CN1087262A - 控释羟可酮组合物 - Google Patents
控释羟可酮组合物 Download PDFInfo
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- CN1087262A CN1087262A CN93106378A CN93106378A CN1087262A CN 1087262 A CN1087262 A CN 1087262A CN 93106378 A CN93106378 A CN 93106378A CN 93106378 A CN93106378 A CN 93106378A CN 1087262 A CN1087262 A CN 1087262A
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- oxycodone
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Images
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Abstract
本发明涉及一种能基本上减少止痛所需每日剂
量范围的方法,它包括给病人口服固体控释制剂10
至40mg,在服用后2—4.5小时该制剂给出平均最大
血药浓度6至60mg/ml,每12小时重复服用以达
稳定状态后,10—14小时内达到羟可酮平均最小的
血药浓度为3至30ng/ml。口服160mg羟可酮或
其盐,服用后2—4.5小时达到平均最大血药浓度约
240ng/ml,每12小时重复服用以达稳定状态后,10
—14小时内达到羟可酮平均最小的血药浓度为
120ng/ml。
Description
本发明涉及一种控释制剂,以及通过使用该制剂而降低止痛的每日剂量范围的方法。
对用鸦片型(opioid)止痛药来止痛的每日剂量调查结果表明约90%病人需要约8倍量范围的每日剂量来止痛。这个特别宽广的剂量范围使测定过程特别费时和费物质,并使病人在难以忍受的长时间内不能止痛。
为了用鸦片型止痛药止痛,通常所观察和报道的是在给药剂量及所给的药物方面有值得考虑的个体差异,故而在无不可接受的副作用下鸦片型止痛药的止痛剂量在病人中也有值得考虑的差别,这就要求部分医生通过测定的耗时过程来确定个体病人适当的用药剂量,这需要在适当的剂量确定前于几天的一个时段或有时在更长的时间内仔细地评估及推断疗效和副作用以进行剂量的调整,The American Pain Society的第3版中,“Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain”一文指出医生应当“了解在不同病人的最佳止痛药剂量。研究表明,在所有年龄组中,即使在患有同样手术损伤的初用鸦片的病人中,用以镇痛的所需鸦片剂量有极大的差别…,这个极大的差别就强调了写下止痛药使用指令的必要性,该止痛药使用指令包括补充剂量、使用静脉内大丸药及输液以快速镇痛的规定,在转用另一个药前通过剂量测定来给出每个止痛药的适当用量。
因此,在相当窄的每日剂量范围内可接受地止痛的鸦片型止痛药治疗可以改进止痛的疗效及质量。
该技术领域已知诸如吗啡、氢吗啡酮或其盐的鸦片型止痛的控释组合物应当在适当的基质中制得。例如,美国专利4,990,341(Goldie)(已转让于本发明的申请人),阐述了氢吗啡酮组合物,当用USP Paddle方法在100转/分(rpm)于900ml水缓冲液(pH在1.6-7.2间)中,在37℃下测得该组合物的体外剂型溶解率。1小时后氢吗啡酮释放了12.5-42.5%(重量),2小时后释放了约25-55%(重量),4小时后释放了45-75%(重量),6小时后释放了55-85%(重量)。
本发明的一个目的提供了一种从实质上改进止痛疗效及质量的方法。
本发明的另一个目的是提供一种能从实质上改进止痛疗效及质量的鸦片型止痛药剂的配方。
本发明的另一个目的是提供从基本上减少在约90%病人中需要的止痛的每日剂量范围约有8倍差别的一种方法及制剂配方。
本发明的另一个目的是提供能基本上减少对所有病人所需的止痛的每日剂量的差别的一种方法及制剂配方。
本发明的再一个目的是提供能从基本上减少测定病人止痛用的鸦片型止痛药所需的时间和物质的方法。
本发明的再一个目的是提供一种控释的鸦片型制剂配方,该配方能从基本上减少个体所需的鸦片型药物的止痛剂量差异而无不可接受的副作用。
上述目的及其它目的可凭借本发明得以实现,本发明涉及固体控释口服剂型,该剂型包括在基质中的约10-40mg羟可酮或其盐,其中剂型的体外溶解率(用USP Paddle方法在100rpm下于900ml水质缓冲液(pH在1.6-7.2)中在37℃下测定)1小时后释放的羟可酮为12.5-42.5%(重量),2小时后释放了25-56%(重量)的羟可酮,4小时后释放了45-75%(重量)的羟可酮,6小时后释放了55-85%(重量)的羟可酮,体外释放率基本上是不依赖pH值的,这样在服用该剂型后2-4.5小时可得到体内羟可酮的血浆血药峰值。
USP Paddle方法是例如在美国药典第XXⅡ版(1990)中述及的Paddle方法。
在本申请中,“基本不依赖pH”表明在任何给定的时间内,在如pH1.6及其它pH值如7.2下羟可酮的释放量(用USP Paddle方法在100rpm,于900ml水缓冲液中在体外测量)的差别为10%(重量)或更少。在所有情况下,释放量是至少3个实验的平均值。
本发明进一步涉及能从基本上减少约90%病人用于止痛的每日剂量的范围的方法,该方法包括口服约10-40mg羟可酮或其盐的固体控释制剂,所述的剂型在服用后平均约2-4.5小时达到平均的最大羟可酮血药浓度约为6-60ng/ml,在重复q12h用药(即每12小时口服一次)以达稳定状态后,在平均约10-14小时时达到最小血药浓度约3-30ng/ml。
本发明进一步涉及能基本减少所有病人止痛所需的每日剂量的范围的方法,该方法包括口服剂量直至约160mg羟可酮或其盐的固体控释制剂,所述的剂型配方在服用后约2-4.5小时处达到平均最大的羟可酮血药浓度约240ng/ml,在重复q12h用法(即每12小时服用)以达稳定状态后于约10-14小时达到最小羟可酮血药浓度约120ng/ml。
本发明进一步涉及控释羟可酮制剂配方,它包括约10-40mg羟可酮或其盐,在服用平均约2-4.5小时该制剂提供了最大的羟可酮血药浓度约6-60ng/ml,在重复q12h用法以达到稳定状态后约10-14小时处达到了平均最小血药浓度约3-30ng/ml。
本发明进一步涉及一种控释羟可酮制剂配方,它可包括直至约160mg羟可酮或其盐,在服用约2-4.5小时处该制剂提供了最大的羟可酮血药浓度约240ng/ml,在重复q12h用法以达到稳定状态后,约10-14小时处达到了平均最小血药浓度约120ng/ml。
下面附图用于阐述本发明的实施例,但本发明的范围系由权利要求所包括,而不是由这些附图所限定。
图1-4是实施例17中对于疼痛强度差异及止痛效果而定的时间一疗效曲线;
图5是根据本发明及参照标准而制得的以一个10mg控释羟可酮制剂的平均血浆羟可酮浓度曲线。
现已惊奇地发现本发明的控释羟可酮制剂可接受的止痛剂量范围相对比较窄,在约90%病人中约4倍差异范围(每12小时10-40mg,连续周转的剂量)。这对90%病人在使用鸦片型止痛药时一般的范围约8倍差异是一个鲜明的对照。
以12小时使用约10-40mg剂量的控释羟可酮以使约90%病人止痛相对于采用其它剂量范围较宽的mμ-激动剂的止痛药以减轻厉痛而言,是本发明独有特征的一个实例。也应当指出剩余的10%的病人也可成功地使用12小时控释羟可酮,其用量范围比其它类似止痛药的剂量范围相对地要窄。基本上这些10%的病人每12小时使用的控释羟可酮不为10-40mg,一般使用每12小时大于40mg而小于160mg的一种或加倍的剂量强度,如10、20、40、80和160mg单位剂量或和其他药物合用。相反地,用其它相似的如吗啡的止痛药,对剩余10%病人要更宽的剂量范围。例如,已观察到每天的口服相当于吗啡1-20多克范围。相似地,口服氢吗啡酮也要在很宽的剂量范围内。
吗啡被认为是原型的鸦片型止痛药,它已被制成12小时控释的制剂配方(即,MS Contin
片剂,可从Purdue Pharma L.P买到)。尽管服用控释羟可酮和控释吗啡都是12小时连接使用的方法均具有定性临床药代动力学的特征,但本发明的羟可酮与市售的吗啡制剂(如MS Contin
)相比可以以超约1/2剂量范围使用以控制90%病人的严重疼痛。
对每12小时使用的控释羟可酮与每6小时使用相同每日总剂量的立即释放的口服羟可酮进行重复剂量研究以比较而得到可比拟的吸收程度及最大和最小血药浓度,立即释放的产品在口服后1小时,而控释产品在口服后约2-4.5小时达到最大血药浓度。用MS Contin
片剂与立即释放吗啡进行相似的重复剂量研究,结果得到与本发明控释羟可酮制剂可比较的相关的结果。
对于以本发明控释羟可酮制剂、立即释放口服羟可酮或非肠胃道给药羟可酮等形式的羟可酮与口服及非肠胃道给药的、其中已与羟可酮就剂量应答试验及相关的止痛潜在力分析进行和鸦片型相比较时,它基本不偏离剂量应答曲线的平行性。Beaver等在“Analgesic Studies of Codeine and Oxycodone in Patient with Cancer Ⅱ,Comparisons of Insramuscular Oxycodone lvith lntramuscular Morphine and Codeine”(J.Pharmaeol and Exp Ther,207卷第1号101-108页)一文中报道了非肠胃道给药羟可酮与非肠胃道给药的吗啡相比较的剂量应答斜率以及口服与非肠胃道给药的羟可酮相比较的剂量应答的斜率。
已对包括羟可酮、吗啡、氢吗啡酮、左啡诺、美沙酮、哌苷啶、海洛因的mμ-激动剂鸦片型止痛药进行剂量应答研究及相关止痛分析的综述表明它们都不明显偏离剂量应答关系的平行性。这成为建立相关止痛潜力因子和剂量比率的一个基本原理,当病人从一个mμ-激动剂止痛药转换成使用另一个时可以通常采用该比率而与前者的剂量无关。除非剂量应答曲线平行,否则当用一种药替换另一种药时在宽广的剂量范围中转换因子将会变得无效。
本发明的控释羟可酮制剂对约90%病人以每12小时使用约10-40mg范围的剂量使用可以减轻约90%病人的中度疼痛至剧痛,与其它对大部分有效的止痛方法须要以上剂量范围的2倍以提供最有效及人道的方法来控制须要重复剂量的鸦片型止痛药相比具有临床重要性。在鸦片型止痛药测定过程期间,通过本发明控释的羟可酮制剂的效应可以基本上减少医生、护士的时间及病人必须耐受的难以忍受的疼痛的时间。
进一步的临床重要性在于,每12小时服用80mg控释羟可酮可以止痛,例如使带有中等程度的疼痛及剧痛的约95%病人减轻疼痛,每12小时服用160mg控释羟可酮可以,例如可使所有病人减轻疼痛。
为了得到在至少12小时内有疗效的控释药剂,在药学领域一般是生产出一种在服用后4-8小时时出现血药浓度峰值(单剂量的研究)的制剂。令人惊奇地发现本发明在使用羟可酮时,服药后2-4.5小时即出现血药峰值,并能止痛持效至少12小时,最令人惊奇的是,用这类制剂所得的止痛效力大于正常的服用后2小时正常期间所得的羟可酮血药峰值所给出的止痛效力。
本发明组合物的进一步优点是羟可酮的释药率基本上与pH无关,这样就可避免由于口服而使剂量一下子释放。换言之,羟可酮在整个胃肠道中可以均匀地释放。
本发明的口服剂型可以,例如以在胶囊中的颗粒,球体或丸粒形式或其它任何合适的固体形式存在。但较好的是,口服剂型是片剂。
本发明的口服剂型较好地含有1-500mg,最好含有10-160mg的盐酸羟可酮,可替换的是,该剂型可含有摩尔等当量的其它羟可酮盐或羟可酮碱。
本发明的基质可以是使羟可酮在体外的溶解率范围窄并使羟可酮在不依赖pH状态下释药的任何基质。虽然可使用具有控制药物释放的包衣的一般释放基质,但较好的基质是控释基质。在控释基质中适当的物质包括:
(a)亲水聚合物,如胶、纤维素醚类,丙烯酸树脂及蛋白质衍生物。在这些聚合物中,纤维素醚,特别是羟烷基纤维素及羟烷基纤维素较好。口服剂型可含有1%-80%(重量)的至少一种疏水性或亲水性聚合物。
(b)可消化的、取代或非取代长链(C8-C50,特别是C12-C40)的烃类,如脂肪酸、脂肪醇、脂肪酸甘油酯、矿物油和植物油及蜡。较好的烃类的熔点是25-90℃。在这些长链烃类物质中,脂肪(脂族)醇较好,口服剂型可含有直至60%(重量)的至少一种可消化的长链烃。
(c)聚亚烷基二醇类。口服剂型可含有直至60%(重量)至少一种聚亚烷基二醇类。
一种特别合适的基质包括至少一种水溶性羟烷基纤维素,至少一种C12-C36,较好的是C14-C22的脂族醇以及任选的至少一种聚亚烷基二醇。
至少一种羟烷基纤维素较好的是羟基(C1-C6)烷基纤维素,如羟丙基纤维素,羟丙甲基纤维素以及,最好的是羟乙基纤维素。特别是可通过羟可酮所需的精确释药率可以推定出本发明口服剂型中所需的至少一种羟烷基纤维素的用量,但较好的是口服剂型含有5-25%,较好的是6.25-15%(重量)的至少一种羟烷基纤维素。
至少一种脂族醇可以是,例如,月桂醇,肉豆蔻醇或十八烷醇。但在本发明口服剂型中较好的至少一种脂族醇的例子是鲸蜡醇或鲸蜡基十八烷醇。如上所述,通过羟可酮所需的精确释药率来推定至少一种脂族醇在本发明口服剂型中的用量。也可以根据至少一种聚亚烷基二醇是否在口服剂型中存在,当无聚亚烷基二醇时,口服剂型较好地含有20-50%(重量)至少一种脂族醇。当至少一种聚亚烷基二醇存在于口服剂型中时,至少一种脂族醇和至少一种聚亚烷基二醇的总重量较好的是占整个剂型的20-50%(重量)。
在一个较好实例中,控释组合物包括占整个剂型约5-25%(重量)丙烯酸树脂及8-40%(重量)脂族醇。最好的丙烯酸树脂是Eudragit
RS PM,可从Rohm Pharma买到。
在本发明的一个较好剂型中,至少一种羟烷基纤维素或丙烯酸树脂与至少一种脂肪醇/聚亚烷基二醇的比率可在极大的程度上决定了羟可酮从制剂中释放出来的速率。至少一种羟烷基纤维素与至少一种脂族醇/聚亚烷基二醇的比率较好的在1∶2-1∶4之间,最好在1∶3-1∶4之间。
至少一种聚亚烷基二醇可以是,例如聚丙二醇或较好的是聚乙二醇。至少一种聚亚烷基二醇的平均分子量较好地在1000和15000之间,最好在1500和12000之间。
另一种合适的控释基质包括烷基纤维素(特别是乙基纤维素),C12-C36脂族醇类及,任选的聚亚烷基二醇。
除了上述组份外,控释基质也含有适量的其它物质,例如,药学领域中常规的稀释剂、润滑剂、粘合剂、成粒辅剂、着色剂、调味剂及滑动剂。
作为控释基质的替代物,本发明基质也可用具有控制药物释放的包衣的一般控释基质,这方面最好的实例是该剂型包括膜包衣的含有活性组份及非水溶性的成球剂的球体。术语球体在药学领域中是指直径在0.5-2.5mm,特别是在0.5-2mm之间的球状颗粒。
成球剂可以是药学上可接受的物质,它与活性组份一起被球体化而形成球体,较好的是微晶纤维素。
合适的微晶纤维素是,例如,Avicel pH 101(商标,FMC公司)。根据本发明较好的方面,膜包衣球体可含有70-99%(重量),较好的是80-95%(重量)的成球剂,较好的是微晶纤维素。
除了活性组份和成球剂外,球体也可含有粘合剂。该药学技术领域的人员都了解适当的粘合剂,如低粘度、水溶性聚合物。但是,较好的是水溶性羟基低烷基纤维素,如羟丙基纤维素。另外(或替换)的是,球体可含有水不溶性聚合物,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。
该球体较好地用准许羟可酮(或盐)以能控制在水介质中释放速率的物质进行包衣。选择薄包衣从而使活性组份在体外的释药率高于上述所列出的(1小时后释放12.5-42.5%(重量)等)。
薄包衣一般包括一种水不溶性物质,如
(a)蜡,单独使用或与脂肪醇混合使用,
(b)虫胶或玉米醇溶蛋白,
(c)一种水不溶性纤维素,特别是乙基纤维素,
(d)聚甲基丙烯酸酯,特别是Eudragit
,
较好的是,薄包衣包括不溶性物质和水溶性物的混合物。水不溶性物与水溶性物的比率,在其它因素之中可由所需的释药率及所选择物质的溶解特征来决定。
水溶物可以是,例如,聚乙烯吡咯烷酮,或者较好的是水溶性纤维素,较好的是羟丙甲基纤维素。
用于薄包衣的合适的水不溶性和水溶性物质混合物包括虫胶和聚乙烯吡咯烷酮,较好的是乙基纤维素和羟丙甲基纤维素。
为了有助于制成本发明的固体、控释的口服剂型,本发明的另一个方面是提供一种固体、控释口服剂型的制备方法,该方法包括使氢吗啡酮或其盐掺入控释基质中,例如通过下列方法而使其掺入基质,
(a)使至少一种水溶性羟烷基纤维素和羟可酮或羟可酮盐形成颗粒,
(b)将羟烷基纤维素的颗粒与至少一种C12-C36脂族醇混合,以及
(c)任意地,压制成颗粒使颗粒成形,较好地,通过湿粒法使羟烷基纤维素羟可酮与水制成颗粒。在该方法特定的较好实例中,在制湿粒步骤中加入水的量为干的羟可酮重量的1.5-5倍,较好是1.75-3.5倍。
本发明的固体、控释、口服剂型也可通过下列步骤制成薄包衣球体,
(a)使包括羟可酮或羟可酮盐和非水溶成球剂混合物混合,
(b)挤出混合物以得到挤出物,
(c)使挤出物成球,
(d)用薄包衣来包覆球体。
本发明固体、控释口服剂型及其制备方法下面仅通过实施例作阐述。
下述实施例说明了本发明的各个方面。但是不论如何它们不能认为是限定权利要求。
实施例1
盐酸羟可酮30mg控释片-用水质生产方法
将所需量的盐酸羟可酮、喷雾干燥的乳糖和Eudragit
RS PM传送入一个大小合适的混合容器中,混合约5分钟。在混合粉末的同时,用足量水将该混合物制粒,得到湿润的粒状物质。然后将这些颗粒在流化床干燥器中于60℃干燥,通过8目筛网。再将这些颗粒干燥和通过12目筛网。在约60-70℃熔融所需量的十八烷醇,使在混合颗粒时,加入已熔融的十八烷醇。并将热的颗粒移入混合器中。
将包衣的颗粒从混合器中取出,冷却。然后通过12目筛网。在合适的掺合机中混合所需量的滑石粉和硬脂酸镁,使颗粒润滑。在适当的压片机上压成重量为375mg的片剂。实施例1的片剂处方列于下表1中。
表 1
盐酸羟可酮30mg片剂的处方
组分 mg/片 %(重量)
盐酸羟可酮 30.0 8
乳糖(喷雾干燥) 213.75 57
纯化水 适量*--
十八烷醇 75.0 20
滑石粉 7.5 2
硬脂酸镁 3.75 1
总计 375.0 100
*在生产中使用并作为最终产物的残留量。
利用USP篮法测定(Basketmethod)实施例1的片剂,37℃,100RPM、第1小时pH为1.2的胃液700ml,再换成pH为7.5的液体900ml。结果列于下表2中。
表 2
羟可酮30mg控释片的溶解
小时 溶解的羟可酮%
1 33.1
2 43.5
4 58.2
8 73.2
12 81.8
18 85.8
24 89.2
实施例2
盐酸羟可酮10mg控释片-用有机液生产方法
将所需量的盐酸羟可酮和喷雾干燥的乳糖传送入一个大小合适的混合器中,混合约6分钟。将约40%所需的Eudragit
