羟丙基甲基纤维素初始隔离层，接着包Eudragit L30D-55肠溶衣，接着包羟丙基甲基纤维素的最后隔离层，得到33kg的包衣多颗粒。将该批填充在2号HPMC胶囊中，填充重量为206mg。
在0.1N HCl中2小时内释放小于10％限度，在pH 6.8磷酸盐缓冲液中45分钟内释放大于80％限度。该批在体外符合释放的特征。一个月的稳定性数据显示，在40℃/75％RH下多颗粒一个月内稳定。当前，该批在室温下长达一年是稳定的，在40℃/75％RH下长达6个月是稳定的。在室温条件下超过一年的稳定性研究正在进行中。该批于室温下一年的稳定性结果显示在下表II中。
与Protonix 40mg片剂相比，在pH6.8磷酸盐缓冲液中球形体填充胶囊在体外释放(溶出)更迅速。
表II：泮托拉唑钠球形体填充胶囊(40mg)的稳定性，
泮托拉唑钠球形体填充胶囊(40mg)的稳定性(续表)
BRL＝小于报道的限度(0.05％) NMT＝不大于 NLT＝不小于 RRT＝相对保留时间
a：提供泮托拉唑钠球形体(40mg/206mg)初始和再验证的溶出度结果，其为用于制备泮托拉唑钠球形体填充胶囊(40mg)的新进批。
b：对应于RRT＝1.39的杂质。
实施例4-批A制剂用小猎犬(Beagle)的评价
泮托拉唑钠多颗粒制剂在体外释放的数据显示比目前销售的片剂释放更迅速。这提供更容易的吸收，从而更快起效。与单一的单层片剂相比，狗的数据清楚显示多颗粒中泮托拉唑钠更早的药物水平。更快起效提供迅速缓解胃痛及其他胃肠(GI)疾病。
在小猎犬(n＝5)中评价了泮托拉唑钠制剂。泮托拉唑的平均(SD)药动学参数和相对生物利用度在下表III中举例说明。
如上所述，给予狗非优化的实验室批的泮托拉唑钠多颗粒制剂显示滞后(lag)时间比目前销售的片剂更小。在如下片剂中，AUC指平 均浓度对记录时间作图的曲线下面积。Cmax指给药后在血样中的最大观测浓度值。Tmax指当出现Cmax时的时间点。Tlag指给药之后在血液循环中观察到有效量药物之前的时间；t1/2(hr)提供药物消除的半衰期。相对生物利用度比较了产品从肠的吸收度与静脉内给药的吸收度(假设100％)。
表III
泮托拉唑的平均(SD)药动学参数和相对生物利用度
a：AUC和Cmax归一化至40mg剂量
b：相对于市售产品片剂
泮托拉唑钠多颗粒制剂的狗试验数据给出与目前市售片剂相似的AUC。不受理论的束缚，认为通过降低球形核中崩解剂交聚维酮的水平(与片剂中的水平比较)和加入功能性赋形剂聚山梨醇酯80可使多颗粒更快地释放并得到相似的AUC。
实施例5-泮托拉唑钠倍半水合物：赋形剂制剂
进行该研究以测定泮托拉唑钠倍半水合物与羟丙甲纤维素2208、十二烷基硫酸钠(SLS)、交聚维酮和聚山梨醇酯-80的相容性。
A.研究设计
该研究由两组样品组成。第一组包含药物和赋形剂。第二组包含药物、赋形剂和约2μl水。将水连同药物和赋形剂一起研究是为了观察存在其它水分是否引起任何不相容。
将赋形剂与药物按下表中所示的比例混合。将赋形剂和药物在玻璃小瓶中称重。然后将小瓶旋转15秒。类似地，制备第二组样品。向这些小瓶中加入约2μl水(在实验室可用吸管加入最少量的水)。然后将小瓶旋转5秒。最后，将第一和第二组小瓶盖上并放置在稳定性室中。测试条件为40℃/75％RH和51℃、3周。
B.结果
在下表IV中用回收百分率表示该药物-赋形剂相容性研究的结果。相容或不相容的选择标准基于90-110％的回收百分率。
表IV：药物：赋形剂相容性结果
由表中所示结果可得出下列结论。在40℃/75％RH下，连续3 周，羟丙甲纤维素2208、SLS、交聚维酮和聚山梨醇酯-80与泮托拉唑钠倍半水合物相容。在40℃/75％RH和51℃加水和不加水连续3周，羟丙甲纤维素2208、SLS和交聚维酮与泮托拉唑钠倍半水合物相容。
