CN103476403A - Controlled release formulations of opioids - Google Patents

Controlled release formulations of opioids Download PDF

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CN103476403A
CN103476403A CN 201180056278 CN201180056278A CN103476403A CN 103476403 A CN103476403 A CN 103476403A CN 201180056278 CN201180056278 CN 201180056278 CN 201180056278 A CN201180056278 A CN 201180056278A CN 103476403 A CN103476403 A CN 103476403A
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oxycodone
salt
opioid
pharmaceutical formulation
ml
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CN 201180056278
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Chinese (zh)
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E·M·鲁德尼克
M·瓦尚
G·W·佩斯
J·贝里
F·D·L·伊格莱西亚
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Qrx制药有限公司
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/485Morphinan derivatives, e.g. morphine, codeine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5026Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings

Abstract

Pharmaceutical formulations containing opioid components that each has a release profile. The components may provide immediate or controlled release of the opioid. The invention is also directed to methods of controlling release of one or more opioid compounds and methods of treating pain.

Description

阿片样物质的控释制剂 Controlled release formulations of opioids

[0001] 相关申请的交叉引用 CROSS [0001] REFERENCE TO RELATED APPLICATIONS

[0002] 本申请要求2010年9月24日提交的美国临时申请系列号61/386,277和2011年2月9日提交的美国申请系列号13/024,319的优先权,这两者均整体援引加入本文。 [0002] This application claims priority September 24, 2010 of US Provisional Application Serial No. 61 / 386,277, and February 9, 2011 filed US Application Serial No. 13 / 024,319, which both reference in its entirety Join this article.

技术领域 FIELD

[0003] 本发明涉及包含阿片样物质组分的药物制剂,所述阿片样物质组分各自具有释放特征谱(profile)。 [0003] The present invention relates to a pharmaceutical formulation comprising the opioid component, the opioid release component each having a spectral characteristic (profile). 所述组分可以提供阿片样物质的即释或控释。 The components may provide immediate release or controlled release of the opioid. 本发明还涉及一种或多种阿片样物质化合物的控释方法以及治疗疼痛的方法。 The present invention further relates to a method for controlled release of one or more species of the compounds and methods of opioid treatment of pain.

背景技术 Background technique

[0004] 阿片样物质是常用于治疗各种急性和慢性、中度至严重疼痛的一类缓解疼痛的处方药。 [0004] Opioids are commonly used in the treatment of various acute and chronic, moderate to severe pain, pain relief for a class of prescription drugs. 然而,阿片样物质可以被快速吸收并通过代谢失活被身体系统性排出。 However, opioids can be quickly absorbed by the body systemic metabolic inactivation is discharged. 为了治疗患者,特别是严重疼痛的患者,阿片样物质的给药常需要以频繁的间隔,小心地剂量给药以维持阿片样物质的有效稳态血液水平,从而提供持续镇痛。 For treating patients, especially in patients with severe pain, opioids administered at frequent intervals often require carefully administered in a dosage effective to maintain the steady-state blood levels of an opioid to provide sustained analgesia. 否则,阿片样物质的血液水平可能波动而导致很差和不一致的疼痛缓解。 Otherwise, blood levels of opioid fluctuations may result in poor and inconsistent pain relief.

[0005] 与阿片样物质的给药相关的这些困难表明需要开发阿片样物质的疗法,其可以在给药之后维持血液中阿片样物质的一致水平并避免疼痛缓解的波动。 [0005] These difficulties associated with the administration of opioid indicates a need to develop opioid therapy, which can maintain a consistent blood levels of opioids in pain relief after administration and to avoid fluctuations.

发明内容 SUMMARY

[0006] 本发明涉及用于治疗疼痛的药物制剂,所述药物制剂包含这样的组分,所述组分包含阿片样物质化合物并具有不同的释放特征谱。 [0006] The present invention relates to a pharmaceutical formulation for the treatment of pain, the pharmaceutical formulation comprises such a component, said component comprising an opioid compound and having different profiles of release. 本发明还涉及一种或多种阿片样物质化合物的控释方法以及治疗疼痛的方法。 The present invention further relates to a method for controlled release of one or more species of the compounds and methods of opioid treatment of pain.

[0007] 本发明的药物制剂可以包含一种或多种组分,所述组分具有一种或多种释放特征谱,其中至少一种所述组分包含具有阿片样物质受体激动剂活性的化合物。 [0007] The pharmaceutical formulations of the invention may comprise one or more components, the components having one or more spectral release profile, wherein said component comprises at least one of the opioid receptor agonist activity has compound of. 在其中有超过一种组分的实施方案中,所述组分可以具有相同的释放特征谱,或者所述组分可以具有不同的释放特征谱。 In which more than one component in the embodiment, the components may have the same release profile spectrum, or the components may have different profiles of release.

[0008] 在一些实施方案中,具有阿片样物质受体激动剂活性的化合物可以具有针对μ (“ μ ”,吗啡受体)、σ (“。”,苯环利定受体)、K (“ K ”,酮基环佐辛(ketocyclazocine)受体)或δ (“ δ ”, endorphinlenkephalin受体)阿片样物质受体的激动剂活性。 [0008] In some embodiments, opioid receptor agonist having activity for the compound may have a μ ( "μ", opioid receptor), σ ( ".", Phencyclidine receptor), K ( "K", keto cyclazocine (ketocyclazocine) receptors) or δ ( "δ", endorphinlenkephalin receptor) opioid receptor agonist activity. 这类化合物可以包括吗啡、可待因、氢吗啡酮、氢可酮、羟考酮、双氢可待因、双氢吗啡、羟吗啡酮、它们的混合物或它们的盐。 Such compounds may include morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydroergotamine, morphine, oxymorphone, mixtures thereof or salts thereof. 在某些实施方案中,组分可以包含不同比例的两种阿片样物质化合物。 In certain embodiments, the components may contain different ratios of the two opioid compound. 在具体实施方案中,组分可以包含约3:2重量比的吗啡和羟考酮或者它们的盐。 In a particular embodiment, the component may comprise from about 3: 2 weight ratio of morphine and oxycodone or a salt thereof.

[0009] 在一些实施方案中,所述组分可以具有即释特征谱或控释特征谱。 [0009] In some embodiments, the components may have profiles of immediate release or controlled release characteristic spectrum.

[0010] 在某些实施方案中,所述制剂可以包含一种或多种额外的组分,例如至少2种、至少3种、至少4种或至少5种组分。 [0010] In certain embodiments, the formulation may comprise one or more additional components, such as at least 2, at least three, at least four or at least five components. 在一些实施方案中,所述一种或多种额外的组分可以包含一种或多种活性物质。 In some embodiments, the one or more additional components may comprise one or more active substances. 在一些实施方案中,所述一种或多种活性物质可以是具有阿片样物质受体激动剂活性的化合物。 In some embodiments, the one or more active substances may be compounds opioid receptor agonist activity. 在一些实施方案中,所述一种或多种活性物质可以是一种或多种非阿片样物质镇痛化合物,或者一种或多种非阿片样物质镇痛化合物与一种或多种具有阿片样物质受体激动剂活性的化合物或者它们的药学可接受的盐、酯或前药的混合物。 In some embodiments, the one or more active substances may be one or more non-opioid analgesic compound, or one or more non-opioid analgesic compound having one or more opioid receptor agonist activity of the compounds or their pharmaceutically acceptable salt, ester or prodrug mixtures. 在某些实施方案中,所述一种或多种活性物质可以是一种或多种混合阿片样物质化合物,或者一种或多种混合阿片样物质化合物与一种或多种具有阿片样物质受体激动剂活性的化合物或者它们的药学可接受的盐、酯或前药的混合物。 In certain embodiments, the one or more active substances may be mixed with one or more opioid compound, or a compound of one or more substances mixed with one or more of an opioid with an opioid receptor agonist activity of the compounds or their pharmaceutically acceptable salt, ester or prodrug mixtures.

[0011] 在本发明的实施方案中,所述药物制剂可以包含一种或多种阿片样物质组分,其中至少一种所述阿片样物质组分是包含阿片样物质的控释阿片样物质组分。 [0011] In an embodiment of the present invention, the pharmaceutical formulation may include one or more opioid component, wherein said at least one opioid controlled release component comprising an opioid opioid components. 在某些实施方案中,所述阿片样物质选自吗啡、可待因、氢吗啡酮、氢可酮、羟考酮、双氢可待因、双氢吗啡、羟吗啡酮、它们的混合物以及它们的盐。 In certain embodiments, the opioid is selected from morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydroergotamine, morphine, oxymorphone, and mixtures thereof their salts. 在具体实施方案,所述阿片样物质为羟考酮或其盐。 In a particular embodiment, the opioid is oxycodone or a salt thereof.

[0012] 在某些实施方案中,所述药物制剂在重复给药后提供约4.5-约8小时的至最大阿片样物质的血浆浓度的时间(Tniax)。 [0012] In certain embodiments, the pharmaceutical formulation to provide from about 4.5 to about 8 hours after repeated dosing plasma concentration (Tniax) to the maximum opioid. 在具体实施方案中,重复给药后Tniax为约5-约6小时或者约6小时。 In a specific embodiment, after repeated administration Tniax about 5 to about 6 hours or about 6 hours.

[0013] 在一些实施方案中,所述控释组分在重复给药后提供约13-约16小时的至最小羟考酮血浆浓度的时间(U。在具体实施方案中,重复给药后Tniin为约14小时。在一些实施方案中,重复给药在稳态条件中进行。 After [0013] In some embodiments, the controlled release component provides from about 13 to about 16 hours after repeated administration to a minimum plasma concentration of oxycodone one time (in the U. The specific embodiments, repeated administration Tniin is about 14 hours. in some embodiments, the administration is repeated in a steady state condition.

[0014] 在一些实施方案,以50rpm在水中于37° C下在USP I型装置中测量时,所述药物制剂的溶出在2小时后释放约O-约20%的阿片样物质,或者在4小时后释放约15-约60%的阿片样物质,或者在6小时后释放约25-约80%的阿片样物质,或者在8小时后释放约35-约85%的阿片样物质,或者在10小时后释放约45-约95%的阿片样物质,或者在12小时后释放约60-约100%的阿片样物质。 [0014] In some embodiments, at 50rpm when measured in water at 37 ° C for in USP Type I apparatus, the dissolution of the pharmaceutical formulation is released from about 20% to about O- opioid After 2 hours, or released after 4 hours from about 15 to about 60% of the opioid, or from about 25 to about 80% release of the opioid after 6 hours, or from about 35 to about 85% release of the opioid after 8 hours, or release from about 45 to about 95% of the opioid after 10 hours, or from about 60 to about 100% release of the opioid after 12 hours.

[0015] 在某些实施方案中,当所述药物制剂包含约2mg阿片样物质时,所述药物制剂在重复给药后可以提供约1-约3ng/mL或者约2ng/mL的平均最大血浆浓度(Cmax)。 [0015] In certain embodiments, when the pharmaceutical formulation comprises from about 2mg opioid, the pharmaceutical formulation may be provided after repeated administration of from about 1 to about 3ng / mL, or about a mean maximum plasma 2ng / mL of concentration (Cmax). 在一些实施方案中,重复给药可以在稳态条件中进行。 , Repeated dosing may be performed in steady state conditions in some embodiments. 在某些实施方案中,在单次给药后,约O-约24小时的曲线下面积(AUC24)可以为约14.7ng ^hiVmL-约23.0ng ^hiVmL,或者约15.8ng *hr/ml约21.0ng.hr/mL,或者约17.1ng.hr/mL-约19.7ng.hr/mL。 In certain embodiments, after a single dose, area under the curve of about O- about 24 hours (AUC24) may be from about 14.7ng ^ hiVmL- about 23.0ng ^ hiVmL, or from about 15.8ng * hr / ml to about 21.0ng.hr/mL, or about 17.1ng.hr/mL- about 19.7ng.hr/mL.

[0016] 在某些实施方案中,当所述药物制剂包含约5mg阿片样物质时,所述药物制剂在重复给药后可以提供约3-约7ng/mL或者约5ng/mL的平均Cniax。 [0016] In certain embodiments, when the pharmaceutical formulation comprises from about 5mg opioid, the pharmaceutical formulation may be provided after repeated administration from about 3 to about 7ng / mL, or about the average Cniax 5ng / mL of. 在一些实施方案中,重复给药可以在稳态条件中进行。 , Repeated dosing may be performed in steady state conditions in some embodiments. 在某些实施方案中,在单次给药后,AUC24可以为约40.2ng *hr/ml约62.8ng.hr/mL,或者约43.2ng.hr/mL-约57.2ng.hr/mL,或者约46.7ng.hr/ml,-约53.7ng.hr/mL。 In certain embodiments, after a single administration, AUC24 may be from about 40.2ng * hr / ml to about 62.8ng.hr/mL, or from about 43.2ng.hr/mL- about 57.2ng.hr/mL, or about 46.7ng.hr/ml,- about 53.7ng.hr/mL.

[0017] 在某些实施方案中,当所述药物制剂包含约IOmg阿片样物质时,所述药物制剂在重复给药后可以提供约5-约15ng/mL或者约10ng/mL的平均Cniax。 [0017] In certain embodiments, when the pharmaceutical formulation comprises from about IOmg opioid, the pharmaceutical formulation may be provided after repeated administration of from about 5 to about 15ng / mL, or about the average Cniax 10ng / mL of. 在一些实施方案中,重复给药可以在稳态条件中进行。 , Repeated dosing may be performed in steady state conditions in some embodiments. 在某些实施方案中,在单次给药后,AUC24可以为约80.5ng.hr/mL-约125.9ng.hr/mL,或者约86.6ng.hr/mL-约114.8ng.hr/mL,或者约93.7ng.hr/mL-约107.7ng.hr/mL。 In certain embodiments, after a single administration, AUC24 may be from about 80.5ng.hr/mL- about 125.9ng.hr/mL, or from about 86.6ng.hr/mL- about 114.8ng.hr/mL, or about 93.7ng.hr/mL- about 107.7ng.hr/mL.

[0018] 在某些实施方案中,当所述药物制剂包含约20mg阿片样物质时,所述药物制剂在重复给药后可以提供约10-约30ng/mL或者约20ng/mL的平均C_。 [0018] In certain embodiments, when the pharmaceutical formulation comprises from about 20mg opioid, the pharmaceutical formulation may be provided after repeated administration of from about 10 to about 30ng / mL, or about the average C_ 20ng / mL of. 在一些实施方案中,重复给药可以在稳态条件中进行。 , Repeated dosing may be performed in steady state conditions in some embodiments. 在某些实施方案中,在单次给药后,AUC24可以为约166.0ng.hr/mL-约259.3ng.hr/mL,或者约178.5ng.hr/mL-约236.6ng.hr/mL,或者约193.0ng.hr/mL-约222.0ng.hr/mL。 In certain embodiments, after a single administration, AUC24 may be from about 166.0ng.hr/mL- about 259.3ng.hr/mL, or from about 178.5ng.hr/mL- about 236.6ng.hr/mL, or about 193.0ng.hr/mL- about 222.0ng.hr/mL.

[0019] 在某些实施方案中,当所述药物制剂包含约40mg阿片样物质时,所述药物制剂在重复给药后可以提供约25-约55ng/mL或者约40ng/mL的平均C_。 [0019] In certain embodiments, when the pharmaceutical formulation comprises from about 40mg opioid, the pharmaceutical formulation may be provided after repeated administration of about 25 to about 55ng average C_ / mL or from about 40ng / mL to. 在一些实施方案中,重复给药可以在稳态条件中进行。 , Repeated dosing may be performed in steady state conditions in some embodiments. 在某些实施方案中,在单次给药后,AUC24可以为约338.5ng.hr/mL-约528.9ng.hr/mL,或者约363.9ng.hr/mL-约482.3ng.hr/mL,或者约393.5ng.hr/mL-约452.7ng.hr/mL。 In certain embodiments, after a single administration, AUC24 may be from about 338.5ng.hr/mL- about 528.9ng.hr/mL, or from about 363.9ng.hr/mL- about 482.3ng.hr/mL, or about 393.5ng.hr/mL- about 452.7ng.hr/mL.

[0020] 在某些实施方案中,当所述药物制剂包含约80mg阿片样物质时,所述药物制剂在重复给药后可以提供约50-约110ng/mL或者约80ng/mL的平均C_。 [0020] In certain embodiments, when the pharmaceutical formulation comprises from about 80mg opioid, the pharmaceutical formulation may be provided after repeated administration of from about 50 to about 110ng / mL or from about 80ng / C_ mL of average. 在一些实施方案中,重复给药可以在稳态条件中进行。 , Repeated dosing may be performed in steady state conditions in some embodiments. 在某些实施方案中,在单次给药后,AUC24可以为约868.4ng.hr/mL-约1356.9ng.hr/mL,或者约933.5ng.hr/mL-约1237.5ng.hr/mL,或者约1009.5ng.hr/mL-约1161.5ng.hr/mL。 In certain embodiments, after a single administration, AUC24 may be from about 868.4ng.hr/mL- about 1356.9ng.hr/mL, or from about 933.5ng.hr/mL- about 1237.5ng.hr/mL, or about 1009.5ng.hr/mL- about 1161.5ng.hr/mL.

[0021] 在一些实施方案中,所述药物制剂在重复给药后提供约0.5-约40ng/mL或者约4-约15ng/mL的平均最小羟考酮血浆浓度(Cmin)。 [0021] In some embodiments, the pharmaceutical formulation providing a mean minimum plasma concentration of oxycodone from about 0.5 to about 40ng / mL or from about 4 to about 15ng / mL of (Cmin of) after repeated dosing. 在一些实施方案中,重复给药在稳态条件中进行。 In some embodiments, the administration is repeated in a steady state condition.

[0022] 在某些实施方案中,所述药物制剂包含第二控释阿片样物质组分。 [0022] In certain embodiments, the second pharmaceutical formulation comprises a controlled release opioid component. 在一些实施方案中,所述第二控释阿片样物质组分包含选自以下组中的阿片样物质:吗啡、可待因、氢吗啡酮、氢可酮、羟考酮、双氢可待因、双氢吗啡、羟吗啡酮、它们的混合物以及它们的盐。 In some embodiments, the second component comprising a controlled release opioid is selected from the group of opioids: morphine, codeine, hydromorphone, hydrocodone, oxycodone, codeine dihydrocodeine because, dihydroergotamine, morphine, oxymorphone, mixtures thereof and the salts thereof.

[0023] 在某些实施方案中,所述药物制剂包含即释阿片样物质组分。 [0023] In certain embodiments, the pharmaceutical formulation comprises immediate release opioid component. 在一些实施方案中,所述即释阿片样物质组分包含选自以下组中的阿片样物质:吗啡、可待因、氢吗啡酮、氢可酮、羟考酮、双氢可待因、双氢吗啡、羟吗啡酮、它们的混合物以及它们的盐。 In some embodiments, the immediate release opioid component selected from the group comprising opioids: morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydrotestosterone morphine, oxymorphone, mixtures thereof and the salts thereof. 在其他实施方案中,所述即释阿片样物质组分中的阿片样物质为吗啡或其盐。 In other embodiments, the immediate release opioid component opioid is morphine or a salt thereof. 在其他实施方案中,所述制剂中总吗啡或其盐与总羟考酮或其盐的重量比为约3:2吗啡或其盐比羟考酮或其盐。 In other embodiments, the total weight of the formulation of morphine or a salt thereof with oxycodone or a salt thereof of the total ratio of about 3: 2 ratio of morphine to oxycodone or a salt thereof, or a salt thereof.

[0024] 在某些实施方案中,所述药物制剂包含第二阿片样物质组分和第三阿片样物质组分,其中:(a)所述第二阿片样物质组分为即释阿片样物质组分且包含具有K激动剂活性的阿片样物质;并且(b)所述第三阿片样物质组分为控释阿片样物质组分且包含具有μ激动剂活性的阿片样物质。 [0024] In certain embodiments, the pharmaceutical formulation comprises a second component and a third opioid opioid component, wherein: (a) the second group divided opioid immediate release opioid and having a composition of matter comprising K opioid agonist activity; and (b) said third component is an opioid controlled release opioid comprising an active component and having a μ opioid agonists. 在一些实施方案中,具有K激动剂活性的阿片样物质为羟考酮或其盐,而具有μ激动剂活性的阿片样物质为吗啡或其盐。 In some embodiments, the agonist activity with K opioid oxycodone or a salt thereof, having agonist activity at μ opioid is morphine or a salt thereof.

[0025] 在某些实施方案中,所述控释阿片样物质组分包含吗啡或其盐。 [0025] In certain embodiments, the controlled release opioid component comprises morphine or a salt thereof. 在一些实施方案中,所述控释阿片样物质组分包含量为约3:2重量比的吗啡或其盐和羟考酮或其盐。 In some embodiments, the controlled release component comprises the opioid in an amount of from about 3: 2 ratio by weight of morphine or a salt thereof, and oxycodone or a salt thereof.

[0026]在本发明的实施方案中,所述药物制剂可以包含一种或多种阿片样物质组分用于有此需要的人,其中所述一种或多种阿片样物质组分包含一种或多种释放特征谱,并且至少一种所述阿片样物质组分是包含羟考酮或其盐的控释阿片样物质组分;当包含约2mg的总剂量的羟考酮或其盐时,药物制剂在重复给药后提供约4.5-约7.5小时、或者约5-约6小时、或者约6小时的Tmax,并且在单次给药后提供约14.7ng.hr/mL-约23.0ng.hr/mL>或者约15.8ng.hr/mL-约21.0ng.hr/mL、或者约17.1ng.hr/mL-约19.7ng.hr/mL 的AUC24。 [0026] In an embodiment of the present invention, the pharmaceutical formulation may include one or more opioid component for people in need, wherein the one or more opioid component comprises a release profiles of two or more, and at least one of the opioid component comprising a controlled release component opioid oxycodone or a salt thereof; when it is contained in a total dose of about 2mg oxycodone or a salt thereof , the pharmaceutical formulation after repeated administration of from about 4.5 to about 7.5 hours, or from about 5 to about 6 hours, or Tmax of about 6 hours, and to provide from about 23.0 to about 14.7ng.hr/mL- after a single administration ng.hr/mL> or from about 15.8ng.hr/mL- about 21.0ng.hr/mL, or from about about 19.7ng.hr/mL 17.1ng.hr/mL- the AUC24. 重复给药可以在稳态条件中进行。 Repeated administrations may be performed in a steady state condition.

[0027] 在某些实施方案中,所述药物制剂配制为不同于约2mg羟考酮或其盐的总剂量的羟考酮或其盐,并且具有与2mg AUC24成比例的AUC24。 [0027] In certain embodiments, the pharmaceutical formulation is formulated to be different from about 2mg total dose of oxycodone or a salt thereof of the oxycodone or salt thereof and having a proportional 2mg AUC24 and AUC24. 在一些实施方案中,总剂量AUC24与2mg AUC24成线性比例。 In some embodiments, the total dose of 2mg AUC24 AUC24 linearly proportional.

[0028] 在某些实施方案中,当包含约2mg的总剂量的羟考酮或其盐时,所述药物制剂在重复给药后提供约1-约3ng/mL或者约2mg的C_。 [0028] In certain embodiments, when the total dose of about 2mg comprising oxycodone or a salt thereof, the pharmaceutical formulation to provide from about 1 to about 3ng / mL or from about 2mg C_ after repeated administration. 在一些实施方案中,重复给药在稳态条件中进行。 In some embodiments, the administration is repeated in a steady state condition. 在一些实施方案中,所述药物制剂配制为不同于约2mg羟考酮或其盐的总剂量的羟考酮或其盐,并且具有与2mg Cmax成比例的Cmax。 In some embodiments, the pharmaceutical formulation is formulated differently than a total dose of about 2mg oxycodone or oxycodone salt, or a salt thereof, and having a Cmax of 2mg proportional Cmax. 在一些实施方案中,总剂量Cmax与2mgCniax成线性比例。 In some embodiments, the total dose and Cmax linearly proportional 2mgCniax.

[0029] 在某些实施方案中,当包含约2mg的总剂量时,所述药物制剂在重复给药后提供约13-约16小时的Tniintl在一些实施方案中,重复给药在稳态条件中进行。 [0029] In certain embodiments, when the total dose of about 2mg containing a medicament formulation to provide from about 13 to about 16 hours after repeated administration Tniintl In some embodiments, repeated administration at steady state conditions carried out.

