CN102813654A - 含有羟氢可待酮和烯丙羟吗啡酮的药物制剂 - Google Patents
含有羟氢可待酮和烯丙羟吗啡酮的药物制剂 Download PDFInfo
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Abstract
本发明是关于一种含有用于治疗疼痛的羟氢可待酮及纳洛酮的贮存稳定性药物制剂,其特征在于活性化合物是以持续、稳定及独立的方式自该制剂释放。
Description
本申请是申请日为2003年4月4日、申请号为03807796.5(国际申请号为PCT/EP03/03540)、发明名称为“含有羟氢可待酮和烯丙羟吗啡酮的药物制剂”的发明专利申请的分案申请。
技术领域
本发明涉及一种含有羟氢可待酮(oxycodone)及纳洛酮(naloxone)的贮存稳定的药物制剂。
背景技术
治疗癌症、风湿病及关节炎等疾病造成的严重疼痛是治疗这些疾病的核心。肿瘤患者所感受到的疼痛范围包括骨膜及骨头本身的疼痛,以及内脏痛与软组织痛。所有这类疼痛使得患者日常生活难以忍受且经常导致抑郁状态。因此,可让病人生活质量持续改善成功的疼痛治疗,与综合疗法(此疗法是针对该疾病的实际病因加以治疗)的成功同等重要。
有关成功疼痛治疗的重要性,世界卫生组织(WHO)已经开发出治疗肿瘤疼痛患者的四步骤模式。此模式在日常操作上已经证明是有效的,且可延伸至患有慢性疼痛的患者、或患有癌症以外的疾病所造成的疼痛类型的患者。根据疼痛的强度、性质及位置,此疗法过程中可区分出四步骤,且直到所使用的疼痛缓解药物的效果不再足够,则需要下一步骤(Ebell.H.J.;Bayer A.(Ed.):Die Schmerzbehandlung von Tmuorpatienten,Thieme 1994(Supportive Maβnahmen in der Onkologie,Band 3)和Zech,D.;Grond,S.;Lynch,J.;Hertel,D.;Lehmann,K.:Validation of World Health Organisation Guidelines for Cancer Pain Relief:a 10-year prospective study,Pain(1995),63,65-76)。
根据WHO的这种四步骤模式,类鸦片(opioid)止痛剂在治疗疼痛上扮演着核心角色。除了代表这种药学活性药剂原型的吗啡之外,类鸦片止痛剂也包括羟氢可待酮、二氢吗啡酮(hydromorphone)、二烟酰吗啡 (nicomorphine)、二氢可待因(dihydrocodeine)、海洛因(diamorphine)、阿片金碱(papaveretum)、可待因、乙基吗啡、苯基哌啶及其衍生物;美沙酮(methadone)、右丙氧芬(dextropropoxyphene)、叔丁啡(buprenorphine)、喷他佐辛(pentazocine)、痛立定(tilidine)、曲马多(tramadol)及二氢可待因酮(hydrocodone)。WHO的ATC分类法(解剖学治疗化学分类法)指明一药学活性药物是否代表一类鸦片止痛剂。类鸦片止痛剂的显著疼痛缓解作用是由于模拟内源性、吗啡样作用物质(内源性阿片样物质)的作用所致,该内源性吗啡样作用物质的生理学功能在于控制疼痛刺激的接收与处理。
类鸦片抑制疼痛刺激的扩散。除了立即压抑脊髓内由类鸦片所引起的神经元兴奋性讯息传导作用之外,一种自脑杆发射至脊髓的神经途径活化作用也有关联。此活化作用导致脊髓内的疼痛扩散现象受到抑制。再者,类鸦片限制丘脑接收疼痛,并通过对边缘系统(limbic sytem)发生作用而影响情感性疼痛的评价。
类鸦片受体可于体内不同位置发现。肠与脑的受体对通过类鸦片的疼痛治疗尤其重要,特别是当这些受体被占据而导致不同副作用时。
若类鸦片止痛剂以高亲合性结合至类鸦片受体、且诱使疼痛的接收受到强烈抑制,则该类鸦片止痛剂视为强效的激动剂。以高亲合力与类鸦片受体结合但不引起疼痛接收减少从而拮抗类阿片激动剂的物质被设计为拮抗剂。根据结合行为及所诱发的活性,类鸦片可分类为单纯激动剂、混合型激动剂/拮抗剂、及单纯拮抗剂。举例而言,单纯拮抗剂包括例如纳曲酮(naltrexone)、纳洛酮(naloxone)、纳美芬(nalmefene)、烯丙吗啡(nalorphine)、环丁甲羟氢吗啡(nalbuphine)、纳洛酮爱新(naloxoneazinen)、甲基纳曲酮(methylnaltrexone)、凯迪赛新(ketylcyclazocine)、若宾纳芬明(norbbinaltorphimine)、纳屈吲哚(naltrindol)、6-β-纳龙头(naloxol)及6-β-纳淬头(naltrexol)(Forth W.,;Henschler,D.;Rummel W.;Starke,K.:Allgemeine und Spezielle Pharmakologie und Toxikologie,7.Auflage,1996,Spetrum Akademischer Verlag,Heidelberg Berlin Oxford)。
由于其良好的止痛功效,羟氢可待酮、痛立定、叔丁啡及喷他佐辛等化合物早已以治疗疼痛的药物形式而使用。例如 (其中羟氢可待因是止痛活性的化合物)及 (其中痛立定是止痛活性的化合物)等药物已经证实对治疗疼痛有效。
然而,使用类鸦片止痛剂治疗疼痛可能一并伴随着不理想的副作用。故长期使用类鸦片止痛剂可导致心理及生理依赖性。
特别是受疼痛所苦的患者对于类鸦片止痛剂的生理依赖性会导致耐药性的发展,这意味着伴随着长期摄入药物,患者为了要获得疼痛缓解,则渐渐提高疼痛缓解药物的剂量。类鸦片止痛剂令人心情愉快的作用经常造成疼痛缓解药物的滥用。药物滥用及心理依赖性是常见现象,尤其发生在青少年之间。这些危险性的影响尤其是由强效止痛能力的物质引起的,影响范围由不理想的习惯到完全发展为成瘾。但是这些物质是合法地使用于医疗用途上,且药物中不能没有这些物质。
除了上述缺点之外,使用类鸦片止痛剂治疗疼痛通常也会导致下列不理想的副作用:例如顽固性便秘、呼吸压抑(breath depression)、呕吐及镇静。比较不常观察到是,迫切需要喝水或无法喝水。已经完成各种尝试来对抗上瘾过程发生于疼痛治疗中的其他副作用。可利用例如传统治疗等方法造成这类尝试。就药物成瘾而言,可尝试药物停止疗法;就顽固性便秘而言,可施用通泻剂。
其他尝试通过施用对抗该类鸦片止痛剂的拮抗剂,其目的在于将上瘾和习惯养成倾向以及其他副作用减少至最低。这类拮抗剂可以是纳曲酮或纳洛酮。
目前有关如何施用上述活性化合物而能避免不理想的习惯养成及依赖性,或甚至成瘾已经有许多建议与教导。
美国专利US 3,773,955及3,966,940建议,当肠胃外给药时,为了预防依赖性增进作用例如心情愉快等,将止痛剂与纳曲酮组合制剂。至今尚无法避免顽固性便秘等副作用。
为了限制经口用药形式的肠胃外滥用,美国专利US 4,457,933建议将吗啡与纳曲酮于特定剂量范围内组合。该专利也没有提及如何避免顽固性便秘等副作用。
同样为了避免滥用,美国专利US 4,582,835描述一种不是肠胃外施用或舌下施用的制剂,其含有叔丁啡与纳曲酮的组合。
德国专利申请DE 0 352 361 A1涉及通过口服类鸦片止痛剂与拮抗剂治疗疼痛治疗过程中的顽固性便秘,该拮抗剂是纳曲酮或纳洛酮的前药形式。避免类鸦片止痛剂的滥用并非该申请案的重点。
德国专利申请DE 43 25 465 A1也涉及利用含有类鸦片止痛剂与拮抗剂的制剂治疗疼痛治疗过程中的顽固性便秘。该案揭示的技术特征为:拮抗剂(可以是烯丙烃吗啡酮)的剂量一定要比类鸦片止痛剂(优选吗啡)的剂量更高。这是为了确保拮抗剂可表现抗顽固性便秘的功效,但不降低激动剂的止痛活性。避免类鸦片止痛剂的滥用并非该申请案的重点。
为了要避免疼痛治疗过程中的副作用,例如顽固性便秘及呼吸抑制,市面上已经导入可经口施用的制剂,其含有类鸦片止痛剂与类鸦片拮抗剂(纳洛酮)。Windrop/Sterling公司的药品 含有喷他佐辛与纳洛酮。Godeke公司的药品 含有痛立定-纳洛酮的组合。
除了强止痛功效、减少成瘾可能性及避免副作用之外,适用于疼痛治疗的药物还应该提供更多特征。
一般而言,药物必须配制成活性化合物于标准贮存条件下尽可能稳定的方式。药物也必须配制成活性化合物预定的释放模式(release profiles)不随长期贮存而改变的形式。
再者,(同样也就激动剂/拮抗剂的组合而论)每一个单一活性化合物的释放模式应该可以视需要选择。为了达到此目的,所采用的措施不应该阻扰、甚至阻止其它活性化合物(例如,就不同活性化合物的组合时)的释放模式。因此,释放模式应该没有相互依赖性。
适用于疼痛治疗的药物应该含有活性化合物的剂量为患者只有在极少情况下才必须服用,或者应该以患者只有在极少情况下才必须服用该药物的方式调配。疼痛缓解剂的用药流程愈简单,患者愈能掌握其为何应该且应该以多高频率服用哪一个片剂,则病人更能确实遵照医生的命令。只是偶尔才有服用疼痛缓解剂的必要,将使得病人服用该疼痛解除剂的意愿高(顺从性)。
曾经尝试经由使用所谓的缓释制剂(即,活性化合物以长时间自药物释放的药物制剂)来减少止痛药物必须用药的频率,藉此增加患者的顺从性。这种缓释制剂也使得“类鸦片止痛剂的缓释可减少该活性化合物的成瘾可能性”一事得以理解。
由于活性化合物的成瘾可能性并非由该化合物本身决定,而是由施用该化合物的方式及所得到的药效学而定。除了类鸦片的促精神作用之外,大脑与类鸦片接触的频率,比该活性化合物本身而言,更是产生依赖性风险的决定性指标(Nolte,T.:STK-Zeitschrift fur angewandte Schmerztherapie,2001, Vol.2)。
根据先前提及的欧洲专利申请EP 0 352 361 A,类鸦片止痛剂或拮抗剂都没有配制成以持续方式释放。故此种制剂能有效作用的时间受到限制,且该制剂必须每天施用多次,无法达到所期望的病人顺从性。此专利申请案中也没有揭示该制剂配方的优点是以活性化合物的经时稳定和独立释放为特征。该制剂的贮存稳定性也未记载于该案的技术内容中。
德国专利申请DE 43 25 465 A1揭示的配方可预防疼痛治疗过程中发生的顽固性便秘,其是利用持续释放类鸦片止痛剂,超量存在的拮抗剂则一定不能以持续方式释放。由于纳洛酮的高首过效应,因此必须使用相当大量的该化合物。此专利申请案并没有揭示制剂的优点,也无该制剂的配方,该制剂是以活性合物的经时稳定和独立释放为特征。这类制剂的贮存稳定性并非该案技术内容的重点。故医生根据此案技术内容而使用制剂时,每次当他想增加剂量,就必须进行大量的滴定实验。
Godeke公司提供商品名为 的疼痛缓解剂,其含有痛立定-纳洛酮的组合。根据产品说明,其是使用一种配方可让两种活性化合物以持续方式释放。所使用的基质包括适当比例的水可膨胀物质(HPMC),故该基质被视为一种可膨胀(可能有部分腐蚀性)的扩散基质(diffusion matrix)。此种已知配方的缺点为,痛立定与纳洛酮是给予相同的质量比,但绝对含量不同,故两种化合物会呈现不同的释放模式。激动剂与拮抗剂的释放速率互相独立,可能是由所使用的持续释放配方所致。因此,医生若想要增加剂量,即使并不改变痛立定:纳洛酮的质量比时,由于他无法确定两种组分的释放模式将维持不变,医生必须对于每一位个体患者进行大量滴定实验。因此,医生对于该止痛剂可采用的治疗上有用的剂量范围受到限制。
发明内容
本发明的目的之一是提供一种具有高止痛活性的用于疼痛治疗的药物制剂,其特征在于降低了滥用可能性及副作用,该制剂也以用药频率降低为 特征,故该制剂也提供更高的顺从性以及每位患者独立适应剂量的能力。本发明的另一目的在于提供在疼痛治疗中有效的药物制剂的配方,其确保该药物制剂的活性化合物经历一段长贮存期间仍是稳定的,且即使经过长期贮存之后,该活性化合物的释放可再现地保持不变且独立。
本案独立权利要求的特征组合能够实现本发明的这些目的,本发明的其他目的可参见本发明的说明内容。本发明的优选实施方案则定义于从属权利要求中。
根据本发明,其目的通过提供一种含有羟氢可待酮及纳洛酮的贮存稳定性药物制剂而达成,其中该制剂调配制成得活性化合物以持续、稳定及独立的方式释放。
通过羟氢可待酮(止痛有效的量)及纳洛酮的组合,确保本发明的制剂呈现有效的止痛活性,同时抑制或至少显著降低常见的副作用,例如顽固性便秘、呼吸压抑及发展为成瘾。长期稳定的基质配方能长期地确保激动剂与拮抗剂总是以预先设定的百分比释放,且其释放速率彼此之间互不干扰。如此,阻止了该药物的滥用,该滥用需要羟氢可待酮可自该配方选择性地提取出来。根据本发明的配方使得激动剂无法从没有对应量的拮抗剂的制剂选择性地提取出来,此与所选择的激动剂与拮抗剂的绝对及相对含量无关。
再者,根据本发明的药物的配方确保相对含量一样的活性化合物会呈现一样的释放模式,与绝对含量无关。当最佳的激动剂/拮抗剂比例为已知时,则此种独立的释放行为给医师提供止痛活性物质大范围的可使用的绝对剂量。因此,每一位个别的患者有可能舒服自在地调整剂量,逐步增加剂量,或者若有必要,逐步降低剂量。由医药观点而言,个别患者具有可调整剂量的能力是极为有用的。
本发明的技术特征,包括持续、稳定且独立地释放活性化合物,更可保证根据本发明所生产的药物制剂是以用药频率低为其特征,因此可达到高度的患者顺从性。此外,本发明的制剂允许医生针对个别患者调整剂量。本发明的制剂保证可使用大范围的活性化合物所适用的绝对剂量,并保证活性化合物即使在长期贮存之后仍可恢复功效、且有相同的释放模式。
根据本发明,活性化合物的持续释放是指药学活性物质自药物释放所经历的时间比该物质由用于快速释放的已知配方所释放的时间更长。优选释放经历2至24小时,2至20小时,更优选历经2至16小时或2至12小时, 此是根据合乎法律与管制要求的说明。
根据本发明,能够确保活性化合物自制剂如上所述般持续释放的药物配方称之为阻滞((retard)配方、持续释放配方或缓释(prolonged release)配方。本发明的技术内容中,“持续释放”并不表示活性化合物自配方或药物释放是以pH-依赖性方式。根据本发明,活性化合物的释放是以不依赖pH的方式。根据本发明,“持续释放”一词是表示活性化合物历经长时间自药物释放。此并不意味着在某一特定位置控制释放,故并不表示该活性化合物只在胃内释放,或仅在肠道释放。(当然此种在特定位置的释放可分别通过药物的肠溶衣实现,但目前此种方式似乎并无好处。)
根据本发明,“独立释放”是指假定至少存在两种活性化合物,改变一种化合物的绝对含量并不影响另一化合物的释放模式,故另一化合物的释放模式没有改变。根据本发明的配方,此种独立释放行为不依赖于测量释放的pH值、标的或制备方法。pH独立性尤其应用于酸性范围,即pH值小于7。释放模式(或释放行为)定义为活性化合物自配方释放的随时间、所释放的每一种活性化合物的量(以占活性化合物总量的百分比表示)的变化。释放模式的测定是利用已知测试方法。
详言之,例如以乙羟氢可待酮的释放模式为例,若具有相同配方的对应制剂中含有12mg羟氢可待酮、但含有6mg纳洛酮,则可发现具有12mg羟氢可待酮与4mg纳洛酮的羟氢可待酮/纳洛酮-组合并不改变乙羟氢可待酮的释放模式。
独立释放的特征优选涉及一种将具有实质上相等组成的制剂的释放模式作一比较的状况。具有实质上相等组成的制剂具有不同含量的活性化合物,但实质上影响释放行为的组合组份基本上是相同的。
若比较上述制剂(第一制剂含有12mg羟氢可待酮与4mg纳洛酮,第二制剂含有12mg羟氢可待酮与6mg纳洛酮),假设两种制剂的总重量相同,若纳洛酮含量的差异被取代为配方中一种通常不会影响释放行为的组成份时,则将得到相同的羟氢可待酮与纳洛酮的释放模式。如下文实施例部分所示,纳洛酮的含量差异可被取代为一典型的药学惰性填充剂,例如乳糖,此取代不改变释放模式。
本领域技术人员知道,若两种制剂的差异在于活性化合物的含量,将该化合物的含量取代为该配方的释放行为所必须的物质时,例如乙基纤维素或 脂肪醇,可产生释放行为的差异。因此,独立释放特征优选应用在下列配方,其具有不同含量的活性化合物,而实质上影响释放行为的组成份是相同的、或至少高度相似(设定比较具有相同总重的配方)。
根据本发明,“稳定释放行为”或“稳定释放模式”定义为若绝对含量改变,每单位时间所释放的每一种活性化合物的绝对含量百分比不明显改变且充分地保持恒定(故不实质上改变)。充分恒定的百分比是指每单位时间所释放的百分比与平均值的差异不超过20%,优选不超过15%,更优选不超过10%。平均值是由释放模式的六次测量值计算出来的。当然,每单位时间的释放量必须符合法律与管制要求。
详言之,若设定一种羟氢可待酮/纳洛酮的组合含有12mg羟氢可待酮与4mg纳洛酮,于最初的4小时释放25%的羟氢可待酮及20%的纳洛酮。若该羟氢可待酮/纳洛酮的组合含有24mg羟氢可待酮及8mg纳洛酮,于最初的4小时也释放25%羟氢可待酮及20%纳洛酮。两种情况中,差异都将不超过平均值的20%(此例子的平均值为25%的羟氢可待酮及20%的纳洛酮)。
如同简要描述独立释放行为,稳定释放特征也优选指一种将具有实质上相等组成的制剂的释放模式作一比较的状况。这类制剂的活性化合物含量不同,但就影响释放的制剂组分而言,这类制剂的组成相同或至少高度相似。典型地,活性化合物的含量差异将以实质上不影响该制剂的释放行为的药学惰性赋形剂取代。这类药学赋形剂可以是乳糖,其为药物制剂中的典型填充剂。本领域技术人员将充分理解此稳定释放特征不能应用在下列制剂,其中活性化合物含量的差异被实质上影响该制剂释放行为的已知物质取代,例如乙基纤维素或脂肪醇。
实施例部分中已经说明,若一制剂含有20mg羟氢可待酮与1mg纳洛酮、或含有20mg羟氢可待酮与10mg纳洛酮,其差异在于纳洛酮被乳糖取代,如此具有相同重量的两种制剂提供相同的释放模式,故这两种制剂呈现持续、稳定且独立的释放行为。
根据本发明,“贮存稳定的”或“贮存稳定性”表示在标准条件下(于室温及一般湿度下至少2年),药物配方中的活性化合物含量与最初含量的差异不超过一般药典的说明或指导方针所示的数值。根据本发明,贮存稳定性也指根据本发明制备的制剂可在标准条件下(60%相对湿度,25℃)贮存,如同获得上市许可所需的条件。
根据本发明,“贮存稳定的”或“时间稳定的”也表示在标准条件下贮存之后,活性化合物呈现的释放模式同该化合物不贮存而立即使用一样。根据本发明,释放模式有关的可接受的变化特征在于,每单位时间的释放量变化相对于平均值不超过20%,优选不超过15%,且特别优选不超过10%。平均值是由释放模式的六次测量值计算出来的。
优选地,根据美国药典(USP)的药蓝(Basket Method)方法,于pH=1.2或pH=6.5利用HPLC测定活性化合物自持续释放配方中的释放。
贮存稳定性的测定优选按照USP的药篮方法,于pH=1.2、利用HPLC进行。
根据本发明,“非可膨胀的(non-swellable)”或“基本上非可膨胀的”扩散基质是一种基质配方,活性化合物的释放不受该基质的膨胀(尤其是在病人体内的相关靶位置的生理液体内)的影响(或至少相当程度不受影响)。
根据本发明,“基本上非可膨胀的”扩散基质也指一种基质,其体积于水溶液中(尤其是在病人体内相关靶位置的生理液体内)将增加约300%,优选约200%,更优选约100%、约75%或约50%,甚至更优选约30%或约20%,且最优选约15%、约10%、约5%或约1%。
本发明的技术内容中,“激动剂”或“止痛剂”总是指羟氢可待酮。本发明的技术内容中,“拮抗剂”总是指纳洛酮。
根据本发明制备的制剂可经口、经鼻、经直肠和/或通过吸入而施用于疼痛治疗。根据本发明,肠胃外用药并未设想。特别优选经口施用的配方。
尽管并未详细说明,术语“激动剂”或“拮抗剂”总是包括可药用且同等作用的衍生物、盐类等。例如,若提及羟氢可待酮或纳洛酮,除了游离碱之外,还包括其盐酸盐、硫酸盐、硫酸氢盐、酒石酸盐、硝酸盐、柠檬酸盐、酒石酸氢盐、磷酸盐、苹果酸盐、马来酸盐、氢溴酸盐、氢磺酸盐、富马酸盐、琥珀酸盐等。
根据本发明,激动剂及拮抗剂以下述方式配制:使两者以持续、独立且稳定的方式由所制得的药物制剂中释放。此并不意味着拮抗剂比激动剂过量。相反,在含有激动剂/拮抗剂的组合的配方中(其显示根据本发明的释放模式),优选激动剂比拮抗剂过量。
激动剂的过量根据组合制剂中拮抗剂的单位剂量的含量而定。类鸦片激动剂的过量程度通常以激动剂相对于拮抗剂的重量比表示。
羟氢可待酮及纳洛酮的情况下,激动剂相对于拮抗剂的优选重量比在最大为25:1的重量比范围内,特别是重量比范围为15:1、10:1、5:1、4:1、3:1、2:1及1:1。
所使用的激动剂与拮抗剂的绝对含量依赖于活性化合物的选择。根据本发明,必须注意到激动剂与拮抗剂是以独立且稳定的方式,由已经制备成稳定释放的药物制剂释放。
若使用羟氢可待酮与纳洛酮来调配组合制剂,每单位剂量优选包含10至150mg、更优选包含10至80mg羟氢可待酮(应用的典型剂量),并优选包含1至50mg纳洛酮。
本发明的其他优选实施方案中,该制剂可含有5至50mg羟氢可待酮、10至40mg羟氢可待酮、10至30mg羟氢可待酮、或约20mg羟氢可待酮。本发明的优选实施方案也可包括每单位剂量具有1至40mg纳洛酮、1至30mg纳洛酮、1至20mg纳洛酮、或1至10mg纳洛酮的制剂。