在该研究中没有研究化合物的降解。然而，于40℃/75％RH的加速条件下研究了儿科临床制剂[泮托拉唑钠倍半水合物45.24％w/w；微晶纤维素27.25％w/w；聚山梨醇酯80 5％w/w；交聚维酮15％w/w；羟丙甲纤维素22081％w/w；碳酸钠6.5％w/w；纯化水适量]，长达6个月稳定，提供2年的室温有效期。
在下表V中提供儿科制剂的组成。
实施例6-泮托拉唑钠制剂在成人受试者中的评价
在该研究中，将如所述配制的临床儿科用制剂40mg泮托拉唑钠通过散置在苹果酱中以片剂形式或以用非活性粉末混合物和水(各组中为8)制备的悬液水溶液形式给予健康的成人(n＝24)。
在下表VI中，栏1提供药动学(PK)参数AUC(浓度曲线下面积)、AUCT为浓度时间曲线下面积、及最大浓度Cmax。第二栏提供供试品/参照品的几何平均(GM)比。第三栏提供GM比的置信区间。[FDA认为如果供试品和参照品之间AUC和Cmax几何平均比的90％置信区间(CI)落在80-125％，则供试品与参照品生物等效]。-使用WinNonlin软件计算置信区间。
表VI：人PK研究结果
A.散置在苹果酱中的球形体：
B.混悬液中的球形体：
与散置制剂和混悬制剂相比较，片剂吸收的滞后时间更长。片剂中全部药物在短的时间间隔内释放，从而得到更高的Cmax。至于球形制剂，药物在较长的时间间隔内从各球形体中释放，从而Cmax比片剂低。然而，对3种制剂而言，给药后泮托拉唑在循环中保持的时间相似。
本文所有的证明文献通过引用结合到本文中。本领域技术人员将认识到对本文描述的具体实施方案中描述的条件和工艺的细小修改可以变化，而不会背离本发明。这些细小的修改和变化在权利要求书所定义的本发明范围内。
Claims (1)
1.在胃条件下释放缓慢而在中性pH下释放迅速的泮托拉唑多颗粒，所述多颗粒的每一个包含：
球形核，其包含，基于干的未包衣的球形核计，约40％w/w游离泮托拉唑，25％w/w至30％w/w的微晶纤维素、4％w/w至6％w/w的聚山梨醇酯80、14％w/w至16％w/w的交聚维酮、0.5％w/w至2％w/w的羟丙基甲基纤维素2208和5％w/w至8％w/w的碳酸钠；
所述球形核上的初始隔离层，该初始隔离层包含羟丙基甲基纤维素；和
所述初始隔离层上的肠溶衣；
其中所述多颗粒的平均直径为0.7 mm至1.25 mm。
2. 权利要求1的多颗粒，其中所述约40％游离泮托拉唑是约45% w/w泮托拉唑钠倍半水合物的形式。
3. 权利要求1的多颗粒，其中所述球形核中的所述交聚维酮存在的量为约15％w/w。
4. 权利要求1的多颗粒，其中所述球形核中的所述微晶纤维素存在的量为约27％w/w。
5. 权利要求1的多颗粒，其中所述球形核中的所述聚山梨醇酯80存在的量为约5％w/w。
6. 权利要求1的多颗粒，其中所述球形核中的所述羟丙基甲基纤维素2208存在的量为约1％w/w。
7. 权利要求1的多颗粒，其中所述多颗粒的平均直径为1 mm。
8． 权利要求1的多颗粒，其中所述多颗粒还包含所述肠溶衣上的最后隔离层。
9． 权利要求8的多颗粒，其中所述最后隔离层占所述多颗粒0.1-10%重量。
10. 权利要求8的多颗粒，其中所述最后隔离层包含羟丙基甲基纤维素。
11． 权利要求1的多颗粒，其中所述初始隔离层占未包衣的球形核2% w/w至4% w/w。
12. 权利要求1的多颗粒，其中所述肠溶衣包含30% w/w Eudragit L 30 D-55共聚物、15% w/w滑石粉、3%柠檬酸三乙酯和pH调节剂；所述量按所述多颗粒重量计。
13. 权利要求1的多颗粒，其中所述球形核保留1％w/w至2％w/w的水，基于干的未包衣的球形核计。