[0030] 在本发明的实施方案中,所述药物制剂可以包含一种或多种阿片样物质组分用于有此需要的人,其中所述一种或多种阿片样物质组分包含一种或多种释放特征谱,并且至少一种所述阿片样物质组分是包含羟考酮或其盐的控释阿片样物质组分;当包含约5mg的总剂量的羟考酮或其盐的时,所述药物制剂在重复给药后提供约4.5-约7.5小时、或者约5-约6小时、或者约6小时的Tmax,并且在单次给药后提供约40.2ng.1ί;gamma/ιΛ-约62.8ng *hr/mL、或者约43.2ng.hr/mL-约57.2ng.hr/mL、或者约46.7ng.hr/mL-约53.7ng.hr/mL的AUC24。 [0030] In an embodiment of the present invention, the pharmaceutical formulation may include one or more opioid component for people in need, wherein the one or more opioid component comprises a release profiles of two or more, and at least one of the opioid component comprising a controlled release component opioid oxycodone or a salt thereof; when it is contained in a total dose of about 5mg of oxycodone or a salt thereof when, the pharmaceutical formulation after repeated administration of from about 4.5 to about 7.5 hours, or from about 5 to about 6 hours, or Tmax of about 6 hours, and about 40.2ng.1ί provided after single administration; Gamma / ιΛ- about 62.8ng * hr / mL, or from about 43.2ng.hr/mL- about 57.2ng.hr/mL, or from about about 53.7ng.hr/mL 46.7ng.hr/mL- the AUC24. 重复给药可以在稳态条件中进行。 Repeated administrations may be performed in a steady state condition.

[0031] 在某些实施方案中,所述药物制剂配制为不同于约5mg羟考酮或其盐的总剂量的羟考酮或其盐,并且具有与5mg AUC24成比例的AUC24。 [0031] In certain embodiments, the pharmaceutical formulation is formulated to be different from about 5mg total dose of oxycodone or a salt thereof of the oxycodone or salt thereof and having a proportional 5mg AUC24 and AUC24. 在一些实施方案中,总剂量AUC24与5mg AUC24成线性比例。 In some embodiments, the total dose of 5mg AUC24 AUC24 linearly proportional.

[0032] 在某些实施方案中,当包含约5mg的总剂量的羟考酮或其盐时,所述药物制剂在重复给药后提供约3-约7ng/mL或者约5ng/mL的C_。 [0032] In certain embodiments, when the total dose of about 5mg comprising oxycodone or a salt thereof, the pharmaceutical formulation to provide from about 3 to about 7ng / mL or from about C_ 5ng / mL after repeated administration . 在一些实施方案中,重复给药在稳态条件中进行。 In some embodiments, the administration is repeated in a steady state condition. 在一些实施方案中,所述药物制剂配制为不同于约5mg羟考酮或其盐的总剂量的羟考酮或其盐,并且具有与5mg Cmax成比例的(:_。在一些实施方案中,总剂量Cmax与5mgCmax成线性比例。 In some embodiments, the pharmaceutical formulation is formulated to be different from the total dose of about 5mg oxycodone or oxycodone salt or salt thereof and having a Cmax proportional 5mg (: _ In some embodiments. , total dose and Cmax linearly proportional 5mgCmax.

[0033] 在某些实施方案中,当包含约5mg的总剂量的羟考酮或其盐时,所述药物制剂在重复给药后提供约13-约16小时的Tniintl在一些实施方案中,重复给药在稳态条件中进行。 [0033] In certain embodiments, when the total dose of about 5mg comprising oxycodone or a salt thereof, the pharmaceutical formulation to provide from about 13 to about 16 hours after repeated administration Tniintl In some embodiments, repeated administration in a steady state condition.

[0034] 在本发明的实施方案中,所述药物制剂可以包含一种或多种阿片样物质组分用于有此需要的人,其中所述一种或多种阿片样物质组分包含一种或多种释放特征谱,并且至少一种所述阿片样物质组分是包含羟考酮或其盐的控释阿片样物质组分;当包含约IOmg的总剂量的羟考酮或其盐的时,所述药物制剂在重复给药后提供约4.5-约7.5小时、或者约5-约6小时、或者约6小时的Tmax,并且在单次给药后提供约80.5ng.hr/mL-约125.9ng.hr/mL、或者约86.6ng.hr/mL-约114.8ng.hr/mL、或者约93.7ng.hr/mL-约107.7ng.hr/mL的AUC24。 [0034] In an embodiment of the present invention, the pharmaceutical formulation may include one or more opioid component for people in need, wherein the one or more opioid component comprises a release profiles of two or more, and at least one of the opioid component comprising a controlled release component opioid oxycodone or a salt thereof; and when the total dose comprises about IOmg oxycodone or a salt thereof when, the pharmaceutical formulation after repeated administration of from about 4.5 to about 7.5 hours, or from about 5 to about 6 hours, or Tmax of about 6 hours, and about 80.5ng.hr/mL provided after single administration - about 125.9ng.hr/mL, or from about 86.6ng.hr/mL- about 114.8ng.hr/mL, or from about about 107.7ng.hr/mL 93.7ng.hr/mL- the AUC24. 重复给药可以在稳态条件中进行。 Repeated administrations may be performed in a steady state condition.

[0035] 在某些实施方案中,所述药物制剂配制为不同于约IOmg羟考酮或其盐的总剂量的羟考酮或其盐,并且具有与IOmg AUC24成比例的AUC24。 [0035] In certain embodiments, the pharmaceutical formulation is formulated differently than a total dose of about IOmg oxycodone or oxycodone salt, or a salt thereof, and having a proportional AUC24 and IOmg AUC24. 在一些实施方案中,总剂量AUC24与1Omg AUC24成线性比例。 In some embodiments, the total dose AUC24 1Omg AUC24 linearly proportional.

[0036] 在某些实施方案中,当包含约IOmg的总剂量的羟考酮或其盐时,所述药物制剂在重复给药后提供约5-约15ng/mL或者约10ng/mL的C_。 [0036] In certain embodiments, when the total dose comprises about IOmg oxycodone or a salt thereof, the pharmaceutical formulation to provide from about 5 to about 15ng / mL, or about 10ng mL of C_ / after repeated dosing . 在一些实施方案中,重复给药在稳态条件中进行。 In some embodiments, the administration is repeated in a steady state condition. 在一些实施方案中,所述药物制剂配制为不同于约IOmg羟考酮或其盐的总剂量的羟考酮或其盐,并且具有与IOmg Cmax成比例的Cmax。 In some embodiments, the pharmaceutical formulation is formulated differently than a total dose of about IOmg oxycodone or oxycodone salt, or a salt thereof, and having a Cmax and Cmax IOmg proportional. 在一些实施方案中,总剂量Cmax与IOmg Cmax成线性比例。 In some embodiments, the total dose IOmg Cmax and Cmax linearly proportional.

[0037] 在某些实施方案中,当包含约IOmg的总剂量的羟考酮或其盐时,所述药物制剂在重复给药后提供约13-约16小时的Tniintl在一些实施方案中,重复给药在稳态条件中进行。 [0037] In certain embodiments, when the total dose of about IOmg comprising oxycodone or a salt thereof, the pharmaceutical formulation to provide from about 13 to about 16 hours after repeated administration Tniintl In some embodiments, repeated administration in a steady state condition.

[0038] 在本发明的实施方案中,所述药物制剂可以包含一种或多种阿片样物质组分用于有此需要的人,其中所述一种或多种阿片样物质组分包含一种或多种释放特征谱,并且至少一种所述阿片样物质组分是包含羟考酮或其盐的控释阿片样物质组分;当包含约20mg的总剂量的羟考酮或其盐的时,所述药物制剂在重复给药后提供约4.5-约7.5小时、或者约5-约6小时、或者约6小时的Tmax,并且在单次给药后提供约166.0ng.hr/mL-约259.3ng.hr/mL、或者约178.5ng.hr/mL-约236.6ng.hr/mL、或者约193.0ng.hr/mL-约222.0ng.hr/mL的AUC24。 [0038] In an embodiment of the present invention, the pharmaceutical formulation may include one or more opioid component for people in need, wherein the one or more opioid component comprises a release profiles of two or more, and at least one of the opioid component comprising a controlled release component opioid oxycodone or a salt thereof; when it is contained in a total dose of about 20mg of oxycodone or a salt thereof when, the pharmaceutical formulation after repeated administration of from about 4.5 to about 7.5 hours, or from about 5 to about 6 hours, or Tmax of about 6 hours, and about 166.0ng.hr/mL provided after single administration - about 259.3ng.hr/mL, or from about 178.5ng.hr/mL- about 236.6ng.hr/mL, or from about about 222.0ng.hr/mL 193.0ng.hr/mL- the AUC24. 重复给药可以在稳态条件中进行。 Repeated administrations may be performed in a steady state condition.

[0039] 在某些实施方案中,所述药物制剂配制为不同于约20mg羟考酮或其盐的总剂量的羟考酮或其盐,并且具有与20mg AUC24成比例的AUC24。 [0039] In certain embodiments, the pharmaceutical formulation is formulated to be different from about 20mg total daily dose of oxycodone or a salt thereof of the oxycodone or salt thereof and having a proportional 20mg AUC24 and AUC24. 在一些实施方案中,总剂量AUC24与20mg AUC24成线性比例。 In some embodiments, the total dose of 20mg AUC24 AUC24 linearly proportional.

[0040] 在某些实施方案中,当包含约20mg的总剂量的羟考酮或其盐时,所述药物制剂在重复给药后提供约10-约30ng/mL或者约20ng/mL的C_。 [0040] In certain embodiments, when the total dose comprises about 20mg of oxycodone or a salt thereof, the pharmaceutical formulation to provide from about 10 to about 30ng / mL, or about C_ 20ng / mL after repeated administration . 在一些实施方案中,重复给药在稳态条件中进行。 In some embodiments, the administration is repeated in a steady state condition. 在一些实施方案中,所述药物制剂配制为不同于约20mg羟考酮或其盐的总剂量的羟考酮或其盐,并且具有与20mg Cmax成比例的(:_。在一些实施方案中,总剂量Cmax与20mg Cmax成线性比例。 In some embodiments, the pharmaceutical formulation is formulated to be different from the total dose of about 20mg oxycodone or oxycodone salt, or a salt thereof, and having a Cmax proportional 20mg (: _ In some embodiments. a total dose of 20mg Cmax and Cmax linearly proportional.

[0041] 在某些实施方案中,当包含约20mg的总剂量的羟考酮或其盐时,所述药物制剂在重复给药后提供约8小时的!1-。 [0041] In certain embodiments, when the total dose comprises about 20mg of oxycodone or a salt thereof, a pharmaceutical formulation provides about 8 hours after repeated administration! 1-. 在一些实施方案中,重复给药在稳态条件中进行。 In some embodiments, the administration is repeated in a steady state condition. 在一些实施方案中,所述药物制剂配制为不同于约20mg羟考酮或其盐的总剂量,并且具有与20mgCmin成比例的Cmin。 In some embodiments, the pharmaceutical formulation is formulated to about 20mg total daily dose of oxycodone or a salt thereof is different from, and having the 20mgCmin Cmin proportional. 在一些实施方案中,总剂量Cmin与20mg Cmin成线性比例。 In some embodiments, the total dose of 20mg Cmin Cmin linearly proportional.

[0042] 在本发明的实施方案中,所述药物制剂可以包含一种或多种阿片样物质组分用于有此需要的人,其中所述一种或多种阿片样物质组分包含一种或多种释放特征谱,并且至少一种所述阿片样物质组分是包含羟考酮或其盐的控释阿片样物质组分;当包含约40mg的总剂量的羟考酮或其盐的时,所述药物制剂在重复给药后提供约4.5-约7.5小时、或者约5-约6小时、或者约6小时的Tmax,并且在单次给药后提供约338.5ng.hr/mL-约528.9ng.hr/mL、或者约363.9ng.hr/mL-约482.3ng.hr/mL、或者约393.5ng.hr/mL-约452.7ng.hr/mL的AUC24。 [0042] In an embodiment of the present invention, the pharmaceutical formulation may include one or more opioid component for people in need, wherein the one or more opioid component comprises a release profiles of two or more, and at least one of the opioid component comprising a controlled release component opioid oxycodone or a salt thereof; when it is contained in a total dose of about 40mg of oxycodone or a salt thereof when, the pharmaceutical formulation after repeated administration of from about 4.5 to about 7.5 hours, or from about 5 to about 6 hours, or Tmax of about 6 hours, and about 338.5ng.hr/mL provided after single administration - about 528.9ng.hr/mL, or from about 363.9ng.hr/mL- about 482.3ng.hr/mL, or from about 393.5ng.hr/mL- AUC24 of about 452.7ng.hr/mL. 重复给药可以在稳态条件中进行。 Repeated administrations may be performed in a steady state condition.

[0043] 在某些实施方案中,所述药物制剂配制为不同于约40mg羟考酮或其盐的总剂量的羟考酮或其盐,并且具有与40mg AUC24成比例的AUC24。 [0043] In certain embodiments, the pharmaceutical formulation is formulated to be different from the total dose of about 40mg oxycodone or oxycodone salt thereof or a salt thereof, and has 40mg AUC24 proportional AUC24. 在一些实施方案中,总剂量AUC24与40mg AUC24成线性比例。 In some embodiments, the total dose of 40mg AUC24 AUC24 linearly proportional.

[0044] 在某些实施方案中,当包含约40mg的总剂量的羟考酮或其盐时,所述药物制剂在重复给药后提供约25-约55ng/mL或者约40ng/mL的C_。 [0044] In certain embodiments, when the total dose comprises about 40mg of oxycodone or a salt thereof, the pharmaceutical formulation to provide from about 25 to about 55ng mL or from about 40ng / mL of C_ / after repeated dosing . 在一些实施方案中,重复给药在稳态条件中进行。 In some embodiments, the administration is repeated in a steady state condition. 在一些实施方案中,所述药物制剂配制为不同于约40mg羟考酮或其盐的总剂量的羟考酮或其盐,并且具有与40mg Cmax成比例的(:_。在一些实施方案中,总剂量Cmax与40mg Cmax成线性比例。 In some embodiments, the pharmaceutical formulation is formulated to be different from the total dose of about 40mg oxycodone or oxycodone salt or salt thereof and having a Cmax proportional 40mg (: _ In some embodiments. a total dose of 40mg Cmax and Cmax linearly proportional.

[0045] 在某些实施方案中,当包含约40mg的总剂量的羟考酮或其盐时,所述药物制剂在重复给药后提供约13-约16小时的Tniintl在一些实施方案中,重复给药在稳态条件中进行。 [0045] In certain embodiments, when the total dose comprises about 40mg of oxycodone or a salt thereof, the pharmaceutical formulation to provide from about 13 to about 16 hours after repeated administration Tniintl In some embodiments, repeated administration in a steady state condition.

[0046] 在本发明的实施方案中,所述药物制剂可以包含一种或多种阿片样物质组分用于有此需要的人,其中所述一种或多种阿片样物质组分包含一种或多种释放特征谱,并且至少一种所述阿片样物质组分是包含羟考酮或其盐的控释阿片样物质组分;当包含约80mg的总剂量的羟考酮或其盐的时,所述药物制剂在重复给药后提供约4.5-约7.5小时、或者约5-约6小时、或者约6小时的Tmax,并且在单次给药后提供约868.4ng.hr/mL-约1356.9ng.hr/mL> 或者约933.5ng.hr/mL-约1237.5ng.hr/mL> 或者约1009.5ng.hr/mL-约1161.5ng.hr/mL的AUC24。 [0046] In an embodiment of the present invention, the pharmaceutical formulation may include one or more opioid component for people in need, wherein the one or more opioid component comprises a release profiles of two or more, and at least one of the opioid component comprising a controlled release component opioid oxycodone or a salt thereof; when it is contained in a total dose of about 80mg of oxycodone or a salt thereof when, the pharmaceutical formulation after repeated administration of from about 4.5 to about 7.5 hours, or from about 5 to about 6 hours, or Tmax of about 6 hours, and about 868.4ng.hr/mL provided after single administration - about 1356.9ng.hr/mL> or from about 933.5ng.hr/mL- about 1237.5ng.hr/mL> or from about 1009.5ng.hr/mL- about 1161.5ng.hr/mL the AUC24. 重复给药可以在稳态条件中进行。 Repeated administrations may be performed in a steady state condition.

[0047] 在某些实施方案中,所述药物制剂配制为不同于约80mg羟考酮或其盐的总剂量的羟考酮或其盐,并且具有与80mg AUC24成比例的AUC24。 [0047] In certain embodiments, the pharmaceutical formulation is formulated to be different from the total dose of about 80mg oxycodone or oxycodone salt thereof or a salt thereof, and has 80mg AUC24 proportional AUC24. 在一些实施方案中,总剂量AUC24与80mg AUC24成线性比例。 In some embodiments, the total dose of 80mg AUC24 AUC24 linearly proportional.

[0048] 在某些实施方案中,当包含约SOmg的总剂量的羟考酮或其盐时,所述药物制剂在重复给药后提供约50-约110ng/mL或者约80ng/mL的Cniax。 [0048] In certain embodiments, when the total dose comprises about SOmg oxycodone or a salt thereof, the pharmaceutical formulation to provide from about 50 to about 110ng / mL after repeated administration or from about 80ng / mL of Cniax . 在一些实施方案中,重复给药在稳态条件中进行。 In some embodiments, the administration is repeated in a steady state condition. 在一些实施方案中,所述药物制剂配制为不同于约80mg羟考酮或其盐的总剂量的羟考酮或其盐,并且具有与80mg Cmax成比例的(:_。在一些实施方案中,总剂量Cmax与80mg Cmax成线性比例。 In some embodiments, the pharmaceutical formulation is formulated to be different from the total dose of about 80mg oxycodone or oxycodone salt or salt thereof and having a Cmax proportional 80mg (: _ In some embodiments. a total dose of 80 mg of Cmax and Cmax linearly proportional.

[0049] 在某些实施方案中,当包含约SOmg的总剂量的羟考酮或其盐时,所述药物制剂在重复给药后提供约13-约16小时的Tniintl在一些实施方案中,重复给药在稳态条件中进行。 [0049] In certain embodiments, when the total dose comprises about SOmg oxycodone or a salt thereof, the pharmaceutical formulation to provide from about 13 to about 16 hours after repeated administration Tniintl In some embodiments, repeated administration in a steady state condition.

[0050] 用于人中吸收的一种或多种具有阿片样物质受体激动剂活性的化合物的控释方法包括给药包含一种或多种组分的药物制剂,其中所述一种或多种阿片样物质组分包含一种或多种释放特征谱,并且至少一种所述阿片样物质组分是包含阿片样物质的控释阿片样物质组分。 [0050] for one kind of absorption in humans or more compounds having a controlled release of the opioid receptor agonist activity comprising administering a pharmaceutical formulation comprising one or more components, wherein the one or more opioids component comprises one or more profiles of release, and said at least one opioid controlled release component comprising an opioid component of opioids. 在某些实施方案中,向人给药的药物制剂是本发明的药物制剂。 In certain embodiments, the pharmaceutical formulation for administration to a human a pharmaceutical formulation of the invention.

[0051] 治疗人的疼痛的方法包括给药包含一种或多种组分的药物制剂,其中所述一种或多种阿片样物质组分包含一种或多种释放特征谱,并且至少一种所述阿片样物质组分是包含阿片样物质的控释阿片样物质组分。 [0051] A method for treating pain in a human comprising administering a pharmaceutical formulation comprising one or more components, wherein the one or more opioid release component comprises one or more spectral characteristics, and at least a kinds of the opioid component comprising a controlled release opioid component of opioids. 在某些实施方案中,向人给药的药物制剂是本发明的药物制剂。 In certain embodiments, the pharmaceutical formulation for administration to a human a pharmaceutical formulation of the invention.

附图说明 BRIEF DESCRIPTION

[0052] 图1a和Ib提供本发明的阿片样物质制剂的两个实施方案的示意图。 [0052] FIGS. 1a and Ib is a schematic view of two embodiments of the opioid formulation of the present invention provides.

[0053] 图2提供用于本发明的阿片样物质制剂的羟考酮包衣的团粒的靶释放特征谱。 [0053] FIG. 2 provides a pellet opioid formulation of the present invention is coated oxycodone release profiles of target.

[0054] 图3提供用于本发明的阿片样物质制剂的吗啡包衣的团粒的靶释放特征谱。 [0054] FIG. 3 provides for opioid morphine formulations of the present invention is coated pellets release profiles of target.

[0055] 图4提供用于本发明的阿片样物质制剂的用尤特奇L30D-55包衣的羟考酮颗粒的靶释放特征谱。 [0055] Figure 4 provides for opioid formulation of the present invention with a target release profiles of coated particles oxycodone Eudragit L30D-55.

[0056] 图5提供本发明的阿片样物质制剂中总羟考酮释放的靶释放特征谱。 The opioid formulation of the present invention provides [0056] FIG. 5, the total release of oxycodone release profiles of target.

[0057] 图6提供用于本发明的双阿片样物质包衣片剂的总羟考酮和吗啡释放的靶释放特征谱。 Target release profile [0057] Figure 6 provides a dual opioid coated tablet of the present invention for total release of oxycodone and morphine spectrum.

[0058] 图7提供证实用于制备用于本发明的羟考酮颗粒的方法的示意图。 [0058] Figure 7 provides a schematic diagram of a method confirmed the oxycodone particles of the present invention is used for preparing.

[0059] 图8提供证实用于制备用于本发明的羟考酮核心团粒的方法的示意图。 [0059] Figure 8 provides a schematic of a method for confirmed oxycodone core pellets of the present invention are prepared for.

[0060] 图9提供证实用于制备用于本发明的吗啡核心团粒的方法的示意图。 [0060] Figure 9 provides a schematic view of a method for preparing confirmed morphine pellet core for the present invention. [0061] 图10提供证实用于包衣用于本发明的吗啡或羟考酮核心团粒的方法的示意图。 [0061] Figure 10 provides a schematic diagram of a method of coating a confirmed oxycodone morphine pellet core or hydroxyalkyl present invention.

[0062] 图11提供证实用于制备用于本发明的双阿片样物质包衣片剂的方法的示意图。 [0062] Figure 11 provides a schematic diagram of a method for preparing confirmed opioid double-coated tablet for the present invention.

[0063] 图12提供制备用于临床研究的延长释放的中间羟考酮团粒的流程图(实施例2)。 [0063] Figure 12 provides a flowchart of oxycodone pellets prepared intermediate hydroxyalkyl extended release for clinical studies (Example 2).

[0064] 图13提供治疗后72小时中本发明的两种阿片样物质制剂(制剂A和制剂B)和参考制剂(与Oxy Contin® 20mg(羟考酮CR)共给药的MS Contin® 30mg(吗啡CR))的羟考酮血浆浓度特征谱。 72 hours of two opioid formulation (Formulation A and Formulation B) of the present invention and a reference formulation (with Oxy Contin® 20mg (oxycodone CR) after co-administration to provide a therapeutic MS [0064] FIG. 13 Contin® 30mg (morphine CR)) hydroxy plasma concentration profiles of oxycodone.

[0065] 图14提供治疗后24小时中本发明的两种阿片样物质制剂(制剂A和制剂B)和参考制剂(与Oxy Contin® 20mg (羟考酮CR)共给药的MS Contin® 30mg (吗啡CR))的羟 [0065] FIG. 14 MS after 24 hours of treatment provided of two opioid formulation (Formulation A and Formulation B) of the present invention and a reference formulation (with Oxy Contin® 20mg (oxycodone CR) coadministered Contin® 30mg (morphine CR)) hydroxy

考酮血浆浓度特征谱。 Plasma concentration profiles of oxycodone.

[0066] 图15提供预期的羟考酮血浆特征谱,其来自12小时间隔的多剂量的本发明的阿片样物质制剂的给药。 [0066] Figure 15 provides the desired plasma profiles of oxycodone, which is administered opioid formulation of the present invention, multiple dose intervals from 12 hours.

[0067] 图16提供预期的羟考酮血浆特征谱,其来自多剂量的具有不同剂量给药强度的本发明的阿片样物质制剂的给药。 Provide the expected [0067] FIG. 16 plasma profiles of oxycodone administered opioid formulations from which multiple dose administration of the present invention having different strength dose.

