CN111374959A - 含有改性瓜尔胶的药物软明胶胶囊剂型 - Google Patents
含有改性瓜尔胶的药物软明胶胶囊剂型 Download PDFInfo
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- CN111374959A CN111374959A CN202010063854.XA CN202010063854A CN111374959A CN 111374959 A CN111374959 A CN 111374959A CN 202010063854 A CN202010063854 A CN 202010063854A CN 111374959 A CN111374959 A CN 111374959A
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- soft gelatin
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Abstract
药物软明胶胶囊剂型,其包括(a)壳,其包含明胶;和(b)填充物,其包含至少一种活性成分、一种或多种聚乙二醇和改性瓜尔胶。所述药物软明胶胶囊剂型在贮存之后保持其壳完整性(硬度)和填充粘度。
Description
本申请是中国专利申请号201480022804.X(PCT/US2014/0271 45),申请日2014年03月14日,发明名称为“含有改性瓜尔胶的 药物软明胶胶囊剂型”的分案申请。
相关申请的交叉引用
本申请要求2013年3月15日提交的美国专利申请No.61/794,906 的利益,将其全部内容通过引用并入本文。
发明背景
发明领域
本发明涉及药物软明胶胶囊剂型,其可以有利地用于***给药在 粘膜-粘合性(muco-adhesively)增强的胶囊填充物中的可药用活性成 分。本发明的软明胶胶囊剂型经贮存时间后保持其壳完整性(硬度)和 填充粘度。
相关技术的说明
软明胶药物配制物具有一些优点,比如它们易于吞服,它们掩蔽 了气味和使人不愉快的味道,且一旦吞服,它们很快地释放它们的内 含物。然而,已知软明胶胶囊在贮存期间溶出度降低,其最终可以阻 止或有害地影响药物释放。溶出度的降低通常归于胶囊壳中明胶的交 联,导致薄膜形成。可以通过各种技术,比如在具有低级过氧化物和 醛的胶囊填充物中使用赋形剂或者使用不易于薄膜形成以使交联剂的 形成最小化的明胶等级,以使薄膜形成最小化。例如,通过在氮气下 贮存填充物,控制制备环境的温度和湿度,使加热过程的温度和热暴 露时间最小化,测定赋形剂的甲醛或低分子量醛水平,和使用耐水和/ 或耐光包装,也可以使制备方法最优化。
申请人发现即使当采用多种步骤使薄膜形成最小化时,含有在填 充物中的离子组分比如聚丙烯酸的软明胶胶囊在贮存后可显示出不稳 定的溶出特性。据信,不受理论的束缚,软明胶胶囊的填充物中包含 的聚丙烯酸与壳中的明胶相互作用,抑制破裂且因此改变溶出特性。 因此,提供在填充物中应用非离子组分以避免贮存后不稳定的溶出特 性的软明胶胶囊剂型可能是有利的。
使用软明胶胶囊***给药可药用活性成分不仅需要经贮存时间稳 定的溶出特性,而且需要包含随时间推移保持一致粘性且具有粘膜- 粘合性质的可药用活性成分的填充物,所述粘膜-粘合性质能确保一致 且有效地将活性成分应用至***腔的粘膜壁。
因此,有利地是提供药物软明胶胶囊剂型,其不包含离子组分, 但是其可以递送在粘膜-粘合性增强的填充物中的低剂量药物比如雌 激素,同时保持其壳完整性(硬度)和填充粘度,即使在该胶囊已经贮 存超过一年,优选地18个月,或更优选地两年。
发明简述
本发明涉及药物软明胶胶囊剂型,包含:(a)壳,包含明胶和增 塑剂;和(b)填充物,包含至少一种可药用活性成分、一种或多种聚乙 二醇和改性瓜尔胶。所述药物软明胶胶囊剂型在贮存后保持其壳完整 性(硬度),并且包括经贮存时保持其粘度的有利的凝胶基质填充物。
在一个实施方案中,本发明的药物软明胶胶囊剂型用于***给药。 在又另一个实施方案中,改性瓜尔胶为羟丙基瓜尔胶。