根据本发明,选择羟氢可待酮与纳洛酮的比例,必须保证得到根据本发明的两种活性物质的释放模式,且激动剂可发挥其止痛功效;并采取可减少或消除激动剂的习惯成性或成瘾增进作用及副作用的方式来选择拮抗剂的剂量,但不(实质上)影响激动剂的止痛作用。根据本发明,形成习惯及成瘾,以及顽固性便秘与呼吸压抑,皆视为具有止痛作用的类鸦片激动剂的副作用。
根据本发明,可使用普遍常用的配方,只要这些配方能确保活性化合物以持续、独立且稳定的方式自该制剂释放。根据本发明,必须选择可让活性化合物贮存稳定的配方。
优选使用基于基质(Matrix-based)的阻滞(retardation)配方,作为提供根据本发明的激动剂与拮抗剂释放的配方。根据本发明,特别优选基于基本上非可膨胀性扩散基质的配方。此时,不优选具有腐蚀性基质或可膨胀的扩散基质的配方。
根据本发明,必须选择可提供活性化合物持续释放的基质,使该活性化合物以持续、独立且稳定的方式释放。优选此种基质含有基于乙基纤维素的聚合物,而乙基纤维素是特别优选的聚合物。特别优选含有市售的商品名为 的聚合物的基质。尤其优选使用 E-7-7050。
具有本发明释放行为的配方特别包括下述基质,该基质含有乙基纤维素 与至少一种脂肪醇作为实质上影响该基质释放特性的组分。乙基纤维素及至少一种脂肪醇的含量可明显不同,如此可得到具有不同释放模式的制剂。尽管创新的(inventive)制剂通常含有上述两种组分,有些情况下,优选制剂只含有乙基纤维素或脂肪醇作为决定释放的组分。
根据本发明的基质可用来生产以持续、独立且稳定的方式释放活性化合物、且每单位时间释放等量活性化合物的制剂。具体是指,就含有12mg羟氢可待酮及4mg纳洛酮的羟氢可待酮/纳洛酮组合而言,在最初4小时内释放25%的可待酮及25%的羟丙羟吗啡酮;相应地,就含有24mg羟氢可待酮及8mg纳洛酮的羟氢可待酮/纳洛酮组合而言,在最初4小时内释放25%的羟氢可待酮及25%的纳洛酮;此两种情况下的变化都不超过平均值(此时为25%的羟氢可待酮或纳洛酮)的20%。
从医药方面考虑,两种活性化合物有这种相同的释放行为是理想的。
本发明的优选实施方案是关于15分钟之后释放1%至40%、优选5%至35%、更优选10%至30%、进一步优选15%至25%的羟氢可待酮和/或纳洛酮的制剂的制备。本发明的其他优选实施方案中,15%至20%、20%至25%、约15%、约20%或约25%的羟氢可待酮和/或纳洛酮于15分钟之后释放。
本发明的另一优选实施方案是关于1小时之后,释放25%至65%、优选30%至60%、更优选35%至55%、特别优选40%至50%的羟氢可待酮和/或纳洛酮的制剂。本发明的优选实施方案也涉及40%至45%、45%至50%、约40%、约45%或约50%的羟氢可待酮和/或纳洛酮于1小时之后释放的制剂。
本发明又一优选实施方案是关于2小时之后,释放40%至80%、优选45%至75%、更优选45%至70%、进一步优选45%至50%、50%至55%、55%至60%、60%至65%或65%至70%的羟氢可待酮和/或纳洛酮的制剂。优选实施方案也包括约45%、约50%、约55%、约60%、约65%或约70%的羟氢可待酮和/或纳洛酮于2小时之后释放的制剂。
本发明的一个优选实施方案是关于4小时之后,释放70%至100%、优 选75%至95%、更优选80%至95%、进一步优选80%至90%的羟氢可待酮和/或纳洛酮的制剂。本发明的优选实施方案也涉及80%至85%、85%至90%、约80%、约85%、或约90%的羟氢可待酮和/或纳洛酮于4小时之后释放的制剂。
本发明的一个优选实施方案也涉及7小时之后,释放70%至100%、优选75%至100%、更优选80%至95%、进一步优选80%至85%、85%至90%、或90%至95%的羟氢可待酮和/或纳洛酮的制剂。本发明的优选实施方案也涉及约80%、约85%、约90%或约95%的羟氢可待酮和/或纳洛酮于7小时之后释放的制剂。
本发明又一个优选实施方案是关于12小时之后,释放85%至100%、优选90%至100%、更优选95%至100%、进一步优选约95%或100%的羟氢可待酮和/或纳洛酮的制剂。
根据本发明,提供按照本发明而释放活性化合物的配方,除了形成基质的聚合物之外,还可含有填充剂及添加物,例如粒化辅助剂、润滑剂、着色剂、流动剂及增塑剂。
乳糖、葡萄糖或蔗糖、淀粉类及其水解产物、微晶纤维素、纤维素(cellatose)、山梨糖醇或甘露糖醇等糖醇类,多溶性钙盐例如磷酸氢钙、磷酸二钙或磷酸三钙,可用来作为填充剂。
聚维酮(povidone)可用来作为粒化辅助剂。
可优选使用硬脂酸镁和/或硬脂酸钙作为润滑剂,也可优选使用脂肪酸类(例如硬脂酸)、或脂肪类(例如氢化蓖麻油)。
也可使用聚乙二醇及脂肪醇[例如鲸蜡醇、和/或硬脂醇、和/或十六醇十八醇混合物(cetostearylalcohol)],作为影响阻滞作用(retardation)的添加物。
若使用填充剂及添加物,例如着色剂及上述润滑剂、流动剂及增塑剂,则必须注意到,根据本发明,只可使用保证得到根据本发明的活性化合物的释放模式的上述组合与基质形成物质和/或基质形成物质。
配方的所有附加成分以可让释放基质获得一种基本上非水膨胀、或非缓冲液膨胀(non-buffer-swellable)且非腐蚀性扩散的基质的特性的方式进行选择。
根据本发明,配方特别优选含有乙基纤维素或 E-7-7050作为基质构筑物质,硬脂醇作为脂肪醇,硬脂酸镁作为润滑剂,乳糖作为填充剂,及聚维酮作为粒化辅助剂。
根据本发明,配方可以制成任何常见的用药形式,原则上,此用药形式适合阻滞配方并保证活性化合物以本发明的方式释放。尤其适合者是片剂、多层片剂及胶囊。可使用其他用药形式,例如颗粒剂或粉剂,但只有提供足够阻滞作用及根据本发明的释放行为的用药形式是可接受的。
药物制剂也可包括薄膜包衣。然而,必须保证该薄膜涂料不会负面影响活性化合物自基质释放的性质,及活性化合物于基质中的贮存稳定性。此种薄膜包衣可以染色,或者若有需要,可含有活性化合物的初次剂量。该初次剂量的活性化合物将立刻释放,如此可非常快速地达到治疗有效的血浆浓度。
可利用累加式(build-up)或削减式(build-down)造粒法制造根据本发明的药物制剂或其前驱物。优选实施方案是采用喷雾造粒和随后干燥颗粒的制法。另一优选实施方案是于滚筒中或粒化圆盘上,通过用累加式造粒法制造颗粒。然后利用适合的添加物与方法将该颗粒压成例如片剂。
本领域技术人员熟知应用在制药技术上的造粒技术。实施例(参见下文)揭示本发明的具体实施方案。然而,为了要达到特定目的而修改该制法的参数,此乃属于本领域技术人员可充分理解的范畴之内。
根据本发明,利用挤压(extrusion)技术制造药物制剂或其前驱物的方法特别有利。在一个优选实施方案中,利用熔解挤压法制造药物制剂或其前驱物,其是使用配备同向或反向转动的挤压器(包含两个螺杆(screw))。另一优选实施方案是通过挤压制造的方法,其利用含有一个或一个以上螺杆的挤压器。这些挤压器也可包括捏合元件。
挤压法也是制药技术上一种已经充分建立的生产方法,为本领域技术人员公知。本领域技术人员可充分理解,为了生产具有所需特性的产物,于挤压制法过程中可改变各种参数,例如进料速度、旋转速度、不同挤压器区域的加热温度(若可以做到的话)、水含量等。实施例部分提供根据本发明的制剂的多种实施例,其是利用挤压法制得的。
上述参数将由所使用的挤压器的特殊种类而决定。挤压过程中,加热区(本发明配方的组分于其中熔解)的温度可以为40至120℃、优选50至100 ℃、更优选50至90℃、进一步优选50至70℃、最优选50至65℃,特别是使用反向转动双螺旋挤压器(例如Leistritz Micro 18GGL)的情况。本领域技术人员将可充分理解,并非每一个加热区都必须加热。特别是进料器(将组分混合之处)的后面,可能有必要冷却为约25℃。旋转速度可以是每分钟100至500次旋转(rpm)、优选100至250rpm、更优选100至200rpm、且最优选约150rpm,特别是使用反向转动双螺旋挤压器(例如Leistritz Micro 18GGL)的情况。喷嘴的几何构形及直径可视所需加以选择。常用挤压器的喷嘴直径通常是1至10mm、优选2至8mm、最优选3至5mm。可用来生产本发明制剂的挤压器,其螺杆(screw)长度相对于直径的比率通常约为40:1。
一般而言,加热区的温度必须加以选择,以不会产生破坏该药学活性化合物的温度。选择进料速度与旋转速度以使药学活性化合物以持续、独立且稳定的方式自利用挤压法所制得的制剂释放,且该药学活性化合物于基质中可稳定贮存。例如,若增加进料速度,则旋转速度必须相对地增加以确保得到相同的阻滞作用。
本领域技术人员知道上述全部参数皆取决于特殊生产条件(挤压器种类、螺旋几何构形、组分的数量等等),可能有必要加以修改,以使通过挤压法制得的制剂提供持续、独立且稳定的释放,及上述贮存稳定性。
本领域技术人员可由实施例(参见下文)推知,通过改变挤压过程中的参数,以及改变实质上负责该制剂的释放行为的化合物的组成关系,可得到具有不同释放模式的制剂。故本发明允许首先制备具有所需的羟氢可待酮及纳洛酮的释放模式的制剂,例如,通过改变脂肪醇或基质形成聚合物乙基纤维素的含量,以及制备参数,例如温度、旋转速度(挤压过程中)、或制造片剂过程中的压力。
一旦获得具有所欲释放模式的制剂,则根据本发明的创新制剂可允许本领域技术人员改变该制剂中于上文列示的活性化合物的含量。含有不同量的活性化合物、但具有实质上相同组成的制剂,将可提供持续、稳定且独立释放的特性。
因此,实施例部分公开多种实施例,证实可通过改变用量(例如乙基纤维素)而得到具有不同释放模式的制剂。其他实施例证实一旦建立了某一制剂具有所欲的释放模式,若活性化合物的含量差异被药学活性赋形剂(例如乳糖)取代,则改变纳洛酮的含量并不影响该制剂的释放行为。
附图说明
图1:挤压器的螺旋几何构造;
图2:不同含量的羟氢可待酮的释放速率;
图3A-B:羟氢可待酮、纳洛酮在不同pH下的释放;
图5A:Ox/Na1-10-片剂的扫描式电子显微镜照片,放大25倍;
图5B:Ox/Na1-10-片剂的扫描式电子显微镜照片,放大200倍;
图6A:Oxy/Na1-Extr-片剂的扫描式电子显微镜照片,放大40倍;
图6B:Oxy/Na1-Extr-片剂的扫描式电子显微镜照片,放大100倍;
具体实施方式
展现本发明极为有利的实施方案的实施例列示于下文。也提供其他实施例验证本发明的制剂与常见配方比较下的优点。这些实施例不应该被解释成限制本发明的可能实施方案。
实施例1:利用喷雾造粒法(spray granulation)生产非可膨胀性扩散基质中含有不同量的羟氢可待酮/纳洛酮的片剂
下表列出的组分含量用来制备根据本发明的羟氢可待酮/纳洛酮片剂。
为了要制备片剂,于翻滚式搅拌器(Bohle)中混合羟氢可待酮盐酸盐、纳洛酮盐酸盐、聚维酮30及乳糖Flow Lac 100,然后在流化浴造粒装置(GPCG3)中使用 E-7-7050进行喷雾粒化。将此原料通过Comill 1.4mm筛网过筛。于强力切割搅拌器(Collette)中与熔融的脂肪醇进行另一造粒步骤。通过上述方法制得的全部片芯具有123mg重量(按干物量计)。
实施例2:利用挤压法生产在非可膨胀性扩散基质中含有羟氢可待酮和纳洛酮的片剂
下表列出的组分含量是用来制造根据本发明的羟氢可待酮/纳洛酮的片剂。
制剂(名称) | Oxy/Na 1-Extr |
羟氢可待酮盐酸盐 | 20mg |
纳洛酮盐酸盐 | 10mg |
Kollidon 30 | 6mg |
乳糖Flow Lac 100 | 49.25mg |
乙基纤维素45cpi | 10mg |
硬脂醇 | 24mg |
滑石粉 | 2.5mg |
硬脂酸镁 | 1.25mg |
将上表列示用量的羟氢可待酮盐酸盐、乙基纤维素45cpi、聚维酮30、硬脂醇及乳糖Flow Lac 100在翻滚式搅拌器(Bohle)中混合。随后利用反向转动双螺旋挤压器,型号为Micro 18GGL(Leistritz AG,Nurnberg,德国),挤压该混合物。加热区1的温度是25℃,加热区2的温度是50℃,加热区3至5的温度是60℃,加热区6至8的温度是55℃,加热区9的温度是60℃,加热区10的温度是65℃。螺旋转动速度是每分钟150转(rpm),所得的熔解温度是87℃,进料速度是1.5kg/h,喷嘴开口的直径是3mm。经挤压的原料用Frewitt 0.68×1.00mm的筛网过筛。然后混合辗磨后的挤压物与滑石粉及硬脂酸镁(其事先经过添加至1mm手动式筛网之上的处理),随后压制成片剂。挤压器有一螺旋几何构造,如图1所示。
实施例3:实施例1制得的羟氢可待酮/纳洛酮片剂的释放模式
于pH=1.2、使用HPLC根据USP的药蓝方法历经12小时测量的活性化合物的释放。测试了片剂Ox/Nal-0、Ox/Nal-5及Ox/Nal-10。
由图2与下列所列数值可确认一事实,基于 的非可膨胀性扩散基质而言,不同含量的羟氢可待酮的释放速率仍能维持相同(稳定),不受纳洛酮含量的影响。相应地,在羟氢可待酮含量不同时,也观察到纳洛酮有稳定的释放模式。
释放数值涉及羟氢可待酮或纳洛酮(第2列),其是以百分比表示。例如,纳洛酮于420分钟的释放平均值为92.7%。于420分钟的最大偏差是1%。Oxy及Na1分别表示羟氢可待酮及纳洛酮,且指明所测定的活性化合物。
实施例4:实施例2制得的羟氢可待酮/纳洛酮片剂于不同pH值的释放模式
活性化合物自片剂的释放是于pH=1.2历经12小时测量的;或者,于pH=1.2历经1小时测量的,然后于pH=6.5历经11小时测量。根据USP的药篮方法,利用HPLC测定释放速率。
下列的释放速率是于pH=1.2历经12小时测量的。
下表的释放速率是于pH=1.2历经1小时测量,以及于pH=6.5历经11小时测量的。
释放数值涉及羟氢可待酮或纳洛酮(第2列),其是以百分比表示。Oxy及Na1分别表示羟氢可待酮及纳洛酮,且指明所测定的活性化合物。
将实施例4表格与实施例3表格中的数值相比较,明确得知活性化合物以等量自制剂释放,不受制备方法的影响。例如,420分钟时,89.4%的羟氢可待酮自喷雾造粒型片剂释放(Ox/Na1-10-片剂,参见实施例3),而420分钟时,92.9%的羟氢可待酮自经挤压的片剂释放(Oxy/Na1-Extr-1.2-O,实施例4)。羟氢可待酮自挤压型片剂释放的数值、与羟氢可待酮自喷雾造粒型片剂释放的平均值(420分钟时,91.9%)相差1.1%。420分钟时,93.5%的纳洛酮自喷雾造粒的片剂释放(Ox/Na1-10-片剂,参见实施例3),而420分钟时,93.9%的纳洛酮自挤压型片剂释放(Ox/Na1-Extr-1.2-O,实施例4)。纳洛 酮自挤压型片剂释放的数值、与烯丙烯吗啡酮自喷雾造粒型片剂释放的平均值(420分钟时,92.7%)相差1.3%。
再者,由实施例4表格的数值比较及图3a及3b可以推断,释放速率不受pH的影响,羟氢可待酮、纳洛酮的释放维持相同且稳定。
检视7小时期间的活性物质自片剂释放的情形。根据USP的药篮方法,于pH=1.2测定 片剂1小时,然后利用HPLC于pH=6.5另外再测试6小时,该 片剂含有50mg痛立定与4mg纳洛酮(Ti/Na1-50/4)、或含有100mg痛立定与8mg纳洛酮(Ti/Na1-100/8)、或含有150mg痛立定与12mg纳洛酮(Ti/Na1-150/12)。
由图4A和4B以及下表所示数值[就具有适量HPMC的可膨胀的(且可能是腐蚀性)扩散基质而言]知道,不同含量的痛立定的释放情形明显不同,且不同含量的纳洛酮的释放情形不是稳定的。此适用于纳洛酮。这表示在该pH时,活性化合物的释放情形并非互不依赖的。
释放数值涉及痛立定或纳洛酮(第2列),其是以百分比表示。纳洛酮的释放平均值,例如于420分钟时,为78.87%。于420分钟的最大偏差是20.4%。Ti1及Na1分别表示痛立定及纳洛酮,且指明所测定的活性化合物。
为了进行电子显微镜,使用含有20mg羟氢可待酮及10mg纳洛酮的片剂,此片剂通过实施例1的喷雾造粒法制备(Ox/Na1-10)、或通过实施例2的挤压法制备(Oxy/Na1-Extr)。再者,使用含有100mg痛立定及8mg纳洛酮的 N片剂。图5A及5B显示Ox/Na1-10-片剂的扫描式电子显微镜照片的不同放大倍数,该片剂含有本发明配方,且是利用喷雾造粒法制备。图6A及6B显示Oxy/Na1-Extr-片剂的扫描式电子显微镜照片的不同放大倍数,该片剂含有本发明配方,且是利用挤压法制备。图7A及7B显示 N-片剂的扫描式电子显微镜照片。
由这些图示的比较,可以清楚看见,含有本发明配方的片剂具有实质上比较细致且比较均质结构的表面,比 片剂的裂痕更少,无论该片剂是否是以喷雾造粒法或挤压法生产的。结构上的差异可能就是不同制剂有不同释放行为的原因。
实施例7:利用挤压法生产非可膨胀性扩散基质中含有不同羟氢可待酮/纳洛酮含量的片剂
下表列出的组分含量是用来生产根据本发明的羟氢可待酮/纳洛酮片剂。
如上所述(实施例2)进行挤压法,采用下列参数:
OxN20/1-Extr-A:温度:55-63℃
rpm(转速(screw)):150rpm
进料速度:1.5kg/h
OxN20/1-Extr-B:温度:55-63℃
rpm(转速):155rpm
进料速度:1.5kg/h
OxN20/1-Extr-C:温度:55-63℃
rpm(转速):1505rpm
进料速度:1.5kg/h
OxN20/10-Extr-A:温度:55-63℃
rpm(转速):160rpm
进料速度:1.75kg/h
利用常见的打片装置进行片剂生产,采用下列参数:
OxN20/1-Extr-A:rpm:40rpm
压力:9kN
OxN20/1-Extr-B:rpm:42rpm
压力:8.9kN
OxN20/1-Extr-C:rpm:36rpm
压力:9kN
OxN20/10-Extr-A:rpm:36rpm
压力:7.5kN
应用USP的药篮方法,于pH=1.3使用HPLC历经12小时测量活性化合物的释放。测试了下列片剂:OxN20/1-Extr-A、OxN20/1-Extr-B、OxN20/1-Extr-C及OxN20/10-Extr-A。
由下表所列的数值可知,就以乙基纤维素为基础的非可膨胀性扩散基质而言,不同含量的纳洛酮的释放速率实质上维持相同,不受到羟氢可待酮含量的影响。相应的,这些制剂提供该活性化合物的独立且稳定的释放。
释放数值涉及羟氢可待酮或纳洛酮(第2列),其是以百分比表示。纳洛酮的释放平均值,例如于420分钟时,为92.3%。于420分钟的最大偏差是7.4%。Oxy及Na1分别表示羟氢可待酮及纳洛酮,且指明所测定的活性化合物。
因此,一旦具有所欲释放模式的制剂发展出来,则可以改变该活性化合物的含量,但不显著改变活性化合物的释放模式。含有不同量的活性化合物的制剂仍可提供一种持续、独立且稳定的释放。
实施例8:利用挤压法生产非可膨胀性扩散基质中含有羟氢可待酮/纳洛酮的片剂
下列实施例表明,利用本发明的配方、可制得含有羟氢可待酮及纳洛酮、并具有特别释放行为的制剂。
下表列出组分的含量是用来生产根据本发明的羟氢可待酮/纳洛酮的片剂。
如上所述(实施例2)进行挤压法,采用下列参数:
OxN20/1-Extr-D:温度:55-63℃
rpm(转速):150rpm
进料速度:1.5kg/h
OxN20/1-Extr-E:温度:55-63℃
rpm(转速):150rpm
进料速度:1.5kg/h
OxN20/10-Extr-B:温度:55-63℃
rpm(转速):160rpm
进料速度:1.75kg/h
OxN20/10-Extr-C:温度:55-63℃
rpm(转速):160rpm
进料速度:1.75kg/h
OxN20/10-Extr-D:温度:55-63℃
rpm(转速):150rpm
进料速度:1.5kg/h
OxN20/10-Extr-E:温度:55-63℃
rpm(转速):150rpm
进料速度:1.5kg/h
利用常见的压片装置进行片剂生产,采用下列参数:
OxN20/1-Extr-D:rpm:39rpm
压力:11kN
OxN20/1-Extr-E:rpm:39rpm
压力:10.5kN
OxN20/10-Extr-B:rpm:36rpm
压力:9.5kN
OxN20/10-Extr-C:rpm:36rpm
压力:7.8kN
OxN20/10-Extr-D:rpm:39rpm
压力:9kN
OxN20/10-Extr-E:rpm:39rpm
压力:7.5kN
应用USP的药篮方法,于pH=1.2、使用HPLC历经12小时测量活性化合物的释放。测试了下列片剂:OxN20/1-Extr-D、OxN20/1-Extr-E、OxN20/10-Extr-B、OxN20/10-Extr-C、OxN20/10-Extr-D及OxN20/10-Extr-E。
释放数值涉及羟氢可待酮或纳洛酮(第2列),其是以百分比表示。Oxy 及Na1分别表示羟氢可待酮及纳洛酮,且指明所测定的活性化合物。