[0068] 图17提供预期的羟考酮血浆特征谱,其来自12小时间隔的多剂量的本发明的阿片样物质复合制剂(即释+控释)的给药。 [0068] Figure 17 provides the desired plasma profiles of oxycodone, an opioid from its complex formulation of the present invention the multi-dose 12-hour intervals (immediate release + release) administration.

[0069] 图18提供预期的羟考酮血浆特征谱,其来自多剂量的具有不同剂量给药强度的本发明的阿片样物质复合制剂(即释+控释)的给药。 [0069] Figure 18 provides the desired plasma profiles of oxycodone, (+ release immediate release) administration of the opioid from its complex formulation of the present invention the multi-dose administering different dosage strength.

[0070] 图19提供硫酸吗啡的释放特征谱,其来自不同%包衣水平的使用(a)RS/RL=90/10和(b) RS/RL=80/20的季胺基甲基丙烯酸酯共聚物(AmmonioMethacrylate Copolymer)B型(RS)和A型(RL)包衣比例的包含硫酸吗啡和盐酸羟考酮的包衣球形颗粒(beadlet)。 Release profile [0070] Figure 19 provides the spectra morphine sulfate, using coating levels of from different% (a) RS / RL = 90/10, and (b) RS / RL = ammonio methacrylate 80/20 the coating ratio copolymer (AmmonioMethacrylate copolymer) B type (RS) and a type (RL) comprising morphine sulfate and oxycodone hydrochloride coated spherical granules (beadlet).

[0071] 图20提供盐酸羟考酮的释放特征谱,其来自不同%包衣水平的使用(a)RS/RL=90/10和(b)RS/RL=80/20的季胺基甲基丙烯酸酯共聚物B型(RS)和A型(RL)包衣比例的包含硫酸吗啡和盐酸羟考酮的包衣球形颗粒。 Release profile [0071] Figure 20 provides a spectrum of oxycodone hydrochloride, using coating levels of from different% (a) RS / RL = 90/10, and (b) RS / RL = quaternary amine A 80/20 acrylate copolymer type B (RS) and a type (RL) comprises morphine sulfate as the coating ratio and the oxycodone hydrochloride coated spherical granules.

[0072] 图21提供不同%肠溶包衣水平的肠溶包衣片剂(使用90/10比例的季胺基甲基丙烯酸酯共聚物B型(RS)和A型(RL)的50%包衣球形颗粒)中的硫酸吗啡的释放特征谱。 [0072] FIG 21% enteric coating to provide different levels of an enteric coated tablet (90/10 ratio ammonio methacrylate copolymer Type B (RS) and A type (RL) 50% morphine release profile of coated spherical granules) sulfuric acid spectrum.

[0073] 图22提供不同%肠溶包衣水平的肠溶包衣片剂(使用90/10比例的季胺基甲基丙烯酸酯共聚物B型(RS)和A型(RL)的50%包衣球形颗粒)中的盐酸羟考酮的释放特征 [0073] FIG 22% enteric coating to provide different levels of an enteric coated tablet (90/10 ratio ammonio methacrylate copolymer Type B (RS) and A type (RL) 50% release profile of oxycodone hydrochloride coated spherical granules) of

-1'TfeP曰。 -1'TfeP said.

[0074] 图23提供低、中或高硬度水平的肠溶包衣片剂(10%和15%包衣水平)中的硫酸吗啡的释放特征谱。 [0074] Figure 23 provides a low release profile of morphine or high levels of hardness enteric coated tablets (10% and 15% coating level) sulfuric acid spectrum.

[0075] 图24提供低、中或高硬度水平的肠溶包衣片剂(10%和15%包衣水平)中的盐酸羟考酮的释放特征谱。 [0075] FIG 24 provides a low release profile of oxycodone hydrochloride or high levels of hardness enteric coated tablets (10% and 15% coating level) in the spectrum.

[0076] 图25提供盐酸羟考酮的释放特征谱,其来自不同%包衣水平的使用RS/RL=85/15的季胺基甲基丙烯酸酯共聚物B型(RS)和A型(RL)包衣比例的包含盐酸羟考酮的包衣球形颗粒。 Release profile [0076] Figure 25 provides a spectrum of oxycodone hydrochloride, using RS from different levels of coating% / RL = 85 quaternary amine / 15 methacrylate copolymer Type B (RS) and A ( RL) comprising the coating ratio of oxycodone hydrochloride coated spherical granules.

[0077] 图26提供盐酸羟考酮的释放特征谱,其来自不同%包衣水平的使用RS/RL=80/20的季胺基甲基丙烯酸酯共聚物B型(RS)和A型(RL)包衣比例的包含盐酸羟考酮的包衣球形颗粒。 [0077] Figure 26 provides the release profile of oxycodone hydrochloride spectrum, using RS from different levels of coating% / RL = 80 quaternary amine / 20 methacrylate copolymer Type B (RS) and A ( RL) comprising the coating ratio of oxycodone hydrochloride coated spherical granules.

[0078] 图27提供盐酸羟考酮的释放特征谱,其来自不同%包衣水平的使用RS/RL=80/20和RS/RL=85/15的季胺基甲基丙烯酸酯共聚物B型(RS)和A型(RL)包衣比例的包含盐酸羟考酮的包衣球形颗粒。 [0078] Figure 27 provides the release profile of oxycodone hydrochloride spectrum, using RS from different levels of coating% / RL = ammonio methacrylate copolymers B 80/20 and RS / RL = 85/15 in type as the coating ratio (RS) and a type (RL) comprising oxycodone hydrochloride coated spherical granules.

具体实施方式 detailed description

[0079] 本发明涉及通过用于人吸收的具有阿片样物质激动剂活性的化合物的控释来缓解急性或慢性疼痛的药物制剂和方法。 [0079] The present invention relates to pharmaceutical formulations and methods to relieve acute or chronic pain by the compounds for controlled release opioid agonist having activity of human absorption. 本发明的药物制剂和方法可以向患者提供有效镇痛,同时减少或消除在阿片样物质镇痛化合物给药时通常经历的不期望的副作用。 Pharmaceutical formulations and methods of the present invention can provide effective analgesia to a patient, while reducing or eliminating undesirable side effects when administered compound opioid analgesic substance commonly experienced. 由于化合物的控释,可以获得化合物在特定时间中基本上恒定速率的释放,对应于考虑的治疗所需的剂量,从而可以实行坚持严格的剂量方案,例如需要以设定的间隔每天多达几次给药药物。 Since the controlled release compound, the compound can be obtained a substantially constant rate of release at a particular time, corresponding to the desired therapeutic dosage to be considered, so that the implementation can adhere to strict dosage regimen, such as the need to set intervals up to several per day Drug administration.

[0080] 本发明的一方面涉及包含一种或多种组分的药物制剂,所述组分具有一种或多种释放特征谱,其中至少一种所述组分包含具有阿片样物质受体激动剂活性的化合物并具有控释特征谱。 [0080] In one aspect the present invention relates to a pharmaceutical formulation comprising one or more components, the components having one or more release characteristic spectrum, wherein at least one of said components comprises a opioid receptor agonistic activity and a compound having controlled release characteristics in the spectrum. 本发明的另一方面涉及将本发明的药物制剂向有此需要的人给药。 Another aspect of the invention relates to a human a pharmaceutical formulation of the invention need to be administered.

[0081] 本文所述的制剂和方法用来治疗不同类型的疼痛,包括神经性疼痛和伤害性疼痛、躯体疼痛和内脏疼痛。 [0081] The formulations and methods described herein are used to treat different types of pain, including neuropathic pain and nociceptive pain, somatic pain and visceral pain. 在各种实施方案中,本文所述的制剂和方法用来治疗糖尿病性神经病、三叉神经痛、疱疹后遗疼痛和丘脑疼痛综合征(中枢性疼痛)。 In various embodiments, the formulations and methods described herein are used to treat diabetic neuropathy, trigeminal neuralgia, postherpetic pain and thalamic pain syndrome (central pain). 神经性疼痛常与伤害性疼痛共存,并且本发明的化合物和盐可以用来治疗混合疼痛状态,即神经性和伤害性疼痛的组合。 Neuropathic pain and nociceptive pain often coexist, and compounds and salts of the present invention may be used to treat pain in a mixed state, i.e., a combination of nociceptive and neuropathic pain. 例如,损伤组织和神经的创伤、烧伤(烧伤皮肤以及神经末梢)以及外部神经压迫可以引起神经性和伤害性疼痛。 For example, neural trauma and tissue injury, burn (burn skin and nerve endings) can cause nerve compression and external neuropathic and nociceptive pain. 外部神经压迫的实例包括肿瘤神经压迫和来自压在神经上的椎间盘突出的坐骨神经痛。 Examples of external nerve compression and nerve compression include tumor sciatica nerve from pressure on the disc. 在其他实施方案中,所述制剂和方法用来治疗腰痛、癌症痛、骨关节炎痛、纤维肌痛和术后疼痛。 In other embodiments, the formulations and methods for the treatment of low back pain, cancer pain, osteoarthritis pain, postoperative pain, and fibromyalgia. 在各种其他实施方案中,所述制剂和方法用来治疗与炎症相关的疼痛、骨痛和关节疾病。 In various other embodiments, the formulations and methods for treating pain associated with inflammation, bone pain and joint disorders. 本发明的制剂和方法可以用来治疗由各种疾病状况引起的疼痛,包括但不限于手术或创伤后的疼痛、与内科疾病相关的疼痛等。 Formulations and methods of the present invention can be used to treat pain caused by various disease states, including, but not limited to, pain after surgery or trauma, pain associated with other medical disorders.

[0082] 本发明包括可以给药以提供两种阿片样物质的制剂。 [0082] The present invention comprises a formulation may be administered to provide the two opioids. 本发明的目的是通过一种阿片样物质激活脑中的某些阿片样物质受体,以及在受体被第一阿片样物质占据后在某些时间点使第二阿片样物质到达。 Object of the present invention is to activate certain opioid receptor in the brain by an opioid, as well as after the receptor is occupied by a first opioid certain point of time reaches the second opioid. 设计双阿片样物质的延长释放的片剂以完成这一点。 Design of double extended release opioid tablet to accomplish this. 例如,在包含羟考酮和吗啡的制剂中,需要延迟吗啡的释放直至羟考酮在受体处至少一个半小时,并且优选超过I小时。 For example, the formulation comprising oxycodone and morphine, a morphine release needs to be delayed until at least the oxycodone receptors hour and a half, and preferably more than I hour. 还需要以从CNS室消除大体上相同的速率重新供应羟考酮用于摄入脑。 Needed to eliminate substantially the same rate from the CNS to re-supply chamber oxycodone for brain uptake. 预期羟考酮的延迟和释放速率应当在本文所述的延迟的改进释放的团粒组分以及掺入该团粒的制剂(例如但不限于片剂和胶囊剂)中互相近似。 Delay and the expected rate of release of oxycodone should be improved delayed release pellets of the components described herein and incorporated into the formulation of the pellets (e.g., but not limited to, tablets and capsules) approximate to each other.

[0083] 具有阿片样物质受体激动剂活性的化合物 [0083] opioid receptor agonist compound having activity

[0084] 所述药物制剂的组分可以包含具有阿片样物质受体激动剂活性的化合物。 [0084] The components of the pharmaceutical formulation may comprise a compound having an opioid receptor agonist activity. 这类化合物可以具有针对μ_、K-、O-或δ-阿片样物质受体(包括其他分类的受体亚型)的激动剂活性。 Such compounds may have agonist activity against μ_, K-, O- or δ- opioid receptors (including receptor subtypes other classification) of. 具有阿片样物质受体激动剂活性的化合物可以是天然存在的、半合成的或全合成的阿片剂化合物,其衍生物或类似物,或者其药学可接受的盐、酯或前药。 The compound having the opioid receptor agonist activity may be naturally occurring, semisynthetic or fully synthetic opiate compounds, derivatives or analogs thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof. 天然存在的阿片剂是在罂粟的树脂中发现的生物碱化合物,并且包括吗啡、可待因和蒂巴因。 Naturally occurring opiates found in poppy alkaloid resin compound, and includes morphine, codeine and thebaine. 半合成或全合成的阿片剂包括但不限于双氢吗啡、异可待因、双氢可待因、双氢吗啡酮(dihydrornorphinone)、二氢可待因酮、3,6- 二醋吗啡、吗啡酮(morphinone)、6_ 脱氧吗啡、海洛因、羟吗啡酮、羟考酮、6-亚甲基-双氢吗啡、氢可酮、埃托啡、bupemorphine、纳洛酮或纳曲酮。 Semi-synthetic or wholly synthetic opioids include, but are not limited to, dihydroergotamine, morphine, codeine, isobutyl, dihydrocodeine, hydromorphone dihydrotestosterone (dihydrornorphinone), hydrocodone, diamorphine 3,6 , hydromorphone (morphinone), 6_ deoxy morphine, heroin, oxymorphone, oxycodone, 6- methylene-Dihydro - morphine, hydrocodone, etorphine, bupemorphine, naloxone or naltrexone.

[0085] 具有μ -阿片样物质受体激动剂活性的化合物可以包括但不限于吗啡(以及结构上相关的类似物和衍生物)、阿维莫泮、丁丙诺啡、可待因、6-地索吗啡、双氢吗啡、二氢吗啡酮、双氢可待因、二氢可待因酮、3,6- 二醋吗啡、6-亚甲基-双氢吗啡、地芬诺酯、羟蒂巴酚、毒扁豆酚碱、埃托啡、芬太尼、氢可酮、左芬啡烷、美沙酮、羟吗啡酮、尼可吗啡、哌替啶、哌西那朵、他喷他多、蒂巴因和trimebutane。 [0085] having a μ - opioid receptor agonist activity of compounds may include, but are not limited to, morphine (and structurally related analogues and derivatives thereof), alvimopan, buprenorphine, codeine, 6 - desomorphine, dihydroergotamine, morphine, hydromorphone, dihydrocodeine, hydrocodone, diamorphine 3,6, 6-methylene dihydro - morphine, diphenoxylate, thebaine hydroxyalkyl phenol, phenol physostigmine base, etorphine, fentanyl, hydrocodone, morphine left Fen alkoxy, methadone, oxymorphone, nicomorphine, pethidine, piperazine West tis, tapentadol , thebaine and trimebutane.

[0086] 具有K -阿片样物质受体激动剂活性的化合物可以包括但不限于阿西马多林、布托啡诺、布马佐辛、环佐辛、右美沙芬、强啡肽、依那朵林、酮佐辛、纳布啡、纳夫拉啡、norbuprenorphine、轻考酮、喷他佐辛、salvinorinA、2_methoxymethyl salvinorin B 及其乙氧基甲基和氟乙氧基甲基同系物、螺朵林以及替氟多。 [0086] with K - opioid receptor agonist activity of compounds may include, but are not limited to 阿西马多林, butorphanol, bremazocine, cyclazocine, dextromethorphan, dynorphin, by tis Lin, ketones nalbuphine, Na Fula brown, norbuprenorphine, light oxycodone, pentazocine, salvinorinA, 2_methoxymethyl salvinorin B and ethoxymethyl and ethoxymethyl-fluoro homologues, Lin and for multi-spiro flower fluorine.

[0087] 具有δ-阿片样物质受体激动剂活性的化合物可以包括但不限于δ啡肽、ethoxymetopon、Ieu-脑啡肽、met-脑啡肽、mitragyna speciosa (kratom)、帽柱木喊、mitragynine-pseudoindoxyl N-phenethyl-14-norbuprenorphine、去甲氯氮平和7_spiroindanyloxymorphone0 [0087] having δ- opioid receptor agonist activity of compounds may include, but are not limited to, δ enkephalin, ethoxymetopon, Ieu- enkephalin, Met- enkephalin, mitragyna speciosa (kratom), mitragynine call, mitragynine-pseudoindoxyl N-phenethyl-14-norbuprenorphine, norepinephrine and clozapine 7_spiroindanyloxymorphone0

[0088] 在某些实施方案中,所述化合物选自吗啡、可待因、氢吗啡酮、氢可酮、羟考酮、双氢可待因、双氢吗啡、羟吗啡酮、它们的混合物以及它们的药学可接受的盐。 [0088] In certain embodiments, the compound is selected from morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydroergotamine, morphine, oxymorphone, mixtures thereof and pharmaceutically acceptable salts thereof.

[0089] 盐包括但不限于盐酸盐、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、琥珀酸盐等。 [0089] The salts include, but are not limited to hydrochloride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate, phosphate, malate, maleate, hydrobromide, hydroiodide, fumarate, succinate and the like.

[0090] 所述药物制剂的组分可以包含超过一种化合物,其中所述超过一种化合物以一定重量比存在。 [0090] The components of the pharmaceutical formulation may comprise more than one compound, wherein said more than one compound at a certain weight ratio. 例如,所述组分可以包含两种化合物,其中所述化合物以2:1、2:2、2:3、2:5、3:1或3:4重量比存在。 For example, the components may comprise two compounds, wherein the compound is 2: 1,2: 2,2: 3,2: 5,3: 3 or 1: 4 weight ratio.

[0091] 在具体实施方案中,所述化合物是约3:2重量比的吗啡和羟考酮,或者它们的药用盐。 [0091] In a particular embodiment, the compound is from about 3: 2 weight ratio of morphine and oxycodone, or a pharmaceutically acceptable salt thereof. 包含化合物的药物组合物可以以高达18mg吗啡和12mg羟考酮每剂量的总量给药,所述化合物包含约3:2重量比的吗啡和羟考酮,或者它们的药用盐。 Pharmaceutical compositions comprising a compound may be up to a total amount of 18mg of morphine and oxycodone 12mg per dose administration, the compound comprises from about 3: morphine and oxycodone 2 weight ratio, or a pharmaceutically acceptable salt thereof. 在一些实施方案中,包含化合物的药物制剂可以以高达约600mg吗啡或其药用盐以及约400mg羟考酮或其药用盐每天的量给药,所述化合物包含约3:2重量比的吗啡和羟考酮,或者它们的药用盐。 In some embodiments, the pharmaceutical formulation comprising the compound can be up to about 600mg of morphine or a pharmaceutically acceptable salt thereof and about 400mg oxycodone or a pharmaceutically acceptable salt thereof daily dose of the compound comprises from about 3: 2 weight ratio morphine and oxycodone, or a pharmaceutically acceptable salt thereof.

[0092] 组分的释放特征谱和特征 [0092] The release characteristics and features of the spectral components

[0093] 所述药物制剂中的至少一种组分包含具有阿片样物质受体激动剂活性的化合物并具有控释特征谱。 [0093] at least one component comprising a compound having the opioid receptor agonist activity and a pharmaceutical formulation with controlled release characteristic spectrum.

[0094] 所述制剂可以包含额外的组分,其中所述额外的组分可以具有所述化合物的即释特征谱或控释特征谱。 [0094] The formulation may comprise additional components, wherein said additional components can have immediate release characteristics or controlled release of the compound spectral characteristic spectrum.

[0095] 如本文所用,术语“即释”指其中用于吸收的化合物的释放基本上没有延迟的释放特征谱。 [0095] As used herein, the term "immediate release" means a release profile for release of the compound wherein substantially no delay absorption spectrum.

[0096] 如本文所用,术语“控释”指其中与即释特征谱相比化合物的释放有修改的释放特征谱。 [0096] As used herein, the term "controlled release" refers to release characteristic wherein the release has a modified spectrum as compared to immediate release profiles of compounds. 控释特征谱的类型包括延迟释放、延长释放和脉冲释放特征谱。 Release profiles of the type comprising a delayed release, extended release and pulsatile release characteristic spectrum.

[0097] 如本文所用,术语“延迟释放”指其中用于吸收的化合物的释放有延迟的释放特征 [0097] As used herein, the term "delayed release" refers to release of the compound for absorption where there is a delayed release profile

-1'TfeP曰。 -1'TfeP said.

[0098] 如本文所用,术语“延长释放”指其中活性化合物以这样的速率释放的释放特征谱:在约8小时、或约10小时、或约12小时、或约15小时、或约20小时、或约24小时、或约30小时、或约35小时或甚至更长的时间中,血液水平维持在治疗范围内,但是低于有毒水平。 [0098] As used herein, the term "extended release" refers to wherein the release characteristics of the active compound release at such a rate Spectrum: about 8 hours, or about 10 hours or about 12 hours, or about 15 hours or about 20 hours , or about 24 hours or about 30 hours, or about 35 hours, or even longer, the blood levels are maintained within the therapeutic range but below toxic levels. 按照本发明的释放特征谱,术语“延长释放”与“即释”和“延迟释放”释放特征谱区分。 Spectral release characteristics according to the present invention, the term "extended release" release and "immediate release" and "delayed-release" distinguishing characteristic spectrum. 如本文所用,“延迟-延长释放”指其中活性化合物的释放延迟,但是仍比“即释释放”释放特征谱延长更长的释放特征谱。 As used herein, "delay - extended release" refers to release of the active compound wherein the delay, but still higher than the "release immediate release" extended release profiles of the release profiles of the longer.

[0099] 如本文所用,术语“脉冲释放”指其中化合物以间隔释放用于吸收的释放特征谱。 [0099] As used herein, the term "pulsed release" refers to release characteristic wherein the release compound interval for absorption spectrum.

[0100] 即释组分 [0100] Immediate release component

[0101] 即释组分可以提供化合物的总剂量的约1%_约50%通过所述药物制剂递送。 [0101] The immediate release component may provide the total dose of from about 1% to about 50% of the compound by _ the pharmaceutical formulation delivery. 例如,即释组分可以提供化合物的总剂量的至少约5%、或者约10%-约30%、或者约45%-约50%通过所述制剂递送。 For example, immediate release component may provide at least about 5% of the total dose of the compound, or from about 10% - about 30%, or from about 45% - about 50% of the formulation through the delivery. 在可选实施方案中,即释组分提供化合物的总剂量的约2、4、5、10、15、20、 In an alternative embodiment, the immediate release component to provide a total dose of about 2,4,5,10,15,20 compound,

25、30、35、40、45或50%通过所述制剂递送。 25,30,35,40,45, or 50% of the formulation through the delivery.

[0102] 即释组分可以是在给药后迅速分解以释放阿片样物质化合物的成分的混合物。 [0102] The immediate release component can be rapidly decomposed to release the opioid compound of the mixture of ingredients after administration. 这可以采用例如颗粒、粒子、粉末、液体和团粒的形式。 This may take the form, for example, particle, granule, powder, liquid and pellet employed.

[0103] 控释组分 [0103] Controlled Release Component

[0104] 控释组分可以提供化合物的总剂量的约30-95%通过所述药物制剂递送。 [0104] The controlled release component may provide about 30-95% of the total dose of the compound by the pharmaceutical formulation delivery. 例如,即释组分可以提供化合物的总剂量的约70-90%或约80%通过所述药物制剂递送。 For example, immediate release component may provide about 70-90%, or about 80% of the total dose of the compound by the pharmaceutical formulation delivery. 在可选实施方案中,控释组分提供化合物的总剂量的约30、35、40、45、50、55、60、65、70、75、80、85、90或95%通过所述制剂递送。 In an alternative embodiment, the controlled release component provides 30,35,40,45,50,55,60,65,70,75,80,85,90, or about 95% of the formulation by the total dose of the compound deliver.

[0105] 控释组分可以具有重复或单次给药后约1-约25小时,或者给药后约20、17、15、12、11、8、6、5、4、3、2 或I 小时的Tmax0 [0105] The controlled release component may have from about 1 to about 25 hours after single or repeated administration, or after administration or about 20,17,15,12,11,8,6,5,4,3,2 I hour Tmax0

[0106] 在某些实施方案中,控释组分可以具有重复给药后约4.5-约8小时、或者重复给药后约5-约6小时、或者重复给药后约6小时的Tmax。 [0106] In certain embodiments, the controlled release component may have from about 4.5 to about 8 hours after repeated dosing, repeated, or about 5 to about 6 hours after administration, or from about 6 hours after repeated administration Tmax.

[0107] 控释组分可以具有重复给药后约10-约25小时,或者给药后约12、13、14、15、16、 [0107] The controlled release component may have from about 10 to about 25 hours after repeated administration, or after administration of about 12,13,14,15,16,

17、18、19 或20 小时的1^。 17,18, 19 or 20 hours, 1 ^.