本发明的另一个实施方案是药物软明胶胶囊剂型,包含:(a)壳, 包含明胶和增塑剂;和(b)填充物,包含至少一种可药用活性成分、一 种或多种聚乙二醇和改性瓜尔胶,其中经约-1.0至约1.0的log剪切率, 所述填充物在包封之后具有的log粘度大于在包封之前所述填充物的 log粘度的约1至约2倍。在一个实施方案中,所述填充物为亲水性凝 胶的形式,并且该亲水性凝胶是在填充物包封之后原位形式的。
附图说明
图1为描绘在向填充物中加入10%和20%水的90%PEG 400:10%PEG 3350配制物的流变学曲线的图。每个值为至少5次平 行测定(n≥5)的平均值。
图2为描绘在向填充物中加入10%和20%水的普通瓜尔胶配制物 的流变学曲线的图。每个值为至少5次平行测定(n≥5)的平均值。
图3为描绘在向填充物中加入10%、20%和30%水的改性瓜尔胶 配制物的流变学曲线的图。每个值为至少5次平行测定(n≥5)的平 均值。
图4为描绘水含量对于含或不含改性瓜尔胶的配制物的粘合度的 影响的图。每个值为至少5次平行测定(n≥5)的平均值±标准偏差。
图5为描绘本发明的一个实施方案的软明胶胶囊剂型在包封前和 包封后的流变学曲线的图,所述软明胶胶囊剂型含有改性瓜尔胶/PEG 400填充物配制物。每个值为至少5次平行测定(n≥5)的平均值。
图6为描绘在t=0、t=1个月、t=6个月和t=15个月贮存之后, 本发明的一个实施方案的改性瓜尔胶/PEG 400填充配制物的流变学 曲线的图。每个值为至少5次平行测定(n≥5)的平均值。
图7为描绘贮存对于本发明的一个实施方案的药物软明胶胶囊剂 型的硬度的影响的图,所述剂型含有改性瓜尔胶/PEG 400填充配制 物。每个值为至少5次平行测定(n≥5)的平均值±标准偏差,变异 系数小于7%。
图8为本发明的多个实施方案的溶出度曲线。每个值为3次平行 测定(n=3)的平均值。
图9为描绘在包封前、包封后和整个干燥过程的每天,本发明的 一个实施方案的改性瓜尔胶/PEG 400填充配制物的流变学曲线和干 燥的影响的图。每个值为3次平行测定(n=3)的平均值。
发明详述
本发明的一实施方案涉及药物软明胶胶囊剂型,包含:(a)壳,包 含明胶和增塑剂;和(b)填充物,包含至少一种可药用活性成分、一 种或多种聚乙二醇和改性瓜尔胶。
本发明的药物软明胶胶囊剂型可以口服或***给药,但是当*** 使用时,提供特别有利的性质。一个特别的实施方案包括药物软明胶 胶囊剂型,其中所述可药用活性成分为***,并且其为***给药。
如本文使用的“可药用”指所述组分适于口服或***给药至人类。 在一个实施方案中,组分必须被认为适于应用至***环境。
软明胶胶囊是众所周知的,通常描述为软胶囊。它们包括一片、 密封的明胶基壳,其包含溶液、悬浮液或称为填充配制物、填充材料 或填充物的半固体。软明胶胶囊的明胶布卢姆强度(Bloom strength) 通常为约150至约200布卢姆(bloom)(或克)。示例性的软胶囊制造商 包括Catalent Pharma Solutions,Somerset,N.J.,Pharmagel Engineeringspa,Lodi,Italy,和Soft Gel Technologies Inc., Commerce,CA。本发明的软明胶胶囊为包含明胶基壳和填充物的药 物剂型。
在本发明的一个实施方案中,所述壳可以包括明胶和增塑剂。所 述壳可以任选地包括遮光剂和/或染料。明胶是通过部分水解源自动物 的皮肤、白色***和骨骼的胶原蛋白获得的,所述动物包括牛、 猪和鱼。其主要包括水溶性蛋白(84-90%w/w)与无机盐(1-2%w/w)和 水(8-15%w/w)。蛋白级分包含多肽链中酰胺键连接的氨基酸。
胶原蛋白是纤维蛋白,且是动物皮肤、骨骼和***的主要成 分。其由具有分子量约300,000Da的三个多肽链的三螺旋组成。变性 包括破坏氢键以使胶原螺旋不稳定,导致分子量和固有粘度显著降低。 通过使骨骼或皮肤在水中煮沸水解胶原蛋白会产生低产量的物理性质 差的不纯明胶。因此,商业生产明胶包括初始去除污染物,之后借助 稀酸进行热变性得到A型明胶或借助稀碱进行热变性得到B型明胶。 明胶实际上是两性的,A型明胶的等电点范围为6.0至9.0,B型明胶 的等电点范围为4.7至5.3。据信碱性水解引起胶原蛋白中天门冬酰胺 和谷氨酰胺氨基酸的脱酰胺度更大,产生与酸性水解相比更大数量的 游离羧酸。合适的A型明胶的实例包括而不限于酸性骨明胶。合适的 B型明胶的实例包括而不限于石灰骨(lime bone)明胶。