此实施例证实,若用乙基纤维素及脂肪醇是作为实质上影响该制剂的释放特性的基质组分,则可生产具有特定释放模式的制剂。一旦制得具有所需释放特性的制剂,则可改变活性化合物的含量。该制剂将仍可提供持续、独立且稳定的释放行为(参见实施例7)。
Claims (32)
1.一种含有羟氢可待酮和纳洛酮的贮存稳定的药物制剂,其特征在于所述活性化合物是以持续、稳定并且独立的方式从该制剂中释放。
2.权利要求1所述的制剂,其特征在于羟氢可待酮和/或纳洛酮以可药用和同等活性衍生物的形式存在,该衍生物例如游离碱、盐类等。
3.权利要求2所述的制剂,其特征在于羟氢可待酮和/或纳洛酮以它们的盐酸盐、硫酸盐、硫酸氢盐、酒石酸盐、硝酸盐、柠檬酸盐、酒石酸氢盐、磷酸盐、苹果酸盐、马来酸盐、氢溴酸盐、氢碘酸盐、富马酸盐或琥珀酸盐的形式存在。
4.上述权利要求中任意一项所述的制剂,其特征在于羟氢可待酮的量超过纳洛酮的单位剂量。
5.上述权利要求中任意一项所述的制剂,其特征在于纳洛酮的剂量为1至50mg。
6.上述权利要求中任意一项所述的制剂,其特征在于羟氢可待酮的剂量为10至150mg,优选10至80mg。
7.上述权利要求中任意一项所述的制剂,其特征在于羟氢可待酮与纳洛酮的重量比范围最大为25:1,优选最大为20:1、15:1,特别优选5:1、4:1、3:1、2:1或1:1。
8.上述权利要求中任意一项所述的制剂,其特征在于该制剂含有基本上非可膨胀性且非腐蚀性的扩散基质。
9.权利要求所述8的制剂,其特征在于该扩散基质至少含有乙基纤维素和至少一种脂肪醇作为实质上影响活性化合物释放行为的组分。
10.权利要求8或9所述的制剂,其特征在于该制剂不含有相应的碱和/或水可膨胀的物质,尤其是丙烯酸衍生物和/或羟烷基纤维素衍生物。
11.上述权利要求中任意一项所述的制剂,其特征在于该制剂含有常规填充物和添加物,尤其是润滑剂、流动剂和增塑剂等。
12.权利要求11所述的制剂,其特征在于该制剂含有硬脂酸镁、硬脂酸钙和/或月桂酸钙和/或脂肪酸作为润滑剂,优选硬脂酸。
13.权利要求11所述的制剂,其特征在于该制剂含有高度分散的硅石,优选高度分散性硅石,滑石粉、玉米淀粉、氧化镁及硬脂酸镁和/或硬脂酸钙作为流动剂。
14.一种贮存稳定的药物制剂,该制剂在基本上非可膨胀性扩散基质中含有羟氢可待酮及纳洛酮,其特征在于,该基质的实质性释放特征受到乙基纤维素及至少一种脂肪醇影响,且该制剂所含羟氢可待酮与纳洛酮的重量比范围最大为25:1,优选最大为20:1、15:1,特别优选5:1、4:1、3:1、2:1或1:1。
15.权利要求14所述的制剂,其特征在于羟氢可待酮及纳洛酮是以可药用且同等活性的衍生物的形式存在,该衍生物为例如游离碱、盐类等。
16.权利要求15所述的制剂,其特征在于羟氢可待酮及纳洛酮以盐酸盐、硫酸盐、硫酸氢盐、酒石酸盐、硝酸盐、柠檬酸盐、酒石酸氢盐、磷酸盐、苹果酸盐、马来酸盐、氢溴酸盐、氢碘酸盐、富马酸盐或琥珀酸盐的形式存在。
17.权利要求14至16中任意一项所述的制剂,其特征在于羟氢可待酮的量超过纳洛酮的单位剂量。
18.权利要求14至17中任意一项所述的制剂,其特征在于纳洛酮的量为1至50mg。
19.权利要求14至18中任意一项所述的制剂,其特征在于羟氢可待酮的量为10至150mg,优选10至80mg。
20.权利要求14至19中任意一项所述的制剂,其特征在于该制剂含有基本上非可膨胀性且非腐蚀性的扩散基质。
21.权利要求20所述的制剂,其特征在于该扩散基质至少含有乙基纤维素及至少一种脂肪醇作为实质上影响活性化合物释放行为的组分。
22.权利要求20或21所述的制剂,其特征在于该制剂不含有相应的碱和/或水可膨胀的物质,尤其是丙烯酸衍生物和/或羟烷基纤维素衍生物。
23.权利要求14至22中任意一项所述的制剂,其特征在于该脂肪醇包括月桂醇、肉豆蔻醇、硬脂醇、十六醇十八醇混合物、蜡醇和/或鲸蜡醇,特别优选硬脂醇。
24.权利要求14至23中任意一项所述的制剂,其特征在于该制剂含有普通填充物及添加物,尤其是润滑剂、流动剂、增塑剂等。
25.权利要求所述24的制剂,其特征在于该制剂含有硬脂酸镁、硬脂酸钙和/或月桂酸钙和/或脂肪酸作为润滑剂,优选硬脂酸。
26.权利要求所述24的制剂,其特征在于该制剂含有高度分散的硅石,优选高度分散性硅石,滑石粉、玉米淀粉、氧化镁及硬脂酸镁和/或硬脂酸钙作为流动剂。
27.上述权利要求中任意一项所述的制剂,其特征在于用市售的含有乙基纤维素的聚合物混合物,优选E-7-7050代替乙基纤维素。
28.上述权利要求中任意一项所述的制剂,其特征在于将该制剂制备成口服制剂、鼻用制剂、直肠用制剂或吸入制剂。
29.上述权利要求中任意一项所述的制剂,其特征在于该制剂是片剂、丸剂、胶囊、颗粒剂和/或粉剂。
30.上述权利要求中任意一项所述的制剂,其特征在于该制剂或其前体通过累加式或削减式造粒法制备。
31.权利要求1或29中任意一项所述的制剂,其特征在于该制剂或其前体通过挤压法制备。
32.上述权利要求中任意一项所述的制剂,其特征在于,根据药物许可指导方针,该制剂可于标准条件下(60%相对湿度,25℃)贮存至少两年。
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Families Citing this family (139)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6375957B1 (en) | 1997-12-22 | 2002-04-23 | Euro-Celtique, S.A. | Opioid agonist/opioid antagonist/acetaminophen combinations |
AU773642C (en) | 1997-12-22 | 2006-04-06 | Mundipharma Pty Limited | Opioid agonist/antagonist combinations |
US10179130B2 (en) | 1999-10-29 | 2019-01-15 | Purdue Pharma L.P. | Controlled release hydrocodone formulations |
KR101216270B1 (ko) | 1999-10-29 | 2012-12-31 | 유로-셀티크 소시에떼 아노뉨 | 서방성 하이드로코돈 제형 |
PT2092936E (pt) | 2000-02-08 | 2013-06-20 | Euro Celtique Sa | Formulações orais de agonistas de opióides resistentes a adulteração |
AUPQ899700A0 (en) | 2000-07-25 | 2000-08-17 | Borody, Thomas Julius | Probiotic recolonisation therapy |
CA2427815C (en) | 2000-10-30 | 2007-07-10 | Euro-Celtique S.A. | Controlled release hydrocodone formulations |
US20110104214A1 (en) | 2004-04-15 | 2011-05-05 | Purdue Pharma L.P. | Once-a-day oxycodone formulations |
CA2446550C (en) | 2001-05-11 | 2012-03-06 | Endo Pharmaceuticals, Inc. | Abuse-resistant controlled-release opioid dosage form |
DE60230632D1 (de) | 2001-07-18 | 2009-02-12 | Euro Celtique Sa | Pharmazeutische kombinationen von oxycodon und naloxon |
DE60232417D1 (de) | 2001-08-06 | 2009-07-02 | Euro Celtique Sa | Opioid-agonist-formulierungen mit freisetzbarem und sequestriertem antagonist |
CN102813654A (zh) | 2002-04-05 | 2012-12-12 | 欧洲凯尔蒂克公司 | 含有羟氢可待酮和烯丙羟吗啡酮的药物制剂 |
US7776314B2 (en) | 2002-06-17 | 2010-08-17 | Grunenthal Gmbh | Abuse-proofed dosage system |
MY142204A (en) | 2002-07-25 | 2010-10-29 | Pharmacia Corp | Pramipexole once-daily dosage form |
MY135852A (en) | 2003-04-21 | 2008-07-31 | Euro Celtique Sa | Pharmaceutical products |
DE10336400A1 (de) | 2003-08-06 | 2005-03-24 | Grünenthal GmbH | Gegen Missbrauch gesicherte Darreichungsform |
US8075872B2 (en) | 2003-08-06 | 2011-12-13 | Gruenenthal Gmbh | Abuse-proofed dosage form |
US20070048228A1 (en) | 2003-08-06 | 2007-03-01 | Elisabeth Arkenau-Maric | Abuse-proofed dosage form |
DE102005005446A1 (de) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Bruchfeste Darreichungsformen mit retardierter Freisetzung |
DE10361596A1 (de) | 2003-12-24 | 2005-09-29 | Grünenthal GmbH | Verfahren zur Herstellung einer gegen Missbrauch gesicherten Darreichungsform |
US8025899B2 (en) | 2003-08-28 | 2011-09-27 | Abbott Laboratories | Solid pharmaceutical dosage form |
US8377952B2 (en) | 2003-08-28 | 2013-02-19 | Abbott Laboratories | Solid pharmaceutical dosage formulation |
MXPA06003392A (es) * | 2003-09-25 | 2006-06-08 | Euro Celtique Sa | Combinacion farmaceutica de hidrocodona y naltrexona. |
GB0501638D0 (en) * | 2005-01-28 | 2005-03-02 | Euro Celtique Sa | Particulates |
GB0403098D0 (en) | 2004-02-12 | 2004-03-17 | Euro Celtique Sa | Extrusion |
TWI350762B (en) | 2004-02-12 | 2011-10-21 | Euro Celtique Sa | Particulates |
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 |
DE102004032049A1 (de) | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Gegen Missbrauch gesicherte, orale Darreichungsform |
CN101005830B (zh) | 2004-08-13 | 2010-09-29 | 贝林格尔·英格海姆国际有限公司 | 包含普拉克索或其可药用盐的延长释放片剂、其制备方法及用途 |
EP2431026A1 (en) * | 2004-08-13 | 2012-03-21 | Boehringer Ingelheim International GmbH | Extended release pellet formulation containing Pramipexole or a pharmaceutically acceptable salt thereof, method for manufacturing the same and use thereof |
EP2319499A1 (en) * | 2005-01-28 | 2011-05-11 | 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 |
EP1810678A1 (de) | 2006-01-19 | 2007-07-25 | Holger Lars Hermann | Verwendung einer Kombination von Morphin und Naloxon zur Drogensubstitution |
AU2011202866B2 (en) * | 2006-01-27 | 2012-06-14 | Mundipharma Pty Limited | Tamper resistant dosage forms |
EP1813276A1 (en) * | 2006-01-27 | 2007-08-01 | Euro-Celtique S.A. | Tamper resistant dosage forms |
US20080069891A1 (en) | 2006-09-15 | 2008-03-20 | Cima Labs, Inc. | Abuse resistant drug formulation |
DE202006018609U1 (de) * | 2006-08-29 | 2007-05-16 | Euro-Celtique S.A. | Verwendung von Opioidformulierungen in nadellosen Vorrichtungen zur Medikamentenverabreichung |
EP1897543A1 (en) | 2006-08-30 | 2008-03-12 | Euro-Celtique S.A. | Buprenorphine- wafer for drug substitution therapy |
US8445018B2 (en) | 2006-09-15 | 2013-05-21 | Cima Labs Inc. | Abuse resistant drug formulation |
US20080171762A1 (en) * | 2007-01-16 | 2008-07-17 | Ockert David M | Treatment of pain with naloxone |
DE102007011485A1 (de) | 2007-03-07 | 2008-09-11 | Grünenthal GmbH | Darreichungsform mit erschwertem Missbrauch |
CA2923102C (en) * | 2007-08-13 | 2019-10-15 | Abuse Deterrent Pharmaceutical Llc | Abuse resistant drugs, method of use and method of making |
RU2007137044A (ru) * | 2007-10-05 | 2009-04-10 | Общество С Ограниченной Ответственностью "Концерн О3" (Ru) | Лекарственное средство, обладающее гемопоэзстимулирующим и гепатопротекторным действием |
CA2644179C (en) * | 2007-11-21 | 2018-09-25 | Pharmascience Inc. | Novel pharmaceutical composition comprising a disintegration matrix |
RU2493830C2 (ru) | 2008-01-25 | 2013-09-27 | Грюненталь Гмбх | Лекарственная форма |
BRPI0912014A2 (pt) | 2008-05-09 | 2019-03-06 | Grünenthal GmbH | processo para a preparação de uma formulação em pó intermediária e uma forma de dosagem sólida final sob uso de uma etapa de congelamento por atomização |
RU2478388C2 (ru) * | 2008-07-07 | 2013-04-10 | Еуро-Селтик С.А. | Фармацевтическая композиция, содержащая опиоидный антагонист, для лечения задержки мочи |
US9192578B2 (en) * | 2008-08-20 | 2015-11-24 | Board Of Regents, The University Of Texas System | Hot-melt extrusion of modified release multi-particulates |
CA2741984C (en) | 2008-10-30 | 2018-06-12 | Gruenenthal Gmbh | Novel and potent tapentadol dosage forms |
WO2010078486A2 (en) | 2008-12-31 | 2010-07-08 | Upsher-Smith Laboratories, Inc. | Opioid-containing oral pharmaceutical compositions and methods |
SI2405915T1 (sl) | 2009-03-10 | 2019-03-29 | Euro-Celtique S.A. | Farmacevtski sestavki s takojšnjim sproščanjem, ki vsebujejo oksikodon in nalokson |
GB0909680D0 (en) | 2009-06-05 | 2009-07-22 | Euro Celtique Sa | Dosage form |
JP2012533585A (ja) | 2009-07-22 | 2012-12-27 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | 酸化感受性オピオイドのための不正使用防止剤形 |
BR112012001547A2 (pt) * | 2009-07-22 | 2016-03-08 | Gruenenthal Gmbh | forma de dosagem farmacêutica extrusada por fusão a quente |
BR112012008317A2 (pt) | 2009-09-17 | 2016-03-22 | Upsher Smith Lab Inc | produto de liberação sustentada compreendendo uma combinação de uma amina não-opioide e uma droga anti-inflamatória não-esteroidal |
US9125867B2 (en) * | 2010-02-24 | 2015-09-08 | Invincible Biotechnology | Diversion- and/or abuse-resistant compositions and methods for making the same |