[0108] 在某些实施方案中,控释组分可以具有重复给药后约13-约16小时、或者重复给药后约14小时的Tmin。 [0108] In certain embodiments, the controlled release component may have about 13 to about 16 hours after repeated administration, or about 14 hours after repeated administration, Tmin.

[0109] 以50rpm在水中于37° C下在USP I型装置中测量时,控释组分的溶出在2小时后释放约O-约20%的化合物或其盐,或者在4小时后释放约15-约60%的化合物或其盐,或者在6小时后释放约25-约80%的化合物或其盐,或者在8小时后释放约35-约85%的化合物或其盐,或者在10小时后释放约45-约95%的化合物或其盐,或者在12小时后释放约60-约100%的化合物或其盐。 [0109] In 50rpm when measured in water at 37 ° C for in USP Type I apparatus, the dissolution of the controlled release component is released about 20% to about O- or a salt thereof after 2 hours, or released after 4 hours from about 15 to about 60% or a salt thereof, is released after 6 hours, or from about 25 to about 80% of the compound or a salt thereof, or the compound is released from about 35 to about 85% after 8 hours, or a salt thereof, or is released after 10 hours from about 45 to about 95% of the compound, or a salt thereof, or the compound is released from about 60 to about 100% after 12 hours, or a salt thereof.

[0110] 控释组分可以包含约2mg-约80mg化合物。 [0110] The controlled release component may comprise from about 80mg to about 2mg- compound. 当控释组分包含约2mg时,所述控释组分在重复给药后可以提供约1-约3ng/mL或者约2ng/mL的平均C_。 When the controlled release component comprises from about 2mg, the controlled release component may be provided after repeated administration of from about 1 to about 3ng / mL, or about the average C_ 2ng / mL of. 在单次给药后,AUC24可以为约14.7ng.hr/mL-约23.0ng.hr/mL,或者约15.8ng.hr/mL-约21.0ng.hr/mL,或者约17.1ng.hr/mL-约19.7ng.hr/mL。 After a single administration, AUC24 may be from about 14.7ng.hr/mL- about 23.0ng.hr/mL, or from about 15.8ng.hr/mL- about 21.0ng.hr/mL, or from about 17.1ng.hr/ mL- about 19.7ng.hr/mL.

[0111] 当控释组分包含约5mg时,所述控释组分在重复给药后可以提供约3-约7ng/mL或者约5ng/mL的平均Cmax。 [0111] When the controlled release component comprises about 5mg, the controlled release component may be provided after repeated administration from about 3 to about 7ng / mL, or about the average Cmax 5ng / mL of. 在单次给药后,AUC24可以为约40.2ng.hr/mL-约62.8ng *hr/mL,或者约43.2ng.hr/mL-约57.2ng.hr/mL,或者约46.7ng.hr/mL-约53.7ng.hr/mL。 After a single administration, AUC24 40.2ng.hr/mL- may be from about to about 62.8ng * hr / mL, or from about 43.2ng.hr/mL- about 57.2ng.hr/mL, or from about 46.7ng.hr/ mL- about 53.7ng.hr/mL.

[0112] 当控释组分包含约IOmg时,所述控释组分在重复给药后可以提供约5-约15ng/mL或者约10ng/mL的平均Cmax。 [0112] When the controlled release component comprises about IOmg, the controlled release component may be provided after repeated administration of from about 5 to about 15ng mean Cmax / mL or from about 10ng / mL to. 在单次给药后,AUC24可以为约80.5ng.1ι;/ιΛ-约125.9ng *hr/mL,或者约86.6ng.hr/mL-约114.8ng.hr/mL,或者约93.7ng.hr/mL-约107.7ng.hr/ΠίΤ,η After a single administration, AUC24 may be from about 80.5ng.1ι; / ιΛ- about 125.9ng * hr / mL, or from about 86.6ng.hr/mL- about 114.8ng.hr/mL, or from about 93.7ng.hr / mL- about 107.7ng.hr/ΠίΤ,η

[0113] 当控释组分包含约20mg时,所述控释组分在重复给药后可以提供约10-约30ng/mL或者约20ng/mL的平均Cmax。 [0113] When the controlled release component comprises from about 20mg, the controlled release component may be provided after repeated administration of from about 10 to about 30ng / mL, or about the average Cmax 20ng / mL of. 在单次给药后,AUC24可以为约166.0ng.hr/mL-约259.3ng.hr/mL,或者约178.5ng.hr/mL-约236.6ng.hr/mL,或者约193.0ng.hr/mL-约222.0ng.hr/mL。 After a single administration, AUC24 may be from about 166.0ng.hr/mL- about 259.3ng.hr/mL, or from about 178.5ng.hr/mL- about 236.6ng.hr/mL, or from about 193.0ng.hr/ mL- about 222.0ng.hr/mL.

[0114] 当控释组分包含约40mg时,所述控释组分在重复给药后可以提供约25-约55ng/mL或者约40ng/mL的平均Cmax。 [0114] When the controlled release component comprises from about 40mg, the controlled release component may be provided after repeated administration of about 25 to about 55ng mean Cmax / mL or from about 40ng / mL to. 在单次给药后,AUC24可以为约338.5ng.hr/mL-约528.9ng.hr/mL,或者约363.9ng.hr/mL-约482.3ng.hr/mL,或者约393.5ng.hr/mL-约452.7ng.hr/mL。 After a single administration, AUC24 may be from about 338.5ng.hr/mL- about 528.9ng.hr/mL, or from about 363.9ng.hr/mL- about 482.3ng.hr/mL, or from about 393.5ng.hr/ mL- about 452.7ng.hr/mL.

[0115] 当控释组分包含约80mg时,所述控释组分在重复给药后可以提供约50-约110ng/mL或者约80ng/mL的平均Cmax。 [0115] When the controlled release component comprises from about 80mg, the controlled release component may provide a mean Cmax of about 50 to about 110ng / mL or from about 80ng / mL after repeated administration. 在单次给药后,AUC24可以为约868.4ng.hr/mL-约1356.9ng.hr/mL,或者约933.5ng.hr/mL-约1237.5ng.hr/mL,或者约1009.5ng.hr/mL-约1161.5ng.hr/mL。 After a single administration, AUC24 may be from about 868.4ng.hr/mL- about 1356.9ng.hr/mL, or from about 933.5ng.hr/mL- about 1237.5ng.hr/mL, or from about 1009.5ng.hr/ mL- about 1161.5ng.hr/mL.

[0116] 在一些实施方案中,控释组分在重复给药后提供约0.5-约40ng/mL或者约4_约15ng/mL 的平均Cmin。 [0116] In some embodiments, the controlled release component provides from about 0.5 to about 40ng / mL or from about 4_ about 15ng / mean Cmin mL after repeated administration.

[0117] 在某些实施方案中,Tmax、Tmin、平均Cmax和Cmin可以在通过稳态条件中重复给药后确定。 [0117] In certain embodiments, Tmax, Tmin, the mean Cmax and Cmin after repeated administration may be determined by the steady state conditions. 如本文所用,术语“稳态”表示给定药物的血浆水平已达到,并且用随后剂量的所述药物将其维持在一定水平,该水平在或高于最低有效治疗水平并低于化合物的最低有毒血浆水平。 As used herein, the term "steady state" represents a given drug plasma levels are reached, and with subsequent doses of the drug will be maintained at a certain level, the level at or above the minimum effective therapeutic level and below the lowest compound toxic plasma levels. 对于阿片样物质镇痛剂如羟考酮,最低有效治疗水平会通过给定患者中实现疼痛缓解的量部分确定。 Determining the amount of pain relief for part of opioid analgesics such as oxycodone, the minimum effective therapeutic level will be achieved in a given patient. 医学领域的技术人员会理解疼痛测量是高度主观的,并且在患者之间可以出现巨大的个体差异。 Medical skill in the art would understand that pain measurement is highly subjective and great individual differences can occur between patients. 很显然,每个剂量的给药之后,浓度通过最大然后再次降至最小。 Obviously, after administration of each dose, and then again to minimize the maximum concentration.

[0118] 稳态可以描述如下:在时间t=0(第一剂量给药的时间)浓度C也为O。 [0118] steady state may be described as follows: at time t = 0 (the time of the first dose) is also concentration C is O. 然后浓度通过第一最大,然后降至第一最小。 Then the concentration of the first maximum, first minimum and then reduced. 在浓度降至O之前,将另一剂量给药,从而浓度的第二次增加不从O开始。 Before concentration to O, the other dosing, thereby increasing the second concentration does not start O. 在这个第一浓度最小的基础上,将第二剂量给药后,曲线通过第二最大(其在第一最大之上),并且降至第二最小(其在第一最小之上)。 In this first concentration minimum on the basis of, after the second dose, curve (which is above the first maximum) second maximum and a second minimum reduced (which is above the first minimum). 因此,由于重复剂量以及相关的活性物质的逐步累积,血液血浆曲线逐步上升,直至其稳定至吸收和消除平衡的点。 Thus, due to the repeated doses and the associated gradual accumulation of the active substance, the blood plasma curve gradually increased, until it points to the stable equilibrium absorption and elimination. 吸收和消除平衡并且浓度在定义的最小和定义的最大之间不断振荡的这种状态称为稳态。 Absorption and elimination equilibrium concentration in this state and the minimum and maximum definitions defined between the continuous oscillation is called steady state.

[0119] 组分的活性物质 [0119] Component active substance

[0120] 所述一种或多种额外的组分可以包含一种或多种活性物质。 [0120] The one or more additional components may comprise one or more active substances. 例如,所述活性物质可以是如本文讨论的具有阿片样物质受体激动剂活性的任何化合物。 For example, the active substance may be any active compound having the opioid receptor agonist as discussed herein.

[0121] 所述活性物质还可以包含一种或多种非阿片样物质镇痛化合物,或者一种或多种非阿片样物质镇痛化合物与一种或多种具有阿片样物质受体激动剂活性的化合物或者它们的药学可接受的盐、酯或前药的混合物。 The [0121] active material may further comprise one or more non-opioid analgesic compound, or one or more non-opioid analgesic and one or more compound having opioid receptor agonist is active compound thereof or a pharmaceutically acceptable salt, ester or prodrug of a mixture. 非阿片样物质镇痛化合物可以发挥作用以通过与结合至阿片样物质受体无关的其他机制来缓解疼痛。 Non-opioid analgesic compounds may play a role in binding by other mechanisms unrelated to the opioid receptor to relieve pain. 例如,所述非阿片样物质镇痛化合物可以是非留类抗炎化合物(NSAID),其实例包括但不限于吡罗昔康、氯诺昔康(1moxicam)、替诺昔康、水杨酸(阿司匹林)和其他水杨酸盐如二氟尼柳;2_芳基丙酸如布洛芬、卡洛芬、芬布芬、非诺洛芬、氟比洛芬(flubiprofen)、酮洛芬、铜咯酸、洛索洛芬、萘普生、奥沙普秦、噻洛芬酸和舒洛芬;正芳基邻氨基苯甲酸如甲芬那酸(metenamicacid)和甲氧芬那酸;芳基链烷酸如双氯芬酸、醋氯芬酸、阿西美辛、依托度酸、吲哚美辛(idomethacin)、舒林酸和托美丁等;或者它们的混合物。 For example, a non-opioid analgesic anti-inflammatory compound may be left non-compound (NSAID), examples of which include but are not limited to, piroxicam, lornoxicam (1moxicam), tenoxicam, salicylate (aspirin) and other salicylates such as diflunisal; 2_ arylpropionic acids such as ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen (flubiprofen), ketoprofen, copper slightly acid, loxoprofen, naproxen, oxaprozin, tiaprofenic acid and suprofen; Masayoshi anthranilic acid group such as mefenamic acid (metenamicacid) mefenamic acid and methoxy; aryl-alkanoic acids such as diclofenac, aceclofenac, acemetacin, etodolac, indomethacin (idomethacin), sulindac, tolmetin, and the like; or mixtures thereof.

[0122] 非阿片样物质镇痛化合物还可以是C0X-1或C0X-2抑制剂化合物,包括但不限于 [0122] Non-opioid analgesic compound also can be C0X-1 or C0X-2 inhibitor compounds, including but not limited to

塞来考昔(Celebrex")、艾托考昔、芦米考昔、帕瑞考昔、罗非考昔、伐地考昔或它们的混合 Celecoxib (Celebrex "), etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, or a mixture thereof

物。 Thereof. 非阿片样物质镇痛剂还可以是钙通道结合剂如加巴喷丁或普瑞巴林,或者它们的衍生物、类似物或前药,或者它们的混合物。 Non opioid analgesics may also be a calcium channel binding agent such as gabapentin or pregabalin, or a derivative, analog or prodrug thereof, or a mixture thereof.

[0123] 在某些实施方案中,非镇痛化合物为加巴喷丁酯(Solzira™),其为加巴喷丁的前药,化学名为1-[[[[1-(2_甲基-1-氧代丙氧基)乙氧基]羰基]氨基]甲基]环己烷乙酸。 [0123] In certain embodiments, the non-analgesic compound is gabapentin ester (Solzira ™), which is called a prodrug of gabapentin, chemical - [[[[1- (methyl-1-oxo 2_ propoxy) ethoxy] carbonyl] amino] methyl] cyclohexanecarboxylic acid. 加巴喷丁、普瑞巴林和加巴喷丁酯的结构如下所示: Gabapentin, pregabalin, and gabapentin ester structure is shown below:

[0124]FORMULA[0125] 所述活性物质还可以是一种或多种混合阿片样物质化合物,或者一种或多种混合阿片样物质化合物与一种或多种具有阿片样物质受体激动剂活性的化合物或者它们的药学可接受的盐、酯或前药的混合物。 [0124] FORMULA the [0125] active substance may also be one or more mixed opioid compound, or one or more mixed opioid compound with one or more opioid receptor agonists having active compound thereof or a pharmaceutically acceptable salt, ester or prodrug of a mixture. 混合阿片样物质化合物是通过用接头组分将两种或更多种阿片样物质化合物共价结合在一起而形成的化合物。 Mixed opioid compound is a compound formed by a linker component combines two or more covalently opioid compound. 接头组分可以是稳定的,或者可以在生理条件下水解以提供母体阿片样物质化合物。 Linker component may be stable, or may be hydrolyzed to provide the parent opioid compound under physiological conditions. 混合阿片样物质化合物描述于2009年2月18日提交的Holaday等人的美国临时申请系列号61/153,537。 Holaday et al., US Provisional Application Serial No. mixed opioid compounds described in the February 18, 2009, filed 61 / 153,537. 混合阿片样物质化合物还描述于Portoghese等人的国际专利申请公开第W02006/073396号。 Mixed opioid compound is also described in Portoghese et al., International Patent Application Publication W02006 / 073396 Number.

[0126] 混合阿片样物质化合物可以包含通过共价接头组分连接的两种或更多种具有阿片样物质受体激动剂活性的化合物。 Mixed opioid compound [0126] can comprise by covalent compound having two or more opioid receptor agonist activity linker connecting component. 混合阿片样物质化合物还可以包含连接至非阿片样物质活性物质(包括但不限于如上文所述的非阿片样物质镇痛化合物)的具有阿片样物质受体激动剂活性的化合物。 Mixed opioid compound may further comprise (including, but not limited to the above described non-opioid analgesic compound) a compound having the opioid receptor agonist activity is connected to the non-opioid active substance. 在一些实施方案中,所述非阿片样物质活性物质为加巴喷丁、普瑞巴林或加巴喷丁酯。 In some embodiments, the non-opioid active substance is gabapentin, pregabalin or gabapentin butyl.

[0127] 混合阿片样物质化合物可以包含通过共价接头键合在一起的两种或更多种阿片剂化合物。 Mixed opioid compound [0127] may comprise a linker by covalent bonding together two or more opiate compound. 所述阿片剂化合物可以包括但不限于上文所述的阿片剂化合物。 A tablet may include the compounds described above, but is not limited to the opiate compound.

[0128] 活性化合物可以通过各种化学键键合至接头组分,优选在活性物质上不妨碍活性物质的生物学活性的位置。 [0128] The active compounds can be chemically bonded to the various linker components, preferably does not interfere with the biological activity of the active position of the material on the active material. 通常,活性物质可以通过活性化合物上的反应基团键合至接头或者在可以被激活以与接头组分反应的位置键合。 Typically, the active substance can bond reactive group on the linker bonded to the active compound or may be activated to react with the position of the joint component bonding.

[0129] 组分制备 [0129] Preparation of Component

[0130] 为了获得本文所述的药物组合物的组分,以适当浓度使用赋形剂的组合以提供特性和期望的药物动力学。 [0130] In order to obtain the components of the pharmaceutical composition described herein, at concentrations suitable excipients and to provide the desired pharmacokinetic properties. 用于本文所述的药物组合物的赋形剂可商购,并且列于USP或NF。 Excipients for pharmaceutical compositions described herein may be commercially available, and listed in USP or NF. 选择有助于每种活性即释组分的功能和目的并且还有助于最终组分的赋形剂。 Select facilitate immediate release of each active component of the function and purpose of the final composition and also helps the vehicle. 技术人员会理解所用的这些赋形剂的浓度可以如期望地增加或减少以增加或减少最终阿片样物质制剂中的特定特性。 Art will appreciate that the concentration of these excipients used may be increased or decreased as desired to increase or decrease certain properties of the final opioid formulation. 本文所用的包衣材料也可商购并列于USP或NF,USP或NF援引加入本文。 As used herein, the coating materials are also commercially available and listed in USP or NF, USP or NF incorporated herein by reference.

[0131]用来制备本文所述的化合物-阿片样物质延长释放片剂的技术是已知的药物制备方法的组合。 [0131] compounds described herein are prepared for - opioid art extended release tablets are known in the preparation of a medicament combined method. 用于制备每种活性即释的单元过程已用于几种可商购的产品,因此可大规模化。 Each active unit processes for preparing immediate release have been used in several commercially available products, thus large scale. 制备化合物-阿片样物质延长释放片剂的两个重要方面是不同类型的延迟的改进释放的团粒的制备和性能。 Preparation of compound - opioid two important aspects extended release tablets are prepared, and performance improvements of different types of delayed release pellets. 在双阿片样物质羟考酮/吗啡化合物产物的实例中,延迟的改进释放的羟考酮团粒和延迟的改进释放的吗啡团粒的制备和性能的重要性相似。 In the example the substance oxycodone / morphine compound bis opioid product, like the importance of preparation and properties of morphine pellet improved improved delayed release oxycodone pellets and delayed release. 这些团粒应当在片剂压实后与自由流动的未压片的团粒表现相同。 These pellets and the pellets should not exhibit the free-flowing tabletting same tablet after compaction. 这个重要特征最好通过充分塑化包衣网络来完成以避免片剂压实期间在加压下包衣的开裂和脆性断裂。 This important feature is preferably accomplished by the network to prevent the coating sufficiently plasticized during the coating of tablets compacted under a pressure of brittle fracture and cracking.

[0132] 加入用于即释组分的化合物的材料可以是但不限于微晶纤维素、玉米淀粉、预胶化淀粉、马铃薯淀粉、大米淀粉、羧甲基淀粉钠、羟丙基纤维素、羟丙基甲基纤维素、羟乙基纤维素、乙基纤维素、壳聚糖、羟基壳聚糖、羟甲基化壳聚糖、交联的壳聚糖、交联的羟甲基壳聚糖、麦芽糖糊精、甘露醇、山梨醇、右旋糖、麦芽糖、果糖、葡萄糖、左旋糖、蔗糖、聚乙烯吡咯烷酮(PVP)、丙烯酸衍生物(卡波普、尤特奇等)、聚乙二醇如低分子量PEG(PEG2000-10000)以及具有20,000道尔顿以上的分子量的高分子量PEG (Polyox)。 [0132] Compound was added for immediate release component material may be, but is not limited to, microcrystalline cellulose, corn starch, pregelatinized starch, potato starch, rice starch, sodium carboxymethyl starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, chitosan, ethylcellulose, chitosan, hydroxy chitosan, hydroxymethylated chitosan, crosslinked, crosslinked hydroxymethyl shell polysaccharides, maltodextrin, mannitol, sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose, polyvinylpyrrolidone (PVP), acrylic acid derivative (carbopol, etc. Eudragit), poly low molecular weight glycols such as PEG (PEG2000-10000) having a molecular weight above 20,000 daltons molecular weight PEG (Polyox). 这些材料以1.0-60%(W/W)的范围存在可以是有用的。 These materials may be useful to present the range 1.0-60% (W / W) of.

[0133] 此外,在这个系统中具有其他成分可以是有用的,以便在摄取或给药后辅助药物的溶出或组分的分解。 [0133] Further, with the other ingredients may be useful in this system, to assist dissolution or decomposition of components of the drug after ingestion or administration. 这些成分可以是表面活性剂,如十二烷基硫酸钠、单甘油酸钠、脱水山梨醇单油酸酯、脱水山梨醇单油酸酯、聚氧乙烯脱水山梨醇单油酸酯、硬脂酸甘油酯、甘油单油酸酯、单丁酸甘油酯,非离子表面活性剂之一如表面活性剂的普流罗尼克线,或者具有表面活性特性的任何其他材料,或者上述物质的任何组合。 These components may be a surfactant, such as sodium lauryl sulfate, sodium monoglyceride, sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, stearyl any combination of acid, glyceryl monooleate, glyceryl mono butyrate, one of the non-ionic surfactant such as Pluronic line of surface-active agent, or any other material having surface active properties, or the foregoing . 这些材料可以以0.05-15%(ff/W)的比例存在。 These materials may be present in a ratio of 0.05-15% (ff / W) of.

[0134] 控释组分中的材料与即释组分中的材料相同,但是有额外的聚合物整合入组分,或者作为团粒或颗粒上的包衣。 [0134] Materials and immediate release component of the controlled release component in the same material, but with additional polymers integrated into the component, or as a coating on the pellets or granules. 可用于这个目的的材料的种类可以是但不限于乙基纤维素、羟丙基甲基纤维素、羟丙基纤维素、羟乙基纤维素、羧甲基纤维素、甲基纤维素、硝化纤维素、尤特奇R、和尤特奇RL、卡波普、或者具有超过8,000道尔顿的分子量的聚乙二醇。 The types of materials can be used for this purpose may be, but is not limited to ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, nitrocellulose cellulose, Eudragit R, and Eudragit RL, carbopol, or with more than 8,000 daltons molecular weight polyethylene glycols. 这些材料可以以4-20% (W/W)的浓度存在。 These materials may be present in a concentration of 4-20% (W / W) of.

[0135] 在某些实施方案中,组分可以具有pH敏感的延迟释放特征谱或非pH敏感的延迟释放特征谱。 [0135] In certain embodiments, the components can have a pH-sensitive delayed release profiles of non-pH-sensitive delayed release characteristic spectrum. PH敏感的延迟释放组分中的材料可以与即释组分中的材料相同,但是有额外的聚合物整合入组分,或者作为团粒或颗粒上的包衣。 PH-sensitive delayed release component may be the same material in the immediate release component material, but with additional polymers integrated into the component, or as a coating on the pellets or granules. 可用于这个目的的材料的种类可以是但不限于醋酞纤维素、尤特奇L和纤维素衍生物的其他邻苯二甲酸盐。 The types of materials can be used for this purpose may be, but are not limited to cellulose acetate phthalate, Eudragit L other phthalate and cellulose derivatives. 这些材料可以以4-20% (W/W)的浓度存在。 These materials may be present in a concentration of 4-20% (W / W) of.

[0136] pH敏感的延迟释放组分中的材料可以与即释组分中的材料相同,但是有额外的聚合物整合入组分,或者作为团粒或颗粒上的包衣。 [0136] pH-sensitive delayed release component may be the same material in the immediate release component material, but with additional polymers integrated into the component, or as a coating on the pellets or granules. 可用于这个目的的材料的种类可以是但不限于具有4,000道尔顿以上分子量的聚乙二醇(PEG)(碳蜡、Polyox)、蜡如白蜡或蜂蜡、石蜡、丙烯酸衍生物(尤特奇)、丙二醇以及乙基纤维素。 The types of materials can be used for this purpose may be, but is not limited to having the above 4,000 Daltons molecular weight polyethylene glycol (PEG) (Carbowax, as Polyox), waxes such as white wax or bees wax, paraffin, acrylic acid derivatives (esp Tec), propylene glycol, and ethyl cellulose. 通常,这些材料可以以这种组分的0.5-25%(W/W)的范围存在。 Typically, these materials may be present in the range of 0.5 to 25% of such a component (W / W) of.

