CN1957909B - Methods of reducing alcohol-induced dose dumping for opioid sustained release oral dosage forms - Google Patents

Methods of reducing alcohol-induced dose dumping for opioid sustained release oral dosage forms Download PDF

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CN1957909B
CN1957909B CN 200610143171 CN200610143171A CN1957909B CN 1957909 B CN1957909 B CN 1957909B CN 200610143171 CN200610143171 CN 200610143171 CN 200610143171 A CN200610143171 A CN 200610143171A CN 1957909 B CN1957909 B CN 1957909B
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release
reducing
alcohol
forms
induced
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CN 200610143171
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CN1957909A (en )
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G·萨斯延
N·达瓦
J·哈斯特德
L·波斯
G·卡萨德瓦尔
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阿尔扎公司
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Abstract

降低鸦片样物质持续释放口服剂型的由醇诱导的剂量突然释放的方法。 Sustained release oral dosage form by a sudden release of alcohol-induced dose of opioid is reduced. 本发明公开了持续释放给药鸦片样物质(包括但不限于氢吗啡酮和羟考酮)的方法,其显示了改进了的与醇水溶液联合给药时的性质。 The present invention discloses a sustained release opioid administration (including but not limited to hydromorphone and oxycodone) method, showing improved properties when administered in combination with aqueous alcohol.

Description

降低鸦片样物质持续释放口服剂型的由醇诱导的剂量突然释放的方法 Reducing the opioid sustained release oral dosage form, dose of the alcohol-induced sudden release methods

技术领域 FIELD

[0001] 本发明涉及鸦片样物质(包括但不限于氢吗啡酮和羟考酮)持续释放给药的方法,其在与醇水溶液联合给药时表现出改进的性质。 [0001] The present invention relates to opioid (including but not limited to hydromorphone and oxycodone) sustained release administration, which exhibits improved properties when administered in combination with aqueous alcohol.

背景技术 Background technique

[0002] 乙醇诱导的鸦片样物质持续释放口服剂型的剂量突然释放对于服用这种口服剂型的患者来说是一个严重的问题。 Dose [0002] ethanol-induced opioid sustained release oral dosage form of the sudden release for patients taking the oral dosage form is a serious problem.

[0003] 鸦片样物质持续释放口服剂型被设计在延续的时期内向患者递送鸦片样物质。 [0003] Opioid sustained release oral dosage forms are designed within the patient during the continuation of the delivery of opioids. 经常用一剂鸦片样物质持续释放口服剂型来代替多剂鸦片样物质瞬时释放口服剂型。 Often an opioid sustained release oral dosage forms in place of a multi-agent instant release opioid oral dosage form. 例如,存在对于每天一次(qd)和每天两次(bid)施用鸦片样物质持续释放口服剂型的巨大需求来减轻患者整天的痛苦。 For example, there is a once daily (qd) and twice daily (bid) administration of opioid sustained release oral dosage form of the huge demand to alleviate the suffering of patients all day long.

[0004]因此,这种剂型(尤其是每天一次的鸦片样物质持续释放口服剂型)所含的鸦片样物质的量显著高于传统上在瞬时释放鸦片样物质口服剂型中所包含的量。 [0004] Thus, the dosage form (especially once per day opioid sustained release oral dosage form) the amount of opioid contained in an amount significantly higher than in the conventional instant release opioid oral dosage form contains. 引起这种鸦片样物质持续释放口服剂型的剂量突然释放的任何情况可导致鸦片样物质药物过量,造成呼吸衰弱并甚至可能死亡。 This situation caused any dose opioid sustained release oral dosage form of the substance can lead to sudden release of opioid overdose, causing respiratory weakness and possibly even death.

[0005] 本发明人认识到一种造成剂量突然释放(S卩,瞬时释放)的方式是通过鸦片样物质持续释放口服剂型与醇水溶液(尤其是乙醇水溶液)联合给药造成的递送率的加快。 Accelerate the delivery rate [0005] The present inventors recognized way cause sudden release dose (S Jie, instant release) is achieved by opioid sustained release oral dosage form with aqueous alcohol (particularly aqueous ethanol) caused by coadministration . 各种醇能增加鸦片样物质从鸦片样物质持续释放口服剂型中以不希望的高速率释放,甚至导致剂量突然释放/瞬时释放。 All kinds of alcohol can increase the opioid from the opioid sustained release oral dosage form to an undesirable high rate of release, and even lead to sudden release of dose / instantaneous release.

[0006] 因此,希望能开发鸦片样物质持续释放口服剂型和相关方法,其不具有现有技术涉及的醇诱导的剂量突然释放(尤其是乙醇诱导的剂量突然释放)的问题。 [0006] Accordingly, it is desirable to develop oral opioid sustained release dosage forms and related methods, which do not have the prior art alcohol-induced dose related sudden release (especially ethanol-induced sudden release dose) problem. 甚至更希望那些鸦片样物质持续释放口服剂型和相关方法是每天用一次或每天用两次的鸦片样物质持续释放口服剂型和相关方法。 It is even more desirable that the opioid sustained release oral dosage forms and related methods are used once or twice daily opioid oral sustained release dosage forms and related methods every day.

发明内容 SUMMARY

[0007] 在一个方面,本发明涉及一种方法,其包括:提供每天用一次的含氢吗啡酮的氢吗啡酮持续释放口服剂型和能提供每天用一次剂量的持续释放剂量结构;向患者联合给药每天用一次的氢吗啡酮持续释放口服剂型和醇水溶液;从每天用一次的氢吗啡酮持续释放口服剂型中释放出氢吗啡酮;其中,醇水溶液含等于或大于约20%体积/体积浓度的醇;而且其中,在每天用一次的氢吗啡酮持续释放口服剂型和醇水溶液向患者联合给药时所达到的平均单剂最大血浆氢吗啡酮浓度同在每天用一次的氢吗啡酮持续释放口服剂型不和醇水溶液联合给药而单独向患者给药时所达到的平均单剂最大血浆氢吗啡酮浓度之间的比率等于或小于约1.8: I。 [0007] In one aspect, the present invention relates to a method, comprising: providing a sustained release dosage structure once per day with a daily dose of hydromorphone in a hydrogen-containing hydromorphone and a sustained release oral dosage form provides; joint to a patient administered once per day hydromorphone sustained release oral dosage forms and alcohol aqueous solution; from once a day hydromorphone sustained release oral dosage forms release hydromorphone; wherein the aqueous alcohol solution containing equal to or greater than about 20% volume / volume the concentration of alcohol; and wherein, when administered in combination to a patient once per day hydromorphone sustained release oral dosage forms and the alcohol aqueous solution achieved an average single dose maximum plasma hydromorphone concentrations with once a day in the hydromorphone sustained the ratio between the average concentration of one single dose maximum plasma hydromorphone release oral dosage forms administered in combination with aqueous alcohol and not separately administered to a patient to achieve equal to or less than about 1.8: I.

[0008] 在另一个方面,本发明涉及一种方法,其包括:提供每天用一次的含氢吗啡酮的氢吗啡酮持续释放口服剂型和能提供每天用一次剂量的持续释放剂量结构;向患者联合给药每天用一次的氢吗啡酮持续释放口服剂型和醇水溶液;从每天用一次的氢吗啡酮持续释放口服剂型中释放出氢吗啡酮;其中,醇水溶液含等于或大于约20%体积/体积浓度的醇;而且其中,在每天用一次的氢吗啡酮持续释放口服剂型和醇水溶液向患者联合给药时所达到的单个患者单剂最大血浆氢吗啡酮浓度同在每天用一次的氢吗啡酮持续释放口服剂型不和醇水溶液联合给药而单独向患者给药时所达到的单个患者单剂最大血浆氢吗啡酮浓度之间的比率等于或小于约5: I。 [0008] In another aspect, the present invention relates to a method, comprising: providing a sustained release dosage structure once per day with a daily dose of hydromorphone in a hydrogen-containing hydromorphone and a sustained release oral dosage form provides; to a patient administered in combination with once per day hydromorphone sustained release oral dosage forms and alcohol aqueous solution; releasing hydromorphone from the once a day hydromorphone sustained release oral dosage form; wherein the aqueous alcohol solution containing equal to or greater than about 20% vol / volume concentration of alcohol; and wherein, a single patient when administered in combination to a patient once per day hydromorphone sustained release oral dosage forms and the alcohol aqueous solution to achieve a single dose maximum plasma hydromorphone concentration in the same once per day hydromorphone the ratio between the maximum plasma hydromorphone concentration of one single patient, and the sustained release oral dosage forms administered in combination with aqueous alcohol is not separately administered to a patient to achieve a single dose of less than or equal to about 5: I.

[0009] 在另一个方面,本发明涉及一种方法,其包括:提供每天用一次的含氢吗啡酮的氢吗啡酮持续释放口服剂型和能提供每天用一次剂量的持续释放剂量结构;向患者联合给药每天用一次的氢吗啡酮持续释放口服剂型和醇水溶液;从每天用一次的氢吗啡酮持续释放口服剂型中释放出氢吗啡酮;其中,每天用一次的氢吗啡酮持续释放口服剂型释放小于或等于约80重量百分比的氢吗啡酮的剂量,所述氢吗啡酮的剂量从每天用一次的氢吗啡酮持续释放口服剂型以如下方式测得:(a)利用含测试介质的体外测试方法和(b)在体外测试方法起始后约2小时内;而且其中,测试介质含醇水溶液,所述醇水溶液含等于或大于约20%体积/体积浓度的醇。 [0009] In another aspect, the present invention relates to a method, comprising: providing a sustained release dosage structure once per day with a daily dose of hydromorphone in a hydrogen-containing hydromorphone and a sustained release oral dosage form provides; to a patient once daily administered in combination with hydromorphone sustained release oral dosage forms and alcohol aqueous solution; from once a day hydromorphone sustained release oral dosage forms release hydromorphone; wherein, once a day hydromorphone sustained release oral dosage forms release less than or equal to about 80 weight percent of the dose of hydromorphone, the dose of hydromorphone from the sustained release oral dosage form once a day hydromorphone measured in the following manner: (a) using an in vitro test medium containing the test method and (b) in vitro test method starting within about 2 hours; and wherein the test medium is alcoholic solution, said alcohol-containing aqueous solution is equal to or greater than about 20% volume / volume concentration of alcohol.

[0010] 在另一个方面,本发明涉及一种方法,其包括:提供含氢吗啡酮的氢吗啡酮持续释放口服剂型和一种持续释放剂量结构;向患者联合给药氢吗啡酮持续释放口服剂型和醇水溶液;从氢吗啡酮持续释放口服剂型中释放出氢吗啡酮;其中,醇水溶液含等于或大于约20%体积/体积浓度的醇;而且其中,在该剂型和醇水溶液向患者联合给药时所达到的平均单剂最大血浆氢吗啡酮浓度同在该剂型不和醇水溶液联合给药而单独向患者给药时所达到的平均单剂最大血浆氢吗啡酮浓度之间的比率等于或小于约1.8: I。 [0010] In another aspect, the present invention relates to a method, comprising: providing a hydrogen containing hydromorphone sustained release oral hydromorphone sustained release dosage forms and one structure; sustained release oral coadministration to the patient hydrogen hydromorphone dosage forms and the alcohol aqueous solution; from the hydromorphone sustained release oral dosage forms release hydromorphone; wherein the aqueous alcohol solution containing equal to or greater than about 20% volume / volume concentration of alcohol; and wherein, the joint to the patient in the dosage form and the alcohol aqueous solution hydromorphone mean single dose maximum plasma concentration when administered achieved with a ratio between the concentration of one dosage form and administered in combination an alcohol aqueous solution without separately administered to a patient to achieve a mean single dose maximum plasma hydromorphone equal or less than about 1.8: I.

[0011] 在另一个方面,本发明涉及一种方法,其包括:提供含氢吗啡酮的氢吗啡酮持续释放口服剂型和一种持续释放剂量结构;向患者联合给药氢吗啡酮持续释放口服剂型和醇水溶液;从氢吗啡酮持续释放口服剂型中释放出氢吗啡酮;其中,醇水溶液含等于或大于约20%体积/体积浓度的醇;而且其中,在该剂型和醇水溶液向患者联合给药时所达到的单个患者单剂最大血浆氢吗啡酮浓度同在该剂型不和醇水溶液联合给药而单独向患者给药时所达到的单个患者单·剂最大血浆氢吗啡酮浓度之间的比率等于或小于约5: I。 [0011] In another aspect, the present invention relates to a method, comprising: providing a hydrogen containing hydromorphone sustained release oral hydromorphone sustained release dosage forms and one structure; sustained release oral coadministration to the patient hydrogen hydromorphone dosage forms and the alcohol aqueous solution; from the hydromorphone sustained release oral dosage forms release hydromorphone; wherein the aqueous alcohol solution containing equal to or greater than about 20% volume / volume concentration of alcohol; and wherein, the joint to the patient in the dosage form and the alcohol aqueous solution between the maximum plasma concentration of hydromorphone administered in a single patient during a single dose in one achieved with a concentration of not a single patient and the dosage form is administered in combination and separately to the aqueous alcohol is administered to a patient to achieve a single-agent maximum plasma hydromorphone ratio of less than or equal to about 5: I.

[0012] 在另一个方面,本发明涉及一种方法,其包括:提供含氢吗啡酮的氢吗啡酮持续释放口服剂型和一种持续释放剂量结构;向患者联合给药氢吗啡酮持续释放口服剂型和醇水溶液;从氢吗啡酮持续释放口服剂型中释放出氢吗啡酮;其中,氢吗啡酮持续释放口服剂型释放小于约80重量百分比的氢吗啡酮的剂量,所述氢吗啡酮的剂量以如下方式测得: [0012] In another aspect, the present invention relates to a method, comprising: providing a hydrogen containing hydromorphone sustained release oral hydromorphone sustained release dosage forms and one structure; sustained release oral coadministration to the patient hydrogen hydromorphone and alcohol aqueous solution dosage forms; hydromorphone from the sustained release oral dosage forms release hydromorphone; wherein hydromorphone sustained release oral dosage form releases less than about 80 weight percent of the dose of hydromorphone, hydromorphone dosage to measured in the following manner:

(a)利用含测试介质的体外测试方法和(b)在体外测试方法起始后约2小时内;而且其中,测试介质含醇水溶液,所述醇水溶液含等于或大于约20%体积/体积浓度的醇。 (A) using an in vitro test medium containing the test method and (b) in vitro test method starting within about 2 hours; and wherein the test medium is alcoholic solution, said alcohol-containing aqueous solution is equal to or greater than about 20% volume / volume concentration of alcohol.

[0013] 在一个方面,本发明涉及一种方法,其包括:提供每天用一次的含鸦片样物质的鸦片样物质持续释放口服剂型和一种能提供每天用一次剂量的持续释放剂量结构;向患者联合给药每天用一次的鸦片样物质持续释放剂型和醇水溶液;从每天用一次的鸦片样物质持续释放剂型中释放出鸦片样物质;其中,醇水溶液含等于或大于约20%体积/体积浓度的醇;而且其中,在每天用一次的鸦片样物质持续释放剂型和醇水溶液向患者联合给药时所达到的平均单剂最大血浆鸦片样物质浓度同在每天用一次的鸦片样物质持续释放剂型不和醇水溶液联合给药而单独向患者给药时所达到的平均单剂最大血浆鸦片样物质浓度之间的比率等于或小于约1.8: I。 [0013] In one aspect, the present invention relates to a method, comprising: providing a once daily opioid containing the opioid and the sustained release oral dosage capable of providing sustained release dosage once daily doses structure; the administered in combination with a patient per day opioid sustained release dosage forms and the alcohol aqueous solution; releasing opioid from the once a day opioid sustained release dosage form; wherein the aqueous alcohol solution containing equal to or greater than about 20% volume / volume the concentration of alcohol; and wherein, to a patient when administered in combination with a opioid sustained release dosage forms and the daily alcohol aqueous solution to achieve an average single dose maximum plasma opioid concentrations with once a day opioid sustained release the ratio between the average single dose maximum plasma opioid dosage form does not matter concentration and the alcohol solution is administered in combination upon administration to a patient alone reached equal to or less than about 1.8: I.

[0014] 在另一个方面,本发明涉及一种方法,其包括:提供每天用一次的含鸦片样物质的鸦片样物质持续释放剂型和一种能提供每天用一次剂量的持续释放剂量结构;向患者联合给药每天用一次的鸦片样物质持续释放口服剂型和醇水溶液;从每天用一次的鸦片样物质持续释放剂型中释放出鸦片样物质;其中,醇水溶液含等于或大于约20%体积/体积浓度的醇;而且其中,在每天用一次的鸦片样物质持续释放口服剂型和醇水溶液向患者联合给药时所达到的单个患者单剂最大血浆鸦片样物质浓度同在每天用一次的鸦片样物质持续释放剂型不和醇水溶液联合给药而单独向患者给药时所达到的单个患者单剂最大血浆鸦片样物质浓度之间的比率等于或小于约5: I。 [0014] In another aspect, the present invention relates to a method, comprising: providing a once daily opioid containing an opioid and a sustained release formulation capable of providing sustained release dosage once daily doses structure; the administered in combination with a patient per day opioid sustained release oral dosage forms and alcohol aqueous solution; releasing opioid from the once a day opioid sustained release dosage form; wherein the aqueous alcohol solution containing equal to or greater than about 20% vol / volume concentration of alcohol; and wherein, a single patient when administered in combination to a patient once per day opioid sustained release oral dosage forms and the alcohol aqueous solution to achieve a single dose maximum plasma opioid concentration once a day in the same opioid the ratio between the individual patient and the substance is not a sustained release formulation is administered in combination and separately to the aqueous alcohol administered to a patient achieved a single dose maximum plasma opioid concentration of the substance is equal to or less than about 5: I.

[0015] 在另一个方面,本发明涉及一种方法,其包括:提供每天用一次的含鸦片样物质的鸦片样物质持续释放剂型和一种能提供每天用一次剂量的持续释放剂量结构;向患者联合给药每天用一次的鸦片样物质持续释放口服剂型和醇水溶液;从每天用一次的鸦片样物质持续释放剂型中释放出鸦片样物质;其中,每天用一次的鸦片样物质持续释放剂型释放小于或等于约80重量百分比的鸦片样物质的剂量,从每天用一次的鸦片样物质持续释放剂型释放的所述鸦片样物质的剂量以如下方式测得:(a)利用含测试介质的体外测试方法和 [0015] In another aspect, the present invention relates to a method, comprising: providing a once daily opioid containing an opioid and a sustained release formulation capable of providing sustained release dosage once daily doses structure; the administered in combination with a patient per day opioid sustained release oral dosage forms and alcohol aqueous solution; releasing opioid from the once a day opioid sustained release dosage form; wherein, once a day opioid sustained release dosage form releases less than or equal to about 80 weight percent of the dose of opioid from the once a day opioid sustained release dosage forms of the opioid released measured in the following manner: (a) using an in vitro test medium containing the test Methods and

(b)在体外测试方法起始后约2小时内;而且其中,测试介质含醇水溶液,所述醇水溶液含等于或大于约20%体积/体积浓度的醇。 (B) in vitro test method starting within about 2 hours; and wherein the test medium is alcoholic solution, said alcohol-containing aqueous solution is equal to or greater than about 20% volume / volume concentration of alcohol.

[0016] 在另一个方面,本发明涉及一种方法,其包括:提供含鸦片样物质的鸦片样物质持续释放剂型和一种持续释放剂量结构;向患者联合给药鸦片样物质持续释放剂型和醇水溶液;从鸦片样物质持续释放剂型中释放出鸦片样物质;其中,醇水溶液含等于或大于约20%体积/体积浓度的醇;而且其`中,在剂型和醇水溶液向患者联合给药时所达到的平均单剂最大血浆鸦片样物质浓度同在剂型不和醇水溶液联合给药而单独向患者给药时所达到的平均单剂最大血浆鸦片样物质浓度之间的比率等于或小于约1.8: I。 [0016] In another aspect, the present invention relates to a method, comprising: providing a opioid containing opioid sustained release dosage forms and the structure of a sustained release dosage; administered in combination to the patient opioid sustained release dosage form, and alcohol aqueous solution; from the opioid sustained release dosage form releases the opioid; wherein the aqueous alcohol solution containing equal to or greater than about 20% volume / volume concentration of alcohol; and its `in the joint to a patient in a dosage form and administered aqueous alcohol achieved when an average single dose maximum plasma opioid concentration with the ratio between the dosage form and are not administered in combination with aqueous alcohol to a separately administered to a patient achieved a mean single dose maximum plasma opioid concentration of the substance is equal to or less than about 1.8: I.

[0017] 在另一个方面,本发明涉及一种方法,其包括:提供含鸦片样物质的鸦片样物质持续释放剂型和一种持续释放剂量结构;向患者联合给药鸦片样物质持续释放剂型和醇水溶液;从鸦片样物质持续释放剂型中释放出鸦片样物质;其中,醇水溶液含等于或大于约20%体积/体积浓度的醇;而且其中,在剂型和醇水溶液向患者联合给药时所达到的单个患者单剂最大血浆鸦片样物质浓度同在剂型不和醇水溶液联合给药而单独向患者给药时所达到的单个患者单剂最大血浆鸦片样物质浓度之间的比率等于或小于约5: I。 [0017] In another aspect, the present invention relates to a method, comprising: providing a opioid containing opioid sustained release dosage forms and the structure of a sustained release dosage; administered in combination to the patient opioid sustained release dosage form, and alcohol aqueous solution; from the opioid sustained release dosage form releases the opioid; wherein the aqueous alcohol solution containing equal to or greater than about 20% volume / volume concentration of alcohol; and wherein when administered in combination to a patient in a dosage form and the aqueous alcohol individual patient single dose maximum plasma reach opioid concentration with the ratio between the individual patient and the dosage form is administered in combination without alcohol aqueous solution separately administered to a patient to achieve a single dose maximum plasma opioid concentration of the substance is equal to or less than about 5: I.

[0018] 在另一个方面,本发明涉及一种方法,其包括:提供含鸦片样物质的鸦片样物质持续释放剂型和一种持续释放剂量结构;向患者联合给药鸦片样物质持续释放剂型和醇水溶液;从鸦片样物质持续释放剂型中释放出鸦片样物质;其中,鸦片样物质持续释放剂型释放小于约80重量百分比的鸦片样物质的剂量,从鸦片样物质持续释放剂型释放的所述鸦片样物质的剂量以如下方式测得:(a)利用含测试介质的体外测试方法和(b)在体外测试方法起始后约2小时内;而且其中,测试介质含醇水溶液,所述醇水溶液含等于或大于约20%体积/体积浓度的醇。 [0018] In another aspect, the present invention relates to a method, comprising: providing a opioid containing opioid sustained release dosage forms and the structure of a sustained release dosage; administered in combination to the patient opioid sustained release dosage form, and alcohol aqueous solution; from the opioid sustained release dosage form releases the opioid; wherein the opioid sustained release dosage form releases less than about 80 weight percent of the dose of the opioid, the release opioid from the opioid sustained release dosage form dose-like substances measured in the following manner: (a) using an in vitro test medium containing the test method and (b) in vitro test method starting within about 2 hours; and wherein the test medium is alcoholic solution, the alcohol solution containing equal to or greater than about 20% volume / volume concentration of alcohol.

[0019] 在另一个方面,本发明涉及一种方法,其包括:提供每天用一次的含氢吗啡酮的氢吗啡酮持续释放剂型和一种能提供每天用一次剂量的持续释放剂量结构;向患者联合给药每天用一次的氢吗啡酮持续释放剂型和醇水溶液;从每天用一次的氢吗啡酮持续释放剂型中释放出氢吗啡酮;其中,醇水溶液含等于或大于约20%体积/体积浓度的醇;而且其中,在剂型和醇水溶液向患者联合给药时所达到的单剂最大血浆浓度的时间中位数同在每天用一次的氢吗啡酮持续释放剂型不和醇水溶液联合给药而单独向患者给药时所达到的单剂最大血浆浓度的时间中位数之间的比率为约0.5至约1.0。 [0019] In another aspect, the present invention relates to a method, comprising: providing a hydrogen-containing hydromorphone once a day hydromorphone sustained release dosage forms and dose once daily sustained release dosage capable of providing the structure; the administered in combination with a patient per day hydromorphone sustained release dosage forms and the alcohol aqueous solution once; once released from the hydromorphone sustained release dosage form that day hydromorphone; wherein the aqueous alcohol solution containing equal to or greater than about 20% volume / volume the concentration of alcohol; and wherein, time to maximum plasma concentration of a single dose to a patient when administered in combination with aqueous alcohol in the dosage form and the median achieved with the use of a hydromorphone sustained release dosage form per day is administered in combination and not an aqueous alcohol solution and the ratio between the time a single dose maximum plasma concentration when administered to a patient alone reached a median of about 0.5 to about 1.0.

[0020] 在另一个方面,本发明涉及一种方法,其包括:提供含氢吗啡酮的氢吗啡酮持续释放剂型和一种持续释放剂量结构;向患者联合给药氢吗啡酮持续释放剂型和醇水溶液;从氢吗啡酮持续释放剂型中释放出氢吗啡酮;其中,醇水溶液含等于或大于约20%体积/体积浓度的醇;而且其中,在剂型和醇水溶液向患者联合给药时所达到的单剂最大血浆浓度的时间中位数同在氢吗啡酮持续释放口服剂型不和醇水溶液联合给药而单独向患者给药时所达到的单剂最大血浆浓度的时间中位数之间的比率为约0.5至约1.0。 [0020] In another aspect, the present invention relates to a method comprising: hydromorphone sustained release dosage forms and provides a sustained release dosage hydrogen morphinone structure; sustained release formulation is administered in combination to the patient hydromorphone hydrogen and alcohol aqueous solution; releasing hydromorphone from the sustained release dosage form the hydromorphone; wherein the aqueous alcohol solution containing equal to or greater than about 20% volume / volume concentration of alcohol; and wherein when administered in combination to a patient in a dosage form and the aqueous alcohol time between single dose maximum plasma concentration achieved with a median time to maximum plasma concentration median single dose of hydromorphone sustained release oral dosage forms administered in combination with aqueous alcohol and not individually administered to a patient that is reached ratio of from about 0.5 to about 1.0.

[0021] 在一个方面,本发明涉及一种方法,其包括:提供每天用一次的含鸦片样物质的鸦片样物质持续释放剂型和一种能提供每天用一次剂量的持续释放剂量结构;向患者联合给药每天用一次的鸦片样物质持续释放剂型和醇水溶液;从每天用一次的鸦片样物质持续释放剂型中释放出鸦片样物质;其中,醇水溶液含等于或大于约20%体积/体积浓度的醇;而且其中,在剂型和醇水溶液向患者联合给药时所达到的单剂最大血浆浓度的时间中位数同在每天用一次的鸦片样物质持续释放剂型不和醇水溶液联合给药而单独向患者给药时所达到的单剂最大血浆浓度的时间中位数之间的比率为约0.5至约1.0。 [0021] In one aspect, the present invention relates to a method, comprising: providing a once daily opioid containing an opioid and a sustained release formulation capable of providing sustained release dosage once daily dose of the structure; the patient once daily administered in combination with opioid sustained release dosage forms and the alcohol aqueous solution; releasing opioid from the once a day opioid sustained release dosage form; wherein the aqueous alcohol solution containing equal to or greater than about 20% volume / volume concentration alcohol; and wherein, time to maximum plasma concentration of a single dose to a patient when administered in combination dosage form and the aqueous alcohol with a median achieved with a sustained release opioid dosage form per day is administered in combination and not an aqueous solution of alcohol alone to the ratio between the time a single dose maximum plasma concentration achieved when the patient is administered a median of about 0.5 to about 1.0.

[0022] 在另一个方面,本发明涉及一种方法,其包括:提供含鸦片样物质的鸦片样物质持续释放剂型和一种持续释放剂量结构;向患者联合给药鸦片样物质持续释放剂型和醇水溶液;从鸦片样物质持续释放剂型中释放出鸦片样物质;其中,醇水溶液含等于或大于约20%体积/体积浓度的醇;而且其中,在剂型和醇水溶液向患者联合给药时所达到的单剂最大血浆浓度的时间中位数同在鸦片样物质持续释放剂型不和醇水溶液联合给药而单独向患者给药时所达到的单剂最大血浆浓度的时间中位数之间的比率为约0.5至约1.0。 [0022] In another aspect, the present invention relates to a method, comprising: providing a opioid containing opioid sustained release dosage forms and the structure of a sustained release dosage; administered in combination to the patient opioid sustained release dosage form, and alcohol aqueous solution; from the opioid sustained release dosage form releases the opioid; wherein the aqueous alcohol solution containing equal to or greater than about 20% volume / volume concentration of alcohol; and wherein when administered in combination to a patient in a dosage form and the aqueous alcohol time to maximum plasma concentration achieved the median single dose time to maximum plasma concentration at with a single dose of opioid sustained release dosage form administered in combination with aqueous alcohol and not individually administered to a patient that is reached between the median ratio is from about 0.5 to about 1.0.

附图说明 BRIEF DESCRIPTION

[0023] 图1显示了示例性的根据本发明的渗透泵剂型。 [0023] FIG. 1 shows an exemplary osmotic pump dosage form according to the invention.

[0024] 图2显示了本发明的持续释放剂型的实例。 [0024] Figure 2 shows examples of sustained release formulations of the present invention.

[0025] 图3显示了另一个示例性的剂型。 [0025] FIG. 3 shows another exemplary dosage form.

[0026] 图4显示了另一个示例性的剂型。 [0026] FIG. 4 shows another exemplary dosage form.

[0027] 图5A-5C显示了另一个示例性的剂型。 [0027] Figures 5A-5C illustrate another exemplary dosage form.

[0028] 图6显示了在乙醇水溶液中根据本发明的盐酸氢吗啡酮的16mg片剂的体外累计释放曲线。 [0028] FIG. 6 shows the cumulative release profile aqueous ethanol 16mg vitro hydromorphone hydrochloride tablets of the present invention according to hydromorphone.

[0029] 图7显示了在乙醇水溶液中根据本发明的盐酸氢吗啡酮16mg和PalladoneXL32mg之间的溶解曲线的比较。 [0029] Figure 7 shows in aqueous ethanol according to the comparison between the dissolution profile of the present invention is hydromorphone hydrochloride and hydromorphone 16mg PalladoneXL32mg.

[0030] 图8显示了平均(和SD)氢吗啡酮血浆浓度曲线。 [0030] FIG. 8 shows the mean (and SD) hydromorphone plasma concentration profile.

[0031] 图9显示了平均(和SD)氢吗啡酮血浆浓度曲线。 [0031] FIG. 9 shows the mean (and SD) hydromorphone plasma concentration profile.

[0032] 图10显示了单个Cmax比率:组I醇研究和相同剂量研究。 [0032] Figure 10 shows individual Cmax ratios: Group I Study and alcohols same dose studies.

[0033] 图11显示了单个Cmax比率:组2醇研究和相同剂量研究。 [0033] Figure 11 shows individual Cmax ratios: 2 and the same dose of alcohol research study group.

[0034] 图12显示了盐酸羟考酮从有或无硬脂醇的制剂中的释放。 [0034] FIG. 12 shows the release of oxycodone HCl from the formulation with or without the stearyl alcohol. [0035] 图13显示了盐酸氢吗啡酮从有或无硬脂醇的制剂中的释放。 [0035] FIG. 13 shows the release of hydromorphone HCl from the formulation with or without the stearyl alcohol.

[0036] 图14显示了Eudragit ® RS PO对盐酸羟考酮药物释放的作用。 [0036] FIG. 14 shows the Eudragit ® RS PO on oxycodone HCl drug release effect.

[0037] 图15显示了Eudragit ® RS PO对盐酸氢吗啡酮药物释放的作用。 [0037] FIG. 15 shows the Eudragit ® RS PO Hydromorphone Hydrochloride of the drug release.

[0038] 图16显示了硬脂醇、巴西棕榈蜡和氢化多羟基60蓖麻油对盐酸羟考酮释放功能的作用。 [0038] Figure 16 shows stearyl alcohol, carnauba wax and hydrogenated castor oil, polyhydroxy 60 functions to effect release oxycodone hydrochloride.

[0039] 图17显示了OxyContin⑧片剂的体外溶解曲线。 [0039] FIG. 17 shows the in vitro dissolution profiles OxyContin⑧ tablets.

[0040] 1.所述的鸦片样物质持续释放口服剂型 [0040] 1. The opioid sustained release oral dosage forms

[0041] 在认识到上述现有技术中的问题后,本发明人出人意料地发现了发明方案,其可提供针对醇诱导的剂量突然释放(尤其是乙醇诱导的剂量突然释放)的解决方案。 [0041] In recognition of the above-described problems of the prior art, the present inventors have surprisingly found that the invention of the embodiment, which may be provided for sudden release of alcohol-induced dose (especially ethanol-induced sudden release dose) solution.

[0042] 在本发现中要提到的是现有技术中没有认识到利用本发明的方法和相关持续释放剂型解决醇诱导(尤其是乙醇诱导)引起的剂量突然释放的问题。 [0042] In the present discovery is mentioned that the prior art does not recognize the use of the present invention and a method to solve the problem related to sustained release formulations induced a dose alcohols (especially ethanol-induced) caused by the sudden release. 与本文中披露的那些相似的剂型是针对其防止滥用的性质而应用的,而现有技术中不存在教导或提示认为这些结构可用于解决与醇诱导(尤其是乙醇诱导)的剂量突然释放相关的问题。 Dosage forms similar to those disclosed herein are for preventing the nature of the abuse and its application, while the prior art does not teach or suggest that the presence of these structures can be used to solve the dose with alcohol-induced (especially ethanol-induced) related sudden release The problem. 如,Maloney等的美国公开的专利申请2005163856披露了一种精细的颗粒大小的阳离子交换树脂,其含在羟考酮剂型中,能改善剂型体外提取的表现,可由潜在的滥用者使用。 Such as, Maloney, such as disclosed in U.S. Patent Application No. 2005163856 discloses a cationic particle size of finely-exchange resin, which contain oxycodone in dosage forms, the dosage form can improve the extraction performance in vitro, the potential abuser may be used. 可是Maloney等没有教导或提示该性质可用于解决本发明人着眼的醇水溶液诱导(尤其是乙醇水溶液诱导)的体内剂量突然释放的问题。 Maloney et but not teach or suggest the problem properties in vivo dose of the aqueous alcohol solution may be used to induce (especially aqueous ethanol-induced) of the present invention is focused sudden release. 那个教导或提示是由本发明人提供的。 Teach or suggest that is provided by the present invention.

[0043] 本发明不存在于先于本发明的技术中的其他证据是如下:开发持续释放鸦片样物质剂型技术的其他人实际上受困于醇诱导(尤其是乙醇诱导)的剂量突然释放。 [0043] The present invention is not present in the other prior art evidence of the present invention are as follows: Other people develop sustained-release opioid dosage form art inducing actually suffer alcohol (especially ethanol-induced) sudden release dose. 如,Palladone ® 延期释放氢吗啡酮(Purdue Pharma LP)、Kadian ® (Alpharma US Pharms) Such as, Palladone ® delayed release hydromorphone (Purdue Pharma LP), Kadian ® (Alpharma US Pharms)

·和Avinza ® (Ligand Pharmaceuticals)都被报道有涉及醇诱导(尤其是乙醇诱导)的剂量突然释放的问题。 · And Avinza ® (Ligand Pharmaceuticals) all are reported to have problems involving alcohol-induced dose (especially ethanol-induced) suddenly released. 尽管伴随有醇诱导(尤其是乙醇诱导)的剂量突然释放的风险,但这些产品已被商用的事实证明了,本文中提供的问题和解决方案不包括在本发明的现有技术中。 Despite the risk of sudden release is accompanied by an alcohol-induced dose (especially ethanol-induced), but these commercial products have been proved, the question provided herein and solutions are not included in the prior art of the present invention.

[0044] 在认识到问题和其解决方案后,本发明人考察了许多本发明的实施方案。 [0044] In recognition of the problems and their solutions, the present inventors examined a number of embodiments of the present invention. 在某些实施方案中,可能提供剂型包衣来进行降低或防止醇水溶液诱导的剂量突然释放。 In certain embodiments, the dosage form coating may be provided to reduce or prevent aqueous alcohol induced dose sudden release. 在另外的实施方案中,可选择某些疏水和/或亲水成分来进行降低或防止醇水溶液诱导的剂量突然释放。 In further embodiments, the selectable certain hydrophobic and / or hydrophilic component to reduce or prevent aqueous alcohol induced dose sudden release. 在保护性的剂型包衣方案中,选择的包衣可用于修正释放时间,如肠溶性包衣,或者可防止在醇中溶胀或溶解,如半透膜包衣或某些非肠溶性包衣。 In the embodiment the protective coating formulation, the coating may be selected for correcting the time of release, such as enteric coating, or be prevented from swelling or dissolution in an alcohol, such as certain non-permeable membrane coating or an enteric coating .

[0045] 在选择疏水成分来降低或防止醇水溶液诱导的剂量突然释放的方案中,优选相对不溶于水并最低程度地溶胀于醇水溶液的材料。 [0045] The hydrophobic component is selected to reduce or prevent aqueous alcohol induced dose sudden release, it preferred relatively insoluble in water and are minimally swellable in aqueous alcohol solution of the material. 如,可选疏水聚合物,其相对不溶于并最低程度地溶胀于水,而且在醇水溶液中显示出等量或更少的溶胀和/或溶解性。 The optional hydrophobic polymers, which are relatively insoluble and minimally swellable in water, but exhibit equal or less swelling and / or solubility in aqueous alcohol. 在包括非聚合疏水成分的方案中(包括但不限于蜡或像硬脂醇那样的脂肪酸醇),优选在醇水溶液中比在水中更少溶解/溶胀性的那些。 In the embodiment comprising a non-polymeric hydrophobic ingredients (including but not limited to stearyl alcohol as a wax or a fatty acid such as alcohols), preferably in an aqueous alcohol less than the dissolution / those swellable in water. 在选择亲水成分来降低或防止醇水溶液诱导的剂量突然释放的方案中,优选相对于水更不溶并较少倾向于溶胀于醇水溶液的材料。 The hydrophilic component is selected to reduce or prevent aqueous alcohol induced dose sudden release, preferred with respect to water is more insoluble and swellable in aqueous alcohol solution less prone material. 如,可选亲水聚合物,其相对于水显示出等量或更少的在醇水溶液中的溶胀和/或溶解性。 The optional hydrophilic polymer, relative to an equivalent amount of water or exhibit less swelling and / or solubility in aqueous alcohol. 在包括非聚合亲水成分的方案中,优选在醇水溶液中比在水中更少溶解/溶胀性的那些。 In the embodiment comprising a non-polymeric hydrophilic component, preferably in an aqueous alcohol less than dissolved / those swellable in water.

