CN104856967A

CN104856967A - Coated tamper-resistant controlled release dosage form

Info

Publication number: CN104856967A
Application number: CN201510201680.8A
Authority: CN
Inventors: 黄海涌
Original assignee: Purdue Pharma LP
Current assignee: Purdue Pharma LP
Priority date: 2010-12-22
Filing date: 2011-12-21
Publication date: 2015-08-26
Also published as: CN104856966A

Abstract

The present invention relates to coated tamper resistant controlled release dosage forms. In certain embodiments, the present invention relates to a solid controlled release dosage form comprising: a core comprising a first portion of an opioid analgesic dispersed in a first matrix material; and a shell that coats the core and comprises a second portion of the opioid analgesic dispersed in a second matrix material; wherein the amount of opioid analgesic released from the dosage form is proportional to elapsed time within 20% from 8 to 24 hours as measured by in vitro dissolution in a USP apparatus 1 (basket) at 100rpm in 900ml simulated gastric fluid without enzymes (SGF) at 37 ℃.

Description

Coated against tampering Co ntrolled release dosage form

The divisional application that the application's to be the applying date be December in 2011 21 days, application number are " 201180061540.5 ", denomination of invention is the Chinese patent application of " coated against tampering Co ntrolled release dosage form ", original application is the National Phase in China application of International Application Serial No. PCT/IB2011/003152.

Technical field

The present invention relates to the multilayer dosage form of against tampering (tamper-resistant) and the basic Zero order release of wherein comprised activating agent is preferably provided.

Background technology

Medicine is the object of abuse sometimes.Such as, compared with Orally administered same dose, when parenteral is used, the opioid agonist of given dose can be more effective.Some preparations can be tampered to provide wherein comprised opioid agonist, for illegal use.Co ntrolled release opioid agonist agent formulation is crushed by drug abuser sometimes, or with solvent (such as, ethanol) carry out extracting to provide wherein comprised opioid for oral or parenteral is used time discharge immediately.

Co ntrolled release opioid agonist dosage form can when contacting ethanol release portion opioid, if patient ignores operation instructions and use ethanol and described dosage form simultaneously, then patient also can be caused more promptly to obtain dosage than expection.

U.S. Patent Application Publication No.2009/0081290 discloses tamper resistant dosage form, and in certain embodiments, its Peroral solid dosage form relating to the prolongation release matrix preparation comprising tablet or many particle form extends release pharmaceutical dosage form.Tablet or single many granules can at least be crushed and not broken, it is characterized in that described tablet or single granose thickness after being crushed be equivalent to be crushed before described tablet or single many grain thicknesses be no more than about 60%, and wherein, when not containing simulated gastric fluid (the simulated gastric fluid of enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, when measuring SGF), for the percentage amounts of stripping 0.5 little institute constantly release bioactive agent, the dissolution rate in vitro that the described tablet be crushed or the many granules be crushed provide deviation compared with the corresponding reference tablet be not crushed or the granose dissolution rate in vitro of reference is no more than about 20% point.

Have sustainable existence in the art to the needs of against tampering pharmaceutical oral dosage form, wherein said dosage form preferably provides the release profiles of the basic activating agent for zero level.

With regard to all objects, all lists of references quoted herein and publication by reference entirety are incorporated to.

Summary of the invention

An object of certain embodiments of the present invention is to provide the solid Co ntrolled release dosage form (solid controlledrelease dosage form) of the against tampering comprising activating agent (such as, non-opioid analgesic (opioid analgesic)).

An object of certain embodiments of the present invention is to provide the resistant to crushing solid Co ntrolled release dosage form comprising activating agent (such as, non-opioid analgesic).

An object of certain embodiments of the present invention is to provide the solid Co ntrolled release dosage form comprising non-opioid analgesic, and it is less abused by parenteral than other dosage forms.

An object of certain embodiments of the present invention is to provide the solid Co ntrolled release dosage form comprising non-opioid analgesic, and it is less abused by intranasal than other dosage forms.

An object of certain embodiments of the present invention is to provide the solid Co ntrolled release dosage form comprising non-opioid analgesic, its than other dosage forms less by oral abuse.

Another object of certain embodiments of the present invention is to provide the solid Co ntrolled release dosage form comprising non-opioid analgesic, and it is less transferred (diversion) than other dosage forms.

Another object of certain embodiments of the present invention is to provide a kind of method simultaneously reducing the abuse potential of described dosage form in people patient by the solid Co ntrolled release dosage form treatment pain comprising non-opioid analgesic.

Another object of certain embodiments of the present invention comes disease therapy or disease (such as, pain) by using solid Co ntrolled release dosage form disclosed herein to the patient having this to need.

Another object of certain embodiments of the present invention is to provide the method that one prepares the peroral dosage form of activating agent disclosed herein (such as, non-opioid analgesic).

Another object of certain embodiments of the present invention is to provide medicine (such as, the non-opioid analgesic) purposes in the dosage form for the preparation of disease therapy state (such as, pain).

These objects and other objects are completed by the present invention, in certain embodiments, the present invention relates to the solid Co ntrolled release dosage form comprising core (core) and shell (shell), described core comprises and is dispersed in Part I activating agent in the first host material (such as, non-opioid analgesic), activating agent described in the Part II that described shell coated (encase) described core and comprising is dispersed in the second host material; Wherein, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme in external molten (SGF) measured by In Vitro Dissolution, the amount of the activating agent discharged from described dosage form is proportional in 20% with the elapsed time (elapsedtime) at 8 to 24 hours.

At some in other embodiment, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, the amount of the activating agent discharged from described dosage form was (i) 4 to 24 hours, (ii) 8 to 24 hours, (iii) 12 to 24 hours, (iv) 18 to 24 hours, (v) 4 to 8 hours, (vi) 4 to 12 hours, (vii) 4 to 18 hours, (viii) 8 to 12 hours, (ix) 8 to 18 hours or (x) in 12 to 18 hours at least one and elapsed time proportional in 30%.In some alternate embodiment, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, the amount of the activating agent discharged from described dosage form is all proportional in 30% with the elapsed time at (i) 8 to 24 hours, (ii) 8 to 12 hours and (iii) 8 to 18 hours.

At some in other embodiment, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, the amount of the activating agent discharged from described dosage form was (i) 4 to 24 hours, (ii) 8 to 24 hours, (iii) 12 to 24 hours, (iv) 18 to 24 hours, (v) 4 to 8 hours, (vi) 4 to 12 hours, (vii) 4 to 18 hours, (viii) 8 to 12 hours, (ix) 8 to 18 hours or (x) in 12 to 18 hours at least one and elapsed time proportional in 25%.In some alternate embodiment, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, the amount of the activating agent discharged from described dosage form is all proportional in 25% with the elapsed time at (i) 8 to 24 hours, (ii) 8 to 12 hours and (iii) 8 to 18 hours.

At some in other embodiment, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, the amount of the activating agent discharged from described dosage form was (i) 4 to 24 hours, (ii) 8 to 24 hours, (iii) 12 to 24 hours, (iv) 18 to 24 hours, (v) 4 to 8 hours, (vi) 4 to 12 hours, (vii) 4 to 18 hours, (viii) 8 to 12 hours, (ix) 8 to 18 hours or (x) in 12 to 18 hours at least one and elapsed time proportional in 20%.In some alternate embodiment, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, the amount of the activating agent discharged from described dosage form is all proportional in 20% with the elapsed time at (i) 8 to 24 hours, (ii) 8 to 12 hours and (iii) 8 to 18 hours.

At some in other embodiment, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, the amount of the activating agent discharged from described dosage form was (i) 4 to 24 hours, (ii) 8 to 24 hours, (iii) 12 to 24 hours, (iv) 18 to 24 hours, (v) 4 to 8 hours, (vi) 4 to 12 hours, (vii) 4 to 18 hours, (viii) 8 to 12 hours, (ix) 8 to 18 hours or (x) in 12 to 18 hours at least one and elapsed time proportional in 10%.In some alternate embodiment, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, the amount of the activating agent discharged from described dosage form is all proportional in 10% with the elapsed time at (i) 8 to 24 hours, (ii) 8 to 12 hours and (iii) 8 to 18 hours.

At some in other embodiment, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, the amount of the activating agent discharged from described dosage form was (i) 4 to 24 hours, (ii) 8 to 24 hours, (iii) 12 to 24 hours, (iv) 18 to 24 hours, (v) 4 to 8 hours, (vi) 4 to 12 hours, (vii) 4 to 18 hours, (viii) 8 to 12 hours, (ix) 8 to 18 hours or (x) in 12 to 18 hours at least one and elapsed time exist 5% proportionate relationship.In some alternate embodiment, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, the amount of the activating agent discharged from described dosage form is all proportional in 5% with the elapsed time at (i) 8 to 24 hours, (ii) 8 to 12 hours and (iii) 8 to 18 hours.

In certain embodiments, the present invention relates to the solid Co ntrolled release dosage form comprising core and shell, described core comprises to be dispersed in and comprises Part I activating agent in the first host material of poly(ethylene oxide) (such as, non-opioid analgesic), the coated described core of described shell and comprise activating agent described in the Part II that is dispersed in and comprises in the second host material of poly(ethylene oxide).In some alternate embodiment, only described first host material comprise poly(ethylene oxide) or only described second host material comprise poly(ethylene oxide).

In certain embodiments, the present invention relates to the solid Co ntrolled release dosage form comprising compacting core (compressed core) and pressed coated (compression coating), described core comprises to be dispersed in and comprises Part I activating agent in the first host material of poly(ethylene oxide) (such as, non-opioid analgesic), core described in described coatings and comprise activating agent described in the Part II that is dispersed in and comprises in the second host material of poly(ethylene oxide).

In certain embodiments, the present invention relates to the solid Co ntrolled release dosage form comprising core and shell, described core comprises and is dispersed in Part I activating agent in the first host material (such as, non-opioid analgesic), activating agent described in the Part II that the coated described core of described shell and comprising is dispersed in the second host material; Wherein, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, be less than about 25% in the amount of the 2 little activating agents discharged from described dosage form constantly; Be about 10% to about 30% in the amount of the 4 little activating agents discharged from described dosage form constantly; Be about 20% to about 60% in the amount of the 8 little activating agents discharged from described dosage form constantly; Be about 40% to about 90% in the amount of the 12 little activating agents discharged from described dosage form constantly; And be greater than about 70% in the amount of the 18 little activating agents discharged from described dosage form constantly.

In certain embodiments, the present invention relates to the solid Co ntrolled release dosage form comprising core and shell, described core comprises and is dispersed in Part I activating agent in the first host material (such as, non-opioid analgesic), activating agent described in the Part II that the coated described core of described shell and comprising is dispersed in the second host material; Wherein, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, be less than about 20% in the amount of the 2 little activating agents discharged from described dosage form constantly; Be about 10% to about 30% in the amount of the 4 little activating agents discharged from described dosage form constantly; Be about 30% to about 60% in the amount of the 8 little activating agents discharged from described dosage form constantly; Be about 50% to about 90% in the amount of the 12 little activating agents discharged from described dosage form constantly; And be greater than about 80% in the amount of the 18 little activating agents discharged from described dosage form constantly.

In certain embodiments, the present invention relates to the solid Co ntrolled release dosage form comprising core and shell, described core comprises and is dispersed in Part I activating agent in the first host material (such as, non-opioid analgesic), activating agent described in the Part II that the coated described core of described shell and comprising is dispersed in the second host material; Wherein, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, be less than about 15% in the amount of the 2 little activating agents discharged from described dosage form constantly; Be about 8% to about 20% in the amount of the 4 little activating agents discharged from described dosage form constantly; Be about 20% to about 50% in the amount of the 8 little activating agents discharged from described dosage form constantly; Be about 40% to about 70% in the amount of the 12 little activating agents discharged from described dosage form constantly; About 70% is greater than in the amount of the 18 little activating agents discharged from described dosage form constantly; And be greater than about 90% in the amount of the 24 little activating agents discharged from described dosage form constantly.In certain embodiments, the present invention relates to and comprise the treatment hydrocodone of effective dose or the solid Co ntrolled release dosage form of its officinal salt and Co ntrolled release excipient; Wherein, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, the amount of the non-opioid analgesic discharged from described dosage form is proportional in 20% with the elapsed time at 8 to 24 hours; And described dosage form is collapsible and not broken, after being wherein crushed the thickness of described dosage form be equivalent to be crushed before described dosage form thickness be no more than about 20%; As by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, be littlely no more than about 20% point from the be crushed hydrocodone of dosage form release or amount deviation compared with the dosage form that is not crushed of its salt constantly 0.5.

In some embodiments, the present invention relates to and comprise the treatment hydrocodone of effective dose or the solid Co ntrolled release dosage form of its officinal salt and Co ntrolled release excipient; Wherein, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, be less than about 25% in the amount of the 2 little hydrocodones that discharge from described dosage form constantly or its salt; Be about 10% to about 30% in the amount of the 4 little hydrocodones that discharge from described dosage form constantly or its salt; Be about 20% to about 60% in the amount of the 8 little hydrocodones that discharge from described dosage form constantly or its salt; Be about 40% to about 90% in the amount of the 12 little hydrocodones that discharge from described dosage form constantly or its salt; And be greater than about 70% in the amount of the 18 little hydrocodones that discharge from described dosage form constantly or its salt; And described dosage form is collapsible and not broken, after being wherein crushed the thickness of described dosage form be equivalent to be crushed before described dosage form thickness be no more than about 20%; And as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, be littlely no more than about 20% point from the be crushed hydrocodone of dosage form release or amount deviation compared with the dosage form that is not crushed of its salt constantly 0.5.

In certain embodiments, the present invention relates to and comprise the hydrocodone of the treatment effective dose be dispersed in Co ntrolled release excipient or the solid Co ntrolled release dosage form of its officinal salt; The inside 60% of wherein said dosage form comprises hydrocodone or its salt of at least 80%; Wherein, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, the hydrocodone discharged from described dosage form or the amount of its salt proportional in 20% with the elapsed time at 8 to 24 hours.

In certain embodiments, the present invention relates to the method preparing solid Co ntrolled release dosage form, it comprises: preparation core, and it comprises the Part I activating agent (such as, non-opioid analgesic) be dispersed in the first host material; And by described core coating in shell, described shell comprises activating agent described in the Part II that is dispersed in the second host material; Wherein, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, the amount of the activating agent discharged from described dosage form is proportional in 20% with the elapsed time at 8 to 24 hours.

In certain embodiments, the present invention relates to the method preparing solid Co ntrolled release dosage form, it comprises: preparation core, and it comprises the Part I activating agent (such as, non-opioid analgesic) being dispersed in and comprising in the first host material of poly(ethylene oxide); And by described core coating in shell, described shell comprises activating agent described in the Part II that is dispersed in and comprises in the second host material of poly(ethylene oxide).In some alternate embodiment, prepare corresponding dosage form, make only described first host material comprise poly(ethylene oxide) or only described second host material comprise poly(ethylene oxide).

In certain embodiments, the present invention relates to the method preparing solid Co ntrolled release dosage form, it comprises: preparation compacting core, and it comprises the Part I activating agent (such as, non-opioid analgesic) being dispersed in and comprising in the first host material of poly(ethylene oxide); And by carrying out coated described core to comprise activating agent pressed coated described in the Part II that is dispersed in and comprises in the second host material of poly(ethylene oxide) on the core.In some alternate embodiment, prepare corresponding pressed coated dosage form, make only described first host material comprise poly(ethylene oxide) or only described second host material comprise poly(ethylene oxide).

In certain embodiments, the present invention relates to the method preparing solid Co ntrolled release dosage form, comprising: preparation core, it comprises the Part I activating agent (such as, non-opioid analgesic) be dispersed in the first host material; And by described core coating in shell, described shell comprises activating agent described in the Part II of dispersion on the core in the second host material; Wherein, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, be less than about 25% in the amount of the 2 little activating agents discharged from described dosage form constantly; Be about 10% to about 30% in the amount of the 4 little activating agents discharged from described dosage form constantly; Be about 20% to about 60% in the amount of the 8 little activating agents discharged from described dosage form constantly; Be about 40% to about 90% in the amount of the 12 little activating agents discharged from described dosage form constantly; And be greater than about 70% in the amount of the 18 little activating agents discharged from described dosage form constantly.

In certain embodiments, the present invention relates to the method preparing solid Co ntrolled release dosage form, it comprise by the treatment hydrocodone of effective dose or its officinal salt and Co ntrolled release excipient combined; Wherein, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, be less than about 25% in the amount of the 2 little hydrocodones that discharge from described dosage form constantly or its salt; Be about 10% to about 30% in the amount of the 4 little hydrocodones that discharge from described dosage form constantly or its salt; Be about 20% to about 60% in the amount of the 8 little hydrocodones that discharge from described dosage form constantly or its salt; Be about 40% to about 90% in the amount of the 12 little hydrocodones that discharge from described dosage form constantly or its salt; And be greater than about 70% in the amount of the 18 little hydrocodones that discharge from described dosage form constantly or its salt; And described dosage form is collapsible and not broken, after being wherein crushed the thickness of described dosage form be equivalent to be crushed before described dosage form thickness be no more than about 20%; And, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, be littlely no more than about 20% point from the be crushed hydrocodone of dosage form release or amount deviation compared with the dosage form that is not crushed of its salt constantly 0.5.

In some embodiments, the present invention relates to the method preparing solid Co ntrolled release dosage form, it comprise by the treatment hydrocodone of effective dose or its officinal salt and Co ntrolled release excipient combined; Wherein, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, the hydrocodone discharged from described dosage form or the amount of its salt 8 to 24 hours any two time points and the elapsed time proportional in 20%; And described dosage form is collapsible and not broken, after being wherein crushed the thickness of described dosage form be equivalent to be crushed before described dosage form thickness be no more than about 20%; And, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, be littlely no more than about 20% point from the be crushed hydrocodone of dosage form release or amount deviation compared with the dosage form that is not crushed of its salt constantly 0.5.

In certain embodiments, the present invention relates to the method preparing solid Co ntrolled release dosage form, it comprises and is distributed in Co ntrolled release excipient by the treatment hydrocodone of effective dose or its officinal salt; The inside 60% of wherein said dosage form comprises described hydrocodone or its salt of at least 80%; Wherein, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, the hydrocodone discharged from described dosage form or the amount of its salt proportional in 20% with the elapsed time at 8 to 24 hours.

In certain embodiments, the present invention relates to the method for the treatment of pain in patient or object, it comprises the solid Co ntrolled release dosage form used and comprise non-opioid analgesic disclosed herein.

In some preferred embodiments, the present invention relates to the dosage form of the present invention showing basic zero order release rate after using to patient or object.

