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CN114712308A - 药物制剂 - Google Patents

药物制剂 Download PDF

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CN114712308A
CN114712308A CN202210167383.6A CN202210167383A CN114712308A CN 114712308 A CN114712308 A CN 114712308A CN 202210167383 A CN202210167383 A CN 202210167383A CN 114712308 A CN114712308 A CN 114712308A
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phosphate
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polyoxyethylene sorbitan
polyoxyethylene
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马哈茂德·埃尔-塔米米
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Phosphagenics Ltd
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Phosphagenics Ltd
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Abstract

本发明涉及制剂领域，公开了一种制剂，该制剂中包含主表面活性剂、母育酚磷酸酯、水、活性剂以及任选的油，其中，所述活性剂和/或所述任选的油中含有疏水相。所述制剂具有较好的药物递送效果。

Description

药物制剂
本申请是申请号为201680072343.6、申请日为2016年12月9日、发明名称为“药物制剂”的中国发明专利申请的分案申请。
在本文引用或讨论知识的文件、法令或条款的情况下，该引用或讨论并不是承认该知识的文件、法令或条款或其任意组合在优先权日时是公众可获得的、公众所知的、公知常识的一部分；或者已知与试图解决本文所涉及的任何问题有关。
技术领域
本发明涉及一种制剂，更具体地，涉及一种药物制剂。
背景技术
已经开发药物递送技术来提高活性剂的生物利用度、安全性、持续时间、起效(onset)或释放。
在开发药物递送技术时，可能遇到的问题包括药物递送系统与活性剂的相容性、维持足够和有效的持续时间、潜在的副作用，以及满足患者的便利性和依从性。因此，许多药物递送技术达不到期望的改善和需求。有必要改进或改变药物技术。
发明内容
因此，本发明的第一方面提供了一种制剂，该制剂中包含主表面活性剂、母育酚磷酸酯(tocol phosphate)、水、活性剂以及任选的油，其中，所述活性剂和/或所述任选的油中含有疏水相。
第二方面，本发明提供了一种制剂，该制剂中包含10mg/mL的丙泊酚、20％的聚氧乙烯脱水山梨糖醇单油酸酯、0.05％的单-(生育酚基)磷酸酯和二-(生育酚基)磷酸酯的混合物的乙醇溶液，余量为水。
第三方面，本发明提供了一种制剂，该制剂中包含10mg/mL的丙泊酚、10％的聚氧乙烯脱水山梨糖醇单油酸酯、0.05％的单-(生育酚基)磷酸酯和二-(生育酚基)磷酸酯的混合物的乙醇溶液，余量为水。
具体实施方式
本发明涉及一种制剂，该制剂中包含主表面活性剂、母育酚磷酸酯、水、活性剂以及任选的油，其中，所述活性剂和/或所述任选的油中含有疏水相。
活性剂