在填充物被包封且水已经从胶囊迁移到填充物之后,明胶基软明 胶胶囊通常应当包含明胶壳重量的约1%至约25%、更优选地约1% 至约15%、进一步更优选地约5%至约10%的量的水。不受理论的束 缚,据信在填充之前,明胶胶囊中的水,例如20%至50%重量,至少 部分地迁移以帮助填充物胶凝且增加其粘度。
在一个优选的实施方案中,明胶的存在量为明胶壳重量的约35% 至约85%,更优选约40%至约80%。
在本发明的一个实施方案中,可以使用任何可药用增塑剂。合适 的增塑剂的非限制性实例包括多元醇,比如山梨醇、甘油、甘露醇、 木糖醇和脱水山梨醇;邻苯二甲酸二烷基酯;低级烷基柠檬酸酯,其 中所述低级烷基具有1-6个碳原子;二醇和聚乙二醇,包括具有分子 量范围为约200至约2,000的聚乙二醇,甲氧基-丙烯基-二醇,和1,2- 丙二醇;多羟基醇的酯,比如甘油的单乙酸酯、二乙酸酯和三乙酸酯; 蓖麻油酸及其酯;和上述混合物。
在一个优选的实施方案中,增塑剂的存在量为明胶壳重量的约 10%至约60%、更优选地约20%至约55%、进一步更优选地约30% 至约50%。
在本发明的一个实施方案中,填充物包括至少一种可药用活性成 分、一种或多种聚乙二醇和改性瓜尔胶。填充物不包括对于口服或阴 道给药而言不是药学可接受的量的成分。
合适的可药用活性成分的非限制性实例包括类固醇和低剂量非甾 体化合物、其可药用盐、酯、水合物、前药和衍生物。合适的低剂量 非甾体化合物的非限制性实例包括达非那新、乌地那非(udenafil)和二 膦酸盐化合物如利塞膦酸盐(risedronate)、阿仑膦酸盐(alendronate)、 依替膦酸钠(etidronate)、伊班膦酸盐(ibandronate)、氯膦酸盐(clodronate)和唑来膦酸盐(zoledronate)。优选地,活性成分为*** 或孕激素化合物,比如***、炔雌醇、雌四醇(estetrol)、醋炔诺酮、 依托孕烯、其可药用盐、酯、水合物、前药和衍生物、及其混合物。
如本文使用的短语化合物的“可药用盐”指可药用且具有母体化合 物的期望药理学活性的化合物。可药用盐包括本发明的化合物中存在 的酸性或碱性基团的盐。可药用酸加成盐包括,但不限于盐酸盐、氢 溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸性磷酸 盐、异烟碱、乙酸盐、乳酸盐、水杨酸盐、柠檬酸盐、酒石酸盐、泛 酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、 富马酸盐、葡糖酸盐、葡糖二酸盐(glucaronate)、糖二酸盐、甲酸盐、 苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对-甲苯磺酸 盐和双羟萘酸盐(即,1,1'-亚甲基双-(2-羟基-3-萘甲酸盐))盐。合适的 碱盐包括,但不限于铝、钙、锂、镁、钾、钠、锌和二乙醇胺盐。
如本文使用的术语“酯”指用烷基例如C1至C6烷基或其它有机基 团取代酸的氢制成的有机化合物。各种酯都是本领域众所周知的。酯 的非限制性实例包括甲酸酯、乙酸酯、丙酸酯、乙酰基羟乙酸酯和丁 酸酯。
如本文使用的术语“水合物”指通过加入水形成的化合物。水合物 可以通过本领域任何已知的方法将化合物溶于水中并使其并入水重结 晶成晶体结构来获得。水合物的非限制性实例包括半水合物、一水合 物、脱水物、三水合物和五水合物。
如本文使用的术语“前药”指在体内通过正常代谢过程转化成其活 性形式的药物的非活性前体。各种形式的前药都是本领域众所周知的。
在一个实施方案中,可药用活性成分在本发明的软明胶胶囊中的 存在量为约0.01μg至约500mg,取决于活性成分的期望剂量。
在一个实施方案中,当可药用活性成分为***时,其以药物胶 囊填充物重量的约0.00001%至约2%、更优选地约0.00015%至约 0.0075%、进一步更优选地约0.003%的量包括在本发明的软明胶胶囊 剂型中。
在一个实施方案中,至少一种活性成分为***。在一个优选的 实施方案中,***为17β-***、美雌醇、结合***USP、雌酮、 雌四醇、或炔雌醇、或其盐、酯或前药。其它合适的***包括在美 国专利号7,067,504、7,067,505和7,795,241和美国专利申请公开号 2007/0015741和2007/0004694中的每个中描述的那些。将每个这些专 利和专利申请公开的内容以其全部通过引用并入本文。