Term " zero order release rate " refers to the speed discharged from the activating agent of dosage form, and it does not rely on the residual activity agent concentration in described dosage form, makes described speed relative constancy in a period of time.The dosage form representing zero order release rate shows relatively straight line in the diagram of release bioactive agent percentage comparison time.In certain embodiments of the invention, basic Zero order release is defined as such dosage form, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, the amount of institute's release bioactive agent that described dosage form has 8 to 24 hours or 4 to 12 hours proportional in 20% with the elapsed time.Such as, externally littlely the definition proportional in 20% with the elapsed time in 8 to 24 hours is met from the amount of dosage form release 20% with the 24 little amounts discharging 60 (± 12) % are constantly literal constantly 8.This by the latter's elapsed time (24 hours) and the latter release (60%) be the former time (8 hours) with the former discharge (20%) identical multiple (3) and prove.In order to meet in the definition proportional in 20% of 8 to 24 hours (or any other time period) and elapsed time, only need the end points considering numerical value, but this definition other times point do not got rid of in end points also can be proportional.

In other embodiments of the present invention, basic Zero order release is defined as such dosage form, wherein, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, in the amount of the 2 little activating agents discharged constantly for being less than about 25%; Be about 10% to about 30% in the amount of the 4 little activating agents discharged from described dosage form constantly; Be about 20% to about 60% in the amount of the 8 little activating agents discharged from described dosage form constantly; Be about 40% to about 90% in the amount of the 12 little activating agents discharged from described dosage form constantly; And in the amount of the 18 little activating agents discharged from described dosage form constantly for being greater than about 70%.

For object of the present invention, it is at least 25 that term " poly(ethylene oxide) " is defined as molecular weight, 000 (as general measure in this area) (and preferred molecular weight is at least 100,000) compositions of poly(ethylene oxide) (polyethylene oxide, PEO).Generally the compositions with lower molecular weight is called Polyethylene Glycol.

For object of the present invention, based on rheology measurement, it is at least 1,000 that term " high molecular weight polyethylene oxide (PEO) " is defined as approximate molecular weight, 000.

For object of the present invention, based on rheology measurement, term " low-molecular-weight poly(ethylene oxide) (PEO) " being defined as approximate molecular weight is lower than 1,000,000.

For object of the present invention, term " direct pressing " is defined as and refers to such method, wherein by comprising composition is blended and the method (such as by utilizing the blended and/or convection current mixing method of diffusion) of the step of blend compacting formation dosage form being prepared dosage form (such as Guidance for Industry, SUPAC-IR/MR:Immediate Release and Modified Release Solid OralDosage Forms, Manufacturing Equipment Addendum).

The described dosage form that means the term " flattening " used in the context of flattening dosage form according to the present invention or relational language to stand when shape is except spherical from the basic direction consistent with the minimum diameter (that is, thickness) of described dosage form and the power in any direction applied when described dosage form shape is spherical.

For the object of certain embodiments of the invention, term " resistance to crusing " is defined as such dosage form, it can at least be crushed with bench press described herein (bench press) and not broken.

For object of the present invention, term " non-opioid analgesic " means to be selected from following one or more of compounds: basic opioid agonist (base opioid agonist), mixing opioid agonist-antagonist, partial opioid agonists, its officinal salt, complex, stereoisomer, ether, ester, hydrate and solvate, and composition thereof.

Term used herein " simulated gastric fluid " or " SGF " refer in stripping test for imitating the aqueous solution (such as, the solution of 0.1N HCl) of the condition of stomach.

The difference of the release % after the term " percentage point " the context such as " being no more than about 20% point in amount deviation compared with the dosage form that is not crushed of the 0.5 little activating agent discharged from the dosage form that is crushed constantly " means the release % before flattening and flattens is no more than 20 (that is, 20 or less).Such as, about 20% point of 40% release be no more than from the dosage form that is not crushed is discharged from 60% of the dosage form that is crushed.

The term " percent " irrelevant with " percentage rate (or %) point " or use " % " to be the percentage ratio of ordinary meaning.Such as, 48% is released in 20% of 60% release, and 40% may not in 20% of 60% release on literal.

Term " patient " means such object (being preferably people), it has presented the clinical manifestation that suggestion needs the specific symptoms for the treatment of, to described object prophylactically or pre-defense sector treatment disease, or described object be diagnosed as and suffer from disease to be treated.

Term " object " comprises the definition of term " patient " and comprises term " health objects " (that is, individual (such as, people)), described health objects in all respects in or be completely normal for particular condition.

Term used herein " stereoisomer " locates the common name of all isomers of different individual molecules to only atomic space.It comprises enantiomer and the isomer (diastereomer) not becoming the compound of mirror image each other with more than one chiral centre.

Term " chiral centre " refers to the carbon atom that group different from four is connected.

Term " enantiomer " or " enantiomer " refer to that its mirror image can not be overlapping and therefore have optically active molecule, and wherein enantiomer makes polarized light flat deflect to a direction, and its mirror image then makes polarized light flat deflect in the opposite direction.

Term " raceme " refers to the mixture of enantiomer.

Term " fractionation " refers to the separation of in two enantiomeric forms of molecule or concentrated or consume.

For object of the present invention, " hydrocodone " is defined as and comprises hydrocodone free alkali, and its officinal salt, complex, stereoisomer, ether, ester, hydrate and solvate, and composition thereof.

Term " USP paddle method or basket method " is the paddle method and basket method that such as describe in U.S.Pharmacopoeia XII (1990).

For object of the present invention, term " pH dependency " is defined as there is environmentally pH and the feature (such as, stripping) changed.

For object of the present invention, term " pH independence " is defined as and has substantially not by the feature (such as, stripping) that pH affects.

For object of the present invention, term " bioavailability " is defined as the degree of correlation of to absorb the drug from unit dosage forms (such as, hydrocodone).Also bioavailability is called AUC (that is, area under plasma concentration/time graph).

For object of the present invention, term " Co ntrolled release ", " extend release " or " sustained release " is interchangeable and be defined as with such speed release medicine (such as, hydrocodone): in a period of time at least about 12 hours or longer or at least 24 hours or longer, make blood (such as, blood plasma) concentration maintain in therapeutic domain still lower than toxic concentration.Preferably, Co ntrolled release dosage form can provide once a day or administration twice daily.

Term " C _max" represent the maximal plasma concentration obtained during dosing interval.

Term " C used herein ₂₄" be the plasma concentration of 24 little medicines constantly after application.

Term " T _max" represent reach maximal plasma concentration (C _max) time.

For object of the present invention, by term " C ₂₄/ C _maxratio " plasma concentration being defined as 24 little medicines constantly after application and the ratio of medicine maximum plasma concentration reached in dosing interval.

Term " T _lag" time point of expression before next-door neighbour first measurable plasma concentration.

Term " T _1/2" represent the plasma half-life of eventually last phase.This be for whole end mutually in any concentration reduce the time that half spends.For the concentration of opioid (such as hydrocodone), term " MEAC (minimum effective analgesic concentration) " or " MEAC " are very difficult to quantitatively.But, usually there is the MEAC of blood plasma hydrocodone, then do not provide analgesia lower than this concentration.But, such as have indirect relation between blood plasma hydrocodone level and analgesia, and the higher blood plasma level with extending is usually relevant to outstanding pain relief.Delay (or delayed) is had between the time of peak blood plasma hydrocodone level and peak pharmaceutically-active time.Usually, this is applicable to adopt non-opioid analgesic treatment pain.

For object of the present invention, unless otherwise indicating in detail, otherwise term " patient " or " object " mean the pharmacokinetic parameter that discussion (or claim) relates to individual patient or object.

Term " PATIENT POPULATION " or " subject population " or " health objects colony " mean that (or claim) is discussed and relate at least two patients, object or health objects, at least six patients, object or health objects, or at least ten two patients, object or health objects mean pharmacokinetic parameter.

For object of the present invention, Co ntrolled release preparation disclosed herein is preferably with dose proportional.With the preparation of dose proportional, pharmacokinetic parameter (such as, AUC and C _max) and/or release in vitro be increased to another linearly from a dose intensity.Therefore, pharmacokinetic parameter and the extracorporeal parameter of given dose can be inferred from the parameter of the various dose of same preparation.

Term " is used first " and is meant starting the single dose of the present invention when treating to individual subject, patient or health objects or subject population, PATIENT POPULATION or health objects colony.

The amount that term " stable state " means medicine arrival system is roughly the same with the amount that medicine leaves system.Therefore, when " stable state ", the body of patient with medicine by absorb in blood flow become to the system of patient can approximate phase same rate eliminate medicine.

Accompanying drawing explanation

Fig. 1 is the figure of the stripping of the compositions describing embodiment 1 ~ 4.

Fig. 2 is the figure of the stripping of the compositions describing embodiment 5 and 6.

Fig. 3 is the figure of the stripping of the compositions describing embodiment 7 ~ 12.

Fig. 4 is the figure of the Mean plasma concentration time curve describing embodiment 13 iteration (Iteration) 1.

Fig. 5 is the figure of the Mean plasma concentration time curve describing embodiment 13 iteration 2.

Fig. 6 is the figure of the Mean plasma concentration time curve describing embodiment 13 iteration 3.

Fig. 7 is the figure of the plasma concentration of the compositions describing embodiment 14 ~ 20.

Detailed description of the invention

The present invention relates to controlled release drug preparation, in certain embodiments, compared with perimeter, described preparation comprises the medicine of higher concentration at the interior zone of dosage form.Preferably, interior zone and perimeter are configured to the shell (such as, pressed coated) of internal core (such as, compressed tablet) and coated described core.Activating agent only can comprise in the core or is all included in both core and shell.In some preferred embodiments, activating agent is zero level from the release of dosage form substantially, and this and some replacement therapies (such as, immediate release dosage form) are compared the blood plasma providing administration definitiveness and reduction and fluctuated.

Dosage form of the present invention is preferably against tampering, because they are difficult to crush or grinding (such as, according to flattening standard disclosed herein).This feature makes them be especially suitable for Co ntrolled release non-opioid analgesic product, and it has the heavy dose of non-opioid analgesic being intended to discharge from each dosage unit through a period of time.Drug abuser can obtain Co ntrolled release product usually, and described product crushed, shear, grind, chew, stripping, heating, extraction or otherwise damage, make the major part of dosage form or all inclusions become and can be used for by injection, suck and/or oral consumption and absorbing immediately.

The shell of dosage form of the present invention is preferably difficult to separate reasoningly with core material.Misuser is particularly useful in the embodiment of activating agent in the core compared with shell with increasing amount, because will be difficult to the larger medicine useful load obtaining core.

In certain embodiments, the present invention relates to solid Co ntrolled release dosage form, it comprises: core, and described core comprises the Part I non-opioid analgesic be dispersed in the first host material; And shell, the coated core of described shell and comprise the Part II non-opioid analgesic be dispersed in the second host material.

Can such as by direct pressing, to extrude or molded (molding) forms the core of dosage form.Preferably, internal core provides Co ntrolled release excipient and is the form of compressed tablets.

Can such as by pressed coated, molded, one or more layer be sprayed on be immersed in core in core, by one or more layer or its combination forms the shell of dosage form.Preferably, shell comprises Co ntrolled release excipient and is pressed coated.

In some preferred embodiments, the core of dosage form described herein and the weight ratio of shell are about 1: 0.5 to about 1: 5; About 1: 0.5 to about 1: 2; About 1: 0.6 to about 1: 1.5; Or about 1: 0.8 to about 1: 1.2.

In some preferred embodiments, core and shell visually undistinguishable (such as, passing through color) and not clearly boundary between often kind of component.This contributes to the against tampering of dosage form by hindering the effort of acquisition core, in certain embodiments, described core will comprise most of activating agent.In order to evaluate the color of shell and core, it is CIE L*A*B* value that spendable one is measured.Preferably, the CIE L*A*B* value of core and shell is within 10% each other.Another kind measurement for evaluate color uses RYB or RGB colour wheel (color wheel), and wherein core and shell preferably correspond to same tone or close on tone.

In certain embodiments, the first host material comprises PEO.In other embodiments, the second host material comprises PEO.In other embodiments, the first host material comprises PEO and the second host material comprises PEO.Preferably, poly(ethylene oxide) is all included in two kinds of components.In some such embodiments, the mean molecule quantity in the first host material in the molecular weight of PEO and the second host material is identical or different.In certain embodiments, the molecular weight of the PEO all comprised in two kinds of components is in 20% each other, in 10% or in 5%.

In preferred embodiments more of the present invention, when all there is poly(ethylene oxide) in both the first and second substrate, the molecular weight of the poly(ethylene oxide) that (in the core) molecular weight of poly(ethylene oxide) of using uses lower than in the second host material (in shell) in the first substrate.Such as, in some preferred embodiments, the poly(ethylene oxide) in the first host material can have about 300, and 000 to about 10, the molecular weight of 000, the 000 and poly(ethylene oxide) in the second host material can have about 1,000, the molecular weight of 000 to about 10,000,000.In other preferred embodiments, the poly(ethylene oxide) in the first host material can have about 300, the molecular weight of 000 to about 3,000, the 000 and poly(ethylene oxide) in the second host material can have about 4,000, the molecular weight of 000 to about 10,000,000.In other preferred embodiments, the poly(ethylene oxide) in the first host material can have about 500, the molecular weight of 000 to about 1,000, the 000 and poly(ethylene oxide) in the second host material can have about 6,000, the molecular weight of 000 to about 8,000,000.

In certain embodiments, in Part I, the activating agent (such as, non-opioid analgesic) of (in core) is identical with the activating agent of (in shell) in Part II.In other embodiments, the activating agent in Part I is different from the activating agent in Part II.

In certain embodiments, activating agent (such as, non-opioid analgesic) is about 1: 1 to about 10: 1 with the ratio of activating agent in shell in the core; About 2: 1 to about 8: 1; About 2: 1 to about 5: 1 or about 4: 1.

In certain embodiments, in the first host material, Part I activating agent (such as, non-opioid analgesic) is about 1: 0.25 to about 1: 30 with the weight ratio of poly(ethylene oxide); About 1: 0.5 to about 1: 100; About 1: 0.5 to about 1: 20; About 1: 1 to about 1: 10; About 1: 15 to about 1: 20; About 1: 1.5 to about 1: 4; About 1: 18 or about 1: 2.

In some alternate embodiment, in the second host material, Part II activating agent (such as, non-opioid analgesic) is about 1: 1 to about 1: 200 with the weight ratio of poly(ethylene oxide); About 1: 1 to about 1: 125; About 1: 2 to about 1: 100; About 1: 5 to about 1: 50; About 1: 12 to about 1: 25; About 1: 98 or about 1: 15.

In certain embodiments, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, from the amount of the activating agent (such as, non-opioid analgesic) of dosage form release at 8 to 24 hours with the elapsed time in 20% or in 10% or proportional in 5%.

In certain embodiments, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, from the amount of the activating agent (such as, non-opioid analgesic) of dosage form release at 8 to 18 hours with the elapsed time in 20% or in 10% or proportional in 5%.

In certain embodiments, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, from the amount of the activating agent (such as, non-opioid analgesic) of dosage form release at 8 to 12 hours with the elapsed time in 20% or in 10% or proportional in 5%.

In certain embodiments, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, from the amount of the activating agent (such as, non-opioid analgesic) of dosage form release at 12 to 24 hours with the elapsed time in 20% or in 10% or proportional in 5%.

In certain embodiments, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, from the amount of the activating agent (such as, non-opioid analgesic) of dosage form release at 12 to 18 hours with the elapsed time in 20% or in 10% or proportional in 5%.

In certain embodiments, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, from the amount of the activating agent (such as, non-opioid analgesic) of dosage form release at 4 to 20 hours with the elapsed time in 20% or in 10% or proportional in 5%.

In certain embodiments, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, from the amount of the activating agent (such as, non-opioid analgesic) of dosage form release at 4 to 15 hours with the elapsed time in 20% or in 10% or proportional in 5%.

In certain embodiments, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, from the amount of the activating agent (such as, non-opioid analgesic) of dosage form release at 4 to 10 hours with the elapsed time in 20% or in 10% or proportional in 5%.

In certain embodiments, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, from the amount of the activating agent (such as, non-opioid analgesic) of dosage form release at 8 to 20 hours with the elapsed time in 20% or in 10% or proportional in 5%.

In certain embodiments, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, from the amount of the activating agent (such as, non-opioid analgesic) of dosage form release at 10 to 15 hours with the elapsed time in 20% or in 10% or proportional in 5%.

In certain embodiments, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, about 25% is less than in the amount of the 2 little activating agents (such as, non-opioid analgesic) discharged constantly; 4 little constantly from the amount of activating agent of dosage form release be about 10% to about 30%; 8 little constantly from the amount of activating agent of dosage form release be about 20% to about 60%; 12 little constantly from the amount of activating agent of dosage form release be about 40% to about 90%; And be littlely greater than about 70% from the amount of activating agent of dosage form release constantly 18.

In certain embodiments, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, about 15% is less than in the amount of the 2 little activating agents (such as, non-opioid analgesic) discharged constantly; 4 little constantly from the amount of activating agent of dosage form release be about 10% to about 20%; 8 little constantly from the amount of activating agent of dosage form release be about 30% to about 45%; 12 little constantly from the amount of activating agent of dosage form release be about 50% to about 70%; And be littlely greater than about 90% from the amount of activating agent of dosage form release constantly 18.

In certain embodiments, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, about 10% is less than in the amount of the 2 little activating agents (such as, non-opioid analgesic) discharged constantly; 4 little constantly from the amount of activating agent of dosage form release be about 20% to about 30%; 8 little constantly from the amount of activating agent of dosage form release be about 45% to about 60%; 12 little constantly from the amount of activating agent of dosage form release be about 70% to about 90%; And be littlely greater than about 95% from the amount of activating agent of dosage form release constantly 18.

In certain embodiments, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, from dosage form release activating agent (such as, non-opioid analgesic) amount 8 to 24 hours with the elapsed time proportional in 20%, and show following at least one: (i) is less than about 20% in the amount of 2 little discharged non-opioid analgesic constantly, (ii) be about 10% to about 30% in the amount of 4 little discharged non-opioid analgesic constantly, (iii) be about 30% to about 60% in the amount of 8 little discharged non-opioid analgesic constantly, (iv) be about 50% to about 90% in the amount of 12 little discharged non-opioid analgesic constantly, or (v) is greater than about 80% in the amount of 18 little discharged non-opioid analgesic constantly.

In certain embodiments, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, from dosage form release activating agent (such as, non-opioid analgesic) amount 8 to 24 hours with the elapsed time proportional in 20%, and show following at least one: (i) is less than about 15% in the amount of 2 little discharged non-opioid analgesic constantly, (ii) be about 10% to about 20% in the amount of 4 little discharged non-opioid analgesic constantly, (iii) be about 30% to about 45% in the amount of 8 little discharged non-opioid analgesic constantly, (iv) be about 50% to about 70% in the amount of 12 little discharged non-opioid analgesic constantly, or (v) is greater than about 90% in the amount of 18 little discharged non-opioid analgesic constantly.

In certain embodiments, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, from dosage form release activating agent (such as, non-opioid analgesic) amount 8 to 24 hours with the elapsed time proportional in 20%, and show following at least one: (i) is less than about 10% in the amount of 2 little discharged non-opioid analgesic constantly, (ii) be about 20% to about 30% in the amount of 4 little discharged non-opioid analgesic constantly, (iii) be about 45% to about 60% in the amount of 8 little discharged non-opioid analgesic constantly, (iv) be about 70% to about 90% in the amount of 12 little discharged non-opioid analgesic constantly, or (v) is greater than about 95% in the amount of 18 little discharged non-opioid analgesic constantly.