术语“活性剂”是指为了医疗、治疗、美容和兽医目的而对人或动物具有作用的化学物质，并且包括药物、医药品(pharmaceuticals)、药物化妆品(cosmeceuticals)、营养制品(nutraceuticals)和营养剂。应该理解地是，一些活性剂可归类到这些类别中的不止一种。
在某些实施方式中，所述活性剂不溶于水或微溶于水。
在一些实施方式中，所述活性剂选自由安泼那韦、贝沙罗汀、骨化三醇、氯苯吩嗪、环孢霉素(cyclosporine，或环孢菌素(cyclosporin))、地高辛、度骨化醇、屈大麻酚、度他雄胺、依托泊苷、异维甲酸、伊曲康唑、洛匹那韦、利托那韦、氯雷他定、硝苯吡啶、尼莫地平、苯巴比妥、孕甾酮(progesterone)、利哌利酮(risperidone)、沙奎那韦、西罗莫司、维甲酸、丙戊酸、盐酸胺碘酮(amiodarone HCl)、盐酸氯氮卓(chlordiazepoxide HCl)、地西泮、双氢麦角胺甲磺酸盐、非诺多泮、土霉素、帕立骨化醇、戊巴比妥钠、苯妥英钠、植物甲萘醌、丙泊酚、甲磺酸齐拉西酮、多西他奇(docetaxel)、依托泊苷、氟维司群、癸氟哌啶醇、醋酸亮丙瑞林、醋酸亮丙瑞林植入剂(viadur)、劳拉西泮、紫杉醇、他克莫司、替尼泊苷、庚酸睾酮、环戊丙酸睾酮、环戊丙酸雌二醇和戊柔比星组成的组。
在一种实施方式中，所述活性剂为丙泊酚。
在一些实施方式中，所述制剂适用于被认为是油的活性剂。在其它实施方式中，所述制剂适用于被认为不是油的活性剂。
在一些实施方式中，所述活性剂可以以所述制剂总量的约1mg/mL至约20mg/mL范围内的量存在。在一些实施方式中，所述活性剂可以以所述制剂总量的约1mg/mL至约10mg/mL范围内的量存在。在另一些其它实施方式中，所述活性剂可以以所述制剂总量的约5mg/mL至约10mg/mL范围内的量存在。在一种实施方式中，所述活性剂是以所述制剂总量的约10mg/mL的量存在。在另一种实施方式中，所述活性剂是以所述制剂总量的约5mg/mL的量存在。在又一种实施方式中，所述活性剂是以所述制剂总量的约2mg/mL的量存在。在又一种实施方式中，所述活性剂是以所述制剂总量的约1mg/mL的量存在。
表面活性剂
所述主表面活性剂可以为非离子型表面活性剂、阴离子型表面活性剂、阳离子型表面活性剂或两性离子型表面活性剂。
在一些实施方式中，所述主表面活性剂为非离子型表面活性剂。合适的非离子型表面活性剂包括但不限于，聚乙二醇、丙二醇、蓖麻油聚氧乙烯醚(例如
Figure BDA0003516984500000031
EL)、氢化蓖麻油(例如
Figure BDA0003516984500000032
RH 60)、2-羟基乙基12-羟基硬脂酸酯(2-hydroxyethyl12-hydroxyoctadecanoate)(例如
Figure BDA0003516984500000033
HS 15)、聚氧乙烯单油酸酯(例如PEG单油酸酯)、聚氧乙烯单硬脂酸酯(例如PEG400单硬脂酸酯)、聚氧乙烯单月桂酸酯(例如PEG400单月桂酸酯)、失水山梨糖醇单月桂酸酯(例如
Figure BDA0003516984500000034
20)、油酸三乙醇胺、聚氧乙烯山梨糖醇酐单月桂酸酯(例如
Figure BDA0003516984500000035
20，吐温21)、聚氧乙烯山梨糖醇酐单棕榈酸酯(例如
Figure BDA0003516984500000036
40)、聚氧乙烯山梨糖醇酐单硬脂酸酯(例如
Figure BDA0003516984500000037
60、
Figure BDA0003516984500000038
61)、聚氧乙烯脱水山梨糖醇三硬脂酸酯(例如
Figure BDA0003516984500000039
65)、聚氧乙烯脱水山梨糖醇单油酸酯(例如
Figure BDA00035169845000000310
80、
Figure BDA00035169845000000311
81)和聚氧乙烯脱水山梨糖醇三油酸酯(例如
Figure BDA0003516984500000041
85)。
