CN101627974A - 一日服用一次的羟考酮制剂 - Google Patents
一日服用一次的羟考酮制剂 Download PDFInfo
- Publication number
- CN101627974A CN101627974A CN200910148818A CN200910148818A CN101627974A CN 101627974 A CN101627974 A CN 101627974A CN 200910148818 A CN200910148818 A CN 200910148818A CN 200910148818 A CN200910148818 A CN 200910148818A CN 101627974 A CN101627974 A CN 101627974A
- Authority
- CN
- China
- Prior art keywords
- dosage form
- oxycodone
- pharmaceutically acceptable
- matrix
- cellulose
- 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.)
- Granted
Links
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 title claims abstract description 143
- 229960002085 oxycodone Drugs 0.000 title claims abstract description 116
- 239000000203 mixture Substances 0.000 title claims abstract description 69
- 238000009472 formulation Methods 0.000 title abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 66
- 238000000034 method Methods 0.000 claims abstract description 41
- 239000012730 sustained-release form Substances 0.000 claims abstract description 39
- 238000013268 sustained release Methods 0.000 claims abstract description 28
- 239000002552 dosage form Substances 0.000 claims description 102
- -1 poly(ethylene oxide) Polymers 0.000 claims description 89
- 239000011159 matrix material Substances 0.000 claims description 70
- 239000008187 granular material Substances 0.000 claims description 57
- 239000000463 material Substances 0.000 claims description 51
- 238000002360 preparation method Methods 0.000 claims description 51
- 239000003814 drug Substances 0.000 claims description 45
- 229920000642 polymer Polymers 0.000 claims description 37
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 34
- 230000002045 lasting effect Effects 0.000 claims description 31
- 229920001577 copolymer Polymers 0.000 claims description 22
- 239000007788 liquid Substances 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- BQNSLJQRJAJITR-UHFFFAOYSA-N 1,1,2-trichloro-1,2-difluoroethane Chemical compound FC(Cl)C(F)(Cl)Cl BQNSLJQRJAJITR-UHFFFAOYSA-N 0.000 claims description 21
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 21
- 229960003617 oxycodone hydrochloride Drugs 0.000 claims description 21
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- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 7
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- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
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- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 claims description 3
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- 229940043348 myristyl alcohol Drugs 0.000 claims description 3
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 2
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
本发明涉及含有羟考酮或其药学上可接受的盐的持续释放制剂,它以稳态供患者口服后提供了约0.6-1.0或0.7-1的C24/Cmax羟考酮比平均值,及其方法。
Description
本申请是国际申请号为PCT/US 02/14024,国际申请日为2002年5月2日,进入中国国家阶段的申请号为02811559.7的发明专利申请的分案申请。
发明领域
本发明涉及适合于患者服用的含有羟考酮或其药学上可接受的盐的持续释放制剂。
发明背景
一日服用一次,持续释放的类阿片制剂在美国专利NO.5478577、5672360、5958459、6103261、6143332、5965161、5958452和5968551中揭示,本文引证的所有文献(包括以前发表的文献)为本发明目的本文全部引入作为参考。
发明概要和目的
本发明的目的是提供适合于一日服用一次的羟考酮制剂,以有效地控制疼痛。
本发明优选实施方式的目的是提供一种供患者口服羟考酮的药学上可接受的剂型,该剂型提供超过其较短半寿期而使时间延长的镇痛效果,并具有至少24小时缓解疼痛的持续时间。
本发明达到了上述目的和其它目的,本发明涉及包括镇痛有效量的羟考酮或其药学上可接受的盐以及持续释放物质的剂型,该剂型以稳态供患者口服后的镇痛效果至少约24小时,并且该剂型以稳态供患者口服后的C24/Cmax羟考酮比率为0.6-1.0。
在本发明的某些实施方式中,该剂型以稳态供患者服用后提供了约一个体内羟考酮的Tmax平均值,该值出现在该剂型以稳态给药后约2-17小时(例如约2-8小时)。
在本发明的某些实施方式中,该剂型稳态给药后,体内羟考酮的Tmax平均值出现于约6.5-17小时、约8-16小时、约10-16小时、或约12-16小时。
在本发明的某些实施方式中,该剂型以稳态供患者服用后提供了至少约24小时的镇痛效果,并且以稳态供患者服用后提供了约0.6-1.0比率的C24/Cmax羟考酮平均值。