RS PM粉末分散于乙醇中。在混合粉末的同时,用分散体制粒粉末,继续混合直至形成湿润的颗粒状物质。如果需要还可加入额外量的乙醇以达到制粒终点。将这些颗粒在流化床干燥器中于30℃干燥;然后通过12目筛网。将剩余的Eudragit
RS PM分散于由90份乙醇和10份纯化水组成的溶剂中;并在30℃下被喷洒至位于流化床制粒器/干燥器中的颗粒上。接着将颗粒通过12目筛网。在约60-70℃溶解所需量的十八烷醇。并将热的颗粒再转移至混合器中,在混合的同时加入溶解的十八烷醇。将包衣的颗粒从混合器中取出,冷却。然后通过12目筛网。
在合适的掺合机中混合所需量的滑石粉和硬脂酸镁,使颗粒润滑。在适当的压片机上压成重量为125mg的片剂。
实施例2的片剂(10mg控释羟可酮)处方列于下表3中。
表 3
盐酸羟可酮10mg控释片的处方
组分 mg/片 %(重量)
盐酸羟可酮 10.00 8
乳糖(喷雾干燥) 71.25 57
乙醇 适量*--
纯化水 适量*--
十八烷醇 25.00 20
滑石粉 2.50 2
硬脂酸镁 1.25 1
总计: 125.00mg 100
*仅在生产中使用,并作为最终产物的残留量。
利用USP篮法测定实施例2的片剂,37℃.100RPM.第1小时pH为1.2的胃液700ml,再换成pH为7.5的液体900ml。
结果列于下表4中:
表 4
羟可酮10mg控释片的溶解
小时 溶解的羟可酮%
1 35.9
2 47.7
4 58.5
8 67.7
12 74.5
18 76.9
24 81.2
实施例3-4
羟可酮10和20mg控释片(水质生产法)
然后,将适量的盐酸羟可酮、乳糖和聚乙烯吡咯酮放入流化床制粒器/干燥器(FBD)筒中,并向流化床上的粉末喷洒混悬液。喷洒之后,如果需要减少结块,则将颗粒通过12目筛网。将干燥的颗粒置于混合器中。
同时,在约70℃下熔融所需量的十八烷醇。通过混合将熔融的十八烷醇掺入至颗粒。将上了蜡的颗粒转移至流化床制粒器/干燥器或盘中,干燥至室温或更低的温度。将冷却后的颗粒通过12目筛网。然后将上了蜡的颗粒置于混合器/掺合器中,并用所需量的滑石粉和硬脂酸镁润滑约3分钟,再在适当的压片机上压成重量为125mg的片剂。
实施例3的片剂处方列于下表5中。
表 5
羟可酮10mg控释片的处方
组分 mg/片 %(重量)
盐酸羟可酮 10.0 8.0
乳糖(喷雾干燥) 69.25 55.4
聚乙烯吡咯酮 5.0 4.0
十八烷醇 25.0 20.0
滑石粉 2.5 2.0
硬脂酸镁 1.25 1.0
总计: 125.0 100.0
利用USP篮法测定实施例3的片剂,37℃、100RPM、第1小时pH为1.2的胃液700ml,再换成pH为7.5的液体900ml。结果列于下表6中。
表 6
羟可酮10mg控释片的溶解
小时 溶解的羟可酮%
1 38.0
2 47.5
4 62.0
8 79.8
12 91.1
18 94.9
24 98.7
实施例4的片剂处方列于下表7中:
表 7
羟可酮20mg控释片的处方
组分 Mg/片
盐酸羟可酮 20.0
乳糖(喷雾干燥) 59.25
聚乙烯吡咯酮 5.0
十八烷醇 25.0
滑石粉 2.5
硬脂酸镁 1.25
总计: 125.0
利用USP篮法测定实施例4的片剂,37℃、100RPM、第1小时pH为1.2的胃液700ml,再换成pH为7.5的液体900ml。结果列于下表8中:
表 8
羟可酮20mg控释片的溶解
小时 溶解的羟可酮%
1 31
2 44
4 57
8 71
12 79
18 86
24 89
实施例5-6
在实施例5中,根据实施例1的方法制备盐酸羟可酮30mg控释片。
在实施例6中,根据实施例2的方法制备盐酸羟可酮10mg控释片。
然后,在不同的pH水平即pH值依次为1.3、4.56、6.88和7.5,进行实施例5和6的片剂的溶解研究。
结果列于下表9和10中:
表9-实施例5
盐酸羟可酮30mg片剂的溶解百分比与时间的关系
pH 1 2 4 8 12 18 24
1.3 29.5 43.7 61.8 78.9 91.0 97.0 97.1
4.56 34.4 49.1 66.4 82.0 95.6 99.4 101.1
6.88 33.8 47.1 64.4 81.9 92.8 100.5 105.0
7.5 27.0 38.6 53.5 70.0 81.8 89.7 96.6
表10-实施例6
盐酸羟可酮10mg片剂的溶解百分比与时间的关系
pH 1 2 4 8 12 18 24
1.3 25.9 41.5 58.5 73.5 85.3 90.7 94.2
4.56 37.8 44.2 59.4 78.6 88.2 91.2 93.7
6.88 34.7 45.2 60.0 75.5 81.4 90.3 93.9
7.5 33.2 40.1 51.5 66.3 75.2 81.7 86.8
实施例7-12
在实施例7-12中,根据美国专利No.4,990,341中的处方和方法制备盐酸羟可酮4mg和10mg片剂。
在实施例7中,盐酸羟可酮(10.00mg)用乳糖一水合物(417.5mg)和羟乙基纤维素(100.00mg)湿制粒,颗粒过12目筛。在流化床中于50℃下干燥颗粒,过16目筛。
将熔融的鲸蜡十八烷醇(300.00mg)加入含有颗粒的温热的羟可酮中,彻底混合。在空气中冷却混合物,再次制粒并过16目筛。
加入纯化的滑石粉(15.0mg)和硬脂酸镁(7.5mg)并与颗粒混合。再将颗粒压成片剂。
实施例8以实施例7的方法制备;然而,处方设计中包括10mg盐酸羟可酮片。实施例7和8的处方分别列于下表11和12中:
表 11
实施例7的处方
组分 mg/片 g/批
盐酸羟可酮 4.0 10.0
乳糖-水合物 167.0 417.5
羟乙基纤维素 40.0 100.0
鲸蜡十八烷醇 120.0 300.0
纯化的滑石粉 6.0 15.0
硬脂酸镁 3.0 7.5
表 12
实施例8的处方
组分 mg/片 g/片
盐酸羟可酮 10.0 25.0
乳糖-水合物 167.0 417.5
羟乙基纤维素 40.0 100.0
鲸蜡十八烷醇 120.0 300.0
滑石粉 6.0 15.0
硬脂酸镁 3.0 7.5
在实施例9中,根据在实施例2中引述的美国专利No.4,990,341的方法制备盐酸羟可酮4mg控释片。其生产方法与上述实施例7和8相同。实施例10是根据实施例9制备的,不同之处在于它在每片中含有10mg盐酸羟可酮。实施例9和10的处方分别列于下表13和14中。
表 13
实施例9的处方
组分 mg/片 g/批
盐酸羟可酮 4.0 10.0
无水乳糖 167.0 417.5
羟乙基纤维素 30.0 75.0
鲸蜡十八烷醇 90.0 225.0
滑石粉 6.0 15.0
硬脂酸镁 3.0 7.5
表 14
实施例14的处方
组分 mg/片 g/批
盐酸羟可酮 10.0 25.0
无水乳糖 167.0 417.5
羟乙基纤维素 30.0 75.0
鲸蜡十八烷醇 90.0 225.0
滑石粉 6.0 15.0
硬脂酸镁 3.0 7.5
在实施例11中,根据在实施例3中引述的美国专利No.4,990,341中的相同赋形剂处方制备羟可酮4mg控释片。
将盐酸羟可酮(32.0mg)用乳糖一水合物(240.0mg)、羟乙基纤维素(80.0mg)和异丁烯酸共聚物(240.0mg,Eudragit
L-100-55)湿制粒,颗粒过12目筛。将颗粒在流化床干燥器中于50℃下干燥,过16目筛。
将熔融的鲸蜡十八烷醇(240.0mg)加入至加热的含羟可酮的颗粒中,充分混合。在空气中冷却,再次制粒并过16目筛。将颗粒压成片剂。
实施例12以类似于实施例11的方法制备,不同之处在于它每片中含有10mg盐酸羟可酮。实施例11和12的处方分别列于下表15和16中。
表 15
实施例11的处方
组分 mg/片 g/批
盐酸羟可酮 4.0 32.0
乳糖-水合物 30.0 240.5
羟乙基纤维素 10.0 80.0
异丁烯酸共聚物 30.0 240.0
鲸蜡十八烷醇 30.0 240.0
表 16
实施例12的处方
组分 mg/片 g/批
盐酸羟可酮 10.0 80.0
乳糖-水合物 30.0 240.5
羟乙基纤维素 10.0 80.0
异丁烯酸共聚物 30.0 240.0
鲸蜡十八烷醇 30.0 240.0
然后,根据美国药典XXII(1990)中描述的USP篮法对实施例7-12进行溶解研究。转速为100rpm,在第1小时的介质为模拟的胃液,接着为模拟的肠液,温度为37℃。结果列于下表17中。
表 17
实施例7-12的溶解研究
溶解的羟可酮%
时间
(hrs) 实施例7 实施例8 实施例9 实施例10 实施例11 实施例12
1 23.3 25.5 28.1 29.3 31.3 40.9
2 35.6 37.5 41.5 43.2 44.9 55.6
4 52.9 56.4 61.2 63.6 62.1 74.2
8 75.3 79.2 83.7 88.0 82.0 93.9
12 90.7 94.5 95.2 100.0 91.4 100.0
实施例13-16
临床研究
在实施例13-16中,利用实施例2(有机介质生产法)和实施例3(水质生产)的处方进行随机交叉生物利用度研究。
在实施例13中,利用实施例3中制备的羟可酮片剂对24人进行单剂量禁食/给药研究。
在实施例14中,利用实施例2中制备的羟可酮片剂在服用12小时后,对23人进行稳定状态研究,并与5mg氧可酮立即释放的溶液比较。
在实施例15中,对服用根据实施例3的方法制备的羟可酮片剂的23人进行单剂量研究,并与20mg羟可酮立即释放的溶液比较。
在实施例16中,对服用根据实施例3的方法制备的3×10mg羟可酮片剂的12人进行单剂量研究,并与30mg羟可酮立即释放溶液比较。
实施例13-16的结果列于下表18中。
表 18
AUC Cmax Tmax
实施例 剂量 ng/ml/hr ng/ml hr
13 10mg CR 饥饿 63 6.1 3.8
10mg CR 已喂食 68 7.1 3.6
14 5mg IR q6h 121 17 1.2
10mg CR q12h 130 17 3.2
15 20mg IR 188 40 1.4
2×10mg CR 197 18 2.6
16 30mg IR 306 53 1.2
3×10mg CR 350 35 2.6
30mg CR 352 36 2.9
IR表示立即释放的羟可酮溶液
CR表示控释片剂。
实施例17
临床研究
在实施例17中,利用单剂量、双盲、随机研究对本发明的羟可酮10.20和30mg控释片(CROXY)与15mg立即释放的羟可酮(IROXY)以及立即释放的羟可酮10mg和650mg扑热息痛合用(IROXY/APAP)和安慰剂在腹部或妇科手术后仍有中度或严重病痛的180位病人对在相对止痛效果、可接受性、口服给药的作用的相对持续性等方面作比较。病人可根据其疼痛的轻重分级从第1小时至第12小时给药后每隔1小时。利用标准的尺度比较治疗的疼痛轻重、疼痛缓解的开始及持续时间。
对于每小时的测定、总的疼痛强度的差异(SPID)和总疼痛减轻程度(TOTPAR),所有活性物治疗均显著优于对照剂。在疼痛减轻和最大疼痛强度差异(PID)的CROXY的3个剂量水平中,CROXY 20mg和30mg的剂量反应明显优于10mg剂量。在第1和2小时,IR OXY明显优于CR OXY 10mg。IR OXY/APAP在1小时内明显优于CR OXY的三种剂量,在2-5小时优于CR OXY10mg。在IR OXY/APAP治疗组与3CR OXY治疗的比较中,IR OXY的起始时间明显较短。在减轻疼痛的持续时间中表明3个CR OXY剂量的持续时间长于IR OXY和IR OXY/APAP。没有报导严重的不良反应。结果列于下表19中:
表 19
病人分布
处理组
IR OXY -CR OXY-
15mg 对照剂 10mg 20mg 30mg 2PERC*总计
研究治疗的登记并 31 31 30 30 30 30 182
随机分布
进入研究治疗阶段 31 31 30 30 30 30 182
完成研究 31 30 30 30 30 30 181
未持续研究的人 0 1 0 0 0 0 1
从效果分析中排除 1 1 0 0 0 0 1
在用药后1小时之
前发生呕吐
在研究期间疏忽地 1 0 0 0 0 0 1
接受营救
人口分析:评价安 30 30 30 30 30 30 180
全性和效果
评价安全性 31 31 30 30 30 30 182
在图1-4中显示了疼痛强化、疼痛强化差异和疼痛减轻的时效曲线。在3-11小时,CR OXT 10mg比安慰剂治疗组(对照组)的病人具有显著(P<0.05)的低疼痛强化值,而在10小时,其值也比IR OXY 15mg和Percocrt
低。CR OXY 20mg与对照剂相比在2-11小时具有显著(p<0.05)的低疼痛强化值,在9-11小时具有比CR OXY 10mg、IR OXY 15mg和Percocet显著(p<0.05)的低疼痛值。CR OXY 30mg在2-11小时具有比对照剂显著(p<0.05)低的疼痛值,在2、3和5小时,其疼痛值低于CR OXY 10mg,在10小时其值低于Percocet
。
对于每小时疼痛减轻值的绝对值和目视模拟尺度(CAT和VAS),CR OXY 10mg在3-11小时具有比对照剂显著(p<0.05)高的疼痛减轻值,在10小时具有比IR OXY和Percocet
更高的疼痛减轻值(在11小时,比Percocet
更高)。CR OXY 20mg,在2-12小时具有比对照剂显著(p<0.05)高的减轻值,在9-12小时比Percocet
更高的减轻值。另外,CR OXY在10-12小时具有比IR OXY显著(p<0.05)高的疼痛减轻。CR OXY 30mg在2-12小时比对照剂具有显著(p<0.05)高的疼痛减轻值,在9-12小时其值比Percocet
高,在10小时其值比IR OXY 15mg高。
每个治疗组在总疼痛强度差异(SPID)和总疼痛减轻(TOTPAR)方面都显著(p<0.05)优于对照组。
利用病人秒表方法测定疼痛减轻的持续时间,结果显示CR OXY 10mg、20mg和30mg具有比IR OXY 15mg和2片Percocet
显著(p<0.05)长的作用持续时间。另外,这三种控释处方的治疗时间显著(p<0.05)长于Percocet
。
在治疗前,总共有104位病人(57%)报告了120种不良反应。最常见的是嗑睡、发烧、头昏和头痛。
基于上述研究,得到的结论是本发明的羟可酮控释处方可减轻由于腹部或女性妇科手术引起的中度或严重手术后疼痛等。单剂量的剂量反应为对照剂<10mg<20mg<30mgCR OXY。作用的起始时间为1小时,最大效应出现在2-5小时,持续效应为10-12小时。在慢性疼痛情况下,稳态剂量可以延长该效应。副作用的产生也是在期待之中的,但可以容易地得到控制。头痛可能与剂量有关。还有头昏和嗑睡的报导。
IR OXY 15mg与控释羟可酮相比还具有一个中间峰效应。它的作用持续时间较短(6-8小时)。Percocet
在起始时间、峰效应和安全性方面是相当有效的。其作用持续时间为6-8小时。
总之,CR OXY明显地是一种有效地口服止痛药,它与IR OXY或IR OXY/APAP相比起始时间较慢而其作用时间较长。
实施例18
临床研究
在实施例18中,对21位健康男性进行稳态交叉试验,比较
a.每隔12小时(q12h)给药CR OXY 10mg;和
图5显示了每12小时间隔给药的二种处方的平均羟可酮血浓。其结果以平均值,平均值比率和90%置信区间总结于表20。
从表20中可以看出,除了一例异常外,其余的在二种处方之间未发现显著差异。这例异常作为控释处方的3.18小时的CR OXY的平均tmax显著大于1.38小时的ROX平均值。平均以AUC为基础的生物利用度(ROX=100%)为104.4%,其置信限度90%的范围为90.9-117.9%。这样,就达到了±20%的FDA标准,从而使得该研究结果支持了相同羟可酮利用度的论断。
实施例19
临床研究
在实施例19中,对24位正常、健康男性进行随机单剂量双向交叉研究以比较他们在服用2种羟可酮10mg控释片和20mg(5mg/5ml溶液20ml)的立即释放(IR)盐酸羟可酮溶液后的羟可酮血浓。23位受试者完成了研究,其数据可用于分析。
通过高效液相方法测定血浆羟可酮浓度。根据单个血浆羟可酮浓度与时间关系的数据计算出的Cmax、tmax、AUC和半衰期的算术平均值列于下表21中。
表 21
药代动力学参数 对照产品 测试产品 90%置信区间
IR羟可酮 CR羟可酮
20mg 2×10mgF(%)
Cmax41.60 18.62 44.75 32.5-57.0
(ng/ml)
tmax1.30 2.62 200.83 169.8-232.6
(hours)
AUC 194.35 199.62 102.71 89.5-115.9
(0-36)
(mg x hr/ml)
AUC(0-∞) 194.38 208.93 107.49 92.9-121.9
(ng x hr/ml)
telim3.21 7.98*249.15 219.0-278.8
(hrs)
tabs0.35 0.92*264.17 216.0-310.7
(hrs)
F.%=口服生物利用度
*(CR羟可酮2×10mg/IR羟可酮20mg)
*统计意义(p=0.0001)
对于Cmax、tmax、t1/2(消失)和t1/2(吸收),在CR OXY和I ROXY之间存在着统计意义。这二种治疗在吸收范围上〔AUC(0,36),AUC(0,∞)〕没有统计意义差异。CR OXY相对于IR OXY的90%置信区间,AUC(0.36)为89.5%-115.9%,AUC(0,∞)为92.9%-121.9%。以90%置信区间分析为基础,控释羟可酮片剂在吸收范围AUC(0,36)上与立即释放羟可酮溶液相同。控释羟可酮的吸收约慢1.3小时。这二种治疗在不良反应方面没有统计意义差异,都没有影响该研究的临床异常现象发生。
上述研究论证了使用本发明的控释羟可酮处方的明显的剂量-效应关系,剂量为10、20和30mg,它不偏离为MS Contin良好控制的止痛效果研究而设计的剂量-效果斜率,该斜率可见“用于手术后疼痛的控释口服吗啡(MS Contin
片,MSC)。”,Pain Suppl,5:S149,1990,该文章将30、60、90和120mg的MS Contin与10mg肌注吗啡、对照剂和Bloomfield作了对比,还有“二种口服控释吗啡制剂的止痛效果和效能”(Analgesic Efficacy and Potency of Two Oral Controlled-Relese Morphine Preparations”,Clinical Pharmacology & Therepautics,(未出版),该文章将30和90mg的MS Cotin与30和90mg的其它控释口服吗啡制剂、Oramorph SR 30mg片剂作了比较。
以上提供的实施例并不是全部概括的。对于本技术领域中普通技术人员,本发明的一些变化是明显的,这些变化都包括在本发明的权利要求中。
Claims (11)