在一些实施方式中，所述主表面活性剂的HLB值为8-18。在另一些实施方式中，所述主表面活性剂的HLB值为8-14。具有该范围内HLB值的表面活性剂的实例包括但不限于，聚乙二醇、丙二醇、蓖麻油聚氧乙烯醚(例如
Figure BDA0003516984500000042
EL)、氢化蓖麻油(例如
Figure BDA0003516984500000043
RH 60)、2-羟基乙基12-羟基硬脂酸酯(例如
Figure BDA0003516984500000044
HS 15)、油酸钠、聚氧乙烯单油酸酯(例如PEG单油酸酯)、聚氧乙烯单硬脂酸酯(例如PEG400单硬脂酸酯)、聚氧乙烯单月桂酸酯(例如PEG400单月桂酸酯)、失水山梨糖醇单月桂酸酯(例如
Figure BDA0003516984500000045
20)、油酸三乙醇胺、聚氧乙烯山梨糖醇酐单月桂酸酯(例如
Figure BDA0003516984500000046
20，吐温21)、聚氧乙烯山梨糖醇酐单棕榈酸酯(例如
Figure BDA0003516984500000047
40)、聚氧乙烯山梨糖醇酐单硬脂酸酯(例如
Figure BDA0003516984500000048
60、
Figure BDA0003516984500000049
61)、聚氧乙烯脱水山梨糖醇三硬脂酸酯(例如
Figure BDA00035169845000000410
65)、聚氧乙烯脱水山梨糖醇单油酸酯(例如
Figure BDA00035169845000000411
80、
Figure BDA00035169845000000412
81)和聚氧乙烯脱水山梨糖醇三油酸酯(例如
Figure BDA00035169845000000413
Figure BDA00035169845000000414
85)。
在一些实施方式中，所述主表面活性剂为聚氧乙烯脱水山梨糖醇单油酸酯(例如
Figure BDA00035169845000000415
80)。
在一些实施方式中，仅使用一种主表面活性剂。然而，在另一些实施方式中，可以使用主表面活性剂的组合。例如，聚氧乙烯脱水山梨糖醇单油酸酯(例如
Figure BDA00035169845000000416
80)与其它主表面活性剂的组合。
所述主表面活性剂可以以所述制剂总量的约1重量％至约30重量％范围内的量存在。在一些实施方式中，所述主表面活性剂可以以所述制剂总量的约1重量％至约20重量％范围内的量存在。在其它实施方式中，所述主表面活性剂可以以所述制剂总量的约1重量％至约10重量％范围内的量存在。在又一些实施方式中，所述主表面活性剂可以以所述制剂总量的约10重量％至约20重量％范围内的量存在。在一种实施方式中，所述主表面活性剂可以以所述制剂总量的约20重量％的量存在。在另一种实施方式中，所述主表面活性剂可以以所述制剂总量的约10重量％的量存在。
在一种实施方式中，表面活性剂与所述活性剂的比例大于10：1。已经发现，在这些具体实施方式中这样的比例产生了清澈的溶液。
母育酚磷酸酯
所述母育酚磷酸酯可以选自由生育酚磷酸酯(tocopheryl phosphates)和/或生育三烯酚磷酸酯(tocotrienol phosphates)及其盐组成的组。在本发明的制剂中，所述母育酚磷酸酯可以当作通常形成微乳液所需的助表面活性剂。
母育酚磷酸酯的实例包括但不限于，单-(生育酚基)磷酸酯(mono-(tocopheryl)phosphate)、单-(生育酚基)磷酸酯单钠盐、单-(生育酚基)磷酸酯二钠盐、二-(生育酚基)磷酸酯、二-(生育酚基)磷酸酯单钠盐、单-(生育三烯酚)磷酸酯、单-(生育三烯酚)磷酸酯单钠盐、单-(生育三烯酚)磷酸酯二钠盐、二-(生育三烯酚)磷酸酯、二-(生育三烯酚)磷酸酯单钠盐。所述母育酚磷酸酯也可以为生育酚磷酸酯和/或生育三烯酚磷酸酯的混合物。例如，为单-(生育酚基)磷酸酯和二-(生育酚基)磷酸酯的混合物(“TPM”)。
所述“盐”可以包括如碱金属盐或碱土金属盐的金属盐，例如钠盐、镁盐、钾盐和钙盐。优选为钠盐和钾盐。