In certain embodiments, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, from dosage form release activating agent (such as, non-opioid analgesic) amount 8 to 24 hours with the elapsed time proportional in 20%, and show following at least one: (i) is less than about 15% in the amount of 2 little discharged non-opioid analgesic constantly, (ii) be about 8% to about 20% in the amount of 4 little discharged non-opioid analgesic constantly, (iii) be about 20% to about 50% in the amount of 8 little discharged non-opioid analgesic constantly, (iv) be about 40% to about 70% in the amount of 12 little discharged non-opioid analgesic constantly, v () is greater than about 70% in the amount of 18 little discharged non-opioid analgesic constantly, or (vi) is littlely greater than about 90% from the amount of non-opioid analgesic of dosage form release constantly 24.

Dosage form

In certain embodiments, prepare core by following, by controlled release material, activating agent and optionally other excipient do blended, then by granulating mixture until obtain suitable granule.This process is carried out by dry granulation or wet granulation method.Usual employing wet granulation, wet granular is dry in fluidized bed dryer, then sieve and grind to form suitable size.Usually lubricant is mixed with granule to obtain final core formulation.

The non-limiting list that can be used for being contained in the suitable controlled release material selected according to preparation of the present invention comprises hydrophilic and hydrophobic material, the material of such as release polymer, natural gum, acrylic resin, protein source, wax, Lac and oil (such as castor oil hydrogenated and hydrogenated vegetable oil).More specifically, controlled release material can be that such as alkylcellulose is as ethyl cellulose, acrylic acid and methacrylate polymer and copolymer, and cellulose ether is as hydroxy alkyl cellulose (such as, hydroxypropyl emthylcellulose) and carboxyl alkyl cellulose.Wax comprises such as natural and synthetic wax, fatty acid, fatty alcohol and composition thereof (such as, Cera Flava, Brazil wax, stearic acid and stearyl alcohol).Some embodiment uses the mixture of two or more aforementioned controlled release materials in the substrate of core.But, used according to the inventionly can give any pharmaceutically acceptable hydrophobicity or the hydrophilic controlled release material of the Co ntrolled release of activating agent.

Core also can comprise the other excipient of appropriate amount, and such as, lubricating oil, adhesive, granulating aid, diluent, coloring agent, flavoring agent (such as, bitters) and fluidizer, it is all conventional in pharmaceutical field.

At Handbook of Pharmaceutical Excipients, describe in AmericanPharmaceutical Association (1986) and can be used for the preparation pharmaceutically acceptable diluent of core and the instantiation of excipient, it is incorporated herein by reference.

In some preferred embodiments, the substrate of dosage form of the present invention incorporates poly(ethylene oxide) (such as, high and/or low-molecular-weight PEO).

When the PEO using Brookfield viscometer (Brookfield viscometer) RVF type and rotor (spindle) No.1 to measure at 25 DEG C with 10rpm 2% (by weight), aqueous solution illustrated the viscosity scope of 400 to 800mPa-s (cP) time, think that poly(ethylene oxide) has 1, the approximate molecular weight of 000,000.

When the PEO using Brookfield viscometer RVF type and rotor No.3 to measure at 25 DEG C with 10rpm 2% (by weight), aqueous solution illustrated the viscosity scope of 2000 to 4000mPa-s (cP) time, think that poly(ethylene oxide) has 2, the approximate molecular weight of 000,000.

When the poly(ethylene oxide) using Brookfield viscometer RVF type and rotor No.2 to measure at 25 DEG C with 2rpm 1% (by weight), aqueous solution illustrated the viscosity scope of 1650 to 5500mPa-s (cP) time, think that poly(ethylene oxide) has 4, the approximate molecular weight of 000,000.

When the poly(ethylene oxide) using Brookfield viscometer RVF type and rotor No.2 to measure at 25 DEG C with 2rpm 1% (by weight), aqueous solution illustrated the viscosity scope of 5500 to 7500mPa-s (cP) time, think that poly(ethylene oxide) has 5, the approximate molecular weight of 000,000.

When 1% (by weight) aqueous solution of the poly(ethylene oxide) using Brookfield viscometer RVF type and rotor No.2 to measure at 25 DEG C with 2rpm illustrates 7500 to 10, during the viscosity scope of 000mPa-s (cP), think that poly(ethylene oxide) has 7,000, the approximate molecular weight of 000.

When 1% (by weight) aqueous solution of the poly(ethylene oxide) using Brookfield viscometer RVF type and rotor No.2 to measure at 25 DEG C with 2rpm illustrates 10,000 to 15, during the viscosity scope of 000mPa-s (cP), think that poly(ethylene oxide) has 8, the approximate molecular weight of 000,000.

About lower molecular weight poly(ethylene oxide), when the poly(ethylene oxide) measured at using Brookfield viscometer RVT type and rotor No.1 with 50rpm and 25 DEG C 5% (by weight), aqueous solution illustrated the viscosity scope of 30 to 50mPa-s (cP) time, think that poly(ethylene oxide) has 100, the approximate molecular weight of 000.

When 5% (by weight) aqueous solution of the poly(ethylene oxide) using Brookfield viscometer RVF type and rotor No.2 to measure at 25 DEG C with 2rpm illustrates 8800 to 17, during the viscosity scope of 600mPa-s (cP), think that poly(ethylene oxide) has 900, the approximate molecular weight of 000.

Pressed coated dosage form

In some embodiments utilizing pressed coated, preferably, in coating, all or part of of pharmaceutically acceptable excipient should give enough compressibilityes to provide pharmaceutically acceptable product.Pressed coated in pre-formed core depends in part on selected excipient and agents as the single feature in polymer solubility, mobility, glass transition temperature etc.

Such as can prepare pressed coated dosage form by utilizing the core of preproduction or prepare core (such as, by compacting) before coating.Internal core is prepared: activating agent is carried out wet granulation or dry granulation together with pharmaceutically acceptable figuration by following; Then dry and grind if desired to obtain granule; Add optional extra particulate excipient and/or activating agent and suitably blended; Lubricant is added when needing; And adopt tablet machine compressed granulate.Before pressed coated, optionally with functional coatings or film coating, coating is carried out to gained compacting core.

By utilize above-disclosed any controlled release material with for the blend of the similar method of the blend of core for the preparation of pressed coated.Preferably, pressed coated comprises poly(ethylene oxide).By suppressing blend coating in core.The compacting of core and/or coating can utilize Killion or Fette rotary press to carry out with the press power of such as about 1 to about 20,000 newton.

In certain embodiments, Manesty Dry-Cota press (such as, 900 types) can be utilized.This device is made up of two interconnective press side by side, wherein obtains core with a press, is mechanically transferred to next press afterwards for pressed coated.Every platform press has independently powder feed mechanism, makes to load core blend with a machine, and another machine loads coating blend.Mechanical transfer arm rotates core removed from core press and they are transferred to coating press between machine.Other press that can be used for preparing dosage form of the present invention comprise Elizabeth HataHT-AP44-MSU-C, Killian RLUD and Fette PT 4090, and it has the twin refuelling system for coating blend and preformed core separately.These press are utilized to make the sheet by reclaiming pressed coated realize multiple pressed coated layer.All these press all have such mechanism, tablet vertically and are radially placed in the center in coating blend.

In certain embodiments, a little going up around the institute of internal core with same thickness applying pressed coated, but applying with the different-thickness around internal core.The thinner region of coating will produce the region that from internal core discharge the compacting dosage form of medicine more Zao than other regions.This can such as realize by the core applying pressed coated not being placed in press center when coating simply.

In certain embodiments, hydrophobicity or enteric-soluble coating material also can be adopted to carry out outer coatings (overcoat) to pressed coated dosage form.In other embodiments, the hydrophilic coating of except hydrophobicity or enteric coatings or alternative hydrophobicity or enteric coatings can be adopted to carry out coating to pressed coated dosage form.

In other embodiments, optional coating (such as, hydrophobicity, hydrophilic or enteric solubility) alternatively or extraly can be applied for the intermediate layer between core and pressed coated.

Activating agent

Alfentanil is included, but not limited to for non-opioid analgesic of the present invention, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, Clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphine (diamorphone), dihydrocodeine, paramorphan (dihydromorphine), dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivant, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, Pethidine, meptazinol, metazocine, methadone, metopon, morphine, Myrophine, narceine (narceine), nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphine (nalbuphene), normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum (papaveretum), pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, pirinitramide, proheptazine (propheptazine), Promedol (promedol), properidine, third oxygen is fragrant, sufentanil, tilidate, tramadol, its officinal salt, complex (such as, with cyclodextrin), stereoisomer, ether, ester, hydrate, solvate, and mixture.

Preferably, non-opioid analgesic is selected from codeine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, tramadol, its officinal salt, complex, stereoisomer, ether, ester, hydrate, solvate and mixture.

In certain embodiments, non-opioid analgesic is selected from hydrocodone, its officinal salt, complex, stereoisomer, ether, ester, hydrate, solvate and mixture.Preferably, non-opioid analgesic is Hycodan (hydrocodone bitartrate).

Opioid used according to the invention can comprise one or much more individual asymmetric center, and can produce enantiomer, diastereomer or other stereoisomer forms.The present invention mean to contain all this may form and raceme thereof and fractionation form and its compositions.When compound described herein comprises alkene double bond or other geometric asymmetry centers, it is intended to both the geometric isomers comprising E and Z-type.The present invention is also intended to comprise all tautomers.

Officinal salt includes, but are not limited to inorganic acid salt, such as hydrochlorate, hydrobromate, sulfate, phosphate etc.; Acylate, such as formates, acetate, trifluoroacetate, maleate, tartrate etc.; Sulfonate, such as mesylate, benzene sulfonate, tosilate etc.; Amino acid salts, such as arginine salt, agedoite salt, glutamate, Glu etc.; Slaine, such as sodium salt, potassium salt, cesium salt etc.; Alkali salt, such as calcium salt, magnesium salt etc.; And organic amine salt, such as triethylamine salt, pyridiniujm, picoline salt, ethanolamine salt, triethanolamine salt, hexanamine salt, N, N '-double benzyl ethylenediamine salt etc.

In addition, according to the present invention, can use may by the activating agent abused except non-opioid analgesic.Such activating agent comprises such as tranquilizer (tranquilizer), CNS inhibitor, CNS analeptic, tranquilizer, somnifacient, analeptic (comprising appetite suppressant as phenylpropanolamine) and Cannabinoids (cannabinoids) etc.More specifically, activating agent can be selected from barbiturates, such as phenobarbital, quinalbarbitone, pentobarbital, secbutabarbital, talbumal (talbutal), allopropylbarbital, enphenemal, butalbital, its officinal salt, etc.; Benzene phenodiazine class, such as diazepam, chlorine nitrogen alprazolam, triazolam, estazolam, clonazepam, flunitrazepam, its officinal salt, etc.; Analeptic, such as gamma-hydroxybutyric acid ester/salt (gamma-hydroxybutyrate), dextro-amphetamine, methylphenidate, sibutramine, methylenedioxy methamphetamine, its officinal salt, etc.; Other materials, such as dronabinol (marinol), meprobamate and carisoprodol; And all its officinal salt, complex, stereoisomer, ether, ester, hydrate, solvate and mixture.

In other embodiments, according to the present invention, other therapeutical active agent can be combinationally used separately or with opioid.The example of such therapeutical active agent comprises hydryllin (such as, dimenhydrinate, diphenhydramine, chlorphenamine and dexbrompheniramine maleate), non-steroidal anti-inflammatory agent (such as, naproxen, diclofenac, indomethacin, ibuprofen, sulindac, Cox-2 inhibitor), acetaminophen, town vomitory (such as, metoclopramide, methyl naltrexone), Anti-epileptics (such as, phenytoin (phenyloin), first propylamine fat and nitrazepam), vasodilation (such as, nifedipine, papaverine (papaverine), diltiazem and nicardipine), anti-tussive agents and expectorant, antiasthmatics (such as theophylline), antacid, spasmolytic (such as, atropine, scopolamine), antidiabetic (such as, insulin), diuretic (such as, etacrynic acid, bendroflumethiazide (bendrofluthiazide)), antihypotensive (such as, Propranolol, clonidine), depressor (such as, clonidine, methyldopa), bronchodilator (such as, albuterol), steroid (such as, hydrocortisone, triamcinolone, prednisone), antibiotic (such as, tetracycline), hemorrhoid agent, psychotropic drugs (psychotropic), diarrhea, mucolytic, Decongestant (such as, pseudoephedrine), aperient, vitamin, and officinal salt, complex, stereoisomer, ether, ester, hydrate, solvate, and mixture.

Hydrocodone embodiment

Co ntrolled release peroral dosage form of the present invention preferably comprises about 0.5mg its officinal salt to about 1250mg hydrocodone or equivalent amount.In other embodiments, described dosage form comprises about 2mg its officinal salt to about 200mg hydrocodone or equivalent amount, or about 16mg is to its officinal salt of about 120mg hydrocodone or equivalent amount.In certain preferred aspects, described dosage form comprises about 20mg, about 30mg, about 40mg, about 60mg, about 80mg, about 100mg or about 120mg Hycodan.

Suitable hydrocodone officinal salt comprises Hycodan, Hycodan hydrate, hydrocodone hydrochloride, p-methyl benzenesulfonic acid hydrocodone, phosphoric acid hydrocodone, hydrocodone thiosemicarbazone (hydrocodone thiosemicarbazone), sulphuric acid hydrocodone, trifluoroacetic acid hydrocodone, hydrocodone half pentahydrate, five fluorine p, hydrocodone p-nitrophenyl hydrazone, the adjacent methyloxime of hydrocodone, hydrocodone semicarbazone, hydrobromic acid hydrocodone, mucic acid hydrocodone, oleic acid hydrocodone, hydrocodone hydrophosphate (hydrocodone phosphate dibasic), hydrocodone dihydric phosphate (hydrocodonephosphate monobasic), hydrocodone inorganic salt, hydrocodone organic salt, acetic acid hydrocodone trihydrate, two (hyptafluorobutyric acid) hydrocodone, two (methyl carbamic acid) hydrocodone, two (five fluorine propanoic acid) hydrocodone, two (picolinic acid) hydrocodone, two (trifluoroacetic acid) hydrocodone, hydrocodone hydrochloride hydrate and sulphuric acid hydrocodone pentahydrate.Preferably, hydrocodone exists with bitartrate.

Hydrocodone formulation of the present invention also can comprise one or more of other medicine, and it may or may not with the hydrocodone synergism wherein comprised.The example of this type of other medicine comprises non-steroidal anti-inflammatory agent, comprises ibuprofen, diclofenac, naproxen, benzene ibuprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen (pramoprofen), not Luo Luofen (muroprofen), three ibuprofen (trioxaprofen), suprofen, alminoprofen (aminoprofen), tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflunisal (diflurisal), flufenisal, piroxicam, sudoxicam, isoxicam, and officinal salt, complex, stereoisomer, ether, ester, hydrate, solvate, and mixture.Such non-steroidal anti-inflammatory agent also comprises cyclooxygenase-2 inhibitors, such as celecoxib (celecoxib), meloxicam, nabumetone, nimesulide, and officinal salt, complex, stereoisomer, ether, ester, hydrate, solvate and mixture.

Other medicines can prepared altogether with hydrocodone comprise nmda receptor antagonist, such as dextrorphan, dextromethorphan, 3-(1-naphthyl)-5-(phosphonomethyl)-L-Phe, 3-(1-naphthyl)-5-(phosphonomethyl)-DL-phenylalanine, 1-(3,5-3,5-dimethylphenyl) naphthalene, 2-(3,5-3,5-dimethylphenyl) naphthalene, 2SR, 4RS-4-(((1H-TETRAZOLE-5-base) methyl) oxygen base) piperidines-2-carboxylic acid, 2SR, 4RS-4-((((1H-TETRAZOLE-5-base) methyl) oxygen base) methyl) piperidines-2-carboxylic acid, E and Z 2SR-4-(O-(1H-TETRAZOLE-5-base) methyl) ketoxime base) piperidines-2-carboxylic acid, 2SR, 4RS-4-((1H-TETRAZOLE-5-base) sulfenyl) piperidines-2-carboxylic acid, 2SR, 4RS-4-((1H-TETRAZOLE-5-base) sulfenyl) piperidines-2-carboxylic acid, 2SR, 4RS-4-(5-sulfydryl-1H-TETRAZOLE-1-base) piperidines-2-carboxylic acid, 2SR, 4RS-4-(5-sulfydryl-2H-tetrazolium-2-base) piperidines-2-carboxylic acid, 2SR, 4RS-4-(5-sulfydryl-1H-TETRAZOLE-1-base) piperidines-2-carboxylic acid, 2SR, 4RS-4-(5-sulfydryl-2H-tetrazolium-2-base) piperidines-2-carboxylic acid, 2SR, 4RS-4-(((1H-TETRAZOLE-5-base) sulfenyl) methyl) piperidines-2-carboxylic acid, 2SR, 4RS-4-((5-sulfydryl-1H-TETRAZOLE-1-base) methyl) piperidines-2-carboxylic acid, 2SR, 4RS-4-((5-sulfydryl-2H-tetrazolium-2-base) methyl) piperidines-2-carboxylic acid, and officinal salt, complex, stereoisomer, ether, ester, hydrate, solvate, and mixture.

Other suitable medicines that can be included in hydrocodone formulation of the present invention comprise acetaminophen and aspirin.

In some preferred embodiments, hydrocodone formulations of the present invention is suitable for using once a day and provides the curve of blood plasma of opposing straight, and after this means to use, the blood plasma level of hydrocodone provides the C of about 0.55 to about 1.0 ₂₄/ C _maxratio.In certain embodiments, use described dosage form after C ₂₄/ C _maxratio is about 0.55 to about 0.85, about 0.55 to about 0.75 or about 0.60 to about 0.70.

In some preferred embodiments, use after hydrocodone formulations of the present invention the T of the hydrocodone of about 4 to about 20 hours is provided _max(h).In certain embodiments, use described dosage form after T _mmaxfor about 6 to about 12 hours, about 8 to about 10 hours, about 4 to about 10 hours, about 8 to about 14 hours or about 14 to about 20 hours.

In other embodiments, use after the hydrocodone that comprises in dosage form of the every 20mg of solid Co ntrolled release dosage form of the present invention or its officinal salt provide about 200 to 450 or about 250 to 400 AUC (ng*h/mL).

In certain embodiments, use after comprise 20mg hydrocodone or its officinal salt solid Co ntrolled release dosage form provide about 200 to about 450, about 250 to about 400, about 275 to about 350, about 300 to 330 or the AUC (ng*h/mL) of about 280 to about 320.

In certain embodiments, use after comprise 120mg hydrocodone or its officinal salt solid Co ntrolled release dosage form provide about 1000 to about 3000, about 1500 to about 2400, about 1700 to about 2200, about 1800 to about 2100 or the AUC (ng*h/mL) of about 1900 to about 2100.