在本发明的某些实施方式中,该剂型以稳态供患者服用后提供了至少约24小时的镇痛效果,并且以稳态供患者服用后提供了约0.60-1.0或0.7-1.0比率的C24/Cmax羟考酮平均值。在本发明的某些实施例中,用美国药典的篮式法(USP Basket Method),在100rpm,900ml含水缓冲液、pH为1.6-7.2、37℃条件下测得该剂型的羟考酮或其药学上可接受的盐的体内释放速率为:1小时时为0%-约40%、4小时时约为8%-70%、8小时时约为20%-80%、12小时时约为30%-95%、18小时时约为35%-95%、以及24小时时约为大于50%。
在某些优选实施方式中,本发明的持续释放口服剂型以稳态供患者服用后提供了约一个对于24小时给药是有效的羟考酮的血浆浓度。它由以稳态服用后4-24小时之间羟考酮的W50来表征。在某些实施方式中,以稳态服用后W50至少是4小时,优选至少12小时,以及更优选至少18小时。
在某些优选实施方式中,本发明持续释放口服剂型包括其中含有持续释放物质和羟考酮或其药学上可接受的盐的基体。在某些实施方式中将该基体压制成药片,并且可任选地用包衣包裹,这样,除了基体的持续释放物质以外,该包衣也可控制羟考酮或其药学上可接受的盐从制剂中释放,以使有效组分的血液浓度长时间保持在治疗范围内。在某些可供选用的实施方式中,基体被封入胶囊。
在某些实施方式中,本发明的持续释放口服剂型包括其中含有羟考酮或其药学上可接受的盐的大量药学上可接受的持续释放基体,该剂型在患者服用后其羟考酮的血浆浓度长时间保持在治疗范围内。
根据本发明制备的制剂优选以片剂、胶囊、或任何其它合适的单位剂型存在。
在某些实施方式中,本发明的持续释放口服剂型是一种渗透性剂型,它包括其中含有羟考酮或其药学上可接受的盐的单层或双层片芯、可膨胀聚合物、包围片芯的半渗透膜、以及设在半渗透膜内供羟考酮或药学上可接受的盐持续释放的通道,以使患者服用后,其有效成分的血液浓度长时间保持在治疗范围内。
在某些实施方式中,本发明的持续释放口服剂型包括其中含有羟考酮或药学上可接受的盐的基本上均质的片芯、可膨胀聚合物、包围片芯的半渗透膜、以及设在半渗透膜内供羟考酮或药学上可接受的盐持续释放的通道,以使患者服用后,其有效成分的血液浓度长时间保持在治疗范围内。
在本发明的某些实施方式中,提供了约在患者需要这种治疗的相关条件下治疗疼痛的方法。该方法包括使患者服用有效量的上述持续释放剂型中的羟考酮或其医药学上可接受的盐。
在某些实施方式中,本发明涉及持续释放剂型在产生患者一日口服一次的镇痛制剂中的用途,该剂型包括其中含有羟考酮或其药学上可接受的盐以及持续释放物质的药学上可接受的基体,该制型以稳态供患者服用后提供至少约24小时的镇痛效果和0.6-1.0的C24/Cmax羟考酮比平均值。
在某些实施方式中,本发明涉及持续释放口服剂型的用途,该剂型包括其中含有药物层和位移层的双层片芯,以及包围双层片芯的半渗透性壁。所述药物层包括具有镇痛有效量的羟考酮或其药学上可接受的盐,所述取代层包括渗透性聚合物,所述半渗透性壁具有通道设于其内用于释放所述羟考酮或其药学上可接受的盐,从而该剂型以稳态供患者服用后提供至少约24小时的镇痛效果和0.6-1.0的C24/Cmax羟考酮比平均值。
在某些实施例中,本发明涉及持续释放剂型的用途,该剂型包括其中含有羟考酮或药学上可接受的盐以及持续释放物质的大量持续释放基体,从而以稳态供患者服用后提供至少24小时的镇痛效果和0.6-1.0比率C24/Cmax羟考酮平均值。
本文使用的术语“Cmax”是指用药间隔内达到的药物的最高血浆浓度。
本文使用的术语“C24”是指服用后24小时药物的血浆浓度。
本文使用的术语“Tmax”是指所述剂型服用后直到用药间隔内药物的血浆浓度达到最高血浆浓度所消逝的时间。
用于本发明目的的术语“W50”是指药物的血浆浓度等于或大于峰值浓度的50%的持续时间,该参数用观察到数据的线性内插法确定,且表示血浆浓度曲线图中第一条(或仅一条)向上倾斜交叉和最后一条(或仅一条)向下倾斜交叉之间的时间差。
用于本发明目的所定义的术语“C24/Cmax”是指服用后24小时药物的血浆浓度与用药间隔内达到的药物的最高血浆浓度之比。
术语“USP篮式法”是指在美国药典XXII(1990)中所述的篮式法,将该法引入本文作为参考。
术语“稳态”是指到达体系的药物量大致与离开体系的药物量相同。于是,在“稳态”时,患者体内消除去药物的速率大致与患者体内通过吸收进入血流中所获得药物的速率相同。
用于本发明目的的术语“半渗透性壁”是指所述壁在使用环境下(包括胃肠道)对外部流体(例如含水的流体或生物的流体)的通过是可渗透的,而对药物是不可渗透的。
用于本发明目的的术语“可膨胀聚合物”是指该聚合物暴露于含水的流体或生物的流体后,吸收所述流体导致其容积增大。
用于本发明目的的术语“平均值”,在用于确定药物动力学值(例如Tmax)时,它表示通过对患者群总体所测得的算术平均值。
词组“药学上可接受的盐”包括(但不限于):金属盐,例如钠盐、钾盐、铯盐等;碱土金属,例如钙盐、镁盐等;有机胺盐,例如三乙胺盐、吡啶盐、甲基吡啶盐、乙醇胺盐、三乙醇胺盐、二环已胺盐、N,N’-二苄基亚乙基二胺盐等;无机酸盐,例如盐酸盐、氢溴化物、硫酸盐、磷酸盐等;有机酸盐,例如甲酸盐、乙酸盐、三氟乙酸盐、马来酸盐、富马酸盐、酒石酸盐等;磺酸盐,例如甲磺酸盐、苯磺酸盐、对甲苯磺酸盐等;氨基酸盐,例如精氨酸盐、天冬氨酸盐、谷氨酸盐等。
发明描述
在本发明的某些实施方式中,用美国药典篮式法(USP Basket Method),在100rpm、900ml含水缓冲液、pH 1.6-7.2、37℃测得所述持续释放剂型提供的羟考酮或其药学上可接受的盐在体内的释放速率为:1小时时约为40%、4小时时约为8%-70%、8小时时约为20%-80%、12小时时约为95%、18小时时约为35%-95%、以及24小时时约为大于50%。
在本发明的某些实施方式中,羟考酮血液浓度(以稳态服用后)大于或相当于最高血液浓度(T≥0.75Cmax)的75%的时间周期可为4小时或4小时以上,优选6小时或6小时以上。
在本发明的某些实施例中,所述剂型以稳态服用后羟考酮血液浓度达到其最高浓度(Tmax)的时间约为2-17小时,优选约6.5-17小时,更优选约8-16小时,特别优选约10-16小时或12-16小时。
在本发明的某些实施方式中,所述剂型以稳态服用后提供的C24/Cmax比为0.6-1.0、0.7-0.99或0.8-0.95。
在本发明的其它实施方式中,所述剂型以稳态服用后提供的C24/Cmax比为0.7-0.10、0.72-0.99或0.74-0.95。
在本发明的某些实施方式中,所述剂型以稳态服用后提供的C24/Cmax比为0.6-0.10、0.7-0.99或0.8-0.95,以及Tmax约为6.5-17小时、约8-16小时、约10-16小时或约12-16小时。在本发明的其它一些实施方式中,所述剂型以稳态服用后提供的C24/Cmax比为0.7-1.0、0.72-0.99或0.74-0.95,以及Tmax约为2-17小时。
在本发明的某些实施方式中,将所述剂型和食物一起服用不会明显增加或减少羟考酮的吸收程度。
本发明的持续释放口服剂型包括约1-640mg羟考酮或其药学上可接受的盐(例如,盐酸羟考酮)、优选约5-500mg,更优选约10-320mg,以及特别优选约10-160mg。
本发明的其它优选实施方式中,本发明的持续释放剂型包括约10-160mg盐酸羟考酮或者除了盐酸盐以外的等效量的羟考酮或其药学上可接受的盐。
本发明包括服用方法,该方法在患者需要解痛时,根据本文所揭示的药物动力学参数,按照一日一次基准服用约1-640mg羟考酮或其药学上可接受的盐。优选地,所述方法包括服用约5-500mg羟考酮或其药学上可接受的盐。
根据本发明的服用方法特别适用于治疗急性疼痛和慢性疼痛,尤其是治疗与终末期疾病(如癌症)有关的疼痛,慢性背痛,以及手术后疼痛。
剂型
在某些实施方式中,所述剂型包括持续释放物质,它是与羟考酮或其药学上可接受的盐一起掺入基体内,以提供持续释放的羟考酮。持续释放物质可以是疏水性的或亲水性的,这视需要而定。本发明的口服剂型可制成颗粒、球形体、基体多颗粒等,它包括在持续释放基体内的羟考酮或其药学上可接受的盐,它可压制成药片或封入胶囊。本发明的口服剂型可任选地包括其它药学上可接受的组分(例如,稀释剂、粘合剂、着色剂、润滑剂等)。
在某些实施方式中,本发明的口服药剂型可以是渗透性剂型,它具有推压组合物或置换组合物,该组合物作为双层片芯中的一层用于从所述剂型中推压羟考酮或其药学上可接受的盐;它还具有包围片芯的半渗透性壁组合物,其中所述壁设有至少一个出口装置或通道,用于从所述剂型中输送羟考酮。另一方面,渗透性剂型的片芯可包括其中含有受控释放聚合物和羟考酮或其药学上可接受的盐的单层片芯。
本发明的剂型服用后可较好地提供至少约24小时的镇痛效果。
持续释放基体的制剂