所述母育酚磷酸酯可以被中和，也可以不被中和。如果被中和，则将其中和至接近中性的pH，更优选中和至5-7的pH范围内。
在被包含在所述制剂中之前，所述母育酚磷酸酯可以先制成溶液。合适的溶剂包括任何与水混溶的溶剂，例如醇溶剂。合适的醇溶剂包括C1-C6的醇，优选乙醇或异丙醇。在一些实施方式中，可以使用高达2.5％的醇溶剂来制备母育酚磷酸酯溶液。
所述制剂中可以含有占所述制剂总量约0.01重量％至约5重量％范围内的量的母育酚磷酸酯。在一些实施方式中，所述制剂中可以含有占所述制剂总量约0.03重量％至约0.15重量％范围内的量的母育酚磷酸酯。在一种实施方式中，所述制剂中可以含有占所述制剂总量约0.03重量％的量的母育酚磷酸酯。在另一种实施方式中，所述制剂中可以含有占所述制剂总量约0.125重量％的量的母育酚磷酸酯。
任选的油
本发明的制剂还可以包含任选的油。所述油可以为任意的适合于医药产品的油。
在一些实施方式中，所述油为植物油或蔬菜油，例如芥花籽油、棉籽油、芝麻油、玉米油、葵花油、红花油和大豆油。
所述油还可以选自矿物油或合成油，例如脂肪酸的单甘油酯或二甘油酯和中链甘油三酯。
赋形剂
本发明的制剂可以任选地进一步包含一种或多种赋形剂。本发明领域的技术人员会理解可包含在本发明制剂中的合适的赋形剂，例如，一种或多种稳定剂。赋形剂的选择和量取决于制剂的预期用途、施用方式和/或剂型。
制备
所述制剂可以通过多种技术制备。例如，所述制剂可以通过制药领域中公知的任何方法制备，例如Remington J.P.,The Science and Practice of Pharmacy,ed.A.R.Gennaro,20th edition,Lippincott,Williams and Wilkins Baltimore,Md.(2000)中描述的方法。
一种制备所述制剂的方法涉及将所述活性剂和/或任选的油与所述主表面活性剂和母育酚磷酸酯或母育酚磷酸酯在醇溶剂中的溶液结合，然后加入水。
所述制剂可以任选地还包含本领域公知的一种或多种赋形剂(例如稳定剂)。
所述制剂的pH可以任选地用合适的酸或碱，或通过使用在水相中的缓冲剂来调节。用于调节pH的合适碱的实例为NaOH。合适的缓冲剂的实例包括磷酸盐缓冲液和柠檬酸盐缓冲液。在一种实施方式中，所述制剂的pH通过加入水相后被立即调节。
在一些实施方式中，所述制剂的pH为或被调节至4-10的范围内。
然后将组分混合，可能形成乳液。在一些实施方式中，使用标准混合设备混合所述组分。在其它实施方式中，使用高剪切混合设备来混合所述组分。
如果所述活性剂被认为是油，其可以含有或可以是所述疏水相。在这些实施方式中，所述疏水相也可以不包含所述任选的油。如果所述活性剂被认为不是油，则所述制剂还可以包含油。所述任选的油可以含有或可以是所述疏水相。在这种实施方式中，所述疏水相也可以包含所述活性剂。所述活性剂可以替代地或额外地存在于水相中。
包含油和水的组合物通常产生乳液。因此，本发明所述的制剂可以是乳液。然而，已经发现，母育酚磷酸酯的存在可以将油-水(oil-and-water)转变成微乳液或纳米乳液。因此，在一些实施方式中，所述乳液可以是微乳液或纳米乳液。
通常，“微乳液”是热力学稳定的。本发明所述的微乳液是透明的，因此粒度会低于可见范围。根据本领域的文献，不可见的粒径在5-50nm的范围内，且可见的粒径在50-200nm的范围内。与浑浊制剂相比，清澈制剂可以认为在美学上是优越的。此外，作为微乳液，本发明所述的制剂不太可能需要稳定剂的存在。然而，在一些实施方式中，所述制剂还可以包含稳定剂。
给药途径
根据效果可将给药途径大致分为三类，即：“局部”，其期望的效果是局部的，所以物质直接应用于需要其作用的地方；“肠内”，其期望的效果是系统性的(非局部)，因此物质是通过消化道被给予的；以及“肠胃外”，其所需效果是系统性的，因此物质是通过消化道以外的途径被给予的。
本发明所述的制剂适用于局部、肠内或肠胃外给药。