In other embodiments, use after the hydrocodone that comprises in dosage form of the every 20mg of solid Co ntrolled release dosage form of the present invention provide about 5 to the C of about 40, about 10 to about 30 _max(ng/mL).

In certain embodiments, use after comprise 20mg hydrocodone or its officinal salt solid Co ntrolled release dosage form provide about 5 to about 40, about 10 to about 30, about 12 to about 25, about 14 to about 18 or the C of about 12 to about 17 _max(ng/mL).

In certain embodiments, use after comprise 120mg hydrocodone or its officinal salt solid Co ntrolled release dosage form provide about 30 to about 120, about 60 to about 180, about 100 to about 160, about 110 to about 150 or the C of about 100 to about 140 _max(ng/mL).

In certain embodiments, use after solid Co ntrolled release dosage form of the present invention provide about 7 to about 22,10 to about 20, about 12 to about 18, about 13 to the T of about 17 or about 14 to about 16 hydrocodones _max(h).

In other embodiments, use after solid Co ntrolled release dosage form of the present invention provide about 5 to about 10, about 6 to about 9, about 7 or about 8 the T of hydrocodone _1/2(h).

In other embodiments, use after solid Co ntrolled release dosage form of the present invention provide about 0.01 to about 0.2, about 0.1 to about 0.18, about 0.3 to about 0.17 or the T of hydrocodone of about 0.06 to about 0.15 _lag(h).

In other embodiments, solid Co ntrolled release dosage form of the present invention provides about 0.2 to about 0.8, about 0.3 to about 0.7 or the C of hydrocodone of about 0.4 to about 0.6 ₂₄/ C _maxratio.

In certain embodiments, reach after using under fasting state (fasted state) in above-mentioned average body intrinsic parameter any one or all.

In certain embodiments, the average A UC (ng*h/mL) using rear hydrocodone on the feed under state (fed state) exceeds less than 20%, less than 16% or less than 12% than the AUC (ng*h/mL) using rear hydrocodone in the fasted state.

In certain embodiments, the average C of rear hydrocodone is used on the feed under state _max(ng/mL) than the C using rear hydrocodone in the fasted state _maxexceed less than 80%, less than 70% or less than 60%.

In certain embodiments, the average T of rear hydrocodone is used on the feed under state _maxh () is for using the T of rear hydrocodone in the fasted state _max25% within, within 20% or within 15%.

In certain embodiments, the average T of rear hydrocodone is used on the feed under state _1/2h () is for use rear T in the fasted state _1/28% within, within 5% or within 2%.

In certain embodiments, the average T of rear hydrocodone is used on the feed under state _lagthan the T after using in the fasted state _1/2exceed less than 150%, less than 125% or less than 100%.

In certain embodiments, reach after using described dosage form first to colony's (average data) of people's object, patient or health objects (individual data items) or people's object, patient or health objects in above-mentioned body intrinsic parameter any one or all.

In some alternate embodiment, reach after using described dosage form to colony's stable state of people's object, patient or health objects or people's object, patient or health objects in above-mentioned body intrinsic parameter any one or all.

Ripening preparation

In certain embodiments, method of the present invention also comprises the step making final dosage form ripening (curing).

For the embodiment comprising poly(ethylene oxide) in Co ntrolled release preparation, maturation stage can comprise the poly(ethylene oxide) melted at least in part in preparation.In certain embodiments, in preparation at least about 20% or melt at least about the poly(ethylene oxide) of 30%.Preferably, during maturation stage, in preparation at least about 40% or at least about 50% or at least about 60% or at least about 75% or melt at least about the poly(ethylene oxide) of 90%.In a preferred embodiment, the poly(ethylene oxide) of about 100% melts.

In other embodiments, maturation stage comprises the temperature making preparation stand a period of time rising.In some such embodiments, curing temperature is at least equally high with the softening temperature of poly(ethylene oxide).According to some embodiment, curing temperature is at least about 60 DEG C, at least about 62 DEG C, about 62 DEG C to about 90 DEG C, about 62 DEG C to about 85 DEG C, about 62 DEG C to about 80 DEG C, about 65 DEG C to about 90 DEG C, about 65 DEG C to about 85 DEG C or about 65 DEG C to about 80 DEG C.Curing temperature is preferably about 68 DEG C to about 90 DEG C, about 68 DEG C to about 85 DEG C, about 68 DEG C to about 80 DEG C, about 70 DEG C to about 90 DEG C, about 70 DEG C to about 85 DEG C, about 70 DEG C to about 80 DEG C, about 72 DEG C to about 90 DEG C, about 72 DEG C to about 85 DEG C or about 72 DEG C to about 80 DEG C.Curing temperature can be at least about 60 DEG C, at least about 62 DEG C, lower than about 90 DEG C or lower than about 80 DEG C.Preferably, it is in the scope of about 62 DEG C to about 72 DEG C or about 68 DEG C to about 72 DEG C.Preferably, curing temperature is at least equally high with the lower limit of the softening range of poly(ethylene oxide), or is at least about 62 DEG C or at least about 68 DEG C.More preferably, curing temperature is in the softening range of poly(ethylene oxide) or be at least about 70 DEG C.In other embodiments, curing temperature is at least equally high or be at least about 72 DEG C with the upper limit of the softening range of poly(ethylene oxide).In other embodiments, curing temperature higher than the upper limit of the softening range of poly(ethylene oxide), or is at least about 75 DEG C or at least about 80 DEG C.

Those wherein maturation stage relate to make preparation stand a period of time raise temperature embodiment in, this period is called the curing time (curing time) below.In order to measure the curing time, define starting point (starting point) and the end point (end point) of maturation stage.For object of the present invention, the starting point of maturation stage is defined as time point when reaching curing temperature.

In certain embodiments, be platform sample form (plateau-like form) between the temperature curve display ripening starting point during maturation stage and end point.In such embodiments, be defined as the end point of maturation stage and terminate when heating or at least reduce (such as by terminate or reduces heating and/or by beginning cooling step subsequently) and temperature be down to subsequently than curing temperature low exceed about 10 DEG C and/or be down to poly(ethylene oxide) softening range lower limit below (such as lower than about 62 DEG C) time time point.When reaching curing temperature and therefore starting maturation stage, the deviation of curing temperature can be there is in maturation stage process.As long as these deviates are no more than about ± 10 DEG C, preferably about ± 6 DEG C and more preferably from about ± 3 DEG C, such deviation is sustainable.Such as, if maintain the curing temperature at least about 75 DEG C, then measured temperature temporarily can be increased to the value of about 85 DEG C, about 81 DEG C or about 78 DEG C, and measured temperature also temporarily can be reduced to the value of about 65 DEG C, about 69 DEG C or about 72 DEG C.Reduce larger and/or below the lower limit that temperature is reduced to the softening range of poly(ethylene oxide) (such as less than about 62 DEG C) in temperature, maturation stage is interrupted, and namely reaches end point.By again reaching curing temperature to restart ripening.

In other embodiments, be parabolic or triangular form between the temperature curve display ripening starting point during maturation stage and end point.After this means starting point (namely reaching time point during curing temperature), temperature is increased to further and reaches maximum, then declines.In some such embodiments, the end point of maturation stage is defined as time point when temperature is down to below curing temperature.

Depend on the equipment (that is, ripening device used) that ripening is used, ripening device used interior different temperatures can be measured to characterize curing temperature.

In certain embodiments, maturation stage can be carried out in an oven.In some such embodiments, measure oven interior temperature.Based on this, when maturation stage occurs in an oven, curing temperature is defined as the target inside temperature of baking oven, and the starting point of maturation stage is defined as time point when oven interior temperature reaches curing temperature.The end point of maturation stage is defined as (1) in platform sample temperature curve, when stop or at least reduce heating and subsequently oven interior temperature be down to than curing temperature low exceed about 10 DEG C and/or be down to high molecular weight polyethylene oxide softening range lower limit below (such as less than about 62 DEG C) time time point, or (2) in parabola shaped or triangular temperature profile, the time point when oven interior temperature is down to below curing temperature.Preferably, when oven interior temperature reach at least about 62 DEG C, at least about 68 DEG C, at least about 70 DEG C, start maturation stage at least about when 72 DEG C or curing temperature at least about 75 DEG C.In some preferred embodiments, temperature curve during maturation stage shows platform sample form, wherein curing temperature (i.e. the internal temperature of baking oven) is at least about 68 DEG C, about 70 DEG C, about 72 DEG C, about 73 DEG C, or be in the scope of about 70 DEG C to about 75 DEG C, and the curing time is preferably about 30 minutes to about 20 hours, about 30 minutes to about 15 hours, about 30 minutes to about 4 hours or about 30 minutes to about 2 hours.In certain embodiments, the curing time is about 30 minutes to about 90 minutes.

In other embodiment, ripening occur in be heated by air-flow and comprise hot-air supply (entrance) and air vent (exhaust) ripening device used in, such as coating pan or fluid bed.Hereinafter ripening device usedly be called convection curing device by this.So ripening device used in, entering air temperature (namely entering the temperature of the heated air of convection curing device) and/or air vent air themperature (namely leaving the temperature of the air of convection curing device) can be measured.During maturation stage, also can measure or at least estimate the formulation temperature of convection curing device inside, such as, by using infrared radiation thermometer (such as IR rifle (IR gun)) or using the temperature probe measuring tempeature be positioned near preparation being placed in ripening device used inside.Based on this, when maturation stage occurs in convection curing device, can as given a definition curing temperature and measurement curing time.

In one embodiment (method 1), curing temperature is defined as target entries air themperature, and the starting point of maturation stage is defined as time point when entering air temperature reaches curing temperature.The end point of maturation stage is defined as (1) in platform sample temperature curve, when stop or at least reduce heating and subsequently entering air temperature be down to than curing temperature low exceed about 10 DEG C and/or be down to high molecular weight polyethylene oxide softening range lower limit below (such as less than about 62 DEG C) time time point, or (2) in the temperature curve of parabolic or triangular form, the time point when entering air temperature is down to below curing temperature.Preferably, when entering air temperature reach at least about 62 DEG C, at least about 68 DEG C, at least about 70 DEG C, at least about 72 DEG C or curing temperature at least about 75 DEG C time, start maturation stage according to method 1.In a preferred embodiment, temperature curve during maturation stage shows platform sample form, wherein curing temperature (i.e. target entries air themperature) is preferably at least about 72 DEG C, such as about 75 DEG C, and be preferably about 15 minutes to about 2 hours, such as about 30 minutes or about 1 hour according to the curing time that method 1 is measured.

In another embodiment (method 2), curing temperature is defined as target exhaust mouth air themperature, and the starting point of maturation stage is defined as time point when air vent air themperature reaches curing temperature.The end point of maturation stage is defined as (1) in platform sample temperature curve, when stop or at least reduce heating and be down to rear exhaust port air themperature than curing temperature low exceed about 10 DEG C and/or be down to high molecular weight polyethylene oxide softening range lower limit below (such as less than about 62 DEG C) time time point, or (2) in the temperature curve of parabolic or triangular form, the time point when air vent air themperature is down to below curing temperature.Preferably, when air vent air themperature reach at least about 62 DEG C, at least about 68 DEG C, at least about 70 DEG C, start maturation stage at least about when 72 DEG C or curing temperature at least about 75 DEG C according to method 2.In some preferred embodiments, temperature curve during maturation stage shows platform sample form, wherein curing temperature (i.e. target exhaust mouth air themperature) is preferably at least about 68 DEG C, at least about 70 DEG C or at least about 72 DEG C, such as target exhaust mouth air themperature is about 68 DEG C, about 70 DEG C, about 72 DEG C, about 75 DEG C or about 78 DEG C, and be preferably about 1 minute to about 2 hours or about 5 minutes to about 90 minutes according to the curing time that method 2 is measured, the such as curing time is about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 60 minutes, about 70 minutes, about 75 minutes or about 90 minutes.In a preferred embodiment, it is about 15 minutes to about 1 hour according to the curing time that method 2 is measured.

In another embodiment (method 3), curing temperature is defined as the target temperature of preparation, and the time point when temperature (can such as be measured by the IR rifle) starting point of maturation stage being defined as preparation reaches curing temperature.The end point of maturation stage is defined as (1) in platform sample temperature curve, when stop or at least reduce heating and subsequently the temperature of preparation be down to than curing temperature low exceed about 10 DEG C and/or be down to high molecular weight polyethylene oxide softening range lower limit below (such as less than about 62 DEG C) time time point, or (2) in the temperature curve of parabolic or triangular form, the time point when the temperature of preparation is down to below curing temperature.Preferably, when the temperature of preparation reach at least about 62 DEG C, at least about 68 DEG C, at least about 70 DEG C, start maturation stage at least about when 72 DEG C or curing temperature at least about 75 DEG C according to method 3.

In another embodiment (method 4), curing temperature is defined as use be placed in ripening device used inside be positioned at the target temperature that the temperature probe (such as metal wire thermocouple (wirethermocouple)) near preparation measures, and the time point when temperature starting point of maturation stage being defined as serviceability temperature probe measurement reaches curing temperature.The end point of maturation stage is defined as (1) in platform sample temperature curve, when stop or at least reduce heating and the temperature of serviceability temperature probe measurement be subsequently down to than curing temperature low exceed about 10 DEG C and/or be down to poly(ethylene oxide) softening range lower limit below (such as less than about 62 DEG C) time time point, or (2) in the temperature curve of parabolic or triangular form, the time point when the temperature of serviceability temperature probe measurement is down to below curing temperature.Preferably, when the temperature of serviceability temperature probe measurement reach in ripening device used at least about 62 DEG C, at least about 68 DEG C, at least about 70 DEG C, at least about 72 DEG C or at least about the temperature of 75 DEG C, start maturation stage.In a preferred embodiment, temperature curve during maturation stage shows platform sample form, wherein curing temperature is at least about 68 DEG C, such as about 70 DEG C, and is preferably about 15 minutes to about 2 hours or about 60 minutes or about 90 minutes according to the curing time that method 4 is measured.

If ripening occurs in convection curing device, then measure the curing time by any one in said method.

In certain embodiments, curing temperature is defined as target temperature range, such as, curing temperature is defined as target entries air temperature range or target exhaust mouth air temperature range.In such embodiments, the starting point of maturation stage is defined as the time point reaching and prescribe a time limit under target temperature range, the end point of maturation stage is defined as when stop or at least reduce heating and subsequently temperature be down to lower than the lower limit of target temperature range exceed about 10 DEG C and/or be down to poly(ethylene oxide) softening range lower limit below (such as less than about 62 DEG C) time time point.

The curing time (namely preparation stands a period of time of curing temperature) that can such as measure according to said method be at least about 1 minute or at least about 5 minutes.Depend on concrete preparation and curing temperature, the curing time can be about 1 minute to about 24 hours, about 5 minutes to about 20 hours, about 10 minutes to about 15 hours, about 15 minutes to about 10 hours or about 30 minutes to about 5 hours not etc.According to some embodiment, the curing time be about 15 minutes to about 30 minutes not etc.According to wherein curing temperature be at least about 60 DEG C, at least about 62 DEG C, at least about 68 DEG C, at least about 70 DEG C, at least about 72 DEG C or at least about other embodiments of 75 DEG C or the change from about 62 DEG C to about 85 DEG C or from about 65 DEG C to about 85 DEG C, the curing time be preferably at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, at least about 75 minutes, at least about 90 minutes or at least about 120 minutes.Wherein curing temperature be such as at least about 62 DEG C, at least about 68 DEG C, at least about 70 DEG C, at least about 72 DEG C or at least about 75 DEG C or in the certain preferred embodiments of about 62 DEG C to about 80 DEG C, about 65 DEG C to about 80 DEG C, about 68 DEG C to about 80 DEG C, about 70 DEG C to about 80 DEG C or about 72 DEG C to about 80 DEG C, the curing time be preferably at least about 1 minute, at least about 5 minutes, at least about 10 minutes, at least about 15 minutes or at least about 30 minutes.In the embodiment that some is such, the curing time can be selected to make it short as far as possible, also realize the result (such as, the against tampering of raising) expected simultaneously.Such as, the curing time, preferably no more than about 5 hours, is no more than about 3 hours or is no more than about 2 hours.Preferably, the curing time is about 1 minute to about 5 hours, about 5 minutes to about 3 hours, about 15 minutes to about 2 hours or about 15 minutes to about 1 hour.Any combination of curing temperature disclosed herein and curing time all falls within the scope of the invention.

In certain embodiments, the poly(ethylene oxide) that compositions only exists in the formulation just stands curing temperature when having reached its softening temperature and/or melted at least in part.In the embodiment that some is such, the curing time can be less than about 5 minutes, and the such as curing time can be and is greater than 0 minute to about 3 hours, about 1 minute to about 2 hours or about 2 minutes to about 1 hour.By selecting the poly(ethylene oxide) in preparation to be heated to immediately, that at least its softening temperature makes high molecular weight polyethylene oxide melt at least in part is ripening device used, can carry out instant ripening.Like this ripening device used is such as microwave oven, Vltrasonic device, light-irradiating device (such as UV irradiation devices), hyperfrequency (UHF) field or well known to a person skilled in the art any other device.

The large I of preparation determines the curing time needed for against tampering and the curing temperature that realize expectation.

In certain embodiments, maturation stage causes the density of preparation to reduce, and makes density through ripening preparation lower than the density of the preparation carried out before maturation stage.Preferably, the density of the preparation of ripening reduces at least about 0.5% compared with the density of the preparation of non-ripening.More preferably, the density of the preparation of ripening reduces at least about 0.7%, at least about 0.8%, at least about 1.0%, at least about 2.0% or at least about 2.5% compared with the density of the preparation of non-ripening.

In certain embodiments, at the temperature of at least softening point of poly(ethylene oxide), solid Co ntrolled release dosage form ripening at least 1 minute, at least 5 minutes or at least 15 minutes are made.

In other embodiments, at the temperature of at least softening point of poly(ethylene oxide), the ripening of solid Co ntrolled release dosage form is made about 1 minute to about 48 hours, about 5 minutes to about 24 hours, about 15 minutes to about 1 hour or about 30 minutes.

Can such as at least about 60 DEG C, at least about 65 DEG C, at least about 70 DEG C, at least about the temperature of 75 DEG C under or at the temperature of about 72 DEG C, make the ripening of solid Co ntrolled release dosage form.

In some alternate embodiment, the ripening of solid Co ntrolled release dosage form can be made at the temperature of about 60 DEG C to about 90 DEG C, about 62 DEG C to about 72 DEG C, about 65 DEG C to about 85 DEG C, about 70 DEG C to about 80 DEG C, about 75 DEG C to about 80 DEG C or about 70 DEG C to about 75 DEG C.