JP5840201B2 (ja) | 2010-05-10 | 2016-01-06 | ユーロ−セルティーク エス.エイ. | 活性剤を負荷した顆粒と追加の活性剤の組合せ |
DE112011101605T5 (de) | 2010-05-10 | 2013-04-25 | Euro-Celtique S.A. | Pharmazeutische Zusammensetzung umfassend Hydromorphon und Naloxon |
KR20130030261A (ko) | 2010-05-10 | 2013-03-26 | 유로-셀티큐 에스.에이. | 활성제-무함유 과립 및 그를 포함하는 정제의 제조 |
WO2011143120A1 (en) | 2010-05-11 | 2011-11-17 | Cima Labs Inc. | Alcoholres i stant metoprolol - containing extended - release oral dosage forms |
WO2012016287A2 (en) | 2010-08-04 | 2012-02-09 | Borody Thomas J | Compositions for fecal floral transplantation and methods for making and using them and devices for deuvering them |
DE112011102708T5 (de) * | 2010-08-13 | 2013-05-29 | Euro-Celtique S.A. | Verwendung von Bindemitteln zur Herstellung von lagerungsstabilen Formulierungen |
WO2012028319A1 (en) | 2010-09-02 | 2012-03-08 | Grünenthal GmbH | Tamper resistant dosage form comprising inorganic salt |
WO2012028318A1 (en) | 2010-09-02 | 2012-03-08 | Grünenthal GmbH | Tamper resistant dosage form comprising an anionic polymer |
US9012469B2 (en) * | 2010-09-30 | 2015-04-21 | Astrazeneca Ab | Crystalline naloxol-peg conjugate |
JP6121334B2 (ja) | 2010-12-13 | 2017-04-26 | サリックス ファーマシューティカルズ,インコーポレイテッド | 胃および結腸製剤ならびにそれらを作製するための方法および使用するための方法 |
US9968638B2 (en) | 2011-03-09 | 2018-05-15 | Regents Of The University Of Minnesota | Compositions and methods for transplantation of colon microbiota |
AT511581A1 (de) | 2011-05-26 | 2012-12-15 | G L Pharma Gmbh | Orale retardierende formulierung |
CN103857386A (zh) | 2011-07-29 | 2014-06-11 | 格吕伦塔尔有限公司 | 提供药物立即释放的抗破碎片剂 |
BR112014002022A2 (pt) | 2011-07-29 | 2017-02-21 | Gruenenthal Gmbh | comprimido resistente à violação proporcionando liberação de fármaco imediata |
CN103764370B (zh) * | 2011-08-29 | 2017-01-18 | 爱克斯普乐器械有限公司 | 实验室挤出机 |
WO2013050539A2 (en) * | 2011-10-06 | 2013-04-11 | Grünenthal GmbH | Tamper-resistant oral pharmaceutical dosage form comprising opioid agonist and opioid antagonist |
EA201400590A1 (ru) | 2011-11-17 | 2014-11-28 | Грюненталь Гмбх | Устойчивая к разрушению пероральная фармацевтическая лекарственная форма, содержащая фармакологически активный ингредиент, опиоидный антагонист и/или средство, вызывающее отвращение, полиалкиленоксид и анионный полимер |
US20130225697A1 (en) | 2012-02-28 | 2013-08-29 | Grunenthal Gmbh | Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer |
EA201491875A1 (ru) | 2012-04-17 | 2015-04-30 | Пурдью Фарма Л.П. | Системы и способы лечения индуцированного опиоидами побочного фармакодинамического ответа |
AU2013248351B2 (en) | 2012-04-18 | 2018-04-26 | Grunenthal Gmbh | Tamper resistant and dose-dumping resistant pharmaceutical dosage form |
US10064945B2 (en) | 2012-05-11 | 2018-09-04 | Gruenenthal Gmbh | Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc |
WO2013176774A1 (en) | 2012-05-25 | 2013-11-28 | Arizona Board Of Regents | Microbiome markers and therapies for autism spectrum disorders |
AU2013271336B2 (en) | 2012-06-04 | 2017-11-30 | Centre For Digestive Diseases | Compositions and methods for treating Crohn's Disease and related conditions and infections |
JP6454640B2 (ja) | 2012-07-27 | 2019-01-16 | レッド ヒル バイオファーマ リミテッドRedHill Biopharma Ltd. | 結腸排出促進における使用のための製剤および製剤製造方法 |
US10485798B2 (en) | 2012-08-22 | 2019-11-26 | Aptapharma Inc. | Methylnaltrexone nasal formulations, methods of making, and use thereof |
CN104981246A (zh) * | 2012-12-14 | 2015-10-14 | 特雷维治疗股份有限公司 | 治疗瘙痒的方法 |
MX2015013231A (es) | 2013-03-15 | 2016-06-07 | Inspirion Delivery Technologies Llc | Composiciones que disuaden el abuso y metodos de utilizacion. |
WO2014176632A1 (en) | 2013-04-30 | 2014-11-06 | Borody Thomas J | Compositions and methods for treating microbiota-related psychotropic conditions and diseases |
JP6161801B2 (ja) | 2013-05-24 | 2017-07-12 | ローズ テクノロジーズ | オピオイドケタール化合物及びその使用 |
MX2015016254A (es) | 2013-05-29 | 2016-04-20 | Gruenenthal Gmbh | Forma de dosificacion resistente al uso indebido con perfil de liberacion bimodal. |
BR112015026549A2 (pt) | 2013-05-29 | 2017-07-25 | Gruenenthal Gmbh | forma de dosagem à prova de violação contendo uma ou mais partículas |
AU2014289187B2 (en) | 2013-07-12 | 2019-07-11 | Grunenthal Gmbh | Tamper-resistant dosage form containing ethylene-vinyl acetate polymer |
JP2016525138A (ja) | 2013-07-23 | 2016-08-22 | ユーロ−セルティーク エス.エイ. | 疼痛および腸内ディスバイオシスをもたらす疾患および/または腸内細菌移行に対するリスクを高める疾患に罹患している患者における痛みの治療への使用のためのオキシコドンおよびナロキソンの組み合わせ |
JP6539274B2 (ja) | 2013-08-12 | 2019-07-03 | ファーマシューティカル マニュファクチュアリング リサーチ サービシズ,インコーポレーテッド | 押出成形された即放性乱用抑止性丸剤 |
WO2015065547A1 (en) | 2013-10-31 | 2015-05-07 | Cima Labs Inc. | Immediate release abuse-deterrent granulated dosage forms |
UA116405C2 (uk) | 2013-11-13 | 2018-03-12 | Євро-Селтік С.А. | Гідроморфон та налоксон для лікування болю та синдрому опіоїдної дисфункції кишечнику |
CA2931553C (en) | 2013-11-26 | 2022-01-18 | Grunenthal Gmbh | Preparation of a powdery pharmaceutical composition by means of cryo-milling |
EP3079661B1 (de) | 2013-12-11 | 2021-05-05 | Algobate AG | Naloxon-monopräparat und mehrschichttablette |
US10105360B2 (en) | 2013-12-11 | 2018-10-23 | Develco Pharma Schweiz Ag | Method and composition for the treatment of opioid induced constipation |
US10172797B2 (en) | 2013-12-17 | 2019-01-08 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
US9492444B2 (en) | 2013-12-17 | 2016-11-15 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
CA2875384A1 (en) | 2013-12-20 | 2015-06-20 | AntiOP, Inc. | Intranasal naloxone compositions and methods of making and using same |
EP3777838A1 (en) | 2014-03-14 | 2021-02-17 | Opiant Pharmaceuticals, Inc. | Nasal drug products and methods of their use |
US10085937B2 (en) | 2014-03-14 | 2018-10-02 | Adapt Pharma Limited | Nasal drug products and methods of their use |
US9480644B2 (en) | 2014-03-14 | 2016-11-01 | Opiant Pharmaceuticals, Inc. | Nasal drug products and methods of their use |
US9561177B2 (en) | 2014-03-14 | 2017-02-07 | Adapt Pharma Limited | Nasal drug products and methods of their use |
MX2016014738A (es) | 2014-05-12 | 2017-03-06 | Gruenenthal Gmbh | Formulacion en capsula de liberacion inmediata resistente a alteraciones que comprende tapentadol. |
WO2015181059A1 (en) | 2014-05-26 | 2015-12-03 | Grünenthal GmbH | Multiparticles safeguarded against ethanolic dose-dumping |
ES2809458T3 (es) | 2014-07-17 | 2021-03-04 | Pharmaceutical Manufacturing Res Services Inc | Forma de dosificación llena de líquido, disuasoria del abuso y de liberación inmediata |
US10729685B2 (en) | 2014-09-15 | 2020-08-04 | Ohemo Life Sciences Inc. | Orally administrable compositions and methods of deterring abuse by intranasal administration |
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 |
EP3229785A2 (de) * | 2014-12-08 | 2017-10-18 | Develco Pharma Schweiz AG | Naloxon-monopräparat und mehrschichttablette |
AU2016251854A1 (en) | 2015-04-24 | 2017-10-19 | Grunenthal Gmbh | Tamper-resistant dosage form with immediate release and resistance against solvent extraction |
BR112017024264B1 (pt) | 2015-05-14 | 2022-07-12 | Crestovo Holdings Llc | Composições para transplante de flora fecal e métodos de preparação e utilização das mesmas, e dispositivos para sua administração |
WO2016191356A1 (en) | 2015-05-22 | 2016-12-01 | Arizona Board Of Regents On Behalf Of Arizona State University | Methods for treating autism spectrum disorder and associated symptoms |
JP2018526414A (ja) | 2015-09-10 | 2018-09-13 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | 乱用抑止性の即放性製剤を用いた経口過剰摂取に対する保護 |
EP3352773A4 (en) | 2015-09-24 | 2019-03-27 | San Diego State University (SDSU) Foundation DBA San Diego State University Research Foundation | ANTIBACTERIAL AND PROTECTIVE BACTERIOPHAGE FORMULATIONS AND PROCESS FOR THE PREPARATION AND USE THEREOF |
US9943513B1 (en) | 2015-10-07 | 2018-04-17 | Banner Life Sciences Llc | Opioid abuse deterrent dosage forms |
WO2017172406A1 (en) * | 2016-03-31 | 2017-10-05 | Mallinckrodt Llc | Extended release, abuse deterrent dosage forms |
US10335405B1 (en) | 2016-05-04 | 2019-07-02 | Patheon Softgels, Inc. | Non-burst releasing pharmaceutical composition |
US20170360848A1 (en) | 2016-06-15 | 2017-12-21 | Arizona Board Of Regents On Behalf Of Arizona State University | Methods for treating autism spectrum disorder and associated symptoms |
US10849936B2 (en) | 2016-07-01 | 2020-12-01 | Regents Of The University Of Minnesota | Compositions and methods for C. difficile treatment |
US20180036352A1 (en) | 2016-08-03 | 2018-02-08 | Crestovo Holdings Llc | Methods for treating ulcerative colitis |
EP3290027A1 (en) * | 2016-09-02 | 2018-03-07 | Develco Pharma Schweiz AG | Method and composition for the treatment of opioid induced constipation |
WO2018071536A1 (en) | 2016-10-11 | 2018-04-19 | Crestovo Holdings Llc | Compositions and methods for treating primary sclerosing cholangitis and related disorders |
US10092601B2 (en) | 2016-10-11 | 2018-10-09 | Crestovo Holdings Llc | Compositions and methods for treating multiple sclerosis and related disorders |