在一个优选的实施方案中,至少一种活性成分选自***、其盐、 酯、水合物、前药及其衍生物。在一个优选的实施方案中,***为 17β-***。17β-***的可药用盐是众所周知的,包括而不限于17β- ***盐酸盐、β-***17-(β-D-葡糖苷酸)钠盐和β-***3-(β-D- 葡糖苷酸)17-硫酸二钾盐。17β-***的酯也是众所周知的,包括而不 限于***-3-乙酸酯、***-17-乙酸酯、***-3,17-二乙酸酯、雌 二醇-3,17-戊酸酯、***-3-戊酸酯、***-17-戊酸酯、***3- 苯甲酸酯、***环戊烷丙酸酯(cypionate)、***二丙酸酯和雌二 醇庚酸酯。17β-***的水合物也是众所周知,包括而不限于半水合 物。17β-***的前药也是众所周知,包括而不限于美国专利No. 7,067,505中描述的前药。在一个优选的实施方案中,17β-***为17β- ***半水合物。在另一个优选的实施方案中,活性成分为雌四醇。
如本文使用的短语“改性瓜尔胶”指通过使用反应性官能团取代高 分子主链上的游离羟基而化学改性的瓜尔胶。本发明中使用的改性瓜 尔胶包括改性瓜尔胶的混合物。优选地,改性瓜尔胶为羟丙基瓜尔胶 (例如,以商品名市售可获得的HP120(Rhodia))。优选地, 取代水平高于约0.6、更优选约1.0至约1.5,最优选约1.2。在本发明的一个实施方案中,改性瓜尔胶在填充物中的存在量为所述填充物总 重量的约0.5%至约3.0%,更优选约0.5%至约1.5%。据发现加入聚 乙二醇,比如PEG 3350,有助于解决弹性问题,包括在更低水平的改 性瓜尔胶的下述实施例中讨论的问题。
填充物包括一种或多种聚乙二醇。在本发明的一个实施方案中, 聚乙二醇具有的分子量范围为约200至约900。在一个优选的实施方 案中,聚乙二醇具有小于900的分子量。在本发明的一个实施方案中, 填充物包括至少一种另外的具有分子量大于900的聚乙二醇。在本发 明的一个实施方案中,填充物包括两种聚乙二醇,第二种聚乙二醇具 有的分子量大于900,第一种和第二种聚乙二醇的重量比范围为约 99:1至约1:99。在一个优选的实施方案中,PEG 400和PEG 3350以 60:40至95:5范围的重量比存在,更优选地PEG 400:PEG3350的重 量比范围为90:10至95:5。
在本发明的一个实施方案中,填充物可以任选地包含溶剂。合适 的溶剂的非限制性实例包括丙二醇、丙酮、乙醇、丁二醇、二甘醇单 乙基醚、二丙二醇、甘油、聚乙烯二醇、矿物油、花生油、芝麻油。 在一个优选的实施方案中,溶剂为丙二醇。在本发明的一个实施方案 中,溶剂在填充物中的存在量为所述填充物总重量的约1%至20%、 更优选约5%至约15%、进一步更优选约5%重量。
在本发明的一个实施方案中,填充物也包含抗氧剂。合适的抗氧 剂的非限制性实例包括生育酚、丁基化羟基甲苯、丁基化羟基茴香醚、 没食子酸十二酯、没食子酸辛酯、没食子酸丙酯、抗坏血酸棕榈酸酯、 抗坏血酸钠和麝香草酚。在一个优选的实施方案中,抗氧剂为生育酚。
本发明的发明人发现在贮存期间包含离子组分比如聚丙烯酸的软 明胶胶囊的溶出度降低。然而,使薄膜形成最小化的上述各种已知技 术没有有助于减轻该问题。然后,本发明人得出结论:溶出度的降低 不是由于薄膜形成引起的,并且猜测其可能由填充物中明胶与阴离子 聚合物的相互作用引起。
如前所述,虽然不希望受理论的束缚,发现因为填充物中的聚丙 烯酸比如聚卡波非是阴离子聚合物,其与明胶相互作用,导致形成不 溶性物质,其降低了软明胶胶囊剂型的溶出稳定性。除了聚丙烯酸之 外,填充物中的其它阴离子聚合物也与明胶相互作用,导致形成不溶 性物质。这种阴离子聚合物的非限制性实例包括聚(甲基乙烯基醚/马 来酸酐)(Gantrez)#、卡波姆、羧甲基纤维素钙、羧甲基纤维素钠和海 藻酸盐比如海藻酸钙、海藻酸钾、海藻酸钠和海藻酸。