1、一种从基本上减少病人控制疼痛所需每日剂量范围的方法,其特征在于该方法包括口服使用包括约10-40mg羟可酮或其盐的控释剂型,在服药后约2-4.5小时达到平均最大羟可酮血药浓度约为6-60ng/ml,每12小时重复使用以达稳定状态后,在10-14小时处达平均最小血药浓度约为3-30ng/ml。
2、一种从基本上减少所有病人控制疼痛所需每日剂量范围的方法,其特征在于该方法包括口服使用包括约10-160mg羟可酮或其盐的控释剂型,在服药后约2-4.5小时达到平均最大羟可酮血药浓度约为240ng/ml,每12小时重复使用以达稳定状态后,在10-14小时处达平均最小血药浓度约为120ng/ml。
3、一种用于口服的控释羟可酮制剂,其特征在于它包括约10-40mg羟可酮或其盐,在服药后平均约2-4.5小时达到平均最大羟可酮血药浓度约为6-60ng/ml,每12小时重复使用以达稳定状态后,在10-14小时内达平均最小血药浓度约为3-30ng/ml。
4、一种用于口服的控释羟可酮制剂,其特征在于它包括约10-160mg羟可酮或其盐,在服药后平均约2-4.5小时达到平均最大羟可酮血药浓度约为6-240ng/ml,每12小时重复使用以达稳定状态后,在10-14小时内达平均最小血药浓度约为3-120ng/ml。
5、一种固体控释口服剂型,其特征在于它包括:
(a)10-160mg羟可酮或其盐;
(b)选自由亲水性聚合物、疏水性聚合物、有约8-50碳原子的可消化的取代或未取代的烃类、聚亚烷基醇类醇及其混合物的组中的有数量的控释基质;以及
(c)适量的药学稀释剂服用后2-4.5小时所述组合物给出平均最大血药浓度为6-240ng/ml,每12小时重复使用以达到稳定状态后10-14小时处达到平均最小血药浓度为3-120ng/ml。
6、根据权利要求5所述的控释组合物,其特征在于所述控释基质包括一种丙烯酸树脂。
7、一种固体控释口服剂型,其特征在于它包括:
(a)止痛有效量的球体,它包括羟可酮或其盐以及成球剂或丙烯酸聚合物或共聚物,羟可酮在所述剂型中的总量为10-160mg;
(b)控制羟可酮或羟可酮盐在水介质中的释放速率的薄膜包衣,其中所述的组合物在体外有一剂量溶解率;
服用后约2-4.5小时,所述组合物达到平均最大羟可酮血药浓度6-240ng/ml,每12小时重复使用以达到稳定状态后平均约10-14小时达到最小血药浓度约3-30ng/ml。
8、根据权利要求7所述的控释组合物,其特征在于其中所述的膜包衣包括选自由虫胶或玉米醇溶蛋白,水不溶性纤维素或聚甲基丙烯酸酯所组成的组。
9、一种口服的控释片剂,其特征在于它包括约10-160mg羟可酮或羟可酮盐分散于控释基质中,当用USP Paddle方法在100rpm900毫升水质缓冲液(pH在1.6-7.2)于37℃下测量时,所述片剂的体外溶解率1小时后释放羟可酮为12.5-42.5%之间(重量),2小时后释放羟可酮25-55%(重量),4小时后释放羟可酮45-75%(重量),6小时后释放羟可酮55-85%(重量),体外释放率基本上不依赖pH,在服用该制剂后2-4.5小时得到体外平均最大羟可酮血药浓度约6-240ng/ml,每12小时重复使用以达稳定状态后约10-14小时达平均最小血药浓度3-30ng/ml。
10、根据权利要求9所述的剂型,其特征在于其中体外溶解率1小时后羟可酮释放17.5-38%(重量),2小时后羟可酮释放30-50%(重量),4小时后羟可酮释放50-70%(重量),6小时后羟可酮释放60-80%(重量)。
11、根据权利要求9所述的剂型,其特征在于其中体外溶解率为1小时后羟可酮释放17.5-32.5%(重量),2小时后羟可酮释放35-45%(重量),4小时后羟可酮释放55-65%(重量),6小时后羟可酮释放65-75%(重量)。
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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Publication number | Priority date | Publication date | Assignee | Title |
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US5891471A (en) * | 1993-11-23 | 1999-04-06 | Euro-Celtique, S.A. | Pharmaceutical multiparticulates |
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EP2311460A1 (en) * | 2001-07-06 | 2011-04-20 | Endo Pharmaceuticals Inc. | Oxymorphone controlled release formulations |
US8329216B2 (en) | 2001-07-06 | 2012-12-11 | Endo Pharmaceuticals Inc. | Oxymorphone controlled release formulations |
SI1416842T1 (sl) | 2001-07-18 | 2009-06-30 | Euro Celtique Sa | Farmacevtske kombinacije oksikodona in naloksona |
US20030068375A1 (en) | 2001-08-06 | 2003-04-10 | Curtis Wright | Pharmaceutical formulation containing gelling agent |
WO2003015531A2 (en) * | 2001-08-06 | 2003-02-27 | Thomas Gruber | Pharmaceutical formulation containing dye |
US20030157168A1 (en) | 2001-08-06 | 2003-08-21 | Christopher Breder | Sequestered antagonist formulations |
ES2326794T3 (es) | 2001-08-06 | 2009-10-20 | Euro-Celtique S.A. | Formulaciones de agonistas opioides con antagonista liberable y secuestrado. |
US20030044458A1 (en) | 2001-08-06 | 2003-03-06 | Curtis Wright | Oral dosage form comprising a therapeutic agent and an adverse-effect agent |
US20040234602A1 (en) | 2001-09-21 | 2004-11-25 | Gina Fischer | Polymer release system |
US20040253310A1 (en) | 2001-09-21 | 2004-12-16 | Gina Fischer | Morphine polymer release system |
CA2459976A1 (en) * | 2001-09-26 | 2003-04-03 | Penwest Pharmaceuticals Company | Opioid formulations having reduced potential for abuse |
PE20030527A1 (es) * | 2001-10-24 | 2003-07-26 | Gruenenthal Chemie | Formulacion farmaceutica con liberacion retardada que contiene 3-(3-dimetilamino-1-etil-2-metil-propil) fenol o una sal farmaceuticamente aceptable del mismo y tabletas para administracion oral que la contienen |
CN1301104C (zh) * | 2002-02-21 | 2007-02-21 | 大塚制药株式会社 | 缓释制剂及其制造方法 |
US7666876B2 (en) * | 2002-03-19 | 2010-02-23 | Vernalis (R&D) Limited | Buprenorphine formulations for intranasal delivery |
ES2546010T3 (es) | 2002-04-05 | 2015-09-17 | Euro-Celtique S.A. | Preparación farmacéutica que contiene oxicodona y naloxona |
US20050106249A1 (en) * | 2002-04-29 | 2005-05-19 | Stephen Hwang | Once-a-day, oral, controlled-release, oxycodone dosage forms |
DE60325715D1 (de) * | 2002-04-29 | 2009-02-26 | Alza Corp | Methoden und darreichungsformen zur kontrollierten freisetzung von oxykodon |
RU2004134728A (ru) * | 2002-05-31 | 2005-06-10 | Алза Корпорейшн (Us) | Дозированные формы и композиции для осмотической доставки различных дозировок оксикодона |
US7776314B2 (en) | 2002-06-17 | 2010-08-17 | Grunenthal Gmbh | Abuse-proofed dosage system |
US20040001889A1 (en) | 2002-06-25 | 2004-01-01 | Guohua Chen | Short duration depot formulations |
US10004729B2 (en) | 2002-07-05 | 2018-06-26 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
US8840928B2 (en) | 2002-07-05 | 2014-09-23 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
WO2004004693A1 (en) | 2002-07-05 | 2004-01-15 | Collgegium Pharmaceutical | Abuse-deterrent pharmaceutical compositions of opiods and other drugs |
US8557291B2 (en) | 2002-07-05 | 2013-10-15 | Collegium Pharmaceutical, Inc. | Abuse-deterrent pharmaceutical compositions of opioids and other drugs |
US20040058946A1 (en) * | 2002-07-05 | 2004-03-25 | Buchwald Stephen L. | Abuse-resistant prodrugs of oxycodone and other pharmaceuticals |
US7168140B2 (en) * | 2002-08-08 | 2007-01-30 | Milliken & Company | Flame resistant fabrics with improved aesthetics and comfort, and method of making same |
CA2495182A1 (en) * | 2002-08-15 | 2004-02-26 | Noramco, Inc. | Oxycodone-hydrochloride polymorphs |
PT1551372T (pt) | 2002-09-20 | 2018-07-23 | Alpharma Pharmaceuticals Llc | Subunidade de sequestração e composições e métodos relacionados |
US20050020613A1 (en) * | 2002-09-20 | 2005-01-27 | Alpharma, Inc. | Sustained release opioid formulations and method of use |
US20040110781A1 (en) * | 2002-12-05 | 2004-06-10 | Harmon Troy M. | Pharmaceutical compositions containing indistinguishable drug components |
US9107804B2 (en) | 2002-12-10 | 2015-08-18 | Nortec Development Associates, Inc. | Method of preparing biologically active formulations |
GB0300531D0 (en) | 2003-01-10 | 2003-02-12 | West Pharm Serv Drug Res Ltd | Pharmaceutical compositions |
ATE454169T1 (de) * | 2003-03-13 | 2010-01-15 | Controlled Chemicals Inc | Oxycodon- konjugate mit niedrigerem missbrauch- potential und ausgedehnter tätigkeitsdauer |
EP1782834A3 (en) * | 2003-03-13 | 2007-08-01 | Controlled Chemicals, Inc. | Oxycodone conjugates with lower abuse potential and extended duration of action |
ES2360102T3 (es) | 2003-03-26 | 2011-05-31 | Egalet A/S | Sistema para la liberación controlada de morfina. |
US20040202717A1 (en) | 2003-04-08 | 2004-10-14 | Mehta Atul M. | Abuse-resistant oral dosage forms and method of use thereof |
MY135852A (en) | 2003-04-21 | 2008-07-31 | Euro Celtique Sa | Pharmaceutical products |
US9579286B2 (en) * | 2003-04-21 | 2017-02-28 | Purdue Pharma L.P. | Tamper resistant dosage form comprising co-extruded, sequestered adverse agent particles and process of making same |
US8158149B2 (en) * | 2004-05-12 | 2012-04-17 | Chelsea Therapeutics, Inc. | Threo-DOPS controlled release formulation |
WO2004100929A1 (en) | 2003-05-12 | 2004-11-25 | Synergia Pharma, Inc. | Threo-dops controlled release formulation |
US20060165790A1 (en) * | 2003-06-27 | 2006-07-27 | Malcolm Walden | Multiparticulates |
TWI357815B (en) * | 2003-06-27 | 2012-02-11 | Euro Celtique Sa | Multiparticulates |
CN1826100B (zh) * | 2003-07-17 | 2010-12-22 | 旗帜药物胶囊公司 | 控释制剂 |
US8075872B2 (en) | 2003-08-06 | 2011-12-13 | Gruenenthal Gmbh | Abuse-proofed dosage form |
DE102004020220A1 (de) * | 2004-04-22 | 2005-11-10 | Grünenthal GmbH | Verfahren zur Herstellung einer gegen Missbrauch gesicherten, festen Darreichungsform |
DE102005005446A1 (de) * | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Bruchfeste Darreichungsformen mit retardierter Freisetzung |
DE502004004205D1 (de) * | 2003-08-06 | 2007-08-09 | Gruenenthal Gmbh | Gegen missbrauch gesicherte darreichungsform |
US20070048228A1 (en) * | 2003-08-06 | 2007-03-01 | Elisabeth Arkenau-Maric | Abuse-proofed dosage form |
DE10336400A1 (de) | 2003-08-06 | 2005-03-24 | Grünenthal GmbH | Gegen Missbrauch gesicherte Darreichungsform |
DE10361596A1 (de) * | 2003-12-24 | 2005-09-29 | Grünenthal GmbH | Verfahren zur Herstellung einer gegen Missbrauch gesicherten Darreichungsform |