[0046] 用于本发明实践中来实现所期望的包衣、和疏水和疏水成分的一项技术是对审议中的材料塑膜并测试这些材料在醇水溶液存在时的溶胀性。 [0046] used in the practice of the present invention to achieve the desired coating, and a hydrophobic component and a hydrophobic technology is plastic film material consideration and test these materials swellable in the presence of an aqueous alcohol solution. 大量筛选技术可用于该膜测试,从而提供大量的合适材料。 A large number of screening techniques may be used to test the membrane, thereby providing a large number of suitable materials. 相似的技术可用于评估期望用于本发明实践中的材料的溶解性。 Similar techniques may be used to evaluate the solubility of the material desired for the practice of the present invention. 发现用于本发明实践中的材料的工作实施例可在本文其它部分中找到。 Example material was found in the practice of this invention for other work can be found in section herein.

[0047] 如以下实施例(尤其是实施例5)所披露的发明方案所示,可能在与醇水溶液联合给药时控制从鸦片样物质持续释放口服剂型中释放鸦片样物质的量。 [0047] The following Examples (in particular Example 5) shown in the disclosed embodiment of the invention, possible to control the amount of the sustained release oral dosage form releases the opioid from the opioid when administered in combination with aqueous alcohol. 在下述方案中,醇水溶液(如乙醇水溶液)不造成鸦片样物质从本发明方法所实践的剂型方案中失控、瞬时释放。 In the following embodiment, the aqueous alcohol (e.g. aqueous ethanol) does not cause uncontrolled opioid from the dosage form of the method according to the present invention is practiced in instant release. 如,在实施例5中,当以固定状态给药治疗时,观察到氢吗啡酮释放率依赖于乙醇浓度增加,造成Cmax的轻微增加和中值Tmax的减少(相对于用0%乙醇的6h,用醇则Tmax最小值为4小时,而相对于0%乙醇,用40%乙醇处理,观察到任何个体中Cmax最大增加2.5倍)。 As in Example 5, when the treatment is administered in a fixed state, it was observed hydromorphone release rate depends on the ethanol concentration increases, resulting in a slight increase in the Cmax and Tmax values ​​decrease (relative to the 0% ethanol 6h with an alcohol of the Tmax minimum of 4 hours, with respect to the 0% ethanol, treated with 40% ethanol, it was observed in any individual Cmax maximum 2.5-fold increase). 可是,会导致潜在致命缺陷的严重剂量突然释放没有出现。 However, potentially fatal dose can cause serious defects sudden release did not occur.

[0048] 在实施例5中,在服药后2小时的第一个时间点,血浆鸦片样物质(在本例中为氢吗啡酮)浓度接近于定量极限;之后,在所有喂药和固定组的4种处理方式中,血浆浓度缓慢升高。 [0048] In Example 5, the first time point of 2 hours after administration, plasma opioid (in the present embodiment as hydromorphone) close to the concentration limit of quantification; then, in all fixed and given medicines group the 4 treatments, the plasma concentration gradually increased. Tmax中位数介于12和16小时,而Tmax范围在各组处理方式之间是相似的。 The median Tmax of between 12 and 16 hours and Tmax ranging between treatment groups was similar. 这些数据提示示例剂型的受控释放性质在乙醇存在下也得以保持,没有“剂量突然释放”。 These data suggest that the controlled release properties of the dosage form examples are also maintained in the presence of ethanol, there is no "dose sudden release." 受控释放性质的保持与本发明方案的体外结果一致,其在实施例1和2中披露了在持续暴露于乙醇超过24小时下也不显示出剂量突然释放。 Consistent with in vitro results and maintain a controlled release properties of the present invention, which Examples 1 and 2 is disclosed in the continuous exposure to ethanol over 24 hours at a dose not exhibit a sudden release.

[0049] 本发明氢吗啡酮剂型的这些数据与称为Palladone ® (得自Purdue Pharma)的氢吗啡酮常规制剂所报道的结果相反。 [0049] These data hydrogen hydromorphone dosage form of the present invention and the result is called Palladone ® (available from Purdue Pharma) hydromorphone conventional formulations reported the opposite. 对于那个产品,可见到在体内和体外都有大量“剂量突然释放”。 For that product, you can see there are a lot of "dose sudden release" in vivo and in vitro. 在体外,如实施例2所示,在乙醇中约90%药物在I小时内释放。 In vitro, as shown in Example 2 embodiment, about 90% of drug is released in I h in ethanol. 在个体受试者体内,对于4 %、20 %和40 %乙醇来说,相对于O %乙醇,Cmax增加的最大倍数据报道分别为约2.0、5.7和15.7,而对于4%、20%和40%乙醇来说,相对于0%乙醇,对于所有受试者的平均增加值Cmax的增加最大倍数据报道分别为约1.1、2.1和5.8。 In an individual subject, for the 4%, 20% and 40% for ethanol, with respect to O% ethanol, a Cmax fold increase in the maximum data reported were about 2.0,5.7 and 15.7, whereas for the 4%, 20%, and 40% ethanol, the ethanol relative to 0%, the maximum fold increase in average data for all subjects Cmax values ​​increased coverage of about 1.1, 2.1 and 5.8 respectively.

[0050]用于本发明实践的`材料在本发明内容中有描述,尤其是在实施例1-3和7-11中。 [0050] `material for the practice of the present invention are described in the context of the present invention, particularly in Examples 1-3 and 7-11. 公开了许多用于实践本发明的材料。 It discloses a number of materials used in the practice of the present invention. 令人感兴趣的是OxyContin ® ,可得自Purdue PharmaLP的延长释放羟考酮产品,如实施例12所测试的,在存在醇水溶液时会显示出剂量突然释放的最轻微现象。 Interestingly OxyContin ®, available from Purdue PharmaLP extended release oxycodone products, as described in Example 12 is tested embodiment, in the presence of aqueous alcohol solution will show the slightest phenomenon of sudden release of the dose. 作为本发明的一部分,已经发现赋形剂硬脂醇可造成OxyContin ®能抗醇诱导的剂量突然释放。 As part of the present invention, it has been found excipient stearyl alcohol may cause OxyContin ® resistant to alcohol-induced dose sudden release. 该发现是本发明出人意料的性质的证据。 The present inventors have surprisingly found evidence properties. OxyContin ®已经用了多年,但其抗醇诱导的剂量突然释放的性质和该抗性潜在机制的发现直到本文描述了该发现才知道。 OxyContin ® has been used for many years, but found that its anti-alcohol-induced dose sudden release of nature and the potential mechanisms of resistance until the paper describes the discovery to know. 可在本文其它部分找到除了包括硬脂醇的其他制剂策略,其可用于开放持续释放剂型及相关方法来提供对醇水溶液诱导的剂量突然释放的抵抗性。 Can be found elsewhere herein, among other formulation strategies include stearyl alcohol, which may be open sustained release formulations and related methods for providing resistance to aqueous alcohol induced dose sudden release. 某些这类实施方案如实施例7-11所示。 Certain such embodiments as shown in Examples 7-11.

[0051] 现在,以下将更详细地描述本发明。 [0051] Now, the present invention is described in more detail.

[0052] I1.定义 [0052] I1. Definition

[0053] 除了有另外说明,所有百分比均为重量百分比。 [0053] In addition otherwise noted, all percentages are percentages by weight.

[0054] 本文中应用的所有公开文献全文都纳入本文参考,就好像它们在本文中复述过一样。 All publications full text [0054] applied herein are incorporated herein by reference, as if they had the same repeat in this article.

[0055] 本发明可通过参考本文提供的以下定义、附图和示例内容来进行最好的理解。 [0055] The present invention can provide herein by reference to the following definitions, the drawings and examples be best understood content.

[0056] “给药”或“用药”意思是给患者以药学上有效的方式提供药物。 [0056] "administering" or "administration" is meant to a patient in a pharmaceutically effective way of providing a drug. [0057] “醇”指有机化合物,其具有从I至约5个碳原子,其中羟基(-0H)与碳原子相连,所述碳原子依次还连有其它氢和/或碳原子。 [0057] "alcohol" refers to an organic compound having from I to about 5 carbon atoms, wherein the hydroxyl group connected (-0H) carbon atoms, the carbon atoms in turn is also connected other hydrogen and / or carbon atoms. 在优选的实施方案中,醇包括乙醇。 In a preferred embodiment, the alcohol comprises ethanol.

[0058] “表观终止半衰期” (tl/2)算作0.693/k,其中“k”指表观排除率常数,可通过在终止对数-线性排除阶段中的对数转换血浆浓度的线性衰减来估计。 [0058] "Apparent half-terminated" (tl / 2) counted as 0.693 / k, where "k" means the apparent rate constant negative, may be terminated by a number of - linear linear negative logarithmic conversion stage plasma concentration attenuation estimates.

[0059] “醇水溶液”指含水和醇的组合物。 [0059] "aqueous alcohol solution" refers to a composition of water and alcohol. 在醇水溶液中存在有可变数量的醇。 In the presence of aqueous alcohol with a variable number of alcohol. 优选醇水溶液中,醇水溶液含约I体积/体积百分比(v/v%,即醇体积/醇水溶液总体积,以百分比表示)至约lOOv/V1^醇,更优选醇水溶液含醇浓度等于或大于约20V/V%,更优选醇水溶液含醇浓度等于或大于约25V/V%,并更优选醇水溶液含醇浓度等于或大于约40V/V%。 Aqueous solution, preferably an alcohol, the alcohol solution containing about volume / volume percent (v / v%, of the total volume, i.e. an alcohol volume / alcohol solution, expressed as a percentage) I to about lOOv / V1 ^ alcohol, more preferably an aqueous alcohol solution containing alcohol concentration is equal to or greater than about 20V / V%, and more preferably an alcohol solution containing alcohol concentration is equal to or greater than about 25V / V%, and more preferably an alcohol solution containing alcohol concentration is equal to or greater than about 40V / V%.

[0060] “曲线下面积”或“AUC”是在血浆药物浓度曲线下所测得的面积。 [0060] "Area Under the Curve" or "AUC" is the plasma drug concentration curve at the measured area. 通常,AUC专用于指血浆药物浓度曲线所经过的时间间隔的和,如AUC开始-终止。 Typically, dedicated to the AUC and plasma drug concentration curve refers to the elapsed time interval, such as AUC begins - terminated. 因此AUC0-48指O至48小时间所加得的血浆药物浓度曲线的AUC,其中O通常是向患者给药药物或含药物的剂型的时间。 Thus AUC0-48 refers to the AUC O 48 hour period was added plasma drug concentration profile, where O is usually time or administration of the drug to the patient a dosage form containing a drug. AUCt指O小时至最终在时间t检测得到浓度时的血浆药物浓度曲线下面积,其通过梯形法则算得。 AUCt refers to the O h to a final time t area under the plasma concentration curves obtained during density detection, which calculated by the trapezoidal rule. AUCinf指外推到无限处的AUC值,其算作AUCt和外推到无限处的面积的和,其可通过时间t (Ct)浓度除以k而算得。 AUCinf refers to the AUC value extrapolated to infinity at which counted AUCt and the area extrapolated to infinity, and at that time can be calculated by t (Ct) divided by the concentration of k. (如果无法评估个体的tl/2值,则将该治疗的平均tl/2值用于计算AUCinf。)。 (If not assessed tl / 2 values ​​of the individual, the treatment of the average tl / 2 value is used to calculate AUCinf.). “平均、单剂、血浆药物浓度曲线下面积AUCinf”指平均AUCinf,其根据在不同情况下几个患者或向相同患者多次给药而获得,能足够清除给药影响,从而在向每个患者单次给药剂型之后使药物水平回归于给药前水平。 "Mean, single dose, area under the plasma drug concentration curve AUCinf" refers to the mean AUCinf, which is obtained in accordance with multiple administration of several different situations in the same patient or a patient, sufficient scavenging can be administered so that to each after the patient a single dosage form drug levels return to pre-dose levels.

[0061] “C”指患者血浆、或血清中的药物浓度,通常用每单位体积的质量来表示,典型的有纳克每毫升。 [0061] "C" refers to the patient's plasma, or serum drug concentrations, usually mass per unit volume expressed, are typically nanograms per milliliter. 通常,该浓度可指本文中的“药物血浆浓度”、“血浆药物浓度”或“血浆浓度”。 Typically, this concentration may be referred to as "drug plasma concentration" herein, "plasma drug concentration" or "plasma concentration." 给药后任何时间的血浆药物浓度被称作C时间,如C9h或C24h等。 Plasma drug concentration at any time after administration and the like is referred to as C time, as C9h or C24h. 给药剂型后不插值而直接从试验数据中得到的最大血浆浓度被称作C_,在所指出的时间内得到的平均血浆浓度被称为Cavg或C平均。 Interpolation is not directly referred to from C_ maximum plasma concentration data obtained after administration of test formulations, the mean plasma concentration obtained within the indicated time is referred to as Cavg or C average. “平均、单剂、最大血浆浓度”指平均Cmax,其根据在不同情况下几个患者或向相同患者多次给药而获得,能足够清除给药影响,从而在向每个患者单次给药剂型之后使药物水平回归于给药前水平。 "Mean, single dose, maximum plasma concentration" refers to the mean Cmax, which is obtained in accordance with multiple administration of several different situations in the same patient or a patient, sufficient scavenging can be administered to each patient in a single direction after the drug agent type levels return to pre-dose levels. “患者个体、单剂、最大血浆浓度”指平均Cmax,其根据在单个患者单次给药而获得,能足够清除给药影响,从而在向每个患者单次给药剂型之后使药物水平回归于给药前水平。 An "individual, single dose, maximum plasma concentration patient" refers to the mean Cmax, in which a single dose is obtained according to the individual patient, administration can be sufficient to remove the influence, so that the return to drug levels after a single administration of a dosage form to each patient at pre-dose level.

[0062] 在实施方案中,本发明方法包括,从鸦片样物质持续释放剂型(优选每天用一次或每天用两次的鸦片样物质持续释放剂型)中释放出鸦片样物质(诸如但不限于氢吗啡酮和羟考酮),其中,在鸦片样物质持续释放剂型和醇水溶液向患者联合给药时所达到的平均单剂最大血浆鸦片样物质浓度同在鸦片样物质持续释放剂型不和醇水溶液联合给药而单独向患者给药时所达到的平均单剂最大血浆鸦片样物质浓度之间的比率等于或小于约1.8: 1,更优选等于或小于约1.6: 1,并甚至更优选等于或小于约1.4: I。 [0062] In an embodiment, the method of the present invention comprises, from the opioid sustained release dosage form (preferably once a day or by opioid sustained release formulation twice daily) in the release of the opioid (such as, but not limited to hydrogen hydromorphone and oxycodone), wherein the opioid sustained release mean single dose maximum plasma opioid concentration alcohol aqueous solution and the dosage to the patient when administered in combination is achieved in the same opioid sustained release dosage forms and the alcohol solution is not and the ratio between the combined administration separately to the patient when administered to achieve a mean single dose maximum plasma opioid concentration of the substance is equal to or less than about 1.8: 1, more preferably equal to or less than about 1.6: 1, and even more preferably equal to or less than about 1.4: I.

[0063] 在实施方案中,本发明方法包括,从鸦片样物质持续释放剂型中释放出鸦片样物质(诸如但不限于氢吗啡酮和羟考酮),其中,在鸦片样物质持续释放剂型(优选每天用一次或每天用两次的鸦片样物质持续释放剂型)和醇水溶液向患者联合给药时所达到的单个患者单剂最大血浆鸦片样物质浓度同在鸦片样物质持续释放剂型不和醇水溶液联合给药而单独向患者给药时所达到的单个患者单剂最大血浆鸦片样物质浓度之间的比率等于或小于约5: 1,优选等于或小于约4: 1,更优选等于或小于约3: I。 [0063] In an embodiment, the method of the present invention comprises, releasing opioid (such as, but not limited to hydromorphone and oxycodone) from the opioid sustained release dosage form, wherein the sustained release dosage forms of opioid ( preferably once daily or twice daily by a single patient when the opioid sustained release dosage form is administered in combination), and aqueous alcohol to a patient achieved a single dose maximum plasma opioid concentration in the same opioid sustained release formulations and no alcohol administered in combination and the ratio between the aqueous solution separately to the individual patient when the patient is administered a single dose achieved maximum plasma opioid concentration of the substance is equal to or less than about 5: 1, preferably equal to or less than about 4: 1, more preferably equal to or less than about 3: I.

[0064] “共给药”、“共用药”和“联合给药”都指向患者在有限时间内给药两种或更多种物质,优选在180分钟内,更优选在60分钟内,甚至更优选在45分钟内,更优选在30分钟内,并更优选在15分钟内。 [0064] The "co-administration", "co-administration" and "administered in combination" point two kinds of administering to a patient in a limited time or more substances, preferably within 180 minutes, more preferably within 60 minutes, even more preferably within 45 minutes, more preferably within 30 minutes, and more preferably within 15 minutes.

[0065] “剂型”指处在介质、载体、媒介或设备中的适合向患者给药的鸦片样物质。 [0065] "dosage form" means suitable for administration to a patient of opioids in the medium, carrier, or media device. “ 口服剂型”指适合口服给药的剂型。 "Oral dosage form" means a dosage form suitable for oral administration. 在实施方案中,本发明的剂型可包含用于持续释放鸦片样物质的持续释放剂量结构,并任选用于瞬时释放鸦片样物质的瞬时释放成分。 In an embodiment, the dosage form of the present invention can comprise a sustained release dosage structures for sustained release of the opioid and optionally the instantaneous release of ingredients for instant release of the opioid. 在实施方案中,本发明的剂型可包括或不包括,鸦片样物质拮抗剂,如纳曲酮、纳洛酮、或其他常规鸦片样物质拮抗剂。 In an embodiment, the dosage form of the present invention may or may not include, opioid antagonists such as naltrexone, naloxone, or other conventional opioid antagonist.

[0066] “剂量”指药物单位。 [0066] "dose" refers to a pharmaceutical unit. 通常,以剂型来确定剂量。 Typically, a dosage form to determine the dose. 根据各种用药方案可向患者以剂量给药。 The dosage may be administered in various regimen to the patient. 一般用药方案包括每天一次(qd)、每天两次(bid)和每天三次(tid)。 General medicine program includes daily (qd), twice daily (bid) and three times a day (tid). 用于本发明实践中的鸦片样物质剂量介于约0.0Olmg至约5000mg,优选约0.0lmg至约IOOOmg,更优选约0.1mg至约750mg,优选约0.5mg至约500mg,更优选约0.5mg至约250mg,更优选约Img至约IOOmg,并最优选约Img至约50mg。 Opioid dosage for the practice of the present invention is between about 0.0Olmg to about 5000mg, preferably from about to about 0.0lmg IOOOmg, more preferably from about 0.1mg to about 750mg, preferably about 0.5mg to about 500mg, more preferably from about 0.5mg to about 250mg, more preferably from about to about Img IOOmg, and most preferably from about Img to about 50mg.

[0067] “瞬时释放剂型”指向患者给药剂型后小于或等于约45分钟内释放等于或大于约75%的药物的剂型。 [0067] "instant release dosage form" is less than or equal to the release point to the patient the dosage form is equal to or greater than about 75% of the pharmaceutical dosage form of about 45 minutes.

[0068] “每天一次”(即qd)或“每天两次”(即bid)指根据本发明方法的用药频率。 [0068] "once a day" (i.e., qd) or "twice a day" (i.e. bid) refers to the frequency of administration, according to the method of the present invention. 如,每天一次用药一般指每24小时内用药一次,如qd。 For example, once a day, generally refers to the drug administered once every 24 hours, as qd.

[0069] “鸦片样物质”指与鸦片样物质受体结合的试剂,所述鸦片样物质受体理论上在中枢神经系统和胃肠道中被发现,而且其选自罂粟碱和半合成或全合成的鸦片样物质。 [0069] "opioid" refers to a receptor binding to opioid agents, the theory opioid receptors are found in the gastrointestinal tract and the central nervous system, and which is selected from semisynthetic or fully papaverine and synthetic opioids. 罂粟碱的实例包括吗啡、可待因和二甲基吗啡。 Papaverine Examples include morphine, codeine and thebaine. 半合成鸦片样物质的实例包括二乙酰吗啡(海洛因)、羟考酮、氢可酮、二氢可待因、氢吗啡酮、氧吗啡酮和尼克吗啡。 Examples of semi-synthetic opioids include diacetylmorphine (heroin), oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone and morphine Nick. 全合成的鸦片样物质的实例包括美沙酮、盐酸左旋美沙酮乙酯(LAAM)、哌替啶(度冷丁)、凯托米酮、丙氧芬、右丙氧芬、右吗拉胺、贝齐米特、哌腈米特、喷他佐辛和非那佐辛。 Examples of wholly synthetic opioids comprise methadone, methadone hydrochloride, ethyl L (LAAM), pethidine (meperidine), ketobemidone, propoxyphene, dextropropoxyphene, dextromoramide pull amine, Beiqi Mi special, piritramide, pentazocine and phenazocine. 其他鸦片样物质是本领域技术人员所知的。 Other opioids are known to those of skill. 本发明实践中优选的鸦片样物质包括口服生物相容的鸦片样物质。 The preferred practice of the invention include oral opioid biocompatible opioid. 更优选的鸦片样物质包括吗啡、·吗啡酮、氢可酮、氧吗啡酮和羟考酮。 More preferred opioids comprise morphine, hydromorphone ·, hydrocodone, oxymorphone and oxycodone. 鸦片样物质包括药学上可接受的盐、和游离碱或游离酸形式的本发明鸦片样物质。 Opioids include pharmaceutically acceptable salts, free base or free acid form of the present invention opioid. 在实施方案中,本发明的鸦片样物质持续释放口服剂型包括约0.0lmg至约IOOOmg鸦片样物质,优选约0.1mg至约500mg鸦片样物质,更优选约0.25mg至约300mg鸦片样物质,更优选约Img至约IOOmg鸦片样物质。 In an embodiment, the present invention opioid sustained release oral dosage forms include from about to about IOOOmg 0.0lmg opioids, preferably from about 0.1mg to about 500mg opioids, more preferably from about 0.25mg to about 300mg opioids, more preferably from about to about Img IOOmg opioids. 应注意到,本发明鸦片样物质在水和/或醇水溶液中的溶解度会有显著不同。 It should be noted, the present invention opioid solubility in water and / or aqueous alcohol have significantly different. 在实施方案中,持续释放剂型中的鸦片样物质的量和/或该鸦片样物质醇水溶液溶解性可正面或负面影响本发明持续释放剂型和/或相关方法在醇水溶液中的剂量突然释放表现。 In an embodiment, the amount of the sustained release opioid dosage form and / or the opioid alcohol aqueous solution Solubility positive or negative effect of the present invention dose sustained release formulation and / or related methods in aqueous alcohol sudden release performance . 如,在某些实施方案中,大量高醇水溶液不溶性的鸦片样物质和/或鸦片样物质形式可增加醇水溶液诱导的剂量突然释放的可能性。 For example, in certain embodiments, the likelihood of aqueous alcohol-induced dose sudden release of a large amount of high aqueous alcohol insoluble opioid and / or opioid form can be increased. 相反,在某些实施方案中,大量高醇水溶液溶解性的鸦片样物质和/或鸦片样物质形式可降低醇水溶液诱导的剂量突然释放的可能性。 In contrast, in certain embodiments, a large number of high solubility in aqueous alcohol opioid and / or opioid form can reduce the likelihood of aqueous alcohol-induced dose sudden release.

[0070] “口服持续释放剂量结构”指适合向患者口服给药的结构,其包含一种或多种药物,其中该结构能持续释放药物。 [0070] "oral sustained release dosage structure" means a structure suitable for oral administration to a patient, which comprises one or more drugs, wherein the structure of the sustained release drug. “渗透性口服持续释放剂量结构”指口服持续释放剂量结构,其中该结构通过渗透机制来持续释放药物。 "Osmotic oral sustained release dosage structure" means an oral sustained release dosage structure, wherein the structure to sustained release drug by osmotic mechanism.

[0071] “患者”指需要治疗干预的动物,优选哺乳动物,更优选人。 [0071] "Patient" means an animal in need, preferably a mammal for therapeutic intervention, more preferably a human.

[0072] “药学上可接受的盐”指任何盐,其阴离子不显著造成盐的毒性或药理学活性,而且例如,它们是药物碱的药物等价体。 [0072] "Pharmaceutically acceptable salts" means any salt whose anion does not significantly cause toxicity or pharmacological activity of the salt, and for example, a base drug are pharmaceutical equivalents. 合适的药学上可接受的盐包括酸加成盐,如其可通过药物化合物同合适的药学上可接受的酸反应生成,所述酸如盐酸、硫酸、延胡索酸、马来酸、琥珀酸、乙酸、苯甲酸、柠檬酸、酒石酸、碳酸或磷酸。 Suitable pharmaceutically acceptable salts include acid addition salts, as it may be acceptable with a pharmaceutically suitable pharmaceutical compounds by reaction of an acid, such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.

[0073] 所以,有代表性的药学上可接受的盐包括但不限于以下:乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、溴化物、钙依地酸盐、樟磺酸盐、碳酸盐、氯化物、克拉维酸盐、柠檬酸盐、二盐酸化物、依地酸盐、乙二磺酸盐、依托酸盐、乙磺酸盐、延胡索酸盐、葡庚糖酸盐、葡萄糖酸盐、谷氨酸盐、乙二醇基阿散酸盐(glycollylarsanilate)、己基间苯二酹盐、海巴明盐(hydrabamine)、氢溴酸盐、盐酸盐、轻基萘甲酸盐、碘化物、异硫代硫酸盐、乳酸盐、乳糖酸盐、月桂酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物、甲基硝酸盐、甲基硫酸盐、mucate、萘磺酸盐、硝酸盐、N-甲基葡糖胺铵盐、油酸盐、双羟萘酸盐(双羟萘酸盐)、棕榈酸盐、泛酸盐、磷酸盐/ 二磷酸盐、聚半乳糖醛酸盐、水杨酸盐、硬脂酸盐、硫酸盐、 [0073] Thus, representative pharmaceutically acceptable salts include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate , bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycol Chios scattered salt (, glycollylarsanilate), inter-hexyl xylylene sprinkle salt, hydrabamine salts (glucamine, hydrabamine), hydrobromide, hydrochloride, light-yl-naphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methylsulfate, mucate, napsylate, nitrate, N- methylglucamine ammonium salt, oleate, pamoate ( embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, 式乙酸盐、琥珀酸盐、鞣酸盐、酒石酸盐、茶氯酸盐、甲苯磺酸盐、三乙基碘化物和戊酸盐。 The acetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. 有代表性的药学上可接受的鸦片样物质盐包括但不限于盐酸氢吗啡酮、盐酸羟考酮、硫酸吗啡、盐酸氧吗啡酮和酒石酸氢氢可酮。 Representative pharmaceutically acceptable salts of opioids include, but are not limited to hydromorphone hydrochloride, oxycodone hydrochloride, morphine sulfate, oxymorphone hydrochloride and hydrocodone bitartrate.

[0074] “血浆药物浓度曲线”或“药物血浆浓度曲线”或“血浆浓度曲线”或“血浆曲线”或“血浆浓度曲线”指通过对血浆药物浓度或药物血浆浓度或血浆浓度与时间绘图而获得的曲线。 [0074] "plasma drug concentration curve" or "drug plasma concentration curve" or "plasma concentration profile" or "plasma profile" or "plasma concentration curve" refers to the plasma drug concentration or drug plasma concentration, or plasma concentration versus time plot and curve obtained. 通常,习惯上在时间范围上的O点(通常在X轴上)是向患者给药药物或含药物的剂型的时间。 Typically, in the time range O points (typically on the X axis) the time is customary to administration of the drug or drug-containing dosage form of the patient.

[0075] “延长的时间期”指大于约2小时的连续时间期,优选大于约4小时,更优选大于约8小时,更优选大于约10小时,更优选大于约14小时,最优选大于约14小时并至多约24小时。 [0075] "prolonged time period" means that greater than about 2 hours of continuous period of time, preferably greater than about 4 hours, more preferably greater than about 8 hours, more preferably greater than about 10 hours, more preferably greater than about 14 hours, most preferably greater than about 14 hours and up to about 24 hours.

[0076] “释放的速率”或“释放率”指每单位时间从剂型中释放的药物的量,如每小时释放的药物的毫克数(mg/hr)。 [0076] "rate of release" or "release rate" refers to the release per unit time of the amount of drug from the dosage form, such as the number of milligrams of drug released per hour (mg / hr). 剂型的药物释放率可以是体外测得的药物释放率,即在合适的条件下并以合适的测试介质测得的每单位时间从剂型中释放的药物的量。 Rate of drug release dosage form may be measured in vitro drug release rate, i.e. the amount per unit time and in the appropriate test medium measured at the release from the dosage form of the drug under appropriate conditions.

[0077] 在优选的实施方`案中,可以通过将剂型置于去离子水、金属圈或金属框形样品支架中测试来确定本文中所称的释放率,所述支架与USP VII型温浴分度器相连,测试在37°C的恒温水浴中进行。 [0077] In a preferred embodiment `case, may be placed in deionized water, the metal ring-shaped metal frame or sample holder test to determine the release rate as referred to herein, the stent and USP VII warm bath type dosage forms by the indexer is connected in the test water bath of 37 ° C. 以预先设置的间隔收集释放速率溶液等分部分,然后注入适合用与紫外线或折射指数检测仪一起使用的色谱系统来定量测试间隔期间释放的药物的量。 Release rate of the solution was collected at intervals of a preset aliquot portion, and then injected into the chromatographic system suitable for use with UV or refractive index detector to quantitate the drug released during the testing intervals amount. 在其他实施方案中,其他常见和体外应用的释放率测试也可以用于本发明的实践中,如使用USP II 型设备,如DistekPremiere ® 5100。 In other embodiments, other common release rate testing and in vitro applications can also be used in the practice of the present invention, such as the type using USP II apparatus, such as a DistekPremiere ® 5100.

[0078] 在实施方案中,利用体外测试方法,本发明的鸦片样物质持续释放剂型从鸦片样物质持续释放剂型中释放少于或等于约80重量百分比的、优选少于或等于约70重量百分比的、更优选少于或等于约60重量百分比的、更优选少于或等于约50重量百分比的、更优选少于或等于约40重量百分比的、最优选少于或等于约25重量百分比的鸦片样物质剂量。 [0078] In an embodiment, using an in vitro test method, the opioid sustained release formulations of the present invention release less than or equal to about 80 percent by weight of the opioid sustained release dosage form, preferably less than or equal to about 70 weight percent , more preferably less than or equal to about 60 weight percent, more preferably less than or equal to about 50 weight percent, more preferably less than or equal to about 40 weight percent, most preferably less than or equal to about 25 weight percent of opium like substance dose. 在优选的实施方案中,体外测试方法,如本文中公开的体外测试方法,或其他常规的体外测试方法,包括了测试媒介,鸦片样物质持续释放剂型在测试期间被置于该媒介中。 In a preferred embodiment, the in vitro testing methods such as in vitro testing methods disclosed herein, or other methods conventional in vitro tests, including a test media, the opioid sustained release dosage form is placed in the medium during the test. 在实施方案中,测定从本发明鸦片样物质持续释放剂型中释放的鸦片样物质的量一段时间,优选在开始体外测试方法后约24小时的时间,更优选在开始体外测试方法后约12小时的时间,并更优选在开始体外测试方法后约2小时的时间。 In an embodiment, determining the amount of a time released from opioid present invention is a sustained release dosage form opioids, preferably at about 24 hours after the start of in vitro testing methods, and more preferably from about 12 hours after the start of in vitro testing methods time period, and more preferably after the start of in vitro testing methods for about 2 hours.

[0079] 在实施方案中,测试媒介包括含醇的醇水溶液。 [0079] In an embodiment, the test media comprises aqueous alcohol solution containing alcohol. 在优选的实施方案中,测试媒介包括含醇浓度等于或大于约20%体积/体积(醇体积/测试媒介总体积)的醇水溶液,优选等于或大于约25%体积/体积,更优选等于或大于约30%体积/体积,更优选等于或大于约35%体积/体积,最优选等于或大于约40%体积/体积。 In a preferred embodiment, the test media comprising alcoholic concentration equal to or greater than about 20% volume / volume (alcohol volume / test vehicle total volume) aqueous alcohol solution, preferably equal to or greater than about 25% volume / volume, more preferably equal to or greater than about 30% volume / volume, more preferably greater than or equal to about 35% v / v, most preferably greater than or equal to about 40% volume / volume.

[0080] “持续释放”或“持续的释放”指在长时间内连续释放或连续地释放药物或药物剂量。 [0080] "sustained release" or "sustained release" means continuous release or continuously releasing the drug or drug doses over a long time.

[0081] “持续释放剂量结构”指一种或多种物理部件,其提供持续释放药物或药物剂量。 [0081] "sustained release dosage structure" refers to one or more physical components, which provides a sustained release of the drug or drug dose.

[0082] “持续释放剂型”指一种剂型类型,其提供持续释放药物或药物剂量。 [0082] "sustained release dosage form" refers to a type of dosage form that provides sustained release of the drug or drug dose.

[0083] “中位、单剂、达到最大血浆浓度的时间Tmax”指中位数,其根据几个患者或向相同患者多次给药而获得,能足够清除给药影响,从而在向每个患者单次给药之后,经过从向患者给药含药物的剂型到该药物达到Cmax的时期,使药物水平回归于给药前水平,其不进行插值而直接从试验数据中获得。 [0083] "median single dose, time to maximum plasma concentration Tmax of" refers to the median, which is obtained according to several patients or multiple administrations to the same patient, can be enough to remove the influence of administration so that each of the patients after single administration, after a period of time to reach Cmax of the drug from the dosage form containing the drug to be administered to a patient, the drug levels return to pre-dose levels, which is not directly obtained by interpolating the data from the experiment. 在实施方案中,在剂型和醇水溶液向患者联合给药时所达到的单剂最大血浆浓度的时间中位数同在鸦片样物质持续释放剂型不和醇水溶液联合给药而单独向患者给药时所达到的单剂最大血浆浓度的时间中位数之间的比率为约0.5至约1.0,优选约0.6至约1.0,更优选约0.7至约1.0,最优选约0.75至约1.0。 In an embodiment, time to maximum plasma concentration of a single dose and dosage form in combination with aqueous alcohol to a patient achieved in the same median opioid sustained release dosage form administered in combination with aqueous alcohol and not separately administered to the patient time to maximum plasma concentration achieved when a single dose of the ratio between the number of bits is from about 0.5 to about 1.0, preferably from about 0.6 to about 1.0, more preferably from about 0.7 to about 1.0, most preferably from about 0.75 to about 1.0.

[0084] “治疗有效量”指药物的量,其能在研究者、兽医、药师或其他临床医师所寻找的组织系统、动物或人中得到生物或药物应答,包括改善要治疗的疾病或病症的症状。 [0084] "therapeutically effective amount" refers to the amount of the drug, which can in organization systems researcher, veterinarian, pharmacist or other clinician are looking for, animal or human to get a biological or drug response, including the improvement of a disease or disorder to be treated symptoms.

[0085] II1.剂型 [0085] II1. Dosage

[0086] 在实施方案中,本发明的持续释放剂型配制成可向需要的患者给药的剂型。 [0086] In an embodiment, the sustained release formulations of the present invention is formulated into dosage forms can be administered to a patient in need thereof. 现在将描述持续释放剂型和利用持续释放剂型的治疗方法。 We will now be described sustained release dosage forms and methods of treatment using the sustained release dosage form. 可以理解,下述持续释放剂型仅仅是示例性的。 It will be appreciated, the following sustained release formulations are merely exemplary.

[0087] 各种持续释放剂型适合于本发明。 [0087] Various sustained release dosage form suitable for the present invention. 在某些实施方案中,剂型是口服给药的,其大小和形状如同常规的片剂或胶囊,口服剂型可根据各种不同方法之一来制造。 In certain embodiments, the dosage form is administered orally, its size and shape as a conventional tablet or capsule, oral dosage form may be manufactured according to one of various different methods. 如Pharmaceutical Sciences, Remington,第18 版,pp.1676-1686 (1990), Mack 出版公司;The Pharmaceutical and Clinical Pharmacokinetics,第3 版,pp.1-28 (1984), Lea 和Febreger, Philadelphia所述,如,剂型可制备成分散体系,如忙存体或模床体,溶解系统,如胶囊溶解体(包括如,“少时药丸”和颗粒)和模床溶解体,及联合扩散/溶解体和离子交换树脂体。 As Pharmaceutical Sciences, Remington, 18th Ed., Pp.1676-1686 (1990), Mack Publishing Company; The Pharmaceutical and Clinical Pharmacokinetics, 3rd edition, pp.1-28 (1984), Lea and Febreger, Philadelphia said, For example, dosage forms may be prepared as dispersions, such as busy storage body or molded bed, dissolution system, such as capsules dissolved materials (including, for example, "little time pills", and granules) and the mold bed dissolution thereof, and combination diffusion / dissolution thereof and ion exchange resin body.

[0088] 渗透剂型一般利用渗透压来产生驱动力,如果存在,通过允许流体自由分散而不允许药物或渗透剂分散的半透膜,将液体吸入形成(至少部分)的小室。 [0088] The osmotic dosage forms typically utilize osmotic pressure to generate a driving force, if present, by allowing free fluid dispersion without allowing the drug or osmotic agent dispersed in a semipermeable membrane, forming the liquid into the (at least partially) of the chamber. 渗透系统的显著优点是不依赖于PH操作并因而在长时间中以渗透决定的速率持续释放,甚至剂型转移到胃肠道要面对显著不同pH值的差异微环境。 A significant advantage to osmotic systems is not dependent on the PH and therefore to operate permeation rate determined in sustained release in time, and even transferred to the gastrointestinal tract a dosage form face significantly different pH values ​​of differences microenvironment. 这类剂型的综述可在Santus和Baker,“Osmoticdrug delivery:a review of the patentliterature,,,Journal of Controlled Release35(1995) 1-21中找到,其纳入本文参考。美国专利N0.3845770、3916899、3995631、4008719、4111202、 4160020、4327725、4578075、4681583、5019397 和5156850 披露了用于持续分配活性剂的渗透体。 Review of such dosage forms can be, "Osmoticdrug delivery in Santus and Baker: a review of the patentliterature ,,, Journal of Controlled Release35 (1995) 1-21 is found, which is incorporated herein by reference U.S. Patent No. N0.3845770,3916899,3995631. , 4008719,4111202, and 5156850 disclose 4160020,4327725,4578075,4681583,5019397 body for the sustained osmotic dispensing the active agent.