研究了作为填充物中聚丙烯酸的合适替代物的各种聚合物,比如 聚卡波非。为了研究流动性质,特别地为了确定粘度和在25℃/60% RH下贮存后其是如何变化的,进行所述填充物配制物的流变学分析。 在本发明的一个实施方案中,药物软明胶胶囊剂型基本上不含聚丙烯 酸,其可以递送低剂量药物比如***,并且甚至在该胶囊贮存长达 1年或更优选地两年之后保持其硬度和填充粘度。如本文使用的基本 上不含指没有聚丙烯酸或存在量不会引起溶出不稳定性,例如小于填 充物重量的1%百分比。
粘度是软胶囊填充物的一个重要的质量属性,因为它对于体内保 持且因此对于最终软胶囊产品的临床益处具有显著的影响。通过使用 锥板流变仪,在25℃下进行连续流动流变学来测量下述实施例中阐述 和试验的样品的填充物配制物的粘度。对于每个平行测定,测试2个 尺寸20的椭圆形软胶囊或同等量的包封前填充物的含量。将样品应用 于流变仪的下板,并使其在测定前平衡5分钟。采用10个样品,以十 进制(per decade),剪切速率从0.1增加至10s-1。在本发明的一个实施 方案中,如上在零log剪切率下测量在包封之后填充物的粘度范围为 约1至约5log粘度。
软胶囊的胶囊壳完整性(硬度)是另一个关键的质量属性,因为样 品必须保持合适的硬度,以确保它们可以被患者处理和适当地给药。 使用Bareiss硬度测试器测量下述试验中阐述和试验的样品的硬度。 该仪器是通过将软胶囊压在连接测力计的塞子和自动上升的平台之间 来操作的。将软胶囊水平置于平台上,使其缝轮廓与平台平行排列。 该平台自动上升,测力计指示器显示软胶囊对压缩力的抗力的值。该 值以牛顿(N)显示,并且代表试验中软胶囊的硬度。
现在,参照下述实施例来阐述本发明的特定实施方案。应当理解, 公开这些实施例是为了阐述本发明,而不应当以任何方式限制本发明 的范围。
实施例
为了确定阴离子聚合物比如聚卡波非的可替代聚合物,并且评价 其结合到亲水性填充配制物中的适合性,研究了多种聚合物。所研究 的聚合物包括羟丙甲基纤维素、角叉菜胶、普通瓜尔胶、羟丙基瓜尔 胶和羟乙基纤维素(HEC)。通过进行如上所述的连续流动流变学来测 量填充物配制物的粘度。首先制备包含聚卡波非的配制物,以提供用 可替代聚合物制备的凝胶的视觉比较。该填充物为在重力下流动的透 明均匀的凝胶。加入羟丙甲基纤维素聚卡波非不会引起形成均匀的凝 胶,而是整个填充物中呈固结的团块(consolidated mass)。角叉菜胶和 HEC在所研究的水平下不形成凝胶。在另一方面,改性瓜尔胶(例如, 羟丙基瓜尔胶)形成随聚合物的水平增加而粘度显著增加的粘性凝胶。 与聚卡波非凝胶相比,包含2%和3%羟丙基瓜尔胶的配制物非常粘, 因此也研究了较低水平1.5%和1.75%的羟丙基瓜尔胶。这些较低水平 改善了凝胶的流动性质,然而,注意到所述配制物是非常有弹性的, 其可能存在包封和有效密封形成的问题。
研究了在包含PEG 400和PEG 3350的配制物中,聚乙二醇对填 充物粘度的影响。研究了在60:40至90:10范围的不同比例的PEG 400:PEG 3350。据发现增加PEG 400的含量减低了配制物的粘度,具 有90:10比例的配制物能够在重力下流动。还发现向这些***提供递 增水平的水会导致粘度损失,如图1中对于90%PEG 400:10%PEG 3350配制物的流变学曲线所示和表1中在零log剪切率下的粘度数据 所示。在将该混合物冷却至室温之前,在60℃下,将10%、20%和 30%w/w的水加入到填充物中。向填充物中加入30%w/w的水导致粘度完全丧失,出现沉淀,且不能在流变仪上进行试验。
表1
%水 | 粘度(Pa s) | Log粘度 |
0 | 156.15 | 2.22 |
10 | 56.72 | 1.75 |
20 | 26.7 | 1.43 |
然后,为了使配制物抵抗粘度的变化,将一些亲水性聚合物结合 到配制物(90%PEG 400:10%PEG 3350)中。这些包括HEC、羟丙基 纤维素(HPC)、普通瓜尔胶和改性瓜尔胶。当与图1中的数据相比, HEC、HPC和普通瓜尔胶不会保持配制物的粘度,如图2的实施例流 变学曲线所示,由此增加水的水平导致粘度统计学显著地(p<0.5)降低。 将普通瓜尔胶配制物在零log剪切率的粘度数据显示在表2中。
表2
%水 | 粘度(Pa s) | Log粘度 |
0 | 22.57 | 1.35 |
10 | 16.14 | 1.21 |
20 | 11.55 | 1.06 |