US20050053659A1 (en) * | 2003-09-10 | 2005-03-10 | Pace Gary W. | Methods and compositions for reducing the risk associated with the administration of opioid analgesics in patients with diagnosed or undiagnosed respiratory illness |
US20050074493A1 (en) * | 2003-10-03 | 2005-04-07 | Mehta Atul M. | Extended release formulations of opioids and method of use thereof |
US7201920B2 (en) | 2003-11-26 | 2007-04-10 | Acura Pharmaceuticals, Inc. | Methods and compositions for deterring abuse of opioid containing dosage forms |
US8883204B2 (en) * | 2003-12-09 | 2014-11-11 | Purdue Pharma L.P. | Tamper resistant co-extruded dosage form containing an active agent and an adverse agent and process of making same |
EP1691892B1 (en) * | 2003-12-09 | 2007-02-28 | Euro-Celtique S.A. | Tamper resistant co-extruded dosage form containing an active agent and an adverse agent and process of making same |
TWI350762B (en) | 2004-02-12 | 2011-10-21 | Euro Celtique Sa | Particulates |
GB0403098D0 (en) | 2004-02-12 | 2004-03-17 | Euro Celtique Sa | Extrusion |
BRPI0508769A (pt) * | 2004-03-30 | 2007-08-28 | Euro Celtique Sa | forma de dosagem resistente a adulteração compreendendo um adsorvente e um agente adverso |
TW201509943A (zh) | 2004-03-30 | 2015-03-16 | Euro Celtique Sa | 含有小於25ppm14-羥可待因酮之羥可酮鹽酸鹽之組成物、醫藥劑型、延遲釋出口服劑型及醫藥上可以接受的包裝 |
US20050226929A1 (en) * | 2004-04-12 | 2005-10-13 | Jianbo Xie | Controlled release opioid analgesic formulation |
EP1604666A1 (en) | 2004-06-08 | 2005-12-14 | Euro-Celtique S.A. | Opioids for the treatment of the Chronic Obstructive Pulmonary Disease (COPD) |
EP1604667A1 (en) * | 2004-06-08 | 2005-12-14 | Euro-Celtique S.A. | Opioids for the treatment of the restless leg syndrome |
US20070224269A1 (en) * | 2004-06-10 | 2007-09-27 | Rubino Orapin P | Controlled Release Pharmaceutical Formulation |
HUE037643T2 (hu) | 2004-06-12 | 2018-09-28 | Collegium Pharmaceutical Inc | Visszaélésre nem alkalmas gyógyszerkészítmények |
DE102004032049A1 (de) | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Gegen Missbrauch gesicherte, orale Darreichungsform |
DE102004032103A1 (de) * | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Gegen Missbrauch gesicherte, orale Darreichungsform |
GB2418854B (en) | 2004-08-31 | 2009-12-23 | Euro Celtique Sa | Multiparticulates |
US9326959B2 (en) | 2004-09-01 | 2016-05-03 | Purdue Pharma, L.P. | Opioid dosage forms having dose proportional steady state Cave and AUC and less than dose proportional single dose Cmax |
LT2767292T (lt) | 2004-09-17 | 2016-12-12 | Durect Corporation | Palaikomosios vietinės anestezijos mišinys su saib |
US20080152595A1 (en) * | 2004-11-24 | 2008-06-26 | Acura Pharmaceuticals, Inc. | Methods and compositions for deterring abuse of orally administered pharmaceutical products |
EP1830886B1 (en) | 2004-12-27 | 2016-04-13 | Eisai R&D Management Co., Ltd. | Method for stabilizing anti-dementia drug |
US20090208579A1 (en) * | 2004-12-27 | 2009-08-20 | Eisai R & D Management Co., Ltd. | Matrix Type Sustained-Release Preparation Containing Basic Drug or Salt Thereof, and Method for Manufacturing the Same |
US20060280789A1 (en) * | 2004-12-27 | 2006-12-14 | Eisai Research Institute | Sustained release formulations |
CA2594373A1 (en) * | 2005-01-28 | 2006-08-03 | Euro-Celtique S.A. | Alcohol resistant dosage forms |
DE102005005449A1 (de) * | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Verfahren zur Herstellung einer gegen Missbrauch gesicherten Darreichungsform |
EP1695700A1 (en) * | 2005-02-28 | 2006-08-30 | Euro-Celtique S.A. | Dosage form containing oxycodone and naloxone |
EP1702558A1 (en) | 2005-02-28 | 2006-09-20 | Euro-Celtique S.A. | Method and device for the assessment of bowel function |
US20060281775A1 (en) * | 2005-06-14 | 2006-12-14 | Applied Pharmacy Services, Inc. | Two-component pharmaceutical composition for the treatment of pain |
US7884136B2 (en) | 2005-06-27 | 2011-02-08 | Biovail Laboratories International S.R.L. | Modified-release formulations of a bupropion salt |
US20070027105A1 (en) | 2005-07-26 | 2007-02-01 | Alza Corporation | Peroxide removal from drug delivery vehicle |
GB2431875A (en) * | 2005-10-31 | 2007-05-09 | Alza Corp | Methods of reducing alcohol-induced dose dumping for opioid sustained release oral dosage forms |
CN1957909B (zh) * | 2005-10-31 | 2013-09-11 | 阿尔扎公司 | 降低鸦片样物质持续释放口服剂型的由醇诱导的剂量突然释放的方法 |
PL116330U1 (en) * | 2005-10-31 | 2007-04-02 | Alza Corp | Method for the reduction of alcohol provoked rapid increase in the released dose of the orally administered opioide with prolonged liberation |
US20090022798A1 (en) * | 2007-07-20 | 2009-01-22 | Abbott Gmbh & Co. Kg | Formulations of nonopioid and confined opioid analgesics |
US20090317355A1 (en) * | 2006-01-21 | 2009-12-24 | Abbott Gmbh & Co. Kg, | Abuse resistant melt extruded formulation having reduced alcohol interaction |
US20100172989A1 (en) * | 2006-01-21 | 2010-07-08 | Abbott Laboratories | Abuse resistant melt extruded formulation having reduced alcohol interaction |
EP3332788A1 (en) | 2006-02-03 | 2018-06-13 | Opko Renal, LLC | Treating vitamin d insufficiency and deficiency with 25-hydroxyvitamin d2 and 25-hydroxyvitamin d3 |
US20070212414A1 (en) * | 2006-03-08 | 2007-09-13 | Penwest Pharmaceuticals Co. | Ethanol-resistant sustained release formulations |
CN101400731A (zh) * | 2006-03-15 | 2009-04-01 | 城北化学工业株式会社 | 稳定化的聚烯烃类树脂和聚烯烃类树脂的稳定化方法 |
US20070281016A1 (en) * | 2006-06-06 | 2007-12-06 | Endo Pharmaceuticals Inc., A Delaware Corporation | Sustained release oxycodone composition with acrylic polymer and surfactant |
US20070281017A1 (en) * | 2006-06-06 | 2007-12-06 | Endo Pharmaceuticals Inc., A Delaware Corporation | Sustained release oxycodone composition with acrylic polymer and metal hydroxide |
US20080069891A1 (en) | 2006-09-15 | 2008-03-20 | Cima Labs, Inc. | Abuse resistant drug formulation |
PL2526932T3 (pl) | 2006-06-19 | 2017-12-29 | Alpharma Pharmaceuticals Llc | Kompozycja farmaceutyczna |
ES2670029T3 (es) | 2006-06-21 | 2018-05-29 | Opko Ireland Global Holdings, Ltd. | Terapia usando agente de repleción de la vitamina D y agente de reemplazo de la hormona de la vitamina D |
BRPI0714484A2 (pt) * | 2006-08-16 | 2013-04-24 | Auspex Pharmaceuticals Inc | composto, mÉtodo de tratar um mamÍfero sofrendo de uma doenÇa ou condiÇço, mÉtodo de tratar um memÍfero sofrendo de uma doenÇa, desordem, sintoma ou condiÇço e composiÇço farmacÊutica |
US8445018B2 (en) | 2006-09-15 | 2013-05-21 | Cima Labs Inc. | Abuse resistant drug formulation |
US8653066B2 (en) | 2006-10-09 | 2014-02-18 | Charleston Laboratories, Inc. | Pharmaceutical compositions |
US8337883B2 (en) | 2006-11-03 | 2012-12-25 | Durect Corporation | Transdermal delivery systems |
DE102007011485A1 (de) | 2007-03-07 | 2008-09-11 | Grünenthal GmbH | Darreichungsform mit erschwertem Missbrauch |
US11752158B2 (en) | 2007-04-25 | 2023-09-12 | Eirgen Pharma Ltd. | Method of treating vitamin D insufficiency and deficiency |
CA2683514C (en) | 2007-04-25 | 2019-07-09 | Proventiv Therapeutics, Llc | Method of safely and effectively treating and preventing secondary hyperparathyroidism in chronic kidney disease |
KR101691876B1 (ko) | 2007-04-25 | 2017-01-02 | 사이토크로마 인코포레이티드 | 비타민 d 화합물과 밀랍성 담체를 포함하는 경구 조절성 방출 조성물 |
US8202542B1 (en) | 2007-05-31 | 2012-06-19 | Tris Pharma | Abuse resistant opioid drug-ion exchange resin complexes having hybrid coatings |
AU2008258596B2 (en) | 2007-06-04 | 2013-02-14 | Egalet Ltd | Controlled release pharmaceutical compositions for prolonged effect |
US20090124650A1 (en) * | 2007-06-21 | 2009-05-14 | Endo Pharmaceuticals, Inc. | Method of Treating Pain Utilizing Controlled Release Oxymorphone Pharmaceutical Compositions and Instructions on Effects of Alcohol |
US20080318994A1 (en) * | 2007-06-21 | 2008-12-25 | Endo Pharmaceuticals, Inc. | Method of Treating Pain Utilizing Controlled Release Oxymorphone Pharmaceutical Compositions and Instruction on Dosing for Renal Impairment |
US20080318993A1 (en) * | 2007-06-21 | 2008-12-25 | Endo Pharmaceuticals, Inc. | Method of Treating Pain Utilizing Controlled Release Oxymorphone Pharmaceutical Compositions and Instruction on Dosing for Hepatic Impairment |