Flatten operation

In certain embodiments, dosage form of the present invention is collapsible and substantially do not damage the release of activating agent or the integrity of dosage form.Compared with the thickness of the minimum diameter of the non-shape that is crushed, flat is the description of the thickness of minimum diameter for the shape that is crushed.The thickness of the minimum diameter of the shape that is not crushed when original shape is aspherical based on (i), or (ii) thickness of diameter when original shape is spherical, this compares and is expressed as thickness %.Use calibrator (such as, digital thickness gauge or digital calipers) detect thickness.Flat pressure is applied by any possible method.With regard to testing the object of dosage form of the present invention, carver type bench press (except as otherwise noted) can be used thus the thickness of realize target flattening degree/reduction.According to certain embodiments of the present invention, flatten and do not cause dosage form to be broken into fragment; But edge crack and cracking may be there is.

In certain embodiments of the invention, hammer can be used for flattening dosage form.In such flattening method, from the direction that the thickest size with dosage form is substantially vertical, manually apply hammering.Afterwards as above-disclosed same way describes compression.

In other embodiments, Schleuniger equipment can be used relative to such as Remington ' sPharmaceutical Sciences, 18th edition, nineteen ninety, the crushing strength (breaking strength) described in the 89th chapter " Oral Solid DosageForms " 1633-1665 page or hardness test are to measure flattening.In such a embodiment, between pair of plates arranged in parallel, extrude dosage form, make applying power the direction substantially vertical from the thickest size with dosage form, thus flatten dosage form.According to the thickness based on the size be crushed before carrying out crushing strength test, % can be flattened to describe the flattening of dosage form with term.Crushing strength (or hardness) is defined as power when making institute's test dosage forms broken.It is resistant to breakage that not broken but dosage form that is that be out of shape due to applied force is considered under this specific power.

The another kind test of dosing form intensity uses Texture instrument (Texture Analyzer) as TA-XT2 Texture instrument (Texture Technologies Corp., 18Fairview Road, Scarsdale, N.Y.10583) indentation test (indentation test).In the method, dosage form is placed in the stainless steel stent top with slight concave surface, is then thrust by the descending probe of Texture instrument, the rustless steel spherical probes of 1/8 inch diameter of such as TA-8A.Before starting to measure, under making dosage form directly be aligned in probe, make descending probe that centrality is thrust (i.e. the central authorities of dosage form) in tablet, and make from the diameter perpendicular with dosage form and substantially direction in line apply the power of descending probe with its thickness.First, starting to test front speed makes the probe of Texture instrument shift to dosage form sample.When probe contacts with dosage form surface, reach set trigger force, probe continues move with test speed and thrust dosage form.The degree of depth or distance are thrust for each of probe, measures corresponding power.When probe reached desired maximum thrust the degree of depth time, it changes direction and back moves to test rear speed, gathers measured value further simultaneously.Cracking forces (cracking force) is defined as the first maximum power in local reached in corresponding power/distance map, and uses such as Texture instrument software " Texture Expert Exceed, Version 2.64English " to calculate.

For the object of certain embodiments of the invention, term " resistance to crusing " is defined as finger and above-mentioned bench press can be adopted it at least to be flattened as following thickness and chip-proof dosage form: be no more than about 60% thickness, preferably more than about 50% thickness, be most preferably not exceeding about 20% thickness, 10% thickness or 5% thickness more preferably no more than about 40% thickness, even more preferably no more than about 30% thickness.

In certain embodiments, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, littlely about 10% point, or 20% point is no more than at 15% from amount deviation compared with the amount discharged in the 0.5 little dosage form that is never crushed constantly of activating agent (such as, non-opioid analgesic) of the dosage form release that is crushed constantly 0.5.

In some alternate embodiment, solid Co ntrolled release dosage form is collapsible and not broken, after being wherein crushed the thickness of dosage form be equivalent to be crushed before dosage form thickness be no more than about 60%, before being crushed, dosage form thickness is no more than about 50%, before being crushed dosage form thickness be about no more than 40%, before being crushed dosage form thickness be no more than about 30% or before being crushed dosage form thickness be no more than about 20%.

Set forth following examples should not be understood to limit described herein and claimed the present invention particularly for helping to understand the present invention.Think and can such version of the present invention in those skilled in the art's visual field (comprise now known or all equivalents of developing subsequently substitute) and the change of preparation or the minimum change of experimental design drop in the scope of the present invention that is incorporated to herein.

Embodiment

More fully the present invention is described referring now to appended embodiment.However, it should be understood that following explanation is only illustrative, and limitation of the present invention should be considered as by any way.

Embodiment 1

High molecular weight polyethylene oxide (PEO 303-MW 7,000,000) is used to prepare the 400mg tablet (tablet A) comprising 20mg Hycodan, as shown in the following Table 1.

Table 1 (tablet A)

In order to prepare core, Manesty F3 type list station tablet machine (single station ManestyType F 3tablet press) is configured circular standard concave instrument (concave plaintooling) of 7.94mm.As shown in table 1 above, weigh up equivalent part of the Powdered core blend of the target weight of 200mg, load punch die, then suppress the core forming tablet A.

In order to prepare shell, by the circular standard concave instrument of Manesty F3 type list station tablet machine configuration 10.32mm.100mg shell blend as shown in table 1 is loaded in punch die.The tablet core of above-mentioned preparation is manually concentrated on center of die (top in powder bed), other 100mg shell blend is placed in the top of punch die tablet.Afterwards by rotate pinch roller manually pressed material to form pressed coated tablet A.

Being placed on by several pressed coated tablet A tablets of upper described preparation and being placed in target temperature is that pallet upper 30 minute of the Hotpack 435304 type baking oven of 72 DEG C is with ripening.

At 37 DEG C, in 900ml is not containing the simulated gastric fluid (SGF) of enzyme, the stripping through the tablet A tablet of ripening is tested with 100rpm afterwards in USP device 1 (basket).For the result of the preparation of embodiment 2 ~ 4, result is shown in Fig. 1.

Embodiment 2

High molecular weight polyethylene oxide (PEO 303-MW 7,000,000) is used to prepare the 500mg tablet (tablet B) comprising 20mg Hycodan, as shown in the following Table 2.

Table 2 (tablet B)

In order to prepare core, by the circular standard concave instrument of Manesty F3 type list station tablet machine configuration 8.73mm.As shown in Table 2, weigh up equivalent part of the Powdered core blend of the target weight of 300mg, load punch die, then suppress the core forming tablet B.

In order to prepare shell, by the circular standard concave instrument of Manesty F3 type list station tablet machine configuration 11.11mm.As shown in table 2, the Part I of 200mg shell blend is placed in punch die.The tablet core of above-mentioned preparation is manually concentrated on center of die (top in powder bed), the remainder of 200mg shell blend is placed in the top of punch die tablet.Afterwards by rotate pinch roller manually pressed material to form pressed coated tablet B.

Being placed on by the several pressed coated tablet B tablets prepared as mentioned above and being placed in target temperature is that pallet upper 30 minute of the Hotpack 435304 type baking oven of 72 DEG C is with ripening.

At 37 DEG C, in 900ml is not containing the simulated gastric fluid (SGF) of enzyme, the stripping through the tablet B tablet of ripening is tested with 100rpm afterwards in USP device 1 (basket).For the result of the preparation of embodiment 1 and 3 ~ 4, result is shown in Fig. 1.

Embodiment 3

The 500mg tablet (tablet C) containing 20mg Hycodan has been prepared in use high molecular weight polyethylene oxide (PEO 303-MW 7,000,000), as shown in the following Table 3.

Table 3 (tablet C)

In order to prepare core, by the circular standard concave instrument of Manesty F3 type list station tablet machine configuration 9.53mm.As shown in Table 3, weigh up equivalent part of the Powdered core blend of the target weight of 300mg, load punch die, then suppress the core forming tablet C.

In order to prepare shell, by the circular standard concave instrument of Manesty F3 type list station tablet machine configuration 11.11mm.As shown in table 3, the Part I of 200mg shell blend is placed in punch die.The tablet core of above-mentioned preparation is manually concentrated on center of die (top in powder bed), the remainder of 200mg shell blend is placed in the top of punch die tablet.Afterwards by rotate pinch roller manually pressed material to form pressed coated tablet C.

Being placed on by the several pressed coated tablet C tablets prepared as mentioned above and being placed in target temperature is that pallet upper 30 minute of the Hotpack 435304 type baking oven of 72 DEG C is with ripening.

At 37 DEG C, in 900ml is not containing the simulated gastric fluid (SGF) of enzyme, the stripping through the tablet C tablet of ripening is tested with 100rpm afterwards in USP device 1 (basket).For the result of the preparation of embodiment 1 ~ 2 and 4, result is shown in Fig. 1.

Embodiment 4

High molecular weight polyethylene oxide (PEO 303-MW 7,000,000) is used to prepare the 475mg tablet (tablet D) comprising 20mg Hycodan, as shown in the following Table 4.

Table 4 (tablet D)

In order to prepare core, by the circular standard concave instrument of Manesty F3 type list station tablet machine configuration 7.94mm.As shown in Table 4, weigh up equivalent part of the Powdered core blend of the target weight of 175mg, load punch die, then suppress the core forming tablet D.

In order to prepare shell, by the circular standard concave instrument of Manesty F3 type list station tablet machine configuration 11.11mm.As shown in table 4, the Part I of 300mg shell blend is placed in punch die.The tablet core of above-mentioned preparation is manually concentrated on center of die (top in powder bed), the remainder of 300mg shell blend is placed in the top of punch die tablet.Afterwards by rotate pinch roller manually pressed material to form pressed coated tablet D.

Being placed on by the several pressed coated tablet D tablets prepared as mentioned above afterwards and being placed in target temperature is that pallet upper 30 minute of the Hotpack 435304 type baking oven of 72 DEG C is with ripening.

At 37 DEG C, in 900ml is not containing the simulated gastric fluid (SGF) of enzyme, the stripping through the tablet D tablet of ripening is tested with 100rpm afterwards in USP device 1 (basket).For the result of the preparation of embodiment 1 ~ 3, result is shown in Fig. 1.

Embodiment 5

By low-molecular-weight poly(ethylene oxide) (PEO 205-MW 600,000) for core and by high molecular weight polyethylene oxide (PEO 303-MW 7,000,000) the 500mg tablet (tablet E) containing 120mg hydrocodone is prepared for shell, as shown in the following Table 5.

Table 5 (tablet E)

In order to prepare core, by the circular standard concave instrument of Manesty F3 type list station tablet machine configuration 8.73mm.As shown in Table 5, weigh up equivalent part of the Powdered core blend of the target weight of 300mg, load punch die, then suppress the core forming tablet E.

In order to prepare shell, by the circular standard concave instrument of Manesty F3 type list station tablet machine configuration 11.11mm.As shown in table 5, the Part I of 200mg shell blend is placed in punch die.The tablet core of above-mentioned preparation is manually concentrated on center of die (top in powder bed), the remainder of 200mg shell blend is placed in the top of punch die tablet.By rotate pinch roller manually pressed material to form pressed coated tablet E.

Being placed on by the several pressed coated tablet E tablets prepared as mentioned above afterwards and being placed in target temperature is that pallet upper 30 minute of the Hotpack 435304 type baking oven of 72 DEG C is with ripening.

At 37 DEG C, in 900ml is not containing the simulated gastric fluid (SGF) of enzyme, the stripping through the tablet E tablet of ripening is tested with 100rpm afterwards in USP device 1 (basket).For the result of the preparation of embodiment 5 and 6, result is shown in Fig. 2.

Embodiment 6

The 500mg tablet (tablet F) containing 120mg hydrocodone has been prepared in use high molecular weight polyethylene oxide (PEO 303-MW 7,000,000), as shown in the following Table 6.

Table 6 (tablet F)

In order to prepare core, by the circular standard concave instrument of Manesty F3 type list station tablet machine configuration 8.73mm.As shown in Table 6, weigh up the aliquot of the Powdered core blend of the target weight of 300mg, load punch die, then suppress the core forming tablet F.

In order to prepare shell, by the circular standard concave instrument of Manesty F3 type list station tablet machine configuration 11.11mm.As shown in table 6, the Part I of 200mg shell blend is placed in punch die.The tablet core of above-mentioned preparation is manually concentrated on center of die (top in powder bed), the remainder of 200mg shell blend is placed in the top of punch die tablet.By rotate pinch roller manually pressed material to form pressed coated tablet F.

Being placed on by the several pressed coated tablet F tablets prepared as mentioned above afterwards and being placed in target temperature is that pallet upper 30 minute of the Hotpack 435304 type baking oven of 72 DEG C is with ripening.

At 37 DEG C, do not contain the stripping of test tablet F tablet in the simulated gastric fluid (SGF) of enzyme afterwards in 900ml with 100rpm in USP device 1 (basket).For the result of the preparation of embodiment 5 and 6, result is shown in Fig. 2.

Embodiment 7 ~ 12

According to having prepared the six kinds of different pressed coated tablets (being called sheet G ~ L) comprising 20mg Hycodan (tablet G, H and I) or 120mg Hycodan (tablet J, K and L) with following table 7 (20mg) or table 8 (120mg).

Table 7 (tablet G, H, I)

Table 8 (tablet J, K, L)

High shear granulator (Collette 75L) is loaded with Hycodan, microcrystalline Cellulose and hydroxypropyl cellulose.When oar and chipper (chopper) are opened, water is added into (such as, 8 ~ 15%) in mixture.Make wet granular by the scalping of Quadro Comil grinding mechanism.Sieved wet granular is carried out drying in Vector VFC-3 fluidized bed dryer.Make dry granule by the dusting cover of Quadro Comil grinding mechanism.

16Q " V " shape blender is loaded and blended 5 minutes with PEO POLYOX WSR 205 and the granule ground.Sieved magnesium stearate to be added in mixture and blended 1 minute to prepare core blend.

16Q " V " shape blender is loaded and blended 5 minutes with the red No.30 aluminum color lake of PEO POLYOX WSR 303, D & C and the granule that grinds.Sieved magnesium stearate to be added in mixture and blended 1 minute to prepare dry coating blend.

Adopt DryCota press that core blend and dry coating blend are pressed into dry coated tablet.Core blend to be loaded in side hopper (hopper) and core weight is adjusted to target 300mg.Afterwards, dry coating blend to be loaded in the hopper of both sides and total tablet weight is adjusted to target.After weight regulates, start compacting and run and run press with such as 6rpm.

Weigh about 10kg pressed coated tablet and carry out spray coating to the target weight of about 1.0% (by weight) with Opadry (Opadry) Coating Suspension in the Compu-Lab coating pan of porous 24 inches and increase.Carry out spray coating as follows.Heat up by entering air temperature being set to 55 DEG C to make sheet bed.Once exhaust port temperatures reaches 39 DEG C, so start film coating with the spray rate of the pot of 12rpm speed and about 44mL/ minute.Continue film coating until realize target weight increases by 1% (this ripening in step x is part coating, because the final coating that 4% weight increases in step xii becomes sticky between the maturation period).

Through tablet ripening in perforated coating pan of part coating.Entering air temperature is set as 85 DEG C, pot speed is set as about 10rpm.By tablet ripening about 30 minutes under the exhaust port temperatures of 72 DEG C.

After ripening, by inlet temperature being set as 22 DEG C to make tablet cools in the pot rotated.Continue cooling until exhaust port temperatures is lower than 28 DEG C.

Afterwards, with the spray rate of the pot of 12rpm speed and about 44mL/ minute, the tablet through ripening is increased (1% coating before by weight, comprising) with the target final weight obtaining 4.0% with extra Coating Suspension spray coating in perforated coating pan.

Film-coated tablet is transferred in (tared) polyethylene liner cylinder (drum) of taring.

For 20mg and the 120mg tablet of these pressed coateds, stripping result (% through time release active matter) is at Fig. 3 and with shown in following table 9 and 10.

As shown in the stripping of above-described embodiment, affecting activating agent from the factor of dosage form stripping is core: shell weight ratio and tablet weight.In addition, the stripping digital proof more than illustrated, preparation of the present invention shows the release as basic zero level disclosed herein.

Embodiment 13

The random open label crossing research in NAM and female subject is carried out with the hydrocodone formulations (HYD) of embodiment 7 ~ 12.This research is made up of iteration (Iteration) (repeating the method for research design by the unique object group of experience one group of predetermined treatment) at every turn.Carry out following iteration:

iteration 1:

N＝36

At random, single dose, 3 kinds of treatments, 3 period crossover.

HYD 20mg, at a slow speed release tablet, fasting state (tablet G)

HYD 20mg, middling speed release tablet, fasting state (tablet H)

HYD 20mg, immediate-release tablet, fasting state (tablet I)

iteration 2:

N＝36

At random, single dose, 3 kinds of treatments, 3 period crossover.

HYD 120mg, at a slow speed release tablet, fasting state (tablet J)

HYD 120mg, middling speed release tablet, fasting state (tablet K)

HYD 120mg, immediate-release tablet, fasting state (tablet L)

iteration 3:

N＝16

At random, single dose, 2 kinds of treatments, 2 period crossover.

HYD 120mg, at a slow speed release tablet, fasting state (tablet J)

HYD 120mg, at a slow speed release tablet, fed conditions (tablet J)

Under such as specified fasting or fed conditions, by preparation, single dose is Orally administered with 8 ounces of (oz.) (240mL) water separately.

Because this research is carried out in Healthy People object, use opioid antagonists naltrexone hydrochloride to be down to minimum by the adverse events relevant to opioid.

Screening process

The screening carried out in 28 days before using initial dose make a house call (screening visit) time following screening process is carried out to all possible object:

-informed consent.

The informed consent of-optional Drug Discovery sampling.

The informed consent of-optional hair sampling.

-body weight, height, body-mass index (BMI) and Demographic data.

-include/evaluation of exclusion standard in.

-medical history and medication history, comprise concomitant medication.

-sit down vital sign (contraction/relaxation blood pressure, pulse rate, breathing rate, oral temperature) after about 5 minutes and SpO ₂.

-other vital signs (contraction/relaxation blood pressure and pulse rate) of standing after about 2 minutes.

-HDYF? inquire while measurement vital sign.

-routine physical examination.

Clinical laboratory evaluations (comprising biochemistry, hematology and urinalysis) after-at least 4 h fast.

-12 lead electrocardiogram (ECG).QTcF is no more than 450 milliseconds (msec).

-hepatitis examination (comprising hbs antigen [HBsAg], antibody to hepatitis C [HCV-Ab IgG]).

The examination of-ethanol, cotinine (cotinine) and selected Drug abuse.

-Serum Pregnancy is tested, only female subject; Follicle-stimulating hormone (FSH) urged by serum, only postmenopausal women.

-Serum Pregnancy test (only female subject).

-serum follicule-stimulating hormone (FSH) (FSH) test (only postmenopausal women)

Inclusive criteria

-the object that meets following standard is included in this research.

-written informed consent is provided.

-the age is at the masculinity and femininity of 18 to 50 years old (comprising end value).

-body weight at 50 to 100kg (110 to 220 pounds (1b)) and BMI at 18 to 34 (kg/m ²) (comprising end value).

-medical history, health check-up, vital sign and ECG confirm as health and without remarkable anomaly.

-Women of childbearing age must use fully and reliable contraceptive method (such as containing barrier, intrauterine device, the hormonal contraceptive of other spermicide foam or jelly).Postmenopausal women must menopause >=1 year and have the serum FSH of rising.