当与图1中的数据相比时,在向填充物中加入10%和20%w/w 水,用羟丙基瓜尔胶代替普通瓜尔胶得到可以保持其粘度的配制物, 如图3所示。与其它样品不同,向填充物中加入30%水时,该配制物 也保持完整,没有出现沉淀。当加入水而不是进行稀释时,羟丙基瓜 尔胶能够更快地水合,引起配制物胶凝。将羟丙基瓜尔胶配制物在零 log剪切率的粘度数据显示在表3中。
表3
%水 | 粘度(Pa s) | Log粘度 |
0 | 39.56 | 1.60 |
10 | 85.47 | 1.93 |
20 | 52.25 | 1.72 |
30 | 22.63 | 1.36 |
通过测量从填充物的表面去除水合的粘蛋白盘状物(mucin disk) 所需的力,研究在加入和不加入水下改性瓜尔胶对于所述配制物的粘 膜-粘合度的影响。将约15g的材料置于玻璃烧杯中,并使用 TA.XTplus质地分析仪测量从样品表面去除预水合的粘蛋白盘状物 所需的力。所述粘蛋白盘状物由1:1比例的2g的粘蛋白和Avicel PH105组成,使用单冲压片机(single station press)在7吨的压力下, 使用25 mm平表面模具(flat facedtooling)压制。将该盘状物用5% w/w粘蛋白溶液预水合,吸取以去除过量的溶液,并将探针附着在质 构仪的测力计上。将该探针手动降低以确保与试验材料均匀接触。在 30秒之后,开始试验,使探针将该盘状物以0.5mm/s的速度从样品 中升高,并记录所得合力-距离曲线上的最大力。对于每个样品,每次 都用试验的新盘状物和新样品进行三次平行测定。在加入6%w/w的 水之前和之后,测试填充物材料以模拟水分从胶囊壳材料进入且诱导 胶凝。
表4中呈现的结果表明包含改性瓜尔胶引起样品的粘合度显著增 加。它们也表明在填充物材料胶凝之后粘合度显著增加。
所研究的根据本发明的示例性的填充物配制物列在表4中。
表4
表5
表6
包封对改性瓜尔胶/PEG 400填充物配制物的影响显示在图5中。 结果证实填充物包封后的粘度显著增加。包封之后的填充物为亲水性 凝胶的形式,并且经在约-1.0至约1.0的log剪切率,在包封之后具 有的log粘度大于在包封之前填充物的log粘度的约1至约2倍。这 应归于从胶囊壳迁移的水对所述改性瓜尔胶/PEG 400填充物的水合, 并且导致形成粘性凝胶物质。在包封之前填充材料中水的水平典型地 小于1.0%w/w,在包封之后升高至约6.0至11.0%w/w。该高度粘稠 的填充物将很难使用标准软胶囊制备技术来包封,因此在包封之后原 位形成凝胶的能力克服了该困难,并因此提供显著的优势。包封前和 包封后填充物在零log剪切率的粘度数据显示在表7中。
表7
填充物材料 | 粘度(Pa s) | Log粘度 |
包封前 | 24.77 | 1.39 |
包封后 | 63.66 | 1.80 |
将上述用箔盖包装到泡罩中的药物软明胶胶囊剂型贮 存在25℃/60%RH下,稳定至少15个月。开始时和在t=1、3、6和 15个月,试验所述软胶囊的硬度和填充物粘度。如上所述,使用Bareiss 硬度测试器测量软胶囊的硬度。如上所述,通过进行连续流动流变学 测量填充物的粘度。
贮存对改性瓜尔胶/PEG 400填充物配制物的影响显示在图6中。 这些结果证实这些***在25℃/60%RH下稳定性贮存15个月之后保 持其粘度。
贮存对软胶囊的硬度的影响呈现在图7中。这些结果表明在所述 软胶囊在25℃/60%RH下稳定性贮存15个月之后保持其硬度,即, 硬度没有明显降低,其会不利地影响患者处理和给药所述剂型的能力 的明显降低。
如从图6和图7的结果可见,包含改性瓜尔胶/PEG 400填充物配 制物的药物软明胶胶囊剂型在25℃/60%RH下稳定性贮存15个月之 后是物理稳定的。
研究根据本发明的一个实施方案的包含PEG/改性瓜尔胶填充物 配制物的药物软明胶胶囊剂型的溶出性质。将500mg的填充物配制 物包封在由酸骨明胶和特定山梨醇/甘油掺合物A810组成的凝胶材料 中,所述掺合物A810为1,4-脱水山梨醇、山梨醇和甘露醇(脱水山梨 醇溶液NF)和甘油USP的掺合物。使用水制备凝胶材料,直到得到约 40%重量的湿凝胶质量溶液,然而,在包括许多干燥步骤的胶囊制备 过程结束时,胶囊典型地具有软明胶胶囊重量的约2%至15%的水。 对于该研究,选择八个不同的填充物。将所研究的根据本发明的多个 实施方案的填充物配制物的组合物列在表8中。