据认为，所述制剂最适合肠胃外给药，尤其是作为可注射制剂。
具有局部效果的局部给药途径的实例包括表皮(epicutaneous)(在皮肤上)。
具有系统性(非局部)效果的肠内给药途径的实例包括涉及胃肠道任何部位的任何形式的给药，例如口服(进入口腔)、鼻内(进入鼻腔)、直肠内(进入直肠)，以及阴道内(进入阴道)。口服给药包括口腔给药(通过牙龈附近的脸颊吸收)和舌下给药(在舌头下)。
通过具有系统性效果的注射、输注或扩散的肠胃外给药途径的实例包括静脉内(进入静脉)、动脉内(进入动脉)、肌内(进入肌肉)、心内(进入心脏)、皮下(在皮肤之下)、经皮(通过针刺进入皮肤)、皮内(进入皮肤本身)、鞘内(进入椎管)、腹膜内(输注或注射入腹膜)、膀胱内输注(输注至膀胱内)、硬膜外(注射或输注至硬膜外腔)、透皮(transdermal)或经皮(transcutaneous)(通过完整皮肤扩散)、经粘膜(通过粘膜扩散)、吹入(通过鼻腔扩散)、吸入(通过口腔扩散)，以及乳房内(进入乳房组织)。
在本文中，除上下文另有要求外，词语“包括(comprise)”、“含有(comprises)”和“包含(comprising)”分别表示“包括(include)”、“含有(includes)”和“包含(including)”，即当本发明被描述或定义为包含指定的特征时，相同发明的各种实施方式还可以包括附加特征。
实施例
现参考以下非限制性实施例来描述本发明的各实施方式或方面。
实施例1
通过向活性剂中加入母育酚磷酸酯，然后加入主表面活性剂，再加入水，接着搅拌5-10分钟并几乎不摇动来制备以下微乳液。
Figure BDA0003516984500000081
Figure BDA0003516984500000091
Figure BDA0003516984500000101
在上述每种制剂中，母育酚磷酸酯(即，单-(生育酚基)磷酸酯和二-(生育酚基)磷酸酯的混合物)以2.5％的最终浓度提供在乙醇或异丙醇中。
实施例2
通过将单-(生育酚基)磷酸酯和二-(生育酚基)磷酸酯的混合物(TPM)溶解在乙醇(EtOH)中，加入
Figure BDA0003516984500000102
80(T-80)并混合来制备以下微乳液。然后加入水并根据需要调节pH。将所述制剂混合24小时。结果见表1。
表1
Figure BDA0003516984500000111
最初认为，将pH调节至7会使制剂澄清(因此上述测量)。然而，观察到保持其天然pH对于维持透明制剂是有效的。
选择制剂B1、E1和H1以制备更大规模(100g)。
实施例3
通过制备TPM在EtOH中的原料浓缩物(stock concentration)，然后加入
Figure BDA0003516984500000121
80(T-80)，随后加入丙泊酚，搅拌至均匀，然后加入水，以制备以下微乳液。
通过将2.5克TPM与10克EtOH溶解在20mL的玻璃闪烁瓶(glass scintillationvial)中来制备所述TPM在EtOH中的原料浓缩物。通过在40℃磁热板上搅拌过夜来使TPM/EtOH原料浓缩物溶液溶解。
根据表2中规定的量应用以下方法(见下文)。
将“x”克TPM/EtOH储备液(stock solution)(上述制备的)移入100mL的玻璃瓶中，然后加入“x”克T-80。
然后在TPM/EtOH/T-80制备液(preparation)中加入“x”克丙泊酚，并在40℃的热板上搅拌至均匀。
添加足够量的MilliQ水以使得最终制剂为100克。
在磁力板上搅拌过夜。
表2：制剂组分
<u>B1</u> <u>E1</u> <u>H1</u> <u>Z1</u>
TPM/EtOH储备液 0.5克 0.5克 0.5克 0.5克
T-80 10克 20克 10克 20克
丙泊酚 1克 2克 2克 1克
QS MilliQ水 88.5克 77.5克 87.5克 78.5克
结果
在100mL玻璃瓶中配制后，将各20mL分装到小瓶中。