JP5730572B2 (ja) * | 2007-09-13 | 2015-06-10 | シマ ラブス インク. | 濫用抵抗性製剤 |
PT2057984E (pt) | 2007-11-09 | 2010-03-10 | Acino Pharma Ag | Comprimidos retard com hidromorfona |
CA2706658A1 (en) | 2007-12-06 | 2009-06-18 | Durect Corporation | Methods useful for the treatment of pain, arthritic conditions or inflammation associated with a chronic condition |
AU2008346870A1 (en) * | 2007-12-17 | 2009-07-16 | Alpharma Pharmaceuticals, Llc | Pharmaceutical composition |
US8623418B2 (en) | 2007-12-17 | 2014-01-07 | Alpharma Pharmaceuticals Llc | Pharmaceutical composition |
US20100151014A1 (en) * | 2008-12-16 | 2010-06-17 | Alpharma Pharmaceuticals, Llc | Pharmaceutical composition |
EP2240022B1 (en) | 2008-01-09 | 2016-12-28 | Charleston Laboratories, Inc. | Bilayered tablets comprising oxycodone and promethazine |
EP2249811A1 (en) * | 2008-01-25 | 2010-11-17 | Grünenthal GmbH | Pharmaceutical dosage form |
US20090246276A1 (en) | 2008-01-28 | 2009-10-01 | Graham Jackson | Pharmaceutical Compositions |
US9226907B2 (en) | 2008-02-01 | 2016-01-05 | Abbvie Inc. | Extended release hydrocodone acetaminophen and related methods and uses thereof |
KR101094231B1 (ko) | 2008-02-18 | 2011-12-14 | 하나제약 주식회사 | 서방성 고형 제제 및 그의 제조방법 |
WO2009114648A1 (en) | 2008-03-11 | 2009-09-17 | Depomed Inc. | Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic |
US8372432B2 (en) | 2008-03-11 | 2013-02-12 | Depomed, Inc. | Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic |
EP3112476B1 (en) | 2008-04-02 | 2023-08-02 | EirGen Pharma Ltd. | Methods, compositions, uses, and kits useful for vitamin d deficiency and related disorders |
US20100004762A1 (en) * | 2008-04-24 | 2010-01-07 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Computational system and method for memory modification |
US20100125561A1 (en) * | 2008-04-24 | 2010-05-20 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Computational system and method for memory modification |
US20100041958A1 (en) * | 2008-04-24 | 2010-02-18 | Searete Llc | Computational system and method for memory modification |
US9282927B2 (en) | 2008-04-24 | 2016-03-15 | Invention Science Fund I, Llc | Methods and systems for modifying bioactive agent use |
US9662391B2 (en) * | 2008-04-24 | 2017-05-30 | The Invention Science Fund I Llc | Side effect ameliorating combination therapeutic products and systems |
US20100069724A1 (en) * | 2008-04-24 | 2010-03-18 | Searete Llc | Computational system and method for memory modification |
US20090270694A1 (en) * | 2008-04-24 | 2009-10-29 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Methods and systems for monitoring and modifying a combination treatment |
US20100130811A1 (en) * | 2008-04-24 | 2010-05-27 | Searete Llc | Computational system and method for memory modification |
US20100081861A1 (en) * | 2008-04-24 | 2010-04-01 | Searete Llc | Computational System and Method for Memory Modification |
US9560967B2 (en) * | 2008-04-24 | 2017-02-07 | The Invention Science Fund I Llc | Systems and apparatus for measuring a bioactive agent effect |
US20100280332A1 (en) * | 2008-04-24 | 2010-11-04 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Methods and systems for monitoring bioactive agent use |
US9649469B2 (en) * | 2008-04-24 | 2017-05-16 | The Invention Science Fund I Llc | Methods and systems for presenting a combination treatment |
US8876688B2 (en) * | 2008-04-24 | 2014-11-04 | The Invention Science Fund I, Llc | Combination treatment modification methods and systems |
US20100041964A1 (en) * | 2008-04-24 | 2010-02-18 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Methods and systems for monitoring and modifying a combination treatment |
US20090269329A1 (en) * | 2008-04-24 | 2009-10-29 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Combination Therapeutic products and systems |
US20090271009A1 (en) * | 2008-04-24 | 2009-10-29 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Combination treatment modification methods and systems |
US9239906B2 (en) * | 2008-04-24 | 2016-01-19 | The Invention Science Fund I, Llc | Combination treatment selection methods and systems |
US20090312595A1 (en) * | 2008-04-24 | 2009-12-17 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | System and method for memory modification |
US20100076249A1 (en) * | 2008-04-24 | 2010-03-25 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Computational system and method for memory modification |
US20090270688A1 (en) * | 2008-04-24 | 2009-10-29 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Methods and systems for presenting a combination treatment |
US20100081860A1 (en) * | 2008-04-24 | 2010-04-01 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Computational System and Method for Memory Modification |
US20090271122A1 (en) * | 2008-04-24 | 2009-10-29 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Methods and systems for monitoring and modifying a combination treatment |
US20100100036A1 (en) * | 2008-04-24 | 2010-04-22 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Computational System and Method for Memory Modification |
US20090271347A1 (en) * | 2008-04-24 | 2009-10-29 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Methods and systems for monitoring bioactive agent use |
US20100042578A1 (en) * | 2008-04-24 | 2010-02-18 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Computational system and method for memory modification |
US20100063368A1 (en) * | 2008-04-24 | 2010-03-11 | Searete Llc, A Limited Liability Corporation | Computational system and method for memory modification |
US9026369B2 (en) * | 2008-04-24 | 2015-05-05 | The Invention Science Fund I, Llc | Methods and systems for presenting a combination treatment |
US9449150B2 (en) * | 2008-04-24 | 2016-09-20 | The Invention Science Fund I, Llc | Combination treatment selection methods and systems |
US8930208B2 (en) * | 2008-04-24 | 2015-01-06 | The Invention Science Fund I, Llc | Methods and systems for detecting a bioactive agent effect |
US9064036B2 (en) * | 2008-04-24 | 2015-06-23 | The Invention Science Fund I, Llc | Methods and systems for monitoring bioactive agent use |
US20090312668A1 (en) * | 2008-04-24 | 2009-12-17 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Computational system and method for memory modification |
US20090271375A1 (en) * | 2008-04-24 | 2009-10-29 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Combination treatment selection methods and systems |
US20100022820A1 (en) * | 2008-04-24 | 2010-01-28 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Computational system and method for memory modification |
US20100017001A1 (en) * | 2008-04-24 | 2010-01-21 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Computational system and method for memory modification |
HUE030803T2 (en) | 2008-05-09 | 2017-06-28 | Gruenenthal Gmbh | Process for the preparation of an intermediate powder formulation and a final solid dosage form using a spraying step \ t |
US20090291975A1 (en) * | 2008-05-20 | 2009-11-26 | Warren Stern | Dual opioid pain therapy |
ES2635733T3 (es) * | 2008-07-07 | 2017-10-04 | Euro-Celtique S.A. | Uso de antagonistas opioideos para tratar la retención urinaria |
US20100260844A1 (en) | 2008-11-03 | 2010-10-14 | Scicinski Jan J | Oral pharmaceutical dosage forms |
NZ594207A (en) | 2009-02-06 | 2013-03-28 | Egalet Ltd | Immediate release composition resistant to abuse by intake of alcohol |
EP3045043B1 (en) | 2009-02-26 | 2020-04-29 | Relmada Therapeutics, Inc. | Extended release oral pharmaceutical compositions of 3-hydroxy-n-methylmorphinan and method of use |
SG174286A1 (en) | 2009-03-10 | 2011-10-28 | Euro Celtique Sa | Immediate release pharmaceutical compositions comprising oxycodone and naloxone |
US8811578B2 (en) * | 2009-03-23 | 2014-08-19 | Telemanager Technologies, Inc. | System and method for providing local interactive voice response services |
EP2445487A2 (en) | 2009-06-24 | 2012-05-02 | Egalet Ltd. | Controlled release formulations |
WO2011006012A1 (en) | 2009-07-08 | 2011-01-13 | Charleston Laboratories Inc. | Pharmaceutical compositions |
EP2456427B1 (en) | 2009-07-22 | 2015-03-04 | Grünenthal GmbH | Hot-melt extruded controlled release dosage form |