在本发明的一个优选实施方式中,持续释放载体可与羟考酮或其药学上可接受的盐一起掺入基体内,而基体提供羟考酮的持续释放。
根据本发明可包括在持续释放基体中的不限于所列举的合适的持续释放物质,包括疏水性和/或亲水性物质,例如,树胶、纤维素醚、丙烯酸树脂、蛋白质衍生的物质、蜡、虫胶、以及油类(例如,氢化蓖麻油和氢化植物油)。然后,根据本发明可使用能赋予持续释放羟考酮或其药学上可接受的盐的任何药学上可接受的疏水性或亲水性持续释放物质。优选的持续释放聚合物包括烷基纤维素,例如,乙基纤维素、丙烯酸和甲基丙烯酸聚合物及共聚物;以及纤维素醚,特别是羟烷基纤维素(尤其是羟丙基甲基纤维素)和羧烷基纤维素。优选的丙烯酸和甲基丙烯酸聚合物及共聚物包括甲基丙烯酸甲酯、甲基丙烯酸甲酯共聚物、甲基丙烯酸乙氧基乙酯、丙烯酸乙酯、甲基丙烯酸三甲基铵乙酯、甲基丙烯酸氰基乙酯、甲基丙烯酸氨基烷酯共聚物、聚丙烯酸、聚甲基丙烯酸、甲基丙烯酸烷基胺的共聚物、聚甲基丙烯酸甲酯、聚甲基丙烯酸酐、聚甲基丙烯酸酯、聚丙烯酰胺、聚甲基丙烯酸酐、甲基丙烯酸缩水甘油酯共聚物。某些优选的实施方式是在本发明的基体中使用任何上述持续释放物质的混合物。
所述基体也可包括粘合剂。在这样的实施方式中,优选有助于从持续释放基体中持续释放羟考酮或其药学上可接受的盐的粘合剂。
如果包括附加的疏水性粘合剂物质,它优选自天然的和合成的蜡、脂肪酸、脂肪醇、及其混合物。实施例中包括蜂蜡、巴西棕榈蜡、硬脂酸和硬脂醇。这里列举的并非是全部。在某些优选实施方式中,在基体的组成中包括二种或多种疏水性粘合剂物质的组合物。
根据本发明可供优选使用的疏水性粘合剂物质包括易消化,长链(C8-C50,特别是C12-C40),取代的或非取代的烃,例如脂肪酸、脂肪醇、脂肪酸的甘油酯、矿物油和植物油、天然蜡和合成蜡、以及聚亚烷基二醇。优选熔点为25℃~90℃的烃类。在长链烃的粘合剂物质中,在某些实施方式中,优选脂肪(脂族)醇。所述口服剂型可含有高达80%(按重量计)的至少一种易消化的长链烃。
在某些实施例中,所述的疏水性粘合剂物质可包括天然蜡或合成蜡、脂肪醇(例如,月桂醇、肉豆寇醇、十八烷醇、鲸蜡醇、或优选的十六烷醇和十八烷醇的混合物)、脂肪酸、包括但不限于脂肪酸酯、脂肪酸甘油酯(单甘油酯、二甘油酯和三甘油酯)、氢化脂肪、烃类、正蜡、硬脂酸、硬脂醇、以及具有烃主链的疏水性物质和亲水性物质。合适的蜡包括,例如蜂蜡、甘氨蜡、蓖麻蜡和巴西棕榈蜡。用于本发明目的的蜡样物质定义为通常在室温时为固体,其熔点为约30~100℃的任何物质。在某些优选实施例中,所述剂型包括其中含有羟考酮或其药学上可接受的盐以及至少一种水溶性羟烷基纤维素的持续释放基体,至少一种C12~C36,优选C14~C22的脂肪醇,以及任选的至少一种聚亚烷基二醇。所述羟烷基纤维素优选C1~C6羟烷基纤维素,例如羟丙基纤维素、羟丙基甲基纤维素,以及特别是羟乙基纤维素。在本发明的口服剂型中,至少一种羟烷基纤维素的量特别可通过所需的羟考酮或羟考酮盐的精确释放速率进行测定。所述脂肪醇可以是,例如月桂醇、肉豆寇醇或十八烷醇。然后,在本发明口服剂型的特别优选实施方式中,至少一种脂族醇是十六烷醇或者是十六烷醇和十八醇的混合物。在本发明的口服剂型中,脂族醇的量可如上述通过所需的羟考酮或羟考酮盐的精确释放速率来确定。它也可取决于至少一种聚亚烷基二醇存在于还是不存在于所述口服剂型中。在至少一种聚亚烷基二醇不存在的情况下,所述口服剂型优选含约20%~50%(按重量计)的脂族醇。然后,当聚亚烷基二醇存在于所述口服剂型中时,脂族醇和聚亚烷基二醇的组合重量优选构成占剂型总量的约20%~50%(按重量计)。
在一个优选实施方式中,例如,至少一种羟烷基纤维素或丙烯酸树脂对至少一种脂肪醇/聚亚烷基二醇的比例在很大程度上决定了羟考酮或羟考酮盐从制剂中的释放速率。在某些实施方式中,羟烷基纤维素对脂肪醇/聚亚烷基二醇的比例优选1∶1~1∶4,特别优选1∶2~1∶3。
在某些实施方式中,例如,聚亚烷基二醇可以是聚丙二醇,或优选聚乙二醇。至少一种聚亚烷基二醇的平均分子量优选在1000和15000之间,特别优选在1500-12000之间。
另一种合适的持续释放基体包括烷基纤维素(特别是乙基纤维素),C12-C36脂族醇,以及任选的聚亚烷基二醇。
除了上述成分外,持续释放基体还可包括合适量的其它物质,例如稀释剂、润滑剂、粘合剂、成粒助剂、着色剂、食用香料和助流剂,它们在药物领域内是常用的。
为了有助于制备本发明的固体持续释放口服剂型,在本发明的另一方面,提供了约一种包括将羟考酮或羟考酮盐掺入持续释放基体中制备本发明固体持续释放口服剂型的方法。
例如可用以下方法掺入基体中:
(a)形成颗粒,它包括至少一种上述的疏水性和/或亲水性物质(如水溶性羟烷基纤维素)与羟考酮或其药学上可接受的盐;
(b)将含有至少一种疏水性和/或亲水性物质的颗粒与至少一种C12-C36脂族醇混合,以及
(c)任选地压制和成型所述颗粒。
所述颗粒可用任何一种本技术领域内熟知的药剂剂型的加工方法成型。例如,在一个优选的方法中,可通过羟烷基纤维素/羟考酮或羟考酮盐与水一起进行湿法成粒使颗粒成型。在该方法的特别优选实施方式中,在湿法成粒步骤阶段加入的水量优选为羟考酮或羟考酮盐的干重的1.5-5倍之间,特别优选为1.75-3.5倍之间。
持续释放基体也可用,例如,熔融成粒工艺或熔融挤出工艺制备。熔融成粒工艺通常包括熔融常规的固体疏水性粘合剂物质(例如蜡),以及将粉状药物掺入其中。为了获得持续释放剂型,有必要将疏水性持续释放物质(例如乙基纤维素或不溶于水的丙烯酸聚合物)掺入熔融蜡(疏水性粘合剂物质)内。经熔融成粒工艺制备持续释放药剂的实施例揭示在例如美国专利NO.4861598中。
另外的疏水性粘合物质可包括一种或多种不溶于水的蜡样热塑性物质,它可与疏水性略小于所述一种或多种不溶于水的蜡样物质的一种或多种蜡样热塑性物质混合。为了达到持续释放,制剂中的各蜡样物质应该在初期释放阶段时在消化道液体中基本不可降解且不溶解。有用的不溶于水的蜡样粘合物质可以具有约低于1∶5000(w/w)的水溶解度。
本发明合适的熔融挤出基体的制备方法例如包括将羟考酮或其药学上可接受的盐与持续释放物质和优选的粘合剂物质一起混合而成均匀混合物的步骤。然后将均匀混合物加热到足以至少软化该混合物到足够使其挤出的温度。然后,例如用双螺杆挤出机挤出所得的均匀混合物,以形成股状物。优选将挤出物冷却,并通过本领域中已知的任何手段切割成多颗粒。接着将基体多颗粒分成单位剂量。挤出物优选具有约0.1~5毫米的直径并提供至少约24小时的羟考酮或其药学上可接受的盐的持续释放时间。
制备本发明熔融挤出制剂的一个任选的方法包括直接将疏水性持续释放物质、羟考酮或其药学上可接受的盐、以及任选的粘合剂物质计量入挤出机中;加热均匀混合物;挤出均匀混合物,从而形成股状物;冷却含有均匀混合物的股状物;将股状物切割成尺寸约0.1~12毫米的基体多颗粒;将所述颗粒分成单位剂量。在本发明的这一方面,人们可了解到一种相对连续的制造过程。
诸如上述的增塑剂可包含在熔融挤出基体中。增塑剂在基体中的含量优选约0.1~30%(按重量计)。根据需要本发明的持续释放基体中可包含其他药物赋形剂,例如滑石、单糖或多糖、着色剂、食用香料、润滑剂等。其含量取决于要达到的所需特性。
可调节挤出机孔径或出口的直径来改变挤出的股状物厚度。另外,挤出机的出口无需是圆形的;它可以是椭圆形、长方形等。可以用热丝切割机、剪切机将排出的股状物切短成颗粒。
熔融挤出的基体多颗粒系统根据挤出机出口孔例如可以是颗粒、球粒或丸粒的形式。为了本发明的目的,术语“熔融挤出的基体多颗粒”和“熔融挤出的基体多颗粒系统”以及“熔融挤出的基体颗粒”指的是大量单位,优选在相似尺寸和/或形状的范围内,并含有一种或多种活性剂和一种或多种赋形剂,优选包括本文所述的疏水性持续释放物质。熔融挤出的基体多颗粒优选在约0.1~12毫米长度和约0.1~5毫米直径的范围内。另外,应当了解熔融挤出的基体多颗粒可以是该尺寸范围内的任何几何形状。在某些实施方式中,挤出物可以简单地切割成所需的长度,并分成治疗活性剂的单位剂量,而无需球化(spheronization)步骤。
在一个优选实施方式中,口服剂型被制备成在胶囊内包含有效量的熔融挤出基体多颗粒。例如,大量熔融挤出基体多颗粒可以一定量装在明胶胶囊内,该量在经胃肠液消化和接触时足以提供有效的持续释放剂量。
在另一实施方式中,采用标准技术用常规压片设备将合适量的多颗粒挤出物压制成口服片剂。Remington’s Pharmaceutical Sciences(Arthur Osol,编辑),1553-1593(1980)中也描述制造片剂(压制型和模塑)、胶囊(硬明胶和软明胶)和药丸的技术及其组合物。