表8
通过下述溶出方法测量药物软明胶胶囊剂型的溶出度。使用USP 装置2测量溶出度,所述装置2采用作为溶出装置的桨,溶出介质体 积为500ml的pH 4.5乙酸盐缓冲液,桨速为50rpm且温度为 37±0.5℃。溶出度曲线显示在图8中。这些结果证实了在本发明中描述的填充物配制物的可药用药物释放特性。
干燥对于填充物粘度的影响呈现在图9中。制备表9中详述的填 充物配制物,并在包封前、包封后和整个干燥过程的每天测定粘度。 将胶囊均匀铺在盘上,并放入干燥箱中。在21-24℃的温度和20-30% 的相对湿度下,在适度干燥条件下干燥该胶囊。这些结果证实一旦填 充物被包封则获得粘度增加,且在整个干燥过程中得到保持。
表9
虽然如上已经参照具体实施方案描述了本发明,但是显而易见的 是,在不背离本文公开的本发明构思下,可以进行许多改变、修饰和 变化。因此,预期涵盖落入附加权利要求书的精神和宽范围内的所有 这样的改变、修饰和变化。将本文引用的所有专利申请、专利、及其 它出版物的全部内容通过引用并入。
Claims (10)
1.药物软明胶胶囊剂型,包含:
壳,包含明胶和增塑剂;和
填充物,包含至少一种可药用活性成分、一种或多种聚乙二醇和改性瓜尔胶。
2.权利要求1的药物软明胶胶囊剂型,其中所述药物软明胶胶囊剂型用于口服或***给药。
3.权利要求2的药物软明胶胶囊剂型,其中所述药物软明胶胶囊剂型用于***给药。
4.权利要求2的药物软明胶胶囊剂型,其中所述至少一种活性成分选自类固醇和低剂量非甾体化合物、其可药用盐、酯、水合物、前药和衍生物。
5.权利要求4的药物软明胶胶囊剂型,其中至少一种活性成分选自***、炔雌醇、雌四醇、醋炔诺酮、依托孕烯、达非那新、乌地那非、利塞膦酸盐、阿仑膦酸盐、依替膦酸钠、伊班膦酸盐、氯膦酸盐和唑来膦酸盐。
6.权利要求4的药物软明胶胶囊剂型,其中所述至少一种活性成分选自***、其盐、酯、水合物、前药及其衍生物。
7.权利要求6的药物软明胶胶囊剂型,其中所述改性瓜尔胶的含量为所述填充物的约0.5%至约3.0%重量。
8.权利要求7的药物软明胶胶囊剂型,其中所述改性瓜尔胶为羟丙基瓜尔胶。
9.药物软明胶胶囊剂型,包含:
壳,包含明胶和增塑剂;和
填充物,包含至少一种可药用活性成分、一种或多种聚乙二醇和改性瓜尔胶,
其中经在约-1.0至约1.0的log剪切率,在包封之后所述填充物具有的log粘度大于在包封之前所述填充物的log粘度的约1至约2倍。
10.权利要求1的药物软明胶胶囊剂型,其中所述改性瓜尔胶为所述填充物的约0.5%至约3.0%重量。
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US (3) | US9795569B2 (zh) |
EP (2) | EP3187170A1 (zh) |
JP (3) | JP6335270B2 (zh) |
KR (1) | KR20150131070A (zh) |
CN (2) | CN105307634B (zh) |
AU (2) | AU2014239994B2 (zh) |
BR (1) | BR112015022946A8 (zh) |
CA (1) | CA2906633C (zh) |
ES (1) | ES2619121T3 (zh) |
HK (1) | HK1218622A1 (zh) |
IL (1) | IL241377B (zh) |
MX (2) | MX364440B (zh) |
RU (1) | RU2676480C2 (zh) |
WO (1) | WO2014152269A1 (zh) |
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CN105307634B (zh) * | 2013-03-15 | 2020-03-10 | 沃纳奇尔科特有限责任公司 | 含有改性瓜尔胶的药物软明胶胶囊剂型 |
AU2016238337B2 (en) | 2015-03-26 | 2020-08-13 | Patheon Softgels Inc. | Liquisoft capsules |
JP2017214299A (ja) * | 2016-05-30 | 2017-12-07 | ライオン株式会社 | 半固形製剤及びその製造方法 |