[0137] 药物制剂 [0137] Pharmaceutical formulations

[0138] 所述药物制剂可以包含一种或多种组分,所述组分具有一种或多种释放特征谱。 [0138] The pharmaceutical formulations may comprise one or more components, the components having one or more release characteristic spectrum. 每种组分可以包含相同的化合物,可以包含不同的化合物或它们的混合物(例如,在相同制剂内,一些组分具有相同的化合物,其他组分具有不同的化合物)。 Each component may comprise the same compound may contain different compounds or mixtures thereof (e.g., within the same formulation, some of the components with the same compound, other components having a different compound). 此外,组分可以包含如本文所述的活性物质。 Further, the component may comprise an active material as described herein.

[0139] 例如,所述制剂可以包含至少一种组分,其中所述一种组分具有控释特征谱。 [0139] For example, the formulation may comprise at least one component, wherein one component having a controlled release characteristics in the spectrum.

[0140] 所述制剂还可以包含至少两种组分(第一和第二组分),其中每种组分具有不同的释放特征谱。 [0140] The formulation may further comprise at least two components (the first and second component), wherein each component has a different release characteristic spectrum. 例如,所述至少两种组分中的第二种在第一组分后至少I小时开始释放其中所含的化合物,由此释放的开始一般在从第一组分开始释放化合物后不超过6小时发生。 For example, the at least two components of a second after the first component begins to release at least I hour compound contained therein, thereby releasing typically begins after the start of release of the compound from the first component does not exceed 6 hours occurred.

[0141] 所述制剂还可以包含至少三种组分(第一、第二和第三组分)。 [0141] The formulation may further comprise at least three components (the first, second and third components). 第一组分可以是即释组分,由此释放化合物的开始在所述制剂给药后基本上不延迟。 The first component may be an immediate release component, thereby releasing the compound does not substantially delay the start after the administration of the preparation. 第二和第三组分是控释组分,从而化合物的释放可以延迟。 The second and third component is a controlled release component, which can delay release of the compound. 控释组分可以是pH敏感或非pH敏感的延迟组分,这取决于制剂的类型。 The controlled release component may be pH-sensitive or pH sensitive delay components, depending on the type of formulation. 从延迟释放组分释放的化合物可以延迟直至开始从即释组分释放化合物之后。 Release from the delayed release of the component compound may be delayed until after the compound starts to release from the immediate release component. 例如,从第二组分释放的化合物可以在从即释组分释放的化合物可以达到血清中的Cniax后的时间达到C_。 For example, the compound may be released from the second component can be achieved time after serum Cniax C_ reaches the compound released from the immediate release component. 从第三组分释放的化合物可以在从第二组分释放的化合物的Cniax之后达到血清中的Cniax。 Compound release can be achieved from the third component in the serum after Cniax Cniax compound released from the second component.

[0142] 在某些实施方案中,即释组分可以在约0.5-约2小时内产生由此释放的化合物的Cniax,而第二组分在不超过约4小时中产生由此释放的化合物的C_。 [0142] In certain embodiments, the immediate release component can be produced Cniax thereby releasing compound in the range of about 0.5 to about 2 hours, and thereby releasing the second component generating compound at no more than about 4 hours the C_. 一般来说,这样的第二组分的Cmax可以在所述制剂给药后不早于2小时达到;然而,可以通过调整本文所述的赋形剂和/或包衣的浓度来在较短时间中达到Cmax,以便获得具有期望的药物动力学特征谱的制剂。 In general, such Cmax second component may not earlier than 2 hours after the administration of the preparation to achieve the; however, by adjusting the excipients described herein, and a concentration of coating / or shorter time to reach Cmax, in order to obtain a formulation having a desirable pharmacokinetic profile spectrum.

[0143] 在某些实施方案中,从第三组分释放化合物可以在开始从第一和第二组分释放化合物之后开始。 [0143] In certain embodiments, the compound is released from the third component may be started after the start of release of the compound from the first and second components. 在一些实施方案中,从第三组分释放的化合物的Cniax可以在8小时内达到。 In some embodiments, the third component Cniax released from the compound can be achieved within 8 hours.

[0144] 所述制剂还可以包含至少4种组分(第一、第二、第三和第四组分),所述至少4种组分中的每种具有不同的释放特征谱。 [0144] The formulation may further comprise at least four components (the first, second, third and fourth components), the at least four kinds of components each having different profiles of release. 例如,从所述至少4种不同组分中的每种释放的化合物可以在不同时间达到Cmax。 For example, the time to reach Cmax at different times for each compound to release from the at least four different components.

[0145] 所述制剂还可以包含至少5种组分(第一、第二、第三、第四和第五组分)。 The [0145] formulation may further comprise at least five components (the first, second, third, fourth and fifth component). 第一组分可以是第一化合物或第一组化合物的即释组分,而第二和第三组分可以是第一化合物或第一组化合物的控释组分。 The first component may be an immediate release component of the first compound or compounds of the first group, while the second and third components of the first component may be a controlled release compound or group of compounds. 第四和第五组分可以是第二化合物或第二组化合物的控释组分。 The fourth and fifth components controlled release component may be a second group of a second compound or compounds. 例如,在某些实施方案中,第一化合物可以为羟考酮,而第二化合物可以为吗啡。 For example, in certain embodiments, the first compound may be a oxycodone, morphine and the second compound may be a.

[0146] 在某些实施方案中,所述制剂可以为胶囊形式,包含分离的片剂或团粒形式的组分。 [0146] In certain embodiments, the formulation may be in the form of a capsule, tablet or pellet form comprising the separation of the components. 因此,例如,即释组分可以为片剂或团粒形式,而控释组分可以为其他片剂或团粒形式,其各自提供其中所含化合物的控释,从而在不同时间达到从各团粒或包含团粒的片剂释放的化合物的Cmax,并且在少于12小时中达到所述制剂的Cmax。 Thus, for example, immediate release component may be a tablet or pellet form, the controlled release component may be another form of tablets or pellets, each of which provides a controlled release of compound contained therein, so as to achieve at different times from each pellet or Cmax compound containing pellets release tablet, and time to reach Cmax of the formulation in less than 12 hours.

[0147] 在某些实施方案中,所述药物制剂本身包含控释特征谱。 [0147] In certain embodiments, the pharmaceutical formulation comprising a controlled release profiles of itself. 例如,可以在所述制剂给药之后约20、17、15、12、11、8、6、5、4、3、2或I小时内达到从所述制剂释放的所有化合物的Cmax。 For example, time to reach Cmax or all of the compounds released from the formulation within I h after administration of the formulation to about 20,17,15,12,11,8,6,5,4,3,2. 在一些实施方案中,可以在所述制剂给药之后少于2、1或0.5小时内达到Cmax。 In some embodiments, the time to reach Cmax may be less than 2,1 or 0.5 hours after administration of the formulation. 在其他实施方案中,可以在所述组分给药之后大于4.5、5、6、7、8、9或10小时内达到Cmax。 In other embodiments, it may be greater than the time to reach Cmax after the administration of the components 4.5,5,6,7,8,9 or 10 hours.

[0148] 所述制剂可以在重复或单次给药后具有约1-约25小时的Tmax,或者在给药后具有约20、17、15、12、11、8、6、5、4、3、2 或I 小时的Tmax0 [0148] The formulation may have from about 1 to about 25 hours after repeated or Tmax single administration, or after administration of about 20,17,15,12,11,8,6,5,4, 3,2 hours or I Tmax0

[0149] 在某些实施方案中,Tmax可以为重复给药后约4.5-约8小时,或者约5-约6小时,或者约6小时。 [0149] In certain embodiments, it may be a Tmax of about 4.5 to about 8 hours after repeated administration, or from about 5 to about 6 hours or about 6 hours. 在一些实施方案中,重复给药在稳态条件中进行。 In some embodiments, the administration is repeated in a steady state condition.

[0150] 所述制剂可以包含约Img-约IOOmg化合物,或者可以包含约2mg-约80mg化合物。 [0150] The formulation may comprise from about about IOOmg Img- compound, or may comprise from about 80mg to about 2mg- compound. 当所述制剂包含约2mg时,所述控释组分在重复给药后可以提供约1-约3ng/mL或者约2ng/mL的平均Cmax。 When the formulation comprises about 2mg, the controlled release component may be provided after repeated administration of from about 1 to about 3ng / mL, or about the average Cmax 2ng / mL of. 在单次给药后,AUC24可以为约14.7ng.hr/mL-约23.0ng.hr/mL,或者约15.8ng.hr/mL-约21.0ng.hr/mL,或者约17.1ng.hr/mL-约19.7ng.hr/mL。 After a single administration, AUC24 may be from about 14.7ng.hr/mL- about 23.0ng.hr/mL, or from about 15.8ng.hr/mL- about 21.0ng.hr/mL, or from about 17.1ng.hr/ mL- about 19.7ng.hr/mL.

[0151] 当所述制剂包含约5mg时,所述控释组分在重复给药后可以提供约3-约7ng/mL或者约5ng/mL的平均Cmax。 [0151] When the formulation comprises about 5mg, the controlled release component may be provided after repeated administration from about 3 to about 7ng / mL, or about the average Cmax 5ng / mL of. 在单次给药后,AUC24可以为约40.2ng.hr/mL-约62.8ng *hr/mL,或者约43.2ng.hr/mL-约57.2ng.hr/mL,或者约46.7ng.hr/mL-约53.7ng.hr/mL。 After a single administration, AUC24 40.2ng.hr/mL- may be from about to about 62.8ng * hr / mL, or from about 43.2ng.hr/mL- about 57.2ng.hr/mL, or from about 46.7ng.hr/ mL- about 53.7ng.hr/mL.

[0152] 当所述制剂包含约IOmg时,所述控释组分在重复给药后可以提供约5-约15ng/mL或者约10ng/mL的平均Cmax。 [0152] When the formulation comprises about IOmg, the controlled release component may provide about 5 to about 15ng mean Cmax / mL or from about 10ng / mL after repeated administration. 在单次给药后,AUC24可以为约80.5ng.1ι;/ιΛ-约125.9ng *hr/mL,或者约86.6ng.hr/mL-约114.8ng.hr/mL,或者约93.7ng.hr/mL-约107.7ng.hr/ΠίΤ,η After a single administration, AUC24 may be from about 80.5ng.1ι; / ιΛ- about 125.9ng * hr / mL, or from about 86.6ng.hr/mL- about 114.8ng.hr/mL, or from about 93.7ng.hr / mL- about 107.7ng.hr/ΠίΤ,η

[0153] 当所述制剂包含约20mg时,所述控释组分在重复给药后可以提供约10-约30ng/mL或者约20ng/mL的平均Cmax。 [0153] When the formulation comprises about 20mg, the controlled release component may be provided after repeated administration of from about 10 to about 30ng / mL, or about the average Cmax 20ng / mL of. 在单次给药后,AUC24可以为约166.0ng.hr/mL-约259.3ng.hr/mL,或者约178.5ng.hr/mL-约236.6ng.hr/mL,或者约193.0ng.hr/mL-约222.0ng.hr/mL。 After a single administration, AUC24 may be from about 166.0ng.hr/mL- about 259.3ng.hr/mL, or from about 178.5ng.hr/mL- about 236.6ng.hr/mL, or from about 193.0ng.hr/ mL- about 222.0ng.hr/mL.

[0154] 当所述制剂包含约40mg时,所述控释组分在重复给药后可以提供约25-约55ng/mL或者约40ng/mL的平均Cmax。 [0154] When the formulation comprises about 40mg, the controlled release component may provide a mean Cmax of about 25 to about 55ng / mL or from about 40ng / mL after repeated administration. 在单次给药后,AUC24可以为约338.5ng.hr/mL-约528.9ng.hr/mL,或者约363.9ng.hr/mL-约482.3ng.hr/mL,或者约393.5ng.hr/mL-约452.7ng.hr/mL。 After a single administration, AUC24 may be from about 338.5ng.hr/mL- about 528.9ng.hr/mL, or from about 363.9ng.hr/mL- about 482.3ng.hr/mL, or from about 393.5ng.hr/ mL- about 452.7ng.hr/mL.

[0155] 当所述制剂包含约80mg时,所述控释组分在重复给药后可以提供约50-约110ng/mL或者约80ng/mL的平均Cmax。 [0155] When the formulation comprises about 80mg, the controlled release component may be provided after repeated administration of about 50 to about 110ng mean Cmax / mL or from about 80ng / mL to. 在单次给药后,AUC24可以为约868.4ng.hr/mL-约1356.9ng.hr/mL,或者约933.5ng.hr/mL-约1237.5ng.hr/mL,或者约1009.5ng.hr/mL-约1161.5ng.hr/mL。 After a single administration, AUC24 may be from about 868.4ng.hr/mL- about 1356.9ng.hr/mL, or from about 933.5ng.hr/mL- about 1237.5ng.hr/mL, or from about 1009.5ng.hr/ mL- about 1161.5ng.hr/mL.

[0156] 在某些实施方案中,Cniin可以在稳态条件中给药组分后约12-约18小时内出现。 [0156] In certain embodiments, Cniin can occur within about 12 to about 18 hours after administration at steady state conditions component. 在一些实施方案中,Cmin可以在所述制剂给药后约12、13、14、15、16、17、18、19或20小时出现。 In some embodiments, Cmin may appear about 12,13,14,15,16,17,18,19, or 20 hours after the administration of the preparation. 在一些实施方案中,Cmin可以在所述制剂给药后少于约10、9、8、7、6、5或4小时出现。 In some embodiments, Cmin may be less than about 10,9,8,7,6,5 or 4 hours after the administration of the preparation occurs. 在一些实施方案中,Cmin可以在所述制剂给药后大于约14、15、16、17、18、19或20小时出现。 In some embodiments, Cmin may be greater than about 14,15,16,17,18,19, or 20 hours after the administration of the preparation occurs. 在特定实施方案中,在给药后超过约12小时出现的Cniin可以在尚未被吸收入血流的制剂给药后长达约1、2、3或4小时出现。 In a particular embodiment, the more than about 12 hours after administration Cniin may occur up to about 3 or 4 hours after administration of the preparation appeared yet absorbed into the blood stream.

[0157] 在某些实施方案中,所述制剂可以具有重复给药后约10-约25小时,或者给药后约12、13、14、15、16、17、18、19 或20 小时的Tmin0 [0157] In certain embodiments, the formulation may have from about 10 to about 25 hours after repeated administration, or about 12,13,14,15,16,17,18,19, or 20 hours post-administration Tmin0

[0158] 在某些实施方案中,所述制剂可以具有重复给药后约13-约16小时、或者重复给药后约14小时的Tmin。 [0158] In certain embodiments, the formulation may have from about 13 to about 16 hours after repeated administration, or about 14 hours after repeated administration, Tmin.

[0159] 在一些实施方案中,所述制剂在重复给药后可以提供约0.5-约40ng/mL或者约4-约15ng/mL 的平均Cmin。 [0159] In some embodiments, the formulation may provide from about 0.5 to about 40ng / mL or from about 4 to about 15ng / mean Cmin mL after repeated administration.

[0160] 以50rpm在水中于37° C下在USP I型装置中测量时,所述制剂的溶出在2小时后释放约O-约20%的化合物或其盐,或者在4小时后释放约15-约60%的化合物或其盐,或者在6小时后释放约25-约80%的化合物或其盐,或者在8小时后释放约35-约85%的化合物或其盐,或者在10小时后释放约45-约95%的化合物或其盐,或者在12小时后释放约60-约100%的化合物或其盐。 [0160] In 50rpm when measured in water at 37 ° C for USP Type I apparatus in the dissolution release formulation of from about 20% to about O- or a salt thereof after 2 hours, from about or released after 4 hours about 60% compound 15 or salt thereof, is released after 6 hours, or from about 25 to about 80% of the compound or a salt thereof, or the compound is released from about 35 to about 85%, or a salt thereof after 8 hours, or 10 hours after the release of about 45 to about 95% of the compound or a salt thereof, or the compound is released from about 60 to about 100% after 12 hours, or a salt thereof.

[0161] 应当理解当在本文中公开制剂在另一组分之后开始释放时,这类术语表示所述制剂设计并旨在产生这样较晚开始的释放。 [0161] It should be understood that when formulations disclosed herein release begins after a further component, such term means that the formulation of such release is designed and intended to produce a late start. 然而,本领域知道,尽管有这样的设计和意图,但是可能出现化合物的一些“渗漏”。 However, the art know, in spite of such design and intent, but some "leakage" of the compound may occur. 这样的“渗漏”不是如本文所用的“释放”。 Such "leakage" is not as used herein, a "release."

[0162] 在具体实施方案中,所述药物制剂可以包含一种或多种组分,所述一种或多种组分包含2:1、2:2、2:3、2:5、3:1或3:4重量比的两种阿片样物质化合物。 [0162] In a particular embodiment, the pharmaceutical formulation may comprise one or more components, comprising one or more components of said 2: 1,2: 2,2: 3,2: 5,3 : 3 or 1: 4 weight ratio of two kinds of opioid compound. 在某些实施方案中,所述组分可以包含约3:2重量比的吗啡和羟考酮。 In certain embodiments, the components may comprise from about 3: 2 by weight of morphine and oxycodone ratio.

[0163] 例如,所述药物制剂可以包含控释组分和即释组分,所述控释组分包含吗啡和羟考酮的混合物,所述即释组分包含羟考酮。 [0163] For example, the pharmaceutical preparations can contain a controlled release component and an immediate release component, said release component comprises a mixture of morphine and oxycodone, the immediate release component comprises oxycodone. 在一些实施方案中,即释组分中的羟考酮的Tmax可以为摄取后约10分钟至约I小时。 In some embodiments, the immediate release component Tmax of oxycodone after ingestion may be from about 10 minutes to about I hour. 在其他实施方案中,Tfflax为约10分钟至约30分钟或45分钟。 In other embodiments, Tfflax is about 10 minutes to about 30 minutes, or 45 minutes. 控释组分可以以较慢的速率在较长的时间中释放。 The controlled release component may be released at a slower rate over a longer time. 例如,在一些实施方案中,控释组分可以在12小时中释放有效量的吗啡和羟考酮的混合物。 For example, in some embodiments, the controlled release component may release an effective amount of a mixture of morphine and oxycodone 12 hours. 在其他实施方案中,控释组分可以在4小时中或8小时中释放有效量的吗啡和羟考酮。 In other embodiments, the controlled release component may be released or 8 hours in an effective amount of morphine and oxycodone for 4 hours. 在其他实施方案中,控释组分可以在15、18、24或30小时中释放有效量的吗啡和羟考酮。 In other embodiments, the controlled release component may release an effective amount of morphine and oxycodone 15,18,24 or 30 hours.

[0164] 在一些实施方案中,较晚释放的活性物质可以从药物制剂脉冲释放,从而化合物的脉冲在摄取该制剂后间隔释放。 [0164] In some embodiments, a later release of the active substance may be released from the pharmaceutical preparation pulse to pulse interval compound release following ingestion of the formulation. 例如,在某些实施方案中,控释组分可以在摄取后约0.5-1小时释放第一脉冲的较晚释放的活性物质,然后在摄取后约4小时后释放第二脉冲,并且在摄取后约8小时后释放药物的第三脉冲。 For example, in certain embodiments, the controlled release component may be released about 0.5 hours after ingestion of the active substance release of the first pulse later, a second pulse is then released after about 4 hours after ingestion, and ingestion drug release after about 8 hours after the third pulse.

[0165] 制剂制备 [0165] Preparation of Formulation

[0166] 在一方面,所述药物组合物是用于口服给药的片剂和胶囊。 [0166] In one aspect, the pharmaceutical composition is for oral administration, tablets and capsules. 这些片剂或胶囊可以包含常规赋形剂如粘合剂、填充剂、润滑剂、崩解剂或湿润剂。 The tablets or capsules may contain conventional excipients such as binders, fillers, lubricants, disintegrants or wetting agents. 在一方面,根据本领域公知的方法将片剂或胶囊包衣。 In one aspect, according to methods known in the art coated tablets or capsules.

[0167] 最佳地,用于这个目的的造粒在压实期间是高度可变形的,从而尽可能最小化指定的释放时间之前来自包衣团粒的任何渗漏。 [0167] Most preferably, granulated for this purpose during the compaction is highly deformable, so that any leakage from the coated pellets prior to minimize the possible release time specified. 在一实施方案中,可以期望具有短暂滞后,或者初始突发延迟,或者在所述制剂的即释团部分中释放羟考酮。 In one embodiment, it is desirable to have a short lag, or delay the initial burst, release or immediate release oxycodone formulations of the moiety. 在一些实施方案中,片剂重量少于约500mg、约450mg、约400mg、约350mg、约300mg、约250mg、约200mg、约150mg、约lOOmg、约50mg、约25mg或约10mg,并且药物负荷是制剂的约20%、约15%、约10%、约5%(w/w)或更少。 In some embodiments, the tablet weight is less than about 500mg, about 450mg, about 400mg, about 350mg, about 300mg, about 250mg, about 200mg, about 150mg, about lOOmg, about 50mg, about 25mg or about 10mg, and drug loading about 20% of the formulation, about 15%, about 10%, about 5% (w / w) or less. 在一实施方案中,目的是具有尽可能高效的片剂大小,同时提供片剂中的团粒的良好均匀性和完整性。 In one embodiment, the object is a tablet having a size as efficient as possible, while providing good uniformity and integrity of the pellet tablet.

[0168] 用于本发明的片剂的崩解剂没有特别限制,只要其是用于药物制品的崩解剂。 [0168] Disintegrants are used in tablets of the present invention is not particularly limited as long as it is a pharmaceutical preparation disintegrants. 实例可以包括交聚维酮、晶态纤维素、具有低取代度的羟丙基纤维素、交联羧甲基纤维素钠、羧甲基纤维素钙、羧基淀粉钠、羧甲基淀粉钠、马铃薯淀粉、小麦淀粉、玉米淀粉、大米淀粉、部分预胶化淀粉以及羟丙基淀粉。 Examples may include crospovidone, crystalline cellulose, hydroxypropyl cellulose having a low degree of substitution, croscarmellose sodium, carboxymethyl cellulose calcium, carboxy starch sodium, sodium carboxymethyl starch, potato starch, wheat starch, corn starch, rice starch, partially pregelatinized starch, and hydroxypropyl starch. 可以使用这些崩解剂中的一种或两种或更多种。 These disintegrants may be used one or two or more kinds. 特别优选交聚维酮。 Particularly preferred crospovidone. 用于包衣本发明的颗粒的崩解剂的种类可以与颗粒内所用的相同或不同。 Kind of disintegrant particles for coating of the present invention may be used within the particles the same or different.

[0169] 用于本发明的片剂的药学可接受的添加剂的实例可以包括赋形剂、润滑剂、pH调节剂、遮味剂、甜味剂、酸化剂、制冷剂、起泡剂、防腐剂、流化剂、抗氧化剂、着色剂、稳定剂、表面活性剂、缓冲剂、香料、粘合剂以及药物增溶剂。 [0169] Examples of a pharmaceutically acceptable tablet of the invention may include excipients additives, lubricants, pH adjusting agents, taste masking agents, sweetening agents, acidifying agents, refrigerants, foaming agents, corrosion agents, flow agents, antioxidants, coloring agents, stabilizers, surfactants, buffers, perfumes, solubilizing the drug and adhesive. 本领域技术人员可以立即列出这些添加剂的具体实例。 Those skilled in the art can list specific examples of these additives immediately.

[0170] 这些添加剂可以适当地配制在颗粒内、在用崩解剂包衣的颗粒外、在崩解剂的包衣中以及在所有这些中,只要它们不损害本发明的优点。 [0170] These additives may be suitably formulated in granules coated with extragranular disintegrant, the disintegrant in the coating and in all of these, as long as they do not impair the advantages of the present invention.