在还有一个优选的实施方式中,挤出物可成形为在美国专利4,957,681(Klimesch等)中所述的片剂。
可任选的是,持续释放基体多颗粒系统、片剂、或胶囊可用持续释放包衣包裹(如本文所述的持续释放包衣)。这种包衣优选包括足量的疏水性和/或亲水性持续释放物质,以得到约2~25%的增重水平,虽然包衣根据例如所需释放速率可更大。
本发明的剂型还可包括其中含有羟考酮或其药学上可接受的盐的熔融挤出基体多颗粒的组合物。另外,剂型也可包括大量立即释放的治疗活性羟考酮或其药学上可接受的盐,以促进疗效。立即释放的羟考酮或其药学上可接受的盐例如可作为分离的多颗粒装入明胶胶囊中,或涂布在例如熔融挤出的基体多颗粒的表面上。
通过例如改变持续释放物质的量、改变增塑剂相对于其他基体组分的量、改变疏水性物质的量、掺入额外的成分或赋形剂、改变制造方法等,可改变本发明熔融挤出制剂的持续释放。
在本发明的另一实施方式中,制备熔融挤出制剂不掺入羟考酮或其药学上可接受的盐,而是在此之后加入挤出物中。这种制剂一般是羟考酮或其药学上可接受的盐与挤出的基体物质一起混合,然后将该混合物制成片剂,以获得缓慢释放的制剂。这种制剂例如在包含于制剂中的治疗活性剂对软化疏水性物质和/或阻滞物质的温度敏感时可能是有利的。
适用于本发明的典型熔融挤出生产系统包括合适的具有可变速度和恒定的转矩控制、开关控制和安培计的挤出机传动马达。另外,生产系统可包括温度控制台,它包括贯穿整个挤出机长度的温度传感器、冷却装置和温度指示器。另外,生产系统可包括挤出机,如由封在有开口或出口处有压模的圆筒或滚筒内的两个反向旋转互相啮合螺杆构成的双螺杆挤出机。进料通过加料斗进入,并由螺杆通过滚筒移动,以及通过压模压成股状物,然后例如通过连续移动带转送,以使其冷却和直接送到制粒机或其他合适装置中,以将股状物挤压到基体多颗粒系统中。制粒机可由辊子、固定刀、旋转切割机等构成。合适的仪器和系统可购自销售者例如新泽西州南哈肯萨克的C.W.Brabender仪器公司。其他合适的仪器对精通本领域的技术人员来说是显而易见的。
本发明的另一方面涉及以一种控制挤出产物中包含的空气量的方式制备前述熔融挤出的基体多颗粒的方法。通过控制挤出物中包含的空气量,可改变羟考酮或其药学上可接受的盐的释放速率。
因此,在本发明的另一方面,以一种在制备过程的挤出阶段期间实质上包含空气的方式制备熔融挤出产物。这可通过例如使用具有真空附属装置的Leistritz挤出机来完成。根据本发明在真空下使用Leistritz挤出机制备的挤出基体多颗粒提供了具有不同物理特性的熔融挤出产物。特别是在使用例如提供SEM(扫描电子显微照片)的扫描电子显微镜放大时该挤出物基本上是无孔的。这种基本无孔的制剂与不在真空下制备的相同制剂相比,可使治疗活性剂较快释放。在真空下使用挤出机制备的基体多颗粒的SEM表现出非常光滑,并且多颗粒比那些不在真空下制备的多颗粒倾向于更坚固。已经观察到,至少在某些制剂中,在真空下使用挤出机提供了约pH依赖性比不在真空下制备的对应制剂强的挤出基体多颗粒产品。
或者,用Werner-Pfleiderer双螺杆挤出机制备熔融挤出产品。
在某些实施方式中,将球状化剂加入粒状物或基体多颗粒中,然后经球状化产生持续释放球形体。然后任选地用持续释放包衣通过诸如上述方法包裹该球形体。
可用于制备本发明基体多颗粒制剂的球状化剂包括任何本领域已知的球状化剂。纤维素衍生物是优选的,微晶纤维素是特别优选的。合适的微晶纤维素例如是以Avicel pH 101(商标,FMC公司)销售的物质。球状化剂在基体多颗粒中含量优选的1-99%(按重量计)。
在某些实施方式中,除了活性成分和球状化剂之外,球形体也可含有粘合剂。诸如低粘度水溶性聚合物的合适粘合剂,对于制药领域的技术人员是熟知的。但是,水溶性羟基低级烷基纤维素如羟丙基纤维素是优选的。另外(或者另一方面)球形体可含有不溶于水的聚合物,特别是丙烯酸聚合物、丙烯酸共聚物,如甲基丙烯酸-丙烯酸乙酯共聚物,或乙基纤维素。
在某些实施方式中,将持续释放包衣施加到持续释放球形体、颗粒或基体多颗粒上。在这些实施方式中,持续释放包衣可包含不溶于水物质,如(a)石蜡,单独使用或和脂肪醇混合使用;或(b)虫胶或玉米醇溶蛋白。包衣优选衍生自疏水性持续释放物质的含水分散液。
在某些实施方式中,为获得持续释放制剂,需要用足量的例如烷基纤维素或丙烯酸聚合物的水性分散液包覆其中含有羟考酮或其药学上可接受的盐的持续释放球形体、颗粒或基体多颗粒和持续释放载体,以获得约2~50%(例如约2~25%的增重水平,以获得持续释放剂型。包衣可根据例如所需的释放速率、水性分散液中包含增塑剂、以及施加包衣的方式而减少或增多。纤维素物质和聚合物(包括烷基纤维素)是适合包覆本发明持续释放球形体、颗粒或基体多颗粒的持续释放物质。举例简单说明,一种优选的烷基纤维素聚合物是乙基纤维素,虽然技术人员可理解其他纤维素和/或烷基纤维素聚合物也可像本发明的所有或部分疏水性包衣那样容易地单独使用或以任何组合使用。
一种市售的乙基纤维素水性分散液是Aquacoat(FMC公司,费城,宾夕法尼亚州,美国)。Aquacoat是通过将乙基纤维素溶解在不溶混于水的有机溶剂中,然后在表面活性剂和稳定剂存在下于水中使其乳化而制成的。在均匀化以产生亚微细粒小液滴后,有机溶剂于真空下蒸发,以形成拟胶乳。在制造阶段期间,不将增塑剂掺入拟胶乳。于是在将拟胶乳用作包衣前,必须在使用前使Aquacoat与合适的增塑剂均匀混合。
另一种乙基纤维素的水性分散液是Surelease(购自Colorcon,Inc.,西点,宾夕法尼亚州,美国)。该产品是通过制造时在分散液中加入增塑剂而制成的。由聚合物、增塑剂(癸二酸二丁酯)和稳定剂(油酸)的热熔制成均匀混合物,然后用碱性溶液稀释,获得可直接施用到持续释放球形体、颗粒或基体多颗粒上的水性分散液。
在本发明的另一优选实施方式中,包括持续释放包衣的持续释放物质是药学上可接受的丙烯酸聚合物,包括但不限于丙烯酸和甲基丙烯酸共聚物、甲基丙烯酸甲酯共聚物、甲基丙烯酸乙氧基乙酯、甲基丙烯酸氰乙酯、聚(丙烯酸)、聚(甲基丙烯酸)、甲基丙烯酸烷基酰胺共聚物、聚(甲基丙烯酸甲酯)、聚甲基丙烯酸酯、聚(甲基丙烯酸酐)、聚(甲基丙烯酸甲酯)共聚物、聚丙烯酰胺、氨烷基甲基丙烯酸共聚物、和甲基丙烯酸缩水甘油酯共聚物。
在某些优选的实施方式中,丙烯酸聚合物是由一种或多种氨溶的甲基丙烯酸酯(ammonio methacrylate)共聚物组成。氨溶的甲基丙烯酸酯共聚物是本领域中熟知的,在国家公式集(NF)XVII记载为丙烯酸和甲基丙烯酸酯与少量季铵基团充分聚合的共聚物。为了获得所需的溶出曲线,可能需要加入二种或多种具有不同物理性质如季铵基团与中性的(甲基)丙烯酸酯的摩尔比不同的氨溶的甲基丙烯酸共聚物。
某些甲基丙烯酸酯型聚合物对于制备可用于本发明的pH依赖性包衣是有用的。例如它们是由甲基丙烯酸二乙基氨基乙酯和其他中性的甲基丙烯酸酯合成的一族共聚物,也称为甲基丙烯酸共聚物或聚甲基丙烯酸酯,以Eudragit购自GMBH和Co.Kg Darmstadt,德国。有几种不同类型的Eudragit。例如,Eudragit E是在酸性介质中溶胀和溶解的甲基丙烯酸共聚物的例子。Eudragit L是一种约在pH<5.7时不溶胀而约在pH>6时溶解的甲基丙烯酸共聚物。Eudragit S是约在pH<6.5时不溶胀而约在pH>7时溶解。Eudragit RL和Eudragit RS是在水中可溶胀的,这些聚合物所吸收的水量是pH依赖性的,但是包覆有Eudragit RL和RS的剂型不是pH依赖性的。
在某些优选实施方式中,丙烯酸包衣包括两种购自Rohm的商标分别为EudragitRL30D和EudragitRS30D的丙烯酸树脂清漆的混合物。EudragitRL30D和EudragitRS30D是丙烯酸和甲基丙烯酸酯与少量季铵基团的共聚物,铵基团与剩余中性的(甲基)丙烯酸酯的摩尔比在EudragitRL30D中为1∶20,在EudragitRS30D中为1∶40。平均分子量约为150000。牌号RL(高渗透率)和RS(低渗透率)是指这些试剂的渗透特性。EudragitRL/RS混合物在水和消化液中不溶解。但是,由其形成的包衣是可溶胀的,并可在水溶液和消化液中渗透。
本发明的EudragitRL/RS分散液可以任何所需的比率一起混合,以最终获得具有所需溶出曲线的持续释放制剂。所需的持续释放制剂例如可由来自100%EudragitRL、50%EudragitRL和50%EudragitRS、以及10%EudragitRL:90%EudragitRS的阻滞型包衣制成。当然,本领域中的技术人员会了解,其他丙烯酸聚合物也可使用,例如EudragitL。在包衣包括疏水性持续释放物质的水性分散液的本发明实施方式中,疏水性物质的水性分散液中还包含有效量的增塑剂会进一步改进持续释放包衣的物理性质。例如,由于乙基纤维素具有较高的玻璃转化温度且在正常包覆条件下不形成软膜,优选在将乙基纤维素用作包衣材料前在含有乙基纤维素包衣的持续释放包衣中加入增塑剂。通常,涂布溶液中的增塑剂含量根据成膜剂的浓度,大多为成膜剂的约1~50%(按重量计)。但是,增塑剂的浓度只能在用颗粒涂布溶液和应用方法仔细实验之后才能正确确定。