PE20120572A1 (es) * | 2009-07-22 | 2012-06-06 | Gruenenthal Chemie | Forma de dosificacion de oxidacion estabilizada resistente a la manipulacion |
US20110046173A1 (en) * | 2009-08-24 | 2011-02-24 | Warren Charles Stern | Combination analgesic opioid pain therapy |
AU2010286354A1 (en) * | 2009-08-31 | 2012-04-19 | Depomed, Inc. | Gastric retentive pharmaceutical compositions for immediate and extended release of acetaminophen |
AU2010300641B2 (en) * | 2009-09-30 | 2016-03-17 | Acura Pharmaceuticals, Inc. | Methods and compositions for deterring abuse |
US20110104272A1 (en) * | 2009-11-05 | 2011-05-05 | Depomed, Inc. | Gastric retentive extended-release dosage forms comprising combinations of acetaminophen and phenylephrine |
US10668060B2 (en) | 2009-12-10 | 2020-06-02 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
US9198861B2 (en) | 2009-12-22 | 2015-12-01 | Mallinckrodt Llc | Methods of producing stabilized solid dosage pharmaceutical compositions containing morphinans |
US8597681B2 (en) | 2009-12-22 | 2013-12-03 | Mallinckrodt Llc | Methods of producing stabilized solid dosage pharmaceutical compositions containing morphinans |
EP2531176B1 (en) * | 2010-02-03 | 2016-09-07 | Grünenthal GmbH | Preparation of a powdery pharmaceutical composition by means of an extruder |
JP5819329B2 (ja) * | 2010-03-09 | 2015-11-24 | アルカーメス ファーマ アイルランド リミテッド | アルコール耐性腸溶性医薬組成物 |
HUE048464T2 (hu) | 2010-03-29 | 2020-07-28 | Opko Ireland Global Holdings Ltd | Módszerek és készítmények mellékpajzsmirigy szintjének csökkentésére |
MX2012012991A (es) | 2010-05-11 | 2012-11-30 | Cima Labs Inc | Formas de dosificacion oral de liberacion prolongada resistentes al alcohol y que contienen metoprolol. |
US20120009261A1 (en) | 2010-07-06 | 2012-01-12 | Grünenthal GmbH | Novel gastro-retentive dosage forms |
PE20131126A1 (es) | 2010-09-02 | 2013-10-21 | Gruenenthal Chemie | Forma de dosificacion resistente a alteracion que comprende un polimero anionico |
NZ607392A (en) | 2010-09-02 | 2015-03-27 | Gruenenthal Chemie | Tamper resistant dosage form comprising inorganic salt |
ES2444591T3 (es) | 2010-10-28 | 2014-02-25 | Acino Pharma Ag | Medicamento con el principio activo hidromorfona con estabilidad al almacenamiento mejorada |
ES2643291T3 (es) | 2010-12-22 | 2017-11-22 | Purdue Pharma L.P. | Formas de dosificación de liberación controlada con cierre inviolable recubiertas |
CA2822769C (en) | 2010-12-23 | 2016-10-04 | Purdue Pharma L.P. | Tamper resistant solid oral dosage forms |
KR20160031038A (ko) | 2011-02-02 | 2016-03-21 | 알파마 파머슈티컬스 엘엘씨 | 오피오이드 효능제 및 격리된 길항제를 포함하는 제약 조성물 |
US9119809B2 (en) | 2011-03-23 | 2015-09-01 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US9498447B2 (en) | 2011-03-23 | 2016-11-22 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US10292937B2 (en) | 2011-03-23 | 2019-05-21 | Ironshore Pharmaceuticals & Development, Inc. | Methods of treatment of attention deficit hyperactivity disorder |
US8927010B2 (en) | 2011-03-23 | 2015-01-06 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US11241391B2 (en) | 2011-03-23 | 2022-02-08 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US8916588B2 (en) | 2011-03-23 | 2014-12-23 | Ironshore Pharmaceuticals & Development, Inc. | Methods for treatment of attention deficit hyperactivity disorder |
US9603809B2 (en) | 2011-03-23 | 2017-03-28 | Ironshore Pharmaceuticals & Development, Inc. | Methods of treatment of attention deficit hyperactivity disorder |
EP4011364B1 (en) | 2011-03-23 | 2023-12-13 | Ironshore Pharmaceuticals & Development, Inc. | Methods and compositions for treatment of attention deficit disorder |
US10905652B2 (en) | 2011-03-23 | 2021-02-02 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US9283214B2 (en) | 2011-03-23 | 2016-03-15 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US8741885B1 (en) | 2011-05-17 | 2014-06-03 | Mallinckrodt Llc | Gastric retentive extended release pharmaceutical compositions |
US8858963B1 (en) | 2011-05-17 | 2014-10-14 | Mallinckrodt Llc | Tamper resistant composition comprising hydrocodone and acetaminophen for rapid onset and extended duration of analgesia |
US9050335B1 (en) | 2011-05-17 | 2015-06-09 | Mallinckrodt Llc | Pharmaceutical compositions for extended release of oxycodone and acetaminophen resulting in a quick onset and prolonged period of analgesia |
HUE031251T2 (en) | 2011-06-30 | 2017-07-28 | Develco Pharma Schweiz Ag | Controlled release oral dosage form containing oxycodone |
EP2736495B1 (en) | 2011-07-29 | 2017-08-23 | Grünenthal GmbH | Tamper-resistant tablet providing immediate drug release |
DK2736497T3 (da) | 2011-07-29 | 2017-11-13 | Gruenenthal Gmbh | Stød-resistent tablet, der tilvejebringer en øjeblikkelig frigivelse af et lægemiddel. |
MX356421B (es) | 2012-02-28 | 2018-05-29 | Gruenenthal Gmbh | Forma de dosificacion resistente a la manipulacion indebida que comprende un compuesto farmacologicamente activo y un polimero anionico. |
WO2013153451A2 (en) * | 2012-04-09 | 2013-10-17 | QRxPharma Ltd. | Controlled release formulations of opioids |
CN110101702A (zh) | 2012-04-17 | 2019-08-09 | 普渡制药公司 | 用于治疗阿片样物质所致不良药效学响应的系统和方法 |
LT2838512T (lt) | 2012-04-18 | 2018-11-12 | GrĆ¼nenthal GmbH | Pažeidimui atspari ir dozės atpalaidavimo nuokrypiui atspari farmacinė vaisto forma |
US10064945B2 (en) | 2012-05-11 | 2018-09-04 | Gruenenthal Gmbh | Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc |
EP2877161A1 (en) | 2012-07-06 | 2015-06-03 | Egalet Ltd. | Abuse deterrent pharmaceutical compositions for controlled release |
EP2872121B1 (en) | 2012-07-12 | 2018-09-05 | SpecGx LLC | Extended release, abuse deterrent pharmaceutical compositions |
US9101636B2 (en) | 2012-11-30 | 2015-08-11 | Acura Pharmaceuticals, Inc. | Methods and compositions for self-regulated release of active pharmaceutical ingredient |
KR101840526B1 (ko) | 2013-02-05 | 2018-03-20 | 퍼듀 퍼머 엘피 | 내변조성 제약 제제 |
CN105120659A (zh) | 2013-03-15 | 2015-12-02 | 度瑞公司 | 用于降低溶解可变性的具有流变改性剂的组合物 |
KR101847947B1 (ko) | 2013-03-15 | 2018-05-28 | 옵코 아이피 홀딩스 Ⅱ 인코포레이티드 | 안정화되고 변형된 비타민 d 방출 제형 |
US10751287B2 (en) | 2013-03-15 | 2020-08-25 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
US10154966B2 (en) | 2013-05-29 | 2018-12-18 | Grünenthal GmbH | Tamper-resistant dosage form containing one or more particles |
MX2015016254A (es) | 2013-05-29 | 2016-04-20 | Gruenenthal Gmbh | Forma de dosificacion resistente al uso indebido con perfil de liberacion bimodal. |
KR20160031526A (ko) | 2013-07-12 | 2016-03-22 | 그뤼넨탈 게엠베하 | 에틸렌-비닐 아세테이트 중합체를 함유하는 템퍼 내성 투여형 |
NZ716267A (en) | 2013-07-23 | 2017-05-26 | Euro Celtique Sa | A combination of oxycodone and naloxone for use in treating pain in patients suffering from pain and a disease resulting in intestinal dysbiosis and/or increasing the risk for intestinal bacterial translocation |
CA3042642A1 (en) | 2013-08-12 | 2015-02-19 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded immediate release abuse deterrent pill |
WO2015065547A1 (en) | 2013-10-31 | 2015-05-07 | Cima Labs Inc. | Immediate release abuse-deterrent granulated dosage forms |
CA2931553C (en) | 2013-11-26 | 2022-01-18 | Grunenthal Gmbh | Preparation of a powdery pharmaceutical composition by means of cryo-milling |
US9492444B2 (en) | 2013-12-17 | 2016-11-15 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
US10172797B2 (en) | 2013-12-17 | 2019-01-08 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
AU2015237723B2 (en) | 2014-03-26 | 2018-04-26 | Sun Pharma Advanced Research Company Ltd. | Abuse deterrent immediate release biphasic matrix solid dosage form |
EP3142646A1 (en) | 2014-05-12 | 2017-03-22 | Grünenthal GmbH | Tamper resistant immediate release capsule formulation comprising tapentadol |
US9872835B2 (en) | 2014-05-26 | 2018-01-23 | Grünenthal GmbH | Multiparticles safeguarded against ethanolic dose-dumping |
TW202136296A (zh) | 2014-06-27 | 2021-10-01 | 美商C2N醫療診斷有限責任公司 | 人類化抗-tau抗體 |
EP3169315B1 (en) | 2014-07-17 | 2020-06-24 | Pharmaceutical Manufacturing Research Services, Inc. | Immediate release abuse deterrent liquid fill dosage form |
SG10201911274TA (en) | 2014-08-07 | 2020-02-27 | Opko Ireland Global Holdings Ltd | Adjunctive therapy with 25-hydroxyvitamin d |