[0089]如美国专利 N0.5633011、5190765、5252338、5620705、4931285、5006346、5024842和5160743所述,渗透持续释放剂型中药物组合物通过扩展层的作用以浆液、悬浮液或溶液从小出口递送,其纳入本文参考。 [0089] The U.S. Pat and the N0.5633011,5190765,5252338,5620705,4931285,5006346,5024842 5160743, osmotic sustained release dosage form by the action of the pharmaceutical composition layer to extend the slurry, suspension or solution from small delivery outlet, which is incorporated herein by reference. 典型的系统包括可扩展的推进层和由半透膜包衣的药物层。 A typical system includes an expandable push layer and a drug layer coated by a semipermeable membrane. 在某些情况下,药物层带有内层来延缓药物组合物释放到使用环境中或形成与半透膜结合的退火包衣。 In certain instances, the drug layer with the inner layer to delay release of the pharmaceutical composition into the environment of use, or formed in conjunction with the semipermeable membrane coating annealing. 在实施方案中,对于渗透持续释放剂型,可用肠溶衣来进一步防止剂量突然释放,优选一种不溶于醇水溶液并且不在醇水溶液和肠PH下溶胀的肠溶衣。 In an embodiment, for the osmotic sustained release formulations, enteric coating can be used to further prevent the sudden release of the dose, preferably an aqueous solution of alcohol is insoluble and not swellable in an alcohol aqueous enteric coated and enteric PH. 为保护半透膜,用亲水薄膜(如聚乙烯醇)或疏水材料包衣半透膜。 It is a protective semipermeable membrane, with a hydrophilic film (e.g., polyvinyl alcohol) coating the semipermeable membrane or hydrophobic materials. 如果该层使较少的乙醇接触半透膜,则可避免或最小化半透膜的溶胀。 If the layer is less that the semi-permeable membrane in contact with ethanol, can avoid or minimize the swelling of the semipermeable membrane.

[0090] 图1显示了示例性的剂型,在现有技术中被称为基本渗透泵剂型。 [0090] FIG. 1 shows an exemplary dosage form, known as osmotic pump dosage form substantially in the prior art. 剂型20,如横截面所示,也被称为基本渗透泵(EOP),包括围绕和包衣内部小室24的半透膜22。 Dosage form 20, as shown in cross-section, also called a basic osmotic pump (the EOP), and comprising a coating surrounding the semipermeable membrane 22 inside the chamber 24. 内部小室包含本文中被称为药物层26的单成分层,包括与选择的赋形剂混合的本发明的物质28。 The interior chamber including a single component layer referred to herein as drug layer 26, comprising a mass 28 of the present invention is mixed with the selected excipients. 赋形剂适于提供一种渗透活性梯度,吸收外环境的液体通过膜22并形成可递送的复合制剂来吸取液体。 Excipients adapted to provide an osmotic activity gradient, the liquid absorbent outer environment through membrane 22 and forms a complex formulation may be delivered to absorb liquid. 赋形剂可包括合适的本文中也称其为药物载体30的悬浮剂、粘合剂32、润滑剂34和被称作渗透剂36的渗透活性剂。 Suitable excipients may include also referred to herein as drug carrier 30, a suspending agent, a binder 32, a lubricant 34, and osmotically active agent referred to as penetrants 36. 用于这些成分的示例性材料科可在本申请内容中找到。 Exemplary materials for these subjects can be found in the ingredients of the present application content.

[0091] 渗透剂型的半透膜22对于外部液体是可渗透的,该液体如水和生物液体,但基本对内部小室中的成分是不可渗透的。 [0091] The osmotic dosage form of the semipermeable membrane 22 is permeable to the external fluid, the liquid such as water and biological liquids, but substantially smaller internal chamber components are impermeable. 在剂型存在期间,用于成膜的材料基本上是不可侵蚀的而且基本不溶于生物液中。 During the dosage form, the material for film formation is not substantially eroded and substantially insoluble in biological fluids. 用于形成半透膜的有代表性的聚合物包括均聚物和共聚物,如纤维素酯、纤维素醚和纤维素酯-醚。 Representative polymers for forming the semipermeable membrane include homopolymers and copolymers, such as cellulose esters, cellulose ethers and cellulose ester - ether. 流量调节剂可与成膜材料混合来形成膜的液体渗透性。 Flow modifier may be mixed with film-forming material to form a liquid permeable membrane. 如,对液体(如水)产生显著渗透性增加的试剂通常基本是亲水的,而对水产生显著渗透性降低的那些通常基本是疏水的。 For example, liquid (such as water) to produce a significant increase in the permeability of an agent typically is substantially hydrophilic, and water permeability reduction is significant that normally is substantially hydrophobic. 示例性的流量调节剂包括多羟基醇、聚烷二醇、聚烯烃二醇(polyalkylenediols)、烧二醇的聚酯等。 Exemplary flow regulating agents include polyhydric alcohols, polyalkylene glycol, a polyolefin diol (polyalkylenediols), burning diol polyesters.

[0092] 操作中,由于存在渗透活性剂而造成的跨膜22渗透梯度导致肠液透过膜,药物层胀溶并在内部小室中形成可递送的复合制剂(如,溶液、悬浮液、浆液或其他流体组合物)。 [0092] In operation, the presence of a transmembrane osmotic agent 22 caused by the osmotic gradient through the membrane resulting in intestinal solution, a drug swelling layer composite formulation may be delivered and formed inside the chamber (e.g., solution, suspension, slurry or other fluid composition). 本发明可递送的制剂从出口38释放出来,液体继续进入内部小室。 Formulations of the present invention may be delivered from the outlet 38 is released, the liquid continues into the interior of the chamber. 即使药物制剂从剂型中释放出来,流体持续吸入内部小室,从而驱动持续的释放。 Even if the drug formulation is released from the dosage form, fluid is continuously sucked into the chamber, thereby driving continued release. 以该方式,本发明的物质以持续和连续的方式长时间释放。 In this manner, the substance of the present invention in a continuous and sustained release manner for a long time.

[0093] 图2显示了本发明持续释放剂型的实施方案。 [0093] FIG. 2 shows an embodiment of the sustained release formulations of the present invention. 该类型剂型在美国专利N0.4612008,5082668和509`1190中有描述,及进一步如下所述。 This type of dosage form is described in U.S. Patent No. N0.4612008,5082668 and 509`1190 in and further described below.

[0094] 图2显示了一类持续释放剂型(即渗透持续释放剂型)的实施方案。 [0094] FIG. 2 shows an embodiment of the class of sustained release formulations (i.e., osmotic sustained release dosage form) of. 第一药物层30包括渗透活性成分,和比第二药物层40更少量的鸦片样物质。 A first drug layer 30 comprises osmotically active component, and the second drug layer 40 is more than the amount of opioid. 第一药物成分层中的渗透活性成分包含渗透剂(如盐)和一种或多种渗透聚合物,其具有相对小的分子量,显示出胀溶性,与药物层40相似,吸入液体使通过出口60出现这些渗透聚合物的释放。 Penetration of the active pharmaceutical ingredient of the first component layer contains osmotic agents (such as salts), and one or more osmopolymer, which has a relatively low molecular weight, exhibit swelling insoluble, the drug layer 40 is similar to the liquid passing through the suction outlet release of these osmopolymers 60 occurs. 其他赋形齐U,如粘合剂、润滑剂、抗氧化剂和着色剂也可包含在第一药物层30中。 Other excipients homogeneous U, such as binders, lubricants, antioxidants and colorants may also be included in first drug layer 30.

[0095] 第二药物层40包含鸦片样物质并混合有选择的赋形剂,其适于提供一种渗透活性梯度,驱动外环境的液体通过膜20并形成可递送的药物制剂来吸取液体。 [0095] Second drug layer 40 comprises opioid in admixture with selected excipients adapted to provide an osmotic activity gradient driving the extracellular environment through the membrane 20 and forms a liquid pharmaceutical formulation can be delivered to absorb liquid. 赋形剂可包括合适的悬浮剂,本文也称为药物载体,但无渗透活性剂,“渗透剂”,如盐,氯化钠。 Excipients may include a suitable suspending agent, also referred herein as a drug carrier, but no osmotically active agent, "penetrant", such as salt, sodium chloride. 已经发现,省略来自该第二药物层的盐(其在剂型中占较多的整体药物比例)以及第一药物层的盐,可提供增强的释放上升率,产生较长的上升率持续时间。 It has been found, the salt is omitted from the second drug layer (which accounts for large proportion of the overall pharmaceutical dosage form) a first drug layer and salts, may provide enhanced release rate of rise, resulting in a longer duration of rising rate.

[0096] 药物层40相对于药物层30有更高的鸦片样物质浓度。 [0096] Drug layer 40 with respect to the drug layer 30 has a higher concentration of the opioid. 第一药物层30中的鸦片样物质浓度和第二药物层40中的鸦片样物质浓度比率优选保持在少于1,并优选少于或等于约0.43以提供所需的基本上升的释放率。 Opioid concentration and the second drug layer 30 in the first drug layer 40 opioid ratio is preferably maintained at a concentration of less than 1, and preferably less than or equal to about 0.43 to provide a substantially ascending release rate desired.

[0097] 药物层40也可含其他赋形剂,如粘合剂、润滑剂等。 [0097] Drug layer 40 may also contain other excipients, such as binders, lubricants and the like. [0098] 药物层40,如药物层30,可进一步包含亲水聚合物载体。 [0098] Drug layer 40, as drug layer 30, further comprises a hydrophilic polymer carrier. 亲水聚合物使鸦片样物质受控递送。 The hydrophilic polymer making controlled delivery of opioids. 这些聚合物的有代表性的实例有100000至750000数均分子量的聚(环氧化物),包括聚(环氧乙烷)、聚(甲醛)、聚(环氧丁烷)、聚(环氧己烷);和有40000至400000平均分子量的聚(羧甲基纤维素),代表性的有聚(羧甲基纤维素碱)、聚(羧甲基纤维素钠)、聚(羧甲基纤维素钾)和聚(羧甲基纤维素锂)。 Representative examples of these polymers are from 100,000 to 750,000 number average molecular weight of the poly (epoxide), include poly (ethylene oxide), poly (formaldehyde), poly (butylene oxide), poly (ethylene hexanes); and an average molecular weight from 40,000 to 400,000 with a poly (carboxymethylcellulose), representative poly (alkali carboxymethylcellulose), poly (sodium carboxymethylcellulose), poly (carboxymethylcellulose cellulose potassium) and poly (lithium carboxymethylcellulose). 药物层40可进一步包含有9200至125000数均分子量的羟丙基烷基纤维素,来增强剂型的递送性质,代表性的有羟丙基乙基纤维素、羟丙基甲基纤维素、羟丙基丁基纤维素和羟丙基戊基纤维素;以及有7000至75000数均分子量的聚(乙烯吡咯烷酮),来增强剂型的流体性质。 Drug layer 40 may further comprise hydroxypropyl alkyl cellulose having a number average molecular weight of 9,200 to 125,000, and to enhance the delivery properties of the dosage form, typically ethyl hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl propylbutyl pentyl cellulose and hydroxypropyl cellulose; and there are from 7000 to 75,000 number average molecular weight of poly (vinylpyrrolidone), to enhance the fluid properties of the dosage form. 这些聚合物中优选有100000至300000数均分子量的聚(环氧乙烷)。 These polymers preferably have a number average molecular weight of 100,000 to 300,000 poly (ethylene oxide). 尤其优选在肠道环境中会腐蚀的载体,即生物腐蚀性载体。 Particularly preferably in the intestinal environment will support corrosion, i.e., bioerodible carriers.

[0099] 其他可以整合进药物层40和/或药物层30的载体包括碳水化合物,其显示出足够的渗透活性,可单独或与其它渗透剂一起使用。 [0099] and the other may be incorporated / carrier into drug layer 40 include carbohydrates or drug layer 30, which exhibit sufficient osmotic activity, may be used alone or in combination with other osmotic agents. 该碳水化合物包含单糖、二糖和多糖,代表性的例子包括麦芽糖糊精(即通过水解玉米淀粉产生的葡萄糖聚合物)和含乳糖、葡萄糖、棉子糖、蔗糖、甘露醇、山梨醇等的糖。 The carbohydrate comprises monosaccharides, disaccharides and polysaccharides example, typically include maltodextrin (i.e. produced by the hydrolysis of corn starch, glucose polymers) containing lactose, glucose, raffinose, sucrose, mannitol, sorbitol and the like sugar. 优选麦芽糖糊精,其具有20个或更少的葡萄糖等价体(DE),优选DE介于约4至约20,并通常为9-20。 Preferably maltodextrin, which has 20 or fewer glucose equivalents (DE), preferably with a DE ranging from about 4 to about 20, and often 9-20. 发现具有9_12个DE的麦芽糖糊精是有效的。 9_12 found maltodextrin has a DE is valid.

[0100] 药物层40和药物层30通常是基本干的、水重量< I %的、通过将载体、鸦片样物质和其他赋形剂压成一层而形成的组合物。 [0100] Drug layer 40 and drug layer 30 typically is a substantially dry, water wt <I%, the composition is formed by the carrier, opioid and other excipients compressed into one layer.

[0101] 根据本发明的模式和方式,药物层40可通过粉碎成颗粒来制成,粉碎产生适用于制造药物层的药物尺寸和伴随的聚合物尺寸,典型地作为含化合物的核芯。 [0101] manner and mode of the invention, the drug layer 40 may be formed into granules by pulverization according to size suitable for pharmaceutical comminution and concomitant polymer sized drug layer, typically as a core containing the compound. 产生颗粒的方式包括造粒、喷雾干燥、过筛、冻干、压碎、研磨、喷气碾磨、微粉化和切割,以产生所要的微米级颗粒大小。 Generation of particles embodiment includes granulation, spray drying, sieving, lyophilization, crushing, grinding, jet milling, micronizing and cut to produce micron sized particles of the desired size.

[0102] 通过减小尺寸的设备来进行该过程,如微型研磨磨、流体能量研磨磨、旋转磨、棰磨、磨擦磨、螺纹梳刀磨(chasermi 11)、球磨、振球磨、碰撞研磨磨、离心研磨磨、粗粒轧碎机和精细轧碎机。 [0102] The process is performed by size reduction equipment, such as the attritor mill, a fluid energy grinding mill, a rotary mill, a problem, grinding, attrition mill, a chaser mill (chasermi 11), a ball mill, vibrating ball mill, impact grinding mill , centrifugal grinding mill, a coarse crusher and a fine crusher. 颗粒大小可通过筛选来确定,包括栅筛筛选、平板筛选、震荡筛选、旋转筛选、摇动筛选、振动·筛选和往复筛选。 The particle size may be determined by screening including grizzly screening plate screening, screening shock, rotary filtering, screening shaking, filtering and the reciprocating vibration and screening. 制备药物和载体颗粒的过程和设备公开在Pharmaceutical Sciences,Reminton,第17版,pp.1585-1594(1985) ;Chemical EngineersHandbook, Perry,第6 版,pp.21-13 至21-19(1984) ;Journal of PharmaceuticalSciences, Parrot,第61 卷,6 期,pp.813-829(1974);和Chemical Engineer, Hixon,pp.94-103(1990)。 And processes and equipment for preparing a pharmaceutical carrier particles are disclosed in Pharmaceutical Sciences, Reminton, 17th ed., Pp.1585-1594 (1985); Chemical EngineersHandbook, Perry, Ed. 6, pp.21-13 to 21-19 (1984) ; Journal of PharmaceuticalSciences, Parrot, Vol. 61, 6, pp.813-829 (1974); and Chemical Engineer, Hixon, pp.94-103 (1990).

[0103] 第一药物层30包括活性剂并混有选择的赋形剂,其适于提供一种渗透活性梯度,驱动外环境的液体通过膜20并形成可递送的药物制剂来吸取液体。 [0103] First drug layer 30 comprises active agent in admixture with selected excipients adapted to provide an osmotic activity gradient, the driving liquid outside environment through membrane 20 and forming a drug delivery formulation may be a liquid suction. 赋形剂可包括合适的悬浮剂,本文也称为药物载体,和渗透活性剂,即“渗透剂”,如盐。 Excipients may include a suitable suspending agent, also referred herein as a drug carrier, and an osmotically active agent, i.e., "osmotic agent" such as salt. 也可含其他赋形剂,如粘合剂、润滑剂等。 It may also contain other excipients, such as binders, lubricants and the like. 出人意料地发现了,当第一成分药物层30包含渗透活性成分,而且比第二成分药物层40中的活性药物的量更少时,则可产生增强升高的释放率,提供升高率的更长的持续时间。 Surprisingly found that when first component drug layer 30 comprises osmotically active ingredient, but less than the amount of active agent in the second component drug layer 40, may be generated to enhance the release rate increased, the rate of rise of providing more long duration.

[0104] 第一成分药物层中的渗透活性成分通常包含渗透剂和一种或多种渗透聚合物,其具有相对小的分子量,显示出胀溶性,与药物层40相似,吸入液体使通过出口60出现这些渗透聚合物的释放。 [0104] penetration of the active ingredient in the first component drug layer typically comprises one or more osmotic agent and an osmopolymer, which has a relatively low molecular weight, exhibit swelling insoluble, the drug layer 40 is similar to the liquid passing through the suction outlet release of these osmopolymers 60 occurs. [0105] 第一药物层和第二药物层间的鸦片样物质浓度比率改变了释放率曲线。 [0105] opioid substance concentration ratio between the first drug layer and second drug layer to change the release rate profile. 释放率曲线被计算为最大释放率和在起始后第一时间点(如在6小时)获得的释放率的差,除以两个数据点间的平均释放率。 Release rate profile is calculated as the difference between the maximum release rate and the release rate of a first time point (e.g., 6 hours) after initiation of the obtained, divided by the average release rate between the two data points.

[0106] 药物层30和药物层40任选在两个药物层中包含表面活性剂和崩解剂。 [0106] Drug layer 30 and drug layer 40 optionally comprises a surfactant and disintegrants in both drug layer. 表面活性剂的实例是具有约10-25HLB值的那些,如聚乙二醇400单硬脂酸酯、聚环氧乙烷_4_山梨聚糖单月桂酸酯、聚环氧乙烷-20-山梨聚糖单油酸酯、聚环氧乙烷-20-山梨聚糖单棕榈酸酯、聚环氧乙烷-20-单月桂酸酯、聚环氧乙烷-40-硬脂酸酯、油酸钠等。 Examples of surfactants are those such as polyethylene glycol 400 monostearate, polyoxyethylene _4_ sorbitan monolaurate, polyethylene oxide having a value of about -20 10-25HLB - sorbitan monooleate, polyoxyethylene -20- sorbitan monopalmitate, polyoxyethylene -20- monolaurate, polyoxyethylene 40-stearate and sodium oil.

[0107] 崩解剂选自淀粉、粘土、纤维素、褐藻酸和胶和交联淀粉、纤维素和聚合物。 [0107] disintegrant is selected from starches, clays, celluloses, alginic acid and gum, and crosslinked starches, celluloses and polymers. 有代表性的崩解剂包括玉米淀粉、土豆淀粉、交联羧甲纤维素(croscarmelose)、交联聚乙烯卩比咯烧酮(crospovidone)、淀粉乙醇酸钠、VeegumHV、甲基纤维素、琼脂、膨润土、羧甲基纤维素、褐藻酸、瓜尔豆胶等。 Representative disintegrants include corn starch, potato starch, croscarmellose cellulose (croscarmelose), slightly cross-linked polyethylene Jie than one burning (crospovidone), sodium starch glycolate, VeegumHV, methyl cellulose, agar , bentonite, carboxymethylcellulose, alginic acid, guar gum and the like.

[0108] 形成的膜20对于外部流体(如水和生物流体)是可渗透过的,而对于paliperidone、渗透剂、渗透聚合物等是不可渗透过的。 [0108] The film 20 for an external fluid (such as water and biological fluids) is permeable over, and for paliperidone, osmotic agents, osmopolymers and the like are not permeated. 如此,其是半渗透的,在剂型存续期间,用于成膜20的选择性半透组合物基本是不可腐蚀的并且基本在生物流体中不溶。 As such, it is semipermeable, during the existence of the dosage form, selectively semipermeable compositions used for film formation 20 is substantially non-corrosive and is essentially insoluble in biological fluids.

[0109] 有代表性的形成膜20的聚合物包括半透均聚物、半透共聚物等。 [0109] Representative formed polymer film 20 include semipermeable homopolymers, semipermeable copolymer. 在当前一个优选的方案中,组合物可包括纤维素酯、纤维素醚和纤维素酯-醚。 In a currently preferred embodiment, the composition may comprise cellulose esters, cellulose ethers and cellulose ester - ether. 纤维素聚合物对于其脱水葡萄糖单位形式,通常具有大于0至多3的取代度”DS”。 Cellulosic polymers for which the anhydroglucose unit forms, generally greater than 0 up to 3 degree of substitution "DS". 取代度指在原始脱水葡萄糖单位中的平均羟基数,其可由取代基替换,或转化成其他基团。 The degree of substitution refers to the average number of hydroxyl groups in the anhydroglucose units of the original, which may be replaced by a substituent, or converted into another group. 脱水葡萄糖单位可用如下基团部分或全部取代:酰基、烷酰基、烯酰基、芳酰基、烷基、烷氧基、齒素、碳烷基、烷基氨基甲酸酯、烷基碳酸酯、烷基磺酸酯、烷基氨基磺酸酯、半透聚合物形成基团等。 Anhydroglucose unit can be used as part or all of a group substituted by: acyl, alkanoyl, alkenoyl, aroyl, alkyl, alkoxy, tooth element, carbon, alkyl carbamate, alkyl carbonates, alkyl sulfonates, alkyl sulfamate, and the like semipermeable polymer forming groups. 半透组合物通常包括选自如下的组中的成员:酰化纤维素、二酰化纤维素、三酰化纤维素、三醋酸纤维素、醋酸纤维素、二醋酸纤维素、三醋酸纤维素、单_、双_、和三-纤维素烷烃酯、单_、双_、三-烯烃酯和单_、双_、三-芳酰基酯等。 Semipermeable compositions typically include those selected from the following group members: cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose triacetate, cellulose acetate, cellulose diacetate, cellulose triacetate single _, _ double, and three - cellulose ester alkanes, mono _, _ double, three - olefins and mono- _, _ double, three - aroyl ester and the like.

[0110] 示例的聚合物包括如,具有1.8至2.3DS并含有32至39.9%乙酰基含量的醋酸纤维素;具有I至2D.S.并含有21至35%乙酰基含量的二醋酸纤维素;具有2至3D.S.并含有34至44.8%乙酰基的三醋酸纤维素等。 [0110] Example of polymers include, for example, of 1.8 to 2.3DS cellulose acetate and containing from 32 to 39.9% acetyl content; having I to 2D.S. and containing 21 to 35% cellulose diacetate acetyl content ; having 2 to 3D.S. and containing from 34 to 44.8% cellulose triacetate acetyl. 更具体的纤维素聚合物包括具有1.8DS并含有 More specific cellulosic polymers include 1.8DS and containing

38.5 %丙酰基含量的丙酸纤维素;含有1.5至7%乙酰基的并含有39至42%乙酰基的醋酸丙酸纤维素;含有2.5至3%乙酰基的、平均含有39.2至45%丙酰基的并含有2.8至5.4%羟基的醋酸丙酸纤维素;具有1.8DS、含有13至15%乙酰基的并含有34至39%丁酰基的醋酸丁酸纤维素;含有2至29%乙酰基的、含有17至53% 丁酰基的并含有0.5至4.7%羟基的醋酸丁酸纤维素;具有2.6至3D.S.的三酰基纤维素,如三戊酸纤维素、三拉玛酸(trilamate)纤维素、三棕榈酸纤维素、三辛酸纤维素和三丙酸纤维素;具有2.2至2.6DS的纤维素二酯,如二琥珀酸纤维素、二棕榈酸纤维素、二辛酸纤维素和二carpylate纤维素等;混合的纤维素酯,如醋酸戊酸纤维素、醋酸琥珀酸纤维素、丙酸琥珀酸纤维素、辛酸醋酸纤维素、棕榈酸戊酸纤维素、醋酸庚酸纤维素等。 Propionyl content of 38.5% cellulose propionate; containing 1.5 to 7% and an acetyl group of cellulose acetate propionate containing 39 to 42% acetyl; containing 2.5 to 3% of an acetyl group, containing an average of 39.2 to 45% propionic acyl groups and containing from 2.8 to 5.4% of the hydroxyl groups of cellulose acetate propionate; having 1.8DS, containing 13 to 15% acetyl and butyryl acetate butyrate contains cellulose is 34-39%; containing 2-29% acetyl containing 17 to 53% butyryl and cellulose acetate butyrate containing 0.5 to 4.7% of a hydroxyl group; an acyl group having three to 2.6 3D.S. of cellulose, cellulose valerate such as tris, tris Rama acid (trilamate ) cellulose, cellulose tripalmitate, cellulose trioctanoate and cellulose tripropionate; having 2.2 to 2.6DS cellulose diesters such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate and two carpylate cellulose; mixed cellulose esters such as cellulose acetate valerate, cellulose acetate succinate, cellulose propionate succinate, cellulose acetate octanoate, cellulose valerate palmitate, cellulose acetate heptanoate acetate, etc. . 半透聚合物在美国专利N0.4077407中公开,它们可以通过如Interscience Publishers, Inc,纽约出版的Encyclopedia ofPolymer Science andTechnology,第3 卷,325-354 页,1964 中所述的方法来合成。 Semipermeable polymers as disclosed in U.S. Patent No. N0.4077407, they can be such as Encyclopedia ofPolymer Science andTechnology Interscience Publishers, Inc, New York, published in Volume 3, pages 325-354, 1964 described in the synthesis method.

[0111] 其它形成半透膜的半透聚合物可包括如,乙醛二甲基醋酸纤维素;乙基氨基甲酸醋酸纤维素;甲基氨基甲酸醋酸纤维素;二甲氨醋酸纤维素;半透聚酰胺;半透聚氨酯;半透磺化聚苯乙烯;如美国专利N0.3173876、3276586、3541005、3541006和3546142所公开的共沉淀聚阴离子和聚阳离子所形成的交联的选择性半透聚合物;如美国专利N0.3133132所公开的半透聚合物;半透聚苯乙烯衍生物;半透聚(苯乙烯磺酸钠);半透聚(乙烯基苄基三甲基氯化铵);半透聚合物,其显示出10-5至10-2(cc.Mil/cm hr.atm)的流体渗透性,其用穿过半透膜的流体静力学或渗透压的差的每个大气压来表示。 [0111] Other semipermeable polymer forming the semipermeable membrane may include, for example, acetaldehyde dimethyl cellulose acetate; cellulose acetate ethylcarbamate; cellulose acetate methyl carbamate; cellulose acetate dimethylamino; half permeable polyamides; semipermeable polyurethanes; semipermeable sulfonated polystyrene; semipermeable crosslinked selective U.S. Patent No. 3,546,142 disclosed and N0.3173876,3276586,3541005,3541006 coprecipitation polyanion and polycation are formed polymers; as disclosed in U.S. Patent N0.3133132 semipermeable polymer; semipermeable polystyrene derivatives; semipermeable poly (sodium styrene sulfonate); semipermeable poly (vinylbenzyl trimethylammonium chloride ); semipermeable polymer which exhibits 10-5 to 10-2 (cc.Mil/cm hr.atm) a fluid permeable, which was passed through the semipermeable membrane of hydrostatic or osmotic pressure difference of each atmospheric pressure to represent. 聚合物在以下文献中是已知的:美国专利N0.3845770、3916899 和4160020 ;和CRCPress,Cleveland.0hio 出版的、Scott, JR 和Roff, ff.J.1971 的Handbook of CommonPolymers„ Polymers are known in the literature: U.S. Patent No. 4,160,020 and N0.3845770,3916899; and CRCPress, Cleveland.0hio published, Scott, JR and Roff, ff.J.1971 the Handbook of CommonPolymers "

[0112] 膜20也可含流量调节剂。 [0112] membrane 20 may also contain a flow regulating agent. 流量调节剂是添加的化合物,其帮助调节流体渗透性或穿过膜20的流量。 Flow regulating agent is a compound added, which help regulate the flow through the fluid permeability or film 20. 流量调节剂是流量增强剂或减少剂。 Flow regulating agents or reducing agent is the flow enhancer. 可预选该试剂以增加或减少液体流量。 The agent can be preselected to increase or decrease fluid flow. 对流体(如水)产生显著增加渗透性的试剂通常基本是亲水的,而对流体(如水)产生显著降低渗透性的试剂基本是疏水的。 Reagent fluid (such as water) to produce a significant increase in permeability is usually substantially hydrophilic, while the fluid (e.g., water) significant permeability reducing agent is substantially hydrophobic. 纳入本文的膜20中的调节剂的量通常从约0.01%至20%重量或更多。 The amount of modifier in the film 20 incorporated herein typically from about 0.01% to 20% by weight or more. 在一个实施方案中增加流量的流量调节剂包括如,多元醇、聚烷二醇、聚烯烃二醇、烷二醇的聚酯等。 In one embodiment the increase in traffic flow regulation embodiment include e.g., polyhydric alcohol, polyalkylene glycol, polyolefin glycols, alkylene glycols such as polyester. 典型的流量增强剂包括聚乙二醇300、400、600、1500、4000、6000、聚(乙二醇-共-乙二醇)等;低分子量二醇,如聚丙二醇、聚丁二醇和聚戊二醇;聚烷二醇,如聚(1,3-丙二醇)、聚(1,4_ 丁二醇)、聚(1,6-己二醇)等;脂肪族二醇,如1,3- 丁二醇、1,4_五亚甲基二醇、1,4-六亚甲基二醇等;烯三醇,如丙三醇、1,2,3- 丁三醇、1,2,4-己三醇、1,3,6-己三醇等;酯,如乙二醇二丙酯、乙二醇丁酯、丁二醇二丙酯、醋酸丙三醇酯等。 Typical flow rates 300,400,600,1500,4000,6000 enhancers include polyethylene glycol, poly (ethylene - co - ethylene glycol) and the like; low molecular weight diols, such as polyethylene glycol, polypropylene glycol, and polybutylene neopentyl glycol; polyalkylene glycols such as poly (1,3-propanediol), poly (1,4_ glycol), poly (1,6-hexanediol) and the like; aliphatic diols such as 1,3 - butanediol, 1,4_ pentamethylene glycol, 1,4-hexamethylene glycol and the like; alkylene triols such as glycerol, 1,2,3-butanetriol, 1,2 , 4-hexanetriol, 1,3,6-hexanetriol and the like; esters such as ethylene glycol, propylene glycol butyl ether, dipropyl glycol, glycerol acetate esters. 代表性的流量降低剂包括如,邻苯二甲酸酯,其用烷基或烷氧基或用烷基和烷氧基取代,如二乙基邻苯二甲酸酯、二甲氧基乙基邻苯二甲酸酯、二甲基邻苯二甲酸酯和[二(2-乙基己基)邻苯二甲酸酯]、芳基邻苯二甲酸酯,如三苯基邻苯二甲酸酯,和丁基苄基邻苯二甲酸酯;不溶性盐,如硫酸钙、硫酸钡、磷酸钙等;不溶性氧化物,如氧化钛;粉状、颗粒状等形式的聚合物,如聚苯乙烯、聚甲基甲基丙烯酸酯、聚碳酸酯和聚砜;酯,如用长链烷基酯化的柠檬酸酯;惰性和基本不透水的填料;与基于纤维素膜形成材料相容的树脂等。 Representative reducing agents include, for example the flow rate, phthalates, or with its alkyl and alkoxy groups substituted with an alkyl or alkoxy group such as diethyl phthalate, dimethoxyethane phthalate, dimethyl phthalate, and [di (2-ethylhexyl) phthalate], aryl phthalates such as triphenyl phthalic dicarboxylate, and butyl benzyl phthalate; insoluble salts, such as calcium sulfate, barium sulfate, calcium phosphate and the like; insoluble oxides such as titanium oxide; powder, or granular form of a polymer, such as polystyrene, polymethyl methacrylate, polycarbonate and polysulfone; esters such as citric acid esters esterified with long chain alkyl groups; inert and substantially water impermeable fillers; and cellulose-based film-forming material compatible resin.

[0113] 其它可用于成膜20的材料用于使壁具有可弯曲性和延长性,并用于制备非膜不易碎体来提供拉扯强度,其包括如,邻苯二甲酸酯增塑剂,如二苄基邻苯二甲酸酯、二己基邻苯二甲酸酯、丁辛基邻苯二`甲酸酯、6至11个碳的直链邻苯二甲酸酯、二-异壬基邻苯二甲酸酯、二-异癸基邻苯二甲酸酯等。 [0113] Other materials may be used for forming wall 20 having a curved extension and resistance, and used to prepare non-film-friable body to provide pull strength, which include, for example, phthalate plasticizers, such as dibenzyl phthalate, dihexyl phthalate, phthalamide Ding Xinji `formate, 6-11 carbon linear phthalate, di - isononyl phthalate, di - isodecyl phthalate. 增塑剂包括非邻苯二甲酸酯,如三醋精、二辛基壬二酸酯、环氧化妥尔油脂肪酸酯、偏苯三酸三异辛基酯、偏苯三酸三异壬基酯、蔗糖醋酸异丁酯、环氧大豆油等。 Comprising non-phthalate plasticizer, such as triacetin, dioctyl azelate, epoxidized tall oil fatty acid ester, trimellitic acid tri-iso-octyl ester, trimellitic acid tri-isononyl ester, sucrose isobutyl acetate, epoxy soybean oil. 纳入本文的膜中增塑剂的量为约0.01%至20%重量或更多。 Incorporated amount of the plasticizer film herein is from about 0.01 to 20% by weight or more.

[0114] 如图2所示,推进层50包含可扩展的层,其与第二药物层40接触成层状排列。 [0114] As shown in FIG 2, the push layer 50 comprises expandable layer in contact with the second drug layer 40 into a layered arrangement. 推进层50包含聚合物,其吸收水或生物流体并膨胀以推动药物组合物穿过器件出口。 The push layer 50 comprises a polymer that absorbs water or biological fluid and swells to push the drug composition through the device outlet.

[0115] 在一个具体实例中,可扩展的层包含由水激活的组合物,其在水存在下膨胀,如在肠液中。 [0115] In one specific example, the expandable layer comprises a water-activated composition that expands in the presence of water, such as in intestinal fluid. 通常,它含有含渗透溶质的渗透组合物,沿半透膜显示出渗透压梯度,对抗所用的环境中存在的外部液体。 Typically, the permeate containing permeable solute-containing composition, exhibit an osmotic pressure gradient along the semipermeable membrane, against an external fluid present in the environment used in the. 在另一个具体实例中,由水激活的层包含水凝胶,其通过外半透膜将流体吸取和/或吸收进入层中。 In another example, activated by aqueous layer comprises a hydrogel, which outer semipermeable membrane by suction fluid and / or absorption into the layer. 半透膜是无毒的。 Semipermeable membrane is non-toxic. 它在操作中保持其理化完整性并基本不与可扩展的层相互作用。 It maintains its physical and chemical integrity during operation and does not substantially interact with the expandable layer.

[0116] 在一个优选的具体实例中,可扩展的层包括含亲水聚合物的水活化层,也称为渗透聚合物。 [0116] In a preferred embodiment, the extensible layer comprises a layer containing a water-activated hydrophilic polymer, also known as osmopolymers. 渗透聚合物显示流体吸收性质。 Fluid-absorbent polymer exhibits penetration properties. 渗透聚合物是可膨胀的、亲水的聚合物,该渗透聚合物与水和生物水溶液相互作用,膨胀或扩大到平衡状态。 The osmopolymers are swellable, hydrophilic polymers, which osmopolymers interact with water and biological aqueous solution, swell or expand to an equilibrium state. 渗透聚合物有能力显示出在水和生物流体中膨胀并在聚合物结构中保留可观部分的吸收了的液体。 The osmopolymers exhibit the ability to swell in water and biological fluids and retain a considerable part of the polymer structure absorbs a liquid. 渗透聚合物膨胀或扩大到非常高的程度,同层显示出2至50倍体积的增加。 The osmopolymers swell or expand to a very high degree, it showed an increase from 2 to 50 volumes of the same layer. 渗透聚合物是非交联或交联的。 Osmopolymer non-crosslinked or crosslinked. 在一个具体实例中,可膨胀、亲水的聚合物膨胀后轻度交联,该交联通过共价或离子键或残余晶体区域来形成。 In one specific example, the expandable, hydrophilic polymers swell after lightly crosslinked, the crosslinking is formed by covalent or ionic bonds or residue crystalline regions. 渗透聚合物可来自植物、动物或合成物。 The osmopolymers can be of plant, animal or synthetic.