[0171] 用于药物制品的任何润滑剂可以无限制地使用。 [0171] Lubricants used in any pharmaceutical preparation may be used without limitation. 用于本发明的片剂的润滑剂的实例可以包括轻质无水硅酸、硬脂酸镁、硬脂酸、硬脂酸钙、硬脂酸铝、单硬脂酸铝、蔗糖脂肪酸酯、聚乙二醇、硬脂酰醇富马酸钠、十八烷醇、滑石、二氧化钛、含水二氧化硅、硅酸镁、合成硅酸铝、磷酸氢钙、硬化蓖麻油、硬化菜籽油、巴西棕榈蜡、蜂蜡、微晶蜡以及十二烷基硫酸钠。 Examples of tablets of the invention may include lubricants light anhydrous silicic acid, magnesium stearate, stearic acid, calcium stearate, aluminum stearate, aluminum monostearate, sucrose fatty acid esters , polyethylene glycol, sodium stearyl fumarate, stearyl alcohol, talc, titanium dioxide, hydrated silicon dioxide, magnesium silicate, synthetic aluminum silicate, calcium hydrogenphosphate, hydrogenated castor oil, hydrogenated rapeseed oil , carnauba wax, beeswax, microcrystalline wax, and sodium lauryl sulfate. 可以使用这些润滑剂中的一种或两种或更多种。 These lubricants may be used one or two or more kinds. 在这些润滑剂中,优选使用选自轻质无水硅酸和硬脂酸镁的一种或多种润滑剂。 Among these lubricants, preferably one or more lubricants are selected from light anhydrous silicic acid and magnesium stearate. 特别地,优选包含在颗粒内的硅酸酐和包含在颗粒外的硬脂酸镁的组合。 In particular, the composition preferably comprises silicon in the acid anhydride and magnesium stearate particles comprising particles outside.

[0172] 当所述制剂为片剂形式时,片剂的形状没有特定限制,只要其可以利用普通制备装置或具有一些修改的制备装置毫无困难地制备。 [0172] When the formulation is in tablet form, the tablet shape is not particularly limited, as long as it can Preparation device prepared using a common or with some modifications of the device without difficulty. 片剂的一般概念的圆片形可以认为是典型实例。 The disc-shaped tablets generally the concept may be considered as typical example. 整个大小没有特别限制。 The entire size is not particularly limited. 例如,较短的直径(圆片片剂的直径)适合在6-20mm的范围中,优选8-12mm。 For example, the shorter diameter (wafer tablets) suitable range 6-20mm, preferably 8-12mm. 厚度也没有特别限制,但是适合为l-lOmm,优选2_8mm。 The thickness is not particularly limited, but is suitably l-lOmm, preferably 2_8mm.

[0173] 在一些实施方案中,可以期望具有初始的短延迟,这通过将还用作遮味剂的延迟释放包衣加入片剂来完成。 [0173] In some embodiments, it may be desirable to have an initial short delay, this is done by the delayed release coating is also used as taste masking agent added to the tablets. 如果期望,这种包衣可以是白色或有色或透明或不透明的。 If desired, this coating can be white or colored, or transparent or opaque. 如果期望,识别NDC码(美国)或相似的识别码也可以印在片剂上。 If desired, the identification code NDC (USA) or similar identifier may be printed on the tablet.

[0174] 用于本发明的片剂的化合物可以用薄膜包衣剂、赋形剂、粘合剂、润滑剂等包衣,这取决于其特性,并且可以加入增塑剂。 [0174] Tablets for compounds of the present invention may be coated with a film agent, excipient, binders, lubricants and other coatings, depending on its properties, and a plasticizer may be added.

[0175] 抗滥用特性 [0175] abuse resistant properties

[0176] 在本发明的另一方面,本文所述的药物组合物具有可用于阻止它们用于产生可能用于非医疗用途的组合物或者作为滥用药物的特性。 [0176] In another aspect of the present invention, the pharmaceutical compositions described herein may be used to prevent them from having to produce a composition may be used for non-medical purposes or as a characteristic of drugs of abuse.

[0177] 有意或无意干预(tamper)延长释放制剂会迅速递送大剂量(将缓释产物转化为即释形式的结果)并产生深远的各种严重和危及生命的副作用,包括呼吸抑制和衰竭、镇静、心血管虚脱、昏迷和死亡。 [0177] intentional or unintentional interference (Tamper) extended release formulation will rapidly deliver large doses (results of the product was converted into a sustained release form of immediate release) and have a profound and life-threatening severe various side effects, including respiratory depression and failure, sedation, cardiovascular collapse, coma and death.

[0178] 成瘾者和休闲吸毒者通常通过各种给药途径使用延长释放的阿片样物质。 [0178] addicts and drug abusers leisure usually extended release opioid by various routes of administration. 常用方法包括(a)肠胃外(例如,静脉内注射)、(b)鼻内(例如,吸食)和(C)间断性或重复口服摄取完整或压碎的片剂或胶囊。 Common methods include (a) parenterally (e.g., intravenously), (B) intranasal (e.g., smoking), and (C) or repeated intermittent complete oral ingestion or crushed tablets or capsules.

[0179] 滥用的一种模式包括从组分提取阿片样物质,这是通过首先将片剂或胶囊与合适的溶剂(例如,水或醇)混合,然后过滤和/或从混合物提取阿片样物质组分用于静脉内注射。 [0179] A mode of abuse of the opioid comprises extracting from the component, this is accomplished by first the tablets or capsules with a suitable solvent (e.g., water or alcohol) were mixed, followed by filtration and / or extraction of the opioid from the mixture component for intravenous injection. 滥用延长释放的阿片样物质的另一种模式包括将药物溶于水、醇或另一“休闲溶剂”以加速其释放并口服摄取内容物,以便提供高峰浓度和最大欣快效果。 Another mode of abuse of extended release opioid comprising the drug dissolved in water, alcohol or other "leisure solvent" to accelerate release oral ingestion and the contents, in order to provide the maximum peak concentration and the euphoric effect.

[0180] 术语“干预”表示通过机械、热和/或化学方式的任何操作,其改变组分的物理特性,例如,如果为缓释形式,将阿片样物质释出用于即释,或者使得阿片样物质激动剂可用于不当用途,如通过可选途径给药,如肠胃外给药。 [0180] The term "interference" means the operation by any mechanical, thermal and / or chemical means which changes the physical properties of the constituents, for example, if a sustained release form of the opioid is released for immediate release, or that opioid agonist available for inappropriate use such as administration by alternative routes, such as parenteral administration. 干预可以例如通过压碎、剪切、研磨、机械提取、溶剂提取、溶剂浸泡、燃烧、加热或它们的任何组合。 Intervention can, for example, by crushing, shearing, grinding, mechanical extraction, solvent extraction, solvent soak, burning, heating or any combination thereof.

[0181] 在本发明的上下文中,术语“滥用”、“阿片样物质激动剂滥用”或“阿片样物质滥用”在指引起这样的阿片样物质激动剂的效果时包括单独或联合其他药物间歇使用、休闲使用和长期使用阿片样物质激动剂:(i)以不符合标准医疗实践的量或者通过不符合标准医疗实践的方法和途径;(ii)在合格的医疗专业人士提供的使用的具体说明书的范围之外在合格的医疗专业人士的监督之外;(iv)在药物的合法制造商提供的批准的适当使用的说明书之外;(V)不在作为药剂用于医疗用途的具体批准的组分中;(vi)有强烈的愿望并努力获得;(vii)有强迫性使用的证据;(viii)通过操纵医疗系统获得,包括伪造医疗史、症状强度、疾病严重程度、患者身份、医生购物、处方伪造;(ix)受损的使用控制;(x)不管伤害;(xi)通过从非医疗来源采购;(xii)通过销售或者通过个体 [0181] In the present context, the term "abuse", "abuse the opioid agonist" or "opioid abuse" refers to cause such effect upon opioid agonists include, alone or in combination with other drugs intermittently specific (ii) the use of qualified medical professionals provided; (i) the amount does not meet the standards of medical practice or by ways and means do not meet the standards of medical practice: use, leisure use and long-term use of opioid agonists outside the scope of the specification beyond the supervision of qualified medical professionals; outside the specification of the appropriate use and (iv) provide legitimate manufacturers of drugs approved; (V) the specific approval of the drug for medical use is not as a components; (vi) have a strong desire and efforts to obtain; (vii) there is evidence of compulsive use; (viii) obtained by manipulating the health care system, including fake medical history, symptom intensity, severity of disease, patient identification, doctors shopping, prescription forgery; (ix) the use of damaged control; (x) regardless of injury; (xi) by purchasing from non-medical sources; (xii) by selling or by individual 移入非医疗供应链;(xiii)医疗未批准或不期望的情绪改变目的。 Into non-medical supply chain; (xiii) Medical unauthorized or unwanted mood changes purposes.

[0182]术语“抗滥用”、“滥用阻止”和“阻止滥用”在本发明的上下文中可交换使用,并且包括这样的药物组合物和方法:(i)抵抗、阻止、劝阻、减少、延迟和/或阻挠有意、无意或偶然物理操纵或干预组分(例如,压碎,剪切,研磨,咀嚼,溶出,熔解,针穿刺,吸入,吹入,通过机械、热和化学方法提取和/或过滤);(ii)抵抗、阻止、劝阻、减少、延迟和/或阻挠在合格的医疗专业人士提供的使用的具体说明书的范围之外、在合格的医疗专业人士的监督之外以及在药物的合法制造商提供的批准的适当使用的说明书之外有意、无意或偶然使用或滥用组分(例如,静脉内使用、鼻内使用、吸入使用和口服摄取以提供高峰浓度) [0182] The term "anti-abuse", "prevent abuse" and "prevent abuse" are used interchangeably in the context of the invention, and includes pharmaceutical compositions and methods: (i) resistance, prevent, discourage, reduced, delayed and / or intentional obstruction, inadvertent or accidental intervention or physical manipulation components (e.g., crushing, shearing, grinding, chewing, dissolution, melting, needle aspiration, inhalation, insufflation, extracted by mechanical, thermal and chemical methods, and / or filtration); (II) resistance, prevent, discourage, to reduce, delay and / or obstruction outside the scope of the detailed description of the use of qualified health care professionals, and in addition to the supervision of qualified medical professional, and a medicament appropriate use instructions approved legitimate manufacturer than intentional, unintentional or accidental use or misuse of the components (e.g., the use of intravenous, intranasal, inhalation and oral ingestion to provide the use of the peak concentration)

抵抗、阻止、劝阻、减少、延迟和/或阻挠有意、无意或偶然将本发明的延长释放组分转化为更即时释放的形式;(iv)抵抗、阻止、劝阻、减少、延迟和/或阻挠休闲吸毒者、成瘾者和具有成瘾病症的疼痛患者寻求生理和心理效果的有意或医源性增加;(V)抵抗、阻止、劝阻、减少、延迟和/或阻挠尝试偷偷将组分给予第三方(例如,在饮料中);(vi)抵抗、阻止、劝阻、减少、延迟和/或阻挠尝试通过操纵医疗系统和从非医疗来源获得组分;(vii)抵抗、阻止、劝阻、减少、延迟和/或阻挠组分销售或转移入非医疗供应链以及用于医疗未批准或不期望的情绪改变目的;(viii)抵抗、阻止、劝阻、减少、延迟和/或阻挠有意、无意或偶然尝试以其他方式改变制造商期望的组分的物理、药学、药理学和/或医学特性。 Resistance, prevent, discourage, to reduce, delay and / or intentional obstruction, inadvertent or accidental convert extended release component of the present invention is more immediate release form; (iv) resistance, prevent, discourage, to reduce, delay and / or obstruction casual drug users, addicts and pain in patients with addictive disorders seek physical and psychological effects of intentionally or iatrogenic increase; (V) resistance, prevent, discourage and reduce, delay and / or thwart attempts to smuggle components are administered a third party (e.g., a beverage); (VI) resistance, prevent, discourage, to reduce, delay and / or hinder attempts to acquire components from non-medical sources by manipulating medical systems and; (VII) resistance, prevent, discourage, to reduce , delay and / or sold or transferred to obstruct component supply chain as well as for non-medical or medical unapproved undesired object mood changes; (VIII) resistance, prevent, discourage, to reduce, delay and / or obstruction intentionally, or unintentionally occasionally otherwise attempt to alter the physical component desired by the manufacturer, pharmaceutical, pharmacological, and / or medical characteristics.

[0183] 当干预药物制剂的组分时,药物制剂减少以即释形式释放的阿片样物质激动剂的量,这又减少组分的阿片样物质的欣快、愉快、强化、奖励、情绪改变和有毒效果。 [0183] When the interference components of the pharmaceutical formulation, the pharmaceutical formulation reduces the amount of substance release opioid agonist in immediate release form, which in turn reduces the euphoric opioid component, happy, strengthen, reward, emotional changes and toxic effects.

[0184] 在具体实施方案中,如果干预,使用某些赋形剂如聚乙烯吡咯烷酮(Kollidon30)或聚氧乙烯35蓖麻油(Cremophor EL™)或十二烷基硫酸钠产生不可用的胶状物质。 [0184] In a particular embodiment, if the intervention, the use of certain excipients such as polyvinyl pyrrolidone (Kollidon30) or polyoxyethylene 35 castor oil (Cremophor EL ™) or sodium lauryl sulfate produced unusable gum substance. 添加水性或水醇溶剂会使得粉碎的赋形剂和药物混合物变为胶状物质,这对阿片样物质的轻易提取造成困难。 Adding water or an aqueous alcoholic solvent causes the pulverized pharmaceutical excipients and the mixture became gelatinous material, which easily causes difficulties in the extraction of the opioid. 混合甲基丙烯酸聚合物和纤维素聚合物的乳浮是引起本发明的这种特征的主要成分的实例。 Cremophor mixing methacrylic acid polymers and cellulose polymers are examples of causes of such features of the present invention is a main component.

[0185] 产生抗滥用的阿片样物质组合物的其他方法在美国公开专利申请US20090082466中提供,其教导整体援引加入本文。 [0185] Other methods to produce abuse resistant opioid compositions is provided in U.S. Patent Application Publication US20090082466, the entire teachings of which are incorporated herein by reference.

[0186] 制剂给药 [0186] The preparation of administration

[0187] 本发明的一方面是一种用于治疗疼痛的方法,所述方法包括给药本文所述的制剂。 In one aspect [0187] of the present invention is a method for treating pain, said method comprising administering the formulation described herein.

[0188] 所述制剂可以例如通过任何以下给药途径给药:舌下、口腔、经粘膜、透皮、肠胃外、口服等。 [0188] The formulation may, for example, any of the following routes of administration: Sublingual, buccal, transmucosal, transdermal, parenteral, oral and the like. 在某些实施方案中,所述制剂可以以适合口服给药的方式制备。 In certain embodiments, the formulations may be prepared in a manner suitable for oral administration. 因此,例如,对于口服给药,每种组分可以用作团粒、颗粒、粉末、液体或粒子,然后其形成单一药物产品,例如,在胶囊中,或者包埋于片剂中,或者悬浮于液体中用于口服给药。 Thus, for example, for oral administration, each component may be used as pellets, granules, powders, liquids or particles, which then form a single pharmaceutical product, for example, in a capsule, tablet, or embedded in, or suspended in liquids for oral administration. 如本文所用,术语“制剂”还指包含至少一种组分的单一药物产品。 As used herein, the term "formulation" also refers to a pharmaceutical product comprising at least one single component.

[0189] 在某些实施方案中,所述制剂用于口服给药,并且可以为片剂或胶囊形式或者为多单位组分形式。 [0189] In certain embodiments, the formulations for oral administration, and may be in the form of tablets or capsules or in the form of a multi-component unit. 所述制剂可以适合每天口服给药1-6次,通常每天1-4次,如每天1-3次、2次,或者每天一次。 The formulations may be adapted for oral administration 1-6 times a day, usually 1 to 4 times a day, 1-3 times a day, 2 times, or once a day. 在本文的上下文中,术语“每天一次”旨在表示仅必需将药物组合物每天给药一次,以便获得有效治疗量的化合物以提供合适的治疗应答。 In the present context the term "once daily" is intended to mean only necessary to compound the pharmaceutical composition is administered once a day, in order to obtain an effective therapeutic amount to provide the appropriate therapeutic response.

[0190] 通过所述制剂的给药提供的化合物的最终剂量以重量计可以为约100!^、约95mg、约90mg、约85mg、约80mg、约75mg、约70mg、约65mg、约60mg、约55mg、约50mg、约45mg、约40mg、约35mg、约30mg、约25mg、约20mg、约15mg、约12mg、约10mg、约8mg、约5mg、约4,mg、约3mg、约2mg 或约Img。 [0190] The final dose of a compound provided by the administration of the formulation by weight may be from about 100! ^, About 95mg, about 90mg, about 85 mg of, about 80mg, about 75mg, about 70mg, about 65mg, about 60mg, about 55mg, about 50mg, about 45mg, about 40mg, about 35mg, about 30mg, about 25mg, about 20mg, about 15mg, about 12mg, about 10mg, about 8mg, about 5mg, about 4, mg, about 3mg, about 2mg, or about Img.

[0191] 阿片样物质化合物的剂量取决于特定物质,用组合物治疗的人或动物的年龄、体重条件等。 [0191] dose of opioid compound depends on the particular substance, the age composition for the treatment of a human or animal, body weight and other conditions. 所有这些因素是本领域技术人员公知的。 All of these factors are known to those skilled in the art.

[0192] 实施例. [0192] Example.

[0193] 参考以下实施例可以更容易地理解本发明,实施例通过说明的方式提供而不是为了限制本发明。 [0193] reference to the following embodiments may be more readily understood from the present invention, an embodiment by way of illustration and not to limit the invention.

[0194] 实施例1:阿片样物质组分 Opioid components: one case of [0194] Embodiment

[0195] 开发用于药物制剂的组分,如表1-8所示。 [0195] Component development for a pharmaceutical formulation, as shown in Table 1-8.

[0196] 表1:靶组分1(羟考酮): [0196] Table 1: Target Component 1 (oxycodone):

[0197] [0197]

Figure CN103476403AD00241

[0198] 1每片的量,基于分散物的固体含量 Amount [0198] of each piece 1, based on the solids content of the dispersion is

[0199] 2加工期间去除 Removing the [0199] 2 during processing

[0200] 表2:靶组分I (吗啡): [0200] Table 2: Target Component I (morphine):

[0201] [0201]

Figure CN103476403AD00242

[0202] 1每片的量,基于分散物的固体含量[0203] 2加工期间去除 [0202] 1 per sheet, during [0203] 2 processing based on the solids content of the dispersion is removed

[0204] 表3:靶组分2(羟考酮): [0204] Table 3: Target Component 2 (oxycodone):

[0205] [0205]

Figure CN103476403AD00251

[0206] 1每片的量,基于分散物的固体含量 Amount [0206] of each piece 1, based on the solids content of the dispersion is

[0207] 2加工期间去除 Removing the [0207] 2 during processing

[0208] 表4:靶组分2(吗啡): [0208] Table 4: Target Component 2 (morphine):

[0209] [0209]

Figure CN103476403AD00252

[0210] 1每片的量,基于分散物的固体含量 Amount [0210] of each piece 1, based on the solids content of the dispersion is

[0211] 2加工期间去除 Removing the [0211] 2 during processing

[0212] 表5:靶组分3(羟考酮): [0212] Table 5: Target Component 3 (oxycodone):

[0213] [0213]

Figure CN103476403AD00261

[0214] 1每片的量,基于分散物的固体含量 Amount [0214] of each piece 1, based on the solids content of the dispersion is

[0215] 2加工期间去除 Removing the [0215] 2 during processing

[0216] 表6:靶组分3(吗啡): [0216] Table 6: Target Component 3 (morphine):

[0217] [0217]

Figure CN103476403AD00271

[0218] 1每片的量,基于分散物的固体含量 Amount [0218] of each piece 1, based on the solids content of the dispersion is

[0219] 2加工期间去除 Removing the [0219] 2 during processing

[0220] 表7:靶组分4(羟考酮): [0220] TABLE 7: 4 Target Component (oxycodone):

Figure CN103476403AD00272

[0222] 1每片的量,基于分散物的固体含量 Amount [0222] of each piece 1, based on the solids content of the dispersion is

[0223] 2加工期间去除[0224] 表8:靶组分4(吗啡): Removing the [0223] 2 during processing [0224] Table 8: Component Target 4 (morphine):

[0225] [0225]

Figure CN103476403AD00281

[0226] 1每片的量,基于分散物的固体含量 Amount [0226] of each piece 1, based on the solids content of the dispersion is

[0227] 2加工期间去除 Removing the [0227] 2 during processing

[0228] 实施例2:阿片样物质制剂的药物动力学特征谱 [0228] Example 2: pharmacokinetic characteristics opioid formulation Spectrum

[0229] A.提供具有以下药物动力学特征谱的羟考酮制剂。 [0229] A. provide oxycodone formulation has the following pharmacokinetic profile spectrum. 利用图7-11所示的图中所述的方法通过调整赋形剂的浓度来获得药物动力学特征谱。 7-11 using the diagram shown in FIG method by adjusting the concentration of the excipient to obtain pharmacokinetic profiles of. 这种8mg羟考酮制剂具有8小时的Cmax和14小时的Cmin。 This formulation has 8mg oxycodone 8 hours and 14 hours Cmax Cmin.

[0230] B.提供具有以下药物动力学特征谱的羟考酮制剂。 [0230] B. oxycodone formulations providing a pharmacokinetic profile the spectrum. 利用图7-11所示的图中所述的方法通过调整阿片样物质化合物和赋形剂的浓度来获得药物动力学特征谱。 7-11 using the diagram shown in FIG method by adjusting the concentration of the opioid compound and excipients to obtain pharmacokinetic profiles of. 这种8mg羟考酮制剂具有6小时的Cmax和16小时的Cmin。 This formulation has 8mg oxycodone of 6 hours and 16-hour Cmax Cmin.

[0231] C.提供具有以下药物动力学特征谱的双阿片样物质羟考酮/吗啡制剂。 [0231] C. to provide a dual opioid oxycodone / morphine preparation the following pharmacokinetic profile spectrum. 利用图7-11所示的图中所述的方法通过调整阿片样物质化合物和赋形剂的浓度来获得药物动力学特征谱。 7-11 using the diagram shown in FIG method by adjusting the concentration of the opioid compound and excipients to obtain pharmacokinetic profiles of. 这种8mg羟考酮/4mg吗啡制剂具有两种阿片样物质的6_20小时的Cmax,以及两种阿片样物质的15-26小时的Cniint5 6_20 hour Cmax oxycodone this 8mg / 4mg morphine preparation having two opioids, and 15-26 hours of two opioids Cniint5

[0232] D.提供具有以下药物动力学特征谱的双阿片样物质羟考酮/吗啡制剂。 [0232] D. providing a dual opioid oxycodone / morphine preparation kinetics following drugs spectrum. 利用图7-11所示的图中所述的方法通过调整阿片样物质化合物和赋形剂的浓度来获得药物动力学特征谱。 7-11 using the diagram shown in FIG method by adjusting the concentration of the opioid compound and excipients to obtain pharmacokinetic profiles of. 这种18mg吗啡/12mg羟考酮制剂具有6小时的Cmax和16小时的Cmin。 Such morphine 18mg / 12mg oxycodone formulation of 6 hours and 16-hour Cmax Cmin.

[0233] 实施例3:制备延长释放中间团粒制剂 [0233] Example 3: Preparation of extended release pellet formulations intermediate

[0234] 制备具有如表9和10所示组成的延长释放中间团粒制剂A和B。 [0234] Preparation as in Table 9 and 10 having the extended release pellet formulations A and B. The intermediate compositions shown in

[0235]表 9:制剂A: [0235] Table 9: Formulation A:

[0236] [0236]

Figure CN103476403AD00291

[0237] *USP=美国药典;NF=国家处方集 [0237] * USP = United States Pharmacopeia; NF = National Formulary

[0238]表 10:制剂B: [0238] Table 10: Formulation B:

[0239] [0239]

Figure CN103476403AD00301

[0240] *USP=美国药典;NF=国家处方集 [0240] * USP = United States Pharmacopeia; NF = National Formulary

[0241] 混合制剂的制备过程在图12的流程图中说明。 [0241] Preparation of a mixed formulation process described in the flowchart of FIG. 12. 为了制备所述制剂,将盐酸羟考酮、微晶纤维素和聚乙烯吡咯烷酮(Kollidon30)通过#20目筛单独手工筛入收集容器。 For the formulation preparation, oxycodone hydrochloride, microcrystalline cellulose and polyvinyl pyrrolidone (Kollidon30) through a # 20 mesh hand sieve into a separate collection vessel. 将筛过的混合物转移入高剪切造粒机的造粒碗并干混3分钟。 The sieved granulation was transferred into the bowl of a high shear granulator and dry blended for 3 minutes.