US9849124B2 (en) | 2014-10-17 | 2017-12-26 | Purdue Pharma L.P. | Systems and methods for treating an opioid-induced adverse pharmacodynamic response |
AU2015336065A1 (en) | 2014-10-20 | 2017-05-04 | Pharmaceutical Manufacturing Research Services, Inc. | Extended release abuse deterrent liquid fill dosage form |
CA2936740C (en) | 2014-10-31 | 2017-10-10 | Purdue Pharma | Methods and compositions particularly for treatment of attention deficit disorder |
WO2016170097A1 (en) | 2015-04-24 | 2016-10-27 | Grünenthal GmbH | Tamper-resistant dosage form with immediate release and resistance against solvent extraction |
WO2017040607A1 (en) | 2015-08-31 | 2017-03-09 | Acura Pharmaceuticals, Inc. | Methods and compositions for self-regulated release of active pharmaceutical ingredient |
WO2017042325A1 (en) | 2015-09-10 | 2017-03-16 | Grünenthal GmbH | Protecting oral overdose with abuse deterrent immediate release formulations |
US9943513B1 (en) | 2015-10-07 | 2018-04-17 | Banner Life Sciences Llc | Opioid abuse deterrent dosage forms |
JP2019507181A (ja) | 2016-03-04 | 2019-03-14 | チャールストン ラボラトリーズ,インコーポレイテッド | 医薬組成物 |
TWI747893B (zh) | 2016-03-28 | 2021-12-01 | 愛爾蘭商歐科愛爾蘭全球控股股份有限公司 | 維生素d治療之方法 |
US10335405B1 (en) | 2016-05-04 | 2019-07-02 | Patheon Softgels, Inc. | Non-burst releasing pharmaceutical composition |
WO2017222575A1 (en) | 2016-06-23 | 2017-12-28 | Collegium Pharmaceutical, Inc. | Process of making more stable abuse-deterrent oral formulations |
US10335375B2 (en) | 2017-05-30 | 2019-07-02 | Patheon Softgels, Inc. | Anti-overingestion abuse deterrent compositions |
WO2019087084A1 (en) | 2017-11-02 | 2019-05-09 | Eman Biodiscoveries Sd. Bhd. | Extract of orthosiphon stamineus, formulations, and uses thereof |
US10722473B2 (en) | 2018-11-19 | 2020-07-28 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
WO2020225773A1 (en) | 2019-05-07 | 2020-11-12 | Clexio Biosciences Ltd. | Abuse-deterrent dosage forms containing esketamine |
CA3167217A1 (en) | 2020-01-13 | 2021-07-22 | Durect Corporation | Sustained release drug delivery systems with reduced impurities and related methods |
CN115702888A (zh) * | 2021-08-13 | 2023-02-17 | 合肥立方制药股份有限公司 | 一种盐酸羟考酮渗透泵缓释片及其制备方法 |
Family Cites Families (104)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US291883A (en) * | 1884-01-15 | Faucet | ||
US2738303A (en) * | 1952-07-18 | 1956-03-13 | Smith Kline French Lab | Sympathomimetic preparation |
US2921883A (en) * | 1957-05-03 | 1960-01-19 | Smith Kline French Lab | Novel coating material for medicaments |
NL263733A (zh) * | 1960-04-19 | 1900-01-01 | ||
US4132753A (en) * | 1965-02-12 | 1979-01-02 | American Cyanamid Company | Process for preparing oral sustained release granules |
US3458622A (en) * | 1967-04-07 | 1969-07-29 | Squibb & Sons Inc | Controlled release tablet |
US3492397A (en) * | 1967-04-07 | 1970-01-27 | Warner Lambert Pharmaceutical | Sustained release dosage in the pellet form and process thereof |
US3634584A (en) * | 1969-02-13 | 1972-01-11 | American Home Prod | Sustained action dosage form |
US3870790A (en) * | 1970-01-22 | 1975-03-11 | Forest Laboratories | Solid pharmaceutical formulations containing hydroxypropyl methyl cellulose |
GB1405088A (en) † | 1971-06-03 | 1975-09-03 | Mundipharma Ag | Slow release formulation |
US3773920A (en) * | 1971-07-14 | 1973-11-20 | Nikken Chemicals Co Ltd | Sustained release medicinal composition |
US3965256A (en) * | 1972-05-16 | 1976-06-22 | Synergistics | Slow release pharmaceutical compositions |
US3845770A (en) * | 1972-06-05 | 1974-11-05 | Alza Corp | Osmatic dispensing device for releasing beneficial agent |
US3916899A (en) * | 1973-04-25 | 1975-11-04 | Alza Corp | Osmotic dispensing device with maximum and minimum sizes for the passageway |
US3922339A (en) * | 1974-06-20 | 1975-11-25 | Kv Pharm Co | Sustained release medicant |
GB1478759A (en) * | 1974-11-18 | 1977-07-06 | Alza Corp | Process for forming outlet passageways in pills using a laser |
US3946899A (en) * | 1975-02-07 | 1976-03-30 | Allain Charles V | Sugar cane planter |
JPS5535031A (en) * | 1978-09-04 | 1980-03-11 | Shin Etsu Chem Co Ltd | Enteric coating composition |
WO1980000659A1 (en) * | 1978-10-02 | 1980-04-17 | Purdue Research Foundation | Food and pharmaceutical coating composition,method of preparation and products so coated |
IE48715B1 (en) * | 1978-12-22 | 1985-05-01 | Elan Corp Plc | New galencial forms for administration of medicaments by oral route,with programmed release and processes for preparing same |
FI63335B (fi) * | 1979-02-02 | 1983-02-28 | Orion Yhtymae Oy | Foerfarande foer framstaellning av tabletter med foerdroejd loslighet av effektaemne |
US4259314A (en) * | 1979-12-10 | 1981-03-31 | Hans Lowey | Method and composition for the preparation of controlled long-acting pharmaceuticals |
DE3024416C2 (de) * | 1980-06-28 | 1982-04-15 | Gödecke AG, 1000 Berlin | Verfahren zur Herstellung von Arzneimitteln mit retardierter Wirkstoff-Freisetzung |
US4464378A (en) * | 1981-04-28 | 1984-08-07 | University Of Kentucky Research Foundation | Method of administering narcotic antagonists and analgesics and novel dosage forms containing same |
DE3126703A1 (de) * | 1981-07-07 | 1983-01-27 | Dr. Karl Thomae Gmbh, 7950 Biberach | Bromhexin-retardform und verfahren zu ihrer herstellung |
US4377568A (en) * | 1981-08-12 | 1983-03-22 | Merck Sharp & Dohme (I.A.) Corp. | Preparation of aqueous alcoholic dispersions of pH sensitive polymers and plasticizing agents and a method of enteric coating dosage forms using same |
US4369172A (en) † | 1981-12-18 | 1983-01-18 | Forest Laboratories Inc. | Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose |
DE3208791A1 (de) * | 1982-03-11 | 1983-09-22 | Röhm GmbH, 6100 Darmstadt | Verfahren zum ueberziehen von arzneiformen mittes eines in wasser dispergierten ueberzugsmittels |
US4389393A (en) * | 1982-03-26 | 1983-06-21 | Forest Laboratories, Inc. | Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose |
US4443428A (en) * | 1982-06-21 | 1984-04-17 | Euroceltique, S.A. | Extended action controlled release compositions |
DE3314003A1 (de) * | 1983-04-18 | 1984-10-18 | Boehringer Ingelheim KG, 6507 Ingelheim | Teilbare tablette mit verzoegerter wirkstofffreigabe und verfahren zu deren herstellung |
US4548990A (en) * | 1983-08-15 | 1985-10-22 | Ciba-Geigy Corporation | Crosslinked, porous polymers for controlled drug delivery |
US4629621A (en) * | 1984-07-23 | 1986-12-16 | Zetachron, Inc. | Erodible matrix for sustained release bioactive composition |
US4894234A (en) * | 1984-10-05 | 1990-01-16 | Sharma Shri C | Novel drug delivery system for antiarrhythmics |
JPS61152765A (ja) * | 1984-12-27 | 1986-07-11 | Nippon Ekishiyou Kk | シクロデキストリン類で包接された化合物を含有した合成樹脂製品及びその製造方法 |
US4600645A (en) * | 1985-01-31 | 1986-07-15 | Warner-Lambert Company | Process for treating dosage forms |
NL8500724A (nl) * | 1985-03-13 | 1986-10-01 | Univ Groningen | Inrichtingen voor geregelde afgifte van werkzame stoffen, alsmede werkwijze ter vervaardiging daarvan. |
ATE84713T1 (de) * | 1985-05-13 | 1993-02-15 | Miles Inc | Verwendung von kalziumantagonisten zur anfertigung von zusammensetzungen fuer entziehungssymptome. |
GB8519310D0 (en) * | 1985-07-31 | 1985-09-04 | Zyma Sa | Granular active substances |
GB8521350D0 (en) * | 1985-08-28 | 1985-10-02 | Euro Celtique Sa | Analgesic composition |
GB8613689D0 (en) * | 1986-06-05 | 1986-07-09 | Euro Celtique Sa | Pharmaceutical composition |
GB8613688D0 (en) * | 1986-06-05 | 1986-07-09 | Euro Celtique Sa | Pharmaceutical composition |
EP0249347B1 (en) † | 1986-06-10 | 1994-06-29 | Euroceltique S.A. | Controlled release dihydrocodeine composition |
US4970075A (en) † | 1986-07-18 | 1990-11-13 | Euroceltique, S.A. | Controlled release bases for pharmaceuticals |
US4861598A (en) * | 1986-07-18 | 1989-08-29 | Euroceltique, S.A. | Controlled release bases for pharmaceuticals |
GB8626098D0 (en) * | 1986-10-31 | 1986-12-03 | Euro Celtique Sa | Controlled release hydromorphone composition |
US5026560A (en) * | 1987-01-29 | 1991-06-25 | Takeda Chemical Industries, Ltd. | Spherical granules having core and their production |