[0117] 渗透聚合物是亲水聚合物。 [0117] The osmopolymers are hydrophilic polymers. 适合本目的的亲水聚合物包括具有30000至5000000分子量的聚(羟基-烷基甲基丙烯酸酯);具有10000至360000分子量的聚(乙烯吡咯烷酮);阴离子和阳离子水凝胶;聚电解复合物;聚(乙烯醇),其具有低的醋酸残基、与乙二醛、甲醛或戊二醛交联,并具有200至30000的聚合度;甲基纤维素、交联的琼脂和羧甲基纤维素的混合物;羟丙基甲基纤维素和羧甲基纤维素钠的混合物,羟丙基乙基纤维素和羧甲基纤维素钠的混合物,羧甲基纤维素钠和甲基纤维素的混合物,羧甲基纤维素钠;羧甲基纤维素钾;不溶于水的、水中膨胀的共聚物,其由细分的马来酐共聚物和苯乙烯、乙烯、丙烯、丁烯或异丁烯的分散体形成,其每个共聚物每摩尔马来酐交联有0.001至约0.5摩尔饱和交联剂;水可膨胀聚合物N-乙烯内酰胺;聚环氧乙烷-聚氧丙烯胶;角豆树胶;聚丙烯酸胶;聚酯胶;p0l Suitable for this purpose include hydrophilic polymers having a 30,000 to 5,000,000 molecular weight poly (hydroxy - alkyl methacrylate); having a 10,000 to 360,000 molecular weight poly (vinyl pyrrolidone); anionic and cationic hydrogels; polyelectrolyte complexes ; poly (vinyl alcohol) having low acetate residual group, glyoxal, formaldehyde or glutaraldehyde cross-linking, and having a degree of polymerization of from 200 to 30,000; methyl cellulose, crosslinked agar and carboxymethyl the mixture of cellulose; a mixture of hydroxypropyl methylcellulose and sodium carboxymethyl cellulose, hydroxypropyl ethylcellulose and sodium carboxymethyl cellulose, sodium carboxymethyl cellulose and methyl cellulose mixture, sodium carboxymethylcellulose; potassium carboxymethylcellulose; water-insoluble, water swollen copolymers consisting of finely divided maleic anhydride copolymer and styrene, ethylene, propylene, butene or isobutene dispersion formed, each per mole of maleic anhydride copolymer crosslinked with a 0.001 to about 0.5 moles of saturated cross-linking agent; the water-swellable polymers N- vinylamides; polyoxyethylene - polyoxypropylene gel; carob gum; polyacrylic gum; gum polyester; P0L yuria胶;聚醚胶;聚酰胺胶;聚纤维素胶;聚树胶;最初干的水凝胶,其吸取和吸收水,其透过玻璃质的水凝胶并降低玻璃温度;等等。 yuria gum; gum polyethers; polyamide gel; poly cellulose gum; poly acacia; initial dry hydrogel which absorbs water and absorb, through its glassy hydrogel and lowers the temperature of the glass; and the like.

[0118] 其它渗透聚合物的代表是形成水凝胶的聚合物,如Carbopol™。 [0118] Representative of other osmopolymers are polymers form hydrogels, such as Carbopol ™. 酸性羧基聚合物,与聚烯丙基蔗糖交联的丙烯酸聚合物,也称作羧聚亚甲基,以及具有250000至4000000分子量的羧乙烯基聚合物;Cyanamer™聚丙烯酰胺;交联的水胀溶性茚马来酐聚合物;具有80000至200000分子量的Good-rite™聚丙烯酸;具有100000至5000000分子量且更高的Polyox™聚环氧乙烧聚合物;淀粉接枝共聚物;Aqua_Keeps™丙烯酸酯聚合物多糖,其含缩合鹿糖单位,如二酯交联的聚gluran ;等等。 Acidic carboxy polymers, acrylic acid polymers cross-linked polyallyl sucrose, also known as carboxypolymethylene, and having a molecular weight of 250,000 to 4,000,000 carboxyvinyl polymers; Cyanamer ™ polyacrylamides; crosslinked water expansion soluble indene maleic anhydride polymers; having a molecular weight from 80,000 to 200,000 Good-rite ™ polyacrylic acids; having a molecular weight of 100,000 to 5,000,000 and higher burning Polyox ™ polyethylene oxide polymers; starch graft copolymers; Aqua_Keeps ™ acrylate acrylate polymer polysaccharides comprising condensed deer which sugar units, such as diester cross-linked polyethylene gluran; and the like. 代表的形成水凝胶的聚合物在以下现有技术中是已知的:美国专利N0.3865108、N0.4002173、N0.4207893 ;和Chemical RubberC0.,Cleveland, Ohio 出版的Scott 和Roff 的Handbook of Common Polymers。 Hydrogel-forming polymer is represented by the following known in the prior art: U.S. Patent No. N0.3865108, N0.4002173, N0.4207893; and Chemical RubberC0, Cleveland, Ohio Scott and Roff, published in the Handbook of. Common Polymers. 含水活化层的渗透聚合物的量为约5%至100%。 The amount of aqueous activated osmopolymer layer is about 5% to 100%.

[0119] 其它制品中的可扩展的层可包括有效渗透化合物,其包含无机或有机化合物,显示出沿半透膜的渗透压梯度,能抗外部流体。 [0119] Other articles expandable osmotic layer may comprise an effective compound comprising inorganic or organic compound, exhibits an osmotic pressure gradient along the semipermeable membrane resistant to external fluid. 有效渗透化合物,如渗透聚合物,将流体吸入渗透系统,因而使可用的流体向后推内壁,即在一些具体实例中,软或硬胶囊的屏障层和/或膜从剂型中推动活性剂。 Effectively penetrate compounds, such as osmopolymers, fluid into the osmotic system, thereby making available fluid to push back the inner wall, i.e., in some instances, soft or hard capsules barrier layers and / or films push the active agent from the dosage form. 有效渗透化合物也称作有效渗透溶质,且也为渗透剂。 Effective compounds also known as osmotic effective solute permeability, and also penetrant. 有用的有效渗透溶质包括硫酸镁、氯化镁、硫酸钾、硫酸钠、硫酸锂、磷酸钾、甘露醇、尿素、肌糖、琥珀酸镁、酒石酸、碳水化合物,如棉子糖、蔗糖、葡萄糖、乳糖、山梨醇及其混合物。 Useful solutes include effectively penetrate magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium phosphate, mannitol, urea, inositol, magnesium succinate, tartaric acid, carbohydrates such as raffinose, sucrose, glucose, lactose , sorbitol, and mixtures thereof. 渗透剂的量为层重量的约5%至100%。 Penetrant amount of about 5 to 100% by weight of the layer. 可扩展的层任选包含渗透聚合物和渗透剂,渗透聚合物和渗透剂的总量等于100 %。 Total extensible layer optionally comprises an osmopolymer and osmotic agent, an osmopolymer and osmotic agent equal to 100%. 有效渗透溶质是现有已知的,如在美国专利N0.4783337中所述的。 Effective osmolyte is conventionally known, as described in U.S. Patent No. N0.4783337.

[0120] 保护性内层、内壁90可透过流体,使之进入膜20限定的小室。 [0120] a protective inner layer, the inner wall 90 permeable to the fluid, so that into the membrane chamber 20 is defined. 壁90提供润滑功能,利于第一药物层30、第二药物层40和推进层50向出口60的移动。 Wall 90 to provide lubrication, facilitates the first drug layer 30, second drug layer 40 and the moving push layer 50 toward the outlet 60. 壁90可由亲水材料和赋形剂形成。 Wall 90 may be formed of a hydrophilic material and an excipient. 壁90促进药物组合物从小室中释放并在递送结束时,尤其在分散期间分散的楽■液、悬浮剂和溶剂很粘的时候,减少保留在小室中的残留药物组合物的量。 Wall 90 to promote the pharmaceutical composition is released from the chamber and the end of delivery, in particular the dispersion during dispersion liquid yue ■, suspending agents and solvents very sticky when retained in the chamber to reduce the amount of residual pharmaceutical composition. 在有疏水剂并无内壁的剂型中,在完成递送后,观察到了大量残余的药物留在器件中。 There is no hydrophobic agent in the dosage form of the inner wall, after the completion of the delivery, the observed large amount of residual drug remaining in the device. 在一些情况下,在释放率测试了24小时后,20%或更大的量留在剂型中。 After In some cases, the release rate testing 24 hours, 20% or greater of the amount remaining in the formulation. 尤其在活性化合物成本高的情况下,该改进带来实质的济上优势,由于其不必在药物层装载大量药物以保证所需递送的最小药物量。 Especially at high cost of the active compound, the improvement which brings substantial economic advantages, because it does not have a large amount of drug loaded in the drug layer to ensure a minimum required amount of drug delivered. 内膜90可形成为压缩核芯外的包衣。 Endometrial coating 90 may be formed outside the compressed core.

[0121] 壁90通常0.01至5mm厚,更通常0.5至5mm厚,其包括选自如下的成员:水凝胶、明胶、低分子量聚环氧乙烷,如少于100000MW,羟烷基纤维素,如羟基乙基纤维素、羟基丙基纤维素、羟基异丙基纤维素、羟基丁基纤维素和羟基苯基纤维素,和羟烷基烷基纤维素,如羟基丙基甲基纤维素,及其混合物。 [0121] wall 90 is typically 0.01 to 5mm thick, more typically 0.5 to 5mm thick, comprising a member selected from the following: hydrogels, gelatin, low molecular weight polyethylene oxide, such as less than 100000MW, hydroxyalkyl cellulose , such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl isopropyl cellulose, hydroxybutyl cellulose, and cellulose-hydroxyphenyl, and hydroxyalkyl alkyl celluloses, such as hydroxypropyl methylcellulose and mixtures thereof. 羟烷基纤维素含数均分子量为9500至1250000的聚合物。 Hydroxyalkyl cellulose having a number average molecular weight of the polymer is 9,500 to 1,250,000. 如,数均分子量为80000至850000的羟基丙基纤维素是有用的。 The number average molecular weight of hydroxypropyl cellulose of 80,000 to 850,000 are useful. 壁90通过上述材料在水溶剂或惰性有机溶剂中形成的常规溶液或悬浮液来制备。 Conventional solutions or suspensions of the wall 90 is formed in an aqueous solvent or an inert organic solvent prepared by the above material.

[0122] 优选的壁90材料包括羟基丙基纤维素、羟基乙基纤维素、羟基丙基甲基纤维素、聚维酮[聚(乙烯吡咯烷酮)]、聚乙二醇及其混合物。 [0122] The preferred material of the wall 90 comprising hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, povidone [poly (vinylpyrrolidone)], polyethylene glycol and mixtures thereof.

[0123] 最优选的是羟基丙基纤维素和聚维酮的混合物(其在有机溶剂中制备,尤其是有机极性溶剂,如有1-8个碳原子的低级醇,优选乙醇)、羟基乙基纤维素和羟基丙基甲基纤维素的混合物(其在水溶液中制备)、和羟基乙基纤维素和聚乙二醇的混合物(其在水溶液中制备)。 [0123] Most preferred are mixtures of hydroxypropyl cellulose and povidone (which is prepared in organic solvents, especially polar organic solvents, if a lower alcohol of 1 to 8 carbon atoms, preferably ethanol), a hydroxyl group mixtures of ethyl cellulose and hydroxypropyl methyl cellulose (prepared in an aqueous solution), and a mixture of hydroxyethyl cellulose and polyethylene glycol (prepared in an aqueous solution). 最优选,壁90包括在乙醇中制备的羟基丙基纤维素和聚维酮的混合物。 Most preferably, the wall 90 comprises a mixture prepared in ethanol hydroxypropyl cellulose and povidone.

[0124] 优选壁90包括约50%至约90%的平均分子量为约80000的羟基丙基纤维素(其被定义为EF)和约10%至约50%的聚乙烯吡咯烷酮(其被称作K29-32)。 [0124] wall 90 preferably comprises from about 50% to about 90% of the average molecular weight of about 80,000 hydroxypropyl cellulose (which is defined as EF) from about 10% to about 50% polyvinylpyrrolidone (which is referred to as K29 -32).

[0125] 通常,用在压缩核芯上的壁90的重量与壁90的厚度和残留在如本文所述的释放率测试中的剂型中药物相关。 [0125] Generally, the weight and the residual wall thickness 90 by the compression of the core in the wall 90 of the release rate test as described herein in a dosage form drug-related. 如在生产操作中,壁90的厚度通过控制包衣操作中所添加的壁90的重量来控制。 As production operations, by weight by controlling the thickness of the wall 90 of the coating operation of the added wall 90 is controlled.

[0126] 当壁90形成为子层,即包衣在包括第一药物层、第二药物层和推进层之一或全部的成片的组合物上,壁90可通过压片过程而填充入核芯上形成的不规则表面中。 [0126] When wall 90 is formed as a sub-layer, i.e., the coating comprising a first drug layer, second drug layer and one or all of the push layer composition into a tablet, the wall 90 may be filled by a tabletting process irregularities formed on the core surface. 在分散药物期间,得到的光滑外表面使包衣的组合物核芯和半透膜之间容易滑动,使得在完成用药时器件中残留较少数量的药物组合物。 During dispersion of the drug, resulting in a smooth outer surface to make the composition easier sliding between the core and a semipermeable membrane coating, so that a smaller number of remaining device upon completion of administration the pharmaceutical composition. 当壁90由胶形成材料制成时,在应用环境中与水的接触容易形成胶或胶样内层,其粘性可促进并增强膜20和药物层30和药物层40之间的滑动性。 When wall 90 is made of plastic material is formed in contact with water application environment easily formed gum or gum-like inner layer, its viscosity can facilitate and enhance the slidability between the film 20 and drug layer 30 and drug layer 40. · ·

[0127] 除了出口之外,锅包衣可方便地用于提供完整的剂型。 [0127] In addition to the outlet, pan coating may be conveniently used to provide the completed dosage form. 在锅包衣系统中,也可以通过将合适膜组合物连续喷在压缩的含药物层、任选的屏障层和推进层的三层或多层核芯上,接着在旋转锅中旋转,由此来根据情况沉积用于壁或膜的壁形成组合物。 In the pan coating system, may be a suitable film composition by continuous spray of the drug-containing layer is compressed, optionally three or more layers on the core barrier layer and the push layer, is then rotated in the rotating pan by according to this composition for the walls of the case or deposited film. 因为其可在商业规模上使用,所以可使用锅包衣器。 Because it can be used on a commercial scale, it is possible to use the pan coater. 可用其他技术来包衣压缩的核芯。 Other techniques can be used for coating the compressed core. 一旦包衣好,在强迫通风炉中或在控温湿炉中干燥膜,去除剂型中的生产用溶剂。 Once the coating is good, or in a forced-air oven dried at controlled temperature and humidity oven film, removing the solvent dosage form production. 通常根据可用的设备、周围条件、溶剂、包衣物、包衣厚度等来选择干燥条件。 The drying conditions are typically selected based on the available equipment, ambient conditions, solvents, laundry bag, coating thickness.

[0128] 也可用其他包衣技术。 [0128] Other coating techniques can also be used. 如,利用空气悬浮过程技术来形成剂型的膜或壁。 E.g., to form a membrane or wall of the dosage form using an air suspension process technology. 该过程包括在气流中悬起并翻动压缩核芯和半透膜形成组合物,直到膜涂到核芯上。 The process comprises suspending in the gas stream from the compression and flip core and a semipermeable membrane forming composition, until the film is coated onto the core. 空气悬浮过程适于独立形成剂型的膜。 Air suspension procedure is adapted to separate a film dosage form. 空气悬浮过程在美国专利N0.2799241 ;J.Am.Pharm.Assoc.,第48卷,pp.451-459 (1959);及,同上,第49卷,pp.82-84 (1960)中有描述。 Air suspension procedure in U.S. Patent No. N0.2799241; J.Am.Pharm.Assoc, Vol. 48, pp.451-459 (1959);. In and, ibid., Vol. 49, pp.82-84 (1960) have description. 也可用Wurster ®空气悬浮包衣器来包衣剂型,如利用氯仿甲醇作为共溶剂来制备膜形成材料。 It may also be Wurster ® air suspension coater to coat a dosage form such as a film prepared by using methanol in chloroform as co-solvent forming material. 可用Aeromatic ®空气悬浮包衣器来使用共溶剂。 Available Aeromatic ® air suspension coater is used co-solvent.

[0129] 在具体实例中,如图2所示,本发明持续释放剂型带有至少一个出口60。 [0129] In a specific example, FIG. 2, sustained release formulations of the present invention with at least one outlet 60. 出口60与压缩核芯一起操作来从剂型中统一释放药物。 Export operations together with the compressed core 60 to unify the release of the drug from the dosage form. 在制备剂型期间或在应用流体环境中由剂型递送药物期间可提供出口。 During preparation or application forms a fluid environment may be provided by the outlet during the delivery of pharmaceutical dosage forms. [0130] 在剂型药物层末端钻一个或多个出口,并可任选水溶性外层,其可着色 [0130] In drilling a drug layer end of the dosage form or more outlets, and optionally a water-soluble layer, which may be colored

[0131](如,Opadry着色层)或澄清(如Opadry Clear ® ),其包衣在剂型上以提供成 [0131] (e.g., Opadry colored layer) or clarification (e.g., Opadry Clear ®), which is to provide a coating on a dosage form into

型剂型。 Type dosage forms.

[0132] 出口60可包括由物质或聚合物形成或成型的开口,所述物质或聚合物可由外膜腐蚀、溶解或裂解,从而形成出口。 [0132] outlet 60 may include an opening formed from a substance or polymer or molded, the outer membrane may be a polymer material or corroding, dissolving or cleavage, so as to form an outlet. 物质或聚合物可包括如,半透壁中的可腐蚀的聚(乙醇)酸或聚(乳)酸;凝胶状丝;可用水去除的聚(乙烯醇);可裂解的化合物,如可用流体去除的孔形成物,其选自无机和有机盐、氧化物和碳水化合物。 Substance or polymer may include, for example, the semipermeable wall erodible poly (ethanol) acid or poly (lactic) acid; gelatinous filament; removing water available poly (vinyl alcohol); cleavable compound, such as available fluid removal holes formed thereof, selected from inorganic and organic salt, oxide and carbohydrate.

[0133] 通过裂解选自以下的物质来形成一个出口、或多个出口来提供统一释放尺度的孔-出山梨醇、乳糖、果糖、葡萄糖、甘露糖、半乳糖、塔罗糖、氯化钠、氯化钾、梓檬酸钠和甘露醇。 [0133] The outlet is formed by a material selected from lysis, or more outlet holes provided uniform release Scale - the sorbitol, lactose, fructose, glucose, mannose, galactose, talose, sodium chloride, , potassium chloride, sodium citrate and mannitol Azusa.

[0134] 为从剂型中统一计量释放药剂,出口可以是任何形状,如圆形、三角形、方形、椭圆形等。 [0134] The uniform metered release of drug from the dosage form, the outlet may be any shape, such as round, triangular, square, elliptical, and the like. 持续释放剂型可在持续释放剂型的空间分离的环境中或一个或多个表面上构建有一个或多个出口。 Or a sustained release dosage forms or may be built with one or more spaces in the outlet surface a plurality of sustained release dosage forms of the isolated environment.

[0135] 钻,包括机械和激光钻,钻透半透膜来形成出口。 [0135] Drilling, including mechanical and laser drilling, drill through a semipermeable membrane to form an outlet. 该出口和用于形成该出口的设备在以下文献中有公开:Theeuwes和Higuchi的美国专利N0.3916899和Theeuwes等的美国专利N0.4088864。 The apparatus for forming an outlet and the outlet are disclosed in the following documents: U.S. Patent No. Theeuwes and Higuchi and Theeuwes et N0.3916899 U.S. Patent No. N0.4088864. 目前优选使用两个等直径的出口。 Presently preferred to use two equal diameter outlet. 在优选的具体实例中,如存在,则出口60穿透子层90到药物层30。 In a preferred embodiment, if present, the sub-layer 60 penetrates into the drug layer 30 outlet 90.

[0136] 通过标准方法制备据图1所示实例的剂型。 [0136] According to the example shown in FIG dosage form prepared by standard methods. 如,通过湿法造粒技术制备剂型。 For example, dosage forms prepared by wet granulation technique. 在湿法造粒技术,用有机溶剂(如变性无水乙醇)混合药物和载体,来作为造粒流体。 In the wet granulation technique, using an organic solvent (e.g., ethanol denatured) mixing the drug and a carrier, as granulating fluid. 剩余成分可溶于造粒流体中,如上述溶剂,该后者制备的湿混合物缓慢加到药物中,在混合器中持续混合。 The remaining ingredients can be dissolved in the granulation fluid, the solvent as described above, the latter prepared wet mixture was slowly added to a drug, continuously mixed in a mixer. 加入造粒流体直到`产生湿混合物,然后将该湿混合物通过预先确定的筛子加到炉托盘上。 `Granulating fluid is added until a wet blend is generated, and then the wet mixture through a sieve applied to a predetermined furnace tray. 在24°C至35°C在加压空气炉中干燥混合物18至24小时。 At 24 ° C to 35 ° C the mixture was dried in a pressurized air oven for 18 to 24 hours. 然后过筛干燥的颗粒。 Then sieved dried granules.

[0137] 接着,硬脂酸镁或其他合适的润滑剂加到药物颗粒中,并将颗粒放入罐形球磨机中并在罐形球磨机上混合10分钟。 [0137] Next, magnesium stearate, or another suitable lubricant is added to the drug particles, and the particles are placed in a ball mill pot and mixed on a ball mill pot for 10 minutes. 如在Manesty ®挤压器或Korsch LCT挤压器中,将组合物压成层。 As Manesty ® Korsch LCT extruder or the extruder, the composition is pressed into layers. 对于三层核芯,药物层组合物和推进层组合物的颗粒或粉顺序被加到合适大小的模具中,对每个头两层进行中间压缩步骤,接着在将最后一层加入模具后进行最后压缩步骤,以形成三层核芯。 For three particles or powder core sequence, and the drug layer composition push layer composition are added to an appropriate sized molds, each of the first two layers of an intermediate compression step, followed by a final layer is added after the last die compression step to form a three layer core. 中间压缩通常在约50-100牛顿的力下进行。 Intermediate compression is usually carried out at a force of about 50-100 newtons. 最终阶段压缩通常在3500牛顿或更大的力下进行,通常为3500-5000牛顿。 The final stage of compression is usually carried out at 3500 Newtons or greater force, typically 3500-5000 newtons. 将压缩的核芯加到干燥压力包衣机(coater press)中,如Kilian ®干燥压力包衣机,接着用上述膜材料包衣。 The drying pressure applied to the compressed cores coater (coater press), as a pressure drying Kilian ® coater, followed by coating the above-mentioned film material.

[0138] 在另一个具体实例中,混合药物和含药物层的其他成分,并压在固体层中。 [0138] In another example, mixing the drug and other ingredients comprising the drug layer, and the pressure in the solid layer. 该层具有的尺寸对应于剂型中占有的层内部面积尺寸,该尺寸也包括对应于推进层的尺寸,以形成其中的接触排列。 The inner layer having dimensions corresponding to the dimensions of floor area occupied in the dosage form, including the size corresponds to the size of the push layer to form a contact arranged therein. 药物和其他成分也可用溶剂混合,并通过常规方法混在固体或半固体形式中,如通过球磨、砑光、搅拌或旋转研磨,然后压成预选的形状。 Drug and other ingredients may also be used mixed solvents, and mixed in a solid or semisolid form by conventional methods, such as by ball milling, calendering, stirring or rotating grinding, and then pressed into a preselected shape. 如果包括的话,则接着将渗透聚合物层以相似方式与药物层接触。 When included, the osmopolymer layer is then in contact with a similar drug layer. 药物制剂和渗透聚合物层的成层可通过常规两层压制技术来完成。 Pharmaceutical formulations and permeation into a layer of the polymer layer may be accomplished by conventional two-layer press techniques. 类似过程可接着用于制备三层核芯。 A similar process can then be used to prepare a three-layer core. 然后压缩核芯可用上述壁材料和半透膜材料包衣。 Compressing the above core is then available for the wall material and the semipermeable membrane material coating.

[0139] 可用的另外的制造过程包括在流化床造粒器中混合每层的粉状成分。 [0139] available additional manufacturing process comprises mixing powdered ingredients for each layer in a fluid bed granulator. 在造粒器中干混粉状成分后,造粒流体(如在水中的聚(乙烯吡咯烷酮))喷在粉末上。 After granulator dry mixed powdered ingredients, granulating fluid (in water such as poly (vinylpyrrolidone)) is sprayed onto the powder. 然后在造粒器中干燥包衣的粉末。 Then dried in a granulator powder coating. 加入造粒流体同时,该方法使所有出现在其中的成分形成颗粒。 Granulating fluid was added at the same time, the method in which all the components present in particulate form. 干燥颗粒后,用混合器,如V-混合器或手提混合器,将润滑剂(如硬脂酸或硬脂酸镁)混入颗粒。 After drying the particles, with a mixer, such as a V- blender or hand mixer, a lubricant (such as stearic acid or magnesium stearate) into particles. 然后以上述方式压颗粒。 In the manner described above and then pressing the particles.

[0140] 适于制造剂型成分的示例性的溶剂包括含水的或惰性的有机溶剂,其不损害系统中所用的材料。 [0140] Exemplary solvents suitable for manufacturing the dosage form components comprise aqueous or inert organic solvent, which is not used in the system of material damage. 溶剂广泛包括:含水溶剂、醇、酮、酯、醚、脂肪族碳水化合物、卤化溶剂、环脂肪族、芳香族、杂环溶剂及其混合物。 Solvents broadly include: aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbon, halogenated solvents, cycloaliphatic, aromatic, heterocyclic solvents and mixtures thereof. 典型的溶剂包括,丙酮、二丙酮醇、甲醇、乙醇、异丙醇、丁醇、乙酸甲酯、乙酸乙酯、乙酸异丙酯、乙酸正丁酯、甲基异丁基酮、甲基丙基酮、正己烷、正庚烷、乙二醇单乙基醚、乙二醇单乙基乙酸酯、二氯甲烷、二氯乙烷、二氯丙烷、四氯化碳硝基乙烷、硝基丙烷四氯乙烷、乙醚、异丙基醚、环己烷、环辛烷、苯、甲苯、石脑油、1,4_ 二氧六环、四氢呋喃、二甘醇二甲醚、水、含无机盐,如氯化钠、氯化钙等的含水溶剂,及其混合物,如丙酮和水、丙酮和甲醇、丙酮和乙醇、二氯甲烷和甲醇、和二氯乙烷和甲醇。 Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropanol, butanol, methyl acetate, ethyl acetate, isopropyl, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene chloride, dichloroethane, dichloropropane, carbon tetrachloride nitroethane, nitropropane tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4_ dioxane, tetrahydrofuran, diglyme, water, containing inorganic salt such as sodium chloride, calcium chloride aqueous solvents, and mixtures thereof such as acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene chloride and methanol, and ethylene dichloride and methanol.

[0141] 本发明实践中的一个重要考量是要通过剂型递送的鸦片样物质的物理状态。 [0141] An important consideration in the practice of the present invention is the physical state of the dosage form to be delivered by the opioid. 在某些具体实例中,鸦片样物质成糊状或呈液态。 In certain instances, opioids or liquid form into a paste. 在这种情况下,固体剂型不适用于本发明的实践。 In this case, it does not apply to solid dosage forms used in the practice of the present invention. 应该替换使用能用于递送物质的糊状或呈液态的剂型。 It can be used interchangeably for the delivery of the pasty material or in liquid dosage forms.

[0142] 本发明提供物质的液体制剂,其和口服渗透装置一起使用。 [0142] The present invention provides a liquid formulation of the substance, and for use with oral osmotic devices. 递送液体制剂的口服渗透装置和使用其的方法是现有已知的,如以下ALZA公司拥有的美国专利6419952、6174547、6551613、5324280、4111201和6174547所描述和要求保护的。 The method of using oral osmotic devices and liquid formulation which delivery is conventionally known, as described in U.S. Patent No. ALZA Corporation has 6419952,6174547,6551613,5324280,4111201 and 6,174,547 described and claimed. 利用口服渗透装置以上升的释放率递送治疗剂的方法可在国际申请W098/06380、W098/23263、和W099/62496中找到。 Using oral osmotic devices ascending release rate method of delivery of therapeutic agents may apply W098 / 06380 International, W098 / 23263, and W099 / 62496 found.

[0143] 用于本发明的示例性的液体载体包括亲脂溶剂(如油和脂)、表面活性剂和亲水溶剂。 [0143] Exemplary liquid carriers for the present invention include lipophilic solvents (e.g., oils and fat), a surfactant and a hydrophilic solvent. 如,示例性的亲脂溶剂包括但不限于Capmul PG-8, CaprolMPGO, Capryol 90,Plurol Oleique CC 497, Capmul MCM, Labrafac PG, N-癸醇,Caprol 10G100,油酸,维生素E,Maisine 35-1, Gelucire 33/01, Gelucire 44/14,月桂醇,Captex 355EP, Captex500,Capylic/Caplic 甘油三酉旨,Peceol, CaprolET, Labrafil M2125CS, Labrafac CC, LabrafilM 1944 CS, Captex 8 277, Myvacet 9-45,异丙基Nyristate, Caprol PGE 860,撤揽油,Plurol Oleique,花生油,Captex 300Low C6,和羊腊酸。 For example, exemplary lipophilic solvents include, but are not limited to, Capmul PG-8, CaprolMPGO, Capryol 90, Plurol Oleique CC 497, Capmul MCM, Labrafac PG, N- decanol, Caprol 10G100, oleic acid, vitamin E, Maisine 35- 1, Gelucire 33/01, Gelucire 44/14, lauryl alcohol, Captex 355EP, Captex500, Capylic / Caplic triglycerides unitary purpose, Peceol, CaprolET, Labrafil M2125CS, Labrafac CC, LabrafilM 1944 CS, Captex 8 277, Myvacet 9-45 , isopropyl Nyristate, Caprol PGE 860, rugby oil, Plurol Oleique, peanut oil, Captex 300Low C6, acid wax, and sheep.

[0144] 如,示例性的表面活性剂包括但不限于维生素E TPGS, Cremophor (EL, EL-P和RH40 级),Labrasol,吐温(20、60、80 级),Pluronic (L-31,L-35,L-42,L-64 和L-121 级),Acconon S-35, Solutol HS-15和Span(20和80级)。 [0144] As exemplary surfactants include but are not limited to, vitamin E TPGS, Cremophor (EL, EL-P, and RH40 level), Labrasol, Tween (20,60,80 level), Pluronic (L-31, L-35, L-42, L-64 and L-121 stage), Acconon S-35, Solutol HS-15, and Span (20 and 80). 如,示例性的亲水溶剂包括但不限于异山梨醇、二甲醚、聚乙二醇(300、400、600、3000、4000、6000和8000级PEG)和丙二醇(PG)。 For example, the exemplary hydrophilic solvents include but are not limited to, isosorbide, dimethyl ether, polyethylene glycol (300,400,600,3000,4000,6000 8000 and PEG) and propylene glycol (PG).

[0145] 熟练技术人员会明白,本发明中可使用任何含足够溶于液体载体中的鸦片样物质剂的制剂,用于向患者给药并用在渗透体中。 [0145] The skilled artisan will appreciate that the present invention may be used in any formulation containing a sufficient dissolved in a liquid carrier opioid agent, for administration to a patient and used in the infiltrated body. 在本发明一个示例性的具体实例中,液体载体是PG, Solutol, Cremophor EL 或其组合。 In a specific example of the present invention, in exemplary liquid carrier is PG, Solutol, Cremophor EL, or a combination thereof.

[0146] 根据本发明的液体制剂也可包括如额外的赋形剂,如抗氧化剂、渗透增强剂等。 [0146] The liquid formulation of the invention may also comprise additional excipients such as an antioxidant, permeation enhancer and the like. 抗氧化剂用于减慢或有效停止任何胶囊中存在的材料自然氧化的速率。 The antioxidant serves to slow or effectively stop the rate of any of the materials present in the capsule of the natural oxide. 有代表性的抗氧化剂包括:抗坏血酸;α生育酚;抗坏血酸棕榈酸酯;抗坏血酸盐;异抗坏血酸盐;丁基羟基茴香醚;丁基轻基甲苯;nordihydroguiaretic酸;大蒜酸的酯,其含至少3个碳原子,含选自如下的成员:丙基没食子酸酯、辛基没食子酸酯、癸基没食子酸酯、癸基没食子酸;6-乙氧基-2,2,4-三甲基-1,2-二氢-guinoline ;N-乙酰_2,6-二-叔-丁基-对-氨基苯酚;丁基酪氨酸;3_叔丁基-4-羟基茴香醚;2_叔丁基-4-羟基茴香醚;4_氯-2,6- 二叔丁基苯酚;2,6-二叔丁基对-甲氧基苯酚;2,6-二叔丁基对-甲酚;聚抗氧化剂;抗坏血酸、异抗坏血酸和抗坏血酸乙酯的三羟基丁内-苯基酮生理上可接受的盐;抗坏血酸钙;抗坏血酸钠;亚硫酸氢钠;等等。 Representative antioxidants include: ascorbic acid; [alpha] -tocopherol; ascorbyl palmitate; ascorbate; erythorbates; butylhydroxyanisole; light-butyl toluene; nordihydroguiaretic acid; esters of garlic acid, which contains at least 3 carbon atoms, containing a member selected from: propyl gallate, octyl gallate, decyl gallate, decyl gallic acid; 6-ethoxy-2,2,4-trimethyl - 1,2-dihydro--guinoline; N- acetyl _2,6- two - tert - butyl - p - amino phenol; butyl tyrosine; 3_-tert-butyl-4-hydroxyanisole; 2_ t butyl-4-hydroxy anisole; 4_-chloro-2,6-di-t-butylphenol; 2,6-di-t-butyl-p - methoxyphenol; 2,6-di-t-butyl-p - cresol ; poly antioxidants; ascorbic acid, erythorbic acid and ascorbic acid within ethyl trihydroxybutylthio - phenone physiologically acceptable salts; calcium ascorbate; sodium ascorbate; sodium bisulfite; and the like. 如,用于本发明的抗氧化剂的量为腔中存在组合物总重量的约0.001%至25%。 For example, the cavity is present from about 0.001 to 25% by weight of the total amount of the composition used in the present invention the antioxidant is. 抗氧化剂在现有技术美国专利N0.2707154、3573936、3637772、4038434、4186465和4559237中是已知的,每篇文献全文均纳入本文参考。 Antioxidant prior art U.S. Patent No. 4,559,237 and in N0.2707154,3573936,3637772,4038434,4186465 are known, the full text of each document are incorporated herein by reference.

[0147] 本发明液体制剂包括渗透增强剂,使药物在应用环境中容易吸收。 Liquid formulations [0147] The present invention includes a permeation enhancer, the drug is easily absorbed in the application environment. 如,这种增强剂能打开胃肠道中的所谓“紧密节点”或修改细胞成分的效应,如P-糖蛋白等。 As such enhancers can be opened in the gastrointestinal tract so-called "tight nodes" or modify the effect of cellular components, such as P- glycoprotein and the like. 合适的增强剂包括如下酸的碱金属盐:水杨酸,如水杨酸钠,辛酸或癸酸,如辛酸钠或癸酸钠,等。 Suitable enhancers include alkali metal salts of the following acids: salicylic acid, such as sodium salicylate, caprylic or capric acid, such as sodium caprylate or sodium caprate, and the like. 增强剂包括如胆汁盐,如去氧胆酸钠。 Enhancers include bile salts such as sodium deoxycholate. 各种P-糖蛋白调节剂在美国专利N0.5112817和5643909中有描述。 Various P- glycoprotein modulators are described in U.S. Patent No. 5,643,909 and in N0.5112817. 各种其他吸收增强化合物和材料在美国专利N0.5824638中有描述。 Various other absorption enhancing compounds and materials are described in U.S. Patent No. N0.5824638 in. 增强剂可单独或与其他增强剂混合使用。 Enhancers may be used alone or mixed with other enhancers.

[0148] 在某些具体实例中,本发明的物质以自乳化制剂来给药。 [0148] In certain instances, the substance of the present invention is a self-emulsifying formulation to be administered. 像其他液体载体,表面活性剂用于防止凝聚,减少成分间的表面张力,增强成分的自由流动,并降低成分滞留在剂型中的可能性。 Like the other liquid carriers, surface active agents for preventing agglomeration, reducing the surface tension between constituents, enhance the free flow of components, and reduce the likelihood of component retention in the dosage form. 本发明的乳剂包含能进行乳化的表面活性剂。 Emulsion of the present invention comprises a surfactant capable of emulsification. 除了以上列出的表面活性剂,示例性的表面活性剂也包括:含9至15摩尔的环氧乙烷的聚环氧乙烷化的蓖麻油,含20摩尔的环氧乙烷的聚环氧乙烷化的山梨聚糖单棕榈酸酯、单和三硬脂酸酯,含4摩尔的环氧乙烷的聚环氧乙烷化的山梨聚糖单硬脂酸酯,含20摩尔的环氧乙烷的聚环氧乙烷化的山梨聚糖三油酸酯,聚环氧乙烷月桂醚,含40至50摩尔的环氧乙烷的聚环氧乙烷化的硬脂酸,含2摩尔的环氧乙烷的聚环氧乙烷化的硬脂醇和含2摩尔环氧乙烷的聚环氧乙烷化油醇。 In addition to the surfactants listed above, exemplary surfactants include: polyethylene oxide of castor oil containing 9 to 15 moles of ethylene oxide, containing 20 moles of ethylene oxide polyepoxide of ethylene oxide sorbitan monopalmitate, mono and tristearate, polyoxyethylene sorbitol of 4 moles of ethylene oxide containing glycan monostearate containing 20 moles of polyethylene oxide of ethylene oxide, sorbitan trioleate, polyoxyethylene lauryl ether, containing 40 to 50 moles of ethylene oxide polyethylene oxide of stearic acid, polyethylene oxide having 2 moles of ethylene oxide of the polyethylene oxide stearyl alcohol and oleyl alcohol comprising 2 moles of ethylene oxide. 表面活性剂可得自Atlas Chemical Industries。 Surfactant available from Atlas Chemical Industries.