[0242] 将与聚氧乙烯35蓖麻油混合的包含净化水的造粒溶液以恒定速率喷洒入造粒碗,以低速叶轮或低速斩波设置混合。 [0242] The polyoxyethylene 35 castor oil and mixing the granulating solution comprising purified water is sprayed at a constant rate into the granulation bowl at a low speed or a low speed impeller mixing chopper setting. 持续视觉评价所得的造粒混合物,并且在需要时将额外的净化水喷洒在团块上。 The resulting mixture was granulated sustained visual evaluation, and if necessary additional purified water is sprayed onto the agglomerates.

[0243] 然后利用挤出机和板滚圆机使造粒混合物进行挤出-滚圆过程。 [0243] Then an extruder spheronizer plate and the granulated mixture was subjected to extrusion - spheronization process. 将湿团块通过0.8mm筛均匀挤入marmurizing碗,在这里挤出物形成适当大小的团粒。 The wet mass was extruded through a 0.8mm sieve bowl marmurizing uniform extrudate form where pellets of appropriate size.

[0244] 利用流化床干燥造粒机将团粒干燥至< 3%的干燥失重(LOD)测试靶标。 [0244] a fluidized bed dryer granulator pellet was dried to <3% loss on drying (LOD) test target. 为了获得优选部分,将干燥的团粒通过#20和MO目大小的不锈钢筛筛入双层聚乙烯内衬纤维鼓用于储存直至团粒喷雾包衣。 In order to obtain the preferred portion of the pellet was dried and passed through a # 20 mesh size MO stainless steel sieve into fiber drums lined with double polyethylene pellets for storage until spray-coating.

[0245] 然后利用流化床干燥器使团粒进行喷雾包衣。 [0245] using a fluidized bed dryer and then spray-coated to make agglomerates. 在不锈钢容器中,利用气动螺旋桨混合器将包衣组分混合入异丙醇/水溶液至少I小时,直至得到澄清溶液。 In a stainless steel container, using a pneumatic propeller mixer into coated components were mixed isopropanol / water solution of at least I hour, until a clear solution was obtained. 在单独的不锈钢容器中,通过将肠溶包衣组分用气动混合器混合至少I小时直至得到澄清溶液来制备肠溶包衣溶液。 In a separate stainless steel vessel, the enteric coating solution was prepared by mixing the enteric coating component at least I hour pneumatic mixer until a clear solution was obtained. 将聚合物包衣溶液喷洒在团粒上,同时持续监测喷洒条件。 The polymer coating solution is sprayed onto the pellets while continuously monitoring the spraying conditions. 将完成的团粒放入双层聚乙烯内衬纤维鼓用于在加工(work-1n-process)中储存直至润滑。 The finished pellets into double polyethylene lined fiber drums until lubrication for storing processing (work-1n-process) in the.

[0246] 将润滑的团粒通过#18和#40目大小的不锈钢筛以获得优选部分,并且放入双层聚乙烯内衬纤维鼓用于储存直至片剂混合。 [0246] The lubricated through a stainless steel sieve pellet # 40 and # 18 mesh size to obtain a preferably partially, and placed in a double polyethylene lined fiber drums until the tablet hybrid storage.

[0247] 实施例4:制剂A和B的药物动力学测试 [0247] Example 4: Pharmacokinetics of the test formulations A and B

[0248] 方法 [0248] Method

[0249] 进行单剂量、三时期、三顺序、三处理交叉研究以比较口服给药如实施例3所述的制剂A或B或者参考制剂(与OxyContin® 20mg(轻考酮CR)共给药的MS Contin®30mg(吗啡CR))的人个体的羟考酮药物动力学特征谱。 [0249] a single dose, three period, three sequence, three crossover study orally treated as in Comparative Formulation Example 3 A or B, or the reference preparation (with OxyContin® 20mg (light oxycodone CR) co-administration oxycodone pharmacokinetic characteristics MS Contin®30mg (morphine CR)) of the spectrum of a human subject.

[0250] 每个个体参与一系列三时期,其中每个时期包含(i)给药前筛查和登记,(ii)制剂的给药,以及(iii)给药后样品收集和随访。 [0250] Each individual participating in a series of three periods, wherein each period comprises (i) pre-dose screening and enrollment administration (ii) of the formulation, and (iii) post-dose sample collection and follow-up. 个体在每个时期中接受不同制剂,并且随机划分以确定将制剂以哪种顺序给药。 Accept different formulation in each individual period, and randomly divided to determine in which order the formulation is administered.

[0251] 给药前筛查和登记包括个体生命征兆的身体检查和记录。 [0251] including registration and pre-dose screening physical examination and recording individual life signs. 将阿片样物质拮抗剂纳曲酮(50mg)在给药之前0.5小时给药。 The administration of naltrexone (50mg) 0.5 hours prior to administration of the opioid antagonist. 在制剂给药后10分钟以及0.5、1、2、3、4、5、5.5、6、 10 minutes after administration of the preparation and 0.5,1,2,3,4,5,5.5,6,

6.5、7、8、10、12、14、18、21、24、48 和72 小时后收集血液样品。 Blood samples were collected after 72 hours and 6.5,7,8,10,12,14,18,21,24,48.

[0252] 用串联质谱法(LC/MS/MS)通过液相色谱测量血液样品的血浆中的吗啡和羟考酮,证实涵盖以下范围: [0252] Measurement of the blood sample by tandem mass spectrometry (LC / MS / MS) in the plasma by liquid chromatography morphine and oxycodone, confirmed covers the following range:

[0253]吗啡 0.25-100ng/mL [0253] Morphine 0.25-100ng / mL

[0254]轻考丽 50-50,000pg/mL [0254] Light test Li 50-50,000pg / mL

[0255] 结果 [0255] results

[0256] 在样品采集时间点,羟考酮的平均血浆浓度如图13 (整个72小时)和图14(第一个24小时)所示。 [0256] In the sample collection time points, mean plasma concentrations of oxycodone 13 (the entire 72 hours) and 14 (first 24 hours) of FIG. 与参考制剂相比,制剂A在处理后5-16小时导致较高的羟考酮血浆水平,虽然此后血浆水平一般较低。 Compared to the reference formulation Formulation A at 5-16 hours post treatment resulted in a higher plasma level of oxycodone, though generally lower plasma levels thereafter. 另一方面,在处理后6小时并持续整个48小时,制剂B与参考制剂相比产生大约相同或更大的羟考酮血浆水平。 On the other hand, 6 hours after treatment and continued throughout the 48 hours of formulation B produce approximately the same or greater oxycodone plasma levels compared to the reference formulation. 在这段时间期间,制剂B提供的羟考酮血浆水平平均比参考制剂提供的血浆水平大30%。 30% greater plasma levels during this time, the plasma level of oxycodone formulations provided an average B than the reference formulation provided.

[0257] 这些数据用来呈现羟考酮血浆特征谱,这由给药多剂量的制剂B所致,如图15和16所示。 [0257] The data used to render the plasma profiles of oxycodone, which caused by multiple doses of the formulation B, 15 and 16 shown in FIG. 图15示出给药4个剂量的制剂B的羟考酮血浆特征谱,并且显示在这个剂量给药方案下,羟考酮血浆水平可以保持在约7-约20ng/mL。 Figure 15 shows plasma profiles oxycodone formulations administered four doses B spectrum, and displayed in this dosage regimen, oxycodone plasma levels may be maintained at about 7 to about 20ng / mL.

[0258] 图16示出可以由不同剂量给药强度所致的羟考酮血浆特征谱,并且集中在血浆水平达到稳态后多剂量方案的单剂量;稳态的特征在于多剂量血浆特征谱中一致的波峰和波谷。 [0258] FIG. 16 shows oxycodone plasma profile can be induced by different doses intensity spectrum, and concentrated in a single dose plasma levels reached a steady state after multiple dose regimen; characterized in that the steady-state plasma profiles of the multi-dose consistent peaks and troughs. 图16显示在稳态下,Cfflax会反映给药剂量的强度。 Figure 16 shows the steady state, Cfflax will reflect the intensity of the administered dose.

[0259] 图17和18示出多剂量的包含即释制剂(10%)和制剂B(90%)的复合物的制剂的羟考酮血浆特征谱的投影。 [0259] FIGS. 17 and plasma profiles of oxycodone formulations of the projection 18 is shown comprising multiple doses of immediate release formulation (10%) and Formulation B (90%) of the complex. 图17证实给药4个剂量的复合制剂的羟考酮血浆特征谱,并且显示在这个剂量给药方案下,羟考酮血浆水平可以保持在约10-约19ng/mL。 17 confirmed that the plasma oxycodone combination preparation administered dose profiles of 4, and displayed in this dosage regimen, oxycodone plasma levels may be maintained at from about 10 to about 19ng / mL.

[0260] 图18示出可以在不同剂量给药强度的复合制剂的给药后导致的羟考酮血浆特征谱。 [0260] FIG. 18 shows the plasma profiles of oxycodone may result in the combination preparation administration after administration of different doses strength. 图18集中在血浆水平达到稳态后多剂量方案的单剂量,稳态的特征在于多剂量血浆特征谱中一致的波峰和波谷。 FIG 18 concentrated in a single dose plasma levels reached a steady state after multiple dosage regimen, wherein the steady-state plasma profiles of multiple doses consistent peaks and troughs. 投影显示在稳态下,Cfflax小于给药剂量。 Projection display in a steady state, Cfflax less than dose.

[0261] 制剂A与参考制剂的羟考酮血浆特征谱的比较以及制剂B与参考制剂的羟考酮血浆特征谱的比较如表11和12所示。 [0261] oxycodone plasma profiles of Comparative Formulation A and Formulation B with the reference formulation and the reference formulation oxycodone plasma profiles of comparison shown in Table 11 and 12.

Figure CN103476403AD00321
Figure CN103476403AD00322

[0266] 虽然制剂A和B的AUCt低于参考制剂的AUCt,但是制剂A和B的AUCt分别在14%和7%之内。 [0266] Formulations A and B, although AUCt AUCt is lower than the reference formulation, but AUCt formulations A and B, respectively, 14% and 7% of. 而且,制剂A和B的Tmax均大于参考制剂的Tmax,这并非预期的。 Further, Tmax Formulations A and B were greater than Tmax of the reference formulation, this is not expected.

[0267] 实施例5:具有羟考酮-吗啡的控释混合物的羟考酮的即释组合物 [0267] Example 5: Oxycodone having - immediate release oxycodone controlled-release composition of the mixture of morphine

[0268] 根据制备片剂领域已知的标准方法制备口服固体口服组分片剂,其包含5.0mg盐酸羟考酮和5.0mg硫酸吗啡的核心作为活性成分以及季胺基甲基丙烯酸酯共聚物、羟丙甲纤维素、乳糖、硬脂酸镁、聚乙二醇400、聚乙烯吡咯烷酮、氢氧化钠、山梨酸、十八烷醇、滑石、二氧化钛和三醋精。 [0268] Tablets prepared according to standard methods known in the art the preparation of oral solid component oral tablet comprising a core 5.0mg 5.0mg oxycodone hydrochloride and morphine sulfate as active ingredient and a quaternary ammonio methacrylate copolymer , hypromellose, lactose, magnesium stearate, polyethylene glycol 400, polyvinyl pyrrolidone, sodium hydroxide, sorbic acid, stearyl alcohol, talc, titanium dioxide and triacetin. 将片剂的外部用控释制剂包衣,所述控释制剂包含IOmg盐酸羟考酮以及明胶、羟丙甲纤维素、玉米淀粉、聚乙二醇、聚山梨酯80、氧化铁红、二氧化硅、月桂基硫酸钠(dodium laurel sulfate)、鹿糖、二氧化钛和氧化铁黄。 The outer coating of tablets with controlled-release formulation, the controlled release formulation comprises oxycodone hydrochloride and IOmg gelatin, hydroxypropylmethyl cellulose, corn starch, polyethylene glycol, polysorbate 80, red iron oxide, titanium silicon oxide, sodium lauryl sulfate (dodium laurel sulfate), deer sugar, titanium dioxide and yellow iron oxide. 将所得片剂向患者给药用于缓解疼痛,并导致有效镇痛而不发生吗啡诱导的呼吸抑制。 The resulting tablets for administration to a patient to relieve pain, an effective analgesic morphine-induced and lead to respiratory depression without the risk.

[0269] 实施例6:制备控释制剂的一般方法 [0269] Example 6: Preparation of controlled-release formulations General Procedure

[0270] 以下制备描述通过实例的方式提供,用于包含硫酸吗啡和盐酸羟考酮的控释压缩片剂的制备。 [0270] Preparation of the following description provided by way of example, for controlled release comprising morphine sulfate and oxycodone hydrochloride prepared tablet compression.

[0271] 团粒核心的制备 Preparation of [0271] the pellet core

[0272] 将活性药物物质(硫酸吗啡和盐酸羟考酮)、微晶纤维素,USP和聚乙烯吡咯烷酮K30,NF分别通过#20目筛手工筛入收集容器。 [0272] The active drug substance (morphine sulfate and oxycodone HCl), microcrystalline cellulose, USP and polyvinylpyrrolidone K30, NF # 20 mesh hand respectively into the collection container through the sieve. 将筛过的混合物转入高剪切造粒机如PMA-25或PMA-65的造粒碗并干混3分钟。 The sieved mixture was transferred to a high shear granulator such as PMA-25 or PMA-65 granulation bowl and dry mixed for 3 minutes.

[0273] 将由以前混合的净化水,USP和聚氧乙烯35蓖麻油,NF的溶液组成的造粒溶液以恒定速率喷洒入造粒碗并以低速叶轮/低速斩波设置混合。 [0273] previously by mixing purified water, USP and polyoxyethylene 35 castor oil, NF solution consisting of granulating solution is sprayed at a constant rate into the bowl and granulated at a low speed impeller / chopper set low mixing. 在连续基础上视觉评价造粒结果,并且如果需要,将额外的净化水,USP喷洒在团块上。 Visual evaluation results granulated on a continuous basis, and, if needed, additional purified water, USP is sprayed onto the agglomerates. 在造粒期结束时,取出样品用于水含量的过程中测试。 At the end of granulation, the samples taken during the water content of the test.

[0274] 采样完成后,使造粒进入挤出滚圆过程,使用Luwa挤出机和板滚圆机或者等同物。 [0274] After sampling is complete, the granulated into the extrusion spheronization process, using an extruder and Luwa spheronizer plate or equivalent. 将湿团块通过0.8mm筛均匀挤入marmurizing碗,在这里挤出物形成适当大小的团粒。 The wet mass was extruded through a 0.8mm sieve bowl marmurizing uniform extrudate form where pellets of appropriate size.

[0275] 利用合适的过程参数用GPCG-3、GPCG-5或等同物进行团粒的流化床干燥至< 5%的干燥失重(LOD)测试靶标。 [0275] The fluidized-bed drying the pellet to be <5% loss on drying (LOD) test target with GPCG-3, GPCG-5 or equivalent using suitable process parameters. 将干燥的团粒通过#20和#40目大小的不锈钢筛筛入双层PE-内衬纤维鼓以获得优选部分用于在制品储存直至团粒喷雾包衣。 The dried pellets through a # 20 and # 40 size mesh sieve into a stainless steel double PE- lined fiber drum to obtain a pellet until the article storage portion for spray-coating is preferred.

[0276] 改进释放包衣球形颗粒的制备 [0276] Preparation of an improved release coated spherical granules

[0277] 利用气动螺旋桨混合器将季胺基甲基丙烯酸酯共聚物和柠檬酸三乙酯混合入不锈钢容器中所含的异丙醇/水溶液至少I小时直至获得澄清溶液。 [0277] means of a pneumatic propeller mixer ammonio methacrylate copolymer and triethyl citrate are mixed into a stainless steel container at least I hour contained in isopropanol / water until a clear solution was obtained. 然后将滑石加入容器,连续搅拌。 The talc was then added to the vessel, continuously stirred. 利用合适的过程参数用配有1.0mm喷嘴的GPCG-5Wurster进行核心团粒的流化床喷雾包衣。 Using suitable process parameters pellet core spray-coating fluidized bed equipped with a 1.0mm nozzle GPCG-5Wurster.

[0278] 肠溶包衣球形颗粒的制备 Preparation of enteric coated spherical granules [0278]

[0279] 在单独的容器中,通过在不锈钢容器中用气动混合器混合甲基丙烯酸共聚物和柠檬酸三乙酯至少I小时来制备肠溶包衣溶液。 [0279] In a separate vessel, I h enteric coating solution was prepared at least by a pneumatic mixer methacrylic acid copolymer and triethyl citrate in a stainless steel container with. 然后将滑石加入容器,连续搅拌。 The talc was then added to the vessel, continuously stirred. 将聚合物包衣溶液以恒定速率连续喷洒以完成在球形颗粒上,同时持续监测喷洒条件。 The polymer coating solution was sprayed continuously at a constant rate to complete on the spherical particles while continuously monitoring the spraying conditions. 将肠溶包衣球形颗粒放入双层聚乙烯内衬纤维鼓用于在制品储存直至润滑。 The enteric coated spherical granules into fiber drums lined with double polyethylene used in the article stored until lubrication.

[0280] 实施例7.控释制剂的溶出测试方法 Example 7. The controlled-release formulations Dissolution Test Method [0280] Embodiment

[0281] 溶出测试方法设计为与自动化溶出采样站(例如,Varian VK8000) 一起使用。 [0281] Dissolution test method is designed for use with automated sample dissolution station (e.g., Varian VK8000). 如果这样的仪器不可用,可以进行适当的调整以手工抽取样品。 If such equipment is not available, appropriate adjustments may be made manually extract samples.

[0282] 装置:USP〈711> 装置2(桨) [0282] Apparatus: USP <711> Apparatus 2 (paddle)

[0283] 自动化溶出采样站 [0283] Automation dissolution sampling station

[0284] 容器大小/类型:约1OOOmL/透明玻璃、圆底容器 [0284] container size / type: about 1OOOmL / transparent glass round bottom vessel

[0285] 旋转速度:始终约50rpm [0285] Rotation speed: always about 50rpm

[0286] 介质和体积: 0-2小时的阶段1 (酸阶段): [0286] Media and Volume: Stage 1 0-2 hours (acid phase):

[0287] 在37.0±0.5° C下750mL酸性溶出介质A保持2小时 [0287] at 37.0 ± 0.5 ° C 750mL acidic dissolution medium A 2 h

[0288] 2-11小时的阶段2 (缓冲阶段): [0288] Stage 2 2-11 hours (buffer stage):

[0289] 在37.0±0.5° C 下1OOOmL,通过将250mL 溶出介质 [0289] at 37.0 ± 0.5 ° C 1OOOmL, eluted by 250mL medium

[0290] B和20mL溶出介质A加入来自阶段I的容器中的介 [0290] B A medium and 20mL dissolution vessel from stage I was added in the medium

[0291] 质的剩余部分而产生。 [0291] The remaining portion of the generated quality. 阶段2介质应具有约6.8的pH。 Stage 2 medium should have a pH of about 6.8.

[0292]测试温度:约 37.0±0.5° C [0292] Test temperature: about 37.0 ± 0.5 ° C

[0293] 沉子: 篮沉子(0.46”χ0.80”)40目,316-SS金属丝布 [0293] sinker: basket sinker (0.46 "χ0.80") 40 mesh, 316-SS wire cloth

[0294] 抽取体积:约1OmL [0294] Extraction Volume: about 1OmL

[0295] 谱时间点:约1、2、3、4、6、9和11小时 [0295] Spectral time: about 11 hours and 1,2,3,4,6,9

[0296] 介质置换:无 [0296] Media Replacement: None

[0297] 采样: 自动化 [0297] Sampling: Automation

[0298] 滤器类型/大小:内嵌10-μ m聚乙烯全流量滤器 [0298] Filter Type / Size: 10-μ m polyethylene embedded full flow filter

[0299] 实施例8:控释阿片样物质制剂组合物[0300] 按照实施例6的方法,制备以下制剂: [0299] Example 8: preparation of a controlled release opioid compositions Matter [0300] The method of Example 6, the following formulation was prepared:

[0301] 表13:使用具有90/10的RS/RL比例的季胺基甲基丙烯酸酯共聚物的改进释放微粒制剂 [0301] Table 13: Use / improvement ammonio methacrylate copolymer RL ratio of quaternary release microparticle formulation with RS 90/10

[0302] [0302]

Figure CN103476403AD00341

[0303] 制备具有不同%包衣水平(例如25%、35%、45%、50%和55%)的季胺基甲基丙烯酸酯RS/RL聚合物的各种制剂。 Ammonio methacrylate RS [0303]% was prepared having different coating levels (e.g. 25%, 35%, 45%, 50% and 55%) / RL polymer in various formulations. 图19(a)和20 (a)分别提供硫酸吗啡和盐酸羟考酮的代表性溶出特征谱。 FIG 19 (a) and 20 (a) are provided morphine sulfate and oxycodone hydrochloride dissolution profiles of the representation.

[0304] 表14.使用吗啡/羟考酮肠溶包衣/改进释放微粒的片剂制剂。 [0304] Table 14. morphine / oxycodone enteric coating / tablet formulations to improve release microparticles.

[0305] [0305]

Figure CN103476403AD00342

[0306] 制备具有不同%肠溶包衣水平(例如,10%、15%、20%、25%、30%和40%)的各种片剂制剂。 [0306] Preparation of enteric coating levels having different% (e.g., 10%, 15%, 20%, 25%, 30% and 40%) in various tablet formulations. 图21和22分别提供硫酸吗啡和盐酸羟考酮的代表性溶出特征谱。 21 and 22 provide morphine sulfate and oxycodone hydrochloride are representative profiles of dissolution.

[0307] 实施例9.各种%改进释放包衣水平和肠溶包衣水平的溶出测试 [0307] Example 9.% of various modified release coating levels and levels of enteric coating dissolution test

[0308] 利用90/10 (第I批,见表13)和80/20 (第2批)的RS/RL聚合物比例包衣两批(~3kg)硫酸吗啡/羟考酮(重量比3:2)核心团粒。 [0308] using a 90/10 (Batch I, see Table 13) and 80/20 (Batch 2) RS / RL coating polymer ratio of two batches (~ 3kg) morphine sulfate / oxycodone (weight ratio 3 : 2) core pellet. 将每批用不同包衣水平(25%、35%、45%、50%和55%)包衣,并且在包衣过程中采集样品。 The batch with a different coating levels (25%, 35%, 45%, 50% and 55%) the coating, and the samples collected during the coating process. 对不同包衣水平的第I批和第2批进行溶出测试(图19和20)。 Dissolution test (FIGS. 19 and 20) of batch I and batch 2 different coating levels.

[0309] 此外,使获得自第I批的包衣团粒(50%RS/RL包衣水平)进行不同%包衣水平(10%、15%、25%、30%和40%)的肠溶包衣以产生肠溶包衣片剂并进行溶出测试(图21和22)。 [0309] In addition, so as to obtain from the first batch of coated pellet I (50% RS / RL coating levels)% different coating levels (10%, 15%, 25%, 30% and 40%) enteric to produce an enteric coating-coated tablets and dissolution test (FIGS. 21 and 22).

[0310] 还分析肠溶包衣片剂批次(使用10%和15%肠溶包衣)的作为片剂硬度的函数(低、中或高)的溶出以确定片剂对各种压制水平的抗性(图23和24)。 Tablet hardness as a function of the (low, medium or high) to determine the dissolution [0310] Enteric-coated tablets Batch further analysis (using 10% and 15% of the enteric coating) tablets of various compression levels resistance (FIGS. 23 and 24).

[0311] 溶出测试的总结在表15中提供。 Summary [0311] Dissolution tests are provided in Table 15.