-be ready to eat the food provided during studying.

-during whole research, avoid strenuous exercise.Object will not start new exercise program or participate in any very violent physical exertion.

Exclusion standard

Possible object is got rid of outside this research by following standard.

-be in the women of trimester of pregnancy (β human chorionic gonadotropin test for positive) or age of sucking.

-current or nearest (in 5 years) medicine or alcohol abuse history.

-may interference medicament absorb, distribution, the medical history of metabolism or excretion or any current disease.

-used containing opioid medicine in 30 days before this research initial administration.

-known the allergies to hydrocodone, naltrexone or related compound.

The medical history of-no matter any n or V that takes place frequently of which kind of cause of disease.

-with any epilepsy of sequela or injury of head medical history.

-before this research starts administration, participated in clinical drug research in 30 days.

-start any major disease before administration in 30 days in this research.

-before beginning administration, use any medicine in 7 days, comprise thyroid hormone treatment (hormonal contraceptive allows), vitamin, medical herbs and/or mineral supplements.

-comprise the abnormal heart disease of any following situation

When examination QTc interval >=450 milliseconds (use Fridericia correction calculation).

Treatments period QTc interval >=480 milliseconds (use Fridericia correction calculation).

-within before drugs 10 hours and 4 hours afterwards, refuse remove foods and refuse to remove completely containing caffeine or xanthic beverage in each restricted period using.

-before starting to use institute's drugs (the 1st day), 48 hours or any time refusal during studying remove consume alcohol beverage.

-smoking history or using drugs use in 45 days nicotine products or urine cotinine test be the positive.

30 days donated bloods or blood products after-any time using before drugs in 60 days or during this research and complete cost study, except needed for this programme.

-use institute's drugs before any time in 14 days or during this research contribute blood plasma, except needed for this programme.

The medicine examination of-urine or ethanol examination are positive findings.

-HBsAg, HCV-Ab IgG are positive findings.

-naloxone HCl excites test for positive.

-there is gill uncle's syndrome (Gilbert ' s Syndrome) or any known liver and gall are abnormal.

-only for the optional hair sampling section of this research, hair (scalp hair) quantity not sufficient is to provide enough samples.

-research worker thinks that object is not suitable for due to the one or more of reason do not specifically not noted in this exclusion standard.

All inclusive criterias will be met and object randomization without any exclusion standard enters into this research.

Be that each object distributes unique object number when examination.Being assigned as ascending order and not having number to omit of object number.Object number is used for all research files.

Check-in flow process

Only at the-1 day of the stage 1, receive object to research unit (study unit) and accept naloxone HCl and excite test.For the object continued in this research, the result of test is necessary for feminine gender.Vital sign and SPO was measured before and after accepting naloxone HCl ₂.

Also following flow process is carried out to all objects when each stage check-in:

-examine and include/exclusion standard in, comprise the wish examined and defer to caffeine and xanthine limitation standard.

-vital sign (after sitting down about 5 minutes) and SpO ₂.

-HDYF (your how are you feeling today (How do you feel))? inquire while measurement vital sign.

-at measurement vital sign and SpO ₂collect clinical laboratory evaluations (only stage 1 the-1 day) afterwards, comprise biochemistry (fasting at least 4 hours), hematology and urinalysis.

-ethanol (by urine or blood alcohol or alcohol content tester inspection), cotinine and selected Drug abuse (passing through urine examination) examination.

-urine pregnancy tests (for all female subject).

The monitoring of-concomitant medication and record.

-AE monitoring and record.

For continuing the object of this research of participation, before administration, the result of drug screening (comprising ethanol and cotinine) must can obtain and be negative.In addition, when checking in and in whole research, the lasting compliance of concomitant medication and other restrictions is examined and is recorded in suitable source file (source documentation).

Treatment stage flow process

Treatment to be studied is pre-determined for each iteration.In iteration, along with data become available, treat and withdraw from from queue (cohort).The repetition that the treatment withdrawn from is treated by all the other replace.

-before the first administration in stage 1, object is randomized to treatment order.

-before institute's drugs administration-12 hours, object 240mL water accepted naltrexone HCl tablet (50mg).

-before institute's drugs is used (except the stage 1), chemistry (fasting at least 4 hours), hematology and urinalysis test are carried out to object.

-object uses institute's drugs with 240mL water as follows:

. for fasted treatment:

After 10 h overnight fast, object 240mL water uses institute's drugs.The object accepting fasted treatment continues fasting in 4 hours upon administration.

. for fed treatment:

After 10 h overnight fast, object is 30 minutes food sanitation standards meal (the higher fatty acid breakfast of FDA) before using institute's drugs with 240mL water.Within after administration at least 4 hours, do not allow feed.Make object very clear, all meals all should eat within the time limit of specifying.

Object accepts institute's drugs dosage when standing or be in rectilinear sitting posture.

Non-administration research day does not need fasting.

-relative to often kind of institute's drugs administration the-12,0,12,24 and 36 constantly little, object 240mL water accepts naltrexone HCl 50mg tablet.

-for the object of hydrocodone dosage accepting 60mg or more, continue to monitor SpO continuously in whole 24 hours before beginning administration and after administration ₂.

-for each stage, within before administration and after administration 1,2,4,6,8,12,24,36,48 and 72 hour, obtain vital sign (after sitting down about 5 minutes) and SpO ₂.

-HDYF (your how are you feeling today)? inquire while measurement vital sign.

Biochemistry (fasting at least 4 hours), hematology and urinalysis test were carried out to object in after-administration 24 hours.

-in addition, within before administration and after administration about 12,24 and 48 hours, 12 are carried out to every object and to lead ECG.If QTcF is more than 480 milliseconds, then this object stops because of the reason of adverse events.

-for each stage, within before administration and after administration 0.5,1,1.5,2,2.5,3,3.5,4,5,6,8,10,12,14,18,24,36,48 and 72 hour, obtain blood sample for measuring hydrocodone plasma concentration from every object.

-one day before administration, object is limited at unit (from check-in to unit) until time of completing of its 48 hours flow processs.Object turns back to unit and carries out 72 hours flow processs.

-during studying, record AE and concomitant medication.

In addition, object is known, research work personnel immediate record is any/all vomiting outbreak be very important and this information to test suitably carry out and result is vital.Object is known, they can not bear punishment by any way because of the situation of report vomiting.Instruction research work personnel carefully record any/all vomit situation.

Study flow process

Study terminate (research completes) time, accept their institute's drugs final dose after 7 to 10 days or give up the study of in early days time in research place, all following flow process is carried out to all objects.

The evaluation of-concomitant medication.

-vital sign (after sitting down about 5 minutes) and SpO ₂.

-HDYF? inquire while measurement vital sign.

-health check-up.

-12 lead ECG.

-clinical laboratory evaluations (comprising biochemistry [fasting at least 4 hours], hematology and urinalysis).

-AE evaluates.

-Serum Pregnancy test (only for female subject).

The PRELIMINARY RESULTS (draft result) of this research is as Fig. 4 ~ 6 with shown in following table 13:

The summary of the preliminary blood plasma hydrocodone pharmacokinetic parameter of table 13

Embodiment 14 ~ 20

According to having prepared the different pressed coated tablet (being called tablet M ~ S) of seven kinds of comprising total 20,30,40,60,80,100 or 120mg Hycodan respectively with following table 14 (tablet M, N, O, P) and table 15 (tablet Q, R, S).

Table 14 (tablet M, N, O, P)

Table 15 (tablet Q, R, S)

Hycodan, microcrystalline Cellulose and hydroxypropyl cellulose are loaded in high-shear mixer.

Close chopper make dry-blended mixture mix 1 minute with low speed, afterwards with at a high speed and mix under opening chopper.Water is added into until with the addition of the water of desired amount in mixture, thus produces wet granular.

Afterwards wet granular is passed through screening grater to remove caking, and be transferred to fluidized bed dryer for drying.

Afterwards dry mixture is passed through fine ga(u)ge screen until obtain target particles magnitude range (< 1.0%).

Afterwards by drying through sieved granule by screening grater, by effective powder collection in rustless steel container.V-arrangement blender is made to load the poly(ethylene oxide) (POLYOX WSR-205) of about half; Effective granule (being used for measuring through adjustment) of appropriate amount; Aluminum color forms sediment; And remaining poly(ethylene oxide) (POLYOX WSR-205), then make mixture blended 10 minutes.

Make V-arrangement blender load magnesium stearate and make mixture blended 2 minutes afterwards, be then discharged in stainless steel drum (drum).

V-arrangement agitator is made to load the poly(ethylene oxide) (POLYOX WSR-303) of about half; Effective granule (being used for measuring through adjustment) of appropriate amount; And remaining poly(ethylene oxide) (POLYOXWSR-303), then make mixture blended 10 minutes.

V-arrangement blender is made to load magnesium stearate afterwards; Blended 2 minutes, be then discharged in stainless steel drum.

The left side of press is set with circular scrobicula instrument (shallow concave tooling) of 8.75mm, the right side of press is set with circular scrobicula bevel edge instrument (shallow concave bevel edge tooling) of 12mm.

Afterwards, core blend (through painted) is loaded to left side hopper (gravity feed systems) to start core compacting.

Core weight is adjusted to target weight (300mg, +/-5%).

Afterwards, dry coating blend (white is to canescence) is loaded to right side hopper (gravity feed systems) to start tablet press.

After core is arranged, the total tablet weight of target (the dry coating of 300mg core+400mg) that initial dry coating filler and dry coating filler are subsequently adjusted to 700mg.

For Opadry color divergence body (target 20% solid), make mixer load the purified water of appropriate amount, adjusting mixer speed is to form eddy current.Through 2 ~ 5 minutes, Opadry coloured powders is added in vessel, and mixing is until produce uniform dispersion (minimum 1 hour).

For Opadry transparent dispersion (target 7.5% solid), make mixer separately load the purified water of appropriate amount, and adjusting mixer speed is to form eddy current.Through 2 ~ 5 minutes (target 3 minutes), transparent for Opadry powder is added in vessel, and mixing is until produce uniform dispersion (minimum 1 hour).

Afterwards, pressed coated tablet be transferred to the coating pan of porous and carry out film coating with Opadry color divergence body, until target weight increases by 0.7% ~ 1.5%.

Heating-up temperature is improved, then for the target exhaust mouth temperature of 72 DEG C, by tablet ripening about 30 minutes, cools afterwards.

Tablet coating is proceeded, until it is 3% (weight comprised from coating increases) that target weight increases with Opadry color divergence body.

Afterwards, with Opadry transparent dispersion, film coating is carried out to tablet, until it is 5% that final goal weight increases.

For 20mg, 30mg, 40mg, 60mg, 80mg, 100mg and 120mg tablet of these pressed coateds, stripping result (the active matter % through time release) is shown in in following table 16.

Table 16

Pressed coated 20,40,60,80, the stripping result (SGF, n=12) of 120mg tablet

Embodiment 21

The incomplete module research (incomplete block study) of random, open label, single dose in NAM and female subject, 5 kinds of treatments, 4 period crossover is carried out with the hydrocodone formulations (HYD) of embodiment 14 ~ 20.This research by maximum 5 kinds of treatments, intersected for 4 stages and form.

HYD tablet strength or the dosage of research are:

1 × 20mg HYD tablet

1 × 40mg HYD tablet

1 × 60mg HYD tablet

1 × 80mg HYD tablet

1 × 120mg HYD tablet

8 ounces of (240mL) water are used to treat respectively as single dose oral administration in the fasted state.

Because this research is carried out in Healthy People object, so use opioid antagonists naltrexone hydrochloride to be down to minimum by the adverse events relevant to opioid.

Object choice

Screening process

When the screening carried out in 28 days before using initial dose is made a house call, following screening process is carried out to all possible object:

-informed consent.

The informed consent of-optional Drug Discovery sampling.

The informed consent of-optional hair sampling.

-body weight, height, body-mass index (BMI) and Demographic data.

-include/evaluation of exclusion standard in.

-medical history and medication history, comprise concomitant medication.

-HDYF? inquire while measurement vital sign.

-routine physical examination.

-12 lead ECG.QTcF is no more than 450 milliseconds.

The examination of-ethanol, cotinine and selected Drug abuse.

-Serum Pregnancy test (only female subject).

Inclusive criteria

The object meeting following standard is included in this research.

-written informed consent is provided.

-be ready to eat the food provided during studying.

-body weight at 50 to 100kg (110 to 220 pounds) and BMI at 18 to 30 (kg/m ²) (comprising end value).

-until research access end is ready to avoid strenuous exercise.Object will not start new exercise program or participate in any very violent physical exertion.

-confirm as health by medical history, health check-up, clinical laboratory's value, vital sign and ECG and without remarkable anomaly.

Exclusion standard

Possible object is got rid of outside this research by following standard.

-current or nearest (in 5 years) medicine or alcohol abuse history.

-in this research institute's drugs beginning administration before past 30 days in use containing opioid medicine.

-known the allergies to hydrocodone, naltrexone or related compound.

-with any epilepsy of sequela or injury of head medical history.

-in this research institute's drugs beginning administration before participated in clinical drug research in 30 days.

-in this research institute's drugs beginning administration before any major disease in 30 days.

-before the beginning administration of institute's drugs, use any medicine in 7 days, comprise thyroid hormone treatment (hormonal contraceptive and under tool is with or without progestogen with the hormone replacement therapy of estrogen form be allow), vitamin, medical herbs and/or mineral supplements.

The QT interval of-any prolongation or the individual of rhythm of the heart disease or family's medical history

-comprise the abnormal heart disease of any following situation

Within-48 hours before starting to use institute's drugs (the 1st day), remove consume alcohol beverage with any time refusal of the end until research is made a house call.

-before starting to use institute's drugs in 30 days or until the research any time donated blood of end of inquiry or blood products, except needed for this programme.

-smoking history or use nicotine products or the test of urine cotinine to be the positive starting to use institute's drugs in 45 days.

The medicine examination of-urine or ethanol examination are positive findings.

-HBsAg, HCV-Ab IgG are positive findings.

-naloxone HCl excites test for positive.

-there is gill uncle's syndrome or any known liver and gall exception.

Unique object number is distributed by for object when examination.Being assigned as ascending order and not having number to omit of object number.Object number is used for all research files.

Check-in flow process

Only at the-1 day of the stage 1, object is received to excite test to studying unit and accepting naloxone HCl.For continuing the object of this research, the result of test is necessary for feminine gender.Vital sign and SPO was measured before and after accepting naloxone HCl ₂.

-vital sign (after sitting down about 5 minutes) and SpO ₂.

-HDYF (your how are you feeling today)? inquire while measurement vital sign.

-urine pregnancy tests (for all female subject).

The monitoring of-concomitant medication and record.

-AE monitoring and record.

For continuing the object of this research of participation, before administration, the result of drug screening (comprising ethanol and cotinine) must can obtain and be negative.In addition, when checking in and in whole research, the lasting compliance of concomitant medication and other restrictions is examined and is recorded in suitable source file.

Treatment stage flow process

Treatment to be studied is pre-determined for each iteration.In iteration, along with data become available, treat and withdraw from from queue.The repetition that the treatment withdrawn from is treated by all the other replace.

After-10 h overnight fast, object 240mL water uses institute's drugs.Object continues fasting in 4 hours upon administration.

Object accepts institute's drugs administration when standing or be in rectilinear sitting posture.

Non-administration research day does not need fasting.

-for each stage, within before administration and after administration 1,2.5,4,6,8,12,24,36,48 and 72 hour, obtain vital sign (after sitting down about 5 minutes) and SpO ₂.

-HDYF (your how are you feeling today)? inquire while measurement vital sign.

Within before-administration and after administration about 12,24 and 48 hours, 12 are carried out to every object and to lead ECG.

-for each stage, within before administration and after administration 0.5,1,2.5,4,6,8,10,12,14,16,18,24,36,48 and 72 hour, obtain blood sample for measuring hydrocodone plasma concentration from every object.

-one day before administration, object is limited at unit (from check-in to unit) until time of completing of its 72 hours flow processs.

-during studying, record AE and concomitant drugs.

Study flow process

The evaluation of-concomitant medication.

-vital sign (after sitting down about 5 minutes) and SpO ₂.

-HDYF? inquire while measurement vital sign.

-health check-up.

-12 lead ECG.

-AE evaluates.

-Serum Pregnancy test (only for female subject).

PRELIMINARY RESULTS is as Fig. 7 with shown in following table 17:

The summary of the preliminary blood plasma hydrocodone pharmacokinetic parameter of table 17

Specific embodiments disclosed in the present embodiment is not limit the scope of the invention, and described embodiment is intended to illustrate aspects more of the present invention, and any embodiment functionally of equal value all falls within the scope of the invention.In fact, except shown in herein and described except, be apparent to those skilled in the art to multiple change of the present invention, and be intended to fall within the scope of the appended claims.

This application claims the priority of the U.S.Provisional Serial 61/426,306 of December in 2010 submission on the 22nd, its disclosure is incorporated to herein by reference.

Other embodiments of the present invention relate to:

1. a solid Co ntrolled release dosage form, it comprises:

Core, it comprises the Part I non-opioid analgesic be dispersed in the first host material; With

Shell, non-opioid analgesic described in the Part II that its coated described core and comprising is dispersed in the second host material;

Wherein, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, the amount of the non-opioid analgesic discharged from described dosage form is proportional in 20% with the elapsed time at 8 to 24 hours.

2. the solid Co ntrolled release dosage form of embodiment 1, wherein said core is compressed tablets.

3. the solid Co ntrolled release dosage form of embodiment 1 or 2, wherein said shell is pressed coated.

4. the solid Co ntrolled release dosage form any one of embodiment 1 to 3, wherein said first host material comprises poly(ethylene oxide).

5. the solid Co ntrolled release dosage form any one of embodiment 1 to 4, wherein said second host material comprises poly(ethylene oxide).

6. the solid Co ntrolled release dosage form any one of embodiment 1 to 3, wherein said first host material and described second host material all comprise poly(ethylene oxide).

7. the solid Co ntrolled release dosage form of embodiment 6, the described poly(ethylene oxide) in wherein said second host material has the viscosity higher than the described poly(ethylene oxide) in described first host material.

8. the solid Co ntrolled release dosage form of embodiment 4, wherein said first host material comprises the poly(ethylene oxide) that mean molecule quantity is about 300,000 to about 10,000,000.

9. the solid Co ntrolled release dosage form of embodiment 8, wherein said first host material comprises the poly(ethylene oxide) that mean molecule quantity is about 500,000 to about 1,000,000.

10. the solid Co ntrolled release dosage form of embodiment 5, it is about 1,000 that wherein said second host material comprises mean molecule quantity, the poly(ethylene oxide) of 000 to about 10,000,000.

The solid Co ntrolled release dosage form of 11. embodiments 10, it is about 6,000 that wherein said second host material comprises mean molecule quantity, the poly(ethylene oxide) of 000 to about 8,000,000.

The solid Co ntrolled release dosage form of 12. embodiments 6, the mean molecule quantity of the described poly(ethylene oxide) in wherein said second host material is about 4,000,000 to about 10,000,000 and the mean molecule quantity of described poly(ethylene oxide) in described first host material is about 300,000 to about 3,000,000.