[0149] 本发明的药物乳化制剂最初可包含油和非离子表面活性剂。 Emulsifying pharmaceutical formulation [0149] The present invention can initially comprise an oil and a nonionic surfactant. 乳剂的油相包含任何药学上可接受的油,其不与水混合。 The oil phase of the emulsion comprises any pharmaceutically acceptable oil which is not miscible with water. 油可以是可食用的液体,如不饱和脂肪酸的非极性酯,这些酯的衍生物·,或这些酯的混合物。 The oil may be an edible liquid such as a non-polar ester of an unsaturated fatty acid, derivatives *, or mixtures of such esters of these esters. 油可以是植物、矿物、动物或来自海洋的油。 Oil can be vegetable, mineral, animal or oil from the sea. 除了以上列出的表面活性剂,无毒油也可包括:花生油,棉子油,芝麻油,玉米油,杏仁油,矿物油,蓖麻油,椰子油,棕榈油,可可油,红花染料,16至18个碳的甘油单和二酯的混合物,不饱和脂肪酸,椰子油中分馏的甘油三酯,从短链10至15个碳原子的脂肪酸中分馏的甘油三酯液体,乙酰化的甘油单酯,乙酰化的甘油二酯,乙酰化的甘油三酯,油酸甘油脂(也称为三油酸甘油脂),甘油棕榈酸酯(也称为甘油三棕榈酸酯),硬脂酸甘油酯(也称为三硬脂酸甘油酯),月桂酸己酯,油酸油醇酯,天然油的醣酵解的乙氧化甘油,带有13个分子的环氧乙烷的支化脂肪酸,以及油酸癸酯。 In addition to surfactants, non-toxic oils listed above may also include: peanut oil, cottonseed oil, sesame oil, corn oil, almond oil, mineral oil, castor oil, coconut oil, palm oil, cocoa butter, safflower dye, 16 to 18 carbon atoms a mixture of mono- and di-esters of unsaturated fatty acids, fractionated coconut oil triglycerides from fractionated fatty acid short chain 10 to 15 carbon atoms, liquid triglycerides, acetylated monoglycerides esters, acetylated diglycerides, acetylated triglycerides, oleic acid glycerides (also known as glycerol trioleate), glycerol palmitate (also known as glyceryl tripalmitate), glyceryl stearate ester (also referred to as stearin), ethoxylated glyceryl hexyl laurate, oleyl oleate, glycolysis natural oil, branched fatty acids with 13 molecules of ethylene oxide, and and decyl oleate. 乳化制剂中的油或油衍生物的浓度为约lwt%至约40wt%,乳化制剂中的所有成分的wt %等于IOOwt %。 Emulsifying formulation concentration of oil or oil derivative is from about lwt% to about 40wt%, wt% of all constituents equals emulsifying formulation IOOwt%. 油公开于Mark Publishing C0.出版的Remington 的Pharmaceutical Sciences, 17 版,pp.403-405(1985), Van NostrandReinhold Co,出版的Van Nostrand Reinhold 的Encyclopedia of Chemistry,4 版,pp.644-645(1984),以及美国专利N0.4259323 中。 Oil disclosed in Mark Publishing C0. Published in Remington's Pharmaceutical Sciences, Edition 17, pp.403-405 (1985), Van NostrandReinhold Co, published by Van Nostrand Reinhold's Encyclopedia of Chemistry, Edition 4, pp.644-645 (1984 ), and US Patent N0.4259323 in.

[0150] 根据治疗情况和所需给药周期,如每12小时,每24小时等,纳入本发明剂型中的鸦片样物质的量一般为组合物重量的约10%至约90%。 [0150] The treatment and the desired period of administration, such as every 12 hours, every 24 hours, etc., into the formulations of the invention in an amount of opioid generally about 10% by weight of the composition to about 90%. 根据所需给药的鸦片样物质的剂量,可给药一种或多种剂型。 The desired dose opioid administration, dosage forms may be administered one or more. [0151] 本发明渗透剂型有两种不同形式,软胶囊形式(如图3所示)和硬胶囊形式(如图4所示)。 Osmotic dosage form [0151] The present invention has two different forms, a soft capsule form (shown in Figure 3) and a hard capsule form (shown in Figure 4). 本发明所用的软胶囊优选其最终形式包含一片体。 It used in the present invention preferably in its final form soft gelatin capsules comprising a body. 一片体胶囊是密封成的,将本文的药物制剂包在胶囊中。 A sealed into the capsule, the pharmaceutical formulations described herein in a capsule packet. 胶囊可由多种方法制成,包括平板方法、旋转模具方法、往复模具方法、和连续方法。 Capsules can be made of a variety of methods, tablet method, the rotating mold method, the reciprocating die process, and a continuous method comprising 平板方法的实例如下。 Examples of tablet method are as follows. 平板过程是用一套模具。 Process is a mold plate. 制备胶囊的薄层形成材料的保暖薄片放置在较低的模具上,制剂浇在其上。 Warm preparative thin layer sheet material forming the capsule is placed on the lower mold, the formulation poured on it. 薄层形成材料的第二薄片放置在顶层模具下的制剂之上。 Forming a second thin sheet material is placed over the formulation of the top mold. 在加热或不加热的条件下,模具置于压力下并施压,形成单位胶囊。 Under heating or without heating, the die is placed under pressure and pressed to form a unit capsule. 用溶剂洗胶囊,从胶囊外去除多余制剂,用半透壁将空气干燥的胶囊制成胶囊。 Capsules washed with a solvent to remove excess formulation from the exterior of the capsule, the semipermeable wall with the air-dried capsule into capsules. 旋转模具过程用两个连续的胶囊薄层形成材料的薄膜,在一对旋转模具和注射楔之间使之收拢。 Rotating mold during the formation of continuous thin film material with two capsules a thin layer, so that a pair of rotating gather between the mold and the injection wedge. 在双重同时操作中,该方法进行填充并封成胶囊。 The double simultaneous operation, the method for filling and sealing a capsule. 在该方法中。 In the process. 胶囊薄层形成材料的薄膜绕在导向辊上,然后在注射楔和旋转模具间下降。 Capsules formed thin film material is wound on the guide roller, and then drops in the injection wedge and rotary dies.

[0152] 重力使胶囊化的制剂流入正向配置泵中。 [0152] gravity of the capsule formulation of the pump flows into the forward configuration. 泵通过注射楔量度制剂并进入旋转模具间的薄层中。 Formulations for injection via the pump and into a measure of the wedge between the rotating sheet mold. 楔底部包括小开口,沿着旋转模具的模具袋排列。 A bottom wedge including small openings, arranged along the rotatable die mold pocket. 对泵送的制剂施压,使薄片进入模具袋,这时胶囊大概是半封闭的,其中胶囊同时填充、成形、密封并从薄层形成材料的薄片上切下。 Formulations pumping pressure, the sheet bags into the mold, when closed about a half of the capsule, wherein the capsule simultaneously filled, shaped, sealed and cut from the sheet material is formed from a thin layer. 通过在旋转模具上用机械压并通过加热楔边薄层形成材料的薄片,由此来密封胶囊。 By using mechanical press and the sheet material is formed by heating the sheet edges of the wedge on the rotary mold, thereby sealing the capsule. 制备后,填充制剂的胶囊在加压空气中干燥,就囊化形成半渗透的薄膜。 After preparation, the formulation filled in capsules pressurized air dried to form a film encapsulated semipermeable.

[0153] 往复模具方法通过在一套垂直模具间两个形成胶囊薄层材料的薄膜来制造胶囊。 [0153] The method of the mold by a reciprocating vertical mold between two thin layer of material to form a capsule membrane is manufactured capsule. 模具关闭、开启、和关闭作为连续的垂直平板沿着薄膜形成一排一排的囊。 The mold is closed, open, and close rows of the balloon is formed as a continuous film along the vertical plate. 用本发明的制剂填充该囊并当该囊移过模具时,对它们密封、成型,并从移动薄膜上切下,成为充满制剂的胶囊。 With the formulations of the invention and to fill the balloon when the balloon moves through the mold, to seal them, shaped, and cut from the moving film, become filled capsule formulation. 将半透胶囊形成薄层涂在其上以产生胶囊。 The semipermeable coated capsule forms a thin layer thereon to produce capsules. 该连续过程是一种制造系统,其也可使用旋转模具,而且除了将液体包成胶囊,还具有额外的特征,即该过程可向软胶囊中持续注入干粉状的活性试剂。 The continuous process is a manufacturing system that can be used rotating mold, and in addition to the liquid coating into the capsule, has the added feature that the process can be continuously injected into the active agent into a dry powder soft capsules. 连续过程注满的胶囊用半透多聚材料包成胶囊,产生胶囊。 Continuous process capsule filled with a semipermeable polymeric material to pack capsules produced capsules. 生产软胶囊的过程在美国专利N0.4627850和美国专利N0.6419952中有描述。 Soft capsule production process are described in U.S. Patents and U.S. Patent No. N0.6419952 in N0.4627850.

[0154] 本发明的剂型也可由可注塑组合物通过注塑技术制备。 Dosage [0154] of the present invention may also be injection molding composition prepared by injection molding techniques. 提供用于注塑入半透膜的可注塑组合物包括热塑聚合物、或该组合物含热塑聚合物和任选的注塑组分的混合物。 Providing a semi-permeable membrane may be injection molded into the injection molding composition comprises a thermoplastic polymer, or a mixture of components of the injection molding composition comprising a thermoplastic polymer and optionally. 用于本目的的热塑聚合物含具有低软化点的聚合物,如低于200摄氏度,优选在40摄氏度至180摄氏度的范围内。 A thermoplastic polymer-containing polymers used for this purpose has a low softening point, such as below 200 degrees C, preferably in the range of 40 degrees to 180 degrees Celsius. 聚合物优选是合成树脂、加成多聚化的树脂,如聚酰胺,得自二环氧化物和初级链烷醇酰胺的树脂、`甘油和邻苯二甲酸酐的树脂、聚甲烷、聚乙烯树脂、末端带有游离或酯化的羧基或羧基酰胺基团的聚合物树脂,如带有丙烯酸、丙烯酰胺、丙烯酸酯、聚己内酯及其与二丙交酯、二乙交酯、戊内酯和癸内酯的共聚物,树脂组合物,其含有聚己内酯和聚环氧化物,以及树脂组合物,其含有聚己内酯、聚烷氧化物,如聚环氧乙烷、聚(纤维素),如聚(羟基丙基甲基纤维素)、聚(羟基乙基甲基纤维素)和聚(羟基丙基纤维素)。 Polymers are preferably synthetic resins, addition polymerized resins, such as polyamides, resins obtained from diepoxides and primary alkanolamides resin, `glycerol and phthalic anhydride, poly methane, polyethylene resin, having a free terminal carboxyl group or esterified carboxyl or amide group polymer resin, such as with acrylic acid, acrylamide, acrylic acid esters, polycaprolactone with dilactide and, diethyl lactide, pentyl and decalactone lactone copolymer, a resin composition comprising polycaprolactone and polyalkylene oxide, and a resin composition comprising polycaprolactone, polyalkylene oxides such as polyethylene oxide, poly (cellulose) such as poly (hydroxypropylmethylcellulose), poly (hydroxy ethyl cellulose) and poly (hydroxypropyl cellulose). 膜形成组合物包括任选的膜形成成分,如聚乙二醇、滑石粉、聚乙烯醇、乳糖、或聚丙烯吡咯烷酮。 Optionally film-forming composition comprising a film forming component, such as polyethylene glycol, talcum, polyvinylalcohol, lactose, or polypropylene pyrrolidone. 用于形成注塑聚合物组合物的组合物可含100%热塑聚合物。 Injection molding a polymer composition for forming the compositions may contain 100% of a thermoplastic polymer. 在另一个实施方案中,组合物含10%至99%热塑聚合物和I %至90%不同的聚合物,总和等于100%。 In another embodiment, the composition contains 10 to 99% thermoplastic polymer, and I% to 90% of a different polymer, equals 100%. 本发明也提供热塑聚合物组合物,其含I %至98 %第一热塑聚合物、I %至90 %不同的第二聚合物和I %至90%不同的第三聚合物,总和等于100%。 The present invention also provides a thermoplastic polymer composition containing I% to 98% of a first thermoplastic polymer, I% to 90% of a second polymer different from I% to 90% and a different third polymer, the sum of equal to 100%.

[0155] 有代表性的组合物含20%至90%热塑聚己内酯和10%至80%聚(环氧化物);组合物含20%至90%聚己内酯和10%至60%聚(环氧乙烷),成分之和等于100% ;组合物含10%至97%聚己内酯、10%至97%聚(环氧化物)和1%至97%聚(环氧乙烷),所有成分之和等于100% ;组合物含20%至90%聚己内酯和10%至80%聚(羟基丙基纤维素),所有成分之和等于100% ;以及组合物含1%至90%聚己内酯、1%至90%聚(环氧乙烷)、1%至90%聚(羟基丙基纤维素)和1%至90%聚(环氧乙烷),所有成分之和等于100%。 [0155] Representative compositions containing 20 to 90% of thermoplastic polycaprolactone and 10 to 80% poly (epoxide); a composition comprising 20 to 90% polycaprolactone and 10% to 60% poly (ethylene oxide) component is equal to 100%; composition contains 10 to 97% polycaprolactone, from 10 to 97% of poly (alkylene oxide) and 1-97% of poly (cyclo ethylene oxide), the sum of all ingredients equal to 100%; composition contains 20 to 90% polycaprolactone and 10 to 80% of poly (hydroxypropylcellulose), the sum of all ingredients equal to 100%; and a combination of composition containing from 1 to 90% polycaprolactone, 1 to 90% poly (ethylene oxide), 1 to 90% of poly (hydroxypropylcellulose) and 1 to 90% poly (ethylene oxide ), the sum of all ingredients equal to 100%. 所述百分数是重量百分数wt %。 The percentages are weight percentage wt%.

[0156] 在本发明的另一个实施方案中,通过在常规的混合器中,如Moriyama™混合器,在65摄氏度至95摄氏度下混合组合物,其含有63wt %聚己内酯、27wt %聚环氧乙烷和IOwt %聚乙二醇,由此可以来制备注塑以提供膜的组合物,其中各成分以如下添加顺序加入混合器,聚己内酯、聚环氧乙烷和聚乙二醇。 [0156] In another embodiment of the present invention, by a conventional mixer, such as a Moriyama ™ mixer at 65 degrees Celsius to 95 degrees Celsius for mixed composition containing polycaprolactone 63wt%, 27wt% poly IOwt% ethylene oxide and polyethylene glycol, whereby the injection may be prepared to provide a composition film, wherein the ingredients added to the mixer in the following addition sequence, polycaprolactone, polyethylene oxide and polyethylene glycol alcohol. 在一个实施方案中,在旋转器中以10至20rpm的速度混合所有成分135分钟。 In one embodiment, the rotator 10 to 20rpm speed mixing all ingredients 135 minutes. 接着,在80摄氏度至90摄氏度下将混合物加入Baker PerkinsKneader™挤压机中,泵速IOrpm而转动速度22rpm,然后冷却至10摄氏度至12摄氏度,达到一致的温度。 Next, at 80 degrees Celsius to 90 degrees C. The mixture was added Baker PerkinsKneader ™ extruder, while the speed of the pump rotational speed of 22 rpm IOrpm, then cooled to 10 ° C to 12 ° C, to reach a uniform temperature. 然后,冷却挤压过的组合物加入Albe制粒机中,在250摄氏度制成长度为5mm的球。 Then, the cooled extruded composition is added Albe granulator, made at 250 ° C for the length of 5mm balls. 接着在200华氏度至350摄氏度(93摄氏度至177摄氏度)下将球装入注塑机Arburg Allrounder™中,加热至熔融聚合组合物,以高压和高速将液体聚合组合物加入模具腔中,直到注满模具,含聚合物的组合物以预选的形状固化。 Next at 200 degrees Fahrenheit to 350 degrees Celsius (93 degrees C to 177 degrees C) charged with the ball in an injection molding machine Arburg Allrounder ™, heated to a molten polymeric composition, pressure, and velocity to the liquid polymeric composition into a mold cavity until the injection full mold, polymer-containing composition curable to a preselected shape. 注塑参数包括筒的I区至5区的带温度为195华氏度(91摄氏度)至375华氏度(191摄氏度)、注塑压为1818bar、速度为55cm3/s、以及模压温度为75摄氏度。 Injection parameters include the I region to the cylindrical region 5 with a temperature of 195 degrees Fahrenheit (91 degrees Celsius) and 375 degrees Fahrenheit (191 degrees Celsius), the injection pressure is 1818bar, rate of 55cm3 / s, and a mold temperature of 75 ° C. 注塑组合物和注塑方法在美国专利N0.5614578中有描述。 Injection molding compositions and injection molding methods are described in U.S. Patent No. N0.5614578 in.

[0157] 或者可将胶囊方便地制成两部分,其中一部分(“盖”)滑过并盖在另一部分(“主体”)上,只要胶囊受到可扩展层的力可变形,并密封以防止液体、活性试剂从主体和盖压缩部分之间泄漏。 [0157] Alternatively the capsule may be made conveniently in two parts, wherein a portion ( "lid") and a cover slip on another part ( "body"), a force can be extended as long as the capsule is deformable layer, and sealed to prevent liquid, active agent from leaking between the body and the cover compression section. 两部分完全围绕包衣含液体、活性制剂的内腔,其可含有用的添加剂。 Two parts completely surrounding a lumen containing a coating liquid, active agent, which may contain additives. 在主体注入预选的制剂后,两部分可合在一起。 After a preselected main injection formulation, the two parts may be bonded together. 通过滑动或将盖层压在主体层上,密封盖和主体,由此进行组装,从而完全围绕和包衣活性试剂制剂。 On the body layer, and a sealing cap body, thereby assembled by sliding the cover or laminate, thereby completely surrounding and coating the active agent formulation.

[0158] 软胶囊的壁厚度通常大于硬胶囊的壁厚度。 [0158] Soft capsule wall thickness is generally greater than the wall thickness of hard capsules. 如,软胶囊的厚度在10-40密耳的数量级上,通常是约20密耳,而硬胶囊的厚度在2-6密耳的数量级上,通常是约4密耳。 The thickness of the soft capsules in the order of 10-40 mils, generally about 20 mils, and the thickness of the hard capsule in the order of magnitude of 2-6 mils, about 4 mils generally.

[0159] 在剂量系统的·一个实施方案中,软胶囊可以是单个单位构型并可围绕有作为可扩展层的非对称水活化层。 [0159] In one embodiment · dosing system embodiment, the soft capsule may be a single unit configuration can be surrounded by a water activatable layer as an asymmetric expandable layer. 可扩展层一般是非对称的,较厚的部分远离出口。 Scalable layer is generally asymmetric, the thicker portion remote from the outlet. 水活化层吸取和/或吸收外部流体时,其膨胀并向胶囊壁和任选的屏障层施加推进压力并从出口挤出活性制剂。 Water suction active layer and / or absorbs external fluid, it expands and applies pressure to promote the capsule wall and, optionally, a barrier layer and active agent extruded from the outlet. 非对称层的存在能确保从剂型中递送最大剂量的试剂,远离出入口的较厚的层部分膨胀并向出口移动。 The presence of an asymmetric layer ensures delivery of a maximum dose of agent from the dosage form, away from the entrance to the thicker layer partially expanded exit port.

[0160] 在另一个构型中,可以不连续部分的形式形成可扩展层,使之不完全包围任选的屏障层包衣的胶囊。 [0160] In another configuration, portions may be discontinuously formed in the form of extensible layer, so as not to completely surround the optional barrier layer coated capsules. 可扩展层可以是单个元件,其形成以适合胶囊在接触面时的形状。 Scalable layer may be a single element, which is formed to fit the contact surface of the capsule shape. 通过成片以形成凹表面,其互补于屏障层包衣的胶囊的外表面,由此可方便地制造可扩展层。 To form into a sheet by a concave surface which is complementary to the outer surface of the barrier layer coated capsule, thereby spreading layer can be easily manufactured.

[0161] 合适的工具,如产生常规成片压力的凸冲压机,可为可扩展层提供必要的互补形状。 [0161] a suitable tool, such as a pressure generating sheet into a convex conventional stamping press can provide the necessary complementary shape for the expandable layer. 在该情况下,可扩展层被造粒并压缩,而不是形成包衣。 In this case, the expandable layer is granulated and compressed, rather than formed coating. 可扩展层通过成片成形的方法是公知的,如在美国专利N0.4915949、5126142、5660861、5633011、5190765、5252338、5620705、4931285、5006346、5024842 和5160743 中有描述。 The method can be extended into a sheet shaped layer are well known, as described in U.S. Patent No. 5,160,743 and in N0.4915949,5126142,5660861,5633011,5190765,5252338,5620705,4931285,5006346,5024842.

[0162] 在一些实施方案中,可首先将屏障层涂在胶囊上,然后成片,可扩展层通过生物相容的粘合剂连于涂有障碍的胶囊上。 [0162] In some embodiments, the barrier layer can be first coated onto the capsule and then into tablets, may be extended by a biocompatible adhesive layer attached to the barrier-coated capsule. 合适的粘合剂包括如,淀粉糊、含水明胶溶液、含水明胶/甘油溶液、基于丙烯酸-乙烯醋酸的粘合剂,如Duro-Tak粘合剂(National Starch andChemical Company)、水溶性亲水聚合物的水溶液,如轻基丙基甲基纤维素、轻基甲基纤维素、羟基乙基纤维素等。 Suitable binders include, for example, starch paste, aqueous gelatin solution, aqueous gelatin / glycerin solution, based on acrylic acid - vinyl acetate adhesive, such as Duro-Tak adhesives (National Starch andChemical Company), water-soluble hydrophilic polymeric an aqueous solution thereof, such as light propyl methyl cellulose, light methylcellulose, hydroxyethyl cellulose and the like. 然后用半透层包衣中间剂型。 Then coated with a semipermeable layer intermediate forms. 开口开在胶囊的边上或末端,对着可扩展层部分。 An opening open at the edge or end of the capsule, opposite the expandable layer section. 但当扩展层吸流体时,其会膨胀。 However, when the spreading layer absorbing fluid, which expands. 由于有半透层约束,膨胀时它会压缩包有障碍的胶囊并从胶囊内向应用环境挤出液体、活性制剂。 Since the semi-permeable layer constraint, it expands when compressed and extruded capsule obstacles liquid, active agent from the capsule within the application environment.

[0163] 硬胶囊通常由两部分组成,盖和主体,在较大的主体注入预选的合适制剂后,其可以合在一起。 [0163] Hard capsules are typically composed of two parts, body and cover, after a preselected appropriate formulation large body implant, which may be bonded together. 可通过滑动或将盖层压在主体层上实现,从而完全围绕包衣有用的试剂制剂。 It can be achieved by a sliding layer on the body or the cover laminate to completely surround a coating formulation useful reagents. 如,通过将不锈钢压模浸溃在含胶囊薄片形成材料的溶液的浴中,用该材料包衣模具,由此制备硬胶囊。 E.g., by dipping stainless steel mold bath in a solution containing the capsule material sheet, coated with the mold material, thereby preparing hard gelatin capsules. 然后在气流中回收、冷却并干燥模具。 In the gas stream is then recovered, dried and cooled mold. 从模具上剥下胶囊并剪裁以产生带有内腔的薄片元件。 Capsule stripped from the mold and cut to produce a sheet member having a lumen. 密封盖在带有制剂的主体上的接合盖以相似方式制造。 Sealing cover joined to the body with a cover formulation manufactured in a similar manner. 然后用半透薄片将封闭并注满的胶囊制成胶囊。 The sheet is then closed with a semipermeable capsule and fill into capsules. 半透薄片可应用于部分前或后的胶囊部分,并整合入最终的胶囊。 Semipermeable sheet may be applied before or after the portion of the capsule part, and integrated into the final capsule. 在另一个实施方案中,硬胶囊可制造为每个部分在其开放的末端带有匹配的锁环,其能整合在一起并锁住重叠的盖和注入制剂后的主体。 In another embodiment, the hard capsules can be manufactured as part of each of its open ends with matching locking ring, which can be integrated with the body and the lid and lock the overlapped injection formulation. 在该实施方案中,一对匹配的锁环形成盖部分和主体部分,这些环提供了将胶囊安全容纳在一起的锁闭方式。 In this embodiment, a pair of matched locking rings are formed cover portion and the body portion, and these rings provide the locking embodiment the capsule receiving security together. 胶囊可用手工注入制剂,或它们可用机器注入制剂。 Formulation capsules may be injected by hand, machine, or they may be injection formulation. 在最终的生产中,用半透薄片,其可透过流体而基本不透过有用的试剂,来将硬胶囊制成胶囊。 In the final production, semipermeable sheet, which may be substantially impermeable to the beneficial agent through the fluid to the capsule is made of hard capsules. 形成硬盖剂型的方法在美国专利N0.6174547、美国专利N0.6596314,6419952 和6174547 中有描述。 A method of forming a hard cap dosage forms are described in U.S. Patent No. N0.6174547, and U.S. Patent No. 6,174,547 there N0.6596314,6419952.

[0164] 硬和软胶囊可含有如,明胶;具有15至30毫泊的粘度和至多150克的毛坯强度的明胶;具有160至250毛坯值的明胶;含有明胶、甘油、水和二氧化钛的组合物;含有明胶、真曙红、氧化铁和二氧化钛的组合物;含有明胶、甘油、山梨醇、山梨酸钾和二氧化钛的组合物;含有明胶、阿拉伯树胶甘油和水的组合物;等等。 [0164] Hard and soft capsules may contain, for example, gelatin; having 15 to 30 mM poise and up to 150 grams blank strength gelatin; with gelatin 160-250 blank value; containing gelatin, glycerin, water, and a combination of titanium dioxide thereof; contains gelatin, true eosin, iron oxide and titanium dioxide composition; comprising gelatin, glycerine, sorbitol, potassium sorbate and titanium dioxide composition; a composition comprising gelatin, acacia glycerine, and water; and the like. 用于形成胶囊膜的材料公开于美国专利N0.4627850和4663148中。 Film material for forming the capsule is disclosed in U.S. Patent 4,663,148 and N0.4627850. 或者,胶囊可由除了明胶之外的材料制成(如参见,BioProgespic制造的产品)。 Alternatively, capsules can be (see, product, BioProgespic manufactured) made of a material other than gelatin addition.

[0165] 例如,胶囊的大小通常为约3至约22量滴(I量滴等于0.0616ml),其形状为椭圆、长方形或其他的。 [0165] For example, the size of the capsule is generally from about 3 to about 22 minims (I minims equal 0.0616ml), in the shape of an elliptical, rectangular or other. 它们可以是标准的形状和各种标准的大小,通常命名为(000)、(00)、(O)、 They may be a standard shape and size of various standards, generally designated (000), (00), (O),

(I)、(2)、(3)、(4)和(5)。 (I), (2), (3), (4) and (5). 最大的数值对应于最小的大小。 The maximum value corresponds to the smallest size. 也可用非标准的形状。 Non-standard shapes may also be used. 对于软胶囊或硬胶囊,如果需要特定的应用,可使用非常规形状。 For soft or hard capsules, if a particular application needs, unconventional shapes may be used.

[0166] 本发明的渗透体可包含半透膜,其可透过外部生物流体并基本不透过鸦片样物质制剂。 [0166] The permeation of the present invention may comprise a semipermeable membrane, and which may be substantially impermeable to the opioid formulation through an external biological fluid. 用于成膜的选择性渗透组合物基本上是不可腐蚀的,并在渗透系统存续期间不溶于生物流体。 Permselective composition for forming a substantially non-corrosive, and insoluble in biological fluids during the existence of the permeation system. 半透膜包含不伤害宿主、鸦片样物质制剂、渗透聚合物、渗透剂等的组合物。 The semipermeable membrane comprises not harm the host, opioid formulation, an osmopolymer, penetrant composition. 用作形成半透膜的材料在本文其它部分有披露。 Materials for forming the semipermeable membrane are disclosed elsewhere herein.

[0167] 半透膜也可包含流量调节剂。 [0167] semipermeable membrane may also comprise flow regulators. 用于流量调节剂的材料在本文其它部分有披露。 Material for the flow regulating agents are disclosed elsewhere herein. 可用于形成半透膜从而为半透膜带来可弯曲和可延伸性质的材料也在本文其它部分有披露。 It may be used to form the semipermeable membrane so as to bring extendable and bendable material properties of the semipermeable membrane are also described elsewhere herein disclosed.

[0168] 半透膜围绕并形成了一个小室,含有一或多层,其中之一是可扩展层,在一些实施方案中,其可含有渗透试剂。 [0168] semipermeable membrane surrounds and forms a chamber, comprising one or more layers, one of which is an expandable layer, in some embodiments, it may contain osmotic agents. 该可扩展层的组合物在本文其它部分有披露。 The composition of the expandable layer are disclosed elsewhere herein.

[0169] 在某些固体和液体的实施方案中,剂型可进一步包含屏障层。 [0169] In certain solid and liquid embodiments, the dosage form may further comprise a barrier layer. 在一些实施方案中,并在递送活性制剂期间,屏障层可受可扩展层施力而变形,而且将会不透过(或少透过)存在于可扩展层、液体活性制剂和应用环境中的流体和材料。 In some embodiments, during delivery and active agents, the barrier layer may be extended by the urging deformed layer, and will be impermeable (or less permeable) present in the expandable layer, the liquid active agent and the application environment fluids and materials. 如果不损害活性制剂的递送率,则可允许某种程度的屏障层渗透性。 If the delivery rate of the active formulation is not impaired, and may be allowed a certain degree of permeability of the barrier layer. 可是优选在递送活性制剂期间,屏障层完全不能通过它传送剂型和应用环境中的流体和材料。 However, preferably during delivery of active agents, the barrier layer not completely transport through it and forms a fluid-application environment and materials. 屏障层受可扩展层施力而变形,从而压缩胶囊从出口挤出液体、活性制剂。 The barrier layer may be extended by the biasing layer is deformed, thereby compressing the capsule out from the outlet liquid, active agent. 在一些实施方案中,屏障层变形到一种程度,使之将可扩展层和半透层间形成出口的区域密封。 In some embodiments, the barrier layer is deformed to an extent, so that the expandable region is formed between the outlet of the transflective layer and the sealing layer. 在该方式中,屏障层变形或流变到有限的程度来密封最初形成开口时可扩展层和半透层暴露的区域,如通过钻等,或在最初操作阶段。 In this embodiment, the barrier layer or the rheological modification to a limited extent to seal the region of the transflective layer and the expandable layer is exposed initially when the opening is formed, such as by drilling, or in the initial operating phase. 密封时,液体渗透进可扩展层的唯一路径是穿过半透层,而且没有回流液体通过开口进入可扩展层。 When sealed, the only path of the liquid permeation into the expandable layer is through the semipermeable layer, and there is no reflux of liquid into the expandable layer through the opening.

[0170] 形成屏障层的合适材料包括如,聚乙烯、聚苯乙烯、乙烯-醋酸乙烯共聚物、聚己内酯和Hytrel™聚酯合成橡胶(杜邦)、醋酸纤维素、醋酸纤维素仿橡胶(如美国专利N0.5024842所述)、醋酸纤维素丙酯、醋酸纤维素丁酯、乙基纤维素、乙基纤维素仿橡胶(如lOColorcon, West Point, Pa所供应的Surelease™或FMC公司,费城,Pa.所供应的Aquacoat™)、硝基纤维素、聚乳酸、聚-乙醇酸、聚乳酸乙醇酸共聚物、胶原、聚乙烯醇、聚醋酸乙烯酯、聚乙烯乙烯基醋酸酯、聚乙烯对苯二甲酸、聚丁二烯苯乙烯、聚异丁烯、聚异丁烯异丙烯共聚物、聚乙烯氯、聚亚乙烯基氯-乙烯氯共聚物、丙烯酸和甲基丙酸烯酸酯的共聚物、甲基异丁烯酸酯和乙基丙烯酸酯的共聚物、丙烯酸酯橡胶(如RohmPharma,Darmstaat,德国所供应的Eudragit™)、聚丙烯、环氧丙烷和环氧乙烷的共聚物、环氧丙烷环氧乙烷 Suitable materials [0170] such as a barrier layer include polyethylene, polystyrene, ethylene - vinyl acetate copolymers, polycaprolactone and Hytrel ™ polyester elastomers (Du Pont), cellulose acetate, cellulose acetate rubber imitation (as described in U.S. Patent No. N0.5024842), cellulose propyl acetate, cellulose butyl acetate, ethyl cellulose, ethyl cellulose imitation rubber (e.g. lOColorcon, West Point, Pa supplied or Surelease ™ of FMC Corporation , Philadelphia, Pa supplied Aquacoat ™), nitrocellulose, polylactic acid, poly - acid, polylactic acid glycolic acid copolymer, collagen, polyvinyl alcohol, polyvinyl acetate, polyethylene vinyl acetate, polyethylene terephthalate, polybutadiene styrene, polyisobutylene, polyisobutylene isoprene copolymer, polyvinyl chloride, polyvinylidene chloride - vinyl chloride copolymer, copolymer of acrylic acid and propionic acid methyl ester was a copolymer of methyl methacrylate and ethyl acrylate, acrylate rubbers (e.g. RohmPharma, Darmstaat, Germany supplied Eudragit ™), polypropylene, copolymers of propylene oxide and ethylene oxide, propylene propane ethylene oxide 嵌段共聚物、乙烯乙烯醇共聚物、聚砜、乙烯乙烯醇共聚物、聚亚二甲苯、聚烷氧基硅烷、聚二甲基硅氧烷、聚乙二醇-硅酮合成橡胶、电磁辐射交联的丙烯酸、硅酮、或聚酯、热交联的丙烯酸、硅酮、或聚酯、丁二烯苯乙烯橡胶、及以上混合物。 Block copolymers, ethylene vinyl alcohol copolymer, polysulfone, ethylene vinyl alcohol copolymer, poly-xylylene, polyalkoxysilanes, polydimethyl siloxane, polyethylene glycol - silicone elastomers, electromagnetic radiation-crosslinked acrylic, silicones, or polyesters, thermally crosslinked acrylic, silicones, or polyesters, butadiene-styrene rubber, and the above mixture.

[0171] 优选的材料可包括,醋酸纤维素、丙烯酸和甲基丙烯酸酯的共聚物、甲基甲基丙烯酸酯和乙基丙烯酸酯的共聚物和丙烯酸酯橡胶。 [0171] Preferred materials can include, cellulose acetate copolymers, acrylic and methacrylic acid esters, methyl methacrylate and ethyl acrylate copolymers and acrylate rubbers. 优选的共聚物包括聚(丁基甲基丙烯酸酯)、(2-二甲基氨基乙基)甲基丙烯酸酯、甲基丙烯酸甲酯)I: 2: 1,150000,其以商标EUDRAGIT E销售;聚(丙烯酸乙酯,甲基丙烯酸甲酯)2: 1,800000,其以商标EUDRAGITNE 30D销售;聚(甲基丙烯酸,甲基甲基丙烯酸甲酯)1: 1,135000,其以商标EUDRAGITL销售;聚(甲基丙烯酸、丙烯酸乙酯)1: 1250000,以商品名EUDRAGITL销售;聚(甲基丙烯酸,甲基丙烯酸甲酯)1: 2135000,以商品名EUDRAGITS销售;聚(丙烯酸乙酯、甲基丙烯酸甲酯、三甲基氨基乙基甲基丙烯酸酯氯化物)I: 2: 0.2,150,000,以商品名EUDRAGIT RL销售;聚`(丙烯酸乙酯,甲基丙烯酸甲酯,三甲基氨基乙基甲基丙烯酸酯氯化物)1: 2: 0.1,150000,其以商标EUDRAGIT RS销售。 Preferred copolymers include poly (butyl methacrylate), (2-dimethylaminoethyl) methacrylate, methyl methacrylate) I: 2: 1,150000, which is sold under the trademark EUDRAGIT E; poly (ethyl acrylate, methyl methacrylate) 2: 1,800000, which is sold under the trademark EUDRAGITNE 30D; poly (methacrylic acid, methyl methacrylate) 1: 1,135000, which is sold under the trademark EUDRAGITL; poly (methacrylic acid, ethyl acrylate) 1: 1,250,000, sold under the trade name EUDRAGITL; poly (methacrylic acid, methyl methacrylate) 1: 2,135,000, sold under the trade name EUDRAGITS; poly (ethyl acrylate, methyl acrylate, trimethylaminoethyl methacrylate chloride) I: 2: 0.2,150,000, sold under the tradename EUDRAGIT RL; `poly (ethyl acrylate, methyl methacrylate, trimethyl aminoethyl methacrylate chloride) 1: 2: 0.1,150000, which is sold under the trademark EUDRAGIT RS. 在每个情况下,比率x: y: z表示单体单位的摩尔比例,而最后数字是聚合物的平均分子量数字。 In each case, the ratio x: y: z indicates the molar ratio of the monomer units and the last number is the number average molecular weight of the polymer. 特别优选含增塑剂的醋酸纤维素,如乙酰三丁基柠檬酸酯和乙基丙烯酸酯甲基甲基丙烯酸酯共聚物,如EudragitNE。 Particularly preferred cellulose acetate containing plasticizers such as acetyl tributyl citrate and ethylacrylate methacrylate copolymers such as EudragitNE.

[0172] 用作屏障层的前述材料可配以增塑剂,来使屏障层适宜变形,从而可扩展层施加的力将压塌屏障层所形成的小室来分配液体、活性制剂。 [0172] as a barrier layer of the material supported by a plasticizer to make the barrier layer suitably deformable, so that the force can be extended cell layer is applied to crush the formed barrier layer to dispense the liquid, active agent. 典型的增塑剂例子如下:多羟基醇、三醋精、聚乙二醇、甘油、丙二醇、醋酸酯、甘油三醋酸酯、三乙基柠檬酸酯、乙酰三乙基柠檬酸酯、甘油酯、乙酰化的单甘油酯、油、矿物油、蓖麻油等。 Examples of typical plasticizers are as follows: polyhydric alcohols, triacetin, polyethylene glycols, glycerine, propylene glycol, acetate, triacetin, triethyl citrate, acetyl triethyl citrate, glycerides , acetylated monoglycerides, oils, mineral oil, castor oil and the like. 根据材料的重量,以10-50重量百分比将增塑剂混入材料中。 The weight of the material, of 10 to 50 weight percent of the plasticizer mixed into the material.

[0173] 可通过常规包衣方法,如美国专利N0.5324280所述的,来使用各种形成屏障层、可扩展层和半透层的层。 [0173] by conventional coating methods, such as U.S. Patent, the use of various N0.5324280 forming a barrier layer, layer and a transflective layer can be extended. 尽管示例和描述的屏障层、可扩展层和半透层适合作为单层,但这些层的每一个都可以由多层组成。 Although illustrated and described the barrier layer, expandable layer and semipermeable layer is adapted as a single layer, but each of these layers may be composed of a plurality of layers. 如为了特别的应用,希望用第一层材料包衣胶囊,从而使具有屏障层渗透性质的第二层更容易包衣。 As for a particular application, it is desirable with a first layer material coated capsules, so that the properties of the barrier layer having a permeability of the second layer more easily coated. 在该情况下,第一和第二层含屏障层。 In this case, the first and the second layer comprising a barrier layer. 相似考虑可应用于半透层和可扩展层。 Similar considerations may be applied to the semipermeable layer and the expandable layer.