WO2022101828A1 (en) * | 2020-11-13 | 2022-05-19 | Pfizer Inc. | Talazoparib soft gelatin capsule dosage form |
CN116531444B (zh) * | 2023-07-06 | 2023-10-10 | 健码制药(广东)有限公司 | 镇咳清肺软胶囊及其制备工艺 |
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2014
- 2014-03-14 CN CN201480022804.XA patent/CN105307634B/zh active Active
- 2014-03-14 BR BR112015022946A patent/BR112015022946A8/pt not_active Application Discontinuation
- 2014-03-14 EP EP16205027.2A patent/EP3187170A1/en not_active Withdrawn
- 2014-03-14 WO PCT/US2014/027145 patent/WO2014152269A1/en active Application Filing
- 2014-03-14 CN CN202010063854.XA patent/CN111374959A/zh active Pending
- 2014-03-14 JP JP2016502347A patent/JP6335270B2/ja active Active
- 2014-03-14 MX MX2015012057A patent/MX364440B/es active IP Right Grant
- 2014-03-14 KR KR1020157026413A patent/KR20150131070A/ko not_active Application Discontinuation
- 2014-03-14 CA CA2906633A patent/CA2906633C/en active Active
- 2014-03-14 ES ES14719974.9T patent/ES2619121T3/es active Active
- 2014-03-14 AU AU2014239994A patent/AU2014239994B2/en active Active
- 2014-03-14 US US14/210,680 patent/US9795569B2/en active Active
- 2014-03-14 EP EP14719974.9A patent/EP2950781B1/en active Active
- 2014-03-14 RU RU2015137612A patent/RU2676480C2/ru active
- 2014-10-27 US US14/524,512 patent/US9820946B2/en active Active
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2015
- 2015-09-09 IL IL241377A patent/IL241377B/en active IP Right Grant
- 2015-09-09 MX MX2019004554A patent/MX2019004554A/es unknown
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2016
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2018
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- 2019-01-09 AU AU2019200116A patent/AU2019200116A1/en not_active Abandoned
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