乙基纤维素的合适增塑剂的例子包括不溶于水的增塑剂,如癸二酸二丁酯、邻苯二甲酸二乙酯、柠檬酸三乙酯、柠檬酸三丁酯、和甘油三乙酸酯,虽然可使用其他不溶于水的增塑剂(如乙酰化单酸甘油酯、邻苯二甲酸酯、蓖麻油等)。柠檬酸三乙酯对于本发明乙基纤维素的水性分散液来说是特别优选的增塑剂。
本发明丙烯酸聚合物的合适增塑剂的例子包括、但不限于柠檬酸酯,如柠檬酸三乙酯NF XVI、柠檬酸三丁酯、邻苯二甲酸二丁酯、和可能的1,2-丙二醇。已证明适合于增强由丙烯酸膜(如EudragitRL/RS清漆溶液)形成的膜的弹性的其他增塑剂包括聚乙二醇、丙二醇、邻苯二甲酸二乙酯、蓖麻油、和甘油三乙酸酯。柠檬酸三乙酯对于本发明乙基纤维素的水性溶液来说是特别优选的增塑剂。
在某些实施方式中,含有羟考酮或羟考酮盐的未包覆/包覆的持续释放球形体、颗粒或基体多颗粒固化达到一个终点,此时持续释放球形体、颗粒或基体多颗粒提供了约一个稳定的溶出度。固化终点可通过比较剂型刚固化后的溶出曲线和剂型暴露于促进储存条件(如,40℃和75%相对湿度至少1个月)后的溶出曲线来确定。固化制剂详细记载于美国专利5,273,760;5,286,493;5,500,227;5,580,578;5,639,476;5,681,585;和6,024,982。可用于本发明的其他持续释放制剂和包衣的例子包括美国专利5,324,351;5,356,467;和5,472,712。
除了上述成分、球形体、颗粒或基体多颗粒还可含有适量的其他物质,如制药领域中常用的稀释剂、润滑剂、粘合剂、成粒助剂、着色剂、食用香料和助流剂,如需要,其量达到制剂的约50%(按重量计)。这些附加物质的量足以提供所需制剂的所需效果。
可用于配制口服剂型的药学上可接受的载体和赋形剂的具体例子记载于《药物赋形剂手册》(Handbook of Pharmaceutical Excipients),美国制药协会(1986),本文引入作为参考。
还已经发现在持续释放包衣中添加少量滑石会减小水性分散液在加工时粘结的倾向,并起抛光剂的作用。
持续释放渗透性剂型
本发明的持续释放剂型也可制成渗透性剂型。渗透性剂型优选包括其中包含药层和传递层或推动层的双层芯,其中双层芯由半渗透性壁包围,并可任选地具有至少一条通道设于其中。
用于本发明的术语“通道”包括孔、小孔、镗孔、细孔、多孔元件,通过它们羟考酮或羟考酮盐可抽吸、扩散或转移经过纤维、毛细管、多孔覆盖层、多孔插入物、微孔构件或多孔组合物。通道还可包括会在使用时的液体环境中侵蚀或从壁上浸出的化合物,以产生至少一条通道。形成通道的代表性化合物包括在壁中可侵蚀的聚乙醇酸、或聚乳酸;凝胶状单丝;水可除去的聚乙烯醇;可浸出化合物,如液体可除去的会形成孔的多糖、酸、盐或氧化物。通道可通过从壁(如山梨醇、蔗糖、乳糖、麦芽糖、或果糖)上浸出化合物来形成,以形成持续释放的平面孔状通道。通道可具有任何形状,如圆形、三角形、正方形和椭圆形,以有助于羟考酮或羟考酮盐从剂型中持续释放。制造剂型时一条或多条通道可以在剂型的一个或多个表面上成互相隔开的关系。通道和形成通道的装置披露于美国专利3,845,770;3,916,899;4,063,064和4,088,864。美国专利4,200,098和4,285,987披露了包括持续释放的平面尺寸、形状和经调整作为释放孔在内的通道,它通过水性浸出形成,以提供约具有持续释放速率的释放孔。
在某些实施方式中,双层芯包括具有羟考酮或羟考酮盐的药物层和置换层或推动层。在某些实施方式中,药物层可包含至少一种聚合物水凝胶。聚合物水凝胶的平均分子量可在约500~6,000,000之间。聚合物水凝胶的例子包括但不限于分子式为(C6H12O5)n·H2O的麦芽糖糊精聚合物,其中n为3~7,500,麦芽糖糊精聚合物的数均分子量为500~1,250,000;以聚环氧乙烷和聚环氧丙烷为代表的重均分子量为50,000~750,000的聚环氧烷,更具体是以重均分子量为100,000、200,000、300,000或400,000中之一的聚环氧乙烷优选;重均分子量为10,000~175,000的碱性羧烷基纤维素,其中碱是钠或钾;烷基是甲基、乙基、丙基或丁基;以及数均分子量为10,000~500,000的乙烯-丙烯酸(包括甲基丙烯酸和乙基丙烯酸)的共聚物。
在本发明的某些实施方式中,传递层或推动层包括渗透性聚合物。渗透性聚合物的例子包括但不限于选自聚环氧烷和羧烷基纤维素。聚环氧烷具有1,000,000~10,000,000的重均分子量。聚环氧烷可选自聚甲醚(polymethylene oxide)、聚环氧乙烷、聚环氧丙烷、平均分子量为1,000,000的聚环氧乙烷、平均分子量为5,000,000的聚环氧乙烷、平均分子量为7,000,000的聚环氧乙烷、平均分子量为1,000,000的交联聚环氧甲烷,以及平均分子量为1,200,000的聚环氧丙烷。典型的渗透性聚合物羧烷基纤维素选自碱性羧烷基纤维素、羧甲基纤维素钠、羧甲基纤维素钾、羧乙基纤维素钠、羧甲基纤维素锂、羧乙基纤维素钠、羧烷基羟基烷基纤维素、羧甲基羟基乙基纤维素、羧乙基羟基乙基纤维素和羧甲基羟基丙基纤维素。用于置换层的渗透性聚合物表现出穿过半渗透性壁的渗透压梯度。渗透性聚合物将液体吸收入剂型从而溶胀和膨胀为渗透性水凝胶(也称为渗透胶),借此将羟考酮或其药学上可接受的盐从渗透性剂型中推出。
推动层也可包括一种或多种渗透有效性化合物,也称为渗透剂和渗透有效性溶质。例如,它们将肠胃道中的环境液体吸收入剂型中,有助于置换层的输送动力学。渗透有效性化合物的例子包括选自渗透性盐和渗透性碳水化合物的物质。渗透剂的具体例子包括但不限于氯化钠、氯化钾、硫酸镁、磷酸锂、氯化锂、磷酸钠、硫酸钾、硫酸钠、磷酸钾、葡萄糖、果糖和麦芽糖。
推动层可任选地包括数均分子量为9,000~450,000的羟丙基烷基纤维素。羟丙基烷基纤维素以选自羟丙基甲基纤维素、羟丙基乙基纤维素、羟丙基异丙基纤维素、羟丙基丁基纤维素、和羟丙基戊基纤维素的物质为代表。
推动层可任选地包括无毒性的着色剂或染料。着色剂或染料的例子包括但不限于美国食品和药品管理局规定的着色剂(FD&C),如FD&C 1号蓝色染料,FD&C 4号红色染料、氧化铁红、氧化铁黄、二氧化钛、炭黑和靛蓝。
推动层还可任选地包含抗氧化剂,以抑制成分氧化。抗氧化剂的一些例子包括但不限于选自抗坏血酸、棕榈酸抗坏血酸酯、丁基化羟基苯甲醚、2种或3种叔丁基-4-羟基苯甲醚的混合物、丁基化羟基甲苯、异抗坏血酸钠、二氢片榍酸(dihydroguareticacid)、山梨酸钾、二硫酸钠、焦亚硫酸钠、山梨酸、抗坏血酸钾、维生素E、4-氯-2,6-二叔丁基苯酚、α-生育酚、和棓酸丙酯。
在某些替代实施方式中,剂型包括其中含有羟考酮或其药学上可接受的盐、药学上可接受的聚合物(如聚环氧乙烷)、任选的崩解剂(如聚乙烯基吡咯烷酮)、任选的吸收增强剂(如脂肪酸、表面活性剂、螯合剂、胆汁盐等)的均匀片芯。均匀片芯被具有通道(如上所述)的半渗透性壁包围,以释放羟考酮或其药学上可接受的盐。
在某些实施方式中,半渗透性壁选自纤维素酯聚合物、纤维素醚聚合物和纤维素酯-醚聚合物。代表性的壁聚合物选自酰化纤维素、二酰化纤维素、三酰化纤维素、乙酸纤维素、二乙酸纤维素、三乙酸纤维素、链烯化单、二和三纤维素、以及炔烃化单、二和三纤维素。用于本发明的聚纤维素的数均分子量为20000~7500000。
用于本发明的其他半渗透性聚合物包括乙醛乙酸二甲基纤维素、乙酸氨基甲酸乙酯纤维素、乙酸氨基甲酸甲酯纤维素、二乙酸纤维素、氨基甲酸丙酯、乙酸二乙氨基乙酸纤维素;半渗透性聚酰胺;半渗透性聚氨酯;半渗透性磺化聚苯乙烯;由聚阴离子和聚阳离子的共沉淀形成的半渗透性交联聚合物披露于美国专利3,173,876;3,276,586;3,541,005;3,541,006和3,546,876;由Loeb和Sourirajan披露于美国专利3,133,132中的半渗透性聚合物;半渗透性交联聚苯乙烯;半渗透性交联聚(苯乙烯磺酸钠);半渗透性交联聚(乙烯基苄基三甲基氯化铵);以及具有2.5×10-8~2.5×10-2(厘米2/小时·大气压)流体渗透性的半渗透性聚合物,该渗透压是在每大气压的半渗透性壁压力差(静水压或渗透压)下表示。用于本发明的其他聚合物是本领域中已知的,披露于美国专利3,845,770;3,916,899和4,160,020;和《常用聚合物手册》(Handbook of Common Polymers),Scott,J.R.和W.J.Roff,1971,CRC出版社,克利夫兰,俄亥俄州。