[0174] 通过机械钻、激光钻、腐蚀可腐蚀的元件、提取、溶解、破裂、或从组合物壁中流出通道,均可形成出口。 [0174] by mechanical drilling, laser drilling, etching erodible element, extracting, dissolving, rupture, or out from the channel wall composition, may form an outlet. 如美国专利N0.4200098所述,出口可以是孔,其通过从膜或层中流掉山梨醇、乳糖等来形成。 As described in U.S. Patent No. N0.4200098, the outlet may be a hole, which is formed by run off sorbitol, lactose or the like from the film layer. 该专利公开了孔径大小受控的孔,其通过溶解、提取、或从壁中流出材料(如从醋酸纤维素中流出山梨醇)来形成。 This patent discloses pores of controlled pore sizes, by dissolving, extracting, or flowing out from the wall material (such as sorbitol from cellulose acetate effluent) is formed. 激光钻的优选形式为应用脉冲激光,从组合物膜中加速去除材料,直至所需深度,从而形成出口。 Preferred form of laser drilling is the use of a pulsed laser, to accelerate the removal of material from the composition of the film, until the desired depth, thereby forming the outlet.

[0175] 图5A-5C显示另一个示例性的剂型,其是现有已知的并在美国专利N0.5534263、5667804和6020000中有描述。 [0175] FIGS. 5A-5C show another exemplary dosage form, it is prior known and are described in U.S. Patent No. 6,020,000 and in N0.5534263,5667804. 简而言之,图5A显示了在胃肠道中消化前的剂型80的剖面图。 Briefly, FIG. 5A shows a cross-sectional view of a dosage form prior to digestion in the gastrointestinal tract 80. 剂型包括含本发明物质的圆柱状基质82。 82 includes a cylindrical matrix formulation containing material of the present invention. 基质82的末端84、86优选是圆的和凸的形状,以此保证容易消化。 Preferred substrates 84, 86 end 82 are rounded and convex in shape in order to ensure easy to digest. 带88、90和92环绕圆柱状基质,其由相对不溶于水环境中的材料形成。 With 88, 90 and 92 surround the cylindrical matrix, which is formed of a relatively water-insoluble material in the environment. 合适材料在上述专利和本文其他部分中有描述。 Suitable materials are described in the aforementioned patents and other parts herein.

[0176] 如图5B所示,剂型80消化后,带88、90、92之间的基质82区域开始腐蚀。 As shown in [0176] FIG. 5B, after digestion of the dosage form 80 with the substrate 82 between the regions 88, 90 begin to corrode. 基质的腐蚀使本发明物质释放到胃肠道的流体环境中。 Etching the substrate of the present invention are released into the fluid environment of the gastrointestinal tract. 如图5C所示,剂型连续穿过胃肠道时,基质持续腐蚀。 5C, the dosage form continuously through the GI tract, the matrix continuous corrosion. 这里,腐蚀基质到一定程度,剂型破成3片94、96、98。 Here, corrosion of the substrate to a certain extent, the dosage form broken into three 96, 98. 腐蚀持续到每片基质部分完全腐蚀。 Etching continues until each portion of the substrate sheet etched. 之后从胃肠道中排出带94、96、98。 After discharge from the gastrointestinal tract with 96, 98.

[0177] 其它从口服剂型中实现持续释放药物的方法是现有已知的。 [0177] Other methods to achieve the sustained release pharmaceutical oral dosage forms are conventionally known. 例如,已知有分散系统,如贮体和基质体,溶解系统,如胶囊溶解系统(包括如,“少时丸”)和基质溶解系统,分散/溶解组合系统和离子交换树脂系统,其在Remington的PharmaceuticalSciences, 1990版,pp.1682-1685中有描述。 For example, known dispersion systems, such as the storage body and matrix dissolution systems, such as capsules dissolution systems (including, for example, "came pills") and matrix dissolution systems, dispersion / dissolution systems and ion-exchange resin composition system in Remington the PharmaceuticalSciences, 1990 edition, pp.1682-1685 are described. 根据这些其他方法制得的剂型包括在本文公开的如下程度范围内:本文以及在权利要求中限定的药物释放特征和/或血浆浓度特征从文字上或等价地描述了这些剂型。 According to these dosage forms prepared by other methods are included within the scope of this disclosure the following extent: as defined herein and in the claims or drug release characteristics and plasma concentration / or equivalent text features from these dosage forms described.

[0178] 在本发明方法其它具体实例中,通过使用肠溶衣,限定的持续释放剂型可防止胃肠道中乙醇的作用。 [0178] In other example of the method of the present invention, by using an enteric coating, sustained release dosage form as defined in the gastrointestinal tract prevented ethanol. 醇,尤其是乙醇,倾向于在上胃肠道(尤其是胃)中被吸收。 Absorbed alcohol, especially ethanol, in the upper gastrointestinal tract tends (especially stomach). 因此,通过阻止药物最初在上胃肠道中释放,肠溶衣的应用可缓和联合给药的醇对发明的持续释放剂型的影响。 Thus, by preventing the drug initially released in the upper gastrointestinal tract, the enteric coating applied alleviated ol combined administration of sustained release dosage forms of the invention.

·[0179] 在优选的具体实例中,肠溶衣含肠聚合物。 * [0179] In a preferred embodiment, the enteric coating comprising an enteric polymer. 优选肠聚合物不迅速溶于乙醇,但可以非常慢地膨胀或溶解。 Preferred enteric polymer is not rapidly dissolve in ethanol, but may swell or dissolve very slowly. 其他聚合物或材料可同肠聚合物混合,只要添加它们不减弱肠溶衣在乙醇中的表现。 Other polymers or materials may be mixed with the enteric polymer, as long as they do not add attenuated enteric coating performance in ethanol. 在某些具体实例中,选择可同肠聚合物混合的聚合物或材料来增强肠聚合物在醇水溶液中的性能。 In certain instances, the choice of polymer material or may be mixed with the enteric polymer to enhance the performance of an enteric polymer in aqueous alcohol. 如,在具体实例中,在醇水溶液中几乎无或无溶胀/溶解性的聚合物或材料同肠聚合物可很好地混合。 For example, in the specific example, the alcohol in the aqueous solution little or no swell / solubility polymer or material can be well mixed with the enteric polymer. 需要增塑剂,如1-20%水平的PEG6000,来防脆性。 We need plasticizers, such as 1-20% level of PEG6000, for preventing brittleness. 适合用于本发明的肠聚合物包含醋酸邻苯二甲酸纤维素,如那些由Eastman Chemical制造的。 Suitable for use in the present invention comprises an enteric polymer cellulose acetate phthalate, such as those manufactured by the Eastman Chemical. 在某些具体实例中,通过溶剂系统,如丙酮或丙酮/乙醇混合物,或通过水分散作用,可制备肠聚合物。 In certain instances, the solvent system, such as acetone or acetone / ethanol mixture, or may be prepared by aqueous dispersion of an enteric polymer. 在一些情况下,利用压缩压模技术来制备肠溶衣。 In some cases, an enteric coating is prepared using compression techniques stamper.

[0180] 在本发明的其它具体实例中,非肠聚合物可用于包衣持续释放剂型,并因而降低醇诱导的剂量突然释放的可能性,特别是乙醇诱导的剂量的突然释放。 [0180] In other examples of the present invention, the non-enteric coating polymers can be used in sustained release formulations, and thus reduce the likelihood of alcohol-induced dose sudden release, especially ethanol-induced sudden release dose. 在具体实例中,可用Eudragit ® RS 100和Eudragit ® RL100。 In a specific example, the available Eudragit ® RS 100 and Eudragit ® RL100. 这些聚合物据报道不溶于水,并缓慢溶于乙醇/水混合物。 It is reported that these polymers insoluble in water and slowly dissolved in ethanol / water mixture. 据报道,它们分别带来低和适度的水渗透性。 According to reports, they are brought low and moderate water permeability. 为了用于持续释放片基质,这些会是在水和在乙醇/水混合物中合理有效的限制速率的薄膜。 In order for the sustained release tablet matrix, these films would be reasonably effective in water and ethanol / water mixture is rate-limiting. 这种结构可根据可控分散释放原理来运行。 This structure can be run according to the principles of controlled release dispersion. 这些薄膜通常通过水分散作用制造并配有增塑剂,如柠檬酸三乙酯,和抗黏附剂,如滑石粉。 These films are typically manufactured and equipped with a plasticizer, such as triethyl citrate, and anti-adhesion agents, such as talc by aqueous dispersion. 在另一具体实例中,可用含有24-28%乙酰基的醋酸纤维素。 In another example, cellulose acetate containing 24-28% available acetyl. 该材料据报道溶于水并较不溶于乙醇/水混合物,因而在剂型和醇(尤其是乙醇)联合给药的时候,可降低醇诱导的剂量突然释放的可能性。 The material is reported dissolved in water and less soluble in ethanol / water mixture, and thus forms an alcohol (especially ethanol), when administered in combination, can reduce the likelihood of alcohol-induced dose sudden release. 非肠聚合物可以是溶液,其利用压缩压模技术包衣或应用。 Non-enteric polymer may be a solution, which is coated with a compression or compression molding technology applications.

[0181 ] 在具体实例中,本发明方法的持续释放剂型可以是基质剂型。 [0181] In a particular example, the sustained release formulations of the present invention may be a method of matrix dosage forms. 基质剂型通常包含胶成分、控制最初破裂的疏水赋形剂、药物、和稀释剂。 Matrix dosage forms typically comprise rubber component, a hydrophobic excipient control, drug, and a diluent initial rupture. 通常,根据剂型总干重,胶成分为20_60wt %而且疏水赋形剂为5_20wt %。 Typically, the total dry weight of the dosage form, and the gel content of the hydrophobic excipient is 20_60wt% 5_20wt%. 这些剂型可通过造粒或混合干燥并压成片来制备。 These dosage forms can be obtained by mixing granulated or dried and compressed into tablets prepared. 或者,将制剂热熔压成可切割的条状并注入胶囊,由此产生本发明的剂型。 Alternatively, the formulation may be melt pressed into cut strips and injected into the capsule, thereby producing the dosage form of the present invention.

[0182] 合适的胶成分包括: [0182] Suitable adhesive components include:

[0183] 1.为获得理想的胀溶和粘性的不同级别的HPMC(K4M,K100,E5)的混合物。 [0183] 1. In order to obtain the desired dissolution and swelling viscous mixtures of different levels of HPMC (K4M, K100, E5) of. HPMC不溶于乙醇,因而可预计在醇/水中比在水中释放得更慢。 HPMC insoluble in ethanol, which is expected to be slower than the release in water in an alcohol / water. 可加入HPC(来自Hercules-Aqualon 的Klucel ® )来阻止水合率。 May be added HPC (from Hercules-Aqualon's Klucel ®) to prevent hydration.

[0184] 2.不同级别的聚环氧乙烧(可得自Dow Chemical的Polyox ® )的混合物。 [0184] 2. Different levels of burning polyethylene oxide (available from Dow Chemical of Polyox ®) mixtures thereof. Polyox在醇/水中比在水中溶胀少得多。 Polyox is much less in an alcohol / water ratio of swelling in water. 建议的级别为POLYOX WSR-205NF,WSR-1105 NF,WSR N-12K NF, WSR N-60K NF, WSR-301 NF, WSR-303 NF, WSR 凝结剂NF。 The recommended level is POLYOX WSR-205NF, WSR-1105 NF, WSR N-12K NF, WSR N-60K NF, WSR-301 NF, WSR-303 NF, WSR coagulant NF. 这些通常含有20-55%的制剂。 These formulations generally contain 20-55%.

[0185] 3.NaCMC(羧甲基纤维素钠)不溶于乙醇,因而可能较不容易在乙醇/水混合物中发生剂量突然释放。 [0185] 3.NaCMC (sodium carboxymethyl cellulose) insoluble in ethanol, and thus may be less likely to occur in an ethanol / water mixture sudden release dose.

[0186] 4.褐藻酸不溶于乙醇,在水中溶胀,因而可预计在乙醇/水中溶胀得较少。 [0186] 4. The alginic acid is insoluble in ethanol, swells in water, and thus can be expected to have less swelling in ethanol / water.

[0187] 5.黄原胶和瓜耳胶基质 [0187] The xanthan gum and guar gum base

[0188] 6.聚乙烯醇据报道溶于水,但不溶于乙醇。 [0188] 6. It is reported that water-soluble polyvinyl alcohol, but insoluble in ethanol.

[0189] 由于低乙醇溶解性,以下用于控制破裂的疏水赋形剂在乙醇/水混合物中等效或更有效; [0189] Because of the low solubility of the alcohol, the following hydrophobic excipients for controlling the rupture of equivalent or more effective in an ethanol / water mixture;

[0190] 1.MC(得自Dow Chemical 的甲基纤维素,Methocel-A Premium® ) [0190] 1.MC (available from Dow Chemical methylcellulose, Methocel-A Premium®)

[0191] 2.掠榈酸硬脂酸甘油酯(Precirol ® AT0_5, Gattefosse) [0191] 2. swept palm glyceryl stearate (Precirol ® AT0_5, Gattefosse)

[0192] 3.山箭酸甘油酯(Compritol ® 888-ATO, Gattefosse) [0192] 3. Mount arrow triglyceride (Compritol ® 888-ATO, Gattefosse)

[0193] 4.硬脂酸钙 [0193] 4. Calcium stearate

[0194] 5.蜡 [0194] The wax

[0195] 6.植物和矿物油 [0195] 6. vegetable and mineral oils

[0196] 7.脂肪族醇 [0196] 7. The aliphatic alcohol

[0197] 8.聚己内酯 [0197] 8. polycaprolactone

[0198] 9.PLGA [0198] 9.PLGA

[0199] 10.松香 [0199] 10. The rosin

[0200] 在具体实例中,疏水赋形剂包含疏水赋形剂,其熔点大于或等于约55摄氏度。 [0200] In a specific example, hydrophobic vehicle comprises a hydrophobic excipient, a melting point of greater than or equal to about 55 degrees Celsius. 该疏水赋形剂包括但不限于,白石蜡、硬脂醇、蜂蜡、Lubritab ® (植物油)、松香、巴西棕榈蜡、和氢化蓖麻油。 The hydrophobic excipients include, but are not limited to, white petrolatum, stearyl alcohol, beeswax, Lubritab ® (vegetable oil), rosin, carnauba wax, and hydrogenated castor oil.

[0201] 用于基质制剂中的稀释剂或填充料通常不显著影响释放曲线。 [0201] A matrix formulation in a diluent or filler is typically not significantly affect the release profile. 可是,在存在醇的情况下小心选择这些赋形剂,稀释剂可显著影响受控释放基质中的起始和释放曲线。 However, in the presence of an alcohol carefully selecting these excipients, diluents can significantly affect the controlled release matrix and the initial release profile. 在具体实例中,选择有益的稀释剂,其在醇水溶液中比在水中有更低的溶解度,从而使核芯水化,因此在醇水溶液环境中限制药物溶解。 In a specific example, useful diluents selected, in which the ratio of the aqueous alcohol solution has a lower solubility in water, so that hydration of the core, thus limiting the drug is dissolved in the alcohol aqueous environment. 在优选的具体实例中,有用的稀释剂包括甘露醇。 In a preferred example, useful diluents include mannitol.

[0202] 较不优选以下疏水赋形剂用于本发明中: [0202] more preferably not less hydrophobic excipients for the present invention:

[0203] 1.EC(来自Dow Chemical的乙基纤维素)通常被使用,但其溶于乙醇。 [0203] 1.EC (ethyl cellulose from Dow Chemical) is typically used, but it was dissolved in ethanol.

[0204] 2.氢化聚氧60蓖麻油。 [0204] 2. The polyoxyethylene hydrogenated castor oil 60.

[0205] 美国专利N0.5871778和5656299披露持续微球制剂在向患者给药时具有几乎为零级的活性成分释放率。 [0205] U.S. Patent No. 5,656,299 disclose sustained N0.5871778 and microsphere formulations having almost zero level upon administration to a patient release rate of the active ingredient. 美国专利N0.5654008、5650173、5770231、6077843、6368632和5965168披露持续释放微粒组合物及其用于活性试剂的可控递送。 U.S. Patent No. 5,965,168 disclose sustained release N0.5654008,5650173,5770231,6077843,6368632 and particulate composition and its use for controlled delivery of active agents.

[0206] 在另一个具体实例中,渗透颗粒可用于本发明的实践中。 [0206] In another embodiment, the particles may be used in the practice of the present permeate invention. 将鸦片样物质Wurster-包衣在极上品的有足够渗透活性的种子或其他物质上。 The opioid coating Wurster- in sufficient permeation of nonpareil seeds or other active substances. 然后,通过另一个Wurster-包衣过程将半透膜包上去。 Then, by another coating process Wurster- semipermeable membrane package up. 对于后者,在包衣的不同时间或阶段去除产品,从而获得一系列包衣厚度。 For the latter, the removal of products at different times or phases of the coating, so as to obtain a series of coating thickness. 水化时,将系统放入水中,由于渗透压作用而破裂释放出药物。 When hydrated, the system into the water, due to the osmotic pressure and rupture to release the drug. 每个颗粒上的破裂时间与膜厚度成比例。 Break time each particle is proportional to the film thickness. 这些颗粒可任选包括一些而没有任何能作为瞬时释放成分的半透涂层,这些颗粒可装入胶囊以形成本发明的持续释放剂型的具体实例。 These particles may optionally include some without any energy semipermeable coating as an instantaneous release component, these particles can be encapsulated to form Specific examples of sustained release formulations of the present invention.

[0207] 如果利用渗透颗粒装载的药物太有限,则然后可用挤压-团成球状技术产生颗粒。 [0207] If the drug loaded particles by osmosis, is too limited, it may then be extruded - spheronized particles techniques. 该方法的优点是更多药物可整合进颗粒,有一个较少的包衣过程。 The advantage of this method is that more of the drug can be incorporated into the particles, there is less of a coating process. 优选的用于挤压-团成球状技术的载体可包括但不限于,PLGA R208、松香、和其他高分子量材料。 It preferred for pressing - groups to support the spherical techniques may include, without limitation, PLGA R208, rosin, and other high molecular weight material. 也可用其他生产颗粒技术,如包衣不含药物的核芯。 Other production techniques can also be particles, such as drug-free core coated. 含药物的颗粒可选地可用不对水呈现半透性的薄膜包衣,并通过联合分散和渗透来控制释放。 Alternatively, the drug-containing particles in the water are not available presentation semipermeable film coating, and to control the release and penetration through the combined dispersion. 在具体实例中,硬化剂和/或疏水材料可整合进持续释放剂结构中,来防止醇诱导的剂量突然释放。 In a specific example, hardeners and / or hydrophobic materials may be integrated into the structure of the sustained release agent, to prevent the sudden release of the alcohol-induced dose. 优选硬化剂和/或疏水材料包括但不限于,脂肪醇、蜡、油`和生物可降解材料;更优选这种材料包括但不限于,硬酯醇、巴西棕榈蜡、蓖麻蜡、和松香。 Preferably hardener and / or hydrophobic materials include, but are not limited to, fatty alcohols, waxes, oils and `biodegradable material; more preferably such materials include, but are not limited to, stearyl alcohol, carnauba wax, castor wax, and a rosin .

[0208] 在具体实例中,也可使用胃潴留系统。 [0208] In a specific example, may be used gastric retention system. 常规胃潴留系统根据其大小(即大于幽门口)和密度(轻于GI内容物而使之浮起)而实现胃潴留。 The gastric retention system of a conventional size (i.e., larger than the pylorus) and density (lighter than GI contents of the float) to achieve gastric retention. 系统可利用的聚合物包括但不限于,聚环氧乙烷(PolyoX)、HPC、HPMC、聚维酮、CMC钠、乙基纤维素等。 System may utilize polymers include, but are not limited to, polyethylene oxide (PolyoX), HPC, HPMC, povidone, the CMC sodium, ethyl cellulose and the like. 疏水材料或蜡的加入可增进这些材料(其倾向于在醇水溶液中形成较弱的胶,因而可造成不令人满意的表现)的性能。 Addition of hydrophobic material may be wax or enhance these materials (which tend to form a weak gel in aqueous alcohol solution, thus resulting in unsatisfactory performance) performance. 可是,疏水材料可显著增加该胃潴留系统从胃进一步进入下游的风险。 However, hydrophobic materials may significantly increase the gastric retention system further downstream from the stomach into the risk.

[0209] 其他类型的胃潴留系统包括黏附的坚固框架和/或整体控制的释放部分。 [0209] Other types of gastric retention system comprises a sturdy frame adhesion and / or release part of the overall control. 这些框架和/或整体控制的释放部分优选由对醇水溶液相对不敏感的材料组成,从而保持胃潴留和控制释放的性质。 The frame and / or integral controlled release portion is preferably relatively insensitive to the aqueous alcohol solution material, thereby maintaining gastric retention and controlled release properties remain.

[0210] 应认识到,本文中所述的剂型和制剂策略仅仅列举了大量要实现本发明物质给药的剂型。 [0210] It should be appreciated that the dosage forms described herein strategy formulation and dosage form only lists a large number of substances to be administered to achieve the present invention. 药学领域技术人员能鉴别出其他合适的制剂策略,尤其因为并非所有制剂策略都能用于所有鸦片样物质。 Pharmacy skilled in the art can identify other suitable formulation strategy, especially because not all formulation strategies can be used for all opioids. 本发明的实践中也可在普通技术人员的技术范围内进行优化。 Practice of this invention can also be optimized within the skill of the ordinary artisan.

[0211] IV.实施例 [0211] IV. Example

[0212] 实施例1:氢吗啡酮片剂,双层16mg系统 [0212] Example 1: hydromorphone tablets, bilayer systems 16mg

[0213] 发明的氢吗啡酮持续释放剂型被调节、设计并成形成为渗透药物递送体,其如下制备:首先,制备药物组合物。 [0213] hydromorphone sustained release dosage form of the invention is adjusted, and designed to be formed into osmotic drug delivery member, was prepared as follows: First, the preparation of pharmaceutical compositions. 8.98kg盐酸氢吗啡酮、2.2kg被称为K29-32的聚维酮(聚乙烯吡咯烷酮)和67.06kg平均分子量200000的聚环氧乙烷加入到流体床造粒器的盆中。 Hydromorphone Hydrochloride 8.98kg, 2.2kg referred Povidone K29-32 (polyvinylpyrrolidone) and 67.06kg average molecular weight of 200,000 a polyethylene oxide was added to a fluid bed granulator bowl. 然后,6.0kg被称为K29-32的并具有40000平均分子量的聚维酮(聚乙烯吡咯烷酮)溶于54.0kg水中以制备粘合剂溶液。 Then, 6.0kg referred to as K29-32 and having an average molecular weight of 40,000 povidone (polyvinylpyrrolidone) was dissolved in 54.0kg of water to prepare a binder solution. 通过喷雾18.0kg粘合剂溶液对干燥原料进行流化床造粒。 Raw material for fluidized bed granulation by spray drying 18.0kg of binder solution. 接着,在造粒机中干燥湿颗粒直到可接受的水含量,并用适合7-网孔筛的磨定径。 Subsequently, the dried wet granules in a granulator until an acceptable water content and with a suitable mesh screen 7- sizing mill. 然后将颗粒传到混合器中,与16g作为抗氧化剂的丁基化的羟基甲苯混合,并用0.20kg硬脂酸镁润滑。 The particles were then passed to a mixer, mixed with 16g of toluene as butylated hydroxy antioxidant and lubricated with magnesium stearate 0.20kg.

[0214] 接着,如下制备推进组合物:24.0kg氯化钠和0.32kg黑氧化铁利用带有21-网孔筛的Quadro Comil定径。 [0214] Next, the following composition was prepared to promote: 24.0kg 0.32kg sodium chloride and black iron oxide using Quadro Comil with a 21- mesh sizing screen. 筛出的材料、1.6kg被称为2910的轻基丙基甲基纤维素和51.44kg平均分子量约7000000的聚环氧乙烷加入到流体床造粒器的盆中。 Sieved material, 1.6kg 2910 is called a light-yl methylcellulose 51.44kg average molecular weight about 7,000,000 and a polyethylene oxide is added to a fluid bed granulator bowl. 然后,制备粘合剂溶液。 Then, binder solution is prepared. 然后,6.0kg被称为2910的并具有5cps平均粘度的轻基丙基甲基纤维素溶于54.0kg水中以制备粘合剂溶液。 Then, 6.0kg of 2910 and is called a light-yl methylcellulose having a viscosity of 5cps average 54.0kg dissolved in water to prepare a binder solution. 通过喷雾24.0kg粘合剂溶液来将干燥的原料进行流化床造粒。 The dried raw material to a fluidized bed granulator by spraying the binder solution 24.0kg. 接着,在造粒机中干燥湿颗粒直到可接受的水含量,并用适合0.094英寸的筛的磨来定径。 Subsequently, the dried wet granules in a granulator until an acceptable water content, and grinding sieve for sizing to 0.094 inches. 然后将颗粒传到混合器中,与40g 丁基化的羟基甲苯混合,并用0.20kg硬脂酸镁润滑。 The particles were then passed to a mixer, 40g of butylated hydroxy toluene were mixed and lubricated with magnesium stearate 0.20kg.

[0215] 接着,氢吗啡酮药物组合物和推进组合物压进两层核芯中。 [0215] Next, the hydromorphone composition and the pharmaceutical composition is pressed into layers to promote the core. 首先,150mg氢吗啡酮药物组合物加到模具腔中并进行预压,然后加入130mg推进组合物并将该层压进直径11/32”的、标准凹面的、双层排列中。 First, 150 mg of hydromorphone pharmaceutical composition is added to the die cavity and pre-press, followed by addition of 130mg advance into the composition and the laminate diameter 11/32 ", the standard concave, bilayer arrangement.

[0216] 双层排列用半透壁包衣。 [0216] tier arrangement coated with the semipermeable wall. 壁形成材料含99%被称为398-10的并具有39.8%平均乙酰基含量的醋酸纤维素、和1%被称为3350的并具有3350平均分子量的聚乙二醇。 Wall-forming material containing 99% referred to the cellulose acetate 398-10 and having an average of 39.8% acetyl content, and 1% is referred to as 3350 and having an average molecular weight of polyethylene glycol 3350. 壁形成组合物溶于96%丙酮和4%水的混合物中,制成6%固体溶液。 Wall forming composition is dissolved in 96% acetone and 4% water mixture to prepare a 6% solids solution. 在平底锅涂布机中将壁形成组合物喷在双层排列之上和周围,直到每片用上了约30mg膜。 Formed in the wall of the pan coater and on the composition sprayed around tier arrangement, until the sheet to spend about 30mg per film.

[0217] 穿过半透壁用激光钻出一个0.64mm的出口通道,使药物层与剂系统外部连通。 [0217] outlet channels drilled through the semipermeable wall by a laser 0.64mm, external drug layer and the agent communication system. 在45°C和45%相对湿度下干燥72小时以去除残余的溶液。 45 ° C and 45% relative humidity for 72 hours and dried to remove residual solution. 干燥后,在45°C和适宜湿度下干燥片剂4小时。 After drying at 45 ° C and dried under a suitable tablet humidity for 4 hours.

[0218] 实施例2:体外释放研究_16mg氢吗啡酮 [0218] Example 2: In vitro release study of hydromorphone _16mg

[0219] 用实施例1的氢吗啡酮片剂进行一系列溶解试验来评估醇对本发明的含16mg氢吗啡酮(为盐酸氢吗啡酮)的·氢吗啡酮持续释放剂型的体外释放特征的影响。 [0219] A series of tests to evaluate the in vitro dissolution affect alcohol 16mg sustained release formulations of the present invention containing hydromorphone · The hydromorphone (The hydromorphone hydrochloride) is a release profile of hydromorphone tablets of Example 1 . 在含0、4、20和40%体积乙醇的水溶液中用VII型溶解浴测定24小时内盐酸氢吗啡酮的释放。 Type VII bath was measured to dissolve to release hydromorphone hydrochloride of 24 hours in an aqueous solution containing 0,4,20 and 40% by volume of ethanol.

[0220] 实施例1的盐酸氢吗啡酮16mg片剂用来确定0%、4%、20%和40%乙醇中的释放率和积累释放曲线。 [0220] Example hydromorphone hydrochloride 16mg tablet 1 is used to determine 0%, 4%, and the accumulated release rate of 20% ethanol and 40% release profile. 从O月稳定时间点开始释放率结果用于0%乙醇(水)条件。 From point O month stabilization time for the results of the release rate of 0% ethanol (water) conditions. 利用从O月稳定延伸点开始的其他样品来产生4 %、20 %和40 %乙醇条件的释放率。 Extending the use of other samples from the stable point O May be produced starting 4%, the release rate of 20% and 40% ethanol condition. 释放率条件如下:设备=USPVII型;介质:含0%、4%、20%和40%体积乙醇的水溶液;体积:50mL ;温度:37±0.5 摄氏度;时间点:2、4、6、8、10、12、14、16、18 和24 小时。 Release rate conditions were as follows: Device Type = USPVII; medium:%, 4%, and 40% aqueous solution of 020% by volume of ethanol containing; Volume: 50 mL; Temperature: 37 ± 0.5 ° C; time: 2,4,6,8 , 10,12,14,16,18 and 24 hours.

[0221] 注意:小心操作使释放率介质蒸发最小化。 [0221] Note: caution that the rate of release medium minimize evaporation. 对于前6个间隔和最后间隔(2-12小时和24小时),在每次间隔前约30分钟加入释放率介质,并在每次间隔完成后立刻从释放率浴中取出释放率试管。 For the first six and last interval intervals (2-12 hours and 24 hours), at intervals of about 30 minutes before each addition of the release of the medium, and after the completion of each time interval immediately removed from the test tube release rate release rate bath. 对于间隔14、16和18,同时将介质至于浴中,使释放率试管在浴中保持约6个半小时。 For interval 14, 16 and 18, while the medium As the bath, so that the release rate of the test tube for about six and a half hours in the bath.

[0222] 介质制备如下: [0222] medium was prepared as follows:

[0223] 4%体积乙醇:将140mL体积的纯乙醇(Sigma-Aldrich, 200验证)加入到3360mL水中并混合均匀。 [0223] 4% ethanol by volume: the volume of 140mL of absolute ethanol (Sigma-Aldrich, 200 validation) was added to 3360mL of water and mixed well.

[0224] 20%体积乙醇:将700mL体积的纯乙醇加入到2800mL水中并混合均匀。 [0224] 20% Ethanol by volume: a volume of 700mL ethanol was added to 2800mL of pure water and mixed well.

[0225] 40%体积乙醇:将1400mL体积的纯乙醇加入到2100mL水中并混合均匀。 [0225] 40% Ethanol by volume: a volume of 1400mL 2100mL of pure ethanol was added to the water and mixed uniformly.

[0226] 如下制备样品:混合后注射4%和20%乙醇中的样品溶液。 [0226] Samples were prepared as follows: a sample solution after mixing and injection of 4% of 20% ethanol. 进行快速研究以确证该方法的准确度。 A quick study to confirm the accuracy of the method. 用20%和40%乙醇稀释成两种在水中以不同浓度制备的标准品,并分别通过HPLC分析,评估%恢复和峰形状。 Diluted standards prepared from two different concentrations with 20% water and 40% ethanol, and were analyzed by HPLC, and% Recovery assess peak shape. 由于在存在40%乙醇的条件下观察到样品的分离峰,而在其他样品溶液中没有观察到,40 %乙醇中的样品溶液需要进一步处理,而4%和20%乙醇中的样品溶液就如此注射。 Since observed in the presence of 40% ethanol to peak separation of the sample, but was not observed in the other sample solution, the sample solution 40% ethanol require further processing, while the sample solution 4% and 20% ethanol on the case injection.

[0227] 为避免分离峰,如下制备40%乙醇中的样品溶液:冷却至室温后,释放率试管中的溶液用40%乙醇水溶液调回50ml并混合均匀。 [0227] In order to avoid peak separation, a sample solution prepared in 40% ethanol: After cooling to room temperature, the test tube was transferred back to the release rate of 50ml with 40% aqueous ethanol solution and mixed well. 然后将2mL体积的样品溶液加入到闪烁瓶中。 The sample was then added to a volume of 2mL of scintillation vials. 用蒸发器(SPD SpeedVac, SPD131DDA, RVT4104Refrigerated Vapor Trap, 0FP-400,Thermo Sawant)在45摄氏度干燥蒸发样品溶液。 Evaporator (SPD SpeedVac, SPD131DDA, RVT4104Refrigerated Vapor Trap, 0FP-400, Thermo Sawant) 45 ° C sample solution dried and evaporated. 2mL体积的水加回闪烁瓶中并混合均勻。 2mL volume of water added back to the scintillation vials and mixed well. 然后将样品溶液注射到HPLC上。 The sample solution was then injected onto HPLC.

[0228] HPLC 条件 [0228] HPLC conditions

[0229]柱:Varian Inertsil Phenyl-3, 5mm, 4.6 X 150mm [0229] Column: Varian Inertsil Phenyl-3, 5mm, 4.6 X 150mm

[0230] 流动相:35%甲醇65%缓冲液(0.1 %磷酸钠,0.2%辛烷磺酸,钠盐,pH = 2.2) [0230] Mobile phase: 35% methanol 65% buffer (0.1% sodium phosphate, 0.2% octane sulfonic acid, sodium salt, pH = 2.2)

[0231]流速:1.5mL/分钟 [0231] flow rate: 1.5mL / min

[0232] 温度:45摄氏度 [0232] Temperature: 45 ° C

[0233] 注射体积:50mL [0233] Injection Volume: 50mL

[0234]波长:280nm [0234] Wavelength: 280nm

[0235] 运行时间:7分钟 [0235] Run time: 7 minutes

[0236] 该测试结果如图6所示。 [0236] The test results shown in Figure 6. 对于本发明的氢吗啡酮持续释放剂型,各种乙醇水溶液不造成剂量突然释放或不可控的释放。 For hydromorphone sustained release dosage form of the present invention, aqueous solutions of ethanol does not cause sudden release or release dosage uncontrollable. 可是,观察到,随着溶解介质中乙醇浓度的增加,释放率有增加的趋势。 However, it was observed with increasing concentration of dissolved ethanol medium, the release rate tends to increase. 相对于0%对照标记物/hr),平均释放率在40%乙醇介质中最大(约10%标记物/hr),在4%乙醇介质中无影响(约6%标记物/hr)。 0% control relative to marker / hr), the maximum average release rate (about 10% marker / hr), no effect on the medium in 4% ethanol 40% ethanol medium (about 6% marker / hr). 相应地,如图1所示,相对于对照,递送90%药物的时间(T90)在4%介质中无影响,在40%介质影响最大。 Accordingly, as shown in FIG. 1, relative to the control, 90% of the delivery time of the drug (T90) had no effect in medium 4%, maximum 40% medium impact. 即使对于40%乙醇条件,T90为12h。 Even with 40% ethanol condition, T90 is 12h. 另外,对片剂的2小时积累释放时间间隔(起始时间)只有最小的影响,反映出对所有评估的乙醇浓度来说没有剂量突然释放。 Further, the accumulation of 2 hours the tablets released only minimal effect on the time interval (starting time), for reflecting the sudden release of the ethanol concentration not evaluated for all doses.

[0237] 表1:氢吗啡酮16mg片剂针对乙醇水溶液的体外释放特性总结 [0237] Table 1: 16mg hydromorphone tablets for the in vitro release profile summary aqueous ethanol

Figure CN1957909BD00331

[0238] 实施例3:体外释放比较研究 [0238] Example 3: Comparative in vitro release studies

[0239] 作为比较,利用II型溶解浴在伏特加酒(Vodka) (27 % v/v乙醇)和水中评估从Palladone XL® 32mg胶囊中释放的盐酸氢吗啡酮,来比较实施例1的氢吗啡酮片剂。 Hydromorphone Example 1 [0239] As a comparison, the use of hydromorphone hydrochloride Form II is dissolved in a bath of vodka (Vodka) (27% v / v ethanol) and water released from the evaluation Palladone XL® 32mg capsules to Comparative Example one tablet. [0240] 溶解参数如下:溶解设备=Varian VK7010溶解单元和VK8000自动取样器;介质:分别为水和伏特加酒(Pavlova,40%体积乙醇);体积:900mL ;搅拌速度:50rpm ;吸取体积:5mL ;温度:37±0.5摄氏度;时间点=T = 1、2、4、6、10、14、18和24小时。 [0240] dissolution parameters: dissolution apparatus = Varian VK7010 dissolution unit and VK8000 Autosampler; medium: are water and vodka (Pavlova, 40% by volume of ethanol); Volume: 900 mL; stirring speed: of 50 rpm; draw Volume: 5 mL ; temperature: 37 ± 0.5 ° C; time = T = 1,2,4,6,10,14,18 and 24 hours. 注意:测试结果显示Pavlova的醇浓度仅为27%。 Note: The test results show that the alcohol concentration was only 27% of Pavlova.

[0241]由于伏特加酒的颜色干扰,分析前蒸发伏特加酒中的样品溶液,具体过程如下:用自动取样器将5mL体积样品溶液装入试管。 [0241] Since the interference color of vodka, wine evaporated vodka sample solution before analysis, the specific process is as follows: with autosampler 5mL volume of the sample solution in a test tube. 冷却至室温后,将2mL体积的样品溶液加入到闪烁瓶中。 After cooling to room temperature, 2mL of the sample volume is added to a scintillation vial. 用蒸发器(SPD SpeedVac, SPD131DDA, RVT4104 冷Refrigerated Vapor Trap,0FP-400, Thermo Savant)在45摄氏度干燥蒸发样品溶液。 Evaporator (SPD SpeedVac, SPD131DDA, RVT4104 cold Refrigerated Vapor Trap, 0FP-400, Thermo Savant) 45 ° C sample solution dried and evaporated. 2mL体积的水加回闪烁瓶中并混合均匀。 2mL volume of water added back to the scintillation vials and mixed well. 然后将样品溶液注射到HPLC上。 The sample solution was then injected onto HPLC. 水中的样品溶液冷却至室温并注射到HPLC上。 Sample solution was cooled to room temperature and water was injected onto the HPLC.

[0242] 水中的样品溶液就如此注射,而伏特加酒中的样品溶液进行蒸发并用水补回,由此制备样品。 [0242] Thus the sample solution to water injection, and the sample solution was evaporated in vodka make up with water, thereby preparing samples. 进行简单的准确性研究,表明两种样品制品没有差异。 Simple accuracy studies showed no difference between the two sample preparation. 对于水中的样品溶液,蒸发干燥标准品达到100.04和180.07mg/mL,分别补2mL水,混匀后进行HPLC分析。 For the sample solution in water, evaporated to dryness and 100.04 standards reached 180.07mg / mL, respectively, up 2mL water and analyzed by HPLC after mixing. 对于伏特加酒中的样品溶液,250.13mg/mL的标准品用伏特加酒稀释到50.03mg/mL,重复三次,蒸发干燥,补2mL水,混匀后进行HPLC分析。 For sample solutions in vodka, 250.13mg / mL standard product was diluted with vodka to 50.03mg / mL, repeated three times, evaporated to dryness, water up 2mL HPLC analysis after mixing. 在两样品制品之间评估等效恢复性。 Evaluation equivalence between the two sample preparation recovery.