Figure CN103476403AD00351

[0314] 图19和20示出在获得所关注的溶出特征谱中,不同%包衣水平的改进释放核心球形颗粒的通用性。 [0314] FIGS. 19 and 20 shown versatility in obtaining dissolution profiles of interest, an improved release coating levels of different core% spherical particles. 全范围的溶出特征谱允许靶向特定体内药物动力学血浆水平并确定体外与体内关联。 Dissolution characteristics of full range spectra allow target specific kinetics in vivo drug plasma levels associated vitro and in vivo and to determine.

[0315] 图21和22还示出在获得所关注的溶出特征谱中,不同%肠溶包衣水平的肠溶包衣的改进释放核心球形颗粒的通用性。 [0315] FIGS. 21 and 22 further illustrates the versatility in obtaining dissolution profiles of interest, the improved enteric coating different level of release% enteric coating a core of spherical particles. 再次,全范围的溶出特征谱允许靶向特定体内药物动力学血浆水平并确定体外与体内关联。 Again, the dissolution characteristics of full range spectra allow target specific kinetics in vivo drug plasma levels associated vitro and in vivo and to determine.

[0316] 图23和24示出压缩力对包含肠溶包衣球形颗粒的片剂的影响,所述肠溶包衣球形颗粒包含硫酸吗啡和盐酸羟考酮的改进释放包衣团粒。 [0316] FIGS. 23 and 24 shows the effect of a compressive force on the enteric coated tablets containing the spherical particles, the improvement comprising enteric coated spherical granules morphine sulfate and oxycodone hydrochloride release coated pellets. 通常已知高压缩力可以显著减少片剂的溶出,特别是当采用已知是脆性的包衣聚合物时,如用季胺基甲基丙烯酸酯共聚物A型和B型。 It is generally known that high compressive forces can significantly reduce the dissolution of the tablet, particularly when using the coating polymers known to be brittle, such as a quaternary ammonio methacrylate copolymer type A and type B. 图23和24证实低或高压缩力不影响片剂的溶出。 23 and 24 confirm the low or high compression force does not affect the dissolution of the tablet. 这个结果是出乎意料的,并且证实制剂/包衣对压缩力的弹性。 This result is unexpected, and demonstrates the formulation / coating the elastic compressive force.

[0317] 实施例10.控释阿片样物质制剂组合物 [0317] Example 10. The controlled release formulation of opioid composition embodiment

[0318] 按照实施例6的方法,制备以下制剂: [0318] Following the procedure of Example 6, the following formulation was prepared:

[0319] 表16:有/无肠溶包衣(尤特奇L100-55C型)的改进释放微粒(RS/RL)的片剂制剂。 [0319] Table 16: with / without enteric coating (Eudragit L100-55C type) modified release tablet formulation microparticles (RS / RL) is.

[0320] [0320]

Figure CN103476403AD00361

[0321] 图25-27分别提供表16提供的制剂的硫酸吗啡和盐酸羟考酮的代表性溶出特征 [0321] FIGS. 25-27 are provided in Table 16 provides the formulations of morphine sulfate and oxycodone hydrochloride dissolution characteristics representative

谱。 Spectrum. 这些图示出在获得所关注的溶出特征谱中,不同%包衣水平的改进释放核心球形颗粒 These figures show in obtaining dissolution profiles of interest, the improved coatings of different levels of% spherical particles release core

的通用性。 Versatility. 还提供允许实现全范围的溶出特征谱的肠溶包衣球形颗粒制剂。 Enteric coated spherical granules characterized in that in the preparation of the full range is also provided to allow the spectrum.

[0322] **** [0322] ****

[0323] 当然,应当理解前述内容仅涉及本发明的某些公开的实施方案,并且其中可以进 [0323] Of course, it should be understood that the foregoing relates only to certain disclosed embodiments of the invention, and which can enter

行许多修改或改变而不背离如所附权利要求书所示的本发明的精神和范围。 Many modifications or alterations row from the spirit and scope of the invention without departing from the appended claims as illustrated in the book.

Claims (45)

  1. 1.一种用于治疗人的疼痛的药物制剂,其包含一种或多种阿片样物质组分,其中: (a)所述一种或多种阿片样物质组分包含一种或多种释放特征谱; (b)至少一种所述阿片样物质组分是包含阿片样物质的控释阿片样物质组分,其中所述阿片样物质为羟考酮或其盐; 其中所述药物制剂在重复给药后提供约4.5-约8小时的至最大羟考酮或其盐的血浆浓度的时间(Tmax)。 CLAIMS 1. A pharmaceutical formulation for the treatment of human pain, which comprises one or more opioid component, wherein: (a) one or more of the opioid component comprises one or more release profiles of; (b) at least one of said opioid controlled release component comprising an opioid component of the opioid, wherein the opioid is oxycodone or a salt thereof; wherein said pharmaceutical preparation provide from about 4.5 to about 8 hours after repeated administration to a maximum of oxycodone or a salt thereof of the plasma concentration time (Tmax).
  2. 2.权利要求1的药物制剂,其中所述控释阿片样物质组分还包含一种或多种选自以下组中的额外的阿片样物质:吗啡、可待因、氢吗啡酮、氢可酮、双氢可待因、双氢吗啡、羟吗啡酮、它们的混合物以及它们的盐。 2. A pharmaceutical formulation as claimed in claim 1, wherein the controlled release opioid component further comprises one or more selected from the group of additional opioids: morphine, codeine, hydromorphone, hydrocodone ketones, dihydrocodeine, dihydroergotamine, morphine, oxymorphone, mixtures thereof and the salts thereof.
  3. 3.权利要求1的药物制剂,其中当包含约2mg的总剂量的羟考酮或其盐时,所述制剂在单次给药后提供约14.7ng.hr/mL-约23.0ng.hr/mL的约O-约24小时的曲线下面积(AUC24)。 When the pharmaceutical formulation of claim 1, wherein when a total dose of about 2mg containing oxycodone or a salt thereof, said formulation providing from about 14.7ng.hr/mL- about 23.0ng.hr/ after a single administration O- mL area of ​​about 24 hours under the curve (AUC24).
  4. 4.权利要求3的药物制剂,其配制为不同于约2mg的总剂量的羟考酮或其盐,并且具有与2mg AUC24成比例的AUC24。 4. A pharmaceutical formulation as claimed in claim 3, which is different from the total formulated dose of about 2mg oxycodone or salt thereof and having a 2mg AUC24 proportional AUC24.
  5. 5.权利要求1的药物制剂,其中当包含约2mg的总剂量的羟考酮或其盐时,所述制剂在稳态条件中重复给药后提供约1-约3ng/mL的平均最大羟考酮或其盐的血浆浓度(Cniax)。 When the pharmaceutical formulation of claim 1, wherein when a total dose of about 2mg containing oxycodone or a salt thereof, said formulation providing a mean maximum hydroxyalkyl about 1 to about 3ng / mL after repeated administration at steady state conditions plasma concentrations of oxycodone or a salt thereof (Cniax).
  6. 6.权利要求5的药物制剂,其配制为不同于约2mg的总剂量的羟考酮或其盐,并且具有与2mg Cmax成比例的Cmax 。 6. A pharmaceutical formulation as claimed in claim 5, formulated as different from the total dose of about 2mg oxycodone or salt thereof and having a Cmax of 2mg proportional Cmax.
  7. 7.权利要求1的药物制剂,其中当包含约5mg的总剂量的羟考酮或其盐时,所述制剂在单次给药后提供约40.2ng.hr/mL-约62.8ng.hr/mL的约O-约24小时的曲线下面积(AUC24)。 When the pharmaceutical formulation of claim 1, wherein when a total dose of about 5mg containing oxycodone or a salt thereof, said formulation providing from about 40.2ng.hr/mL- about 62.8ng.hr/ after a single administration O- mL area of ​​about 24 hours under the curve (AUC24).
  8. 8.权利要求7的药物制剂,其配制为不同于约5mg的总剂量的羟考酮或其盐,并且具有与5mg AUC24成比例的AUC24。 The pharmaceutical formulation of claim 7, formulated as different from the total dose of about 5mg of oxycodone or salt thereof and having a proportional 5mg AUC24 and AUC24.
  9. 9.权利要求1的药物制剂,其中当包含约5mg的总剂量的羟考酮或其盐时,所述制剂在稳态条件中重复给药后提供约3-约7ng/mL的平均最大羟考酮或其盐的血浆浓度(Cmax)。 9. The pharmaceutical formulation as claimed in claim 1, wherein when a total dose of about 5mg containing oxycodone or a salt thereof, said formulation providing a mean maximum hydroxyalkyl about 3 to about 7ng / mL after repeated administration at steady state conditions plasma concentrations of oxycodone or a salt thereof (Cmax).
  10. 10.权利要求9的药物制剂,其配制为不同于约5mg的总剂量的羟考酮或其盐,并且具有与5mg Cmax成比例的(:_。 10. A pharmaceutical formulation as claimed in claim 9, formulated as different from the total dose of about 5mg of oxycodone or salt thereof and having a Cmax proportional 5mg (: _.
  11. 11.权利要求1的药物制剂,其中当包含约IOmg的总剂量的羟考酮或其盐时,所述制剂在单次给药后提供约80.5ng.hr/mL-约125.9ng.hr/mL的约O-约24小时的曲线下面积(AUC24)。 11. The pharmaceutical formulation as claimed in claim 1, wherein when a total dose of about IOmg containing oxycodone or a salt thereof, said formulation providing from about 80.5ng.hr/mL- about 125.9ng.hr/ after a single administration O- mL area of ​​about 24 hours under the curve (AUC24).
  12. 12.权利要求11的药物制剂,其配制为不同于约IOmg的总剂量的羟考酮或其盐,并且具有与IOmg AUC24成比例的AUC24。 12. The pharmaceutical formulation as claimed in claim 11, formulated differently from about IOmg total dose of oxycodone or a salt thereof, and having a proportional AUC24 and IOmg AUC24.
  13. 13.权利要求1的药物制剂,其中当包含约IOmg的总剂量的羟考酮或其盐时,所述制剂在稳态条件中重复给药后提供约5-约15ng/mL的平均最大羟考酮或其盐的血浆浓度(Cmax)。 13. The pharmaceutical formulation as claimed in claim 1, wherein when a total dose of about IOmg containing oxycodone or a salt thereof, said formulation providing a mean maximum hydroxyalkyl about 5 to about 15ng / mL after repeated administration at steady state conditions plasma concentrations of oxycodone or a salt thereof (Cmax).
  14. 14.权利要求13的药物制剂,其配制为不同于约IOmg的总剂量的羟考酮或其盐,并且具有与IOmg Cmax成比例的Cmax。 14. A pharmaceutical formulation as claimed in claim 13, formulated as a total dose of about IOmg different from the oxycodone or salt thereof and having a Cmax and Cmax IOmg proportional.
  15. 15.权利要求1的药物制剂,其中当包含约20mg的总剂量的羟考酮或其盐时,所述制剂在单次给药后提供约166.0ng.hr/mL-约259.3ng.hr/mL的约O-约24小时的曲线下面积(AUC24)。 15. The pharmaceutical formulation as claimed in claim 1, wherein when a total dose of about 20mg comprising oxycodone or a salt thereof, said formulation providing from about 166.0ng.hr/mL- about 259.3ng.hr/ after a single administration O- mL area of ​​about 24 hours under the curve (AUC24).
  16. 16.权利要求15的药物制剂,其配制为不同于约20mg的总剂量的羟考酮或其盐,并且具有与20mg AUC24成比例的AUC24。 16. A pharmaceutical formulation as claimed in claim 15, which is different from the total formulated dose of about 20mg of oxycodone or a salt thereof, and has 20mg AUC24 proportional AUC24.
  17. 17.权利要求1的药物制剂,其中当包含约20mg的总剂量的羟考酮或其盐时,所述制剂在稳态条件中重复给药后提供约10-约30ng/mL的平均最大羟考酮或其盐的血浆浓度(Qnax)。 17. The pharmaceutical formulation as claimed in claim 1, wherein when a total dose of about 20mg comprising oxycodone or a salt thereof, said formulation providing a mean maximum hydroxyalkyl about 10 to about 30ng / mL after repeated administration at steady state conditions plasma concentrations of oxycodone or a salt thereof (Qnax).
  18. 18.权利要求17的药物制剂,其配制为不同于约20mg的总剂量的羟考酮或其盐,并且具有与20mg Cmax成比例的Cmax。 18. A pharmaceutical formulation as claimed in claim 17, which is different from the total formulated dose of about 20mg of oxycodone or salt thereof and having a Cmax and Cmax is proportional to 20mg.
  19. 19.权利要求1的药物制剂,其中当包含约40mg的总剂量的羟考酮或其盐时,所述制剂在单次给药后提供约338.5ng.hr/mL-约528.9ng.hr/mL的约O-约24小时的曲线下面积(AUC24)。 19. The pharmaceutical formulation as claimed in claim 1, wherein when a total dose of about 40mg comprising oxycodone or a salt thereof, said formulation providing from about 338.5ng.hr/mL- about 528.9ng.hr/ after a single administration O- mL area of ​​about 24 hours under the curve (AUC24).
  20. 20.权利要求19的药物制剂,其配制为不同于约40mg的总剂量的羟考酮或其盐,并且具有与40mg AUC24成比例的AUC24。 20. A pharmaceutical formulation as claimed in claim 19, which is different from the total formulated dose of about 40mg of oxycodone or a salt thereof, and has 40mg AUC24 proportional AUC24.
  21. 21.权利要求1的药物制剂,其中当包含约40mg的总剂量的羟考酮或其盐时,所述制剂在稳态条件中重复给药后提供约25-约55ng/mL的平均最大羟考酮或其盐的血浆浓度(Qnax)。 21. the pharmaceutical formulation as claimed in claim 1, wherein when a total dose of about 40mg comprising oxycodone or a salt thereof, said formulation providing a mean maximum hydroxyalkyl about 25 to about 55ng / mL after repeated administration at steady state conditions plasma concentrations of oxycodone or a salt thereof (Qnax).
  22. 22.权利要求21的药物制剂,其配制为不同于约40mg的总剂量的羟考酮或其盐,并且具有与40mg Cmax成比例的Cmax。 22. A pharmaceutical formulation as claimed in claim 21, which is different from the total formulated dose of about 40mg of oxycodone or salt thereof and having a Cmax and Cmax is proportional to 40mg.
  23. 23.权利要求1的药物制剂,其中当包含约80mg的总剂量的羟考酮或其盐时,所述制剂在单次给药后提供约868.4ng.hr/mL-约1356.9ng.hr/mL的约O-约24小时的曲线下面积(AUC24)。 23. the pharmaceutical formulation as claimed in claim 1, wherein when a total dose of about 80mg comprising oxycodone or a salt thereof, said formulation providing from about 868.4ng.hr/mL- about 1356.9ng.hr/ after a single administration O- mL area of ​​about 24 hours under the curve (AUC24).
  24. 24.权利要求23的药物制剂,其配制为不同于约SOmg的总剂量的羟考酮或其盐,并且具有与80mg AUC24成比例的AUC24。 24. A pharmaceutical formulation as claimed in claim 23, which is different from the total formulated dose of about SOmg oxycodone or salt thereof and having 80mg AUC24 proportional AUC24.
  25. 25.权利要求1的药物制剂,其中当包含约SOmg的总剂量的羟考酮或其盐时,所述制剂在稳态条件中重复给药后提供约50-约110ng/mL的平均最大羟考酮或其盐的血浆浓度(Qnax)。 25. the pharmaceutical formulation as claimed in claim 1, wherein when a total dose of about SOmg containing oxycodone or a salt thereof, said formulation providing a mean maximum hydroxyalkyl about 50 to about 110ng / mL after repeated administration at steady state conditions plasma concentrations of oxycodone or a salt thereof (Qnax).
  26. 26.权利要求25的药物制剂,其配制为不同于约SOmg的总剂量的羟考酮或其盐,并且具有与80mg Cmax成比例的Cmax。 26. A pharmaceutical formulation as claimed in claim 25, which is different from the total formulated dose of about SOmg oxycodone or salt thereof and having a Cmax of 80 mg of proportional Cmax.
  27. 27.权利要求1的药物制剂,其包含第二控释阿片样物质组分。 27. A pharmaceutical formulation as claimed in claim 1, comprising a second controlled-release opioid component.
  28. 28.权利要求27的药物制剂,其中所述第二控释阿片样物质组分包含选自以下组中的阿片样物质:吗啡、可待因、氢吗啡酮、氢可酮、羟考酮、双氢可待因、双氢吗啡、羟吗啡酮、它们的混合物以及它们的盐。 28. A pharmaceutical formulation as claimed in claim 27, wherein said second component comprising a controlled release opioid is selected from the group of opioids: morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydroergotamine, morphine, oxymorphone, mixtures thereof and the salts thereof.
  29. 29.权利要求1的药物制剂,其包含即释阿片样物质组分。 29. The pharmaceutical formulation as claimed in claim 1, comprising an immediate release opioid component.
  30. 30.权利要求29的药物制剂,其中所述即释阿片样物质组分包含选自以下组中的阿片样物质:吗啡、可待因、氢吗啡酮、氢可酮、羟考酮、双氢可待因、双氢吗啡、羟吗啡酮、它们的混合物以及它们的盐。 30. A pharmaceutical formulation as claimed in claim 29, wherein said immediate release component comprising an opioid selected from the group of opioids: morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine codeine, dihydrocodeine morphine, oxymorphone, mixtures thereof and the salts thereof.
  31. 31.权利要求30的药物制剂,其中所述即释阿片样物质组分中的阿片样物质为吗啡或其盐。 31. The pharmaceutical formulation as claimed in claim 30, wherein said immediate release opioid component opioid is morphine or a salt thereof.
  32. 32.权利要求31的药物制剂,其中所述制剂中总吗啡或其盐与总羟考酮或其盐的重量比为约3:2吗啡或其盐比羟考酮或其盐。 32. A pharmaceutical formulation as claimed in claim 31, wherein the weight of the total formulation of morphine or a salt thereof with oxycodone or a salt thereof of the total ratio of about 3: 2 ratio of morphine to oxycodone or a salt thereof, or a salt thereof.
  33. 33.权利要求1的药物制剂,其包含第二阿片样物质组分和第三阿片样物质组分,其中: (a)所述第二阿片样物质组分为即释阿片样物质组分,并且包含具有K激动剂活性的阿片样物质;并且(b)所述第三阿片样物质组分为控释阿片样物质组分,并且包含具有μ激动剂活性的阿片样物质。 33. A pharmaceutical formulation as claimed in claim 1, comprising a second component and a third opioid opioid component, wherein: (a) the second group divided opioid immediate release opioid component, and comprising a K opioid agonist activity; and (b) said third component is an opioid controlled release opioid component, and containing the active substance having a μ opioid agonist.
  34. 34.权利要求33的药物制剂,其中具有K激动剂活性的阿片样物质为羟考酮或其盐。 34. A pharmaceutical formulation as claimed in claim 33, wherein the activity with K opioid agonist is oxycodone or a salt thereof.
  35. 35.权利要求33的药物制剂,其中具有μ激动剂活性的阿片样物质为吗啡或其盐。 35. The pharmaceutical formulation as claimed in claim 33, wherein the agonist activity having μ opioid is morphine or a salt thereof.
  36. 36.权利要求1的药物制剂,其中所述控释阿片样物质组分包含吗啡或其盐。 36. The pharmaceutical formulation as claimed in claim 1, wherein the controlled release component comprises the opioid morphine or a salt thereof.
  37. 37.权利要求36的药物制剂,其中所述控释阿片样物质组分包含量为约3:2重量比的吗啡或其盐和羟考酮或其盐。 37. A pharmaceutical formulation as claimed in claim 36, wherein the controlled release component comprises the opioid in an amount of from about 3: 2 ratio by weight of morphine or a salt thereof, and oxycodone or a salt thereof.
  38. 38.权利要求1的药物制剂,其中以约50rpm在水中于约37° C下在USP I型装置中测量时,所述制剂的溶出在2小时后释放约O-约20%的羟考酮或其盐。 38. A pharmaceutical formulation as claimed in claim 1, wherein the measurement at about 50rpm in water at about 37 ° C in a USP Type I apparatus, the formulation is from about O- dissolution release about 20% of the oxycodone after 2 hours or a salt thereof.
  39. 39.权利要求1的药物制剂,其中以约50rpm在水中于约37° C下在USP I型装置中测量时,所述制剂的溶出在4小时后释放约15-约60%的羟考酮或其盐。 39. A pharmaceutical formulation as claimed in claim 1, wherein the measurement at about 50rpm in water at about 37 ° C in a USP Type I apparatus, the dissolution release formulation from about 15 to about 60% of the oxycodone after 4 hours or a salt thereof.
  40. 40.权利要求1的药物制剂,其中以约50rpm在水中于约37° C下在USP I型装置中测量时,所述制剂的溶出在6小时后释放约25-约80%的羟考酮或其盐。 40. A pharmaceutical formulation as claimed in claim 1, wherein the measurement at about 50rpm in water at about 37 ° C in a USP Type I apparatus, the dissolution release formulation from about 25 to about 80% of the oxycodone after 6 hours or a salt thereof.
  41. 41.权利要求1的药物制剂,其中以约50rpm在水中于约37° C下在USP I型装置中测量时,所述制剂的溶出在8小时后释放约35-约85%的羟考酮或其盐。 41. The pharmaceutical formulation as claimed in claim 1, wherein the measurement at about 50rpm in water at about 37 ° C in a USP Type I apparatus, the dissolution release formulation from about 35 to about 85% of the oxycodone after 8 hours or a salt thereof.
  42. 42.权利要求1的药物制剂,其中以约50rpm在水中于约37° C下在USP I型装置中测量时,所述制剂的溶出在10小时后释放约45-约95%的羟考酮或其盐。 42. A pharmaceutical formulation as claimed in claim 1, wherein the measurement at about 50rpm in water at about 37 ° C in a USP Type I apparatus, the dissolution release formulation from about 45 to about 95% of the oxycodone after 10 hours or a salt thereof.
  43. 43.权利要求1的药物制剂,其中以约50rpm在水中于约37° C下在USP I型装置中测量时,所述制剂的溶出在12小时后释放约60-约100%的羟考酮或其盐。 43. The pharmaceutical formulation as claimed in claim 1, wherein the measurement at about 50rpm in water at about 37 ° C in a USP Type I apparatus, the dissolution release formulation from about 60 to about 100% of the oxycodone after 12 hours or a salt thereof.
  44. 44.一种用于人吸收的具有阿片样物质受体激动剂活性的一种或多种化合物的控释方法,其中所述方法包括给药包含一种或多种组分的药物制剂,其中: (a)所述一种或多种阿片样物质组分包含一种或多种释放特征谱; (b)至少一种所述阿片样物质组分是包含阿片样物质的控释阿片样物质组分,其中所述阿片样物质为羟考酮或其盐; 其中所述药物制剂在重复给药后提供约4.5-约8小时的至最大羟考酮或其盐的血浆浓度的时间(Tmax)。 44. A human opioid receptor agonist for absorbing method of controlled release of the active compound or more, wherein the method comprises administering a pharmaceutical formulation comprising one or more components, wherein : (a) one or more of the opioid component comprises one or more release profiles of; (b) at least one of said opioid controlled release component comprising an opioid opioid component, wherein the opioid is oxycodone or a salt thereof; wherein the pharmaceutical formulation after repeated administration of from about 4.5 to about 8 hours to a maximum plasma concentration of oxycodone or a salt time (Tmax ).
  45. 45.一种治疗人的疼痛的方法,所述方法包括给药包含一种或多种组分的药物制剂,其中: (a)所述一种或多种阿片样物质组分包含一种或多种释放特征谱; (b)至少一种所述阿片样物质组分是包含阿片样物质的控释阿片样物质组分,其中所述阿片样物质为羟考酮或其盐; 其中所述药物制剂在重复给药后提供约4.5-约8小时的至最大羟考酮或其盐的血浆浓度的时间(Tmax)。 45. A method of treating pain in a human, said method comprising administering a pharmaceutical formulation comprising one or more components, wherein: (a) one or more of the opioid component comprises one or various release profiles of; (b) at least one of said opioid controlled release component comprising an opioid component of the opioid, wherein the opioid is oxycodone or a salt thereof; wherein said pharmaceutical formulation to provide from about 4.5 to about 8 hours after repeated administration time (Tmax) to the maximum plasma concentration of oxycodone or a salt thereof.
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