在某些实施方式中,半渗透性壁优选是无毒、惰性的,并且在药物的配制期间保持其物理和化学完整性。在某些实施方式中,剂型包含粘合剂。粘合剂的例子包括但不限于治疗上可接受的粘均分子量为5000~350000的乙烯基聚合物,以选自下列的物质为代表:聚正乙烯酰胺、聚正乙烯基乙酰胺、聚乙烯基吡咯烷酮,也称为聚正乙烯基吡咯烷酮、聚正乙烯基己内酯、聚正乙烯基-5-甲基-2-吡咯烷酮、以及聚正乙烯基吡咯烷酮与以下物质的共聚物:乙酸乙烯酯、乙烯醇、氯乙烯、氟乙烯、丁酸乙烯酯、月桂酸乙烯酯和硬脂酸乙烯酯。其他粘合剂包括例如阿拉伯胶、淀粉、明胶、和平均分子量为9,200~250,000的羟丙基烷基纤维素。
在某些实施方式中,剂型包含润滑剂,它可在剂型制造时使用,以防止粘结到压模壁或冲孔表面。润滑剂的例子包括但不限于硬脂酸镁、硬脂酸钠、硬脂酸、硬脂酸钙、油酸镁、油酸、油酸钾、辛酸、十八烷酰富马酸钠、和棕榈酸镁。
在某些优选实施方式中,本发明包括其中含有1~640毫克羟考酮或其药学上可接受的盐、25~500毫克平均分子量为150,000~500,000的聚烯化氧、1~50毫克平均分子量为40,000的聚乙烯基吡咯烷酮、和0~约7.5毫克润滑剂的治疗组合物。
在某些实施方式中,本发明还提供了约1~640毫克羟考酮或其药学上可接受的盐的服用方法,它是通过使患者口服包含半渗透性壁的剂型而服用1~640毫克羟考酮或其药学上可接受的盐来进行的,所述的剂型包括对水性生物液可渗透、但对于羟考酮或药学上可接受的盐的通道不渗透的半渗透性壁,该半渗透性壁包围含有羟考酮药物组合物和推动组合物的内部空间,其中所述的羟考酮组合物包含1~640毫克羟考酮或其药学上可接受的盐、25~500毫克平均分子量为150,000~500,000的聚环氧烷、1~50毫克平均分子量为40,000的聚乙烯基吡咯烷酮、和0~7.5毫克的润滑剂,所述的推动组合物包含15~250毫克平均分子量为3,000,000~7,500,000的聚烯化氧、0~75毫克的渗透剂、1~50毫克的羟烷基纤维素、0~10毫克的氧化铁、0~10毫克的润滑剂和0~10毫克的抗氧化剂;半渗透性壁中的通道用于从剂型中输送羟考酮或其药学上可接受的盐。通过将液体经半渗透性壁吸收入剂型中,使羟考酮或羟考酮盐组合物变得可分配,并使推动组合物膨胀和将羟考酮或羟考酮盐组合物推出通道,从而通过该剂型的结合运作,使羟考酮或羟考酮盐在持续时间内以受控的速率按治疗有效剂量输送。
本发明的剂型可任选地用一种或多种适合于调节释放和保护制剂的包衣来包覆。在一个实施方式中,包衣用来提供例如暴露于肠胃(GI)液时的pH依赖性或非pH依赖性的释放。当需要非pH依赖性的包衣时,包衣设计成达到与环境液体(如GI道)中的pH变化无关的最佳释放。其他优选实施方式包括pH依赖性包衣,它在GI道的所需区域(如胃和小肠)释放羟考酮或其药学上可接受的盐,以提供能向患者提供至少约12小时和优选约24小时或以上镇痛的吸收曲线。制剂组合物还可在GI道的一个所需区域(如胃)释放部分剂量,并在GI管的另一个区域(如小肠)释放其余剂量。
使用pH依赖性包衣的本发明的制剂还可提供重复作用效果,由此未受保护的药物被包覆在肠溶衣上并在胃中释放,而被肠溶衣保护的其余药物进一步向肠胃道下面释放。具有pH依赖性并可用于本发明的包衣包括以下持续释放物质:虫胶、乙酸纤维素邻苯二甲酸酯(CAP)、聚乙酸邻苯二甲酸乙烯酯(PVAP)、羟丙基甲基纤维素邻苯二甲酸酯、甲基丙烯酸酯共聚物、玉米醇溶蛋白等。
在本发明的某些实施方式中,制剂中包括有效量的立即释放型羟考酮或其药学上可接受的盐。立即释放型羟考酮或其药学上可接受的盐的量有效减少羟考酮在血液(如血浆)中达到最大浓度的时间,从而缩短了Tmax。由于单位剂量中包含这种有效量的立即释放型羟考酮或羟考酮,可减少患者处于较强疼痛的时间。在这种实施方式中,有效量的立即释放型羟考酮或羟考酮盐可包覆在本发明片剂上。例如,由于持续释放包衣而延长从制剂释放羟考酮或羟考酮盐时,可在持续释放包衣的顶部包覆立即释放层。另一方面,立即释放层可包覆在片剂的表面上,其中羟考酮或羟考酮盐掺入在持续释放基体中。本领域的技术人员可认识到将立即释放型羟考酮或羟考酮盐部分掺入制剂的其他替代方式。这种替代方式被认为包含在所附权利要求书中。
在另一实施方式中,本发明的持续释放型剂型除羟考酮或羟考酮盐以外还包括可能或不可能与羟考酮或羟考酮盐产生协同作用的非阿片样药物。这种非阿片样药物优选提供额外的镇痛,并包括例如阿司匹林、扑热息痛;非类固醇消炎药(“NSAIDS”)如布洛芬、酮基布洛芬等;N-甲基-D-天冬氨酸盐(NMDA)受体拮抗剂,例如吗啡喃如右美沙芬或右啡烷、或氯胺酮;环氧合酶-II抑制剂(“COX-II抑制剂”);和/或甘氨酸受体拮抗剂。
在本发明的某些实施方式中,本发明可依靠包含额外的非阿片样镇痛药如NSAID或COX-2抑制剂来使用低剂量的羟考酮或羟考酮盐。通过使用低剂量的一种或两种药物,可减少人中与有效镇痛有关的副作用。
合适的非类固醇消炎剂包括布洛芬、双氯芬酸、萘普生、苯噁洛芬、氟比洛芬、非诺洛芬、氟布芬、酮洛芬、吲哚洛芬、吡罗洛芬、卡洛芬、奥沙普嗪、普莫洛芬(pramoprofen)、莫罗洛芬、三恶洛芬、噻丙芬、氨基洛芬、噻洛芬酸、氟洛芬、布氯酸、吲哚美辛、舒林酸、托美丁、佐美酸、硫平酸、齐多美辛(zidometacin)、阿西美辛、芬替酸、环氯茚酸、oxpinac、甲芬那酸、甲氯芬那酸、氟芬那酸、尼氟酸、托芬那酸、二氟尼柳、氟苯柳、吡罗昔康、舒多昔康、伊索昔康、及其药学上可接受的盐、以及它们的混合物等。这些药物的有用剂量对于本领域的技术人员是熟知的。
N-甲基-D-天冬氨酸盐(NMDA)受体拮抗剂在本领域中是熟知的,它包括:例如吗啡喃,如右美沙芬或右啡烷、氯胺酮,或其药学上可接受的盐。为了本发明目的,术语“NMDA拮抗剂”也被认为包括至少部分抑制NMDA受体激活的主要细胞内效果的药物,例如,神经节苷脂如GM1或GT1b,吩噻嗪如三氟拉嗪,或萘磺酰胺如N-(6-氨基thexyl)-5-氯-1-萘磺酰胺。美国专利5,321,012和5,556,838(都为Mayer等)中声称这些药物能抑制对成瘾药物的耐药性和/或依赖性增加,所述的成瘾药物例如麻醉性镇痛药,如吗啡、可待因等,并且美国专利5,502,058(Mayer等)中声称它们能治疗慢性疼痛。如Mayer等的这些专利所述,NMDA拮抗剂可单独包含其中、或与局部麻醉剂如利多卡因组合。
通过使用甘氨酸受体拮抗剂治疗慢性疼痛和这种药物的鉴定记载于美国专利5,514,680中(Weber等)。
COX-2抑制剂已在本领域中报导,已知许多化学结构能产生环氧合酶-2的抑制作用。COX-2抑制剂例如记载于美国专利5,616,601;5,604,260;5,593,994;5,550,142;5,536,752;5,521,213;5,475,995;5,639,780;5,604,253;5,552,422;5,510,368;5,436,265;5,409,944;和5,130,311中。某些优选的COX-2抑制剂包括赛来考昔(SC-58635)、DUP-697、氟舒利(CGP-28238)、美洛昔康、6-甲氧基-2-萘乙酸(6-MNA)、MK-966(也称为Vioxx)、萘丁美酮(6-NMA的药物前体)、尼美舒利、NS-398、SC-5766、SC-58215、T-614;或它们的组合物。COX-2抑制剂在与羟考酮或羟考酮盐组合时,其剂量为每天约0.005~140毫克/公斤体重在治疗上是有效的。或者,每位患者每天约0.25毫克~7克的COX-2抑制剂与羟考酮或羟考酮盐组合服用。
在还有一个实施方式中,可包括除镇痛以外提供所需效果的非阿片样药物,这些效果如止咳、祛痰、减轻充血、抗组胺药物、局部麻醉等。
持续释放型剂型或立即释放剂型中还可包含另外的(非阿片样)治疗有效制剂。另外的药物可与羟考酮或羟考酮盐一起掺入持续释放基体中,可以粉末、颗粒等形成掺入剂型中,或者可以作为分开的持续释放层或立即释放层掺入剂型中。
本发明的持续释放型口服固体剂型可以节制类阿片。本发明的持续释放型口服固体剂型与传统的立即释放型产品相比,基本上能以较低的一日剂量服用,而镇痛效力没有显著差异。与传统立即释放型产品相比,以类似的的一日剂量服用时,使用本发明的持续释放型口服固体剂型能得到更大的效力。
通过以下实施例更完整地描述了本发明。但应了解,以下描述只是举例,而不应以任何方式将其视为对上述本发明的限制。
实施例1
用以下表1所示配方制备羟考酮持续释放基体:
表1