The solid Co ntrolled release dosage form of 13. embodiments 6, the mean molecule quantity of the described poly(ethylene oxide) in wherein said second host material is about 6,000,000 to about 8,000,000 and the mean molecule quantity of described poly(ethylene oxide) in described first host material is about 500,000 to about 1,000,000.

Solid Co ntrolled release dosage form any one of 14. embodiments 1 to 13, the weight ratio of wherein said core and described shell is about 1: 0.5 to about 1: 5.

The solid Co ntrolled release dosage form of 15. embodiments 14, the weight ratio of wherein said core and described shell is about 1: 0.6 to about 1: 1.5.

The solid Co ntrolled release dosage form of 16. embodiments 15, the weight ratio of wherein said core and described shell is about 1: 0.8 to about 1: 1.2.

The solid Co ntrolled release dosage form of 17. embodiments 4, wherein described in described first host material, the weight ratio of Part I non-opioid analgesic and poly(ethylene oxide) is about 1: 0.5 to about 1: 100.

The solid Co ntrolled release dosage form of 18. embodiments 17, wherein described in described first host material, the weight ratio of Part I non-opioid analgesic and poly(ethylene oxide) is about 1: 1 to about 1: 10.

The solid Co ntrolled release dosage form of 19. embodiments 18, wherein described in described first host material, the weight ratio of Part I non-opioid analgesic and poly(ethylene oxide) is about 1: 1.5 to about 1: 4.

The solid Co ntrolled release dosage form of 20. embodiments 5, wherein described in described second host material, the weight ratio of Part II non-opioid analgesic and poly(ethylene oxide) is about 1: 2 to about 1: 200.

The solid Co ntrolled release dosage form of 21. embodiments 20, wherein described in described second host material, the weight ratio of Part II non-opioid analgesic and poly(ethylene oxide) is about 1: 5 to about 1: 50.

The solid Co ntrolled release dosage form of 22. embodiments 21, wherein described in described second host material, the weight ratio of Part II non-opioid analgesic and poly(ethylene oxide) is about 1: 12 to about 1: 25.

Solid Co ntrolled release dosage form any one of 23. embodiments 1 to 22, the described non-opioid analgesic in wherein said Part I is identical with the described non-opioid analgesic in described Part II.

Solid Co ntrolled release dosage form any one of 24. embodiments 1 to 22, the non-opioid analgesic in wherein said Part I is different from the non-opioid analgesic in described Part II.

Solid Co ntrolled release dosage form any one of 25. embodiments 1 to 24, in wherein said core, in non-opioid analgesic and described shell, the ratio of non-opioid analgesic is about 1: 1 to about 10: 1.

The solid Co ntrolled release dosage form of 26. embodiments 25, in wherein said core, in non-opioid analgesic and described shell, the ratio of non-opioid analgesic is about 2: 1 to about 8: 1.

The solid Co ntrolled release dosage form of 27. embodiments 25, in wherein said core, in non-opioid analgesic and described shell, the ratio of non-opioid analgesic is about 2: 1 to about 5: 1.

Solid Co ntrolled release dosage form any one of 28. embodiments 1 to 27, wherein said non-opioid analgesic is selected from alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, Clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphine, dihydrocodeine, paramorphan (dihydromorphine), dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivant, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, Pethidine, meptazinol, metazocine, methadone, metopon, morphine, Myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, pirinitramide, proheptazine, Promedol, properidine, third oxygen is fragrant, sufentanil, tilidate, tramadol, its officinal salt, its hydrate, its solvate, and composition thereof.

The solid Co ntrolled release dosage form of 29. embodiments 28, wherein said non-opioid analgesic be selected from codeine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, tramadol, its officinal salt, its hydrate, its solvate, and composition thereof.

The solid Co ntrolled release dosage form of 30. embodiments 29, wherein said non-opioid analgesic be selected from hydrocodone, its officinal salt, its hydrate, its solvate, and composition thereof.

The solid Co ntrolled release dosage form of 31. embodiments 30, wherein said non-opioid analgesic is Hycodan.

The solid Co ntrolled release dosage form of 32. embodiments 31, wherein the total amount of Hycodan in described dosage form is about 0.5mg to about 1250mg.

The solid Co ntrolled release dosage form of 33. embodiments 31, wherein the total amount of Hycodan in described dosage form is about 2mg to about 200mg.

The solid Co ntrolled release dosage form of 34. embodiments 31, wherein the total amount of Hycodan in described dosage form is about 16mg to about 120mg.

Solid Co ntrolled release dosage form any one of 35. embodiments 1 to 34, the amount of the non-opioid analgesic wherein discharged is proportional in 10% with the elapsed time at 8 to 24 hours.

The solid Co ntrolled release dosage form of 36. embodiments 35, the amount of the non-opioid analgesic wherein discharged is proportional in 5% with the elapsed time at 8 to 24 hours.

Solid Co ntrolled release dosage form any one of 37. embodiments 1 to 34, the amount of the non-opioid analgesic wherein discharged is proportional in 20% with the elapsed time at 8 to 18 hours.

Solid Co ntrolled release dosage form any one of 38. embodiments 1 to 34, the amount of the non-opioid analgesic wherein discharged is proportional in 20% with the elapsed time at 8 to 12 hours.

Solid Co ntrolled release dosage form any one of 39. embodiments 1 to 34, the amount of the non-opioid analgesic wherein discharged is proportional in 20% with the elapsed time at 12 to 24 hours.

Solid Co ntrolled release dosage form any one of 40. embodiments 1 to 34, the amount of the non-opioid analgesic wherein discharged is proportional in 20% with the elapsed time at 12 to 18 hours.

The solid Co ntrolled release dosage form of 41. embodiments 37, the amount of the non-opioid analgesic wherein discharged is proportional in 10% with the elapsed time at 8 to 18 hours.

The solid Co ntrolled release dosage form of 42. embodiments 38, the amount of the non-opioid analgesic wherein discharged is proportional in 10% with the elapsed time at 8 to 12 hours.

The solid Co ntrolled release dosage form of 43. embodiments 39, the amount of the non-opioid analgesic wherein discharged is proportional in 10% with the elapsed time at 12 to 24 hours.

The solid Co ntrolled release dosage form of 44. embodiments 40, the amount of the non-opioid analgesic wherein discharged is proportional in 10% with the elapsed time at 12 to 18 hours.

The solid Co ntrolled release dosage form of 45. embodiments 37, the amount of the non-opioid analgesic wherein discharged is proportional in 5% with the elapsed time at 8 to 18 hours.

The solid Co ntrolled release dosage form of 46. embodiments 38, the amount of the non-opioid analgesic wherein discharged is proportional in 5% with the elapsed time at 8 to 12 hours.

The solid Co ntrolled release dosage form of 47. embodiments 39, the amount of the non-opioid analgesic wherein discharged is proportional in 5% with the elapsed time at 12 to 24 hours.

The solid Co ntrolled release dosage form of 48. embodiments 40, the amount of the non-opioid analgesic wherein discharged is proportional in 5% with the elapsed time at 12 to 18 hours.

Solid Co ntrolled release dosage form any one of 49. embodiments 1 to 48, is wherein less than about 25% in the amount of the 2 little non-opioid analgesic discharged constantly.

Solid Co ntrolled release dosage form any one of 50. embodiments 1 to 49 is wherein about 10% to about 30% in the amount of the 4 little non-opioid analgesic discharged constantly.

Solid Co ntrolled release dosage form any one of 51. embodiments 1 to 50 is wherein about 20% to about 60% in the amount of the 8 little non-opioid analgesic discharged constantly.

Solid Co ntrolled release dosage form any one of 52. embodiments 1 to 51 is wherein about 40% to about 90% in the amount of the 12 little non-opioid analgesic discharged constantly.

Solid Co ntrolled release dosage form any one of 53. embodiments 1 to 52, is wherein greater than about 70% in the amount of the 18 little non-opioid analgesic discharged constantly.

Solid Co ntrolled release dosage form any one of 54. embodiments 1 to 53, is wherein less than about 20% in the amount of the 2 little non-opioid analgesic discharged constantly.

Solid Co ntrolled release dosage form any one of 55. embodiments 1 to 54 is wherein about 10% to about 20% in the amount of the 4 little non-opioid analgesic discharged constantly.

Solid Co ntrolled release dosage form any one of 56. embodiments 1 to 55 is wherein about 20% to about 40% in the amount of the 8 little non-opioid analgesic discharged constantly.

Solid Co ntrolled release dosage form any one of 57. embodiments 1 to 56 is wherein about 40% to about 65% in the amount of the 12 little non-opioid analgesic discharged constantly.

Solid Co ntrolled release dosage form any one of 58. embodiments 1 to 57, is wherein greater than about 80% in the amount of the 18 little non-opioid analgesic discharged constantly.

Solid Co ntrolled release dosage form any one of 59. embodiments 1 to 58, is wherein less than about 15% in the amount of the 2 little non-opioid analgesic discharged constantly.

Solid Co ntrolled release dosage form any one of 60. embodiments 1 to 59 is wherein about 20% to about 30% in the amount of the 4 little non-opioid analgesic discharged constantly.

Solid Co ntrolled release dosage form any one of 61. embodiments 1 to 60 is wherein about 45% to about 60% in the amount of the 8 little non-opioid analgesic discharged constantly.

Solid Co ntrolled release dosage form any one of 62. embodiments 1 to 61 is wherein about 70% to about 90% in the amount of the 12 little non-opioid analgesic discharged constantly.

Solid Co ntrolled release dosage form any one of 63. embodiments 1 to 62, is wherein greater than about 90% in the amount of the 18 little non-opioid analgesic discharged constantly.

The solid Co ntrolled release dosage form of 64. embodiments 6, wherein described dosage form ripening at least 1 minute at the temperature of the softening point of at least described poly(ethylene oxide).

The solid Co ntrolled release dosage form of 65. embodiments 6, wherein described dosage form ripening at least 5 minutes at the temperature of the softening point of at least described poly(ethylene oxide).

The solid Co ntrolled release dosage form of 66. embodiments 6, wherein described dosage form ripening at least 15 minutes at the temperature of the softening point of at least described poly(ethylene oxide).

The solid Co ntrolled release dosage form of 67. embodiments 6, wherein described dosage form ripening about 1 minute to about 48 hours at the temperature of the softening point of at least described poly(ethylene oxide).

The solid Co ntrolled release dosage form of 68. embodiments 6, wherein described dosage form ripening about 5 minutes to about 24 hours at the temperature of the softening point of at least described poly(ethylene oxide).

The solid Co ntrolled release dosage form of 69. embodiments 6, wherein described dosage form ripening about 15 minutes to about 1 hour at the temperature of the softening point of at least described poly(ethylene oxide).

Solid Co ntrolled release dosage form any one of 70. embodiments 64 to 69, wherein described dosage form ripening at least about the temperature of 60 DEG C.

Solid Co ntrolled release dosage form any one of 71. embodiments 64 to 69, wherein described dosage form ripening at least about the temperature of 65 DEG C.

Solid Co ntrolled release dosage form any one of 72. embodiments 64 to 69, wherein described dosage form ripening at least about the temperature of 70 DEG C.

Solid Co ntrolled release dosage form any one of 73. embodiments 64 to 69, wherein described dosage form ripening at least about the temperature of 75 DEG C.

Solid Co ntrolled release dosage form any one of 74. embodiments 64 to 69, wherein described dosage form ripening at the temperature of about 72 DEG C.

Solid Co ntrolled release dosage form any one of 75. embodiments 64 to 69, wherein described dosage form ripening at the temperature of about 60 DEG C to about 90 DEG C.

Solid Co ntrolled release dosage form any one of 76. embodiments 64 to 69, wherein described dosage form ripening at the temperature of about 65 DEG C to about 85 DEG C.

Solid Co ntrolled release dosage form any one of 77. embodiments 64 to 69, wherein described dosage form ripening at the temperature of about 70 DEG C to about 80 DEG C.

Solid Co ntrolled release dosage form any one of 78. embodiments 64 to 69, wherein described dosage form ripening at the temperature of about 75 DEG C to about 80 DEG C.

Solid Co ntrolled release dosage form any one of 79. embodiments 64 to 69, wherein described dosage form ripening at the temperature of about 70 DEG C to about 75 DEG C.

Solid Co ntrolled release dosage form any one of 80. embodiments 1 to 79, wherein said core and described shell visually undistinguishable.

Solid Co ntrolled release dosage form any one of 81. embodiments 1 to 79, wherein said core and described shell have the CIE L*A*B* value each other within 10%.

Solid Co ntrolled release dosage form any one of 82. embodiments 1 to 81, wherein said dosage form is collapsible and not broken, after being wherein crushed the thickness of described dosage form be equivalent to be crushed before described dosage form thickness be no more than about 60%.

The solid Co ntrolled release dosage form of 83. embodiments 82, wherein said dosage form is collapsible and not broken, after being wherein crushed the thickness of described dosage form be equivalent to be crushed before described dosage form thickness be no more than about 50%.

The solid Co ntrolled release dosage form of 84. embodiments 82, wherein said dosage form is collapsible and not broken, after being wherein crushed the thickness of described dosage form be equivalent to be crushed before described dosage form thickness be no more than about 40%.

The solid Co ntrolled release dosage form of 85. embodiments 82, wherein said dosage form is collapsible and not broken, after being wherein crushed the thickness of described dosage form be equivalent to be crushed before described dosage form thickness be no more than about 30%.

The solid Co ntrolled release dosage form of 86. embodiments 82, wherein said dosage form is collapsible and not broken, after being wherein crushed the thickness of described dosage form be equivalent to be crushed before described dosage form thickness be no more than about 20%.

Solid Co ntrolled release dosage form any one of 87. embodiments 82 to 86, wherein, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, be littlely no more than about 20% point from amount deviation compared with the dosage form that is not crushed of the non-opioid analgesic of the dosage form release that is crushed constantly 0.5.

Solid Co ntrolled release dosage form any one of 88. embodiments 82 to 86, wherein, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, be littlely no more than about 15% point from amount deviation compared with the dosage form that is not crushed of the non-opioid analgesic of the dosage form release that is crushed constantly 0.5.

Solid Co ntrolled release dosage form any one of 89. embodiments 82 to 86, wherein, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, be littlely no more than about 10% point from amount deviation compared with the dosage form that is not crushed of the non-opioid analgesic of the dosage form release that is crushed constantly 0.5.

The solid Co ntrolled release dosage form of 90. embodiments 30, it provides the C of the hydrocodone of about 0.55 to about 1.0 after application ₂₄/ C _maxratio.

The solid Co ntrolled release dosage form of 91. embodiments 90, wherein said C ₂₄/ C _maxratio is about 0.55 to about 0.85.

The solid Co ntrolled release dosage form of 92. embodiments 90, wherein said C ₂₄/ C _maxratio is about 0.55 to about 0.75.

The solid Co ntrolled release dosage form of 93. embodiments 90, wherein said C ₂₄/ C _maxratio is about 0.60 to about 0.70.

The solid Co ntrolled release dosage form of 94. embodiments 30, it provides the T of the hydrocodone of about 4 to about 20 hours after application _max(h).

The solid Co ntrolled release dosage form of 95. embodiments 94, wherein said T _maxh () is about 6 to about 12 hours.

The solid Co ntrolled release dosage form of 96. embodiments 94, wherein said T _maxh () is about 8 to about 10 hours.

The solid Co ntrolled release dosage form of 97. embodiments 94, wherein said T _maxh () is about 4 to about 10 hours.

The solid Co ntrolled release dosage form of 98. embodiments 94, wherein said T _maxh () is about 8 to about 14 hours.

The solid Co ntrolled release dosage form of 99. embodiments 94, wherein, after using described dosage form, described T _mmaxh () is about 14 to about 20 hours.

Solid Co ntrolled release dosage form any one of 100. embodiments 90 to 99, wherein saidly uses as using first to health objects.

Solid Co ntrolled release dosage form any one of 101. embodiments 90 to 99, wherein saidly uses using first for the colony to health objects.

Solid Co ntrolled release dosage form any one of 102. embodiments 90 to 99, wherein saidly uses as the stable state to health objects is used.

Solid Co ntrolled release dosage form any one of 103. embodiments 90 to 99, the wherein said stable state used as the colony to health objects is used.

The solid Co ntrolled release dosage form of 104. embodiments 30, it is containing 20mg hydrocodone or its officinal salt of having an appointment.

The solid Co ntrolled release dosage form of 105. embodiments 30, it is containing 120mg hydrocodone or its officinal salt of having an appointment.

The solid Co ntrolled release dosage form of 106. embodiments 30, its after application every 20mg hydrocodone be included in described dosage form the average A UC (ng*h/mL) of about 250 to 400 is provided.

The solid Co ntrolled release dosage form of 107. embodiments 104, it provides about 250 after application to about 400, about 275 to about 350, about 300 to 330 or the average A UC (ng*h/mL) of about 280 to about 320.

The solid Co ntrolled release dosage form of 108. embodiments 105, it provides about 1500 to about 2400, about 1700 to about 2200, about 1800 after application to about 2100 or the average A UC (ng*h/mL) of about 1900 to about 2100.

The solid Co ntrolled release dosage form of 109. embodiments 30, its after application every 20mg hydrocodone be included in described dosage form the average C of about 10 to about 30 is provided _max(ng/mL).

The solid Co ntrolled release dosage form of 110. embodiments 104, it provides about 10 to about 30, about 12 to about 25, about 14 after application to the average C of about 18 or about 12 to about 17 _max(ng/mL).

The solid Co ntrolled release dosage form of 111. embodiments 105, it provides about 60 to about 180, about 100 to about 160, about 110 after application to the average C of about 150 or about 100 to about 140 _max(ng/mL).

The solid Co ntrolled release dosage form of 112. embodiments 30, it provides about 10 to about 20, about 12 to about 18, about 13 after application to about 17 or the average T of about 14 to about 16 _max(h).

The solid Co ntrolled release dosage form of 113. embodiments 30, its provide after application about 5 to about 10, about 6 to about 9, about 7 or about 8 average T _1/2(h).

The solid Co ntrolled release dosage form of 114. embodiments 30, it provides about 0.01 to about 0.2, about 0.1 to about 0.18, about 0.3 after application to about 0.17 or the average T of about 0.06 to about 0.15 _lag(h).

The solid Co ntrolled release dosage form of 115. embodiments 30, wherein said average C ₂₄/ C _maxratio is about 0.2 to about 0.8, about 0.3 to about 0.7 or about 0.4 to about 0.6.

Solid Co ntrolled release dosage form any one of 116. embodiments 106 to 115, wherein uses in the fasted state.

The solid Co ntrolled release dosage form of 117. embodiments 30, wherein uses rear described average A UC (ng*h/mL) under state on the feed than using rear described AUC (ng*h/mL) in the fasted state and exceed less than 20%, less than 16% or less than 12%.