[0243] 24小时后测定水和伏特加酒的样品溶液体积,通过如下基于线性蒸发的公式来计算蒸发率:对于8个时间点每次吸取,蒸发率=(900-最终体积-8X 5)/24小时8X5 =5mL。 [0243] Determination of the volume of the sample solution and water, vodka after 24 hours, by the following formula based on linear evaporation the evaporation rate is calculated: For each time point eight suction, evaporation rate = (900- final volume -8X 5) / 24 hours 8X5 = 5mL. 以溶解曲线计算校正蒸发。 Dissolution profile to calculate a correction evaporated. 用水和伏特加酒的实验分别三次测量确定样品吸取体积。 Experiments with water and vodka were drawn three measurements to determine sample volume.

[0244] HPLC条件如下: [0244] HPLC conditions were as follows:

[0245]柱:可 Varian Znersil Phenyl-3, 5mm,4.6 X I5Omm [0245] Column: can Varian Znersil Phenyl-3, 5mm, 4.6 X I5Omm

[0246] 流动相:35%甲醇65%缓冲液(0.1 %磷酸钠,0.2%辛烷磺酸,钠盐,pH = 2.2) [0246] Mobile phase: 35% methanol 65% buffer (0.1% sodium phosphate, 0.2% octane sulfonic acid, sodium salt, pH = 2.2)

[0247]流速:1.5mL/分钟` [0247] flow rate: 1.5mL / min `

[0248] 温度:45摄氏度 [0248] Temperature: 45 ° C

[0249] 注射体积:IOOmL [0249] Injection volume: IOOmL

[0250]波长:280nm [0250] Wavelength: 280nm

[0251] 运行时间:6.5分钟 [0251] Running time: 6.5 minutes

[0252]由于在较早的时间点样品溶液浓度低,注射体积增加到了 100mL。 [0252] Because of the low concentration in the sample solution earlier time points, injection volume increased to 100mL. 暴露于27%乙醇时,如表2所列和图7所示,相对于水中的21 %标记物,Palladone XL在两小时内递送了100%标记物。 Upon exposure to 27% ethanol, as shown in Table 2 and FIG. 7, with respect to 21% water marker, Palladone XL delivered markers 100% within two hours.

[0253] 表2:Palladone XL 32mg胶囊针对基于乙醇的溶液的体外释放特性总结 [0253] Table 2: Palladone XL 32mg capsules based on in vitro release profile against ethanol is summarized

Figure CN1957909BD00341

[0254] 实施例4:氢吗啡酮片剂,双层16mg系统 [0254] Example 4: hydromorphone tablets, bilayer systems 16mg

[0255] 发明的氢吗啡酮持续释放剂型被调节、设计并成形成为渗透药物递送体,其如下制备:首先,制备药物组合物。 [0255] hydromorphone sustained release dosage form of the invention is adjusted, and designed to be formed into osmotic drug delivery member, was prepared as follows: First, the preparation of pharmaceutical compositions. 8.98kg盐酸氢吗啡酮、2.2kg被称为K29-32的聚维酮(聚乙烯吡咯烷酮)和67.06kg平均分子量200000的聚环氧乙烷加入到流体床造粒器的盆中。 Hydromorphone Hydrochloride 8.98kg, 2.2kg referred Povidone K29-32 (polyvinylpyrrolidone) and 67.06kg average molecular weight of 200,000 a polyethylene oxide was added to a fluid bed granulator bowl. 然后,6.0kg被称为K29-32的并具有40000平均分子量的聚维酮(聚乙烯吡咯烷酮)溶于54.0kg水中以制备粘合剂溶液。 Then, 6.0kg referred to as K29-32 and having an average molecular weight of 40,000 povidone (polyvinylpyrrolidone) was dissolved in 54.0kg of water to prepare a binder solution. 通过喷雾18.0kg粘合剂溶液对干燥原料在流化床中造粒。 18.0kg granulated by spraying the binder solution was dried in the fluidized bed material. 接着,在造粒机中干燥湿颗粒直到可接受的水含量,并用装有7-网孔筛的磨定径。 Subsequently, the dried wet granules in a granulator until an acceptable water content, and equipped with a 7- mesh screen sizing mill. 然后将颗粒传到混合器中,与16g作为抗氧化剂的丁基化的羟基甲苯混合,并用0.20kg硬脂酸镁润滑。 The particles were then passed to a mixer, mixed with 16g of toluene as butylated hydroxy antioxidant and lubricated with magnesium stearate 0.20kg.

[0256] 接着,如下制备推进组合物:24.0kg氯化钠和0.32kg黑氧化铁利用带有21-网孔筛的Quadro Comil定径。 [0256] Next, the following composition was prepared to promote: 24.0kg 0.32kg sodium chloride and black iron oxide using Quadro Comil with a 21- mesh sizing screen. 筛出的材料、1.6kg被称为2910的轻基丙基甲基纤维素和51.44kg平均分子量约7000000的聚环氧乙烷加入到流体床造粒器的盆中。 Sieved material, 1.6kg 2910 is called a light-yl methylcellulose 51.44kg average molecular weight about 7,000,000 and a polyethylene oxide is added to a fluid bed granulator bowl. 然后,制备粘合剂溶液。 Then, binder solution is prepared. 然后,6.0kg被称为2910的并具有5cps平均粘度的轻基丙基甲基纤维素溶于54.0kg水中以制备粘合剂溶液。 Then, 6.0kg of 2910 and is called a light-yl methylcellulose having a viscosity of 5cps average 54.0kg dissolved in water to prepare a binder solution. 通过喷雾24.0kg粘合剂溶液在流化床中对干燥原料造粒。 24.0kg granulated by spraying the binder solution was dried in the fluidized bed material. 接着,在造粒机中干燥湿颗粒直到可接受的水含量,并用装有0.094英寸的筛的磨来定径。 Subsequently, the dried wet granules in a granulator until an acceptable water content, and screen mill equipped with a 0.094 inches to sizing. 然后将颗粒传到混合器中,与40g 丁基化的羟基甲苯混合,并用0.20kg硬脂酸镁润滑。 The particles were then passed to a mixer, 40g of butylated hydroxy toluene were mixed and lubricated with magnesium stearate 0.20kg. 接着,氢吗啡酮药物组合物和推进组合物压进两层核芯中。 Next, hydromorphone and pharmaceutical compositions promoting compositions pressed into the layers of the core. 首先,150mg氢吗啡酮药物组合物加到模具腔中并进行预压,然后加入130mg推进组合物并将该层压进直径11/32”的、标准凹面的、双层排列中。 First, 150 mg of hydromorphone pharmaceutical composition is added to the die cavity and pre-press, followed by addition of 130mg advance into the composition and the laminate diameter 11/32 ", the standard concave, bilayer arrangement.

[0257] 双层排列用半透壁包衣。 [0257] tier arrangement coated with the semipermeable wall. 壁形成材料含99%被称为398-10的并具有39.8%平均乙酰基含量的醋酸纤维素、和1%被称为3350的并具有3350平均分子量的聚乙二醇。 Wall-forming material containing 99% referred to the cellulose acetate 398-10 and having an average of 39.8% acetyl content, and 1% is referred to as 3350 and having an average molecular weight of polyethylene glycol 3350. 壁形成材料溶于96%丙酮和4%水的混合物中,制成6%固体溶液。 Wall-forming material is dissolved in 96% acetone and 4% water mixture to prepare a 6% solids solution. 在平底锅涂布机中将壁形成材料喷在双层排列之上和周围,直到每片用上了约33mg膜。 Formed in the wall of the pan coater and the surrounding material is sprayed on tier arrangement, until the sheet to spend about 33mg per film. 穿过半透壁用激光钻出一个0.64mm的出口通道,使药物层与剂系统外部连通。 Drilled through the semipermeable wall outlet passage of a 0.64mm with a laser, and the external layer of the drug agent communication system. 在45°C和45%相对湿度下干燥72小时以去除残余的溶液。 45 ° C and 45% relative humidity for 72 hours and dried to remove residual solution. 干燥后,在45°C和适宜湿度下干燥片剂4小时。 After drying at 45 ° C and dried under a suitable tablet humidity for 4 hours.

[0258] 然后用有色和澄清涂层包衣干燥的片剂。 [0258] then dried coated tablets with a clear coating and a colored. 黄色Opadry II有色涂层被称为Y-30-12863-A。 Yellow Opadry II color coat is called Y-30-12863-A. 14.4kg黄色Opadry II色混入105.6kg水中,形成着色悬浮液。 14.4kg yellow Opadry II color mixed with 105.6kg of water, to form a colored suspension. 在平底锅涂布机中将着色悬浮液喷到·干片剂之上和周围,直到每片用上了约18mg。 In the pan coater colored suspension was sprayed onto the tablets and the surrounding Gan, until each piece spend about 18mg. 然后,通过将2.4kg被称为YS-1-19025的Opadry澄清剂混入45.6kg水中,来制备澄清涂层溶液。 Then, by clarifying agent 2.4kg Opadry YS-1-19025 is known as mixed with 45.6kg of water, to prepare a clear coating solution. 在平底锅涂布机中将澄清溶液喷到干片剂之上和周围,直到每片用上了约1.5mg。 Clarified in a pan coater was sprayed onto and around the dried tablets until each piece spend about 1.5mg.

[0259] 着色并澄清包衣后,用被称为NS-78-17715的Opacode水基黑墨水将HM16印在每片上。 [0259] After the colored coating and clarification, with the NS-78-17715 referred Opacode The water-based black ink printed on each sheet HM16. 在斜面印刷机上进行印刷。 Printing press on the slope.

[0260] 实施例5:体内研究 In vivo studies: 5 cases of [0260] Embodiment

[0261] 进行阶段I的研究,评估健康受试者的禁食和进食情况下醇对实施例3的氢吗啡酮片剂药物动力学的影响。 [0261] Phase I study performed to assess the effects of drugs on the hydromorphone tablets of Example 3 kinetics alcohol case fasted and fed healthy subjects.

[0262] 研究中参与的是两组24位健康、成年男女,年龄21-45岁(含),体重至少70kg并在身高体形所确定的正常体重的波动25%以内。 [0262] The study involved two sets of 24 healthy, adult men and women, aged 21-45 years old (inclusive), weighing at least 70kg and fluctuate within 25% of body height determined in normal weight. 在两组受试者中,研究是单中心、单剂、公开标记、四次处理、四个时期、四种顺序交叉的研究。 In two subjects, the study was single-center, single-dose, open-label, four treatment, four period studied, four kinds of sequence overlap.

[0263] 组I中,每个受试者在禁食状态下接受以下处理: [0263] Group I, each subject received the following treatment in the fasted state:

[0264] 处理A_16mg实施例3的氢吗啡酮片剂和240mL橙汁 [0264] Processing the hydromorphone tablets of Example 3 and 240mL of juice embodiment A_16mg

[0265] 处理B_16mg实施例3的氢吗啡酮片剂和240mL含4% v/v醇的橙汁 [0265] Processing the hydromorphone tablets of Example 3 containing 240mL of juice and 4% v / v alcohol embodiment B_16mg

[0266] 处理C_16mg实施例3的氢吗啡酮片剂和240mL含20% v/v醇的橙汁[0267] 处理D_16mg实施例3的氢吗啡酮片剂和240mL含40% v/v醇的橙汁 Hydromorphone tablets of Example 3 and 240mL containing 40% v / v alcohol in orange juice [0266] Processing hydromorphone tablets of Example 3 and 240mL containing 20% ​​v / v alcohol in orange juice C_16mg Embodiment [0267] Processing embodiment D_16mg

[0268] 组2中,每个受试者正常早餐后接受以下处理: [0268] 2 group, each subject after normal breakfast accepts the following process:

[0269] 处理E_16mg实施例3的氢吗啡酮片剂和240mL橙汁 Hydromorphone tablets of Example 3 and 240mL of orange juice [0269] Processing embodiment E_16mg

[0270] 处理F_16mg实施例3的氢吗啡酮片剂和240mL含4% v/v醇的橙汁 [0270] Processing F_16mg hydromorphone tablets of Example 3 containing 240mL of juice and 4% v / v alcohol embodiment

[0271] 处理G_16mg实施例3的氢吗啡酮片剂和240mL含20% v/v醇的橙汁 [0271] Processing the hydromorphone tablets of Example 3 and 240mL containing 20% ​​v / v alcohol in orange juice embodiment G_16mg

[0272] 处理H_16mg实施例3的氢吗啡酮片剂和240mL含40% v/v醇的橙汁 [0272] Processing the hydromorphone tablets of Example 3 and 240mL containing 40% v / v alcohol in orange juice embodiment H_16mg

[0273] 处理B、C、D、F、G、和H中的醇用橙汁稀释,通常在约30分钟内喝完而不一口气喝下。 [0273] with an alcohol diluted orange juice B, C, D, F, G, and H in the process, usually without downed the finish in about 30 minutes. 对每次处理,从用药之前约14小时开始,受试者接受约50mg作为鸦片样物质拮抗剂的纳曲酮,用药期间每天两次,用药后持续约48小时。 For each treatment begins about 14 hours prior to dosing, the subject received naltrexone about 50mg as opioid antagonist, twice, after treatment for about 48 hours per day during the treatment. 在处理期之间有约6至14天的清除期,用药后约24小时开始清除期。 Processing of between about 6 to 14-day washout period, about 24 hours after administration washout period began.

[0274] 在每次处理期间,在用药后约0(用药前)、2、4、6、8、10、12、16、20、24、27、30、36、 [0274] During each treatment, after treatment of about 0 (before administration), 2,4,6,8,10,12,16,20,24,27,30,36,

42、和48小时,从每个受试者上收集血样,测量血浆氢吗啡酮浓度。 42, and 48 hours, blood samples were collected from each subject, one measuring the plasma concentration of hydromorphone.

[0275] 用CEDRA公司开发校正的液相色谱-质谱连用(LC/MS/MS)方法分析血浆样品。 [0275] with the corrected CEDRA developed liquid chromatography - mass spectrometry in conjunction (LC / MS / MS) method for analysis of plasma samples. 用乙酸乙酯/己烷溶液提取含氢吗啡酮的人血浆和内标氢吗啡酮-D3,去除有机层并再次提取,然后蒸发干燥。 Extracting hydrogen morphinone ethyl acetate / hexane solution and the internal standard human plasma hydromorphone -D3, the organic layer was removed and extracted again, dried and then evaporated. 重构提取物,每等分注射进装有HPLC柱的SCIEX API 4000 LC/MS/MS中。 Reconstituted extract, per aliquot injected into the HPLC column with SCIEX API 4000 LC / MS / MS in. 以多反应检测(MRM)模式来检测阳离子。 In multiple reaction monitoring (MRM) mode for detection of cations.

[0276] 该方法有效的最小可定量的氢吗啡酮浓度是0.05ng/mL。 [0276] The minimum effective amount of the ketone is hydromorphone concentrations of 0.05ng / mL. 在有效期间,通过绘出分析物:内标率对已知的分·析物浓度,画出分析物的校准曲线。 Validity period, by plotting the analyte: internal standard rate sub-known analyte concentration, analyte calibration curve is drawn. 通过应用I/浓度2、线性重量衰减算法,用校准标准的峰面积率(PAR)勾画出校准曲线。 By applying the I / 2 concentration, a linear decay algorithm by weight, lays out a standard calibration curve calibrated peak area ratio (PAR). 氢吗啡酮的校准曲线在0.05至 The calibration curve of hydromorphone to 0.05

10.0ng/mL的范围内呈线性。 10.0ng / mL of the linear range.

[0277] 基于血浆氢吗啡酮浓度确定以下药物动力学参数: [0277] Plasma concentrations of hydromorphone one determined based on the following pharmacokinetic parameters:

[0278] Cmax-最大观察到的血浆浓度 [0278] Cmax- Maximum observed plasma concentration

[0279] Tmax-最大浓度时的时间 [0279] the time when the maximum concentration Tmax-

[0280] k-表观衰减率常数,其通过在末段对数-线性减少阶段中的线性衰减转化的血浆浓度的对数值来评估。 [0280] k- apparent decay rate constant, by the number of the last paragraph - linear decrease in plasma concentration stage linear attenuation values ​​of the transformed evaluated.

[0281] T1/2-表观半衰期(tl/2)值,其算作0.693/k。 [0281] T1 / 2- apparent half-life (tl / 2) value, counted as 0.693 / k.

[0282] AUCt-从O小时至最后可检测到浓度的时间t内血浆浓度时间曲线下的面积,其通过线性梯形法则确定。 [0282] AUCt- last hour to be detected from O to the area under the concentration time curve of the plasma concentration at time t, which is determined by the linear trapezoidal rule.

[0283] AUCinf-外推到无限处的AUC值,其算作AUCt及外推到无限处的面积的和,其可通过时间t (Ct)浓度除以k而算得。 [0283] AUCinf- AUC value extrapolated to infinity at which counted AUCt and the area extrapolated to infinity, and at that time can be calculated by t (Ct) divided by the concentration of k.

[0284] 在禁食和进食组中,在用药后2小时的第一个时间点上,血浆浓度接近于定量的极限;之后,在所有4种处理方法中,血浆浓度缓慢上升。 [0284] In the group fasted and fed, at a point on the first 2 hours after administration, plasma concentrations close to the limit of quantification; Thereafter, all four processing method, the plasma concentration gradually rises. 每组有一些受试者对一些处理出现无浓度值(弃去)或无法临床解释的低值;从分析中排除掉这些低值受试者。 Each group had no concentration values ​​of some subjects experienced some processed (discarded) or not low clinical interpretation; excluded from the analysis of these low values ​​off the subject. Tmax中位数介于12至16小时。 The median Tmax between 12 to 16 hours. 在禁食情况下,3组醇处理中的Cmax值轻微高于0%醇处理中的值,在4、20和40%醇处理中的比率分别为117、131和128%。 In fasting, a Cmax value in the alcohol treatment group 3 slightly higher than the value in the 0% alcohol treatment, in the ratio of 4, 20 and 40% alcohol treatment was 117,131 and 128%, respectively. 在进食情况下,4种处理中血浆氢吗啡酮浓度曲线相似,造成相对于禁食情况更低的Cmax比率。 In the case of food, the 4 treatments similar plasma hydromorphone concentrations of one curve relative to the resulting lower fasting Cmax ratio. Cmax比率未显示出任何与醇百分比(相对于0%醇处理,4、20、和40%醇处理中分别为114、114、和110% )的相关性。 Cmax ratios did not show any (relative to 0% alcohol treatment, 4, 20, and 40% alcohol treatment as 114,114, and 110%, respectively) and the alcohol percentage correlation.

[0285] 在禁食和进食组中3种醇处理相对于0%醇处理的AUC值在置信区间中都达到了80至125%的生物等价性。 [0285] In the group fasted and fed three kinds of processing with respect to the alcohol of 0% alcohol treatment AUC values ​​of the confidence interval has reached 80 to 125% of bioequivalence. 图8显示4种在禁食情况中给药(组I)处理后的平均浓度曲线。 Figure 8 shows four kinds administered (Group I) in fasting mean concentration curve after treatment. 表3概述了药物动力学参数。 Table 3 summarizes the pharmacokinetic parameters. 图9显示组2中4种组中处理后的平均浓度曲线,其中所有处理都是在标准早餐后给药的。 Figure 9 shows the average concentration of the group 2 curve 4 kinds of the treated group, all of which are processed after a standard breakfast administration. 表4总结了PK参数。 Table 4 summarizes the PK parameters.

[0286]· [0286] ·

Figure CN1957909BD00381

是四个时期、重复研究的设计,其中在两个不同时刻给药两批次的每一个,其间在处理之间进行清除,从而表征受试者内和之间可变的健康受试者用药药物动力可变性。 Is four times repeated study design, wherein each, in two different times during the administration of two batches between the processing clear to characterize variable within and between subjects healthy subject medication pharmacokinetic variability.

[0289] 一般根据实施例1和2所述的方法和技术,批次A和批次B的药品制成本发明的口服渗透持续释放剂型。 [0289] Example 1 General The oral drugs prepared according to the invention and the cost of the method and technology 2, batch A and batch B osmotic sustained release dosage form. 每个受试者在随机安排确定的四个时期顺序中接受以下处理两次之一: Each subject received one of the following processing in sequence four times twice the determined random arrangement:

[0290] 处理A:批次A,用盐酸纳曲酮50mg [0290] Process A: Lot A, with naltrexone hydrochloride 50mg

[0291] 处理B:批次B,用盐酸纳曲酮50mg [0291] Process B: Lot B, substituting 50mg naltrexone hydrochloride

[0292] 本发明氢吗啡酮剂型给药前12小时和给药时给药盐酸纳曲酮50mg。 [0292] 12 hours before the hydrogen present invention hydromorphone dosage forms and administration when administered naltrexone HCl 50mg. 如果需要,在给药氢吗啡酮后12和24小时,再给药另外的50mg剂量纳曲酮。 If desired, at 12 and 24 hours after administration of hydromorphone hydrogen, then an additional 50mg dose administered naltrexone. 用药之间有最少七天的清除期。 There are at least seven-day washout period between medication.

[0293] 测试药物给药后定时收集的血液样品中的血浆中的氢吗啡酮浓度,确定Cmax、Tmax、最终半衰期(tl/2)、和浓度-时间曲线下的面积(AUC0-72和AUC0_inf)。 [0293] hydromorphone concentrations of one blood sample after the test drug administration timed collection in the plasma, is determined Cmax, Tmax,, terminal half-life (tl / 2) and concentration - area under time curve (AUC0-72 and AUC0_inf ).

[0294] 在每次取样时,将十毫升静脉血样品装入含抗凝剂的样品试管中。 [0294] At each sampling time, the ten ml venous blood sample was charged in a sample tube containing an anticoagulant. 收集I小时内离心样品并存于-40摄氏度,直至测试。 Within I hour sample was collected by centrifugation and stored at -40 ° C until testing. 在每次用本发明氢吗啡酮剂型后O (用药前)、2、4、 After each hydromorphone dosage forms according to the present invention, with O (before the medication), 2,4,

6、8、10、12、16、20、24、36、42、48、56、64和72小时的每次用药期间取血样。 6,8,10,12,16,20,24,36,42,48,56,64 and blood samples were taken during the 72 hours of each drug. 用CEDRA公司开发的校正的液相色谱-质谱连用(LC/MS/MS)方法分析血浆样品。 Plasma samples were analyzed in conjunction Mass spectrum (LC / MS / MS) method - developed with correction CEDRA liquid chromatography.

[0295] 该重复给药中的Cmax比率表示个体间的可变性。 [0295] Cmax ratio indicates that repeated administration of the variability among individuals. 该研究中,为每个个体评估Cmax值比率(高值/低值)并与以`前的实施例中Cmax值比率(醇/无醇处理)作比较。 In this study, evaluation Cmax value ratio (the high value / low value) and the `Example before the Cmax value of the ratio (alcohol / alcohol-free process) is compared to each individual. 图10和11分别表示实施例5中的组I和2的比较。 Figures 10 and 11 represent Comparative Examples 5 group I and 2 embodiment. 如这些图中所示,有醇对无醇处理所观察到的Cmax比率范围有相同的比率范围,其代表个体间可变性。 As shown, there is a range of Cmax ratio observed without the alcohol treatment of the alcohol with the same range of ratios of these figures, which represents the inter-individual variability.

[0296] 实施例7:硬化剂和丙烯酸树脂对水中和40/60 (%体积)乙醇/水中羟考酮释放的影响的研究 Effect of hardener and an acrylic resin in water and 40/60 (% by volume) ethanol / water release of oxycodone: [0296] Example 7

[0297] 10克有或没有硬脂醇的每种制剂通过湿法造粒技术来制备。 [0297] 10 g of each formulation, with or without stearyl alcohol were prepared by wet granulation technique. 取所需量的盐酸羟考酮、乳糖和Eudragit ® RS PO,混合于合适的容器中混合5分钟。 Take the required amount of oxycodone hydrochloride, lactose and Eudragit ® RS PO, mixing in a suitable vessel and mixed for 5 minutes. 用水对粉状混合物造粒直至产生湿块。 The powdery mixture is granulated with water until a wet mass. 然后把湿块通过16网孔尺寸的筛,并在合适条件下使之干燥过夜。 The wet mass is then passed through a 16 mesh size sieve, and allowed to dry overnight under suitable conditions. 在小容器中,在水浴中将所需量的硬脂醇熔化。 In a small vessel, the required amount of stearyl alcohol is melted in a water bath. 保持熔化的硬脂醇在水浴中,加入所需量的干燥颗粒并混合,直到颗粒被熔化的硬脂醇完全包衣。 Holding molten stearyl alcohol in a water bath, was added the desired amount of dry particles and mixed until the particles are completely melted stearyl alcohol coating. 从水浴中取出混合物,使之在合适条件下冷却,然后通过16网孔筛定径。 The mixture was removed from the water bath and allowed to cool under suitable conditions, and then passed through a 16 mesh sizing screen. 滑石粉和硬脂酸镁加到包衣的颗粒中并用合适的混合器混合。 Talc and magnesium stearate is added to the coated particles and mixed with a suitable mixer. 然后用合适压片机,如Carver压力器,将颗粒压成375mg片剂。 Then using a suitable tabletting machine, such as a Carver pressure device, the granules compressed into 375mg tablets. 对于未包衣硬脂醇的颗粒,将颗粒压成300mg片剂。 Stearyl alcohol for uncoated particles, the particles are compressed into 300mg tablets.

Figure CN1957909BD00401
Figure CN1957909BD00402

[0298] 实施例8:有或无硬脂醇的盐酸氢吗啡酮片剂制剂 [0298] Example 8: YES or hydromorphone hydrochloride tablet formulation without stearyl alcohol

[0299]用与实施例7相同的生产方法,其中用盐酸氢吗啡酮替换盐酸羟考酮。 [0299] by the same production process as in Example 7, oxycodone hydrochloride wherein the replacement with hydromorphone hydrochloride.

[0300] [0300]

Figure CN1957909BD00411
Figure CN1957909BD00421

[0307] 结果:如图14所示,制剂中缺少Eudragit ® RS PO对水中或水/乙醇介质中的盐酸羟考酮功能无影响。 [0307] Results: As shown in FIG. 14, the formulation lacks Eudragit ® RS PO had no effect on the function of oxycodone hydrochloride in water or a water / ethanol medium. 如图15所示,制剂中缺少Eudragit ® RS PO对水中或水/乙醇介质中的盐酸氢吗啡酮功能无影响。 15, the formulation lacks Eudragit ® RS PO had no effect on the function of hydromorphone hydrochloride in water or a water / ethanol medium.

[0308]实施例11:硬脂醇、氢化的聚氧60蓖麻油和巴西棕榈蜡对盐酸羟考酮功能的相对影响 [0308] Example 11: Effect of relative stearyl alcohol, polyoxy 60 hydrogenated castor oil and carnauba wax to function oxycodone hydrochloride

[0309]接着用与实施例7所详述的相同湿法造粒法制粒。 [0309] Example 7 followed by the same wet granulation detailed embodiment granulated. 可是,硬脂醇用氢化的聚氧60蓖麻油或巴西棕榈腊代替。 However, polyoxy 60 hydrogenated castor oil, stearyl alcohol or with carnauba wax instead. 片剂重量保持在375mg使每片中有30mg鸦片样物质。 375mg tablet weight is maintained at 30mg per tablet has opioids. 制剂如表11所示。 As shown in Table 11 formulation. 片剂在以下介质中释放:乙醇数据=40% EtOH/水=O-4小时,水=4-24小时,水数据:水用作所有间隔的介质。 Release tablet following media: data ethanol = 40% EtOH / water = O-4 hours, water = 4-24 hours, water data: All water is used as the dielectric spacer.

[0310] [0310]

Figure CN1957909BD00431

[0311] 结果:如图16所示,巴西棕榈蜡可用于代替硬脂醇,而不是氢化的聚氧蓖麻油。 [0311] Results: As shown in FIG 16, may be used in place of carnauba wax and stearyl alcohol, and polyoxyethylene castor oil are not hydrogenated.

[0312] 实施例12:测试OxyContin ®剂型 Test OxyContin ® formulation: [0312] Example 12

[0313] 基本在以下条件下进行OxyContin ®剂型体外溶解测试: [0313] OxyContin ® formulation performed substantially in vitro dissolution test under the following conditions:

[0314] 溶解条件: [0314] dissolution conditions:

[0315]设备:USPII 型 [0315] Equipment: USPII type

[0316] 搅拌速度:50rpm [0316] stirring speed: 50rpm

[0317]体积:900mL [0317] Volume: 900mL

[0318]浴温度:37 ±0.5 °C [0318] Bath temperature: 37 ± 0.5 ° C

[0319] 样品体积:5ml [0319] Sample volume: 5ml

[0320] 溶解介质:分别是分析级的水和40%乙醇(每介质η = 6片) [0320] The dissolution medium: were of analytical grade water and 40% ethanol (η = 6 per medium tablets)

[0321]取样间隔:Τ = 0.5、1、2、4、6、8、10 和12 小时 [0321] Sampling interval: Τ = 0.5,1,2,4,6,8,10 and 12 hours of

[0322] 用C18柱分析样品溶液并在286nm波长处UV检测。 [0322] An analytical sample was treated with a C18 column and UV detection at a wavelength of 286nm. 用1.05-100.53 μ g/mL范围内的线性曲线进行定量以提供样品浓度。 Quantified by linear curve within 1.05-100.53 μ g / mL to provide a range of sample concentration. 该特定分析的具体HPLC条件基本如下: HPLC analysis of the specific conditions of the particular substantially as follows:

[0323] HPLC 条件: [0323] HPLC conditions:

[0324]柱:ZorbaxExtended C18, 5 μ , 50 X 4.6mm [0324] Column: ZorbaxExtended C18, 5 μ, 50 X 4.6mm

[0325]流动相:THF:乙腈:34mM 磷酸缓冲液(3: 25: 72, v/v/v) [0325] Mobile phase: THF: acetonitrile: 34mM phosphate buffer (3: 25: 72, v / v / v)

[0326]流速:1.2mL/分钟 [0326] flow rate: 1.2mL / min

[0327] 检测器波长:286.[0328] 注射体积:30 μ L [0327] Detector wavelength: 286 [0328] Injection volume:. 30 μ L

[0329] 柱温度:50摄氏度 [0329] Column temperature: 50 ° C

[0330] 运行时间:4分钟 [0330] Run time: 5 minutes

[0331] 结果如图17所示。 [0331] The results shown in FIG. 17.

[0332] 实施例13: 16mg氢吗啡酮基质 16mg hydromorphone matrix: [0332] Example 13

[0333] 100 克混合物,其含6g 盐酸氢吗啡酮、25gHPMCK100M、I5gHPMCK3Jg PVP K29~32>2g硬脂酸镁和47g微晶纤维素,该混合物在旋转磨中干燥混合3分钟。 [0333] 100 g mixture thereof containing 6g of hydromorphone hydrochloride, 25gHPMCK100M, I5gHPMCK3Jg PVP K29 ~ 32> 2g of magnesium stearate and 47g of microcrystalline cellulose, the mixture was dried in a rotary mill mixing for 3 minutes. 称重267mg样品,然后在Carver压力器上用11/32”标准圆工具和1/2吨压力压缩,从而产生延迟释放的片剂。 267mg samples were weighed, then 11/32 "standard round tool and the 1/2 tons of pressure on a Carver compression pressure, thereby generate a delayed release tablets.

[0334] 实施例14:40mg轻考酮基质 Light 40mg oxycodone matrix: [0334] Example 14

[0335] 100 克混合物,其含15g 盐酸羟考酮、25gHPMC K100M、15gHPMCK3、5g PVP K29-32、2g硬脂酸镁和38g微晶纤维素,该混合物在旋转磨中干燥混合3分钟。 [0335] 100 g mixture, which contained 15g of oxycodone hydrochloride, 25gHPMC K100M, 15gHPMCK3,5g PVP K29-32,2g 38g of magnesium stearate and microcrystalline cellulose, mixing the mixture was dried in a rotary mill for 3 minutes. 称重267mg样品,然后在Carver压力器上用11/32”标准圆工具和1/2吨压力压缩,从而产生延迟释放的片剂。 267mg samples were weighed, then 11/32 "standard round tool and the 1/2 tons of pressure on a Carver compression pressure, thereby generate a delayed release tablets.

[0336] 实施例15:90mg硫酸吗啡基质 [0336] Example 15: 90mg morphine sulfate matrix

[0337] 100 克混合物,其含18g硫酸吗啡、25gHPMCK100M、15gHPMCK3、5gPVP K29_32、2g硬脂酸镁和40g微晶纤维素,该混合物在旋转磨中干燥混合3分钟。 [0337] 100 g mixture containing 18g which morphine sulfate, 25gHPMCK100M, 15gHPMCK3,5gPVP K29_32,2g 40g of magnesium stearate and microcrystalline cellulose, mixing the mixture was dried in a rotary mill for 3 minutes. 称重500mg样品,然后在Carver压力器上用13/32”标准圆工具和3/4吨压力压缩,从而产生延迟释放的片剂。 500mg samples were weighed, then 13/32 "standard round tool and the 3/4 tons of pressure on a Carver compression pressure, thereby generate a delayed release tablets.

[0338] 实施例16:40mg氧吗啡酮HCl基质 Oxymorphone HCl 40mg matrix: [0338] Example 16

[0339] 100 克混合物,其含15g 氧吗啡酮HCl、25gHPMCK100M、15gHPMCK3、5g PVP K29-32、2g硬脂酸镁和38g微晶纤维素,该混合物在旋转磨中干燥混合3分钟。 [0339] 100 g mixture, which contains 15g oxymorphone HCl, 25gHPMCK100M, 15gHPMCK3,5g PVP K29-32,2g 38g of magnesium stearate and microcrystalline cellulose, mixing the mixture was dried in a rotary mill for 3 minutes. 称重267mg样品,然后在Carver压力器上用11/32”标准圆工具和1/2吨压力压缩,从而产生延迟释放的片剂。 267mg samples were weighed, then 11/32 "standard round tool and the 1/2 tons of pressure on a Carver compression pressure, thereby generate a delayed release tablets.

[0340] 实施例17:40mg酸式酒石酸氢可酮基质 [0340] Example 17: 40mg of hydrocodone bitartrate matrix

[0341] 100克混合物,其含15g酸式酒石酸氢可酮、25gHPMC K100M、15gHPMCK3、5g PVPK29-32、2g硬脂酸镁和38g微晶纤维素,该混合物在旋转磨中干燥混合3分钟。 [0341] 100 g mixture, which contained 15g hydrocodone bitartrate, 25gHPMC K100M, 15gHPMCK3,5g PVPK29-32,2g magnesium stearate and 38g of microcrystalline cellulose, the mixture was dried in a rotary mill mixing for 3 minutes. 称重267mg样品,然后在Carver压力器上用11/32”标准圆工具和1/2吨压力压缩,从而产生延迟释放的片剂。` 267mg samples were weighed, then 11/32 "standard round tool and the 1/2 tons of pressure on a Carver compression pressure, thereby generating a delayed release tablets .`

[0342] 实施例18:0R0S ®羟考酮40mg系统 [0342] Example 18: 0R0S ® 40mg oxycodone system

[0343] 首先,通过干燥混合以下材料来制备药物组合物:135.6g聚环氧乙烷N_150、54g盐酸羟考酮、和Sg聚维酮(聚乙烯吡咯烷酮)。 [0343] First, the pharmaceutical compositions are prepared by dry mixing the following materials: 135.6g of polyethylene oxide N_150,54g oxycodone hydrochloride, Sg and povidone (polyvinylpyrrolidone). 在厨房辅助轨道式混合器中混合,缓慢加入70g乙醇。 Auxiliary rail in a kitchen mixer and mixed, 70g of ethanol was slowly added. 产生的湿颗粒通过16网孔箱式筛定径,在平底锅中展开,室温空气中干燥,然后通过16网孔箱式筛二次定径。 16 produced by the wet granulation mesh sizing sieve box, expand in the pan, dried in air at room temperature, and then passed through a 16 mesh sieve box secondary sizing. 最后,将材料装回混合器并混入0.5g硬脂酸镁混合I分钟。 Finally, the material was mixed in the mixer and replace magnesium stearate 0.5g I min.

[0344] 接着,在厨房辅助轨道式混合器中通过干燥混合以下材料来制备推进组合物:147.5g平均分子量为7000K的聚环氧乙烷、40g氯化钠粉末、8g聚维酮K29-32、和2g绿氧化铁。 [0344] Next, in the kitchen mixer auxiliary rail is prepared by dry mixing the following materials to promote the composition: 147.5g average molecular weight of polyethylene oxide 7000K, 4Og sodium chloride powder, 8g povidone K29-32 , and 2g green iron oxide. 混合时,缓慢加入IOOg乙醇。 While mixing, slowly added IOOg ethanol. 产生的湿颗粒通过16网孔箱式筛定径,在平底锅中展开,室温空气中干燥,然后通过16网孔箱式筛二次定径。 16 produced by the wet granulation mesh sizing sieve box, expand in the pan, dried in air at room temperature, and then passed through a 16 mesh sieve box secondary sizing. 最后,将材料置于混合器中并混入 Finally, the material was placed in the mixer and mixed

0.5g硬脂酸镁混合I分钟。 I min 0.5g magnesium stearate.

[0345] 接着,羟考酮组合物和推进组合物压进双层核芯。 [0345] Next, the oxycodone composition and the composition pressed into the advancing core bilayer. 首先,将148mg羟考酮组合物加入到模具腔中并预先压缩,然后加入123mg推进组合物并将该层压进直径11/32”的、标准凹面的、双层排列中。 First, 148mg oxycodone composition into a mold cavity and pre-compressed, then added 123mg promoting composition into the laminate and the diameter of 11/32 ", the standard concave, bilayer arrangement.