US5266311A (en) * | 1987-05-28 | 1993-11-30 | Immunex Corporation | Bovine interleukin-1α |
US5219575A (en) * | 1987-06-26 | 1993-06-15 | Duphar International Research B.V. | Compositions with controlled zero-order delivery rate and method of preparing these compositions |
DE3721721C1 (de) * | 1987-07-01 | 1988-06-09 | Hoechst Ag | Verfahren zur Umhuellung von Granulaten |
US5068110A (en) * | 1987-09-29 | 1991-11-26 | Warner-Lambert Company | Stabilization of enteric coated dosage form |
US4862598A (en) * | 1987-10-01 | 1989-09-05 | Perceptron, Inc. | Quick connect/disconnect repeatable sensor mounting apparatus |
US5019397A (en) * | 1988-04-21 | 1991-05-28 | Alza Corporation | Aqueous emulsion for pharmaceutical dosage form |
US5024842A (en) * | 1988-04-28 | 1991-06-18 | Alza Corporation | Annealed coats |
JPH01287019A (ja) * | 1988-05-12 | 1989-11-17 | Tanabe Seiyaku Co Ltd | 徐放性製剤 |
JP2681373B2 (ja) * | 1988-07-18 | 1997-11-26 | 塩野義製薬株式会社 | 徐放性製剤の製造法 |
JP2850376B2 (ja) * | 1988-08-02 | 1999-01-27 | 日産化学工業株式会社 | 抗癌剤薬効増強剤 |
US4983730A (en) * | 1988-09-02 | 1991-01-08 | Hoechst Celanese Corporation | Water soluble cellulose acetate composition having improved processability and tensile properties |
US5178868A (en) * | 1988-10-26 | 1993-01-12 | Kabi Pharmacia Aktiebolaq | Dosage form |
US5196203A (en) * | 1989-01-06 | 1993-03-23 | F. H. Faulding & Co. Limited | Theophylline dosage form |
US5330766A (en) * | 1989-01-06 | 1994-07-19 | F. H. Faulding & Co. Limited | Sustained release pharmaceutical composition |
US5202128A (en) * | 1989-01-06 | 1993-04-13 | F. H. Faulding & Co. Limited | Sustained release pharmaceutical composition |
US5007790A (en) * | 1989-04-11 | 1991-04-16 | Depomed Systems, Inc. | Sustained-release oral drug dosage form |
US5126145A (en) * | 1989-04-13 | 1992-06-30 | Upsher Smith Laboratories Inc | Controlled release tablet containing water soluble medicament |
US5133974A (en) * | 1989-05-05 | 1992-07-28 | Kv Pharmaceutical Company | Extended release pharmaceutical formulations |
US5122384A (en) * | 1989-05-05 | 1992-06-16 | Kv Pharmaceutical Company | Oral once-per-day organic nitrate formulation which does not induce tolerance |
FR2648020B1 (fr) * | 1989-06-12 | 1992-03-13 | Rhone Poulenc Sante | Utilisation de compositions degradables par voie enzymatique pour l'enrobage d'additifs alimentaires destines aux ruminants |
DK161743C (da) * | 1989-07-03 | 1992-02-17 | Niro Atomizer As | Fremgangsmaade og apparat til agglomerering af et pulverformigt materiale |
EP0418596A3 (en) * | 1989-09-21 | 1991-10-23 | American Cyanamid Company | Controlled release pharmaceutical compositions from spherical granules in tabletted oral dosage unit form |
US5248516A (en) * | 1989-12-19 | 1993-09-28 | Fmc Corporation | Film-forming composition: method of producing same and use for coating pharmaceuticals and foods and the like |
IE66933B1 (en) * | 1990-01-15 | 1996-02-07 | Elan Corp Plc | Controlled absorption naproxen formulation for once-daily administration |
US5206030A (en) * | 1990-02-26 | 1993-04-27 | Fmc Corporation | Film-forming composition and use for coating pharmaceuticals, foods and the like |
JP2542122B2 (ja) * | 1990-04-18 | 1996-10-09 | 旭化成工業株式会社 | 球状核、球形顆粒およびその製造方法 |
DK0472502T3 (da) * | 1990-08-24 | 1995-10-09 | Spirig Ag | Fremgangsmåde til fremstilling af pellets |
JP2669945B2 (ja) * | 1991-02-05 | 1997-10-29 | ファナック株式会社 | ならい制御装置 |
US5132142A (en) * | 1991-03-19 | 1992-07-21 | Glatt Gmbh | Apparatus and method for producing pellets by layering power onto particles |
CA2108575C (en) * | 1991-04-16 | 2002-10-22 | Kouichi Nakamichi | Method of manufacturing solid dispersion |
KR100221695B1 (ko) * | 1991-08-12 | 1999-09-15 | 그린 마틴, 브라이언 쥐 테슬리 | 약학적 구상 제형 |
US5215758A (en) * | 1991-09-11 | 1993-06-01 | Euroceltique, S.A. | Controlled release matrix suppository for pharmaceuticals |
US5266331A (en) * | 1991-11-27 | 1993-11-30 | Euroceltique, S.A. | Controlled release oxycodone compositions |
US5656295A (en) * | 1991-11-27 | 1997-08-12 | Euro-Celtique, S.A. | Controlled release oxycodone compositions |
US5958459A (en) * | 1991-12-24 | 1999-09-28 | Purdue Pharma L.P. | Opioid formulations having extended controlled released |
US5681585A (en) * | 1991-12-24 | 1997-10-28 | Euro-Celtique, S.A. | Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer |
US5968551A (en) * | 1991-12-24 | 1999-10-19 | Purdue Pharma L.P. | Orally administrable opioid formulations having extended duration of effect |
US5273760A (en) † | 1991-12-24 | 1993-12-28 | Euroceltigue, S.A. | Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer |
US5478577A (en) * | 1993-11-23 | 1995-12-26 | Euroceltique, S.A. | Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level |
US5286493A (en) † | 1992-01-27 | 1994-02-15 | Euroceltique, S.A. | Stabilized controlled release formulations having acrylic polymer coating |
GB9202464D0 (en) * | 1992-02-05 | 1992-03-18 | Danbiosyst Uk | Composition for nasal administration |
SE9202250D0 (sv) * | 1992-07-29 | 1992-07-29 | Gacell Lab Ab | Controlled release morphine preparation |
US5324351A (en) * | 1992-08-13 | 1994-06-28 | Euroceltique | Aqueous dispersions of zein and preparation thereof |
US5321012A (en) * | 1993-01-28 | 1994-06-14 | Virginia Commonwealth University Medical College | Inhibiting the development of tolerance to and/or dependence on a narcotic addictive substance |
CA2115792C (en) * | 1993-03-05 | 2005-11-01 | David J. Mayer | Method for the treatment of pain |
SE9301057L (sv) * | 1993-03-30 | 1994-10-01 | Pharmacia Ab | Beredning med kontrollerad frisättning |
IL110014A (en) * | 1993-07-01 | 1999-11-30 | Euro Celtique Sa | Solid controlled-release oral dosage forms of opioid analgesics |
US5879705A (en) * | 1993-07-27 | 1999-03-09 | Euro-Celtique S.A. | Sustained release compositions of morphine and a method of preparing pharmaceutical compositions |
DE4329794C2 (de) * | 1993-09-03 | 1997-09-18 | Gruenenthal Gmbh | Tramadolsalz enthaltende Arzneimittel mit verzögerter Wirkstofffreisetzung |
US5891471A (en) * | 1993-11-23 | 1999-04-06 | Euro-Celtique, S.A. | Pharmaceutical multiparticulates |
US5500227A (en) * | 1993-11-23 | 1996-03-19 | Euro-Celtique, S.A. | Immediate release tablet cores of insoluble drugs having sustained-release coating |
KR100354702B1 (ko) * | 1993-11-23 | 2002-12-28 | 유로-셀티크 소시에떼 아노뉨 | 약학조성물의제조방법및서방형조성물 |
US5411745A (en) * | 1994-05-25 | 1995-05-02 | Euro-Celtique, S.A. | Powder-layered morphine sulfate formulations |
US5460826A (en) * | 1994-06-27 | 1995-10-24 | Alza Corporation | Morphine therapy |
US5965161A (en) * | 1994-11-04 | 1999-10-12 | Euro-Celtique, S.A. | Extruded multi-particulates |
US5811126A (en) * | 1995-10-02 | 1998-09-22 | Euro-Celtique, S.A. | Controlled release matrix for pharmaceuticals |
US6419960B1 (en) * | 1998-12-17 | 2002-07-16 | Euro-Celtique S.A. | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
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1991
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1992
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1995
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1999
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2000
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2001
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2002
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2003
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2004
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2005
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2006
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1090017C (zh) * | 1995-04-28 | 2002-09-04 | 安得克斯制药公司 | 原位形成通道的水溶性药物控释配方 |
CN102716101A (zh) * | 1999-10-29 | 2012-10-10 | 欧罗赛铁克股份有限公司 | 控释氢可酮制剂 |
CN101627974B (zh) * | 2001-05-02 | 2014-07-09 | 欧罗赛铁克股份有限公司 | 一日服用一次的羟考酮制剂 |
CN1774241B (zh) * | 2002-12-13 | 2010-05-05 | 杜雷科特公司 | 包含高粘度液体载体材料的口服递药系统 |
CN101534792B (zh) * | 2006-08-04 | 2013-02-20 | 爱的发 | 包含氧可酮的粒剂和口腔崩解片剂 |
US11304909B2 (en) | 2006-08-25 | 2022-04-19 | Purdue Pharma L.P. | Tamper resistant dosage forms |
US11304908B2 (en) | 2006-08-25 | 2022-04-19 | Purdue Pharma L.P. | Tamper resistant dosage forms |
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