14. 一种产品，其包含泮托拉唑多颗粒，所述多颗粒的每一个包含：
球形核，其包含，基于干的未包衣的球形核计，约40％w/w的游离泮托拉唑，25％w/w至30％w/w的微晶纤维素、4％w/w至6％w/w的聚山梨醇酯80、14％w/w至16％w/w的交聚维酮、0.5％w/w至2％w/w的羟丙基甲基纤维素2208和5％w/w至8％w/w的碳酸钠；
所述球形核上的初始隔离层，该初始隔离层包含羟丙基甲基纤维素；和
所述初始隔离层上的肠溶衣；
其中所述多颗粒的平均直径为0.7 mm至1.25 mm。
15. 权利要求14的产品，其中所述球形核保留1％w/w至2％w/w的水，基于干的未包衣的球形核计。
16. 权利要求14所述的产品，其中所述多颗粒是在悬浮液体中。
17. 权利要求14所述的产品，其中所述多颗粒是胶囊或箔包装。
18. 一种制备权利要求1的泮托拉唑的多颗粒制剂的方法，所述方法包括：
经挤出法和滚圆法制备球形核，该球形核其包含，基于干的未包衣的球形核计，约40％w/w的游离泮托拉唑，25％w/w至30％w/w的微晶纤维素、4％w/w至6％w/w的聚山梨醇酯80、14％w/w至16％w/w的交聚维酮、0.5％w/w至2％w/w的羟丙基甲基纤维素2208和5％w/w至8％w/w的碳酸钠；
将初始隔离层施用于该球形核，该初始隔离层包含羟丙基甲基纤维素；
将肠溶衣施用于所述初始隔离层包衣的球形核，所述肠溶衣包含异丁烯酸与异丁烯酸酯的共聚物，和
任选将最后隔离层施用于包肠溶衣的球形核，所述最后隔离层是所述多颗粒的1wt％，
其中所述多颗粒的平均直径为0.7-1.25 mm。
19. 权利要求18的方法，其中所述球形核保留1％w/w至2％w/w的水，基于干的未包衣的球形核计。
20. 权利要求18的方法，其中所述球形核通过在低剪切混合器中，于25 rpm-35 rpm范围的低剪切条件下混合各组份制备。
21. 权利要求20的方法，其中所述低剪切条件为32 rpm。
22. 权利要求18的方法，其中所述球形核于不超过40℃的低温下干燥8-72小时，至干燥失重百分比为3.4%-4.3%。
23. 权利要求18的方法，所述方法还包括施用占所述多颗粒0.05% w/w-0.1% w/w量的滑石粉层的步骤。
24. 权利要求18的方法，其中所述肠溶衣以悬浮液喷到所述球形核上。
25. 权利要求1的泮托拉唑多颗粒在制备药物中的应用，其中所述药物用于治疗人的胃食管返流疾病、胃溃疡或十二指肠溃疡或佐林格-埃利森综合症。
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| US50781003P | 2003-10-01 | 2003-10-01 | |
| US60/507,810 | 2003-10-01 | ||
| PCT/US2004/033058 WO2005032513A2 (en) | 2003-10-01 | 2004-09-30 | Pantoprazole multiparticulate formulations |
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| US10420730B2 (en) | 2013-04-23 | 2019-09-24 | Zx Pharma, Llc | L-menthol dosage forms having a proteinaceous coating for enhanced storage stability |
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