The solid Co ntrolled release dosage form of 118. embodiments 30, wherein uses rear described average C under state on the feed _max(ng/mL) than using rear described C in the fasted state _max(ng/mL) exceed less than 80%, less than 70% or less than 60%.

The solid Co ntrolled release dosage form of 119. embodiments 30, wherein uses rear described average T under state on the feed _maxh () is for use rear described T in the fasted state _max(h) 25% within, within 20% or within 15%.

The solid Co ntrolled release dosage form of 120. embodiments 30, wherein uses rear described average T under state on the feed _1/2h () is for use rear described T in the fasted state _1/2(h) 8% within, within 5% or within 2%.

The solid Co ntrolled release dosage form of 121. embodiments 30, wherein uses rear described average T under state on the feed _lagh () is than using rear described T in the fasted state _1/2exceed less than 150%, less than 125% or less than 100%.

122. one kinds of solid Co ntrolled release dosage forms, it comprises:

Core, it comprises the Part I non-opioid analgesic being dispersed in and comprising in the first host material of poly(ethylene oxide); With

Shell, its coated described core and comprise non-opioid analgesic described in the Part II that is dispersed in and comprises in the second host material of poly(ethylene oxide).

123. one kinds of solid Co ntrolled release dosage forms, it comprises:

Compacting core, it comprises the Part I non-opioid analgesic being dispersed in and comprising in the first host material of poly(ethylene oxide); With

Pressed coated, its coated described core and comprise non-opioid analgesic described in the Part II that is dispersed in and comprises in the second host material of poly(ethylene oxide).

124. one kinds of solid Co ntrolled release dosage forms, it comprises:

Wherein, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm,

About 25% is less than in the amount of the 2 little non-opioid analgesic discharged from described dosage form constantly;

Be about 10% to about 30% in the amount of the 4 little non-opioid analgesic discharged from described dosage form constantly;

Be about 20% to about 60% in the amount of the 8 little non-opioid analgesic discharged from described dosage form constantly;

Be about 40% to about 90% in the amount of the 12 little non-opioid analgesic discharged from described dosage form constantly; And

About 70% is greater than in the amount of the 18 little non-opioid analgesic discharged from described dosage form constantly.

125. one kinds of solid Co ntrolled release dosage forms, it comprises:

The hydrocodone for the treatment of effective dose or its officinal salt, and Co ntrolled release excipient;

Wherein, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, the hydrocodone discharged from described dosage form or the amount of its salt proportional in 20% with the elapsed time at 8 to 24 hours; And

Described dosage form is collapsible and not broken, after being wherein crushed the thickness of described dosage form be equivalent to be crushed before described dosage form thickness be no more than about 20%; And

As by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, be littlely no more than about 20% point from the be crushed hydrocodone of dosage form release or amount deviation compared with the dosage form that is not crushed of its salt constantly 0.5.

126. one kinds of solid Co ntrolled release dosage forms, it comprises:

About 25% is less than in the amount of the 2 little hydrocodones that discharge from described dosage form constantly or its salt;

Be about 10% to about 30% in the amount of the 4 little hydrocodones that discharge from described dosage form constantly or its salt;

Be about 20% to about 60% in the amount of the 8 little hydrocodones that discharge from described dosage form constantly or its salt;

Be about 40% to about 90% in the amount of the 12 little hydrocodones that discharge from described dosage form constantly or its salt; With

About 70% is greater than in the amount of the 18 little hydrocodones that discharge from described dosage form constantly or its salt;

And

127. one kinds of solid Co ntrolled release dosage forms, it comprises:

Be dispersed in hydrocodone or its officinal salt of the treatment effective dose in Co ntrolled release excipient; Described hydrocodone or its salt of at least 80% are contained in the inside 60% of wherein said dosage form;

Wherein, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, the hydrocodone discharged from described dosage form or the amount of its salt proportional in 20% with the elapsed time at 8 to 24 hours.

The solid Co ntrolled release dosage form of 128. embodiments 127, described hydrocodone or its salt of at least 80% are contained in the inside 50% of wherein said dosage form.

129. one kinds of methods for the treatment of pain in the object having this to need, it comprises uses solid Co ntrolled release dosage form any one of embodiment 1 to 128 to described object.

130. one kinds of methods preparing solid Co ntrolled release dosage form, it comprises:

Preparation core, described core comprises the Part I non-opioid analgesic be dispersed in the first host material; With

By the coated described core of shell, described shell comprises non-opioid analgesic described in the Part II that is dispersed in the second host material;

131. one kinds of methods preparing solid Co ntrolled release dosage form, it comprises:

Preparation core, described core comprises the Part I non-opioid analgesic being dispersed in and comprising in the first host material of poly(ethylene oxide); With

By described core coating in shell, described shell comprises non-opioid analgesic described in the Part II that is dispersed in and comprises in the second host material of poly(ethylene oxide).

132. one kinds of methods preparing solid Co ntrolled release dosage form, it comprises:

Preparation compacting core, described core comprises the Part I non-opioid analgesic being dispersed in and comprising in the first host material of poly(ethylene oxide); With

By carrying out coated described core to be dispersed in non-opioid analgesic pressed coated described in the Part II that comprises in the second host material of poly(ethylene oxide) on the core.

133. one kinds of methods preparing solid Co ntrolled release dosage form, it comprises:

By described core coating in shell, described shell comprises non-opioid analgesic described in the Part II in dispersion the second host material on the core;

Be about 40% to about 90% in the amount of the 12 little non-opioid analgesic discharged from described dosage form constantly; With

134. one kinds of methods preparing solid Co ntrolled release dosage form, it comprises:

By the treatment hydrocodone of effective dose or its officinal salt and Co ntrolled release excipient combined;

Wherein, as by USP device 1 (basket) with 100rpm at 37 DEG C in 900ml is containing the simulated gastric fluid (SGF) of enzyme measured by In Vitro Dissolution, the hydrocodone discharged from described dosage form or the amount of its salt any two time points of 8 to 24 hours and the elapsed time proportional in 20%; And

135. one kinds of methods preparing solid Co ntrolled release dosage form, it comprises:

Be about 40% to about 90% in the amount of the 12 little hydrocodones that discharge from described dosage form constantly or its salt; And

And

136. one kinds of methods preparing solid Co ntrolled release dosage form, it comprises:

The hydrocodone for the treatment of effective dose or its officinal salt are distributed in Co ntrolled release excipient; Described hydrocodone or its salt of at least 80% are contained in the inside 60% of wherein said dosage form;

Claims

1. a solid Co ntrolled release dosage form, it comprises:

Wherein said non-opioid analgesic be selected from hydrocodone, its officinal salt, its hydrate, its solvate, and composition thereof;

2. the solid Co ntrolled release dosage form of claim 1, wherein said core is compressed tablets.

3. the solid Co ntrolled release dosage form of claim 1 or 2, wherein said shell is pressed coated.

4. the solid Co ntrolled release dosage form any one of claims 1 to 3, wherein said first host material comprises poly(ethylene oxide).

5. the solid Co ntrolled release dosage form any one of Claims 1-4, wherein said second host material comprises poly(ethylene oxide).

6. the solid Co ntrolled release dosage form any one of claims 1 to 3, wherein said first host material and described second host material all comprise poly(ethylene oxide), and the described poly(ethylene oxide) wherein preferably in described second host material has the viscosity higher than the described poly(ethylene oxide) in described first host material.

7. the solid Co ntrolled release dosage form of claim 4, it is about 300,000 to about 10,000,000, preferably about 500 that wherein said first host material comprises mean molecule quantity, the poly(ethylene oxide) of 000 to about 1,000,000.

8. the solid Co ntrolled release dosage form of claim 5, it is about 1,000 that wherein said second host material comprises mean molecule quantity, 000 to about 10,000,000, preferably about 6, the poly(ethylene oxide) of 000,000 to about 8,000,000.

9. the solid Co ntrolled release dosage form of claim 6, the mean molecule quantity of the described poly(ethylene oxide) in wherein said second host material is about 4,000,000 to about 10,000,000 and the mean molecule quantity of described poly(ethylene oxide) in described first host material is about 300,000 to about 3,000,000, or the mean molecule quantity of described poly(ethylene oxide) in wherein said second host material is about 6,000,000 to about 8,000,000 and the mean molecule quantity of described poly(ethylene oxide) in described first host material is about 500,000 to about 1,000,000.

10. the solid Co ntrolled release dosage form any one of claim 1 to 9, the weight ratio of wherein said core and described shell is about 1: 0.5 to about 1: 5, is preferably about 1: 0.6 to about 1: 1.5, is more preferably about 1: 0.8 to about 1: 1.2.

The solid Co ntrolled release dosage form of 11. claim 4, wherein described in described first host material, the weight ratio of Part I non-opioid analgesic and poly(ethylene oxide) is about 1: 0.5 to about 1: 100, be preferably about 1: 1 to about 1: 10, be more preferably about 1: 1.5 to about 1: 4.

The solid Co ntrolled release dosage form of 12. claim 5, wherein described in described second host material, the weight ratio of Part II non-opioid analgesic and poly(ethylene oxide) is about 1: 2 to about 1: 200, be preferably about 1: 5 to about 1: 50, be more preferably about 1: 12 to about 1: 25.

Solid Co ntrolled release dosage form any one of 13. claim 1 to 12, in wherein said core, in non-opioid analgesic and described shell, the ratio of non-opioid analgesic is about 1: 1 to about 10: 1, be preferably about 2: 1 to about 8: 1, be more preferably about 2: 1 to about 5: 1.

Solid Co ntrolled release dosage form any one of 14. claim 1 to 13, wherein said non-opioid analgesic is Hycodan.

The solid Co ntrolled release dosage form of 15. claim 14, wherein the total amount of Hycodan in described dosage form is about 0.5mg to about 1250mg, or about 2mg to about 200mg, or about 16mg to about 120mg.

Solid Co ntrolled release dosage form any one of 16. claim 1 to 15, the amount of the non-opioid analgesic wherein discharged 8 to 24 hours with the elapsed time in 10%, preferably proportional in 5%.

Solid Co ntrolled release dosage form any one of 17. claim 1 to 15, the amount of the non-opioid analgesic wherein discharged 8 to 18 hours with the elapsed time in 20%, preferably proportional in 10% or in 5%.

Solid Co ntrolled release dosage form any one of 18. claim 1 to 15, the amount of the non-opioid analgesic wherein discharged 8 to 12 hours with the elapsed time in 20%, preferably proportional in 10% or in 5%.

Solid Co ntrolled release dosage form any one of 19. claim 1 to 15, the amount of the non-opioid analgesic wherein discharged 12 to 24 hours with the elapsed time in 20%, preferably proportional in 10% or in 5%.

Solid Co ntrolled release dosage form any one of 20. claim 1 to 15, the amount of the non-opioid analgesic wherein discharged 12 to 18 hours with the elapsed time in 20%, preferably proportional in 10% or in 5%.

Solid Co ntrolled release dosage form any one of 21. claim 1 to 20, is wherein less than about 25% in the amount of the 2 little non-opioid analgesic discharged constantly, and/or

Be wherein about 10% to about 30% in the amount of the 4 little non-opioid analgesic discharged constantly, and/or

Be wherein about 20% to about 60% in the amount of the 8 little non-opioid analgesic discharged constantly, and/or

Be wherein about 40% to about 90% in the amount of the 12 little non-opioid analgesic discharged constantly, and/or

Wherein be greater than about 70% in the amount of the 18 little non-opioid analgesic discharged constantly.

Solid Co ntrolled release dosage form any one of 22. claim 1 to 21, is wherein less than about 20% in the amount of the 2 little non-opioid analgesic discharged constantly, and/or

Be wherein about 10% to about 20% in the amount of the 4 little non-opioid analgesic discharged constantly, and/or

Be wherein about 20% to about 40% in the amount of the 8 little non-opioid analgesic discharged constantly, and/or

Be wherein about 40% to about 65% in the amount of the 12 little non-opioid analgesic discharged constantly, and/or

Wherein be greater than about 80% in the amount of the 18 little non-opioid analgesic discharged constantly.

Solid Co ntrolled release dosage form any one of 23. claim 1 to 22, is wherein less than about 15% in the amount of the 2 little non-opioid analgesic discharged constantly, and/or

Be wherein about 20% to about 30% in the amount of the 4 little non-opioid analgesic discharged constantly, and/or

Be wherein about 45% to about 60% in the amount of the 8 little non-opioid analgesic discharged constantly, and/or

Be wherein about 70% to about 90% in the amount of the 12 little non-opioid analgesic discharged constantly, and/or

Wherein be greater than about 90% in the amount of the 18 little non-opioid analgesic discharged constantly.

The solid Co ntrolled release dosage form of 24. claim 6, wherein by dosage form described in ripening at the temperature of the softening point of at least described poly(ethylene oxide) at least 1 minute, at least 5 minutes, or within least 15 minutes, obtain described solid Co ntrolled release dosage form.

The solid Co ntrolled release dosage form of 25. claim 6, wherein by dosage form described in ripening at the temperature of the softening point of at least described poly(ethylene oxide) about 1 minute to about 48 hours, or about 5 minutes to about 24 hours, or about 15 minutes to about 1 hour obtain described solid Co ntrolled release dosage form.

The solid Co ntrolled release dosage form of 26. claim 24 or 25, wherein by least about 60 DEG C, at least about 65 DEG C, at least about 70 DEG C, at least about the temperature of 75 DEG C or about 72 DEG C under dosage form described in ripening obtain described solid Co ntrolled release dosage form.

The solid Co ntrolled release dosage form of 27. claim 24 or 25, wherein obtains described solid Co ntrolled release dosage form by dosage form described in ripening at the temperature of about 60 DEG C to about 90 DEG C or about 65 DEG C to about 85 DEG C or about 70 DEG C to about 80 DEG C or about 75 DEG C to about 80 DEG C or about 70 DEG C to about 75 DEG C.

Solid Co ntrolled release dosage form any one of 28. claim 1 to 27, wherein said core and described shell visually undistinguishable, or wherein said core and described shell have the CIE L*A*B* value each other within 10%.

Solid Co ntrolled release dosage form any one of 29. claim 1 to 28, wherein said dosage form is collapsible and not broken, after being wherein crushed the thickness of described dosage form be equivalent to be crushed before described dosage form thickness be no more than about 60%, after being preferably crushed the thickness of described dosage form be equivalent to be crushed before described dosage form thickness be no more than about 50%, or be no more than about 40%, or be no more than about 30%, or be no more than about 20%.

The solid Co ntrolled release dosage form of 30. claim 29, wherein, measured by the middle In Vitro Dissolution of simulated gastric fluid (SGF) by not containing enzyme in USP device 1 (basket) at 37 DEG C in 900ml with 100rpm, littlely about 20% point is no more than from amount deviation compared with the dosage form that is not crushed of non-opioid analgesic of the dosage form release that is crushed constantly 0.5, or be no more than about 15% point, or be no more than about 10% point.

Solid Co ntrolled release dosage form any one of 31. claims 1 to 30, it provides the C of the hydrocodone of about 0.55 to about 1.0 after application ₂₄/ C _maxratio, preferably described C ₂₄/ C _maxratio is about 0.55 to about 0.85, or about 0.55 to about 0.75, or about 0.60 to about 0.70.

Solid Co ntrolled release dosage form any one of 32. claims 1 to 31, it provides the T of the hydrocodone of about 4 to about 20 hours after application _max(h), preferably described T after using described dosage form _maxh () is about 6 to about 12 hours, or about 8 to about 10 hours, or about 4 to about 10 hours, or about 8 to about 14 hours, or about 14 to about 20 hours.

The solid Co ntrolled release dosage form of 33. claim 31 or 32, wherein saidly uses using first for the colony to health objects or health objects, or

The wherein said stable state used as the colony to health objects or health objects is used.

Solid Co ntrolled release dosage form any one of 34. claim 1 to 13, it is containing 20mg hydrocodone or its officinal salt of having an appointment.

Solid Co ntrolled release dosage form any one of 35. claim 1 to 13, it is containing 120mg hydrocodone or its officinal salt of having an appointment.

Solid Co ntrolled release dosage form any one of 36. claim 1 to 13, its after application every 20mg hydrocodone be included in described dosage form the average A UC (ng*h/mL) of about 250 to 400 is provided, and/or its after application every 20mg hydrocodone be included in described dosage form the average C of about 10 to about 30 is provided _max(ng/mL).

The solid Co ntrolled release dosage form of 37. claim 34, it provides about 250 after application to about 400, about 275 to about 350, about 300 to 330 or the average A UC (ng*h/mL) of about 280 to about 320, and/or it provides about 10 to about 30, about 12 to about 25, about 14 after application to the average C of about 18 or about 12 to about 17 _max(ng/mL).

The solid Co ntrolled release dosage form of 38. claim 35, it provides about 1500 after application to about 2400, about 1700 to about 2200, about 1800 to about 2100 or the average A UC (ng*h/mL) of about 1900 to about 2100, and/or it provides about 60 to about 180, about 100 to about 160, about 110 after application to the average C of about 150 or about 100 to about 140 _max(ng/mL).

Solid Co ntrolled release dosage form any one of 39. claim 1 to 13, it provides about 10 to about 20, about 12 to about 18, about 13 after application to about 17 or the average T of about 14 to about 16 _max(h), and/or its provide after application about 5 to about 10, about 6 to about 9, about 7 or about 8 average T _1/2(h), and/or it provides about 0.01 to about 0.2, about 0.1 to about 0.18, about 0.3 after application to about 0.17 or the average T of about 0.06 to about 0.15 _lag(h), and/or wherein said average C ₂₄/ C _maxratio is about 0.2 to about 0.8, about 0.3 to about 0.7 or about 0.4 to about 0.6.

Solid Co ntrolled release dosage form any one of 40. claim 36 to 40, wherein uses in the fasted state.

Solid Co ntrolled release dosage form any one of 41. claim 1 to 13, average A UC (ng*h/mL) after wherein using under state on the feed exceeds less than 20%, less than 16% or less than 12% than the AUC (ng*h/mL) after using in the fasted state, and/or the average C after wherein using under state on the feed _max(ng/mL) than the C after using in the fasted state _max(ng/mL) exceed less than 80%, less than 70% or less than 60%.

Solid Co ntrolled release dosage form any one of 42. claim 1 to 13, the average T after wherein using under state on the feed _maxh () is the T after using in the fasted state _max(h) 25% within, within 20% or within 15%, and/or the average T after wherein using under state on the feed _1/2h () is the T after using in the fasted state _1/2(h) 8% within, within 5% or within 2%, and/or the average T after wherein using under state on the feed _lagh () is than the T after using in the fasted state _1/2exceed less than 150%, less than 125% or less than 100%.

Solid Co ntrolled release dosage form any one of 43. Claims 1-4 2, it for treating the method for pain in the object having this to need.

44. 1 kinds of methods preparing solid Co ntrolled release dosage form, it comprises:

Wherein, as by USP device 1 (basket) with 100rpm at 37 DEG C in the simulated gastric fluid (SGF) of 900ml not synthase measured by In Vitro Dissolution, the amount of the non-opioid analgesic discharged from described dosage form is at 8 to 24 hours proportional in 20% with the elapsed time.