成份 | 数量/单位(mg) | 数量/批量(g) |
盐酸羟考酮 | 30.0 | 150.0 |
喷雾干燥乳糖 | 50.0 | 250.0 |
聚乙烯吡咯烷酮 | 8.0 | 40.0 |
Eudragit RS30D(固体) | 50.0 | 250.0 |
三醋精 | 6.0 | 30.0 |
十八烷醇 | 70.0 | 350.0 |
滑石 | 4.0 | 20.0 |
硬酯酸镁 | 2.0 | 10.0 |
欧巴代红YSI-15597-A | 10.0 | 50.0 |
纯水 | * | * |
合计 | 230.0 | 1150.0 |
*用于制备过程以及仅作为残留水份保持在产品中。
按照如下步骤制备:
1、成粒:将Eudragit/三醋精分散体用流化床造粒机喷雾在盐酸羟考酮、喷雾干燥乳糖和聚乙烯吡咯烷酮上。
2、研磨:排出颗粒,并通过设有约1mm开口(18目筛孔)的研磨机。
3、封蜡:在约50℃时熔融十八烷醇,用高剪切混合器将其加到研磨了的颗粒上,使其在托盘或流化床上被冷却到室温。
4、研磨:将冷却的颗粒通过具有约18目筛孔的研磨机。
5、润滑:用混合器,用滑石和硬脂酸镁润滑所述颗粒。
7、涂膜:用旋转盘将药片包上水性薄膜包衣。
实施例2
用以下表2所示配方制备羟考酮持续释放基体:
表2
成份 | 数量/单位(mg) |
药物层: | |
盐酸羟考酮 | 35.20 |
聚环氧乙烷 | 130.24 |
聚乙烯吡咯烷酯 | 8.8 |
硬脂酸镁 | 1.76 |
置换层: | |
聚环氧乙烷 | 85.96 |
氯化钠 | 40.50 |
羟丙基甲基纤维素 | 6.75 |
氧化铁 | 1.35 |
硬脂酸镁 | 0.34 |
BHT | 0.10 |
半渗透性壁: | |
乙酸纤维素 | 38.6 |
具有上述配方的剂型如下步骤制备:
首先,将175g盐酸羟考酮、647.5g平均分子量为200000的聚环氧乙烷、以及43.75g平均分子量40000的聚乙烯基吡咯烷酮加到混合器中,并混合10分钟。然后,将331g变性无水酒精加到混合的物质中,并连续搅拌10分钟。接着,使湿颗粒通过20目筛孔,并使其在室温干燥20小时,然后再通过16目筛孔。下一步,将所述颗粒输送到混合器中,用8.75g硬脂酸镁混合和润滑。
然后,用于将盐酸羟考酮组合物从剂型推出去的置换组合物或推动组合物,其制备过程如下:首先,将3910g平均分子量为11200的羟丙基甲基纤维素溶解于45339g水中,然后,将101g丁基化羟基甲苯溶解于650g变性无水酒精中,接着,将2.5kg羟丙基甲基纤维素水溶液在连续搅拌下加到丁基化羟基甲苯乙醇溶液中。其次,在连续搅拌下将剩余的羟丙基甲基纤维素水溶液加到丁基化羟基甲苯乙醇溶液中,从而完成了粘合剂溶液的制备。
然后,将36000g氯化钠用装有12目筛孔的Quadro Comil研磨机筛分,使1200g氧化铁通过40目筛孔,将过筛的物质:76,400g平均分子量为7,500,000的药学上可接受的聚环氧乙烷和2,500g平均分子量为11200的羟丙基甲基纤维素加到Glatt流化床造粒机的压辊上。所述压辊连到造粒机上,成粒过程以进行有效成粒开始,接着,所述干粉末被空气悬浮,并混合10分钟。下一步,所述粘合剂溶液从3个喷嘴喷在干粉末上。在成粒过程中所述成粒按如下参数进行监控:总的溶液喷雾速率800g/min;进口温度43℃,以及空气流速4300m3/hr。在溶液喷雾结束时,对45033g所得的经涂布和成粒的颗粒进行35分钟的干燥过程。
接着,将含有盐酸羟考酮的药物组合物和推动组合物用Kilian压片机压制成双层片剂。首先,将176mg的盐酸羟考酮组合物加到模腔中并预压,然后,加入135mg推动组合物,并在3公吨压头下将所述层压成11/32英寸(0.873cm)直径的接触层结构。
用半渗透性壁涂布所述双层结构,所述壁形成组合物包括具有39.8%乙酰基含量的100%乙酸纤维素。将所述壁形成组合物溶解于丙酮∶水(95∶5的重量比)共溶剂中以制得4%固体溶液。用24英寸(60cm)的VectorHi-涂布机将壁形成组合物喷雾在所述双层的上面和周围,一个20mil(0.508mm)出口通道穿过半渗透性壁与药物的羟考酮层连同剂型的外部相连。在45℃和湿度45%时通过72小时的干燥除去残余的溶剂。然后,将渗透性制剂系统在45℃干燥4小时,以除去过量的水。通过上述制备过程制得的剂型包括35.20mg盐酸羟考酮、130.24mg平均分子量为200000的聚环氧乙烷、8.80mg平均分子量为40000的聚乙烯基吡咯烷酮、以及1.76mg硬脂酸镁。所述推动组合物包括85.96mg平均分子量为7500000的聚环氧乙烷、40.50mg氯化钠、6.75mg羟丙基甲基纤维素、1.35mg氧化铁红、0.34mg硬脂酸镁、以及0.10mg丁基化羟基甲苯。所述半渗透性壁包括具有39.8%乙酰基含量的38.6mg醋酸纤维素,所述剂型包括一个20mil(0.508mm)的通道。
实施例3
用以下表3所示配方制备羟考酮持续释放基体:
表3
成份 | 百分数 |
药物层: | 药物层的百分数 |
盐酸羟考酮 | 28.8 |
聚环氧乙烷 | 64.2 |
聚乙烯基吡咯烷酮 | 6 |
硬脂酸镁 | 1 |
置换层: | 置换层的百分数 |
聚环氧乙烷 | 63.675 |
氯化钠 | 30 |
羟丙基甲纤维素 | 5 |
氧化铁 | 1 |
硬脂酸镁 | 0.25 |
BHT | 0.075 |
半透渗壁: | 半渗透性壁的百分数 |
乙酸纤维素 | 95 |
聚乙二醇 | 5 |
具有上述配方的剂型按如下步骤制备:
首先,将1728g盐酸羟考酮、3852g平均分子量为200000的聚环氧乙烷、以及360g平均分子量为40000的乙烯基吡咯烷酮加到行星式混合辊筒上。接着,使干物质混合10分钟。然后,将1616g变性无水酒精缓慢地加到上述混合的物质中,并连续搅拌10分钟。下一步,使配制的湿颗粒通过20目筛孔,再使其在室温干燥20.5小时,并通过16目筛孔。所述颗粒输送到行星式混合器中,用硬脂酸镁混合和润滑。
推动组合物的制备如下:首先,通过将3910g平均分子量为11200的羟丙基甲基纤维素溶解在45339g水中。然后,将101g丁基化羟基甲苯溶解于650g变性无水酒精中。接着,将约2.5kg羟丙基甲基纤维素/水溶液在连续搅拌下加到丁基化羟基甲苯/乙醇溶液中。其次,再在连续搅拌下将剩余的羟丙基甲基纤维素/水溶液加到丁基化羟基甲苯/乙醇溶液中,从而完成了粘合剂溶液的制备。
接着,使1200g氧化铁通过40目筛孔。然后将全部过筛物质,76400g平均分子量为7000000的药学上可接受的聚环氧乙烷、2520g平均分子量为11200的羟丙基甲基纤维素加到Glatt流化床造粒机的辊筒上,所述辊筒连到造粒机上,成粒过程以进行有效成粒开始接着,所述干粉末被空气悬浮,并混合10分钟。下一步,所述粘合剂溶液从3个喷嘴喷在粉末上。
在喷雾所述粘合剂溶液的同时,滤袋每隔1.5分钟摇动10秒钟,从而没有任何可能的粉末沉积物粘合。在溶液喷雾结束时,对45033g所得的经涂布和成粒的颗粒进行35分钟的干燥过程。使机器停掉,并将经涂布的颗粒从造粒机中取出。经涂布的颗粒用具有8目筛孔的Quadro Comil筛分。所述颗粒被输送到Tote转筒中,用281.7硬脂酸镁混合和润滑。请回顾第二句,并弄清楚。
接着,将盐酸羟考酮药物组合物和推动组合物用Kilian压片机压制成双层片剂。首先,将434mg的盐酸羟考酮组合物加到模腔中并预压,然后,加入260mg推动组合物,并在约3公吨压头下将所述层压成0.700英寸(1.78cm)×0.375英寸(0.95cm)椭圆形接触层结构。
用半渗透性壁涂布所述双层结构,所述壁形成组合物包括具有39.8%乙酰基含量的95%乙酸纤维素和5%分子量为3350的聚乙二醇,将所述壁形成组合物溶解于丙酮∶水(95∶5的重量比)共溶剂中以制得4%固体溶液。用24英寸(60cm)的Vector Hi涂布机将壁形成组合物喷雾在所述双层的上面和周围。
其次,二个30mil(0.762mm)出口通道穿过半渗透性壁与药物层连同制剂系统的外部相连。在50℃和湿度45%时通过48小时的干燥除去残余的溶剂。然后,将渗透性剂型在50℃干燥4小时,以除去过量的水。通过上述制备过程制得的剂型包括28.8%盐酸羟考酮、64.2%平均分子量为200000的聚环氧乙烷、6%平均分子量为40000的聚乙烯基吡咯烷酮、以及1%硬脂酸镁。所述推动组合物包括63.675%平均分子量为7000000的聚环氧乙烷、30%氯化钠、5%平均分子量为11200的羟丙基甲基纤维素、1%氧化铁、0.075%丁基化羟基甲苯、以及0.25%硬脂酸镁。所述的半渗透性壁包括具有39.8%乙酰基含量的95wt%乙酸纤维素,以及5wt%平均分子量为3350的聚乙二醇。所述剂型包括二个30mil(0.762mm)的通道,其盐酸羟考酮的平均释放速率约为5mg/hr。