WO2018071537A1 (en) | 2016-10-11 | 2018-04-19 | Crestovo Holdings Llc | Compositions and methods for treating multiple sclerosis and related disorders |
US11040073B2 (en) | 2017-04-05 | 2021-06-22 | Finch Therapeutics Holdings Llc | Compositions and methods for treating diverticulitis and related disorders |
CA3058818A1 (en) | 2017-04-05 | 2018-10-11 | Crestovo Holdings Llc | Compositions and methods for treating parkinson's disease (pd) and related disorders |
AU2018272048A1 (en) | 2017-05-26 | 2019-12-19 | Finch Therapeutics Holdings Llc | Lyophilized compositions comprising fecal microbe-based therapeutic agents and methods for making and using same |
US10335375B2 (en) | 2017-05-30 | 2019-07-02 | Patheon Softgels, Inc. | Anti-overingestion abuse deterrent compositions |
CA3072032A1 (en) | 2017-08-07 | 2019-02-14 | Finch Therapeutics, Inc. | Compositions and methods for maintaining and restoring a healthy gut barrier |
WO2019152002A1 (en) * | 2018-01-31 | 2019-08-08 | Dharma Laboratories LLC | Non-extractable oral solid dosage forms |
US10624856B2 (en) | 2018-01-31 | 2020-04-21 | Dharma Laboratories LLC | Non-extractable oral solid dosage forms |
MX2020008706A (es) | 2018-02-23 | 2020-09-25 | Rhodes Tech | Nuevos compuestos de opioides y sus usos. |
US11166990B2 (en) | 2018-07-13 | 2021-11-09 | Finch Therapeutics Holdings Llc | Methods and compositions for treating ulcerative colitis |
CN112703000A (zh) | 2018-07-23 | 2021-04-23 | 特雷维治疗股份有限公司 | 慢性咳嗽、呼吸急促和呼吸困难的治疗 |
CN113164527A (zh) | 2018-09-27 | 2021-07-23 | 芬奇治疗控股有限责任公司 | 用于治疗癫痫和相关障碍的组合物和方法 |
US11324707B2 (en) | 2019-05-07 | 2022-05-10 | Clexio Biosciences Ltd. | Abuse-deterrent dosage forms containing esketamine |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001058447A1 (en) * | 2000-02-08 | 2001-08-16 | Euro-Celtique, S.A. | Controlled-release compositions containing opioid agonist and antagonist |
Family Cites Families (277)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2770569A (en) | 1952-08-01 | 1956-11-13 | Hoffmann La Roche | Analgesic compositions |
US3173877A (en) | 1957-09-09 | 1965-03-16 | Wyandotte Chemicals Corp | Detergent compositions comprising inorganic esters of epoxyhydrocarbon polymers |
US3173876A (en) * | 1960-05-27 | 1965-03-16 | John C Zobrist | Cleaning methods and compositions |
NL271831A (zh) * | 1960-11-29 | |||
US3493657A (en) | 1961-03-14 | 1970-02-03 | Mozes Juda Lewenstein | Therapeutic compositions of n-allyl-14-hydroxy - dihydronormorphinane and morphine |
US3332950A (en) | 1963-03-23 | 1967-07-25 | Endo Lab | 14-hydroxydihydronormorphinone derivatives |
US3276586A (en) * | 1963-08-30 | 1966-10-04 | Rosaen Filter Co | Indicating means for fluid filters |
NL6714885A (zh) * | 1967-11-02 | 1969-05-06 | ||
US3541006A (en) * | 1968-07-03 | 1970-11-17 | Amicon Corp | Ultrafiltration process |
US3541005A (en) * | 1969-02-05 | 1970-11-17 | Amicon Corp | Continuous ultrafiltration of macromolecular solutions |
US3773955A (en) | 1970-08-03 | 1973-11-20 | Bristol Myers Co | Analgetic compositions |
US3879555A (en) | 1970-11-16 | 1975-04-22 | Bristol Myers Co | Method of treating drug addicts |
US3676557A (en) | 1971-03-02 | 1972-07-11 | Endo Lab | Long-acting narcotic antagonist formulations |
GB1390772A (en) * | 1971-05-07 | 1975-04-16 | Endo Lab | Oral narcotic composition |
FR2183546B1 (zh) * | 1972-05-10 | 1975-06-20 | Servier Lab | |
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 |
US3916889A (en) * | 1973-09-28 | 1975-11-04 | Sandoz Ag | Patient ventilator apparatus |
US3966940A (en) | 1973-11-09 | 1976-06-29 | Bristol-Myers Company | Analgetic compositions |
GB1478759A (en) * | 1974-11-18 | 1977-07-06 | Alza Corp | Process for forming outlet passageways in pills using a laser |
US3966040A (en) * | 1975-03-05 | 1976-06-29 | Hazelwood John E | Combined vibratory feeder drive unit, vibratory feeder bowl, and parts separator |
US4077407A (en) * | 1975-11-24 | 1978-03-07 | Alza Corporation | Osmotic devices having composite walls |
US4126684A (en) * | 1976-02-11 | 1978-11-21 | Ciba-Geigy Corporation | 4-amino-3-p-halophenylbutyric acids and their derivatives used in the control of narcotic abuse |
US4063064A (en) * | 1976-02-23 | 1977-12-13 | Coherent Radiation | Apparatus for tracking moving workpiece by a laser beam |
LU77339A1 (zh) | 1977-05-16 | 1979-01-19 | ||
US4176186A (en) | 1978-07-28 | 1979-11-27 | Boehringer Ingelheim Gmbh | Quaternary derivatives of noroxymorphone which relieve intestinal immobility |
US4200098A (en) * | 1978-10-23 | 1980-04-29 | Alza Corporation | Osmotic system with distribution zone for dispensing beneficial agent |
US4285987A (en) * | 1978-10-23 | 1981-08-25 | Alza Corporation | Process for manufacturing device with dispersion zone |
US4237140A (en) | 1979-05-18 | 1980-12-02 | E. I. Du Pont De Nemours And Company | Analgesic mixture of nalbuphine and acetaminophen |
US4293539A (en) | 1979-09-12 | 1981-10-06 | Eli Lilly And Company | Controlled release formulations and method of treatment |
IE49324B1 (en) | 1979-12-19 | 1985-09-18 | Euro Celtique Sa | Controlled release compositions |
US4457933A (en) * | 1980-01-24 | 1984-07-03 | Bristol-Myers Company | Prevention of analgesic abuse |
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 |
US4401672A (en) | 1981-10-13 | 1983-08-30 | Regents Of The University Of Minnesota | Non-addictive narcotic antitussive preparation |
US4608376A (en) | 1981-10-16 | 1986-08-26 | Carolyn McGinnis | Opiate agonists and antagonists |
US4987136A (en) | 1982-03-16 | 1991-01-22 | The Rockefeller University | Method for controlling gastrointestinal dysmotility |
JPS59500418A (ja) * | 1982-03-16 | 1984-03-15 | ザ ロツクフエラ− ユニバ−シテイ | 胃腸能動作用障害を回復する方法 |
US4443428A (en) | 1982-06-21 | 1984-04-17 | Euroceltique, S.A. | Extended action controlled release compositions |
US4451470A (en) | 1982-07-06 | 1984-05-29 | E. I. Du Pont De Nemours And Company | Analgesic, antagonist, and/or anorectic 14-fluoromorphinans |
US4803208A (en) | 1982-09-30 | 1989-02-07 | Sloan-Kettering Institute For Cancer Research | Opiate agonists and antagonists |
GB8332556D0 (en) | 1983-12-06 | 1984-01-11 | Reckitt & Colmann Prod Ltd | Analgesic compositions |
US5266574A (en) | 1984-04-09 | 1993-11-30 | Ian S. Zagon | Growth regulation and related applications of opioid antagonists |
US4668685A (en) * | 1984-07-05 | 1987-05-26 | E.I. Du Pont De Nemours And Company | Substituted benzoate ester prodrug derivatives of 3-hydroxymorphinans, which are analgesics or narcotic antagonists |
US4626539A (en) * | 1984-08-10 | 1986-12-02 | E. I. Dupont De Nemours And Company | Trandermal delivery of opioids |
DE3434946A1 (de) | 1984-09-22 | 1986-04-03 | Basf Ag, 6700 Ludwigshafen | Diarylacetylene, ihre herstellung und verwendung |
US4573995A (en) | 1984-10-09 | 1986-03-04 | Alza Corporation | Transdermal therapeutic systems for the administration of naloxone, naltrexone and nalbuphine |
GB8430346D0 (en) | 1984-11-30 | 1985-01-09 | Reckitt & Colmann Prod Ltd | Analgesic compositions |
US4806341A (en) | 1985-02-25 | 1989-02-21 | Rutgers, The State University Of New Jersey | Transdermal absorption dosage unit for narcotic analgesics and antagonists and process for administration |
CA1267092A (en) | 1985-02-25 | 1990-03-27 | Martin D. Hynes | Analgesic composition containing codeine |
JPS61280423A (ja) | 1985-06-05 | 1986-12-11 | Kiyuukiyuu Yakuhin Kogyo Kk | 口腔内粘膜貼付剤 |
GB8514665D0 (en) | 1985-06-11 | 1985-07-10 | Eroceltique Sa | Oral pharmaceutical composition |
FR2585246A1 (fr) | 1985-07-26 | 1987-01-30 | Cortial | Procede d'obtention de formes pharmaceutiques solides a liberation prolongee |
GB8521350D0 (en) | 1985-08-28 | 1985-10-02 | Euro Celtique Sa | Analgesic composition |
DE3687575T2 (de) | 1985-09-06 | 1993-07-01 | Baker Norton Pharma | Verwendung von 6-methylen-6-desoxy-n-cyclopropylmethyl-14-hydroxydihydronormorphin. |
US4760069A (en) | 1985-09-23 | 1988-07-26 | Nova Pharmaceutical Corporation | Oximes of oxymorphone, naltrexone and naloxone as potent, selective opioid receptor agonists and antagonists |
US4889860A (en) | 1985-09-23 | 1989-12-26 | Nova Pharmaceutical Corporation | Oximes of oxymorphone, naltrexone and naloxone as potent, selective opioid receptor agonists and antagonists |
US4722928A (en) | 1985-12-02 | 1988-02-02 | E. I. Du Pont De Nemours And Company | N-oxide prodrug derivatives of 3-hydroxy morphinans and partial morphinans having improved oral bioavailability, pharmaceutical compositions, and processes |
US4730048A (en) | 1985-12-12 | 1988-03-08 | Regents Of The University Of Minnesota | Gut-selective opiates |
US4861781A (en) | 1986-03-07 | 1989-08-29 | The University Of Chicago | Quaternary derivatives of noroxymorphone which relieve nausea and emesis |
US4719215A (en) | 1986-03-07 | 1988-01-12 | University Of Chicago | Quaternary derivatives of noroxymorphone which relieve nausea and emesis |
US5316759A (en) | 1986-03-17 | 1994-05-31 | Robert J. Schaap | Agonist-antagonist combination to reduce the use of nicotine and other drugs |