[0346] 双层排列用半透壁包衣。 [0346] tier arrangement coated with the semipermeable wall. 壁形成材料含99%被称为398-10的并具有39.8%平均乙酰基含量的醋酸纤维素、和1%被称为3350的并具有3350平均分子量的聚乙二醇。 Wall-forming material containing 99% referred to the cellulose acetate 398-10 and having an average of 39.8% acetyl content, and 1% is referred to as 3350 and having an average molecular weight of polyethylene glycol 3350. 壁形成材料溶于96%丙酮和4%水的混合物中,制成6%固体溶液。 Wall-forming material is dissolved in 96% acetone and 4% water mixture to prepare a 6% solids solution. 在平底锅包衣机中将壁形成材料喷在双层排列之上和周围,直到每片用上了约43mg膜。 Formed in the wall material in a pan coater and sprayed on tier arrangement around until each film sheet spend about 43mg.

[0347] 穿过半透壁钻出一个1.0mm的出口通道,使药物层与剂系统外部连通。 [0347] drilled through the semipermeable wall of the outlet channel a 1.0mm, external drug layer and the agent communication system. 在45°C和45%相对湿度下干燥72小时以去除残余的溶剂。 At 45 ° C and 45% relative humidity for 72 hours and dried to remove residual solvent. 干燥后,在45°C和适宜湿度下干燥片剂4小时。 After drying at 45 ° C and dried under a suitable tablet humidity for 4 hours.

[0348] 实施例19:90mg OROS⑧硫酸吗啡[0349] 首先,通过干燥混合以下材料来制备药物组合物:135.6g聚环氧乙烷N_80、54g硫酸吗啡、和Sg聚维酮(聚乙烯吡咯烷酮)。 [0348] Example 19: 90mg OROS⑧ morphine sulfate [0349] First, the pharmaceutical compositions are prepared by dry mixing the following materials: 135.6g of polyethylene oxide N_80,54g morphine sulfate, Sg and povidone (polyvinylpyrrolidone) . 在厨房辅助轨道式混合器中混合,缓慢加入70g乙醇。 Auxiliary rail in a kitchen mixer and mixed, 70g of ethanol was slowly added. 产生的湿颗粒通过16网孔箱式筛定径,在平底锅中展开,室温空气中干燥,然后通过16网孔箱式筛二次定径。 16 produced by the wet granulation mesh sizing sieve box, expand in the pan, dried in air at room temperature, and then passed through a 16 mesh sieve box secondary sizing. 最后,将材料装回混合器并混入0.5g硬脂酸镁混合I分钟。 Finally, the material was mixed in the mixer and replace magnesium stearate 0.5g I min.

[0350] 接着,在厨房辅助轨道式混合器中通过干燥混合以下材料来制备推进组合物:147.5g平均分子量为7000K的聚环氧乙烷、40g氯化钠粉末、8g聚维酮K29-32、和2g绿氧化铁。 [0350] Next, in the kitchen mixer auxiliary rail is prepared by dry mixing the following materials to promote the composition: 147.5g average molecular weight of polyethylene oxide 7000K, 4Og sodium chloride powder, 8g povidone K29-32 , and 2g green iron oxide. 混合时,缓慢加入IOOg乙醇。 While mixing, slowly added IOOg ethanol. 产生的湿颗粒通过16网孔箱式筛定径,在平底锅中展开,室温空气中干燥,然后通过16网孔箱式筛二次定径。 16 produced by the wet granulation mesh sizing sieve box, expand in the pan, dried in air at room temperature, and then passed through a 16 mesh sieve box secondary sizing. 最后,将材料置于混合器中并混入 Finally, the material was placed in the mixer and mixed

0.5g硬脂酸镁混合I分钟。 I min 0.5g magnesium stearate.

[0351] 接着,硫酸吗啡组合物和推进组合物压进双层核芯。 [0351] Next, the morphine sulfate composition and pressed into bilayer compositions advancing core. 首先,将333mg硫酸吗啡组合物加入到模具腔中并预先压缩,然后加入280mg推进组合物并将该层压进直径7/16”的、标准凹面的、双层排列中。 First, 333mg of morphine sulfate composition is added to the die cavity and pre-compressed, then added 280mg promoting composition into the laminate and the diameter of 7/16 ", the standard concave, bilayer arrangement.

[0352] 双层排列用半透壁包衣。 [0352] tier arrangement coated with the semipermeable wall. 壁形成材料含95%被称为398-10的并具有39.8%平均乙酰基含量的醋酸纤维素、和5%被称为3350的并具有3350平均分子量的聚乙二醇。 Cellulose acetate containing 95% of the wall-forming material is referred to as 398-10 and having an average of 39.8% acetyl content, and 5% and is referred to as 3350 having an average molecular weight of polyethylene glycol 3350. 壁形成材料溶于96%丙酮和4%水的混合物中,制成6%固体溶液。 Wall-forming material is dissolved in 96% acetone and 4% water mixture to prepare a 6% solids solution. 在平底锅包衣机中将壁形成材料喷在双层排列之上和周围,直到每片用上了约33mg膜。 Formed in the wall material in a pan coater and sprayed on tier arrangement around until each film sheet spend about 33mg.

[0353] 穿过半透壁钻出一个1.0mm的出口通道,使药物层与剂系统外部连通。 [0353] drilled through the semipermeable wall of the outlet channel a 1.0mm, external drug layer and the agent communication system. 在45°C和45%相对湿度下干燥72小时以去除残余的溶液。 45 ° C and 45% relative humidity for 72 hours and dried to remove residual solution. 干燥后,在45°C和适宜湿度下干燥片剂4小时。 After drying at 45 ° C and dried under a suitable tablet humidity for 4 hours.

[0354] 实施例20:40mg OROS ®盐酸氧吗啡酮 [0354] Example 20: 40mg OROS ® oxymorphone hydrochloride

[0355] 首先,通过干燥`混合以下材料来制备药物组合物:135.6g聚环氧乙烷N_80、54g盐酸氧吗啡酮、和Sg聚维酮(聚乙烯吡咯烷酮)。 [0355] First, the pharmaceutical compositions are prepared by mixing the following materials dried `: 135.6g of polyethylene oxide N_80,54g oxymorphone hydrochloride, Sg and povidone (polyvinylpyrrolidone). 在厨房辅助轨道式混合器中混合,缓慢加入70g乙醇。 Auxiliary rail in a kitchen mixer and mixed, 70g of ethanol was slowly added. 产生的湿颗粒通过16网孔箱式筛制粒,移入平底锅中,室温空气中干燥,然后通过16网孔箱式筛二次制粒。 16 produced by the wet granulation mesh box sieve granulator, into a pan, dried in air at room temperature, and then passed through a 16 mesh sieve box second granulation. 最后,将材料装回混合器并混入0.5g硬脂酸镁混合I分钟。 Finally, the material was mixed in the mixer and replace magnesium stearate 0.5g I min.

[0356] 接着,在厨房辅助轨道式混合器中通过干燥混合以下材料来制备推进组合物:147.5g平均分子量为7000K的聚环氧乙烷、40g氯化钠粉末、8g聚维酮K29-32、和2g绿氧化铁。 [0356] Next, in the kitchen mixer auxiliary rail is prepared by dry mixing the following materials to promote the composition: 147.5g average molecular weight of polyethylene oxide 7000K, 4Og sodium chloride powder, 8g povidone K29-32 , and 2g green iron oxide. 混合时,缓慢加入IOOg乙醇。 While mixing, slowly added IOOg ethanol. 产生的湿颗粒通过16网孔箱式筛定径,在平底锅中展开,室温空气中干燥,然后通过16网孔箱式筛二次定径。 16 produced by the wet granulation mesh sizing sieve box, expand in the pan, dried in air at room temperature, and then passed through a 16 mesh sieve box secondary sizing. 最后,将材料置于混合器中并混入 Finally, the material was placed in the mixer and mixed

0.5g硬脂酸镁混合I分钟。 I min 0.5g magnesium stearate.

[0357] 接着,盐酸氧吗啡酮组合物和推进组合物压进双层核芯。 [0357] Next, oxymorphone hydrochloride and the composition pressed into the bilayer composition advancing core. 首先,将148mg氧吗啡酮组合物加入到模具腔中并预先压缩,然后加入123mg推进组合物并将该层压进直径11/32”的、标准凹面的、双层排列中。 First, 148mg oxymorphone composition into a mold cavity and pre-compressed, then added 123mg promoting composition into the laminate and the diameter of 11/32 ", the standard concave, bilayer arrangement.

[0358] 双层排列用半透壁包衣。 [0358] tier arrangement coated with the semipermeable wall. 壁形成材料含99%被称为398-10的并具有39.8%平均乙酰基含量的醋酸纤维素、和1%被称为3350的并具有3350平均分子量的聚乙二醇。 Wall-forming material containing 99% referred to the cellulose acetate 398-10 and having an average of 39.8% acetyl content, and 1% is referred to as 3350 and having an average molecular weight of polyethylene glycol 3350. 壁形成材料溶于96%丙酮和4%水的混合物中,制成6%固体溶液。 Wall-forming material is dissolved in 96% acetone and 4% water mixture to prepare a 6% solids solution. 在平底锅包衣机中将壁形成材料喷在双层排列之上和周围,直到每片用上了约43mg膜。 Formed in the wall material in a pan coater and sprayed on tier arrangement around until each film sheet spend about 43mg.

[0359] 穿过半透壁钻出一个1.0mm的出口通道,使药物层与剂系统外部连通。 [0359] drilled through the semipermeable wall of the outlet channel a 1.0mm, external drug layer and the agent communication system. 在45°C和45%相对湿度下干燥72小时以去除残余的溶液。 45 ° C and 45% relative humidity for 72 hours and dried to remove residual solution. 干燥后,在45°C和适宜湿度下干燥片剂4小时。 After drying at 45 ° C and dried under a suitable tablet humidity for 4 hours. [0360] 实施例21:40mg OROS ®酸式酒石酸氢可酮 [0360] Example 21: 40mg OROS ® hydrocodone bitartrate

[0361] 首先,通过干燥混合以下材料来制备药物组合物:135.6g聚环氧乙烷N_80、54g酸式酒石酸氢可酮、和Sg聚维酮(聚乙烯吡咯烷酮)。 [0361] First, the pharmaceutical compositions are prepared by dry mixing the following materials: 135.6g of polyethylene oxide N_80,54g hydrocodone bitartrate, Sg and povidone (polyvinylpyrrolidone). 在厨房辅助轨道式混合器中混合,缓慢加入70g乙醇。 Auxiliary rail in a kitchen mixer and mixed, 70g of ethanol was slowly added. 产生的湿颗粒通过16网孔箱式筛定径,在平底锅中展开,室温空气中干燥,然后通过16网孔箱式筛二次定径。 16 produced by the wet granulation mesh sizing sieve box, expand in the pan, dried in air at room temperature, and then passed through a 16 mesh sieve box secondary sizing. 最后,将材料装回混合器并混入0.5g硬脂酸镁混合I分钟。 Finally, the material was mixed in the mixer and replace magnesium stearate 0.5g I min.

[0362] 接着,在厨房辅助轨道式混合器中通过干燥混合以下材料来制备推进组合物:147.5g平均分子量为7000K的聚环氧乙烷、40g氯化钠粉末、8g聚维酮K29-32、和2g绿氧化铁。 [0362] Next, in the kitchen mixer auxiliary rail is prepared by dry mixing the following materials to promote the composition: 147.5g average molecular weight of polyethylene oxide 7000K, 4Og sodium chloride powder, 8g povidone K29-32 , and 2g green iron oxide. 混合时,缓慢加入IOOg乙醇。 While mixing, slowly added IOOg ethanol. 产生的湿颗粒通过16网孔箱式筛定径,在平底锅中展开,室温空气中干燥,然后通过16网孔箱式筛二次定径。 16 produced by the wet granulation mesh sizing sieve box, expand in the pan, dried in air at room temperature, and then passed through a 16 mesh sieve box secondary sizing. 最后,将材料置于混合器中并混入 Finally, the material was placed in the mixer and mixed

0.5g硬脂酸镁混合I分钟。 I min 0.5g magnesium stearate.

[0363] 接着,酸式酒石酸氢可酮组合物和推进组合物压进双层核芯。 [0363] Next, the hydrocodone bitartrate composition and the composition pressed into the advancing bilayer cores. 首先,将148mg酸式酒石酸氢可酮组合物加入到模具腔中并预先压缩,然后加入123mg推进组合物并将该层压进直径11/32”的、标准凹面的、双层排列中。 First, 148mg hydrocodone bitartrate composition is added to the die cavity and pre-compressed, then added 123mg promoting composition into the laminate and the diameter of 11/32 ", the standard concave, bilayer arrangement.

[0364] 双层排列用半透壁包衣。 [0364] tier arrangement coated with the semipermeable wall. 壁形成材料含99%被称为398-10的并具有39.8%平均乙酰基含量的醋酸纤维素、和1%被称为3350的并具有3350平均分子量的聚乙二醇。 Wall-forming material containing 99% referred to the cellulose acetate 398-10 and having an average of 39.8% acetyl content, and 1% is referred to as 3350 and having an average molecular weight of polyethylene glycol 3350. 壁形成材料溶于96%丙酮和4%水的混合物中,制成6%固体溶液。 Wall-forming material is dissolved in 96% acetone and 4% water mixture to prepare a 6% solids solution. 在平底锅包衣机中将壁形成材料喷在双层排列之上和周围,直到每片用上了约43mg膜。 Formed in the wall material in a pan coater and sprayed on tier arrangement around until each film sheet spend about 43mg.

[0365] 穿过半透壁钻出一个1.0mm的出口通道,使药物层与剂系统外部连通。 [0365] drilled through the semipermeable wall of the outlet channel a 1.0mm, external drug layer and the agent communication system. 在45°C和45%相对湿度下干燥72小时以去除残余的溶液。 45 ° C and 45% relative humidity for 72 hours and dried to remove residual solution. 干燥后,在45°C和适宜湿度下干燥片剂4小时。 After drying at 45 ° C and dried under a suitable tablet humidity for 4 hours. · ·

Claims (58)

  1. 1.持续释放口服剂型在制备用于减轻口服接受该剂型的患者中与醇诱导的剂量突然释放有关的副作用的药物中的应用,所述口服剂型含鸦片样物质和持续释放剂量结构,其中(a)在存在醇溶液的情况下,所述持续释放剂量结构从所述持续释放剂型中释放出所述鸦片样物质,其中醇溶液含大于或等于约20%体积/体积浓度的醇,而且其中,在所述鸦片样物质持续释放剂型和所述醇溶液向个体联合给药时所达到的平均单剂最大血浆鸦片样物质浓度同在所述鸦片样物质持续释放剂型不和所述醇溶液联合给药而单独向个体给药时所达到的平均单剂最大血浆鸦片样物质浓度之间的比率等于或小于约1.8: I;和(b)所述鸦片样物质选自吗啡、可待因、二甲基吗啡、二乙酰吗啡、氧可酮、二氢可待因酮、二氢可待因、二氢吗啡酮、氧吗啡酮、尼克吗啡、美沙酮、盐酸左旋美沙 1. In the preparation of sustained release oral dosage form for reducing the use of oral dosage form in a patient receiving the dose of the alcohol-induced side effects associated with the sudden release of a medicament, the oral dosage form comprising opioid and a sustained release dosage structure, wherein ( a) in the presence of an alcohol solution, the structure of the sustained release dose of the opioid is released from the sustained release dosage form, wherein the alcohol solution containing greater than or equal to about 20% by volume / volume concentration of alcohol, and wherein , an average single dose maximum plasma opioid concentration in the sample when the opioid sustained release dosage forms and the alcohol solution was administered in combination to a subject achieved with the opioid sustained release dosage forms and the alcohol solution is not combined administration and the ratio between the individual is administered to the achieved average single dose maximum plasma opioid concentration of the substance is equal to or less than about 1.8: I; and (b) said opioid is selected from morphine, codeine, thebaine, diamorphine, oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone, Nick morphine, methadone, L-methadone hydrochloride 酮乙酯、哌替啶、酮羟基哌替唳、丙氧芬、右旋丙氧芬、右旋吗酰胺、苯托酰胺、piritramide、戍唑辛、苯唑星及其药学上可接受的盐,其中所述持续释放口服剂型是渗透持续释放剂型。 On ethyl ketone, meperidine, one for Li-hydroxypiperidine, propoxyphene, dextropropoxyphene, dextromoramide, benzene Torr amide, piritramide, oxazole oct Shu, oxacillin, and pharmaceutically acceptable salts thereof stars wherein the sustained release oral dosage form is a sustained release osmotic dosage form.
  2. 2.根据权利要求1的应用,其中所述比率等于或小于约1.6: I。 2. Use according to claim 1, wherein said ratio is equal to or less than about 1.6: I.
  3. 3.持续释放口服剂型在制备用于减轻口服接受该剂型的患者中与醇诱导的剂量突然释放有关的副作用的药物中的应用,所述口服剂型含鸦片样物质和持续释放剂量结构,其中(a)在存在醇溶液的情况下,所述持续释放剂量结构从所述持续释放剂型中释放出所述鸦片样物质,其中醇溶液含大于或等于约20%体积/体积浓度的醇,而且其中,在所述鸦片样物质持续释放剂型和醇溶液向个体联合给药时所达到的单个患者单剂最大血浆鸦片样物质浓度同在所述鸦片样物质持续释放剂型不和醇溶液联合给药而单独向个体给药时所达到的单个患者单剂最大血浆鸦片样物质浓度之间的比率等于或小于约5: I;和(b)所述鸦片样物质选自吗啡、可待因、二甲基吗啡、二乙酰吗啡、氧可酮、二氢可待因酮、二氢可待因、二氢吗啡酮、氧吗啡酮、尼克吗啡、美沙酮、盐酸左旋美沙 3. In the preparation of sustained release oral dosage form for alleviating the patient receiving oral dosage form with the alcohol-induced sudden release of a medicament dose related side effects in the oral dosage form comprising opioid and a sustained release dosage structure, wherein ( a) in the presence of an alcohol solution, the structure of the sustained release dose of the opioid is released from the sustained release dosage form, wherein the alcohol solution containing greater than or equal to about 20% by volume / volume concentration of alcohol, and wherein , a single patient when administered in combination with the opioid sustained release dosage form to a subject and an alcoholic solution reached a single dose maximum plasma opioid concentration with the opioid sustained release dosage forms and the alcohol solution is not administered in combination and the ratio between the individual single dose maximum plasma opioid concentration of the substance is equal to a single individual patient, the time of administration reached or less than about 5: I; and (b) said opioid is selected from morphine, codeine, dimethyl group of morphine, diamorphine, oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone, Nick morphine, methadone, L-methadone hydrochloride 乙酯、哌替啶、酮羟基哌替唳、丙氧芬、右旋丙氧芬、右旋吗酰胺、苯托酰胺、piritramide、戍唑辛、苯唑星及其药学上可接受的盐,其中所述持续释放口服剂型是渗透持续释放剂型。 Ethyl ester, pharmaceutically meperidine, one for Li-hydroxypiperidine, propoxyphene, dextropropoxyphene, dextromoramide, benzene Torr amide, piritramide, oxazole oct Shu, oxacillin, and pharmaceutically acceptable salts thereof star, wherein the sustained release oral dosage form is a sustained release osmotic dosage form.
  4. 4.根据权利要求3的应用,其中所述比率等于或小于约4: I。 4. Use according to claim 3, wherein said ratio is equal to or less than about 4: I.
  5. 5.持续释放口服剂型在制备用于减轻口服接受该剂型的患者中与醇诱导的剂量突然释放有关的副作用的药物中的应用,所述口服剂型含鸦片样物质和持续释放剂量结构,其中(i)在存在醇溶液的情况下,所述持续释放剂量结构从所述持续释放剂型中释放出所述鸦片样物质,其中醇溶液含大于或等于约20%体积/体积浓度的醇,而且其中,所述鸦片样物质持续释放剂型从所述鸦片样物质持续释放剂型中释放小于或等于约80重量百分比的鸦片样物质剂量,其以如下方式测得:(a)利用含测试介质的体外测试方法和(b)在体外测试方法起始后约2小时内;(ii)所述测试介质含含大于或等于约20%体积/体积浓度的醇溶液;和(iii)所述鸦片样物质选自吗啡、可待因、二甲基吗啡、二乙酰吗啡、氧可酮、二氢可待因酮、二氢可待因、二氢吗啡酮、氧吗啡酮、尼克吗啡、美沙酮、 The preparation of sustained release oral dosage form for alleviating the patient receiving oral dosage form with the alcohol-induced sudden release of a medicament dose related side effects in the oral dosage form comprising opioid and a sustained release dosage structure, wherein ( i) in the presence of an alcohol solution, the structure of the sustained release dose of the opioid is released from the sustained release dosage form, wherein the alcohol solution containing greater than or equal to about 20% by volume / volume concentration of alcohol, and wherein the opioid from said sustained release dosage form releases the opioid sustained release dosage form is less than or equal to about 80 percent opioid dose by weight, which was measured in the following manner: (a) using an in vitro test medium containing the test and the method (b) for about 2 hours after starting the test method in vitro; (ii) containing the test medium containing greater than or equal to about 20% alcohol solution volume / volume concentration; and (iii) the opioid is selected from from morphine, codeine, thebaine, diamorphine, oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone, Nick morphine, methadone, 酸左旋美沙酮乙酯、哌替唳、酮轻基哌替唳、丙氧芬、右旋丙氧芬、右旋吗酰胺、苯托酰胺、piritrami de、戍唑辛、苯唑星及其药学上可接受的盐,其中所述持续释放口服剂型是渗透持续释放剂型。 Acid ethyl ester L-methadone, for the Li piperidine, piperazine keto group for light Li, propoxyphene, dextropropoxyphene, dextromoramide, benzene Torr amide, piritrami de, oxazole oct Shu, oxacillin, and pharmaceutically stars acceptable salt thereof, wherein the sustained release oral dosage form is a sustained release osmotic dosage form.
  6. 6.根据权利要求5的应用,其中所述释放小于或等于约50重量百分比的鸦片样物质剂量。 Application according to claim 5, wherein said release is less than or equal to about 50 percent by weight opioid dose of.
  7. 7.持续释放口服剂型在制备用于减轻口服接受该剂型的患者中与醇诱导的剂量突然释放有关的副作用的药物中的应用,所述口服剂型含鸦片样物质和持续释放剂量结构,其中(a)在存在醇溶液的情况下,所述持续释放剂量结构从所述持续释放剂型中释放出所述鸦片样物质,其中醇溶液含大于或等于约20%体积/体积浓度的醇,而且其中,在所述鸦片样物质持续释放剂型和所述醇溶液向个体联合给药时所达到的单剂最大血浆浓度的时间中位数同在所述持续释放剂型不和所述醇溶液联合给药而单独向个体给药时所达到的最大血浆浓度的时间中位数之间的比率处于约0.5至约1.0之间;和(b)所述鸦片样物质选自吗啡、可待因、二甲基吗啡、二乙酰吗啡、氧可酮、二氢可待因酮、二氢可待因、二氢吗啡酮、氧吗啡酮、尼克吗啡、美沙酮、盐酸左旋美沙酮乙酯、哌替啶 7. In the preparation of sustained release oral dosage form for reducing the Patients receiving oral dosage form with the alcohol-induced dose-related side effects of sudden release of the medicament, the oral dosage form comprising opioid and a sustained release dosage structure, wherein ( a) in the presence of an alcohol solution, the structure of the sustained release dose of the opioid is released from the sustained release dosage form, wherein the alcohol solution containing greater than or equal to about 20% by volume / volume concentration of alcohol, and wherein , time to maximum plasma concentration at a single dose of the opioid and sustained release formulations when the alcohol solution is administered in combination to a subject achieved in the sustained release dosage forms and the alcohol solution is not administered in combination with the number of bits in the and the ratio between the time to maximum plasma concentration when administered alone to a subject achieved a median between about 0.5 to about 1.0; and (b) said opioid is selected from morphine, codeine, dimethyl group of morphine, diamorphine, oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone, Nick morphine, methadone, methadone hydrochloride, ethyl L, meperidine 酮羟基哌替啶、丙氧芬、右旋丙氧芬、右旋吗酰胺、苯托酰胺、piritrami de、戍唑辛、苯唑星及其药学上可接受的盐,其中所述持续释放口服剂型是渗透持续释放剂型。 Hydroxy ketones pethidine, pharmaceutically propoxyphene, dextropropoxyphene, dextromoramide, benzene Torr amide, piritrami de, oxazole oct Shu, oxacillin, and pharmaceutically acceptable salts thereof star, wherein the sustained release oral osmotic dosage form is a sustained release dosage form.
  8. 8.根据权利要求1至7之任一的应用,其中所述持续释放口服剂型提供每天一次或每天两次用药。 Application according to one of claims 1 to 7, wherein said sustained release oral dosage form once or twice daily administration.
  9. 9.根据权利要求1至8之任一的应用,其中所述醇溶液等于或大于约40 %体积/体积。 1-8 according to any one of claims applications, wherein the alcoholic solution is equal to or greater than about 40% volume / volume.
  10. 10.根据权利要求1至9之任一的应用,其中所述持续释放口服剂型进一步含鸦片样物质拮抗剂。 An application according to any one of claims of 1 to 9, wherein said sustained release oral dosage form further containing opioid antagonist.
  11. 11.根据权利要求1至9之任一的应用,其中所述鸦片样物质拮抗剂选自纳曲酮烯丙左吗喃、纳洛酮、纳曲酮、buprenorphine、环丁甲轻氢吗啡、纳洛芬、nalmefene、diprenorphine、环唑辛、etazocine、metazocine 或纳洛酮。 11. The use according to one of claims any one of 1 to 9, wherein said opioid antagonist is selected from naltrexone levallorphan allyl left, naloxone, naltrexone, buprenorphine, hydromorphone cyclobutyloxy A light, nalorphine, nalmefene, diprenorphine, cyclazocine, etazocine, metazocine or naloxone.
  12. 12.根据权利要求1至11之任一的应用,其中所述口服剂型含所述鸦片样物质的量的范围为约Img至约50mg。 According to any one of 1 to 11 12. Use according to claim, wherein the oral dosage form containing an amount of said opioid range of from about Img to about 50mg.
  13. 13.根据权利要求1至12之任一的应用,其中所述渗透剂型包括由半透膜至少部分形成的小室。 According to any one of 1 to 12 applications of a claim, wherein said osmotic dosage form comprising a small chamber at least partially formed by a semipermeable membrane.
  14. 14.根据权利要求13的应用,其中所述半透膜用聚乙烯醇包裹。 Application according to claim 13, wherein the semipermeable membrane wrapped with polyvinyl alcohol.
  15. 15.根据权利要求13或14的应用,其中所述持续释放口服剂型包含混悬剂、悬浮剂或溶液形式的药物组合物、小出口和可扩展层。 15. Use according to claim 13 or claim 14, wherein the dosage form comprises a sustained release oral suspensions, suspensions or solutions in the form of a pharmaceutical composition, and a small outlet spreading layer.
  16. 16.根据权利要求15的应用,其中所述药物层带有与半透膜连接的辅助层或退火包裹层。 Application according to claim 15, wherein the medicament layer is annealed with an auxiliary layer or wrapping layer connected to the semipermeable membrane.
  17. 17.根据权利要求13至16之任一的应用,其中所述渗透持续释放剂型包含肠衣或无肠衣。 17. The use according to any one of claim 13 to 16, wherein said osmotic sustained release dosage form comprising enteric or non-enteric coating.
  18. 18.根据权利要求17的应用,其中所述肠衣含选自CAP、HMPCP和PVAP的材料。 18. The application of claim 17, wherein said casing comprising a material selected from CAP, HMPCP and the PVAP.
  19. 19.根据权利要求1至12之任一的应用,其中所述持续释放口服剂型为基本渗透泵剂型的形式,其含包围并环绕的半透膜和含药物层的内部小室,其含所述药物并混合有一种或多种赋形剂,所述赋形剂适于提供渗透活性梯度并通过形成吸取流体而形成可递送的复合制剂。 19. A according to any one of 1 to 12 applications of a claim, wherein the sustained release oral dosage form of the basic osmotic pump dosage form, which surrounds the containing and surrounding the semipermeable membrane and an inner chamber containing the drug layer, which contains the and mixing the drug with one or more excipients adapted to provide an osmotic activity gradient, and forming a composite formulation may be formed by suction of fluid delivered.
  20. 20.根据权利要求19的应用,其中所述赋形剂包括合适的药物载体、粘合剂、润滑剂、和渗透剂。 20. Application according to claim 19, wherein the excipient includes Suitable pharmaceutical carriers, binders, lubricants, and penetrants.
  21. 21.根据权利要求19或20的应用,其中所述半透膜含选自均聚物和共聚物的聚合物。 21. The use according to claim 19 or claim 20, wherein the semipermeable membrane containing a polymer selected from homopolymers and copolymers.
  22. 22.根据权利要求21的应用,其中所述聚合物选自纤维素酯、纤维素醚和纤维素酯-醚。 22. Application according to claim 21, wherein said polymer is selected from cellulose esters, cellulose ethers and cellulose ester - ether.
  23. 23.根据权利要求19至24之任一的应用,其中所述持续释放口服剂型进一步含流量调节剂。 23. The use according to any one of claim 19 to 24, wherein said sustained release oral dosage further comprising flow rate adjusting agent.
  24. 24.根据权利要求23的应用,其中所述流量选自多羟基醇、聚亚烷基二醇、聚烯二醇、亚烷基二醇的聚酯。 24. The use according to claim 23, wherein said polyhydric alcohol is selected from the flow, polyalkylene glycols, polyalkylene glycols, alkylene glycol polyester.
  25. 25.根据权利要求1至12之任一的应用,其中所述持续释放口服剂型为渗透持续释放剂型的形式,其含有含渗透活性成分的第一药物层、和含比第一药物层更多药物的第二药物层、并任选可扩展层。 25. A according to any one of 1 to 12 applications of a claim, wherein the sustained release oral dosage form is an osmotic sustained release dosage form comprising a first drug layer comprising the active ingredient penetration, and the first drug layer containing more than the second drug layer containing a drug, and optionally expandable layer.
  26. 26.根据权利要求25的应用,其中渗透活性成分选自渗透剂、和吸取流体时显示出胀溶的相对小分子量的一种或多种渗透聚合物。 26. The use according to claim 25, wherein the active ingredient is selected from the permeate penetrant, solvent swelling, and show a relatively small molecular weight polymer is one or more draw fluid permeation.
  27. 27.根据权利要求26的应用,其中所述渗透剂是盐。 27. Application according to claim 26, wherein said osmotic agent is a salt.
  28. 28.根据权利要求25或27的应用,其中第一药物层进一步包括赋形剂。 28. Application according to claim 25 or claim 27, wherein the first layer further comprises a pharmaceutical excipient.
  29. 29.根据权利要求28的应用,其中所述赋形剂选自粘合剂、润滑剂、抗氧化剂和着色剂。 29. Use according to claim 28, wherein said excipient is selected from binders, lubricants, antioxidants and colorants.
  30. 30.根据权利要求25至29之任一的应用,其中所述第二药物层含鸦片样物质并混合有适于提供渗透活性梯度的选择的赋形剂。 30. The use of any one of claim 25 to 29, wherein the second drug layer containing the opioid in a mixture with a gradient adapted to provide selection of osmotically active excipients.
  31. 31.根据权利要求30的应用,其中所述赋形剂是合适的药物载体。 31. The use of claim 30, wherein the excipient is a suitable pharmaceutical carrier.
  32. 32.根据权利要求30的应用,其中第二药物层无渗透活性剂。 32. The use according to claim 30, wherein the second drug layer without penetration of the active agent.
  33. 33.根据权利要求25至32之任一的应用,其中所述持续释放口服剂型进一步包括出□。 33. The use according to any one of claim 25 to 32, wherein said sustained release oral dosage form further comprises a □.
  34. 34.根据权利要求25至30之任一的应用,其中第一和第二药物层进一步包括亲水聚合物载体。 34. Application according to any one of claim 25 to 30, wherein the first and second drug layer further comprises a hydrophilic polymer carrier.
  35. 35.根据权利要求34的应用,其中所述亲水聚合物载体是在肠环境中腐蚀的载体。 35. Application according to claim 34, wherein said carrier is a hydrophilic polymer in a corrosive environment enteric carrier.
  36. 36.根据权利要求25至35之任一的应用,其中所述持续释放口服剂型进一步含半透膜。 36. The use according to any one of claim 25 to 35, wherein said sustained release oral dosage forms further contain a semipermeable membrane.
  37. 37.根据权利要求36的应用,其中所述半透膜包含纤维素酯、纤维素醚、和纤维素酯-醚。 37. The use according to claim 36, wherein the semipermeable membrane comprises cellulose esters, cellulose ethers, cellulose esters and - ethers.
  38. 38.根据权利要求25至37之任一的应用,其中所述持续释放口服剂型进一步含流量调节剂。 38. The use according to any one of claim 25-37, wherein said sustained release oral dosage form further containing flow modifiers.
  39. 39.根据权利要求38的应用,其中所述流量调节剂选自多羟基醇、聚亚烷基二醇、聚烯二醇、亚烷基二醇的聚酯。 Applications 38 39. polyalkylene glycols, polyalkylene glycols, alkylene glycol-containing polyester according to claim, wherein said flow modifier is selected from polyhydric alcohols and more.
  40. 40.根据权利要求25至39之任一的应用,其中可扩展层含有含渗透聚合物或渗透剂的水活性层。 40. The use of any one of claim 25 to 39, wherein the spreading layer may contain water or an active layer comprising an osmopolymer penetrant.
  41. 41.根据权利要求1至12之任一的持续应用,其中所述持续释放口服剂型为软胶囊或硬胶囊的形式。 41. The continued use of any one of 1 to 12 claim, wherein the sustained release oral dosage form of soft capsule or hard capsule.
  42. 42.根据权利要求41的应用,其中所述持续释放口服剂型形式为封闭构型的包裹本文药物制剂的一片软胶囊。 42. The use of claim 41, wherein said sustained release oral dosage form is a soft capsule closed configuration package pharmaceutical formulation described herein.
  43. 43.根据权利要求41或42的应用,其中所述软胶囊包裹有非对称水活化层作为可扩展层和出口。 43. Application according to claim 41 or claim 42, wherein the soft capsule is wrapped with an asymmetric-activated layer as the expandable aqueous layer and an outlet.
  44. 44.根据权利要求41至43之任一的应用,其中所述软胶囊进一步包含障碍层。 44. The use according to any one of claim 41 to 43, wherein said soft capsule further comprises a barrier layer.
  45. 45.根据权利要求41至44之任一的应用,其中可扩展层由不完全覆盖障碍层包裹的胶囊的离散部分来形成。 45. The use according to any one of claim 41 to 44, wherein the spreading layer may be a discrete portion of the capsule is not completely covered by the barrier layer to form a wrapped.
  46. 46.根据权利要求41的应用,其形式为由盖和主体两部分组成的两片硬胶囊。 46. ​​Application according to claim 41, in the form of hard gelatin capsules by two two-part cover and the body.
  47. 47.根据权利要求46的应用,其中所述胶囊用半透薄片包裹成胶囊。 47. Application according to claim 46, wherein the capsule is wrapped with a semipermeable sheet into capsules.
  48. 48.根据权利要求46或47的应用,其中所述硬胶囊用带有匹配的锁环的每个部分来制造,所述锁环在它们的开放末端附近并能整合并锁住重叠的盖和注入制剂后的主体。 48. The use as claimed in claim 46 or 47, wherein the hard capsule produced by each portion of the locking ring with matching, the locking ring in the vicinity of the open end thereof and to integrate and lock cover and overlapping after the formulation into the body.
  49. 49.根据权利要求41至48之任一的应用,其中所述胶囊进一步包含半透膜。 49. Application according to any one of claim 41-48, wherein the capsule further comprises a semipermeable membrane.
  50. 50.根据权利要求49的应用,其中所述半透膜含流量调节剂。 50. The use according to claim 49, wherein said flow regulating agent containing a semipermeable membrane.
  51. 51.根据权利要求48至50之任一的应用,其中所述半透膜包围并形成小室,所述小室含一或多层,其中之一层是可扩展层。 51. The use according to any one of claim 48 to 50, wherein the semipermeable membrane surrounds and forms a chamber, said chamber comprising one or more layers, of which one layer is a diffusion layer.
  52. 52.根据权利要求51的应用,其中所述可扩展层含渗透剂。 52. Application according to claim 51, wherein said spreading layer containing the osmotic agent.
  53. 53.根据权利要求41至52之任一的应用,其中所述持续释放口服剂型进一步含障碍层。 53. The use according to any one of claim 41-52, wherein said sustained release oral dosage form further containing barrier layer.
  54. 54.根据权利要求53的应用,其中所述障碍层配有增塑剂。 54. The use of claim 53, wherein said barrier layer with a plasticizer.
  55. 55.根据权利要求1至12之任一的应用,其中所述持续释放口服剂型为圆柱状基质的形式,其含有鸦片样物质,其中,基质末端是圆形和凸的形状,并且带状物环绕圆柱状基质,所述带状物由相对不溶于水溶液环境的材料形成。 Any one of 1 to 12 55. The application of a claim, wherein the sustained release oral dosage form of a cylindrical substrate, comprising opioids, wherein the substrate is circular and the end of the convex shape and the belt around the cylindrical matrix, the strip is formed from an aqueous environment are relatively insoluble material.
  56. 56.根据权利要求1至12之任一的应用,其中所述持续释放口服剂型为渗透丸的形式,其含有极上品的有足够渗透活性的晶种或其他物质,其用大包裹厚度分布宽的半透薄膜或不半透于水的薄膜包裹。 Any one of 1 to 12 56. The application of a claim, wherein the sustained release oral dosage form osmotic pellet, containing the nonpareil seeds a sufficient penetration or other active substances, which is wrapped with a large thickness distribution width a semi-permeable film or film wrap is not semi-permeable to water.
  57. 57.根据权利要求56的应用,其中胶囊中存在所述渗透丸。 57. Application according to claim 56, wherein the presence of the osmotic pellet capsules.
  58. 58.根据权利要求1至57之任一的应用,其中所述鸦片样物质选自如下组成的组:盐酸二氢吗啡酮、盐酸氧可酮、硫酸吗啡、盐酸氧吗啡酮和酸式酒石酸二氢可待因酮。 Any one of 1 to 57 58. The application of a claim, wherein said opioid is selected from the group consisting of: dihydro hydromorphone hydrochloride, oxycodone hydrochloride, morphine sulfate, oxymorphone hydrochloride and tartrate disuccinic acid hydrogen codeinone.
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