在另一实施方式中,所述剂型可包括65-100wt%的纤维素聚合物,所述纤维素聚合物包括选自纤维素酯、纤维素二酯、纤维素三酯、纤维素醚、纤维素酯一醚、酰化纤维素、二酰化纤维素酯、三乙酸纤维素、乙酸丁酸纤维素等。所述壁也包括0-40wt%的纤维素醚和0-20wt%的聚乙二醇,所述纤维素醚选自羟丙基纤维素和羟丙基甲基纤维素。包括所述壁的所有组分的总量相当于100wt%。用于制备所述剂型的壁的半渗透性聚合物在美国专利3845770、3916899、4008719、4036228和4111201中揭示。
在另一个优选方法中所述壁包括选择性渗透的纤维素醚,乙基纤维素。乙基纤维素包括具有约1.4-3取代度的乙氧基,这相当于40-50%的乙氧基含量,该乙基纤维素的粘度范围约为7-100厘泊或更高。更具体地,所述壁包括45-80wt%乙基纤维素、5-30wt%羟丙基纤维素、以及5-30wt%聚乙二醇,其包括所述壁的所有组分的总重量百分比相当于100wt%。在另一个实施方式中,所述壁包括45-80wt%乙基纤维素、5-30wt%羟丙基纤维素、以及2-20wt%聚乙烯基吡咯烷酮,其包括所述壁的所有组分的总量相当于100wt%。
实施例4
用以下表4所示配方制备10mg羟考酮持续释放胶囊:
表4
成份 | 数量/单位(mg) |
盐酸羟考酮 | 10.0 |
硬脂酸 | 8.25 |
十八烷醇 | 24.75 |
Eudragit RSPO | 77 |
合计 | 120 |
上述配方按如下步骤制备:
1.将十八烷醇薄片通过冲击研磨机。
2.在合适的掺合机/混合器中将盐酸羟考酮、硬脂酸、十八烷醇和Eudragct RSPO掺合。
3.在高温时将掺合物连续给料进入双螺杆挤出机,并收集输送机上的所得的股状物。
4.使所述的股状物在输送机上冷却。
5.用切粒机将所述股状体切断成1mm粒料。
6.将所述粒料筛分为细粒料和并将过大的粒料筛分到粒度约0.8-1.4mm可接受范围。
7.以400mg/胶囊的填充重量装填入胶囊内(装填入2号尺寸的胶囊)。
然后,按如下方法测试粒料的溶出度:
用美国药典(USP)的仪器1(蓝式)在100rpm下测试粒料在900ml模拟胃液(SGF)中和在900ml模拟肠液(SIF)中的纤维光学UV溶出度(在2.82nm处监测)。
溶出参数列于以下表4A中:
表4A
时间(小时) | 在模拟胃液(SGF)中的溶出度(%) | 在模拟肠液(SIF)中的溶出度(%) |
1 | 15 | 10 |
2 | 22 | 15 |
3 | 32 | 22 |
8 | 44 | 29 |
12 | 53 | 34 |
18 | 62 | 40 |
24 | 66 | 44 |
实施例5
用以下表5所示配方制备160mg羟考酮持续释放胶囊:
表5
成份 | 数量/单位(mg) |
盐酸羟考酮 | 160 |
硬脂酸 | 80 |
十八烷醇 | 20 |
Eudragit RSPO | 140 |
合计 | 400 |
上述配方按如下步骤制备:
1、将十八烷醇薄片通过冲击研磨机。
2、在合适的掺合机/混合器中将盐酸羟考酮、硬脂酸、十八烷醇和Eudragit RSPO掺合。
3、在高温时将掺合物连续给料进入双螺杆挤出机,并收集输送机上的所得的股状物。
4、使所述的股状物在输送机上冷却。
5、用切粒机将所述股状体切断成1mm粒料。
6、将所述粒料筛分为细粒料并将过大的粒料筛分到粒度约0.8-1.4mm可接受范围。
7、以400mg/胶囊的填充重量装填入胶囊内(装填入00号尺寸的胶囊)。
溶出度方法:
然后,按如下方法测试粒料的溶出度:
用美国药典(USP)的仪器1(蓝式)在100rpm下测试粒料在900ml模拟胃液(SGF)中和在900ml模拟肠液(SIF)中的纤维光学UV溶出度(在2.82nm处监测)。
上述配方的溶出参数列于以下表5A中:
请保证表5A没有误差信息。
表5A
时间(小时) | 在模拟胃液(SGF)中的溶出度(%) | 在模拟肠液(SIF)中的溶度(%) |
1 | 32 | 20 |
2 | 47 | 28 |
4 | 66 | 42 |
8 | 86 | 60 |
12 | 93 | 70 |
18 | 95 | 77 |
24 | 95 | 80 |
本发明的许多其它变化对本领域技术人员来说是显而易见的,并意味着所述变化在本文权项的范围内。
Claims (18)
1.一种一日服用一次的持续释放口服剂型,其包括:
其中1-640毫克羟考酮或其药学上可接受的盐和持续释放物质组合成药学上可接受的基体,所述的基体包括多个基体多颗粒,每个所述的基体多颗粒的直径为0.1毫米到5毫米,长度为0.1毫米到12毫米;
所述的持续释放物质包含(i)C12-C36脂肪醇,(ii)C8-C50脂肪酸和(iii)甲基丙烯酸氨基烷酯共聚物;
所述剂型以稳态供患者口服后提供了至少24小时的持续释放效果。
2.如权利要求1所述的剂型,其特征在于,所述基体是均质的。
3.如权利要求1所述的剂型,其特征在于,所述基体包含在明胶胶囊内。
4.如权利要求1所述的剂型,其特征在于,所述基体被配制成片剂。
5.如权利要求1所述的剂型,其特征在于,所述羟考酮的药学上可接受的盐是盐酸羟考酮。
6.如权利要求1所述的剂型,其中所述的多个基体多颗粒被装在胶囊内。
7.持续释放剂型在制备治疗疼痛的药物中的应用,所述的持续释放剂型包括药学上可接受的基体,所述的基体包括多个基体多颗粒,每个所述的基体多颗粒的直径为0.1毫米到5毫米,长度为0.1毫米到12毫米,所述的基体多颗粒包含羟考酮或其药学上可接受的盐和持续释放物质,所述的持续释放物质包含(i)C12-C36脂肪醇,(ii)C8-C50脂肪酸和(iii)甲基丙烯酸氨基烷酯共聚物,该持续释放剂型以稳态服用后提供了至少24小时的持续释放效果和0.6-1.0的C24/Cmax羟考酮比平均值。
8.如权利要求7所述的应用,其特征在于,所述剂型以稳态服用后提供了2-17小时的羟考酮的Tmax平均值。
9.如权利要求7所述的应用,其特征在于,所述剂型以稳态服用后提供了8-16小时的羟考酮的Tmax平均值。
10.如权利要求7所述的应用,其特征在于,所述剂型以稳态服用后提供了0.7-0.99的C24/Cmax比平均值。
11.如权利要求7所述的应用,其特征在于,所述剂型以稳态服用后提供了0.8-0.95的C24/Cmax比平均值。
12.如权利要求7所述的应用,其特征在于,当用美国药典篮式方法在100rpm、900ml含水缓冲液、pH 1.6-7.2、37℃测定时,所述剂型提供了羟考酮或其药学上可接受的盐在体内的释放速率为:1小时时为0%-40%,4小时时为8%-70%,8小时时为20%-80%,12小时时为30%-95%,18小时时为35%-95%,以及24小时时为大于50%。
13.如权利要求1所述的口服剂型,其中所述的脂肪醇选自月桂醇、肉豆寇醇、十八烷醇、鲸蜡醇、或十六烷醇和十八烷醇的混合物。
14.如权利要求1所述的口服剂型,其中所述的脂肪醇是硬脂醇。
15.一种一日服用一次的持续释放口服剂型,其包括:
其中1-640毫克羟考酮或其药学上可接受的盐和包括聚环氧烷和羧烷基纤维素的渗透性聚合物组合成片剂,所述的片剂具有双层片芯,其包括:(i)药物层,包含羟考酮或其药学上可接受的盐;以及(ii)置换层,包含渗透性聚合物;所述的双层片芯被半渗透性壁所包围,所述的半渗透性壁中设有通道,用于释放所述羟考酮或其药学上可接受的盐;
所述剂型以稳态供患者口服后提供了至少24小时的持续释放效果。
16.如权利要求15所述的口服剂型,其特征在于,所述的聚环氧烷选自聚甲醚、聚环氧乙烷、聚环氧丙烷和聚环氧乙烷。
17.如权利要求15所述的口服剂型,其特征在于,所述的羧烷基纤维素选自碱性羧烷基纤维素、羧甲基纤维素钠、羧甲基纤维素钾、羧乙基纤维素钠、羧甲基纤维素锂、羧乙基纤维素钠、羧烷基羟基烷基纤维素、羧甲基羟基乙基纤维素、羧乙基羟基乙基纤维素和羧甲基羟基丙基纤维素。
18.一种一日服用一次的持续释放口服剂型,其包括:
其中含有约5-640毫克的羟考酮或其药学上可接受的盐和持续释放物质的多个药学上可接受的基体,所述的持续释放物质包含丙烯酸或甲基丙烯酸聚合物或共聚物和C12-C40脂肪酸的混合物;
所述剂型以稳态供患者服用后提供了至少约24小时的镇痛效果;以及
所述剂型以稳态供所述患者服用后提供了约0.6-1.0的C24-Cmax羟考酮比平均值。
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