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 |
US4769372A (en) | 1986-06-18 | 1988-09-06 | The Rockefeller University | Method of treating patients suffering from chronic pain or chronic cough |
US4785000A (en) | 1986-06-18 | 1988-11-15 | The Rockefeller University | Method of treating patients suffering from chronic pain or chronic cough |
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 |
US5356900A (en) | 1986-10-07 | 1994-10-18 | Bernard Bihari | Method of treating chronic herpes virus infections using an opiate receptor antagonist |
GB8626098D0 (en) | 1986-10-31 | 1986-12-03 | Euro Celtique Sa | Controlled release hydromorphone composition |
US4806543A (en) | 1986-11-25 | 1989-02-21 | Board Of Trustees Of The Leland Stanford Junior University | Method and compositions for reducing neurotoxic injury |
GB8628728D0 (en) | 1986-12-02 | 1987-01-07 | Euro Celtique Sa | Spheroids |
GB8705083D0 (en) | 1987-03-04 | 1987-04-08 | Euro Celtique Sa | Spheroids |
GB8728294D0 (en) | 1987-12-03 | 1988-01-06 | Reckitt & Colmann Prod Ltd | Treatment compositions |
DE3812567A1 (de) * | 1988-04-15 | 1989-10-26 | Basf Ag | Verfahren zur herstellung pharmazeutischer mischungen |
US4873076A (en) | 1988-04-29 | 1989-10-10 | Baker Cummins Pharmaceuticals, Inc. | Method of safely providing anesthesia or conscious sedation |
GB8813064D0 (en) | 1988-06-02 | 1988-07-06 | Euro Celtique Sa | Controlled release dosage forms having defined water content |
US4882335A (en) | 1988-06-13 | 1989-11-21 | Alko Limited | Method for treating alcohol-drinking response |
EP0352361A1 (en) | 1988-07-29 | 1990-01-31 | The Rockefeller University | Method of treating patients suffering from chronic pain or chronic cough |
US5236714A (en) * | 1988-11-01 | 1993-08-17 | Alza Corporation | Abusable substance dosage form having reduced abuse potential |
CA2002492A1 (en) | 1988-11-11 | 1990-05-11 | Sandra T. A. Malkowska | Pharmaceutical ion exchange resin composition |
US5102887A (en) | 1989-02-17 | 1992-04-07 | Arch Development Corporation | Method for reducing emesis and nausea induced by the administration of an emesis causing agent |
US5096715A (en) | 1989-11-20 | 1992-03-17 | Alko Ltd. | Method and means for treating alcoholism by extinguishing the alcohol-drinking response using a transdermally administered opiate antagonist |
US5075341A (en) | 1989-12-01 | 1991-12-24 | The Mclean Hospital Corporation | Treatment for cocaine abuse |
US5086058A (en) | 1990-06-04 | 1992-02-04 | Alko Ltd. | Method for treating alcoholism with nalmefene |
FR2669336B1 (fr) | 1990-11-20 | 1993-01-22 | Adir | Nouveaux derives d'oxazolo pyridines, leurs procedes de preparation et les compositions pharmaceutiques qui les contiennent. |
HU208633B (en) | 1991-02-04 | 1993-12-28 | Alkaloida Vegyeszeti Gyar | Process for production of analgetic compositions as applicable for blocking of opioid-binding spaces /2-receptors/ causing respiration depression |
US5486362A (en) | 1991-05-07 | 1996-01-23 | Dynagen, Inc. | Controlled, sustained release delivery system for treating drug dependency |
JP3178541B2 (ja) | 1991-05-29 | 2001-06-18 | キヤノン株式会社 | 画像処理方法及び装置 |
US5149538A (en) | 1991-06-14 | 1992-09-22 | Warner-Lambert Company | Misuse-resistive transdermal opioid dosage form |
GB9117361D0 (en) * | 1991-08-12 | 1991-09-25 | Euro Celtique Sa | Oral dosage form |
KR100221695B1 (ko) * | 1991-08-12 | 1999-09-15 | 그린 마틴, 브라이언 쥐 테슬리 | 약학적 구상 제형 |
RU2121346C1 (ru) | 1991-09-06 | 1998-11-10 | МакНейлэб, Инк. | Композиция, включающая вещество трамадол и ацетаминофен, и способ лечения с ее использованием |
US5215758A (en) | 1991-09-11 | 1993-06-01 | Euroceltique, S.A. | Controlled release matrix suppository for pharmaceuticals |
US5225440A (en) | 1991-09-13 | 1993-07-06 | The United States Of America As Represented By The Department Of Health And Human Services | Attenuation of the opioid withdrawal syndrome by inhibitors of nitric oxide synthase |
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 |
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 |
US5958459A (en) | 1991-12-24 | 1999-09-28 | Purdue Pharma L.P. | Opioid formulations having extended controlled released |
US5580578A (en) | 1992-01-27 | 1996-12-03 | Euro-Celtique, S.A. | Controlled release formulations coated with aqueous dispersions of acrylic polymers |
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 |
US5968551A (en) * | 1991-12-24 | 1999-10-19 | Purdue Pharma L.P. | Orally administrable opioid formulations having extended duration of effect |
US5472712A (en) * | 1991-12-24 | 1995-12-05 | Euroceltique, S.A. | Controlled-release formulations coated with aqueous dispersions of ethylcellulose |
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 |
US5286493A (en) * | 1992-01-27 | 1994-02-15 | Euroceltique, S.A. | Stabilized controlled release formulations having acrylic polymer coating |
GB9203689D0 (en) | 1992-02-20 | 1992-04-08 | Euro Celtique Sa | Pharmaceutical composition |
GB9204354D0 (en) | 1992-02-28 | 1992-04-08 | Biokine Tech Ltd | Compounds for medicinal use |
ATE404201T1 (de) | 1992-06-22 | 2008-08-15 | Univ California | Glycinrezeptorantagonisten und ihre verwendung |
US5352680A (en) | 1992-07-15 | 1994-10-04 | Regents Of The University Of Minnesota | Delta opioid receptor antagonists to block opioid agonist tolerance and dependence |
US5256669A (en) | 1992-08-07 | 1993-10-26 | Aminotek Sciences, Inc. | Methods and compositions for treating acute or chronic pain and drug addiction |
US5324351A (en) * | 1992-08-13 | 1994-06-28 | Euroceltique | Aqueous dispersions of zein and preparation thereof |
EP0668764A1 (en) | 1992-09-21 | 1995-08-30 | QIN, Bo-yi | Methods for identifying and using low/non-addictive opioid analgesics |
US5472943A (en) | 1992-09-21 | 1995-12-05 | Albert Einstein College Of Medicine Of Yeshiva University, | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other opioid agonists |
US6096756A (en) | 1992-09-21 | 2000-08-01 | Albert Einstein College Of Medicine Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists |
US5633259A (en) | 1992-09-21 | 1997-05-27 | United Biomedical, Inc. | Method for identification of low/non-addictive opioid analgesics and the use of said analgesics for treatment of opioid addiction |
US5580876A (en) | 1992-09-21 | 1996-12-03 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists |
US20010006967A1 (en) | 1992-09-21 | 2001-07-05 | Stanley M. Crain | Method of simultaneously enhancing analgesic potency and attenuating adverse side effects caused by tramadol and other bimodally-acting opioid agonists |
US5512578A (en) | 1992-09-21 | 1996-04-30 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opiod agonists |
US5869097A (en) | 1992-11-02 | 1999-02-09 | Alza Corporation | Method of therapy comprising an osmotic caplet |
US5604260A (en) | 1992-12-11 | 1997-02-18 | Merck Frosst Canada Inc. | 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2 |
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 |
US5585348A (en) | 1993-02-10 | 1996-12-17 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Use of excitatory opioid receptor antagonists to prevent growth factor-induced hyperalgesia |
US5352683A (en) | 1993-03-05 | 1994-10-04 | Virginia Commonwealth University Medical College Of Virginia | Method for the treatment of chronic pain |
CA2115792C (en) | 1993-03-05 | 2005-11-01 | David J. Mayer | Method for the treatment of pain |
US5409944A (en) | 1993-03-12 | 1995-04-25 | Merck Frosst Canada, Inc. | Alkanesulfonamido-1-indanone derivatives as inhibitors of cyclooxygenase |
NZ260408A (en) | 1993-05-10 | 1996-05-28 | Euro Celtique Sa | Controlled release preparation comprising tramadol |
US5457208A (en) | 1993-06-21 | 1995-10-10 | Regents Of The University Of Minnesota | Kappa opioid receptor antagonists |
US5474995A (en) | 1993-06-24 | 1995-12-12 | Merck Frosst Canada, Inc. | Phenyl heterocycles as cox-2 inhibitors |
US5436265A (en) | 1993-11-12 | 1995-07-25 | Merck Frosst Canada, Inc. | 1-aroyl-3-indolyl alkanoic acids and derivatives thereof useful as anti-inflammatory agents |
CN1230154C (zh) * | 1993-07-01 | 2005-12-07 | 欧洲凯尔特公司 | 缓释组合物及制备药用组合物的方法 |
IL110014A (en) * | 1993-07-01 | 1999-11-30 | Euro Celtique Sa | Solid controlled-release oral dosage forms of opioid analgesics |
NZ260883A (en) | 1993-07-01 | 1997-06-24 | Euro Celtique Sa | Oral sustained-release medicaments containing morphine |
US5879705A (en) | 1993-07-27 | 1999-03-09 | Euro-Celtique S.A. | Sustained release compositions of morphine and a method of preparing pharmaceutical compositions |
DE4325465B4 (de) | 1993-07-29 | 2004-03-04 | Zenz, Michael, Prof. Dr.med. | Orales pharmazeutisches Präparat für die Schmerztherapie |
GB9319568D0 (en) | 1993-09-22 | 1993-11-10 | Euro Celtique Sa | Pharmaceutical compositions and usages |
HU218673B (hu) | 1993-10-07 | 2000-10-28 | Euroceltique S.A. | Opioid analgetikumot tartalmazó elnyújtott hatóanyag-felszabadítású orális gyógyszerkészítmény és eljárás előállítására |