根据肉眼观察，制剂B1显示最清晰，而制剂H1显示最不清晰。结果见表3所示。
表3
<u>B1</u> <u>E1</u> <u>H1</u> <u>Z1</u>
外观 清澈 黄色 乳白色 黄色
结论
考虑到不透明的问题并通过TPM的作用解决了这一问题，因为TPM使丙泊酚保持悬浮状态，且最重要的是防止所述制剂中形成油滴。这被认为是制剂B1的情况，因为事实上该制剂的外观是清澈的。
尽管已经通过实施例并参照其可能的实施方式描述了本发明，但是应该理解在不脱离本发明的范围的情况下，可以对本发明进行修改或改进。

Claims (19)

1.一种制剂，其特征在于，该制剂中包含主表面活性剂、母育酚磷酸酯、水、活性剂以及任选的油，其中，所述活性剂和/或所述任选的油中含有疏水相。
2.根据权利要求1所述的制剂，其中，所述制剂为乳液。
3.根据权利要求2所述的制剂，其中，所述乳液为微乳液或纳米乳液。
4.根据前述任意一项权利要求所述的制剂，其中，所述母育酚磷酸酯为生育酚磷酸酯。
5.根据前述任意一项权利要求所述的制剂，其中，所述母育酚磷酸酯为单-(生育酚基)磷酸酯和二-(生育酚基)磷酸酯的混合物。
6.根据前述任意一项权利要求所述的制剂，其中，所述主表面活性剂为非离子型表面活性剂、阴离子型表面活性剂、阳离子型表面活性剂或两性离子型表面活性剂。
7.根据权利要求6所述的制剂，其中，所述主表面活性剂为非离子型表面活性剂。
8.根据权利要求7所述的制剂，其中，所述非离子型表面活性剂选自由聚乙二醇、丙二醇、蓖麻油聚氧乙烯醚、氢化蓖麻油、2-羟基乙基12-羟基硬脂酸酯、聚氧乙烯单油酸酯、聚氧乙烯单硬脂酸酯、聚氧乙烯单月桂酸酯、失水山梨糖醇单月桂酸酯、油酸三乙醇胺、聚氧乙烯山梨糖醇酐单月桂酸酯、聚氧乙烯山梨糖醇酐单棕榈酸酯、聚氧乙烯山梨糖醇酐单硬脂酸酯、聚氧乙烯脱水山梨糖醇三硬脂酸酯、聚氧乙烯脱水山梨糖醇单油酸酯和聚氧乙烯脱水山梨糖醇三油酸酯组成的组。
9.根据权利要求6所述的制剂，其中，所述主表面活性剂的HLB值为8-18。
10.根据权利要求9所述的制剂，其中，所述主表面活性剂的HLB值为8-14。
11.根据前述任意一项权利要求所述的制剂，其中，所述主表面活性剂为聚氧乙烯脱水山梨糖醇单油酸酯。
12.根据前述任意一项权利要求所述的制剂，其中，该制剂中包含一种主表面活性剂。
13.根据前述任意一项权利要求所述的制剂，其中，该制剂中包含主表面活性剂的组合。
14.根据前述任意一项权利要求所述的制剂，其中，所述活性剂不溶于水或微溶于水。
15.根据前述任意一项权利要求所述的制剂，其中，所述活性剂选自由安泼那韦、贝沙罗汀、骨化三醇、氯苯吩嗪、环孢霉素(或环孢菌素)、地高辛、度骨化醇、屈大麻酚、度他雄胺、依托泊苷、异维甲酸、伊曲康唑、洛匹那韦、利托那韦、氯雷他定、硝苯吡啶、尼莫地平、苯巴比妥、孕甾酮、利哌利酮、沙奎那韦、西罗莫司、维甲酸、丙戊酸、盐酸胺碘酮、盐酸氯氮卓、地西泮、双氢麦角胺甲磺酸盐、非诺多泮、土霉素、帕立骨化醇、戊巴比妥钠、苯妥英钠、植物甲萘醌、丙泊酚、甲磺酸齐拉西酮、多西他奇、依托泊苷、氟维司群、安度利可、醋酸亮丙瑞林、醋酸亮丙瑞林植入剂、劳拉西泮、紫杉醇、他克莫司、替尼泊苷、庚酸睾酮、环戊丙酸睾酮、环戊丙酸雌二醇和戊柔比星组成的组。
16.根据前述任意一项权利要求所述的制剂，其中，所述活性剂为丙泊酚。
17.根据前述任意一项权利要求所述的制剂，其中，所述疏水相中不包含所述任选的油。
18.一种制剂，其特征在于，该制剂中包含10mg/mL的丙泊酚、20％的聚氧乙烯脱水山梨糖醇单油酸酯、0.05％的单-(生育酚基)磷酸酯和二-(生育酚基)磷酸酯的混合物的乙醇溶液，余量为水。
19.一种制剂，其特征在于，该制剂中包含10mg/mL的丙泊酚、10％的聚氧乙烯脱水山梨糖醇单油酸酯、0.05％的单-(生育酚基)磷酸酯和二-(生育酚基)磷酸酯的混合物的乙醇溶液，余量为水。
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