US6210714B1 (en) | 1993-11-23 | 2001-04-03 | Euro-Celtique S.A. | Immediate release tablet cores of acetaminophen having sustained-release coating |
DK0654263T3 (da) | 1993-11-23 | 2002-04-29 | Euro Celtique Sa | Fremgangsmåde til fremstilling af et præparat med langvarig frigivelse |
US5891471A (en) | 1993-11-23 | 1999-04-06 | Euro-Celtique, S.A. | Pharmaceutical multiparticulates |
KR100354702B1 (ko) | 1993-11-23 | 2002-12-28 | 유로-셀티크 소시에떼 아노뉨 | 약학조성물의제조방법및서방형조성물 |
US5500227A (en) | 1993-11-23 | 1996-03-19 | Euro-Celtique, S.A. | Immediate release tablet cores of insoluble drugs having sustained-release coating |
US5376662A (en) | 1993-12-08 | 1994-12-27 | Ockert; David M. | Method of attenuating nerve injury induced pain |
US5834477A (en) | 1993-12-08 | 1998-11-10 | The United States Of America As Represented By The Secretary Of The Army | Opiate analgesic formulation with improved safety |
US5843480A (en) | 1994-03-14 | 1998-12-01 | Euro-Celtique, S.A. | Controlled release diamorphine formulation |
US6077533A (en) | 1994-05-25 | 2000-06-20 | Purdue Pharma L.P. | Powder-layered oral dosage forms |
US5411745A (en) * | 1994-05-25 | 1995-05-02 | Euro-Celtique, S.A. | Powder-layered morphine sulfate formulations |
US5958458A (en) * | 1994-06-15 | 1999-09-28 | Dumex-Alpharma A/S | Pharmaceutical multiple unit particulate formulation in the form of coated cores |
US5460826A (en) | 1994-06-27 | 1995-10-24 | Alza Corporation | Morphine therapy |
GB9414699D0 (en) | 1994-07-21 | 1994-09-07 | Slagel David | Aqueous foamable composition |
US5616601A (en) | 1994-07-28 | 1997-04-01 | Gd Searle & Co | 1,2-aryl and heteroaryl substituted imidazolyl compounds for the treatment of inflammation |
US5521213A (en) | 1994-08-29 | 1996-05-28 | Merck Frosst Canada, Inc. | Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2 |
US5593994A (en) | 1994-09-29 | 1997-01-14 | The Dupont Merck Pharmaceutical Company | Prostaglandin synthase inhibitors |
US5866154A (en) * | 1994-10-07 | 1999-02-02 | The Dupont Merck Pharmaceutical Company | Stabilized naloxone formulations |
GB9422154D0 (en) | 1994-11-03 | 1994-12-21 | Euro Celtique Sa | Pharmaceutical compositions and method of producing the same |
US5965161A (en) | 1994-11-04 | 1999-10-12 | Euro-Celtique, S.A. | Extruded multi-particulates |
ES2377126T3 (es) | 1994-12-12 | 2012-03-22 | Omeros Corporation | Solución de irrigación y utilización de la misma para la inhibición perioperatoria del dolor, la inflamación y/o los espasmos en una estructura vascular |
GB9426102D0 (en) | 1994-12-23 | 1995-02-22 | Merck Sharp & Dohme | Pharmacuetical compositions |
US5692500A (en) | 1995-01-09 | 1997-12-02 | Gaston-Johansson; Fannie | Pain measurement and recording tool and method |
US5552422A (en) | 1995-01-11 | 1996-09-03 | Merck Frosst Canada, Inc. | Aryl substituted 5,5 fused aromatic nitrogen compounds as anti-inflammatory agents |
US5578725A (en) | 1995-01-30 | 1996-11-26 | Regents Of The University Of Minnesota | Delta opioid receptor antagonists |
US20020006964A1 (en) * | 1995-05-16 | 2002-01-17 | Young James W. | Methods of using and compositions comprising (+) sibutramine optionally in combination with other pharmacologically active compounds |
US5639780A (en) | 1995-05-22 | 1997-06-17 | Merck Frosst Canada, Inc. | N-benzyl indol-3-yl butanoic acid derivatives as cyclooxygenase inhibitors |
US5510368A (en) | 1995-05-22 | 1996-04-23 | Merck Frosst Canada, Inc. | N-benzyl-3-indoleacetic acids as antiinflammatory drugs |
US5604253A (en) | 1995-05-22 | 1997-02-18 | Merck Frosst Canada, Inc. | N-benzylindol-3-yl propanoic acid derivatives as cyclooxygenase inhibitors |
HUP9700322A3 (en) | 1995-06-09 | 2001-03-28 | Euro Celtique Sa | Formulations and methods for providing prolonged local anesthesia |
US5931809A (en) | 1995-07-14 | 1999-08-03 | Depotech Corporation | Epidural administration of therapeutic compounds with sustained rate of release |
GB9517062D0 (en) * | 1995-08-18 | 1995-10-25 | Scherer Ltd R P | Pharmaceutical compositions |
GB9517883D0 (en) | 1995-09-01 | 1995-11-01 | Euro Celtique Sa | Improved pharmaceutical ion exchange resin composition |
GB9519363D0 (en) | 1995-09-22 | 1995-11-22 | Euro Celtique Sa | Pharmaceutical formulation |
US5811126A (en) | 1995-10-02 | 1998-09-22 | Euro-Celtique, S.A. | Controlled release matrix for pharmaceuticals |
AUPN603895A0 (en) | 1995-10-19 | 1995-11-09 | University Of Queensland, The | Production of analgesic synergy by co-administration of sub-analgesic doses of two strong opioids |
CA2239301A1 (en) | 1995-12-06 | 1997-06-12 | Charles Howard Mitch | Composition for treating pain |
ES2200158T3 (es) | 1996-03-08 | 2004-03-01 | Nycomed Danmark Aps | Cmpuesto de dosificacion de unidades multiples, de liberacion modificada. |
DE69709646T2 (de) | 1996-03-12 | 2002-08-14 | Alza Corp | Zusammensetzung und dosisform mit einem opioid-antagonisten |
US6103258A (en) | 1996-04-12 | 2000-08-15 | Simon; David Lew | Salts and bases of the 17-(Cyclopropylmethyl)-4,5 alpha-epoxy-6-Methylenemorphinan-3,14 diol molecule for optimizing dopamine homeostasis during administration of opioid analgesics |
CA2224859A1 (en) * | 1996-04-17 | 1997-10-23 | Amitabh Gaur | Ligand inhibitors of insulin-like growth factor binding proteins and methods of use therefor |
WO1997045091A2 (en) * | 1996-05-31 | 1997-12-04 | Euro-Celtique, S.A. | Sustained release oxycodone formulations with no fed/fast effect |
WO1998024412A2 (en) * | 1996-12-05 | 1998-06-11 | The Board Of Trustees Of The University Of Illinois | Compounds useful against diseases of the colon and methods for orally administering same |
DE19651551C2 (de) | 1996-12-11 | 2000-02-03 | Klinge Co Chem Pharm Fab | Opioidantagonisthaltige galenische Formulierung |
DE29719704U1 (de) | 1997-02-14 | 1998-01-22 | Goedecke Ag | Stabile Zubereitungen von Naloxonhydrochlorid |
DE59800046D1 (de) | 1997-02-14 | 1999-12-23 | Goedecke Ag | Stabilisierung von naloxonhydrochlorid |
US5968547A (en) | 1997-02-24 | 1999-10-19 | Euro-Celtique, S.A. | Method of providing sustained analgesia with buprenorphine |
DE19710008A1 (de) | 1997-03-12 | 1998-09-17 | Basf Ag | Feste, mindestens zweiphasige Zubereitungsformen eines Opioid-Analgeticums mit verzögerter Freisetzung |
US5780479A (en) | 1997-04-04 | 1998-07-14 | Regents Of The University Of Minnesota | Use of opioid antagonists to treat impulse-control disorders |
US6207142B1 (en) * | 1997-04-14 | 2001-03-27 | Janssen Pharmaceutica N.V. | Compositions containing an antifungal and a cationic agent |
WO1999001111A1 (en) * | 1997-07-02 | 1999-01-14 | Euro-Celtique, S.A. | Stabilized sustained release tramadol formulations |
WO1999005960A1 (en) | 1997-07-30 | 1999-02-11 | Universite De Montreal | Portable and programmable interactive visual analogue scale data-logger device |
EP2246058A1 (en) | 1997-09-04 | 2010-11-03 | Novoneuron, Inc. | Noribogaine in the treatment of pain and drug addiction |
US5972954A (en) | 1997-11-03 | 1999-10-26 | Arch Development Corporation | Use of methylnaltrexone and related compounds |
ATE210983T1 (de) | 1997-11-03 | 2002-01-15 | Stada Arzneimittel Ag | Stabilisiertes kombinationsarzneimittel enthaltend naloxone und ein opiatanalgetikum |
US6274591B1 (en) | 1997-11-03 | 2001-08-14 | Joseph F. Foss | Use of methylnaltrexone and related compounds |
CN1204890C (zh) * | 1997-12-22 | 2005-06-08 | 欧罗赛铁克股份有限公司 | 防止阿片样物质滥用的方法 |
AU773642C (en) | 1997-12-22 | 2006-04-06 | Mundipharma Pty Limited | Opioid agonist/antagonist combinations |
US6375957B1 (en) | 1997-12-22 | 2002-04-23 | Euro-Celtique, S.A. | Opioid agonist/opioid antagonist/acetaminophen combinations |
PL343593A1 (en) * | 1998-03-27 | 2001-08-27 | Upjohn Co | Use of cabergoline in the treatment of restless legs syndrome |
US5957459A (en) | 1998-04-27 | 1999-09-28 | Chae; Myung Joo | Banking card game |
DE19857766A1 (de) | 1998-05-28 | 1999-12-02 | Krewel Meuselbach Gmbh | Retardiertes Schmerzmittel enthaltend Tilidin |
EP0960619B1 (de) | 1998-05-28 | 2004-03-10 | Krewel Meuselbach GmbH | Retardiertes Schmerzmittel enthaltend Tilidin |
DE29818454U1 (de) | 1998-10-15 | 1999-01-14 | Euro Celtique Sa | Opioid-Analgetikum |
SE9803760D0 (sv) | 1998-11-04 | 1998-11-04 | Jan Hedner | Sätt att behandla och diagnostisera syndromet restless legs och motsvarande medel |
FR2787715B1 (fr) | 1998-12-23 | 2002-05-10 | Synthelabo | Composition pharmaceutique comprenant un compose hypnotique ou un de ses sels pharmaceutiquement acceptables |
DE19859636A1 (de) * | 1998-12-23 | 2000-06-29 | Hexal Ag | Kontrolliert freisetzende pharmazeutische Zusammensetzung mit Tilidinmesylat als Wirkstoff |
DE19901085C2 (de) | 1999-01-14 | 2003-12-18 | Lohmann Therapie Syst Lts | Transdermales therapeutisches System mit einer selbstklebenden Matrix, enthaltend organische Säure-Additionssalze von Alkaloiden des Morphin- bzw. Morphinantyps |
US6194382B1 (en) | 1999-03-03 | 2001-02-27 | Albert Einstein College Of Medicine Of Yeshiva University | Method and composition for treating irritable bowel syndrome using low doses of opioid receptor antagonists |
DE19918325A1 (de) | 1999-04-22 | 2000-10-26 | Euro Celtique Sa | Verfahren zur Herstellung von Arzneiformen mit regulierter Wirkstofffreisetzung mittels Extrusion |
US6765010B2 (en) | 1999-05-06 | 2004-07-20 | Pain Therapeutics, Inc. | Compositions and methods for enhancing analgesic potency of tramadol and attenuating its adverse side effects |
US20030178031A1 (en) * | 1999-05-07 | 2003-09-25 | Du Pen, Inc. | Method for cancer pain treatment |
US6419595B1 (en) | 1999-07-09 | 2002-07-16 | Bridgestone Sports Co., Ltd. | Solid golf ball |
US6451007B1 (en) | 1999-07-29 | 2002-09-17 | Dale E. Koop | Thermal quenching of tissue |
US20030118641A1 (en) * | 2000-07-27 | 2003-06-26 | Roxane Laboratories, Inc. | Abuse-resistant sustained-release opioid formulation |
DE19938823A1 (de) | 1999-08-19 | 2001-02-22 | Boehringer Ingelheim Pharma | Medikamentöse Behandlung des Restless Leg Syndroms |
US6258042B1 (en) * | 1999-09-17 | 2001-07-10 | James S. Factor | Visual analog scale and method of use for the diagnosis and/or treatment of physical pain |
US6451806B2 (en) | 1999-09-29 | 2002-09-17 | Adolor Corporation | Methods and compositions involving opioids and antagonists thereof |
DK1225897T3 (da) | 1999-11-01 | 2005-01-10 | John Rhodes | Sammensætning til behandling af obstipation og colon irritabile |
DK1244447T3 (da) | 1999-11-29 | 2007-04-23 | Adolor Corp | Nye fremgangsmåder og sammensætninger indeholdende opioider og deres antagonister |
WO2001052851A1 (en) | 2000-01-22 | 2001-07-26 | Albert Shulman | Methods for the treatment of substance abuse |
US6716449B2 (en) * | 2000-02-08 | 2004-04-06 | Euro-Celtique S.A. | Controlled-release compositions containing opioid agonist and antagonist |
CA2403252A1 (en) | 2000-03-15 | 2001-09-20 | Wolfgang Sadee | Neutral antagonists and use thereof in treating drug abuse |
CA2408106A1 (en) | 2000-05-05 | 2001-11-15 | Pain Therapeutics, Inc. | Opioid antagonist compositions and dosage forms |
AU5956001A (en) | 2000-05-05 | 2001-11-20 | Pain Therapeutics Inc | Novel compositions and methods for enhancing potency or reducing adverse side effects of opioid agonists |
WO2001093852A2 (en) | 2000-06-09 | 2001-12-13 | The Regents Of The University Of California | Method of treating pain using nalbuphine and opioid antagonists |
US7223421B2 (en) * | 2000-06-30 | 2007-05-29 | Mcneil-Ppc, Inc. | Teste masked pharmaceutical particles |
GB0026137D0 (en) | 2000-10-25 | 2000-12-13 | Euro Celtique Sa | Transdermal dosage form |
AR031152A1 (es) * | 2000-10-31 | 2003-09-10 | Upjohn Co | Tratamientos nuevos para el sindrome de piernas inquietas |
GEP20053545B (en) * | 2001-04-19 | 2005-06-10 | Warner Lambert Co | Fused Bicyclic or Tricyclic Amino Acids |
UA81224C2 (uk) | 2001-05-02 | 2007-12-25 | Euro Celtic S A | Дозована форма оксикодону та її застосування |
CA2446550C (en) * | 2001-05-11 | 2012-03-06 | Endo Pharmaceuticals, Inc. | Abuse-resistant controlled-release opioid dosage form |
CN1592609A (zh) | 2001-05-11 | 2005-03-09 | 恩德制药公司 | 抗滥用阿片样物质剂型 |
DE10131113A1 (de) | 2001-06-28 | 2003-01-23 | Siemens Linear Motor Systems G | Rotations-Elektromotor |
WO2003004009A1 (en) | 2001-07-02 | 2003-01-16 | Geneva Pharmaceuticals, Inc. | Pharmaceutical composition |
DE60230632D1 (de) * | 2001-07-18 | 2009-02-12 | Euro Celtique Sa | Pharmazeutische kombinationen von oxycodon und naloxon |
US7144587B2 (en) * | 2001-08-06 | 2006-12-05 | Euro-Celtique S.A. | Pharmaceutical formulation containing opioid agonist, opioid antagonist and bittering agent |
WO2003013433A2 (en) | 2001-08-06 | 2003-02-20 | Euro-Celtique S.A. | Sequestered antagonist formulations |
US7332182B2 (en) * | 2001-08-06 | 2008-02-19 | Purdue Pharma L.P. | Pharmaceutical formulation containing opioid agonist, opioid antagonist and irritant |
US20030044458A1 (en) * | 2001-08-06 | 2003-03-06 | Curtis Wright | Oral dosage form comprising a therapeutic agent and an adverse-effect agent |
DE60232417D1 (de) | 2001-08-06 | 2009-07-02 | Euro Celtique Sa | Opioid-agonist-formulierungen mit freisetzbarem und sequestriertem antagonist |
DE20220910U1 (de) | 2001-08-06 | 2004-08-05 | Euro-Celtique S.A. | Zusammensetzungen zur Verhinderung des Missbrauchs von Opioiden |
JP2005500364A (ja) | 2001-08-06 | 2005-01-06 | ユーロ−セルティーク,エス.エイ. | オピオイドの乱用を防止する組成物と方法 |
AU2002339395A1 (en) | 2001-09-06 | 2003-03-18 | Hans Gregersen | Method an apparatus for stimulating a bodily hollow system and method and apparatus for measuring reactions to stimuli of such system |
US20040234602A1 (en) * | 2001-09-21 | 2004-11-25 | Gina Fischer | Polymer release system |
EP1429744A1 (en) * | 2001-09-21 | 2004-06-23 | Egalet A/S | Morphine polymer release system |
US20030092759A1 (en) * | 2001-09-24 | 2003-05-15 | Abuzzahab Faruk S. | Anticonvulsant derivatives useful for the treatment of restless limb syndrome and periodic limb movement disorder |
PT1482835E (pt) | 2002-03-06 | 2012-12-26 | Euro Celtique Sa | Escala analógica para medição da dor |
ATE510534T1 (de) | 2002-03-14 | 2011-06-15 | Euro Celtique Sa | Naltrexonhydrochlorid-zusammensetzungen |
DE10215067A1 (de) | 2002-04-05 | 2003-10-16 | Euro Celtique Sa | Lagerstabiles pharmazeutisches Präparat, das Oxycodon und Naloxon umfasst |
CN102813654A (zh) | 2002-04-05 | 2012-12-12 | 欧洲凯尔蒂克公司 | 含有羟氢可待酮和烯丙羟吗啡酮的药物制剂 |
DE10215131A1 (de) | 2002-04-05 | 2003-10-16 | Euro Celtique Sa | Matrix zur verzögerten, gleichbleibenden und unabhängigen Freisetzung von Wirkstoffen |
US20030191147A1 (en) * | 2002-04-09 | 2003-10-09 | Barry Sherman | Opioid antagonist compositions and dosage forms |
EP1364649A1 (en) | 2002-05-23 | 2003-11-26 | Cilag AG | Adduct of topiramate and tramadol hydrochioride and uses thereof |
JP4694207B2 (ja) * | 2002-07-05 | 2011-06-08 | コルジウム ファーマシューティカル, インコーポレイテッド | オピオイドおよび他の薬物に関する乱用抑止性の薬学的組成物 |
RU2222260C1 (ru) | 2002-07-08 | 2004-01-27 | Сибирский государственный медицинский университет | Способ дифференцированной оценки степени функциональной активности тонкой кишки |
WO2004026262A2 (en) | 2002-09-23 | 2004-04-01 | Verion, Inc. | Abuse-resistant pharmaceutical compositions |
CN100500130C (zh) | 2003-01-23 | 2009-06-17 | 株式会社太平洋 | 缓释制剂及其制备方法 |
EP2368553B1 (en) | 2003-04-08 | 2014-12-31 | Progenics Pharmaceuticals, Inc. | Pharmaceutical formulations containing methylnaltrexone |
TWI357815B (en) | 2003-06-27 | 2012-02-11 | Euro Celtique Sa | Multiparticulates |
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 |
TWI350762B (en) | 2004-02-12 | 2011-10-21 | Euro Celtique Sa | Particulates |
US7700626B2 (en) * | 2004-06-04 | 2010-04-20 | Adolor Corporation | Compositions containing opioid antagonists |
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 |
GB2418854B (en) | 2004-08-31 | 2009-12-23 | Euro Celtique Sa | Multiparticulates |
EP2319499A1 (en) | 2005-01-28 | 2011-05-11 | Euro-Celtique S.A. | Alcohol resistant dosage forms |
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 |
US20070092576A1 (en) | 2005-10-20 | 2007-04-26 | Adolor Corporation | Compositions containing opioid antagonists |
EP1813276A1 (en) | 2006-01-27 | 2007-08-01 | Euro-Celtique S.A. | Tamper resistant dosage forms |
US20070185145A1 (en) | 2006-02-03 | 2007-08-09 | Royds Robert B | Pharmaceutical composition containing a central opioid agonist, a central opioid antagonist, and a peripheral opioid antagonist, and method for making the same |
WO2007111945A2 (en) | 2006-03-22 | 2007-10-04 | Trustees Of Boston University | Method for management of diarrhea |
AU2007240873A1 (en) | 2006-04-19 | 2007-11-01 | Jill P. Smith | Treatment of inflammatory and ulcerative diseases of the bowel with opioid antagonists |
DE202006018609U1 (de) | 2006-08-29 | 2007-05-16 | Euro-Celtique S.A. | Verwendung von Opioidformulierungen in nadellosen Vorrichtungen zur Medikamentenverabreichung |
TW200817048A (en) | 2006-09-08 | 2008-04-16 | Wyeth Corp | Dry powder compound formulations and uses thereof |
EP2042176A1 (en) | 2007-09-26 | 2009-04-01 | Euro-Celtique S.A. | Use of a combination of an opioid agonist and an opioid antagonist for the treatment of Crohn's disease |
RU2478388C2 (ru) | 2008-07-07 | 2013-04-10 | Еуро-Селтик С.А. | Фармацевтическая композиция, содержащая опиоидный антагонист, для лечения задержки мочи |
SI2405915T1 (sl) | 2009-03-10 | 2019-03-29 | Euro-Celtique S.A. | Farmacevtski sestavki s takojšnjim sproščanjem, ki vsebujejo oksikodon in nalokson |
NO330672B1 (no) | 2009-11-12 | 2011-06-06 | Proxdynamics As | Rotormekanisme for helikoptere |
DE112011102708T5 (de) | 2010-08-13 | 2013-05-29 | Euro-Celtique S.A. | Verwendung von Bindemitteln zur Herstellung von lagerungsstabilen Formulierungen |
-
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001058447A1 (en) * | 2000-02-08 | 2001-08-16 | Euro-Celtique, S.A. | Controlled-release compositions containing opioid agonist and antagonist |
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